Huntington's Chorea and dimethylaminoethanol (deanol).

PubMed

Amsterdam, J D; Dubin, W

1978-07-01

Huntington's Chorea has multiple neurologic and psychiatric manifestations, and its treatment has been the subject of much debate. It appears that no single agent is effective for all patients with Chorea. Furthermore, different biochemical substances may be lacking in various Huntington's patients, i.e., gamma aminobutyric acid (GABA) in some, or a deficiency of acetylcholine (ACH) receptors in others. We approach this disease as a possible "spectrum illness," characterized by a relative deficiency of one substance, or a relative excess of another. If patients do not respond to one family of drugs, they may still benefit from a trial with another drug group.

Xeroderma pigmentosum complementation group F: A rare cause of cerebellar ataxia with chorea.

PubMed

Carré, G; Marelli, C; Anheim, M; Geny, C; Renaud, M; Rezvani, H R; Koenig, M; Guissart, C; Tranchant, C

2017-05-15

The complementation group F of Xeroderma pigmentosum (XP-F) is rare in the Caucasian population, and usually devoid of neurological symptoms. We report two cases, both Caucasian, who exhibited progressive cerebellar ataxia, chorea, a mild subcortical frontal cognitive impairment, and in one case severe polyneuropathy. Brain MRI demonstrated cerebellar (2/2) and cortical (1/2) atrophy. Both patients had only mild sunburn sensitivity and no skin cancer. Mini-exome sequencing approach revealed in ERCC4, two heterozygous mutations, one of which was never described (c.580-584+1delCCAAGG, exon 3), in the first case, and an already reported homozygous mutation, in the second case. These cases emphasize that XP-F is a rare cause of recessive cerebellar ataxia and can in some cases clinically mimic Huntington's disease due to chorea and executive impairment. The association of ataxia, chorea, and sun hypersensitivity are major guidance for the diagnosis, which should not be missed, in order to prevent skin neoplastic complications. Copyright © 2017 Elsevier B.V. All rights reserved.

No evidence of perfusion abnormalities in the basal ganglia of a patient with generalized chorea-ballism and polycythaemia vera: analysis using subtraction SPECT co-registered to MRI.

PubMed

Kim, Woojun; Kim, Joong-Seok; Lee, Kwang-Soo; Kim, Yeong-In; Park, Chong-Won; Chung, Yong-An

2008-10-01

Polycythaemia vera is a well-known cause of symptomatic chorea, however, the pathophysiology of this correlation remains unclear. We report on a patient with generalized chorea-ballism associated with polycythaemia vera, and we present the findings of 99mTc-hexamethylpropylene amine oxime (HMPAO) SPECT done in both the choreic state and the non-choreic state. The SPECT during both the choreic and the non-choreic states did not reveal any definite perfusion changes in specific regions of the brain, as compared with 6 age-matched controls. In addition, the subtraction SPECT co-registered to MRI (SISCOM) analysis did not show any difference in cerebral blood flow during the choreic and non-choreic states. This result suggests that the basic mechanism of chorea associated with polycythaemia vera does not appear to be associated with a reduction in cerebral perfusion to a specific cerebral area, such as the basal ganglia or its thalamocortical connections.

Chorea revealing systemic lupus erythematosus in a 13-year old boy: A case report and short review of the literature.

PubMed

Athanasopoulos, E; Kalaitzidou, I; Vlachaki, G; Stefanaki, S; Tzagkaraki, A; Niotakis, G; Tritou, I; Ladomenou, F

2018-03-29

Among the neurological manifestations of systemic lupus erythematosus (SLE), chorea is rare, presenting in less than 7% of the pediatric SLE patients. It can appear early in the onset of SLE, be the first or even the sole clinical feature of the illness and has strongly been associated with the presence of antiphospholipid antibodies. We report on the case of a 13-year old boy, admitted with acute onset chorea and finally diagnosed with SLE. Subsequently, we present a short review of the literature on the epidemiology, suggested pathogenesis, clinical presentation and treatment of this rare presentation of SLE.

Chorea in Late-Infantile Neuronal Ceroid Lipofuscinosis: An Atypical Presentation.

PubMed

Saini, Arushi Gahlot; Sankhyan, Naveen; Singhi, Pratibha

2016-07-01

Classic late-infantile neuronal ceroid lipofuscinosis is characterized by progressive intellectual and motor deterioration, seizures, vision loss, and early death. Prominent chorea is an atypical feature and is rarely described in children. A four-year-old girl with seizures followed by a year-long progressive cognitive decline and a three month history of intermittent chorea leading to rapid motor deterioration. The onset of illness was marked by seizures occurring as generalized tonic-clonic seizures and myoclonic jerks. There was gradual regression of cognitive milestones with increasing forgetfulness and impaired quality and content of speech. Nine months later, she developed chorea. These movements were associated with clumsiness, incoordination, and progressive loss of motor milestones. She was unable to perform manual tasks or maintain antigravity posture resulting in unsteadiness and frequent falls. The movements were aggravated by action or excitement and were absent in sleep. Magnetic resonance imaging depicted diffuse cerebral and cerebellar atrophy. Sequencing analysis of TPP1 gene showed a novel, homozygous, splice site mutation c.89+1G>A which resulted in nil enzyme activity and a severe phenotype with onset of disease symptoms at an early age of three years. The presence of chorea in late-infantile neuronal ceroid lipofuscinoses is atypical but does not exclude the diagnosis of late-infantile neuronal ceroid lipofuscinoses, especially in children with psychomotor regression, seizures and diffuse brain atrophy. Copyright © 2016 Elsevier Inc. All rights reserved.

Sydenham chorea: clinical, EEG, MRI and SPECT findings in the early stage of the disease.

PubMed

Heye, N; Jergas, M; Hötzinger, H; Farahati, J; Pöhlau, D; Przuntek, H

1993-02-01

An 18-year-old man suffered from acute Sydenham chorea appearing coincidently with beta-haemolytic streptococcal throat infection. Imaging techniques documented lesions of basal ganglia and substantia nigra. In the early course of the disease vascular lesions may be important pathogenetic mechanisms of this acquired movement disorder.

Mutation in GM2A Leads to a Progressive Chorea-dementia Syndrome

PubMed Central

Salih, Mustafa A.; Seidahmed, Mohammed Z.; El Khashab, Heba Y.; Hamad, Muddathir H. A.; Bosley, Thomas M.; Burn, Sabrina; Myers, Angela; Landsverk, Megan L.; Crotwell, Patricia L.; Bilguvar, Kaya; Mane, Shrikant; Kruer, Michael C.

2015-01-01

Background The etiology of many cases of childhood-onset chorea remains undetermined, although advances in genomics are revealing both new disease-associated genes and variant phenotypes associated with known genes. Methods We report a Saudi family with a neurodegenerative course dominated by progressive chorea and dementia in whom we performed homozygosity mapping and whole exome sequencing. Results We identified a homozygous missense mutation in GM2A within a prominent block of homozygosity. This mutation is predicted to impair protein function. Discussion Although discovered more than two decades ago, to date, only five patients with this rare form of GM2 gangliosidosis have been reported. The phenotype of previously described GM2A patients has been typified by onset in infancy, profound hypotonia and impaired volitional movement, intractable seizures, hyperacusis, and a macular cherry red spot. Our findings expand the phenotypic spectrum of GM2A mutation-positive gangliosidosis to include generalized chorea without macular findings or hyperacusis and highlight how mutations in neurodegenerative disease genes may present in unexpected ways. PMID:26203402

Can't stop dancing: could it be St. Vitus' dance?

PubMed

Rogness, Corrie

2008-07-01

To inform providers of one of the rare but significant consequences that result from not diagnosing and treating streptococcal pharyngitis: Sydenham's chorea (St. Vitus' dance). Current Internet sources including review articles, informational articles, online medical textbooks, and professional organization Web sites. It is vital that each case of streptococcal pharyngitis be treated with appropriate antibiotic therapy. Doing so will help prevent the sequelae associated with streptococcal infections, such as acute rheumatic fever (ARF) and Sydenham's chorea. Streptococcal pharyngitis is a common illness that has the potential to cause very serious consequences. The consequences may be life altering, such as suffering permanent heart damage. With appropriate diagnosis and treatment with antibiotics, the sequelae of ARF and Sydenham's chorea can be prevented.

Chorea as a rare manifestation of hyperglycaemia.

PubMed

Patil, Rajesh; Sangoi, Parin; Wasekar, Nilesh; Vishwanathan, Deepti; Jadhav, S G; Joglekar, V K

2013-09-01

We present a case of chorea presenting as a clinical manifestation of hyperglycaemia.The purpose of presenting this case is to highlight the fact that movement disorder may be the clinical presentation of hyperglycaemia and it reverts on treatment of hyperglycaemia. A 66-year-old female known case of type 2 diabetes mellitus and on oral hypoglycaemic drugs presented with abnormal and involuntary movements of the whole body and face since 7 days and high plasma glucose (446 mg/dl) and without ketosis. On controlling the blood sugar, there has been significant decrease in choreiform movements within 48 hrs and complete resolution of involuntary movements found at discharge at 1 week. Movement disorder like chorea may be the clinical presentation of the hyperglycaemia which could completely recover on rapid detection and correction of hyperglycaemia.

[Systemic lupus erythematosus presenting with a choreo-athetosic syndrome associated with antiphospholipid antibodies].

PubMed

Rafai, M A; El Moutawakil, B; Gam, I; Hakim, K; Fadel, H; Kissani, N; Slassi, I

2005-10-01

Chorea is a rare manifestation of systemic lupus erythematosus (1-4 percent), commonly affecting young woman. Chorea is revealing lupic disease in 50 percent, in the other cases it occurs early in the course of the disease. A 33-year-old woman was hospitalized for choreo-athetosic movements prevailing on the left leg and arm accompanied by behavioral and general state deterioration. The biological assessment consolidated the diagnosis of lupic disease associated antiphospholipides antibody (aPL). Cerebral magnetic resonance imaging (MRI) was normal except for cortical and subcortical atrophy. The patient was treated by corticosteroids (1mg/kg/day) and then was lost to follow-up. We review data in the literature on the pathophysiological mechanisms of lupic chorea focusing particularly on role of aPL.

Acetylcholine and choline in cerebrospinal fluid of patients with Parkinson's disease and Huntington's chorea.

PubMed Central

Welch, M J; Markham, C H; Jenden, D J

1976-01-01

Lumbar cerebrospinal fluid (CSF) acetylcholine (ACh) and choline (Ch) levels were measured in patients with Huntington's chorea (N=11), Parkinson's disease (N=8), and subjects at risk for Huntington's chorea (N=4), and all three groups were found not to differ significantly from normal controls (N=10). The values found for lumbar CSF ACh and Ch levels in the normal subjects were comparable with previously reported values. The use of physostigmine, a cholinesterase inhibitor, in collecting the CSF samples did not appear to make a difference with regard to ACh and Ch concentrations. Evidence suggesting a ventricular-lumbar gradient, with lumbar CSF Ch concentration being less than ventricular CSF Ch concentration, was found. Finally, ACh levels in CSF did not correlate with corresponding Ch levels. PMID:132512

Impairment of retinal increment thresholds in Huntington's disease.

PubMed

Paulus, W; Schwarz, G; Werner, A; Lange, H; Bayer, A; Hofschuster, M; Müller, N; Zrenner, E

1993-10-01

We have investigated detection thresholds for a foveal blue test light using a Maxwellian view system in 61 normal subjects, 19 patients with Huntington's chorea, 14 patients with Tourette's syndrome, and 20 patients with schizophrenia. Ten measurements were made: The blue test light (1 degree diameter, 500 msec duration) was presented either superimposed on a yellow adaptation field (5 degree diameter) or 500 msec after switching off this field (transient tritanopia effect). In both cases five different background intensities were presented. The only abnormality found was in patients with Huntington's chorea. During adaptation these patients' thresholds are significantly higher than normal (p < 0.005). No change was found in the transient tritanopia effect. Huntington's disease causes degeneration of several different transmitter systems in the brain. Increment threshold testing allows for noninvasive investigation of patients and confirms the involvement of the retina in the degenerative process in Huntington's chorea.

The Wilson films--Huntington's chorea.

PubMed

Klein, Christine

2011-12-01

Wilson's Queen Square Case 9 with Huntington's chorea shows a 68-year-old man with mild to moderate generalized chorea, impaired fixation, and probable cognitive decline in keeping with a diagnosis of Huntington's disease (HD). An age of onset in the late sixties and a negative family history suggest a relatively small expanded trinucleotide repeat in the HTT gene in the patient and reduced penetrance of an even shorter repeat allele in one of his parents. A highly sensitive and specific gene test has been offered worldwide for diagnostic testing of HD for almost two decades. This test, obviously unavailable at Wilson's times, became the historic frontrunner for guidelines of symptomatic, presymptomatic, and prenatal testing for an adult-onset neurodegenerative disorder. Regarding treatment of HD, however, we are still awaiting the successful translation of research results into the development of effective cause-directed, neuropreventive and neurorestaurative therapies. Copyright © 2011 Movement Disorder Society.

Eighth International Chorea-Acanthocytosis Symposium: Summary of Workshop Discussion and Action Points.

PubMed

Pappas, Samuel S; Bonifacino, Juan; Danek, Adrian; Dauer, William T; De, Mithu; De Franceschi, Lucia; DiPaolo, Gilbert; Fuller, Robert; Haucke, Volker; Hermann, Andreas; Kornmann, Benoit; Landwehrmeyer, Bernhard; Levin, Johannes; Neiman, Aaron M; Rudnicki, Dobrila D; Sibon, Ody; Velayos-Baeza, Antonio; Vonk, Jan J; Walker, Ruth H; Weisman, Lois S; Albin, Roger L

2017-01-01

Chorea-Acanthocytosis (ChAc) is a rare hereditary neurological disorder characterized by abnormal movements, red blood cell pathology, and progressive neurodegeneration. Little is understood of the pathogenesis of ChAc and related disorders (collectively Neuroacanthocytosis). The Eighth International Chorea-Acanthocytosis Symposium was held in May 2016 in Ann Arbor, MI, USA, and focused on molecular mechanisms driving ChAc pathophysiology. Accompanying the meeting, members of the neuroacanthocytosis research community and other invited scientists met in a workshop to discuss the current understanding and next steps needed to better understand ChAc pathogenesis. These discussions identified several broad and critical needs for advancing ChAc research and patient care, and led to the definition of 18 specific action points related to functional and molecular studies, animal models, and clinical research. These action points, described below, represent tractable research goals to pursue for the next several years.

Successful deep brain stimulation surgery with intraoperative magnetic resonance imaging on a difficult neuroacanthocytosis case: case report.

PubMed

Lim, Thien Thien; Fernandez, Hubert H; Cooper, Scott; Wilson, Kathryn Mary K; Machado, Andre G

2013-07-01

Chorea acanthocytosis is a progressive hereditary neurodegenerative disorder characterized by hyperkinetic movements, seizures, and acanthocytosis in the absence of any lipid abnormality. Medical treatment is typically limited and disappointing. We report on a 32-year-old patient with chorea acanthocytosis with a failed attempt at awake deep brain stimulation (DBS) surgery due to intraoperative seizures and postoperative intracranial hematoma. He then underwent a second DBS operation, but under general anesthesia and with intraoperative magnetic resonance imaging guidance. Marked improvement in his dystonia, chorea, and overall quality of life was noted 2 and 8 months postoperatively. DBS surgery of the bilateral globus pallidus pars interna may be useful in controlling the hyperkinetic movements in neuroacanthocytosis. Because of the high propensity for seizures in this disorder, DBS performed under general anesthesia, with intraoperative magnetic resonance imaging guidance, may allow successful implantation while maintaining accurate target localization.

Deanol acetamidobenzoate treatment in choreiform movement disorders.

PubMed

Tarsy, D; Bralower, M

1977-12-01

Deanol acetamidobenzoate was administered in double-blind, crossover fashion with placebo to five patients with tardive dyskinesia, three patients with Huntington's chorea, and one patient with posthemiplegic chorea. No significant effect on dyskinesia was observed. Preliminary administration of physostigmine salicylate to patients with tardive dyskinesia had a variable effect, while benztropine mesylate produced no change. Since the status of deanol as an effective precursor of acetylcholine is uncertain, further trials with putative cholinergic agents remain warranted in choreiform syndromes.

The origin of Huntington's chorea in the Afrikaner population of South Africa.

PubMed

Hayden, M R; Hopkins, H C; Macrea, M; Beighton, P H

1980-08-02

Huntington's chorea is prevalent among the Afrikaner population of South Africa. The origin of the gene for the disorder in this population group has been traced over 14 generations from the present time to the days of the first free burghers at the Cape of Good Hope. Over 200 affected individuals in more than 50 supposedly unrelated families have been found to be ancestrally related through a common progenitor in the 17th century.

Movement disorders in paraneoplastic and autoimmune disease

PubMed Central

Panzer, Jessica; Dalmau, Josep

2013-01-01

Purpose of review The most relevant advances in immune-mediated movement disorders are described, with emphasis on the clinical–immunological associations, novel antigens, and treatment. Recent findings Many movement disorders previously considered idiopathic or degenerative are now recognized as immune-mediated. Some disorders are paraneoplastic, such as anti-CRMP5-associated chorea, anti-Ma2 hypokinesis and rigidity, anti-Yo cerebellar ataxia and tremor, and anti-Hu ataxia and pesudoathetosis. Other disorders such as Sydenham's chorea, or chorea related to systemic lupus erythematosus and antiphospholipid syndrome occur in association with multiple antibodies, are not paraneoplastic, and are triggered by molecular mimicry or unknown mechanisms. Recent studies have revealed a new category of disorders that can be paraneoplastic or not, and associate with antibodies against cell-surface or synaptic proteins. They include anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis, which may cause dyskinesias, chorea, ballismus or dystonia (NMDAR antibodies), the spectrum of Stiff-person syndrome/muscle rigidity (glutamic acid decarboxylase, amphiphysin, GABAA-receptor-associated protein, or glycine receptor antibodies), neuromyotonia (Caspr2 antibodies), and opsoclonus–myoclonus–ataxia (unknown antigens). Summary Neurologists should be aware that many movement disorders are immune-mediated. Recognition of these disorders is important because it may lead to the diagnosis of an occult cancer, and a substantial number of patients, mainly those with antibodies to cell-surface or synaptic proteins, respond to immunotherapy. PMID:21577108

Review of deutetrabenazine: a novel treatment for chorea associated with Huntington's disease.

PubMed

Dean, Marissa; Sung, Victor W

2018-01-01

Deutetrabenazine was recently approved for the treatment of chorea in Huntington's disease (HD) and is the first deuterated medication that has been US Food and Drug Administration (FDA)-approved for therapeutic use. In this article, we review deutetrabenazine's drug design, pharmacokinetics, drug interactions, efficacy, adverse events, comparison with tetrabenazine, dosage, and administration. Deutetrabenazine is a deuterated form of tetrabenazine and is a vesicular monoamine transporter 2 (VMAT2) inhibitor. The substitution of deuterium for hydrogen at key positions in the tetrabenazine molecule allows a longer drug half-life and less frequent daily dosing. Deutetrabenazine is administered twice daily up to a maximum daily dose of 48 mg, which corresponds to a similar daily dose of 100 mg of tetrabenazine. In a Phase III clinical trial (First-HD), there was a statistically significant improvement of chorea in HD subjects, as well as improvements in global impression of change as assessed by both patients and clinicians. This improvement was seen without significant adverse effects as the overall tolerability profile of deutetrabenazine was similar to placebo. Somnolence was the most commonly reported symptom in the deutetrabenazine group. In a study where subjects converted from tetrabenazine to deutetrabenazine in an open-label fashion (ARC-HD) and indirect comparison studies between tetrabenazine and deutetrabenazine, there is a suggestion that while efficacy for chorea is similar, the data may slightly favor tetrabenazine, but adverse effects and tolerability strongly favor deutetrabenazine. These data have not been replicated in true head-to-head studies. Current evidence supports that deutetrabenazine is an effective therapeutic treatment option for chorea in HD and may provide a more favorable adverse effect profile than tetrabenazine. However, more data are needed, particularly in the form of head-to-head studies between deutetrabenazine and other treatment options as well as longer term clinical experience with deutetrabenazine.

Grey matter volume loss is associated with specific clinical motor signs in Huntington's disease.

PubMed

Coppen, Emma M; Jacobs, Milou; van den Berg-Huysmans, Annette A; van der Grond, Jeroen; Roos, Raymund A C

2018-01-01

Motor disturbances are clinical hallmarks of Huntington's disease (HD) and involve chorea, dystonia, hypokinesia and visuomotor dysfunction. Investigating the association between specific motor signs and different regional volumes is important to understand the heterogeneity of HD. To investigate the motor phenotype of HD and associations with subcortical and cortical grey matter volume loss. Structural T1-weighted MRI scans of 79 HD patients and 30 healthy controls were used to calculate volumes of seven subcortical structures including the nucleus accumbens, hippocampus, thalamus, caudate nucleus, putamen, pallidum and amygdala. Multiple linear regression analyses, corrected for age, gender, CAG, MRI scan protocol and normalized brain volume, were performed to assess the relationship between subcortical volumes and different motor subdomains (i.e. eye movements, chorea, dystonia, hypokinesia/rigidity and gait/balance). Voxel-based morphometry analysis was used to investigate the relationship between cortical volume changes and motor signs. Subcortical volume loss of the accumbens nucleus, caudate nucleus, putamen, and pallidum were associated with higher chorea scores. No other subcortical region was significantly associated with motor symptoms after correction for multiple comparisons. Voxel-based cortical grey matter volume reductions in occipital regions were related with an increase in eye movement scores. In HD, chorea is mainly associated with subcortical volume loss, while eye movements are more related to cortical volume loss. Both subcortical and cortical degeneration has an impact on motor impairment in HD. This implies that there is a widespread contribution of different brain regions resulting in the clinical motor presentation seen in HD patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

ADCY5-related dyskinesia

PubMed Central

Chen, Dong-Hui; Méneret, Aurélie; Friedman, Jennifer R.; Korvatska, Olena; Gad, Alona; Bonkowski, Emily S.; Stessman, Holly A.; Doummar, Diane; Mignot, Cyril; Anheim, Mathieu; Bernes, Saunder; Davis, Marie Y.; Damon-Perrière, Nathalie; Degos, Bertrand; Grabli, David; Gras, Domitille; Hisama, Fuki M.; Mackenzie, Katherine M.; Swanson, Phillip D.; Tranchant, Christine; Vidailhet, Marie; Winesett, Steven; Trouillard, Oriane; Amendola, Laura M.; Dorschner, Michael O.; Weiss, Michael; Eichler, Evan E.; Torkamani, Ali; Roze, Emmanuel

2015-01-01

Objective: To investigate the clinical spectrum and distinguishing features of adenylate cyclase 5 (ADCY5)–related dyskinesia and genotype–phenotype relationship. Methods: We analyzed ADCY5 in patients with choreiform or dystonic movements by exome or targeted sequencing. Suspected mosaicism was confirmed by allele-specific amplification. We evaluated clinical features in our 50 new and previously reported cases. Results: We identified 3 new families and 12 new sporadic cases with ADCY5 mutations. These mutations cause a mixed hyperkinetic disorder that includes dystonia, chorea, and myoclonus, often with facial involvement. The movements are sometimes painful and show episodic worsening on a fluctuating background. Many patients have axial hypotonia. In 2 unrelated families, a p.A726T mutation in the first cytoplasmic domain (C1) causes a relatively mild disorder of prominent facial and hand dystonia and chorea. Mutations p.R418W or p.R418Q in C1, de novo in 13 individuals and inherited in 1, produce a moderate to severe disorder with axial hypotonia, limb hypertonia, paroxysmal nocturnal or diurnal dyskinesia, chorea, myoclonus, and intermittent facial dyskinesia. Somatic mosaicism is usually associated with a less severe phenotype. In one family, a p.M1029K mutation in the C2 domain causes severe dystonia, hypotonia, and chorea. The progenitor, whose childhood-onset episodic movement disorder almost disappeared in adulthood, was mosaic for the mutation. Conclusions: ADCY5-related dyskinesia is a childhood-onset disorder with a wide range of hyperkinetic abnormal movements. Genotype-specific correlations and mosaicism play important roles in the phenotypic variability. Recurrent mutations suggest particular functional importance of residues 418 and 726 in disease pathogenesis. PMID:26537056

Chorea--an unusual manifestation in a woman recovering from myxedema coma.

PubMed

Yu, Catherine H Y; Stovel, Rebecca; Fox, Susan

2012-01-01

To report a case of reversible chorea in a woman with myxedema coma. We describe the clinical course, imaging findings, and laboratory test results of a patient who initially presented with myxedema coma and then developed reversible chorea upon treatment. A 33-year-old woman with a known history of primary hypothyroidism presented with a 3-week history of lethargy, progressing to a precipitous decline in consciousness that required intubation. Physical examination revealed concurrent hypothermia and bradycardia. Laboratory investigations demonstrated a thyrotropin concentration greater than 100 mIU/L, a free triiodothyronine concentration of 1.9 pg/mL, and a free thyroxine concentration of 0.24 ng/dL, but no other metabolic abnormalities. She was treated with intravenous levothyroxine therapy on the first 2 days of hospital admission (200 mcg and 250 mcg, respectively). On day 2, she was obeying commands and she was extubated. She began exhibiting choreiform movements. Thyroid function test results revealed a normal free thyroxine concentration (1.10 ng/dL), but an elevated thyrotropin concentration (40.98 mIU/L) and a low free triiodothyronine concentration (1.9 pg/mL). Findings from computed tomography and magnetic resonance imaging of her brain and analysis of cerebrospinal fluid were normal. Her regimen was transitioned to oral levothyroxine, 88 mcg daily, and by day 4, her choreiform movements ceased. Neurologic manifestations of hypothyroidism include psychomotor slowing, memory deficits, and dementia, with myxedema coma at the extreme of this spectrum. Although chorea is a rare manifestation of hyperthyroidism, this is the first report of a patient with acquired, reversible choreiform movement disorder while still being severely hypothyroid and treated with levothyroxine.

ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations.

PubMed

Chen, Dong-Hui; Méneret, Aurélie; Friedman, Jennifer R; Korvatska, Olena; Gad, Alona; Bonkowski, Emily S; Stessman, Holly A; Doummar, Diane; Mignot, Cyril; Anheim, Mathieu; Bernes, Saunder; Davis, Marie Y; Damon-Perrière, Nathalie; Degos, Bertrand; Grabli, David; Gras, Domitille; Hisama, Fuki M; Mackenzie, Katherine M; Swanson, Phillip D; Tranchant, Christine; Vidailhet, Marie; Winesett, Steven; Trouillard, Oriane; Amendola, Laura M; Dorschner, Michael O; Weiss, Michael; Eichler, Evan E; Torkamani, Ali; Roze, Emmanuel; Bird, Thomas D; Raskind, Wendy H

2015-12-08

To investigate the clinical spectrum and distinguishing features of adenylate cyclase 5 (ADCY5)-related dyskinesia and genotype-phenotype relationship. We analyzed ADCY5 in patients with choreiform or dystonic movements by exome or targeted sequencing. Suspected mosaicism was confirmed by allele-specific amplification. We evaluated clinical features in our 50 new and previously reported cases. We identified 3 new families and 12 new sporadic cases with ADCY5 mutations. These mutations cause a mixed hyperkinetic disorder that includes dystonia, chorea, and myoclonus, often with facial involvement. The movements are sometimes painful and show episodic worsening on a fluctuating background. Many patients have axial hypotonia. In 2 unrelated families, a p.A726T mutation in the first cytoplasmic domain (C1) causes a relatively mild disorder of prominent facial and hand dystonia and chorea. Mutations p.R418W or p.R418Q in C1, de novo in 13 individuals and inherited in 1, produce a moderate to severe disorder with axial hypotonia, limb hypertonia, paroxysmal nocturnal or diurnal dyskinesia, chorea, myoclonus, and intermittent facial dyskinesia. Somatic mosaicism is usually associated with a less severe phenotype. In one family, a p.M1029K mutation in the C2 domain causes severe dystonia, hypotonia, and chorea. The progenitor, whose childhood-onset episodic movement disorder almost disappeared in adulthood, was mosaic for the mutation. ADCY5-related dyskinesia is a childhood-onset disorder with a wide range of hyperkinetic abnormal movements. Genotype-specific correlations and mosaicism play important roles in the phenotypic variability. Recurrent mutations suggest particular functional importance of residues 418 and 726 in disease pathogenesis. © 2015 American Academy of Neurology.

Xeroderma pigmentosum is a definite cause of Huntington's disease-like syndrome.

PubMed

Garcia-Moreno, Hector; Fassihi, Hiva; Sarkany, Robert P E; Phukan, Julie; Warner, Thomas; Lehmann, Alan R; Giunti, Paola

2018-01-01

Xeroderma pigmentosum is characterized by cutaneous, ophthalmological, and neurological features. Although it is typical of childhood, late presentations can mimic different neurodegenerative conditions. We report two families presenting as Huntington's disease-like syndromes. The first case (group G) presented with neuropsychiatric features, cognitive decline and chorea. Typical lentigines were only noticed after the neurological disease started. The second case (group B) presented adult-onset chorea and neuropsychiatric symptoms after an aggressive ocular melanoma. Xeroderma pigmentosum can manifest as a Huntington's Disease-like syndrome. Classic dermatological and oncological features have to be investigated in choreic patients with negative genetic tests for Huntington's disease-like phenotypes.

Functional Impact of Sydenham's Chorea: A Case Report

PubMed Central

Gimeno, Hortensia; Barry, Sinead; Lin, Jean-Pierre; Gordon, Anne

2013-01-01

Background Sydenham's chorea (SC) is the most common type of acquired chorea in childhood. In some cases, symptoms (most commonly described in terms of neurological signs) last up to 2 years, and many cases relapse. This report describes the clinical course in terms of functional abilities following diagnosis of SC. Case report Standardized assessments across the domains of activity and participation were administered following diagnosis, prior to and following treatment with haloperidol to measure treatment response and identify occupational therapy intervention needs. SC was observed to significantly reduce the child's participation and independence in activities of daily living. In this case, the standardized assessments administered highlighted difficulties with both motor and process skills. At 1 week after commencing haloperidol, both motor and process skills had improved. Clinically significant changes in self-care and mobility were noted with less improvement with handwriting. At 9 weeks, most symptoms and functional difficulties had resolved. Discussion Given the process difficulties detected in this case, and the possibility of enduring symptoms, the use of functional assessments is advocated in the routine management of SC. These findings illustrate the potential for motor and non-motor sequelae in acute childhood movement disorders and related functional disabling consequences. PMID:23532819

Immune-mediated extrapyramidal movement disorders, including Sydenham chorea.

PubMed

Dale, Russell C

2013-01-01

Immune-mediated extrapyramidal movement disorders typically occur in previously healthy children. Immune-mediated movement disorders may occur as a postinfectious, paraneoplastic, or idiopathic process. Sydenham chorea (SC) is the classical poststreptococcal movement and psychiatric disorder, and may be associated with other features of rheumatic fever. The outcome is typically good, although residual chorea, psychiatric disturbance, and relapses are possible. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is a syndrome of streptococcal-induced tics and obsessive-compulsive disorder. Although a number of investigators have reported an association between streptococcal infection and neuropsychiatric syndromes, the PANDAS hypothesis is controversial. Encephalitis lethargica is an encephalitic illness with parkinsonism, dyskinesias, and psychiatric disturbance as dominant features. The exact disease mechanism is not understood, although an autoimmune process is suspected. NMDA-R encephalitis is a new entity characterized by encephalitis with dramatic psychiatric disturbance, dyskinesias, cognitive alteration, and seizures. Patients have autoantibodies against the NMDA-R that appear to be pathogenic: immune therapies appear warranted to minimize disability. Movement disorders are also described associated with systemic lupus erythematosus and antiphospholipid syndrome. The differential diagnosis and investigation approach of acute-onset movement disorders are also discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

Hysterical chorea: Report of an outbreak and movie documentation by Arthur Van Gehuchten (1861-1914).

PubMed

Giménez-Roldán, Santiago; Aubert, Geneviève

2007-06-15

Psychogenic movement disorders remain a frequent and important clinical problem. First described in the Middle Ages, the dancing mania is considered to be one form of mass hysteria characterized by outbreaks of collective movement disorders. Patients may exhibit a wide variety of movement and gait disturbances, including tremulousness, jerks, or convulsions, usually with a sudden onset. Arthur Van Gehuchten (1861-1914), a distinguished Belgian neuroanatomist and neurologist, reported an outbreak of sudden involuntary movements in 13 adolescent girls residing in an orphanage. The description is to be found in his book Les Maladies nerveuses, completed before 1914 and published posthumously in 1920. The chapter is illustrated with sequential photographs of a girl exhibiting a peculiar gait, which is descriptively referred to as "chorée salutatoire" (saluting chorea). The original film with these pictures has been retrieved and is presented here together with a very similar film excerpt also found in Van Gehuchten's film collection. Van Gehuchten's movie documentation of a psychogenic movement disorder--labeled chorea but which should probably be considered as dystonia according to contemporary classification--appears to be unique. This report illustrates the tremendous value of moving pictures in recording and analyzing movement disorders.

Chorea-acanthocytosis

PubMed Central

Walker, Susan; Dad, Rubina; Thiruvahindrapuram, Bhooma; Ullah, Muhammed Ikram; Ahmad, Arsalan; Hassan, Muhammad Jawad; Scherer, Stephen W.

2018-01-01

Objective To determine a molecular diagnosis for a large multigenerational family of South Asian ancestry with seizures, hyperactivity, and episodes of tongue biting. Methods Two affected individuals from the family were analyzed by whole-genome sequencing on the Illumina HiSeq X platform, and rare variants were prioritized for interpretation with respect to the phenotype. Results A previously undescribed, 1-kb homozygous deletion was identified in both individuals sequenced, which spanned 2 exons of the VPS13A gene, and was found to segregate in other family members. Conclusions VPS13A is associated with autosomal recessive chorea-acanthocytosis, a diagnosis consistent with the phenotype observed in this family. Whole-genome sequencing presents a comprehensive and agnostic approach for detecting diagnostic mutations in families with rare neurologic disorders. PMID:29845114

Pharmaceutical Approval Update.

PubMed

Kaufman, Michele B

2017-08-01

Naldemedine (Symproic) for opioid-induced constipation; deutetrabenazine (Austedo) for chorea associated with Huntington's disease; and infliximab-abda (Renflexis), a Remicade biosimilar, for the treatment of Crohn's disease, rheumatoid arthritis, and other diseases.

Chorea

MedlinePlus

... Strategy Current Research Research Funded by NINDS Basic Neuroscience Clinical Research Translational Research Research at NINDS Focus ... Diversity Resources Jobs at NINDS Director, Division of Neuroscience Director, NIH BRAIN Initiative® Health Scientist Administrator Channels ...

Plants and phytochemicals for Huntington's disease.

PubMed

Choudhary, Sunayna; Kumar, Puneet; Malik, Jai

2013-07-01

Huntington's disease (HD) is a neurodegenerative disorder characterized by progressive motor dysfunction, including chorea and dystonia, emotional disturbances, memory, and weight loss. The medium spiny neurons of striatum and cortex are mainly effected in HD. Various hypotheses, including molecular genetics, oxidative stress, excitotoxicity, metabolic dysfunction, and mitochondrial impairment have been proposed to explain the pathogenesis of neuronal dysfunction and cell death. Despite no treatment is available to fully stop the progression of the disease, there are treatments available to help control the chorea. The present review deals with brief pathophysiology of the disease, plants and phytochemicals that have shown beneficial effects against HD like symptoms. The literature for the current review was collected using various databases such as Science direct, Pubmed, Scopus, Sci-finder, Google Scholar, and Cochrane database with a defined search strategy.

Memantine-induced chorea and dystonia.

PubMed

Borges, Letizia Goncalves; Bonakdarpour, Borna

2017-04-01

Memantine is an uncompetitive N -methyl-d-aspartate receptor antagonist and probably also has an indirect dopaminergic action at high concentrations. We describe a person with Alzheimer's disease who developed chorea and dystonia after inadvertently doubling of her daily dose by taking extended-release (XR) memantine twice daily, rather than once daily (planned dose memantine XR, 21 mg once daily), after the drug was switched from immediate release (IR, 10 mg twice daily). Memantine is rarely associated with movement disorders, but this case emphasises the need for awareness of potential problems when switching from memantine IR to XR. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Sydenham chorea

MedlinePlus

... The provider may also prescribe antibiotics to prevent future RF infections. This is called preventive antibiotics, or ... AE. Other movement disorders. In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine . 25th ed. Philadelphia, PA: ...

Sydenham Chorea (Saint Vitus Dance)

MedlinePlus

... minority of children, usually in the form of endocarditis. In a third of the children with the ... minority of children, usually in the form of endocarditis. In a third of the children with the ...

Genetics Home Reference: chorea-acanthocytosis

MedlinePlus

... Danek A, Rampoldi L, Hardie RJ, Chalmers RM, Wood NW, Bohlega S, Dotti MT, Federico A, Shizuka M, ... Stone C, Rubio JP, Danek A, Chalmers RM, Wood NW, Verellen C, Ferrer X, Malandrini A, Fabrizi ...

A Systematic Review of the Huntington Disease-Like 2 Phenotype.

PubMed

Anderson, David G; Walker, Ruth H; Connor, Myles; Carr, Jonathan; Margolis, Russell L; Krause, Amanda

2017-01-01

Huntington Disease-like 2 (HDL2) is a neurodegenerative disorder similar to Huntington Disease (HD) in its clinical phenotype, genetic characteristics, neuropathology and longitudinal progression. Proposed specific differences include an exclusive African ancestry, lack of eye movement abnormalities, increased Parkinsonism, and acanthocytes in HDL2. The objective was to determine the similarities and differences between HD and HDL2 by establishing the clinical phenotype of HDL2 with the published cases. A literature review of all clinically described cases of HDL2 until the end of 2016 was performed and a descriptive analysis was carried out. Sixty-nine new cases were described between 2001 and 2016. All cases had likely African ancestry, and most were found in South Africa and the USA. Many features were found to be similar to HD, including a strong negative correlation between repeat length and age of onset. Chorea was noted in 48/57 cases (84%). Dementia was reported in 74% patients, and Parkinsonism in 37%. Psychiatric features were reported in 44 out of 47 cases. Patients with chorea had lower expanded repeat lengths compared to patients without chorea. Eye movements were described in 19 cases, 8 were abnormal. Acanthocytes were detected in 4 of the 13 patients tested. Nineteen out of 20 MRIs were reported as abnormal with findings similar to HD. This review clarifies some aspects of the HDL2 phenotype and highlights others which require further investigation. Features that are unique to HDL2 have been documented in a minority of subjects and require prospective validation.

The Pathogenic Role of Low Range Repeats in SCA17.

PubMed

Shin, Jung Hwan; Park, Hyeyoung; Ehm, Gwan Hee; Lee, Woong Woo; Yun, Ji Young; Kim, Young Eun; Lee, Jee-Young; Kim, Han-Joon; Kim, Jong-Min; Jeon, Beom Seok; Park, Sung-Sup

2015-01-01

SCA17 is an autosomal dominant cerebellar ataxia with expansion of the CAG/CAA trinucleotide repeats in the TATA-binding protein (TBP) gene. SCA17 can have various clinical presentations including parkinsonism, ataxia, chorea and dystonia. SCA17 is diagnosed by detecting the expanded CAG repeats in the TBP gene; however, in the literature, pathologic repeat numbers as low as 41 overlap with normal repeat numbers. The subjects in this study included patients with involuntary movement disorders such as cerebellar ataxia, parkinsonism, chorea and dystonia who visited Seoul National University Hospital between Jan. 2006 and Apr. 2014 and were screened for SCA17. Those who were diagnosed with other genetic diseases or nondegenerative diseases were excluded. DNA from healthy subjects who did not have a family history of parkinsonism, ataxia, psychiatric symptoms, chorea or dystonia served as the control. In total, 5242 chromosomes from 2099 patients and 522 normal controls were analyzed. The total number of patients included in the analysis was 2099 (parkinsonism, 1706; ataxia, 345; chorea, 37; and dystonia, 11). In the normal control, up to 44 repeats were found. In the 44 repeat group, there were 7 (0.3%) patients and 1 (0.2%) normal control. In 43 repeat group, there were 8 (0.4%) patients and 2 (0.4%) normal controls. In the 42 repeat group, there were 16 (0.8%) patients and 3 (0.6%) normal controls. In 41 repeat group, there were 48 (2.3%) patients and 8 (1.5%) normal controls. Considering the overlaps and non-significant differences in allelic frequencies between the patients and the normal controls with low-expansions, we could not determine a definitive cutoff value for the pathologic CAG repeat number of SCA17. Because the statistical analysis between the normal controls and patients with low range expansions failed to show any differences so far, we must consider that clinical cases with low range expansions could be idiopathic movement disorders showing coincidental CAG/CAA expansions. Thus, we need to reconsider the pathologic role of low range expansions (41-42). Long term follow up and comprehensive investigations using autopsy and imaging studies in patients and controls with low range expansions are necessary to determine the cutoff value for the pathologic CAG repeat number of SCA17.

Nominal dysphasia and euphoria caused by EBV encephalitis

PubMed Central

Carman, Kursat Bora; Yakut, Ayten; Ekici, Arzu; Isikay, Sedat

2013-01-01

Encephalitis is an uncommon neurological complication of Ebstein-Barr virus (EBV) infection and usually presents with confusion, decreased level of consciousness, fever, epileptic seizure, emotional instability and chorea. We present a patient with EBV encephalitis, characterised by nominal dysphasia, euphoria and personality changes. PMID:23307455

Chorea in a patient with cryopyrin-associated periodic syndrome.

PubMed

Schwarzbach, Christopher J; Schmitt, Wilhelm H; Szabo, Kristina; Bäzner, Hansjoerg; Hennerici, Michael G; Blahak, Christian

2016-01-19

To describe a patient with cryopyrin-associated periodic syndrome (CAPS) with an uncommon neurologic phenotype and a rare underlying genetic mutation. Our patient had CAPS with a rare NLPR3 missense mutation (p.Tyr859Cys) in exon 6 with chorea as the major symptom. Clinical symptoms were associated with persistent inflammatory changes of the CSF and serum and included elevated anticardiolipin immunoglobulin G; MRI showed prolonged gadolinium enhancement of 2 chronic inflammatory lesions. Conventional immunosuppressive treatment with prednisolone and hydroxychloroquine was insufficient. Neurologic symptoms, laboratory/chemical measures, and MRI abnormalities almost completely normalized following interleukin (IL)-1β blockade with anakinra. This case is unique for its uncommon neurologic phenotype, the rare underlying genetic mutation, and the long course of the disease as well as almost complete recovery following appropriate therapy. In addition, the chronic inflammatory white matter lesions observed on brain MRI and the responsiveness to IL-1β blockade with anakinra are unusual. © 2015 American Academy of Neurology.

Ketotic hyperglycemia with movement disorder

PubMed Central

Awasthi, Disha; Tiwari, Akhilesh Kumar; Upadhyaya, Abhinav; Singh, Balwinder; Tomar, Gaurav Singh

2012-01-01

Chorea, hemichorea-hemiballismus and severe partial seizures may be the presenting features of nonketotic hyperglycemia in older adults with type 2 diabetes, but cases in young adults with type 1 diabetes are rare. We hereby report a very rare case of diabetic ketosis with movement disorder in a young patient. PMID:22416165

Post-infectious autoimmune disorders: Sydenham's chorea, PANDAS and beyond.

PubMed

Williams, Kyle A; Swedo, Susan E

2015-08-18

Infections, and the resulting immune response to these infections, have recently received increased recognition as pathogenic mechanisms for neuropsychiatric disorders. Sydenham's chorea (SC), a widely recognized post-streptococcal autoimmune disorder, represents a model for this proposed pathogenesis. In SC, a dysregulated immune response to a streptococcal infection is hypothesized to result in inflammation of neuronal networks, particularly the basal ganglia nuclei. The resulting dysfunction in the basal ganglia nuclei are hypothesized to lead to a constellation of adventitious movements and psychiatric symptoms, which investigations have shown are amenable to immunomodulatory therapies. PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections) has been proposed as a variant of SC, and is hypothesized to share a pathogenic mechanism, despite a unique symptom profile of predominantly psychiatric symptoms. In this review, we present the clinical aspects of both disorders, the data for potential shared etiopathogenesis between them, and the evidence for the therapeutic use of immunomodulatory therapies for the symptoms of SC and PANDAS. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease. Copyright © 2014 Elsevier B.V. All rights reserved.

Evaluation of poststreptococcal illness.

PubMed

Hahn, Ricardo G; Knox, Lynda M; Forman, Todd A

2005-05-15

Group A beta-hemolytic streptococcal pharyngitis, scarlet fever, and rarely asymptomatic carrier states are associated with a number of poststreptococcal suppurative and nonsuppurative complications. As in streptococcal pharyngitis, acute rheumatic fever, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection, and poststreptococcal glomerulonephritis most often occur in children. The hallmarks of rheumatic fever include arthritis, carditis, cutaneous disease, chorea, and subsequent acquired valvular disease. Pediatric autoimmune neuropsychiatric disorders encompass a subgroup of illnesses involving the basal ganglia in children with obsessive-compulsive disorders, tic disorders, dystonia, chorea encephalitis, and dystonic choreoathetosis. Poststreptococcal glomerulonephritis is most frequently encountered in children between two and six years of age with a recent history of pharyngitis and a rash in the setting of poor personal hygiene during the winter months. The clinical examination of a patient with possible poststreptococcal complications should begin with an evaluation for signs of inflammation (i.e., complete blood count, erythrocyte sedimentation rate, C-reactive protein) and evidence of a preceding streptococcal infection. Antistreptolysin O titers should be obtained to confirm a recent invasive streptococcal infection. Other important antibody markers include antihyaluronidase, antideoxyribonuclease B, and antistreptokinase antibodies.

Dopamine depleters in the treatment of hyperkinetic movement disorders.

PubMed

Jankovic, Joseph

2016-12-01

Abnormal involuntary movements often improve in response to anti-dopaminergic drugs. In contrast to classic neuroleptics that block dopamine receptors, drugs that deplete presynaptic dopamine by blocking vesicular monoamine transporter type 2 (VMAT2) seem to be safer and have little or no risk of tardive dyskinesia. This is one reason why there has been a recent emergence of novel VMAT2 inhibitors. Areas covered: Since the approval of tetrabenazine, the classic VMAT2 inhibitor, in the treatment of chorea associated with Huntington disease (HD), other VMAT2 inhibitors (e.g. deutetrabenazine and valbenazine) have been studied in the treatment of HD-related chorea, tardive dyskinesia and tics associated with Tourette syndrome. This review, based largely on a detailed search of PubMed, will summarize the pharmacology and clinical experience with the various VMAT2 inhibitors. Expert commentary: Because of differences in pharmacology and pharmacokinetics these new VMAT2 inhibitors promise to be at least as effective as tetrabenazine but with a lower risk of adverse effects, such as sedation, insomnia, depression, parkinsonism, and akathisia.

In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates, the selective 5-hydroxytryptamine 1a agonist (R)-(+)-8-OHDPAT inhibits levodopa-induced dyskinesia but only with\\ increased motor disability.

PubMed

Iravani, Mahmoud M; Tayarani-Binazir, Kayhan; Chu, Wing B; Jackson, Michael J; Jenner, Peter

2006-12-01

5-Hydroxytryptamine 1a (5-HT(1a)) receptor agonists, such as sarizotan and tandospirone, are reported to reduce levodopa-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques and in Parkinson's disease without worsening motor disability. However, these compounds are not specific for 5-HT(1a) receptors and also possess dopamine antagonist actions. We now report on the effects of (2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin [(R)-(+)-8-OHDPAT], a selective 5-HT(1a) agonist lacking dopaminergic activity, on motor disability and dyskinesia (chorea and dystonia) in levodopa-primed MPTP-treated common marmosets. Administration of (R)-(+)-8-OHDPAT (0.2, 0.6, and 2.0 mg/kg s.c), in conjunction with levodopa/carbidopa (12.5 mg/kg each p.o.) to levodopa-primed animals, dose-dependently reduced levodopa-induced chorea but did not affect dystonic movements. However, (R)-(+)-8-OHDPAT treatment also reduced locomotor activity and the reversal of motor disability. Administration of (R)-(+)-8-OHDPAT alone had no effects of motor behaviors. The effects of (R)-(+)-8-OHDPAT on levodopa-induced motor behaviors were antagonized by the 5-HT(1a) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate (WAY-100635) (1.0 mg/kg s.c.). Administration of (R)-(+)-8-OHDPAT (0.6 mg/kg s.c.) also reduced chorea produced by the administration of the D(2)/D(3) dopamine receptor agonist pramipexole (0.06 mg/kg p.o.) to levodopa-primed MPTP-treated animals. However, again the increase in locomotor activity and reversal of motor disability produced by pramipexole were also inhibited. These data suggest that selective 5-HT(1a) agonists do not provide an effective means of suppressing levodopa-induced dyskinesia, except with worsening of parkinsonism.

Brain Human Monoclonal Autoantibody from Sydenham Chorea Targets Dopaminergic Neurons in Transgenic Mice and Signals Dopamine D2 Receptor: Implications in Human Disease1

PubMed Central

Cox, Carol J.; Sharma, Meenakshi; Leckman, James F.; Zuccolo, Jonathan; Zuccolo, Amir; Kovoor, Abraham; Swedo, Susan E.; Cunningham, Madeleine W.

2013-01-01

How autoantibodies target the brain and lead to disease in disorders such as Sydenham chorea (SC) is not known. SC is characterized by autoantibodies against the brain and is the main neurologic manifestation of streptococcal-induced rheumatic fever. Previously, our novel SC-derived mAb 24.3.1 was found to recognize streptococcal and brain antigens. To investigate in vivo targets of human mAb 24.3.1, VH/VL genes were expressed in B cells of transgenic (Tg) mice as functional chimeric human VH 24.3.1 - mouse constant region IgG1a autoantibody. Chimeric human-mouse IgG1a autoantibody co-localized with tyrosine hydroxylase in the basal ganglia within dopaminergic neurons in vivo in VH 24.3.1 Tg mice. Both human mAb 24.3.1 and IgG1a in Tg sera were found to react with human dopamine D2 receptor (D2R). Reactivity of chorea-derived mAb 24.3.1 or SC IgG with D2R was confirmed by 1) dose dependent inhibitory signaling of D2R as a potential consequence of targeting dopaminergic neurons, 2) reaction with surface-exposed FLAG epitope-tagged D2R, and 3) blocking of Ab reactivity by an extracellular D2R peptide. IgG from SC and a related subset of streptococcal associated behavioral disorders called pediatric autoimmune neuropsychiatric disorder associated with streptococci (PANDAS) with small choreiform movements reacted in ELISA with D2R. Reaction with FLAG-tagged D2R distinguished SC from PANDAS while sera from both SC and PANDAS induced inhibitory signaling of D2R on transfected cells comparable to dopamine. Here we define a mechanism by which the brain may be altered by antibody in movement and behavioral disorders. PMID:24184556

Jean-Martin Charcot Pathologist, Neurologist, Psychiatrist and Physician

PubMed Central

Pandey, Sanjay

2012-01-01

Jean-Martin Charcot is known as father of modern neurology. Before him, neurology was only limited to select disorders like chorea. His contributions were not limited to neurology only, as he was instrumental in many new developments in the field of pathology, psychiatry, and internal medicine. Even after 100 years, Charcot`s clinical methods remain the pillar of modern neurology. PMID:23349597

Aceruloplasminaemia with progressive atrophy without brain iron overload: treatment with oral chelation.

PubMed

Skidmore, F M; Drago, V; Foster, P; Schmalfuss, I M; Heilman, K M; Streiff, R R

2008-04-01

Hereditary aceruloplasminaemia is a disorder of iron metabolism that is characterised by iron accumulation in the brain and other visceral organs. In previously reported cases, individuals with the disorder were noted to have evidence of iron accumulation in the brain. Oral chelating agents have not been used in neurological diseases of iron metabolism. A 54-year-old woman who presented with ataxia, lower extremity spasticity and chorea was evaluated for evidence of the source of neurological dysfunction. Blood studies revealed no detectable ceruloplasmin. Marked iron overload was defined by a liver biopsy, which showed a variegated pattern consistent with a primary cause of iron overload. Review of MRI scans showed progressive brain atrophy without visible iron accumulation occurring over a 5-year period. The history suggested that neurodegeneration was coincident with aggressive oral iron replacement. Oral chelation improved many symptoms. Our findings in this patient suggest that disorders of iron transport such as aceruloplasminaemia can be a cause of neurological symptoms such as chorea and cognitive decline, as well as progressive neurodegeneration in the absence of visible iron on MRI scans. We found that oral iron chelation was effective at improving symptoms.

Neurotensin receptor binding levels in basal ganglia are not altered in Huntington's chorea or schizophrenia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Palacios, J.M.; Chinaglia, G.; Rigo, M.

1991-02-01

Autoradiographic techniques were used to examine the distribution and levels of neurotensin receptor binding sites in the basal ganglia and related regions of the human brain. Monoiodo ({sup 125}I-Tyr3)neurotensin was used as a ligand. High amounts of neurotensin receptor binding sites were found in the substantia nigra pars compacta. Lower but significant quantities of neurotensin receptor binding sites characterized the caudate, putamen, and nucleus accumbens, while very low quantities were seen in both medial and lateral segments of the globus pallidus. In Huntington's chorea, the levels of neurotensin receptor binding sites were found to be comparable to those of controlmore » cases. Only slight but not statistically significant decreases in amounts of receptor binding sites were detected in the dorsal part of the head and in the body of caudate nucleus. No alterations in the levels of neurotensin receptor binding sites were observed in the substantia nigra pars compacta and reticulata. These results suggest that a large proportion of neurotensin receptor binding sites in the basal ganglia are located on intrinsic neurons and on extrinsic afferent fibers that do not degenerate in Huntington's disease.« less

[Development, problems and results of specialty-specific genetic counseling at the Neurology Clinic of the Karl Marx University].

PubMed

Bachmann, H

1987-11-01

Genetic counselling for inherited neurological diseases has been established at the Clinic for Neurology of Karl Marx University. Comprehensive experiences have been got with the specific and sometimes markedly different problems and aims of counselling in Wilsons disease, X-linked recessive muscular dystrophies, myotonic dystrophy and other neuromuscular disorders, Huntingtons chorea and hereditary ataxias.

Calculation of the equilibrium distribution for a deleterious gene by the finite Fourier transform.

PubMed

Lange, K

1982-03-01

In a population of constant size every deleterious gene eventually attains a stochastic equilibrium between mutation and selection. The individual probabilities of this equilibrium distribution can be computed by an application of the finite Fourier transform to an appropriate branching process formula. Specific numerical examples are discussed for the autosomal dominants, Huntington's chorea and chondrodystrophy, and for the X-linked recessive, Becker's muscular dystrophy.

The relevance of "non-criteria" clinical manifestations of antiphospholipid syndrome: 14th International Congress on Antiphospholipid Antibodies Technical Task Force Report on Antiphospholipid Syndrome Clinical Features.

PubMed

Abreu, Mirhelen M; Danowski, Adriana; Wahl, Denis G; Amigo, Mary-Carmen; Tektonidou, Maria; Pacheco, Marcelo S; Fleming, Norma; Domingues, Vinicius; Sciascia, Savino; Lyra, Julia O; Petri, Michelle; Khamashta, Munther; Levy, Roger A

2015-05-01

The purpose of this task force was to critically analyze nine non-criteria manifestations of APS to support their inclusion as APS classification criteria. The Task Force Members selected the non-criteria clinical manifestations according to their clinical relevance, that is, the patient-important outcome from clinician perspective. They included superficial vein thrombosis, thrombocytopenia, renal microangiopathy, heart valve disease, livedo reticularis, migraine, chorea, seizures and myelitis, which were reviewed by this International Task Force collaboration, in addition to the seronegative APS (SN-APS). GRADE system was used to evaluate the quality of evidence of medical literature of each selected item. This critical appraisal exercise aimed to support the debate regarding the clinical picture of APS. We found that the overall GRADE analysis was very low for migraine and seizures, low for superficial venous thrombosis, thrombocytopenia, chorea, longitudinal myelitis and the so-called seronegative APS and moderate for APS nephropathy, heart valve lesions and livedo reticularis. The next step can be a critical redefinition of an APS gold standard, for instance derived from the APS ACTION registry that will include not only current APS patients but also those with antiphospholipid antibodies not meeting current classification criteria. Copyright © 2015 Elsevier B.V. All rights reserved.

More Than Ataxia: Hyperkinetic Movement Disorders in Childhood Autosomal Recessive Ataxia Syndromes.

PubMed

Pearson, Toni S

2016-01-01

The autosomal recessive ataxias are a heterogeneous group of disorders that are characterized by complex neurological features in addition to progressive ataxia. Hyperkinetic movement disorders occur in a significant proportion of patients, and may sometimes be the presenting motor symptom. Presentations with involuntary movements rather than ataxia are diagnostically challenging, and are likely under-recognized. A PubMed literature search was performed in October 2015 utilizing pairwise combinations of disease-related terms (autosomal recessive ataxia, ataxia-telangiectasia, ataxia with oculomotor apraxia type 1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2), Friedreich ataxia, ataxia with vitamin E deficiency), and symptom-related terms (movement disorder, dystonia, chorea, choreoathetosis, myoclonus). Involuntary movements occur in the majority of patients with ataxia-telangiectasia and AOA1, and less frequently in patients with AOA2, Friedreich ataxia, and ataxia with vitamin E deficiency. Clinical presentations with an isolated hyperkinetic movement disorder in the absence of ataxia include dystonia or dystonia with myoclonus with predominant upper limb and cervical involvement (ataxia-telangiectasia, ataxia with vitamin E deficiency), and generalized chorea (ataxia with oculomotor apraxia type 1, ataxia-telangiectasia). An awareness of atypical presentations facilitates early and accurate diagnosis in these challenging cases. Recognition of involuntary movements is important not only for diagnosis, but also because of the potential for effective targeted symptomatic treatment.

Clinical variability of neuroacanthocytosis syndromes-a series of six patients with long follow-up.

PubMed

Dulski, J; Sołtan, W; Schinwelski, M; Rudzińska, M; Wójcik-Pędziwiatr, M; Wictor, L; Schön, F; Puschmann, A; Klempíř, J; Tilley, L; Roth, J; Tacik, P; Fujioka, S; Drozdowski, W; Sitek, E J; Wszolek, Z; Sławek, J

2016-08-01

To provide clinical clues to differential diagnosis in patients with chorea and other movement disorders with blood acanthocytes. We present a long-term video accompanied follow-up of six Caucasian patients with neuroacanthocytosis from several centers, three diagnosed with chorea-acanthocytosis (ChAc): 34-y.o.(no.1), 36-y.o.(no.2), 43-y.o.(no.3), two diagnosed with McLeod Syndrome (MLS): 52-y.o.(no.4), 61-y.o.(no.5) and one 63-y.o.(no.6), a brother of no.5, with clinical suspicion of MLS. Additionally we report pathological findings of the mother of two brothers with MLS reported in our series with acanthocytes on peripheral blood smear The patients had an unremarkable family history and were asymptomatic until adulthood. Patients no. 1,2,4,5,6 developed generalized chorea and patient no. 3 had predominant bradykinesia. Patients no. 1,2,3 had phonic and motor tics, additionally patients no. 1 and 2 exhibited peculiar oromandibular dystonia with tongue thrusting. In patients no. 2 and 3 dystonic supination of feet was observed, patient no. 3 subsequently developed bilateral foot drop. Patients no. 2 and 4 had signs of muscle atrophy. Tendon reflexes were decreased or absent and electroneurography demonstrated sensorimotor neuropathy in patients no. 1,2,3,4,5, except no. 6. Generalized seizures were seen in patients no. 2,3,5,6 and myoclonic jerks in patient no. 1. Cognitive deterioration was reported in patients no. 1,2,3,5,6. Serum creatine kinase levels were elevated in all six patients. We highlight the variability of clinical presentation of neuroacanthocytosis syndromes and the long time from the onset to diagnosis with the need to screen the blood smears in uncertain cases, however, as in one of our cases acanthocytes may even be not found. Based on our observations and data from the literature we propose several red flags that should raise the suspicion of an NA syndrome in a patient with a movement disorder: severe orofacial dyskinesia with tongue and lip-biting (typical of ChAc), feeding dystonia, psychiatric and cognitive disturbances, seizures, peripheral neuropathy, elevation of creatine kinase, elevation of transaminases, hepatosplenomegaly, cardiomyopathy and arrhythmias, and an X-linked pattern of inheritance (McLeod Syndrome, MLS). Copyright © 2016 Elsevier B.V. All rights reserved.

Antibody binding to neuronal surface in Sydenham chorea, but not in PANDAS or Tourette syndrome

PubMed Central

Merheb, V.; Ding, A.; Murphy, T.; Dale, R.C.

2011-01-01

Objective: To test the hypothesis that Sydenham chorea (SC) immunoglobulin G (IgG) autoantibodies bind to specific neuronal surface proteins, whereas IgG from patients with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) or Tourette syndrome (TS) do not bind to neuronal surface proteins. Methods: We used live differentiated SH-SY5Y cells, which have neuronal and dopaminergic characteristics. Using flow cytometry, we measured serum IgG cell surface binding in patients with SC (n = 11), PANDAS (n = 12), and TS (n = 11), and compared the findings to healthy controls (n = 11) and other neurologic controls (n = 11). In order to determine the specificity of binding to neuronal antigens, we also used a non-neuronal cell line, HEK 293. Results: The mean IgG cell surface binding was significantly higher in the SC group compared to all other groups (p < 0.001). By contrast, there was no difference between the PANDAS or TS groups and the controls. Using the non-neuronal HEK-293 cells, there was no significant difference in IgG cell surface binding between any groups. Conclusions: Serum autoantibodies that bind to neuronal cell surface antigens are present in SC, but not in PANDAS or TS. These findings strengthen the hypothesis that SC is due to a pathogenic autoantibody, but weaken the autoantibody hypothesis in PANDAS and TS. PMID:21411742

Antibody binding to neuronal surface in Sydenham chorea, but not in PANDAS or Tourette syndrome.

PubMed

Brilot, F; Merheb, V; Ding, A; Murphy, T; Dale, R C

2011-04-26

To test the hypothesis that Sydenham chorea (SC) immunoglobulin G (IgG) autoantibodies bind to specific neuronal surface proteins, whereas IgG from patients with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) or Tourette syndrome (TS) do not bind to neuronal surface proteins. We used live differentiated SH-SY5Y cells, which have neuronal and dopaminergic characteristics. Using flow cytometry, we measured serum IgG cell surface binding in patients with SC (n = 11), PANDAS (n = 12), and TS (n = 11), and compared the findings to healthy controls (n = 11) and other neurologic controls (n = 11). In order to determine the specificity of binding to neuronal antigens, we also used a non-neuronal cell line, HEK 293. The mean IgG cell surface binding was significantly higher in the SC group compared to all other groups (p < 0.001). By contrast, there was no difference between the PANDAS or TS groups and the controls. Using the non-neuronal HEK-293 cells, there was no significant difference in IgG cell surface binding between any groups. Serum autoantibodies that bind to neuronal cell surface antigens are present in SC, but not in PANDAS or TS. These findings strengthen the hypothesis that SC is due to a pathogenic autoantibody, but weaken the autoantibody hypothesis in PANDAS and TS.

A Rare Case of Psychomotor Disturbances Linked to the Use of an Adulterated Dietary Supplement Containing Sibutramine.

PubMed

Shapira, Barak; Goldstein, Lee; Reshef, Amikam; Poperno, Alina

2016-01-01

Sibutramine, an oral anorexiant, is often found as an adulterant in various counterfeit herbal slimming products and dietary supplements. The use of sibutramine has been associated with various cardiovascular and psychiatric symptoms. Here, we report a rare case of psychomotor disturbances, in a patient with no previously diagnosed movement disorders. A 26-year-old woman developed abnormal behavior, visual hallucinations, hyperkinesia, facial flushing, and dizziness after taking a counterfeit dietary supplement which contained undeclared sibutramine and phenolphtalein. Laboratory work-up revealed microcytic anemia; leucopenia; and elevated erythrocyte sedimentation rate, C-reactive protein levels, and antistreptolysin O titer, but rheumatic fever was ruled out. After a neurologic examination, involuntary movements were classified as chorea. The psychiatric examination result was unremarkable. The patient responded well to haloperidol therapy. Body temperature, erythrocyte sedimentation rate, and C-reactive protein levels eventually normalized. The patient was discharged. This is the first report we are aware of about a transient, chorea-like psychomotor movement disorder associated with sibutramine. Although the causal relationship between sibutramine and the patient's symptoms cannot be proven definitely, the temporal dimension does suggest sibutramine initiation and termination led to onset and resolution of symptoms, respectively. Furthermore, because of the widespread availability of adulterated food supplements containing sibutramine, physicians should be more aware of their implications for patients.

Behavioral, Pharmacological, and Immunological Abnormalities after Streptococcal Exposure: A Novel Rat Model of Sydenham Chorea and Related Neuropsychiatric Disorders

PubMed Central

Brimberg, Lior; Benhar, Itai; Mascaro-Blanco, Adita; Alvarez, Kathy; Lotan, Dafna; Winter, Christine; Klein, Julia; Moses, Allon E; Somnier, Finn E; Leckman, James F; Swedo, Susan E; Cunningham, Madeleine W; Joel, Daphna

2012-01-01

Group A streptococcal (GAS) infections and autoimmunity are associated with the onset of a spectrum of neuropsychiatric disorders in children, with the prototypical disorder being Sydenham chorea (SC). Our aim was to develop an animal model that resembled the behavioral, pharmacological, and immunological abnormalities of SC and other streptococcal-related neuropsychiatric disorders. Male Lewis rats exposed to GAS antigen exhibited motor symptoms (impaired food manipulation and beam walking) and compulsive behavior (increased induced-grooming). These symptoms were alleviated by the D2 blocker haloperidol and the selective serotonin reuptake inhibitor paroxetine, respectively, drugs that are used to treat motor symptoms and compulsions in streptococcal-related neuropsychiatric disorders. Streptococcal exposure resulted in antibody deposition in the striatum, thalamus, and frontal cortex, and concomitant alterations in dopamine and glutamate levels in cortex and basal ganglia, consistent with the known pathophysiology of SC and related neuropsychiatric disorders. Autoantibodies (IgG) of GAS rats reacted with tubulin and caused elevated calcium/calmodulin-dependent protein kinase II signaling in SK-N-SH neuronal cells, as previously found with sera from SC and related neuropsychiatric disorders. Our new animal model translates directly to human disease and led us to discover autoantibodies targeted against dopamine D1 and D2 receptors in the rat model as well as in SC and other streptococcal-related neuropsychiatric disorders. PMID:22534626

Platysmal myoclonus in subclinical hyperthyroidism.

PubMed

Teoh, Hock-Luen; Lim, Erle Chuen-Hian

2005-08-01

Hyperthyroidism is associated with various movement disorders, such as chorea and tremors. We report on a young Chinese woman with an unusual presentation of myoclonus, involving both platysmal muscles, in association with subclinical hyperthyroidism. The myoclonus was preceded by symptoms of hyperthyroidism, namely weight loss, menstrual disturbances, and heat intolerance. The movements abated with clonazepam and hyperthyroidism was treated with carbimazole. The myoclonus recurred briefly when she stopped taking clonazepam, but she has since remained well and euthyroid. Copyright 2005 Movement Disorder Society

Activity of nigral dopaminergic neurons after lesion of the neostriatum in rats.

PubMed

Doudet, D; Gross, C; Seal, J; Bioulac, B

1984-06-04

As shown by post-mortem analysis the major neuropathological trait of Huntington's chorea is a degeneration of the intrinsic neurons of the neostriatum (caudate nucleus and putamen). Such a situation can be reproduced by a destruction of the neostriatum by kainic acid. When injected into the caudate nucleus this excitatory amino acid destroys the intrinsic neurons of the neostriatum and spares fairly well the passing fibers. In the present work, we have chosen to examine the influence of neostriatal destruction on the activity of identified dopaminergic cells in the pars compacta of the substantia nigra. As a key element in the nigro-neostriato-nigral loop, this structure is a relevant site for observing the functional effects of neostriatal lesion. Our research hypothesis was based on the generally accepted view that the suppression of the important neostriato-nigral pathway and in particular the inhibitory GABAergic contingent, could generate a hyperactivity of nigral dopaminergic cells. One may therefore consider that the dopaminergic hyperactivity produces abnormal messages which can influence via several pathways the motoneurons, and which participates in the genesis of the hyperkinetic movements characteristic of chorea. After destruction of the neostriatum, we have shown that the pattern of discharge of most identified nigral dopaminergic neurons becomes greatly disorganized. This drastic change in the pattern of activity cannot be interpreted as the simple 'lift of a brake' on these cells by the suppression of the inhibitory GABAergic striato-nigral tract.

Inherited disorders in the Afrikaner population of southern Africa. Part I. Historical and demographic background, cardiovascular, neurological, metabolic and intestinal conditions.

PubMed

Botha, M C; Beighton, P

1983-10-08

Certain genetic disorders occur with unusually high frequency in the Afrikaner population of southern Africa. Conditions of this type (reviewed in Part I of this article) include familial hypercholesterolaemia, progressive familial heart block, Huntington's chorea, porphyria variegata, Gaucher's disease, cystic fibrosis and familial colonic polyposis. This genetic situation is explicable to some extent on the basis of the demographic development of the Afrikaner population during the 14 generations since the arrival of the first immigrants from Holland more than 330 years ago.

Antidopaminergic Medication is Associated with More Rapidly Progressive Huntington's Disease.

PubMed

Tedroff, Joakim; Waters, Susanna; Barker, Roger A; Roos, Raymund; Squitieri, Ferdinando

2015-01-01

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder leading to progressive motor, cognitive and functional decline. Antidopaminergic medications (ADMs) are frequently used to treat chorea and behavioural disturbances in HD. We aimed to assess how the use of such medications was associated with the severity and progression of the motor aspects of the condition, given that there have been concerns that such drugs may actually promote neurological deterioration. Using multiple linear regression, supplemented by principal component analysis to explore the overall correlation patterns and help identify relevant covariates, we assessed severity and progression of motor symptoms and functional decline in 651 manifest patients from the REGISTRY cohort followed for two years. ADM treated versus non-treated subjects were compared with respect to motor impairment at baseline and progression rate by means of multiple regression, adjusting for CAG-repeat and age. Patients treated with ADMs had significantly worse motor scores with greater functional disability at their first visit. They also showed a higher annual rate of progression of motor signs and disability over the next two years. In particular the rate of progression for oculomotor symptoms and bradykinesia was markedly increased whereas the rate of progression of chorea and dystonia was similar for ADM and drug naïve patients. These differences in clinical severity and progression could not be explained by differences in disease burden, duration of disease or other possible prognostic factors. The results from this analysis suggest ADM treatment is associated with more advanced and rapidly progressing HD although whether these drugs are causative in driving this progression requires further, prospective studies.

Speech–Language Pathology Evaluation and Management of Hyperkinetic Disorders Affecting Speech and Swallowing Function

PubMed Central

Barkmeier-Kraemer, Julie M.; Clark, Heather M.

2017-01-01

Background Hyperkinetic dysarthria is characterized by abnormal involuntary movements affecting respiratory, phonatory, and articulatory structures impacting speech and deglutition. Speech–language pathologists (SLPs) play an important role in the evaluation and management of dysarthria and dysphagia. This review describes the standard clinical evaluation and treatment approaches by SLPs for addressing impaired speech and deglutition in specific hyperkinetic dysarthria populations. Methods A literature review was conducted using the data sources of PubMed, Cochrane Library, and Google Scholar. Search terms included 1) hyperkinetic dysarthria, essential voice tremor, voice tremor, vocal tremor, spasmodic dysphonia, spastic dysphonia, oromandibular dystonia, Meige syndrome, orofacial, cervical dystonia, dystonia, dyskinesia, chorea, Huntington’s Disease, myoclonus; and evaluation/treatment terms: 2) Speech–Language Pathology, Speech Pathology, Evaluation, Assessment, Dysphagia, Swallowing, Treatment, Management, and diagnosis. Results The standard SLP clinical speech and swallowing evaluation of chorea/Huntington’s disease, myoclonus, focal and segmental dystonia, and essential vocal tremor typically includes 1) case history; 2) examination of the tone, symmetry, and sensorimotor function of the speech structures during non-speech, speech and swallowing relevant activities (i.e., cranial nerve assessment); 3) evaluation of speech characteristics; and 4) patient self-report of the impact of their disorder on activities of daily living. SLP management of individuals with hyperkinetic dysarthria includes behavioral and compensatory strategies for addressing compromised speech and intelligibility. Swallowing disorders are managed based on individual symptoms and the underlying pathophysiology determined during evaluation. Discussion SLPs play an important role in contributing to the differential diagnosis and management of impaired speech and deglutition associated with hyperkinetic disorders. PMID:28983422

Role for antibodies in altering behavior and movement.

PubMed

Libbey, Jane E; Fujinami, Robert S

2010-08-01

At the past meeting of INSAR, the role of autoimmunity was discussed in an educational session. This article summarizes this discussion. In immune-mediated diseases, antibodies can contribute to the pathogenesis of the disease and are sometimes the force that drives the disease process. This concept has not been established for autism. In autoimmune diseases, such as systemic lupus erythematosus (SLE), antibodies are found to react with double-stranded DNA. These antibodies also cross-react with N-methyl-D aspartate receptors. Many SLE patients suffer neurologic syndromes of the central nervous system (CNS). Similarly individuals infected with Group A streptococcus (GAS) have antibodies against the GAS carbohydrate, which cross-react with tubulin and lysoganglioside GM1 on neurons. During the acute stage of infection, GAS-infected patients develop Syndenham chorea where the disease process is driven in part by these cross-reactive antibodies. As the antibody levels decrease, the clinical features of Syndenham chorea resolve. In these two immune-mediated diseases, antibodies clearly play a role in the pathogenesis of the diseases. There are reports that mothers of individuals with autism have antibodies that react with brain proteins and when these antibodies are passively transferred to pregnant non-human primates or rodents the offspring has behavioral and nervous system changes. It is still not clear whether the antibodies found in mothers of individuals with autism actually play a role in the disease. More studies need to be performed to identify the proteins recognized by the antibodies and to determine how these could affect development, behavior and changes within the CNS.

Functional decline in Huntington's disease.

PubMed

Feigin, A; Kieburtz, K; Bordwell, K; Como, P; Steinberg, K; Sotack, J; Zimmerman, C; Hickey, C; Orme, C; Shoulson, I

1995-03-01

We prospectively evaluated 129 patients with manifest Huntington's disease (HD) to determine the rate of illness progression and the clinical features that correlate with functional decline. A single examiner evaluated each patient using the HD Functional Capacity Scale. Standardized motor performance was also assessed in 94 of the patients (73%) using the HD Rating Scale. Total Functional Capacity declined at a rate of 0.63 +/- 0.75 U per year. As functional capacity worsened, chorea lessened, and dystonia intensified. There was no correlation between rate of functional decline and age at onset of HD, body weight, gender of affected parent, or history of neuroleptic use.

A case of hyperosmolar hyperglycaemic state with involuntary movements – diagnostic dilemma and clinical considerations

PubMed Central

Abd Hamid, Hanisah; Othman, Hanita; Das, Srijit

2010-01-01

Hyperosmolar hyperglycaemic state (HHS) is a medical emergency which needs immediate medical intervention. A 37-year-old Chinese woman with a history of hypertension attended the Emergency Department. She had a two-day history of involuntary movement, i.e. chorea of the upper limbs, preceded by a one-week history of upper respiratory tract infection. She also had polyuria and polydipsia, although she was never diagnosed as diabetic. The main aim of reporting the present case was to highlight the importance of biochemical investigations involved in the diagnosis of involuntary movements. PMID:22427779

IgLON5-Associated Encephalitis With Atypical Brain Magnetic Resonance Imaging and Cerebrospinal Fluid Changes.

PubMed

Montagna, Massimiliano; Amir, Rizvana; De Volder, Ilse; Lammens, Martin; Huyskens, Jef; Willekens, Barbara

2018-01-01

IgLON5-associated encephalitis is a syndrome with different clinical presentations consisting of sleep dysfunction, bulbar dysfunction, chorea, and progressive supranuclear palsy-like symptoms whereas dysautonomy and cognitive decline usually appear in later stages of the disease. We report a case of a patient with IgLON5-associated encephalitis presenting with rapidly progressive cognitive decline and atypical inflammatory lesions on brain magnetic resonance imaging, oligoclonal bands on cerebrospinal fluid, anti-IgLON5 antibodies exclusively of the IgG1 class, and a fierce inflammatory reaction on brain biopsy, who responded favorably to immunotherapy.

The Immunobiology of Tourette's Disorder, Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus, and Related Disorders: A Way Forward

PubMed Central

Kurlan, Roger; Leckman, James

2010-01-01

Abstract Obsessive-compulsive disorder (OCD) and related conditions including Tourette's disorder (TD) are chronic, relapsing disorders of unknown etiology associated with marked impairment and disability. Associated immune dysfunction has been reported and debated in the literature since the late 80s. The immunologic culprit receiving the most interest has been Group A Streptococcus (GAS), which began to receive attention as a potential cause of neuropsychiatric symptoms, following the investigation of the symptoms reported in Sydenham's chorea (SC) and rheumatic fever, such as motor tics, vocal tics, and both obsessive-compulsive and attention deficit/hyperactivity symptoms. Young children have been described as having a sudden onset of these neuropsychiatric symptoms temporally associated with GAS, but without supporting evidence of rheumatic fever. This presentation of OCD and tics has been termed pediatric autoimmune neuropsychiatric disorders associated with Streptococcus (PANDAS). Of note, SC, OCD, and TD often begin in early childhood and share common anatomic areas—the basal ganglia of the brain and the related cortical and thalamic sites—adding support to the possibility that these disorders might share a common immunologic and/or genetic vulnerability. Relevant manuscripts were identified through searches of the PsycINFO and MedLine databases using the following keywords: OCD, immune, PANDAS, Sydenham chorea, Tourette's disorder Group A Streptococcus. Articles were also identified through reference lists from research articles and other materials on childhood OCD, PANDAS, and TD between 1966 and December 2010. Considering the overlap of clinical and neuroanatomic findings among these disorders, this review explores evidence regarding the immunobiology as well as the relevant clinical and therapeutic aspects of TD, OCD, and PANDAS. PMID:20807070

Intraoperative monitoring of motor symptoms using surface electromyography during stereotactic surgery for movement disorders.

PubMed

Liu, Xuguang; Aziz, Tipu Z; Bain, Peter G

2005-06-01

The authors present practical evidence for the usefulness of intraoperative monitoring with surface electromyograms (sEMGs) from the affected muscles to assist electrode implantation and lesioning in patients with movement disorders. In 22 consecutive patients with various movement disorders, sEMGs were monitored in selected muscles during stereotactic surgery that involved either lesioning or electrode implantation. The electromyograms related to major motor symptoms such as tremor, rigidity, myoclonus, dystonia, and chorea were monitored and characterized on-line by both amplitude and frequency. Major motor symptoms were revealed by sEMGs recorded from the affected muscles. Tremor manifested as highly rhythmic bursts with a narrow frequency band; dyskinesias and chorea appeared as irregularly repeated bursts within a broad frequency range of 1 to 5 Hz; and rigidity and dystonia appeared as sustained high-frequency activity and co-contraction between antagonist muscles. The results suggest that intraoperative monitoring of sEMGs could help to functionally refine and confirm target localization. Surface EMGs could be used (1) as reference signals of the motor symptoms so that other signals, such as the oscillatory local field potentials simultaneously recorded via the implanted electrodes, could be correlated with the sEMGs and used to fine-tune or confirm the target localization; (2) to quantify the effects of acute electrical stimulation on the motor symptoms; and (3) to sensitively detect unwanted capsular responses induced by direct stimulation of the internal capsule. The authors conclude that intraoperative monitoring of sEMGs of the affected muscles of patients with movement disorders during stereotactic surgery provides sensitive and quantitative information that can contribute to improved electrode or lesion placement.

Late-onset Huntington's disease: diagnostic and prognostic considerations.

PubMed

Koutsis, Georgios; Karadima, Georgia; Kladi, Athina; Panas, Marios

2014-07-01

To address diagnostic and prognostic issues in patients with late-onset Huntington's disease (HD). We analyzed a cohort of 41 late-onset (≥60 years) HD patients and compared them to 39 late-onset patients referred for HD testing that were negative for the HD-expansion and to 290 usual-onset (20-59 years) HD patients. Disease severity was assessed by the Total Functional Capacity Scale. Late-onset HD comprised 11.5% of our HD cohort. In total, 70.7% of late-onset HD patients had positive family history compared to 15.4% of late-onset expansion-negative patients (p < 0.001). Clinical features at onset or presentation could not usefully distinguish between late-onset expansion-positive and negative patients, excepting hemichorea, which was absent from the HD group (p = 0.024). Chorea was the first clinical feature in 53.7% and a presenting feature in 90.2% of late-onset HD. The mutation hit rate for late-onset patients was 51.3%, lower than in usual-onset patients (p = 0.04). Frequencies of chorea, cognitive impairment and psychiatric manifestations at onset or presentation were not significantly different between late-onset and usual-onset HD patients. Gait unsteadiness however was more common at presentation in late-onset HD (p = 0.007). Late-onset HD patients reached a severe stage of illness on average 2.8 years earlier than usual-onset HD patients (p = 0.046). A positive family history suggestive of HD, although absent in a third of patients, remains a helpful clue in diagnosing late-onset HD. Prognosis of late-onset HD in terms of Total Functional Capacity appears no better and shows a trend of being somewhat less favorable compared to usual-onset HD. Copyright © 2014 Elsevier Ltd. All rights reserved.

It wasn't Witchcraft--It was Huntington Disease!

PubMed

Penaranda, Eribeth; Garcia, Angel; Montgomery, Lisa

2011-01-01

Huntington disease (HD) is an autosomal-dominant, incurable, progressive disorder that manifests with chorea and behavioral and cognitive impairment. The disease usually occurs during the fourth or fifth decade of life; however, it may present at any age. Clinical suspicion is confirmed by genetic testing. Death occurs, on average, 15 to 20 years after the onset of symptoms. Here we report about a Hispanic woman and her family who were affected by the disease; this case illustrates the role of cultural values and beliefs in the decision-making process, as well as the importance of the physician's cultural competency in fostering a trusting relationship that may lessen the burden of catastrophic diseases on individuals, families, and society at-large.

MRI and clinical manifestations of delayed encephalopathy after carbon monoxide poisoning.

PubMed

Wang, Xiahong; Li, Zhenyu; Berglass, Jacqueline; He, Wenlong; Zhao, Jianmin; Zhang, Min; Gao, Chongyang; Zhang, Caixia; Zhang, Huimin; Yi, Xuewei

2016-11-01

To explore the relationship between the clinical manifestations and functional magnetic resonance images of delayed encephalopathy after carbon monoxide intoxication. Six patients received the MRI were diagnosed with delayed encephalopathy after carbon monoxide (CO) poisoning. Clinical manifestations were observed in each patient. MRI revealed multiple lesions. The majority of the lesions were located in the globus pallidus, sub cortical white matter, and basal ganglia. The cognitive injury, akinetic mutism, fecal and uroclepsia, forced crying, forced laughing and extra pyramidal syndromes such as chorea and parkinsonism were manifested in clinic. Cognitive impairment improved greatly while involuntary movements only improved slightly after several months. Meanwhile brain MRI suggested remarkable improvement. Neuroimaging directly correlated with the clinical manifestations.

Genetic disorders of thyroid metabolism and brain development

PubMed Central

Kurian, Manju A; Jungbluth, Heinz

2014-01-01

Normal thyroid metabolism is essential for human development, including the formation and functioning of the central and peripheral nervous system. Disorders of thyroid metabolism are increasingly recognized within the spectrum of paediatric neurological disorders. Both hypothyroid and hyperthyroid disease states (resulting from genetic and acquired aetiologies) can lead to characteristic neurological syndromes, with cognitive delay, extrapyramidal movement disorders, neuropsychiatric symptoms, and neuromuscular manifestations. In this review, the neurological manifestations of genetic disorders of thyroid metabolism are outlined, with particular focus on Allan-Herndon-Dudley syndrome and benign hereditary chorea. We report in detail the clinical features, major neurological and neuropsychiatric manifestations, molecular genetic findings, disease mechanisms, and therapeutic strategies for these emerging genetic ‘brain-thyroid’ disorders. PMID:24665922

Non-stroke neurological syndromes associated with antiphospholipid antibodies: evaluation of clinical and experimental studies.

PubMed

Chapman, J; Rand, J H; Brey, R L; Levine, S R; Blatt, I; Khamashta, M A; Shoenfeld, Y

2003-01-01

Although many types of neurological disorders and events have been described in association with antiphospholipid antibodies (aPL) and the antiphospholipid syndrome (APS), only ischaemic stroke is reasonably well established and accepted as a diagnostic criterion for the syndrome. We propose to evaluate, classify and rank the association of other neurological manifestations as possible, probable, or definite according to the data available from clinical studies and animal models. By these criteria, none of the neurological disorders or events such as epilepsy, psychiatric disease, dementia, transverse myelitis, multiple sclerosis-like disease, chorea, migraine, Guillian-Barrè syndrome, and sensory-neural hearing loss, can be definitely associated with aPL or APS.

Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients.

PubMed

Pelzl, Lisann; Elsir, Bhaeldin; Sahu, Itishri; Bissinger, Rosi; Singh, Yogesh; Sukkar, Basma; Honisch, Sabina; Schoels, Ludger; Jemaà, Mohamed; Lang, Elisabeth; Storch, Alexander; Hermann, Andreas; Stournaras, Christos; Lang, Florian

2017-01-01

The widely expressed protein chorein fosters activation of the phosphoinositide 3 kinase (PI3K) pathway thus supporting cell survival. Loss of function mutations of the chorein encoding gene VPS13A (vacuolar protein sorting-associated protein 13A) causes chorea-acanthocytosis (ChAc), a neurodegenerative disorder paralleled by deformations of erythrocytes. In mice, genetic knockout of chorein leads to enhanced neuronal apoptosis. PI3K dependent signalling upregulates Orai1, a pore forming channel protein accomplishing store operated Ca2+ entry (SOCE). Increased Orai1 expression and SOCE have been shown to confer survival of tumor cells. SOCE could be up-regulated by lithium. The present study explored, whether SOCE and/or apoptosis are altered in ChAc fibroblasts and could be modified by lithium treatment. Fibroblasts were isolated from ChAc patients and age-matched healthy volunteers. Cytosolic Ca2+ activity ([Ca2+]i) was estimated from Fura-2-fluorescence, SOCE from increase of [Ca2+]i following Ca2+ re-addition after Ca2+-store depletion with sarcoendoplasmatic Ca2+-ATPase (SERCA) inhibitor thapsigargin (1 µM), and apoptosis from annexin-V/propidium iodide staining quantified in flow cytometry. SOCE was significantly smaller in ChAc fibroblasts than in control fibroblasts. Lithium (2 mM, 24 hours) significantly increased and Orai1 blocker 2-Aminoethoxydiphenyl Borate (2-APB, 50 µM, 24 hours) significantly decreased SOCE. Annexin-V-binding and propidium iodide staining were significantly higher in ChAc fibroblasts than in control fibroblasts. In ChAc fibroblasts annexin-V-binding and propidium iodide staining were significantly decreased by lithium treatment, significantly increased by 2-APB and virtually lithium insensitive in the presence of 2-APB. In ChAc fibroblasts, downregulation of SOCE contributes to enhanced susceptibility to apoptosis. Both, decreased SOCE and enhanced apoptosis of ChAc fibroblasts can be reversed by lithium treatment. © 2017 The Author(s). Published by S. Karger AG, Basel.

Amino acid substitution equivalent to human chorea-acanthocytosis I2771R in yeast Vps13 protein affects its binding to phosphatidylinositol 3-phosphate

PubMed Central

Rzepnikowska, Weronika; Flis, Krzysztof; Kaminska, Joanna; Grynberg, Marcin; Urbanek, Agnieszka; Ayscough, Kathryn R.

2017-01-01

Abstract The rare human disorder chorea-acanthocytosis (ChAc) is caused by mutations in hVPS13A gene. The hVps13A protein interacts with actin and regulates the level of phosphatidylinositol 4-phosphate (PI4P) in the membranes of neuronal cells. Yeast Vps13 is involved in vacuolar protein transport and, like hVps13A, participates in PI4P metabolism. Vps13 proteins are conserved in eukaryotes, but their molecular function remains unknown. One of the mutations found in ChAc patients causes amino acids substitution I2771R which affects the localization of hVps13A in skeletal muscles. To dissect the mechanism of pathogenesis of I2771R, we created and analyzed a yeast strain carrying the equivalent mutation. Here we show that in yeast, substitution I2749R causes dysfunction of Vps13 protein in endocytosis and vacuolar transport, although the level of the protein is not affected, suggesting loss of function. We also show that Vps13, like hVps13A, influences actin cytoskeleton organization and binds actin in immunoprecipitation experiments. Vps13-I2749R binds actin, but does not function in the actin cytoskeleton organization. Moreover, we show that Vps13 binds phospholipids, especially phosphatidylinositol 3-phosphate (PI3P), via its SHR_BD and APT1 domains. Substitution I2749R attenuates this ability. Finally, the localization of Vps13-GFP is altered when cellular levels of PI3P are decreased indicating its trafficking within the endosomal membrane system. These results suggest that PI3P regulates the functioning of Vps13, both in protein trafficking and actin cytoskeleton organization. Attenuation of PI3P-binding ability in the mutant hVps13A protein may be one of the reasons for its mislocalization and disrupted function in cells of patients suffering from ChAc. PMID:28334785

Clinical features of movement disorders.

PubMed

Yung, C Y

1983-08-01

The descriptive aspects of all types of movement disorders and their related syndromes and terminologies used in the literature are reviewed and described. This comprises the features of (a) movement disorders secondary to neurological diseases affecting the extrapyramidal motor system, such as: athetosis, chorea, dystonia, hemiballismus, myoclonus, tremor, tics and spasm, (b) drug induced movement disorders, such as: akathisia, akinesia, hyperkinesia, dyskinesias, extrapyramidal syndrome, and tardive dyskinesia, and (c) abnormal movements in psychiatric disorders, such as: mannerism, stereotyped behaviour and psychomotor retardation. It is intended to bring about a more comprehensive overview of these movement disorders from a phenomenological perspective, so that clinicians can familiarize with these features for diagnosis. Some general statements are made in regard to some of the characteristics of movement disorders.

New onset of idiopathic bilateral ear tics in an adult.

PubMed

Agrawal, Amit; Shrestha, Rabin

2009-04-01

Tic disorders are commonly considered to be childhood syndromes. Newly presenting tic disorders during adulthood are uncommon and mostly described in relation to an acquired brain lesion or as incidental tics, particularly in context with other neurological or psychiatric diseases. Tic disorder involving the ears is extremely uncommon with only few studies in English literature. In the present case, we describe an adult patient with new-onset idiopathic tics disorder involving both ears, causing social embarrassment. In addition, our patient had recent onset of the tics without any childhood or family history of tic disorders. The single most important component of management is an accurate diagnosis. At the same time, tics should be differentiated from other movement disorders such as chorea, stereotypy, and dystonias.

[Huntington chorea: perspective changes in presymptomatic diagnosis (updating synthetic review)].

PubMed

Borri, G

1989-01-01

With the advent of recombinant DNA techniques and the identification of closely linked DNA markers, it is now possible to determine whether at-risk subjects have inherited the Huntington's disease (HD) gene. Since the presymptomatic testing is only applicable to those at-risk subjects with diagnosed genetic haplotype segregating with HD in their families, neurologists, neuropsychologists and neurophysiologists purpose to correlate clinical evidences and genetic data. At the present time using neuropsychological tests, nonspecific abnormalities have been observed in visuospatial abilities, memory and in functions associated with the frontal lobes; still the general reduction of visual evoked potential amplitude has to be considered a very interesting finding in the at-risk subjects with probability of having inherited the HD gene.

An Update on Tardive Dyskinesia: From Phenomenology to Treatment

PubMed Central

Waln, Olga; Jankovic, Joseph

2013-01-01

Tardive dyskinesia (TD), characterized by oro-buccal-lingual stereotypy, can manifest in the form of akathisia, dystonia, tics, tremor, chorea, or as a combination of different types of abnormal movements. In addition to movement disorders (including involuntary vocalizations), patients with TD may have a variety of sensory symptoms, such as urge to move (as in akathisia), paresthesias, and pain. TD is a form of tardive syndrome—a group of iatrogenic hyperkinetic and hypokinetic movement disorders caused by dopamine receptor-blocking agents. The pathophysiology of TD remains poorly understood, and treatment of this condition is often challenging. In this update, we provide the most current information on the history, nomenclature, etiology, pathophysiology, epidemiology, phenomenology, differential diagnosis, and treatment of TD. PMID:23858394

Epigenetic memory: the Lamarckian brain

PubMed Central

Fischer, Andre

2014-01-01

Recent data support the view that epigenetic processes play a role in memory consolidation and help to transmit acquired memories even across generations in a Lamarckian manner. Drugs that target the epigenetic machinery were found to enhance memory function in rodents and ameliorate disease phenotypes in models for brain diseases such as Alzheimer's disease, Chorea Huntington, Depression or Schizophrenia. In this review, I will give an overview on the current knowledge of epigenetic processes in memory function and brain disease with a focus on Morbus Alzheimer as the most common neurodegenerative disease. I will address the question whether an epigenetic therapy could indeed be a suitable therapeutic avenue to treat brain diseases and discuss the necessary steps that should help to take neuroepigenetic research to the next level. PMID:24719207

Unusual early-onset Huntingtons disease.

PubMed

Vargas, Antonio P; Carod-Artal, Francisco J; Bomfim, Denise; Vázquez-Cabrera, Carolina; Dantas-Barbosa, Carmela

2003-06-01

Huntington's disease is an autosomal dominant progressive neurodegenerative disorder characterized by involuntary movements, cognitive decline, and behavioral disorders leading to functional disability. In contrast to patients with adult onset, in which chorea is the major motor abnormality, children often present with spasticity, rigidity, and significant intellectual decline associated with a more rapidly progressive course. An unusual early-onset Huntington's disease case of an 11-year-old boy with severe hypokinetic/rigid syndrome appearing at the age of 2.5 years is presented. Clinical diagnosis was confirmed by polymerase chain reaction study of the expanded IT-15 allele with a compatible size of 102 cytosine-adenosine-guanosine repeats L-Dopa mildly ameliorated rigidity, bradykinesia, and dystonia. We conclude that Huntington's disease should be included in the differential diagnoses of regressive syndromes of early childhood.

Anti-streptococcal, tubulin, and dopamine receptor 2 antibodies in children with PANDAS and Tourette syndrome: single-point and longitudinal assessments.

PubMed

Morris-Berry, C M; Pollard, M; Gao, S; Thompson, C; Singer, H S

2013-11-15

Single-point-in-time ELISA optical densities for three putative antibodies identified in Sydenham's chorea, the streptococcal group A carbohydrate antigen, N-acetyl-beta-d-glucosamine, tubulin, and the dopamine 2 receptor, showed no differences in children with PANDAS (n=44) or Tourette syndrome (n=40) as compared to controls (n=24). Anti-tubulin and D2 receptor antibodies assessed in serial samples from 12 PANDAS subjects obtained prior to a documented exacerbation, during the exacerbation (with or without a temporally associated streptococcal infection), and following the exacerbation, showed no evidence of antibody levels correlating with a clinical exacerbation. These data do not support hypotheses suggesting an autoimmune hypothesis in either TS or PANDAS. © 2013.

Symptomatic treatment of neurologic symptoms in Wilson disease.

PubMed

Litwin, Tomasz; Dušek, Petr; Członkowska, Anna

2017-01-01

Wilson disease (WD) is a potentially treatable neurodegenerative disorder. In the majority of cases, treatment with drugs that induce a negative copper balance (usually chelators or zinc salts) leads to improvements in liver function and neurologic signs. However, some patients show severe neurologic symptoms at diagnosis, such as tremor, dystonia, parkinsonism, and chorea. In this patient group, some neurologic deficits may persist despite adequate treatment, and further neurologic deterioration may be observed after treatment initiation. Such patients may require additional treatment to alleviate neurologic symptoms. Apart from general recommendations for WD anticopper treatment, there are currently no guidelines for managing neurologic symptoms in WD. The aim of this chapter is to summarize possible treatments of neurologic symptoms in WD based on the presently available medical literature. © 2017 Elsevier B.V. All rights reserved.

Undulating tongue in Wilson's disease

PubMed Central

Nagappa, M; Sinha, S; Saini, JS; Bindu, PS; Taly, AB

2014-01-01

We report an unusual occurrence of involuntary movement involving the tongue in a patient with confirmed Wilson's disease (WD). She manifested with slow, hypophonic speech and dysphagia of 4 months duration, associated with pseudobulbar affect, apathy, drooling and dystonia of upper extremities of 1 month duration. Our patient had an uncommon tongue movement which was arrhythmic. There was no feature to suggest tremor, chorea or dystonia. It might be described as athetoid as there was a writhing quality, but of lesser amplitude. Thus, the phenomenology was uncommon in clinical practice and the surface of the tongue was seen to “ripple” like a liquid surface agitated by an object or breeze. Isolated lingual dyskinesias are rare in WD. It is important to evaluate them for WD, a potentially treatable disorder. PMID:25024581

[Neurologic manifestations associated with antiphospholipid antibodies. Or what remains of neurolupus?].

PubMed

Hachulla, E; Leys, D; Deleume, J F; Pruvo, J P; Devulder, B

1995-01-01

Antiphospholipid antibody is associated with a clinical syndrome of vascular thrombosis, thrombocytopenia, recurrent fetal loss and livedo reticularis, whether or not a clinical diagnosis of systemic lupus erythematosus (SLE) coexists. Central nervous system involvement in SLE is multifactorial, thrombotic events, antineuronal antibodies, hypertension, infection, side effects of drugs etc. Antiphospholipid antibodies may play a role in focal neurological manifestations in SLE. In the absence of SLE, different neurological symptoms are well associated with antiphospholipid antibodies including stroke, seizures, dementia, migraine, ocular ischemia, chorea, transverse myelopathy, cerebral phlebitis. Other association are more controversal like Guillain Barré syndrome, motor neuron disease, communicating hydrocephalus. In all patients with antiphospholipid antibodies with neurological involvement, cerebral MRI may be performed with an echocardiographic study because a possible association with Libman and Sacks endocarditis, valve dysfunction or cardiac thrombus source of cerebral ischemia.

Tics as an initial manifestation of juvenile Huntington's disease: case report and literature review.

PubMed

Cui, Shi-Shuang; Ren, Ru-Jing; Wang, Ying; Wang, Gang; Chen, Sheng-Di

2017-08-08

Huntington's disease (HD) is an autosomal dominant disorder, typically characterized by chorea due to a trinucleotide repeat expansion in the HTT gene, although the clinical manifestations of patients with juvenile HD (JHD) are atypical. A 17-year-old boy with initial presentation of tics attended our clinic and his DNA analysis demonstrated mutation in the HTT gene (49 CAG repeats). After treatment, his symptoms improved. Furthermore, we performed literature review through searching the databases and summarized clinical features in 33 JHD patients. The most prevalent symptoms are ataxia, and two cases reported that tics as initial and prominent manifestation in JHD. Among them, 88% patients carried CAG repeats beyond 60 and most of them have family history. This case here illustrates the variable range of clinical symptoms of JHD and the necessity of testing for the HD mutation in young patients with tics with symptoms unable to be explained by Tourette's syndrome (TS).

CNS autoimmune disease after Streptococcus pyogenes infections: animal models, cellular mechanisms and genetic factors

PubMed Central

Cutforth, Tyler; DeMille, Mellissa MC; Agalliu, Ilir; Agalliu, Dritan

2016-01-01

Streptococcus pyogenes infections have been associated with two autoimmune diseases of the CNS: Sydenham’s chorea (SC) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus infections (PANDAS). Despite the high frequency of pharyngeal streptococcus infections among children, only a small fraction develops SC or PANDAS. This suggests that several factors in combination are necessary to trigger autoimmune complications: specific S. pyogenes strains that induce a strong immune response toward the host nervous system; genetic susceptibility that predispose children toward an autoimmune response involving movement or tic symptoms; and multiple infections of the throat or tonsils that lead to a robust Th17 cellular and humoral immune response when untreated. In this review, we summarize the evidence for each factor and propose that all must be met for the requisite neurovascular pathology and behavioral deficits found in SC/PANDAS. PMID:27110222

The usefulness of immunotherapy in pediatric neurodegenerative disorders: A systematic review of literature data.

PubMed

Vitaliti, Giovanna; Tabatabaie, Omidreza; Matin, Nassim; Ledda, Caterina; Pavone, Piero; Lubrano, Riccardo; Serra, Agostino; Di Mauro, Paola; Cocuzza, Salvatore; Falsaperla, Raffaele

2015-01-01

Immunotherapeutic strategies to treat neurodegenerative disorders have inspired the scientific community. The aim of our review is to address the translational aspects of neuroimmunology to describe the efficacy of immunotherapy in the treatment of pediatric neurodegenerative disorders. In the studies we analyzed IVIG were found to be efficient in the treatment of post-streptococcal neurodegenerative disorders, even if in PANDAS, plasma-exchange (PE) showed a higher efficiency. IVIG were also successfully used in ADEM and Guillan-Barré syndrome. In Sydenham Chorea the use of methylprednisolone was found in most cases as efficient as IVIG, while in Tourette's Syndrome, Colecoxib was successfully used in one patient. Pediatric Multiple Sclerosis seems to respond better to immunosuppressant agents (Mitoxantrone, Cyclophosphamide, Natalizumab), as well as Neuromyelitis optica (Rituximab, Mycofenolate). The importance of this review relies in the attempt to draw standardized guidelines for immunotherapy in pediatric neurodegeneratve disorders.

The usefulness of immunotherapy in pediatric neurodegenerative disorders: A systematic review of literature data

PubMed Central

Vitaliti, Giovanna; Tabatabaie, Omidreza; Matin, Nassim; Ledda, Caterina; Pavone, Piero; Lubrano, Riccardo; Serra, Agostino; Di Mauro, Paola; Cocuzza, Salvatore; Falsaperla, Raffaele

2015-01-01

Immunotherapeutic strategies to treat neurodegenerative disorders have inspired the scientific community. The aim of our review is to address the translational aspects of neuroimmunology to describe the efficacy of immunotherapy in the treatment of pediatric neurodegenerative disorders. In the studies we analyzed IVIG were found to be efficient in the treatment of post-streptococcal neurodegenerative disorders, even if in PANDAS, plasma-exchange (PE) showed a higher efficiency. IVIG were also successfully used in ADEM and Guillan-Barré syndrome. In Sydenham Chorea the use of methylprednisolone was found in most cases as efficient as IVIG, while in Tourette's Syndrome, Colecoxib was successfully used in one patient. Pediatric Multiple Sclerosis seems to respond better to immunosuppressant agents (Mitoxantrone, Cyclophosphamide, Natalizumab), as well as Neuromyelitis optica (Rituximab, Mycofenolate). The importance of this review relies in the attempt to draw standardized guidelines for immunotherapy in pediatric neurodegeneratve disorders PMID:26266339

Rheumatic fever associated with antiphospholipid syndrome: systematic review.

PubMed

da Silva, Felipe; de Carvalho, Jozélio

2014-01-01

To evaluate the clinical associations between rheumatic fever and antiphospholipid syndrome and the impact of coexistence of these two diseases in an individual. Systematic review in electronics databases, regarding the period from 1983 to 2012. The keywords: "Rheumatic Fever," "Antiphospholipid Syndrome," and "Antiphospholipid Antibody Syndrome" are used. were identified 11 cases described in the literature about the association of rheumatic fever and antiphospholipid syndrome. Clinical presentation of rheumatic fever was characterized by the predominance of carditis (11/11) and chorea (7/11). Regarding the manifestations of APS, the stroke was observed in 7/11 (63.6%), with one of them having probable embolic origin. The present study brings the information that the association between APS and RF is quite rare, however, is of great clinical importance. Doctors who deal with the RF should include in their differential diagnosis the APS, especially in the presence of stroke in patients with RF and whose echocardiogram does not show intracavitary thrombi.

Progressive supranuclear palsy: neuropathologically based diagnostic clinical criteria.

PubMed Central

Collins, S J; Ahlskog, J E; Parisi, J E; Maraganore, D M

1995-01-01

All cases examined postmortem at the Mayo Clinic that met the classic neuropathological criteria for progressive supranuclear palsy (PSP) were identified for retrospective clinical analyses. The necropsy material was re-examined by a second neuropathologist to confirm the pathological diagnosis of PSP, yielding 12 cases. A range of clinical signs were documented in these patients, with numerous findings beyond those noted in the original descriptions of this disorder. Atypical clinical findings included absence of supranuclear gaze palsy (two cases), prominent asymmetry (two), arm dystonia (two), upper limb apraxia (two), myoclonus (two), chorea (one), eyelid opening apraxia (one), and respiratory disturbance (one). A definite clinical diagnosis of PSP had been made during life in only eight of the 12 patients. From the retrospective analysis of these 12 cases, a set of clinical criteria were developed for the premortem diagnosis of PSP emphasising differences from other akinetic-rigid disorders. PMID:7876846

Paraneoplastic movement disorders.

PubMed

Mehta, Shyamal H; Morgan, John C; Sethi, Kapil D

2009-07-01

Neurologic paraneoplastic syndromes (NPSs) result from damage to the nervous system due to the remote effects of cancer not related to metastasis, infection, or metabolic derangements. NPSs are rare, affecting 1 in 10,000 patients with cancer. Pathogenesis is likely related to the immune mechanisms: normal neural tissue is mistakenly attacked due to the similarity in the onconeural antigens expressed by the tumor cells. Among the various "classic" and other NPSs, this review focuses on paraneoplastic movement disorders, including ataxia due to cerebellar degeneration, stiff-person syndrome, opsoclonus-myoclonus syndrome, chorea, parkinsonism, and tremor. The recently described syndrome of paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis is also included, given that these patients have complex movements such as stereotypies and dyskinesias in addition to psychiatric symptoms, altered sensorium, and other neurologic signs. Although variable, treatment and prognosis of NPSs rely heavily on treatment of the underlying malignancy and immunotherapy.

Late-onset nonketotic hyperglycinemia with a heterozygous novel point mutation of the GLDC gene.

PubMed

Brenton, J Nicholas; Rust, Robert S

2014-05-01

Atypical nonketotic hyperglycinemia is characterized by heterogeneous phenotypes that often include nonspecific behavioral problems, cognitive deficits, and developmental delays. We describe a girl with late-onset nonketotic hyperglycinemia presenting at 5 years of age with hypotonia, chorea, ataxia, and alterations in consciousness in the setting of febrile illness. Serum amino acid analysis was mildly elevated; however, urine amino acid analysis was instrumental in demonstrating marked hyperglycinuria. Mutation testing showed a heterozygous novel sequence change/point mutation in the glycine decarboxylase gene. This patient illustrates the importance of obtaining urine amino acids in individuals whose clinical manifestations are suspicious for any form of nonketotic hyperglycinemia, because this testing may provide more prominent evidence of elevations in glycine. She also illustrates the potential for a heterozygous mutation to result in manifestations of an atypical form of nonketotic hyperglycinemia. Copyright © 2014 Elsevier Inc. All rights reserved.

Neurology of Volition

PubMed Central

Kranick, Sarah M.; Hallett, Mark

2016-01-01

Neurological disorders of volition may be characterized by deficits in willing and/or agency. When we move our bodies through space, it is the sense that we intended to move (willing) and that our actions were a consequence of this intention (self-agency) that gives us the sense of voluntariness and a general feeling of being “in control.” While it is possible to have movements that share executive machinery ordinarily used for voluntary movement but lack a sense of voluntariness, such as psychogenic movement disorders, it is also possible to claim volition for presumed involuntary movements (early chorea) or even when no movement is produced (anosognosia). The study of such patients should enlighten traditional models of how the percepts of volition are generated in the brain with regards to movement. We discuss volition and its components as multi-leveled processes with feedforward and feedback information flow, and dependence on prior expectations as well as external and internal cues. PMID:23329204

Acid-$beta$-glycerophosphatase reaction products in the central nervous system mitochondria following x-ray irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roizin, L.; Orlovskaja, D.; Liu, J.C.

A survey of the literature to date on the enzyme histochemistry of intracellular organelles has not yielded any reference to the presence of acid phosphatase reaction products in the mammalian mitochondria of the central nervous system. A combination of Gomori's acid phosphatase method, however, with standard electron microscopy has disclosed the presence of enzyme reaction products in the mitochondria of the central nervous system of rats from 2 hr to 22 weeks after x-ray irradiation, as well as in a cerebral biopsy performed on a patient affected by Huntington's chorea. No enzyme reaction products, on the other hand, were observedmore » in serial sections that had been incubated in substrates either containing sodium fluoride or lacking in $beta$- glycerophosphate. The abnormal mitochondrial enzyme reaction (chemical lesion) is considered to be the consequence of the pathologic process affecting the ultrastructural-chemical organization of the organelle. (auth)« less

Neuronal Antibody Biomarkers for Sydenham’s Chorea Identify a New Group of Children with Chronic Recurrent Episodic Acute Exacerbations of Tic and Obsessive Compulsive Symptoms Following a Streptococcal Infection

PubMed Central

Singer, Harvey S.; Mascaro-Blanco, Adda; Alvarez, Kathy; Morris-Berry, Christina; Kawikova, Ivana; Ben-Pazi, Hilla; Thompson, Carol B.; Ali, Syed F.; Kaplan, Edward L.; Cunningham, Madeleine W.

2015-01-01

Several autoantibodies (anti-dopamine 1 (D1R) and 2 (D2R) receptors, anti-tubulin, anti-lysoganglioside-GM1) and antibody-mediated activation of calcium calmodulin dependent protein kinase II (CaMKII) signaling activity are elevated in children with Sydenham’s chorea (SC). Recognizing proposed clinical and autoimmune similarities between SC and PANDAS (pediatric autoimmune neuropsychiatric disorder associated with a streptococcal infection), we sought to identify serial biomarker changes in a slightly different population. Antineuronal antibodies were measured in eight children (mean 11.3 years) with chronic, dramatic, recurrent tics and obsessive-compulsive disorder (OCD) associated with a group A β-hemolytic streptococcal (GABHS) respiratory tract infection, but differing because they lacked choreiform movements. Longitudinal serum samples in most subjects included two pre-exacerbation samples, Exac), one midst Exac (abrupt recurrence of tic/OCD; temporally association with a GABHS infection in six of eight subjects), and two post-Exac. Controls included four groups of unaffected children (n = 70; mean 10.8 years) obtained at four different institutions and published controls. Clinical exacerbations were not associated with a significant rise in antineuronal antibody titers. CaMKII activation was increased at the GABHS exacerbation point in 5/6 subjects, exceeded combined and published control’s 95th percentile at least once in 7/8 subjects, and median values were elevated at each time point. Anti-tubulin and anti-D2R titers did not differ from published or combined control group’s 95th percentile or median values. Differences in anti-lysoganglioside-GM1 and anti-D1R titers were dependent on the selected control. Variances in antibody titers and CaMKII activation were identified among the institutional control groups. Based on comparisons to published studies, results identify two groups of PANDAS: 1) a cohort, represented by this study, which lacks choreiform movements and elevated antibodies against D2R; 2) the originally reported group with choreiform movements and elevated anti-D2R antibodies, similar to SC. Increased antibody mediated CaMKII activation was found in both groups and requires further study as a potential biomarker. PMID:25793715

[Dyskinesia in Parkinson's disease--major clinical features, aetiology, therapy].

PubMed

Ellrichmann, G; Russ, H; Müller, T

2007-07-01

Parkinson's disease (PD), a slowly, progressive degenerative disorder of the central nervous system, which affects about ten million people world-wide, is currently treated symptomatically. Current treatment aim i. e. to balance the decreased dopamine turnover in striatal neurons. Chronic exposure to dopaminergic agents, however, supports onset of motor complications and dyskinesia in the long term. Dyskinesia appear mainly as chorea, athetosis, dystonia, stereotypia, ballism or a combination. Sometimes excessive abnormal facial, body and limb movements depend on the overall dosage of dopaminergic substitution. This is why the main therapy is based on reducing the total dosage of dopaminergic substances. Either alternative or additional well-tried substances like apomorphine, amantadine or clozapine are used. New possibilities in treatment emerge from substances like sarizotan, istradefylline, fipampezol or talampanel. Even so disability and reduced quality of life in PD patients and their caregivers may exist. This survey describes the major clinical features, aetiology and demographics of treatment-associated dyskinesia in PD.

Glucose transportation in the brain and its impairment in Huntington disease: one more shade of the energetic metabolism failure?

PubMed

Morea, Veronica; Bidollari, Eris; Colotti, Gianni; Fiorillo, Annarita; Rosati, Jessica; De Filippis, Lidia; Squitieri, Ferdinando; Ilari, Andrea

2017-07-01

Huntington's disease (HD) or Huntington's chorea is the most common inherited, dominantly transmitted, neurodegenerative disorder. It is caused by increased CAG repeats number in the gene coding for huntingtin (Htt) and characterized by motor, behaviour and psychiatric symptoms, ultimately leading to death. HD patients also exhibit alterations in glucose and energetic metabolism, which result in pronounced weight loss despite sustained calorie intake. Glucose metabolism decreases in the striatum of all the subjects with mutated Htt, but affects symptom presentation only when it drops below a specific threshold. Recent evidence points at defects in glucose uptake by the brain, and especially by neurons, as a relevant component of central glucose hypometabolism in HD patients. Here we review the main features of glucose metabolism and transport in the brain in physiological conditions and how these processes are impaired in HD, and discuss the potential ability of strategies aimed at increasing intracellular energy levels to counteract neurological and motor degeneration in HD patients.

Anatomy of the human hypothalamus (chiasmatic and tuberal region).

PubMed

Braak, H; Braak, E

1992-01-01

The hypothalamus sensu stricto consists of the chiasmatic, the tuberal and the mamillary region. The present study is confined to the poorly myelinated chiasmatic and tuberal region. Both regions harbor many nuclear grays with relatively clear-cut boundaries embedded in an ill-defined nerve cell assembly referred to as the hypothalamic gray. Prominent components of the chiasmatic region are the magnocellular neurosecretory complex (supraoptic nucleus, paraventricular nucleus, accessory neurosecretory nucleus), the sexually dimorphic intermediate nucleus, the suprachiasmatic and retrochiasmatic nuclei. The dominating structure of the tuberal region is the complex of the ventromedial, posteromedial and dorsomedial nuclei supplemented by the periventricular and infundibular nuclei. Lateral portions of the tuber cinereum harbor the lateral tuberal nucleus and the tuberomamillary nucleus. The lateral tuberal nucleus exhibits pronounced cell loss in Huntington's chorea and is also severely involved in cases of dementia with argyrophilic grains. The large nerve cells of the tuberomamillary nucleus show particularly severe affection in both Alzheimer's (intraneuronal neurofibrillary changes) and Parkinson's disease (Lewy bodies).

Utilisation of psychotropic drugs in patients of the long stay ward.

PubMed

El Hefny, F; Al Haddad, M K; Mathur, V

1992-03-01

A survey of the prescribing of psychotropic drugs was carried out at the Psychiatric Hospital of Bahrain. This retrospective study on 60 inpatients of the Long Stay Ward revealed a man:woman ratio of 2.7. 91% of the men and 88% of the women were over 40 years old. 44 of the 60 patients had a diagnosis of schizophrenia, the rest had dementia, depression, schizoaffective disorders, drug-induced psychosis, general paralysis or Huntington's chorea. 95% of patients received antipsychotic drugs. Thioridazine was the most common drug followed by chlorpromazine. The mean number of drugs/patient was 1.7, with 41.7% of patients receiving only 1 drug. Tardive dyskinesia was observed in 11 patients and 9 experienced varying degrees of tremor. The findings confirm that psychiatric illness treated by psychiatrists need not lead to polypharmacy. As a consequence, its treatment may be less likely to result in adverse reactions than when patients are treated by general practitioners.

From mild ataxia to huntington disease phenocopy: the multiple faces of spinocerebellar ataxia 17.

PubMed

Koutsis, Georgios; Panas, Marios; Paraskevas, George P; Bougea, Anastasia M; Kladi, Athina; Karadima, Georgia; Kapaki, Elisabeth

2014-01-01

Introduction. Spinocerebellar ataxia 17 (SCA 17) is a rare autosomal dominant cerebellar ataxia (ADCA) caused by a CAG/CAA expansion in the TBP gene, reported from a limited number of countries. It is a very heterogeneous ADCA characterized by ataxia, cognitive decline, psychiatric symptoms, and involuntary movements, with some patients presenting with Huntington disease (HD) phenocopies. The SCA 17 expansion is stable during parent-child transmission and intrafamilial phenotypic homogeneity has been reported. However, significant phenotypic variability within families has also been observed. Report of the Family. We presently report a Greek family with a pathological expansion of 54 repeats at the SCA 17 locus that displayed remarkable phenotypic variability. Among 3 affected members, one presented with HD phenocopy; one with progressive ataxia, dementia, chorea, dystonia, and seizures, and one with mild slowly progressive ataxia with minor cognitive and affective symptoms. Conclusions. This is the first family with SCA 17 identified in Greece and highlights the multiple faces of this rare disorder, even within the same family.

From Mild Ataxia to Huntington Disease Phenocopy: The Multiple Faces of Spinocerebellar Ataxia 17

PubMed Central

Panas, Marios; Paraskevas, George P.; Bougea, Anastasia M.; Karadima, Georgia; Kapaki, Elisabeth

2014-01-01

Introduction. Spinocerebellar ataxia 17 (SCA 17) is a rare autosomal dominant cerebellar ataxia (ADCA) caused by a CAG/CAA expansion in the TBP gene, reported from a limited number of countries. It is a very heterogeneous ADCA characterized by ataxia, cognitive decline, psychiatric symptoms, and involuntary movements, with some patients presenting with Huntington disease (HD) phenocopies. The SCA 17 expansion is stable during parent-child transmission and intrafamilial phenotypic homogeneity has been reported. However, significant phenotypic variability within families has also been observed. Report of the Family. We presently report a Greek family with a pathological expansion of 54 repeats at the SCA 17 locus that displayed remarkable phenotypic variability. Among 3 affected members, one presented with HD phenocopy; one with progressive ataxia, dementia, chorea, dystonia, and seizures, and one with mild slowly progressive ataxia with minor cognitive and affective symptoms. Conclusions. This is the first family with SCA 17 identified in Greece and highlights the multiple faces of this rare disorder, even within the same family. PMID:25349749

Familial recurrences of FOXG1-related disorder: Evidence for mosaicism.

PubMed

McMahon, Kelly Q; Papandreou, Apostolos; Ma, Mandy; Barry, Brenda J; Mirzaa, Ghayda M; Dobyns, William B; Scott, Richard H; Trump, Natalie; Kurian, Manju A; Paciorkowski, Alex R

2015-12-01

FOXG1-related disorders are caused by heterozygous mutations in FOXG1 and result in a spectrum of neurodevelopmental phenotypes including postnatal microcephaly, intellectual disability with absent speech, epilepsy, chorea, and corpus callosum abnormalities. The recurrence risk for de novo mutations in FOXG1-related disorders is assumed to be low. Here, we describe three unrelated sets of full siblings with mutations in FOXG1 (c.515_577del63, c.460dupG, and c.572T > G), representing familial recurrence of the disorder. In one family, we have documented maternal somatic mosaicism for the FOXG1 mutation, and all of the families presumably represent parental gonadal (or germline) mosaicism. To our knowledge, mosaicism has not been previously reported in FOXG1-related disorders. Therefore, this report provides evidence that germline mosaicism for FOXG1 mutations is a likely explanation for familial recurrence and should be considered during recurrence risk counseling for families of children with FOXG1-related disorders. © 2015 Wiley Periodicals, Inc.

Huntington Disease (Chorea) in the Middle East

PubMed Central

Scrimgeour, Euan M

2009-01-01

Huntington disease (HD) has been reported in Arab families in several Middle East countries including Saudi Arabia, Oman, Syria, Lebanon, and Egypt and in non-Arab populations in other countries in the region. It is probably under-reported, and until now, has not been recorded in Yemen, the United Arab Emirates, Jordan or in Iraq. The Middle East has always been on the crossroads of trade and travel, and HD was probably introduced to some of these countries in previous times. The prevalence rate in Middle Eastern Arabs is estimated to vary from 3 to 4 per 100,000. Although the HD gene which codes for the protein huntingtin has been identified, the function of this protein is not known. At present, no treatment has been found to delay the onset of HD or to treat it effectively. Although relatively rare, HD has increasingly become a focus of international gene research, with the support and collaboration of the International Huntington Association (IHA). The IHA has been represented in Saudi Arabia and Oman. PMID:21509270

Controlled clinical trial of cannabidiol in Huntington's disease.

PubMed

Consroe, P; Laguna, J; Allender, J; Snider, S; Stern, L; Sandyk, R; Kennedy, K; Schram, K

1991-11-01

Based on encouraging preliminary findings, cannabidiol (CBD), a major nonpsychotropic constituent of Cannabis, was evaluated for symptomatic efficacy and safety in 15 neuroleptic-free patients with Huntington's Disease (HD). The effects of oral CBD (10 mg/kg/day for 6 weeks) and placebo (sesame oil for 6 weeks) were ascertained weekly under a double-blind, randomized cross-over design. A comparison of the effects of CBD and placebo on chorea severity and other therapeutic outcome variables, and on a Cannabis side effect inventory, clinical lab tests and other safety outcome variables, indicated no significant (p greater than 0.05) or clinically important differences. Correspondingly, plasma levels of CBD were assayed by GC/MS, and the weekly levels (mean range of 5.9 to 11.2 ng/ml) did not differ significantly over the 6 weeks of CBD administration. In summary, CBD, at an average daily dose of about 700 mg/day for 6 weeks, was neither symptomatically effective nor toxic, relative to placebo, in neuroleptic-free patients with HD.

Pathogenic variants in TUBB4A are not found in primary dystonia

PubMed Central

Vemula, Satya R.; Xiao, Jianfeng; Bastian, Robert W.; Momčilović, Dragana; Blitzer, Andrew

2014-01-01

Objective: To determine the contribution of TUBB4A, recently associated with DYT4 dystonia in a pedigree with “whispering dysphonia” from Norfolk, United Kingdom, to the etiopathogenesis of primary dystonia. Methods: High-resolution melting and Sanger sequencing were used to inspect the entire coding region of TUBB4A in 575 subjects with primary laryngeal, segmental, or generalized dystonia. Results: No pathogenic variants, including the exon 1 variant (c.4C>G) identified in the DYT4 whispering dysphonia kindred, were found in this study. Conclusion: The c.4C>G DYT4 mutation appears to be private, and clinical testing for TUBB4A mutations is not justified in spasmodic dysphonia or other forms of primary dystonia. Moreover, given its allelic association with leukoencephalopathy hypomyelination with atrophy of basal ganglia and cerebellum and protean clinical manifestations (chorea, ataxia, dysarthria, intellectual disability, dysmorphic facial features, and psychiatric disorders), DYT4 should not be categorized as a primary dystonia. PMID:24598712

Neurodegeneration as the presenting symptom in 2 adults with xeroderma pigmentosum complementation group F

PubMed Central

Shanbhag, Niraj M.; Geschwind, Michael D.; DiGiovanna, John J.; Groden, Catherine; Godfrey, Rena; Yousefzadeh, Matthew J.; Wade, Erin A.; Niedernhofer, Laura J.; Malicdan, May Christine V.; Kraemer, Kenneth H.; Gahl, William A.

2018-01-01

Objective To describe the features of 2 unrelated adults with xeroderma pigmentosum complementation group F (XP-F) ascertained in a neurology care setting. Methods We report the clinical, imaging, molecular, and nucleotide excision repair (NER) capacity of 2 middle-aged women with progressive neurodegeneration ultimately diagnosed with XP-F. Results Both patients presented with adult-onset progressive neurologic deterioration involving chorea, ataxia, hearing loss, cognitive deficits, profound brain atrophy, and a history of skin photosensitivity, skin freckling, and/or skin neoplasms. We identified compound heterozygous pathogenic mutations in ERCC4 and confirmed deficient NER capacity in skin fibroblasts from both patients. Conclusions These cases illustrate the role of NER dysfunction in neurodegeneration and how adult-onset neurodegeneration could be the major symptom bringing XP-F patients to clinical attention. XP-F should be considered by neurologists in the differential diagnosis of patients with adult-onset progressive neurodegeneration accompanied by global brain atrophy and a history of heightened sun sensitivity, excessive freckling, and skin malignancies. PMID:29892709

Principles and approaches to the treatment of immune-mediated movement disorders.

PubMed

Mohammad, Shekeeb S; Dale, Russell C

2018-03-01

Immune mediated movement disorders include movement disorders in the context of autoimmune encephalitis such as anti-NMDAR encephalitis, post-infectious autoimmune movement disorders such as Sydenham chorea, paraneoplastic autoimmune movement disorders such as opsoclonus myoclonus ataxia syndrome, and infection triggered conditions such as paediatric acute neuropsychiatric syndrome. This review focuses on the approach to treatment of immune mediated movement disorders, which requires an understanding of the immunopathogenesis, whether the disease is destructive or 'altering', and the natural history of disease. Factors that can influence outcome include the severity of disease, the delay before starting therapy, use of multimodal therapy and whether the course is monophasic or relapsing. Although the four main conditions listed above have different pathophysiological processes, there are general themes that broadly apply including: early diagnosis and treatment is better, minimise the severity of disease, escalate treatment if the patient is not responding to initial treatments, and minimise relapse. Copyright © 2017. Published by Elsevier Ltd.

Hand activities in infantile masturbation: a video analysis of 13 cases.

PubMed

Hansen, Jonas Kjeldbjerg; Balslev, Thomas

2009-11-01

Infantile masturbation is considered a variant of normal behaviour. The abrupt and spontaneous onset, altered sensorium and autonomic phenomena during episodes may suggest an epileptic fit. Therefore, children with infantile masturbation are often admitted to hospital and undergo unnecessary tests. The purpose of the present study was to provide a detailed description of hand activities in infantile masturbation. The authors reviewed video recordings of 2 boys and 11 girls with infantile masturbation. Position, movements and activities of hands and fingers during episodes were registered. Five patterns of hand activities were registered: Fisting (four infants), grasping of toys, furniture or clothing (ten infants), chorea-like "piano playing" hand movements (two infants), pressure over the diaper/genital region (one infant) and bimanual manipulation of items (four infants). Fisting was primarily observed in the younger infants, and bimanual manipulation was primarily seen in the older infants. Recognizing one or more of the five distinct patterns of hand activities in infantile masturbation may help establishing the diagnosis.

Paraneoplastic autoimmune movement disorders.

PubMed

Lim, Thien Thien

2017-11-01

To provide an overview of paraneoplastic autoimmune disorders presenting with various movement disorders. The spectrum of paraneoplastic autoimmune disorders has been expanding with the discovery of new antibodies against cell surface and intracellular antigens. Many of these paraneoplastic autoimmune disorders manifest as a form of movement disorder. With the discovery of new neuronal antibodies, an increasing number of idiopathic or neurodegenerative movement disorders are now being reclassified as immune-mediated movement disorders. These include anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis which may present with orolingual facial dyskinesia and stereotyped movements, CRMP-5 IgG presenting with chorea, anti-Yo paraneoplastic cerebellar degeneration presenting with ataxia, anti-VGKC complex (Caspr2 antibodies) neuromyotonia, opsoclonus-myoclonus-ataxia syndrome, and muscle rigidity and episodic spasms (amphiphysin, glutamic acid decarboxylase, glycine receptor, GABA(A)-receptor associated protein antibodies) in stiff-person syndrome. Movement disorders may be a presentation for paraneoplastic autoimmune disorders. Recognition of these disorders and their common phenomenology is important because it may lead to the discovery of an occult malignancy. Copyright © 2017 Elsevier Ltd. All rights reserved.

VMAT2 Inhibitors for Tardive Dyskinesia-Practice Implications.

PubMed

Peckham, Alyssa M; Nicewonder, Jessica A

2018-01-01

Tardive dyskinesia is a potentially irreversible, debilitating, hyperkinetic movement disorder that can result from dopamine receptor antagonists. Prompt recognition and resolution of symptoms are instrumental in preventing disease irreversibility, though current treatment options have fallen short of robust, effective, and long-term symptom control. In April 2017, the Food and Drug Administration (FDA) approved 2 new vesicular monoamine transporter 2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, for chorea related to Huntington's disease and tardive dyskinesia, respectively. These agents were pharmacologically modified from tetrabenazine, a VMAT2 inhibitor used off-label in the treatment of tardive dyskinesia. Despite FDA-labeled indications of deutetrabenazine and valbenazine, each agent was explored as a treatment option for those with tardive dyskinesia. In this study, the pharmacologic modifications of the 2 new VMAT2 inhibitors are described, with detailed explanation as to how these may impact clinical practice. The associated case series, observational studies, and clinical trials exploring their use in the treatment of tardive dyskinesia are reported with expert opinion on practice implication.

[Streptococcus pyogenes and the brain: living with the enemy].

PubMed

Dale, R C

Streptococcus pyogenes (or group A beta hemolytic streptococcus) is a pathogenic bacterium that can give rise to a range of invasive and autoimmune diseases, although it is more widely known as the cause of tonsillitis. It is particularly interesting to note that this germ only causes disease in humans. For many years it has been acknowledged that it can cause an autoimmune brain disease (Sydenham s chorea). Yet, the spectrum of post streptococcal brain disorders has recently been extended to include other movement disorders such as tics or dystonia. A number of systematic psychiatric studies have shown that certain emotional disorders generally accompany the movement disorder (particularly, obsessive compulsive disorder). The proposed pathogenetic mechanism is that of a neuronal dysfunction in which antibodies play a mediating role. The antibodies that are produced after the streptococcal infection cross react with neuronal proteins, and more especially so in individuals with a propensity. This represents a possible model of immunological mimicry and its potential importance with respect to certain idiopathic disorders such as Tourette syndrome and obsessive compulsive disorder.

Movement disorders and chronic psychosis

PubMed Central

Morgante, Francesca

2017-01-01

Abstract Purpose of review: To discuss selected peer-reviewed research articles published between 2014 and 2016 and highlight 5 clinically relevant messages related to hyperkinetic and hypokinetic movement disorders in patients with chronic psychosis. Recent findings: A recent population-based study complemented data from clinical trials in showing increased risk of developing extrapyramidal symptoms with antipsychotic use. A community service–based longitudinal study showed that dopamine transporter imaging could help identify subgroups of patients with parkinsonism associated with antipsychotics with a progressive course, potentially manageable with l-dopa. Data from recent noteworthy clinical trials showed that a new VMAT-2 inhibitor and, for pharmacologically refractory tardive dyskinesia, deep brain stimulation of the globus pallidus internus are promising interventions. Finally, a population-based study has confirmed that hyperkinesias (encompassing chorea, dystonia, and stereotypies) may be early predictors of psychosis even in childhood and adolescence. Summary: Movement disorders associated with new-generation antipsychotics, including widely used agents (e.g., aripiprazole), are not rare occurrences. Better monitoring is needed to assess their true effect on patients' quality of life and functioning and to prevent underascertainment. PMID:29185545

Unintended Effects of Orphan Product Designation for Rare Neurological Diseases

PubMed Central

Murphy, Sinéad M; Puwanant, Araya; Griggs, Robert C.

2012-01-01

Since the introduction of the Orphan Drug Act in 1983, designed to promote development of treatments for rare diseases, at least 378 orphan drugs have been approved. Incentives include financial support, tax credits and, perhaps most importantly, extended market exclusivity. These incentives have encouraged industry interest and accelerated research on rare diseases, allowing patients with orphan diseases access to treatments. However, extended market exclusivity has been associated with unacceptably high drug costs; both for newly developed drugs and even for drugs which were previously widely available. We suggest that a paradoxical effect of orphan product exclusivity can be reduced patient access to existing drugs. In addition, the costs of each new drug are arguably unsustainable for patients and for the American health care system. Of all the specialties, neurology has the third highest number of orphan product designations, and neurological diseases account for at least one fifth of rare diseases. Citing the use of tetrabenazine for chorea in Huntington’s disease, adrenocorticotropic hormone for infantile spasms and enzyme replacement therapy with alglucosidase alpha for Pompe’s disease we highlight these paradoxical effects. PMID:23109143

Proposal for a new definition of congenital complete atrioventricular block.

PubMed

Brucato, A; Jonzon, A; Friedman, D; Allan, L D; Vignati, G; Gasparini, M; Stein, J I; Montella, S; Michaelsson, M; Buyon, J

2003-01-01

The classic old definition of congenital heart block by Yater (1929) is still generally accepted: 'Heart block established in a young patient. There must be some evidence of the existence of the slow pulse at a fairly early age and absence of a history of any infection which might cause the condition after birth: notably diphtheria, rheumatic fever, chorea and congenital syphilis'. However, other definitions are used. We systematically reviewed 1825 cases from 38 separate studies. We conclude that complete AV blocks detected in utero in the absence of structural abnormalities differ from blocks detected later in life with respect to pathogenesis (they are generally associated with maternal anti-Ro/SSA antibodies), poorer childhood prognosis, increased risk of developing late-onset dilated cardiomyopathy, different maternal clinical features and increased risk of recurrence in future pregnancies. For these reasons we propose a new modern definition of congenital complete AV block which might be acceptable to cardiologists, rheumatologists, pediatricians and obstetricians: 'an AV block is defined as congenital if it is diagnosed in utero, at birth or within the neonatal period (0-27 days after birth)'.

Basal ganglia, movement disorders and deep brain stimulation: advances made through non-human primate research.

PubMed

Wichmann, Thomas; Bergman, Hagai; DeLong, Mahlon R

2018-03-01

Studies in non-human primates (NHPs) have led to major advances in our understanding of the function of the basal ganglia and of the pathophysiologic mechanisms of hypokinetic movement disorders such as Parkinson's disease and hyperkinetic disorders such as chorea and dystonia. Since the brains of NHPs are anatomically very close to those of humans, disease states and the effects of medical and surgical approaches, such as deep brain stimulation (DBS), can be more faithfully modeled in NHPs than in other species. According to the current model of the basal ganglia circuitry, which was strongly influenced by studies in NHPs, the basal ganglia are viewed as components of segregated networks that emanate from specific cortical areas, traverse the basal ganglia, and ventral thalamus, and return to the frontal cortex. Based on the presumed functional domains of the different cortical areas involved, these networks are designated as 'motor', 'oculomotor', 'associative' and 'limbic' circuits. The functions of these networks are strongly modulated by the release of dopamine in the striatum. Striatal dopamine release alters the activity of striatal projection neurons which, in turn, influences the (inhibitory) basal ganglia output. In parkinsonism, the loss of striatal dopamine results in the emergence of oscillatory burst patterns of firing of basal ganglia output neurons, increased synchrony of the discharge of neighboring basal ganglia neurons, and an overall increase in basal ganglia output. The relevance of these findings is supported by the demonstration, in NHP models of parkinsonism, of the antiparkinsonian effects of inactivation of the motor circuit at the level of the subthalamic nucleus, one of the major components of the basal ganglia. This finding also contributed strongly to the revival of the use of surgical interventions to treat patients with Parkinson's disease. While ablative procedures were first used for this purpose, they have now been largely replaced by DBS of the subthalamic nucleus or internal pallidal segment. These procedures are not only effective in the treatment of parkinsonism, but also in the treatment of hyperkinetic conditions (such as chorea or dystonia) which result from pathophysiologic changes different from those underlying Parkinson's disease. Thus, these interventions probably do not counteract specific aspects of the pathophysiology of movement disorders, but non-specifically remove the influence of the different types of disruptive basal ganglia output from the relatively intact portions of the motor circuitry downstream from the basal ganglia. Knowledge gained from studies in NHPs remains critical for our understanding of the pathophysiology of movement disorders, of the effects of DBS on brain network activity, and the development of better treatments for patients with movement disorders and other neurologic or psychiatric conditions.

Cognitive and noncognitive neurological features of young-onset dementia.

PubMed

Kelley, Brendan J; Boeve, Bradley F; Josephs, Keith A

2009-01-01

The rarity of young-onset dementia (YOD), the broad differential diagnosis and unusual clinical presentations present unique challenges to correctly recognize the condition and establish an accurate diagnosis. Limited data exist regarding clinical features associated with dementia prior to the age of 45. We retrospectively assessed cognitive and noncognitive neurological characteristics of 235 patients who presented for evaluation of YOD to investigate the clinical characteristics of YOD compared to later-onset dementias and to identify clinical features associated with specific etiologies that may aid in the evaluation of YOD. Multiple cognitive domains were affected in most patients, and no significant differences in affected domains existed between groups. Early psychiatric and behavioral features occurred at very high frequencies. Nearly 80% of this YOD cohort had additional noncognitive symptoms or signs as a feature of their disease. Chorea was strongly associated with Huntington disease. Parkinsonism was not seen in patients having an autoimmune/inflammatory etiology. The rarity of YOD and the high frequency of early psychiatric features led to frequent misdiagnosis early in the clinical course. The high frequency of noncognitive symptoms and signs may aid clinicians in distinguishing patients requiring a more extensive evaluation for YOD.

The link between autoimmune diseases and obsessive-compulsive and tic disorders: A systematic review.

PubMed

Pérez-Vigil, Ana; Fernández de la Cruz, Lorena; Brander, Gustaf; Isomura, Kayoko; Gromark, Caroline; Mataix-Cols, David

2016-12-01

Immunological factors are increasingly recognized as being important in a range of neuropsychiatric disorders. We aimed to summarize the disperse and often conflicting literature on the potential association between autoimmune diseases (ADs) and obsessive-compulsive disorder (OCD) and tic disorders. We searched PubMed, EMBASE, and PsycINFO for original studies evaluating the relationship between ADs and OCD/tic disorders until July, 13th 2016. Seventy-four studies met inclusion criteria. Overall, the studies were of limited methodological quality. Rates of OCD were higher in rheumatic fever patients who were also affected by its neurological manifestation, Sydenham's chorea. The literature on other ADs was scarce and the findings inconclusive. Few studies examined the association between ADs and tic disorders. A handful of family studies reported elevated rates of ADs in first-degree relatives of individuals with OCD/tic disorders, and vice versa, potentially suggesting shared genetic and/or environmental mechanisms. In conclusion, at present, there is modest evidence for a possible association and familial co-aggregation between ADs and OCD/tic disorders. We offer some suggestions for future research. Copyright © 2016 Elsevier Ltd. All rights reserved.

The therapeutic potential of G-protein coupled receptors in Huntington's disease.

PubMed

Dowie, Megan J; Scotter, Emma L; Molinari, Emanuela; Glass, Michelle

2010-11-01

Huntington's disease is a late-onset autosomal dominant inherited neurodegenerative disease characterised by increased symptom severity over time and ultimately premature death. An expanded CAG repeat sequence in the huntingtin gene leads to a polyglutamine expansion in the expressed protein, resulting in complex dysfunctions including cellular excitotoxicity and transcriptional dysregulation. Symptoms include cognitive deficits, psychiatric changes and a movement disorder often referred to as Huntington's chorea, which involves characteristic involuntary dance-like writhing movements. Neuropathologically Huntington's disease is characterised by neuronal dysfunction and death in the striatum and cortex with an overall decrease in cerebral volume (Ho et al., 2001). Neuronal dysfunction begins prior to symptom presentation, and cells of particular vulnerability include the striatal medium spiny neurons. Huntington's is a devastating disease for patients and their families and there is currently no cure, or even an effective therapy for disease symptoms. G-protein coupled receptors are the most abundant receptor type in the central nervous system and are linked to complex downstream pathways, manipulation of which may have therapeutic application in many neurological diseases. This review will highlight the potential of G-protein coupled receptor drug targets as emerging therapies for Huntington's disease. Copyright © 2010 Elsevier Inc. All rights reserved.

Chorein interacts with α-tubulin and histone deacetylase 6, and overexpression preserves cell viability during nutrient deprivation in human embryonic kidney 293 cells.

PubMed

Sasaki, Natsuki; Nakamura, Masayuki; Kodama, Akiko; Urata, Yuka; Shiokawa, Nari; Hayashi, Takehiro; Sano, Akira

2016-11-01

The autophagy pathway has recently been implicated in several neurodegenerative diseases. Recently, it was reported that chorein-depleted cells showed accumulation of autophagic markers and impaired autophagic flux. Here, we demonstrate that chorein overexpression preserves cell viability from starvation-induced cell death in human embryonic kidney 293 (HEK293) cells. Subsequent coimmunoprecipitation and reverse coimmunoprecipitation assays using extracts from chorein that stably overexpressed HEK293 cells revealed that chorein interacts with α-tubulin and histone deacetylase 6, a known α-tubulin deacetylater and central component of basal autophagy. Indeed, acetylated α-tubulin immunoreactivity was significantly decreased in chorein that stably overexpressed HEK293 cells. These results suggest that chorein/histone deacetylase 6/α-tubulin interactions may play an important role in starvation-induced cell stress, and their disruption may be one of the molecular pathogenic mechanisms of chorea-acanthocytosis.-Sasaki, N., Nakamura, M., Kodama, A., Urata, Y., Shiokawa, N., Hayashi, T., Sano, A. Chorein interacts with α-tubulin and histone deacetylase 6, and overexpression preserves cell viability during nutrient deprivation in human embryonic kidney 293 cells. © FASEB.

Deanol in Gilles de la Tourette Syndrome: a preliminary investigation.

PubMed

Pinta, E R

1977-03-01

On the basis of its pharmacologic action Deanol (dimethyl aminoethanol) was hypothesized to be of benefit in the Gilles de la Tourette Syndrome. In one case report the addition of Deanol to perphenazine did not result in an improvement of uncontrollable movements or involuntary speech utterances. Gilles de la Tourette Syndrome is a condition combining organic and psychogenic features existing in the interface between two etiologies. Classically the disease begins in childhood and is characterized by the appearance of sudden involuntary movements, involuntary speech utterances frequently consisting of curse words (coprolalia), and imitative phenomena such as echolalia and echopraxia. Neurotic symptomatology such as anxiety and obsessive thinking have also been reported. This condition is regarded neuropharmacologically as a dopaminergic state that responds to drugs with antidopaminergic activity e.g. the phenothiazines and butyrophenones. Deanol (dimethyl aminoethanol) is a putative cholinergic agonist and has reported effectiveness in conditions where there is a predominance of dopaminergic versus cholinergic activity, e.g. levodopa-induced dyskinesias, neuroleptic induced tardive dyskinesia, and Huntington's chorea. Because of its effectiveness in dopaminergic states it was hypothesized that Deanol could also be of benefit in the Gilles de la Tourette Syndrome.

C9ORF72 hexanucleotide repeat expansions are a frequent cause of Huntington disease phenocopies in the Greek population.

PubMed

Koutsis, Georgios; Karadima, Georgia; Kartanou, Chrisoula; Kladi, Athina; Panas, Marios

2015-01-01

An expanded hexanucleotide repeat in C9ORF72 has been identified as the most common genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia in many populations, including the Greek. Recently, C9ORF72 expansions were reported as the most common genetic cause of Huntington disease (HD) phenocopies in a UK population. In the present study, we screened a selected cohort of 40 Greek patients with HD phenocopies for C9ORF72 hexanucleotide repeat expansions using repeat-primed polymerase chain reaction. We identified 2 patients (5%) with pathologic expansions. The first patient had chorea, behavioral-psychiatric disturbance, cognitive impairment, and a positive family history, fulfilling the strictest criteria for HD phenocopy. The second patient was sporadic and had parkinsonism, behavioral-psychiatric disturbance, and cognitive impairment, corresponding to a broader definition of HD phenocopy. These findings identify C9ORF72 expansions as a frequent cause of HD phenocopies in the Greek population, confirming recent findings in other populations and supporting proposed diagnostic testing for C9ORF72 expansions in patients with HD-like syndromes. Copyright © 2015 Elsevier Inc. All rights reserved.

What should we want to know about our future? A Kantian view on predictive genetic testing.

PubMed

Heinrichs, Bert

2005-01-01

Recent advances in genomic research have led to the development of new diagnostic tools, including tests which make it possible to predict the future occurrence of monogenetic diseases (e.g. Chorea Huntington) or to determine increased susceptibilities to the future development of more complex diseases (e.g. breast cancer). The use of such tests raises a number of ethical, legal and social issues which are usually discussed in terms of rights. However, in the context of predictive genetic tests a key question arises which lies beyond the concept of rights, namely, What should we want to know about our future? In the following I shall discuss this question against the background of Kant's Doctrine of Virtue. It will be demonstrated that the system of duties of virtue that Kant elaborates in the second part of his Metaphysics of Morals offers a theoretical framework for addressing the question of a proper scope of future knowledge as provided by genetic tests. This approach can serve as a source of moral guidance complementary to a justice perspective. It does, however, not rest on the-rather problematic--claim to be able to define what the "good life" is.

[Comparative analysis of metabotropic and ionotropic glutamate striatal receptors blockade influence on rats locomotor behaviour].

PubMed

Iakimovskiĭ, A F; Kerko, T V

2013-02-01

The influence of NMDA and metabotropic neostriatal glutamate receptors blockade to avoidance conditioning (in shuttle box) and free locomotor behavior (in open field) in chronic experiments in rats were investigated. The glutamate receptor antagonists were injected bilateral into striatum separately and with the GABA-A receptor antagonist picrotoxin (2 microg), that produced in rats the impairment of avoidance conditioning and choreo-myoklonic hyperkinesis. The most effective in preventing of negative picrotoxin influence on behavior was 5-type metabotropic glutamate receptors antagonist MTEP (3 microg). Separately injected MTEP did not influence on avoidance conditioning and free locomotor behavior. Unlike that, 1-type metabotropic glutamate receptors antagonist EMQMCM (3 microg) impaired normal locomotor behavior and did not prevent the picrotoxin effects. The NMDA glutamate receptors MK 801 (disocilpin--1 and 5 microg) impaired the picrotoxin-induced hyperkinesis, but did not to prevent the negative effects on avoidance conditioning; separately injected MK 801 reduced free locomotor activity. Based on location of investigated receptor types in neostriatal neurons membranes, we proposed that the most effective influence on 5-type metabotropic glutamate receptors is associated with their involvement in "indirect" efferent pathway, suffered in hyperkinetic extrapyramidal motor dysfunction--Huntington's chorea in human.

Huntington's Disease in a Patient Misdiagnosed as Conversion Disorder.

PubMed

Nogueira, João Machado; Franco, Ana Margarida; Mendes, Susana; Valadas, Anabela; Semedo, Cristina; Jesus, Gustavo

2018-01-01

Huntington's disease (HD) is an inherited, progressive, and neurodegenerative neuropsychiatric disorder caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide in Interested Transcript (IT) 15 gene on chromosome 4. This pathology typically presents in individuals aged between 30 and 50 years and the age of onset is inversely correlated with the length of the CAG repeat expansion. It is characterized by chorea, cognitive deficits, and psychiatric symptoms. Usually the psychiatric disorders precede motor and cognitive impairment, Major Depressive Disorder and anxiety disorders being the most common presentations. We present a clinical case of a 65-year-old woman admitted to our Psychiatric Acute Unit. During the 6 years preceding the admission, the patient had clinical assessments made several times by different specialties that focused only on isolated symptoms, disregarding the syndrome as a whole. In the course of her last admission, the patient was referred to our Neuropsychiatric Team, which made the provisional diagnosis of late-onset Huntington's disease, later confirmed by genetic testing. This clinical vignette highlights the importance of a multidisciplinary approach to atypical clinical presentations and raises awareness for the relevance of investigating carefully motor symptoms in psychiatric patients.

[Some neurologic and psychiatric complications in endocrine disorders: the thyroid gland].

PubMed

Aszalós, Zsuzsa

2007-02-18

Thyroid hormones are of primary importance for the perinatal development of the central nervous system, and for normal function of the adult brain. These hormones primarily regulate the transcription of specific target genes. They increase the cortical serotonergic neurotransmission, and play an important role in regulating central noradrenergic and GABA function. Thyroid deficiency during the perinatal period results in mental retardation. Hypothyroidism of the adults causes most frequently dementia and depression. Other less common clinical pictures include myxoedema coma, dysfunction of cerebellum and cranial nerves. Hypothyroidism also increases predisposition of stroke. Peripheral diseases frequently include polyneuropathy, carpal tunnel syndrome, myalgic state, and rarely myokymia. Nearly all the hyperthyroid patients show minor psychiatric signs, and infrequently psychosis, dementia, confusion state, depression, apathetic thyrotoxicosis, thyrotoxic crisis, seizures, pyramidal signs, or chorea occur. The peripheral complications may be indicated by chronic thyrotoxic myopathy, infiltrative ophthalmopathy, myasthenia gravis, periodic hypokalemic paralysis and polyneuropathy. Generalized resistance to thyroid hormone was confirmed in a number of patients with attention deficit-hyperactivity disorder. Significantly elevated antithyroid antibody titers characterize Hashimoto's encephalopathy. This condition is a rare, acute - subacute, serious, life threatening, but steroid-responsive, relapsing-remitting, autoimmune disease.

Induced neural stem cells as a means of treatment in Huntington's disease.

PubMed

Choi, Kyung-Ah; Hong, Sunghoi

2017-11-01

Huntington's disease (HD) is an inherited neurodegenerative disease characterized by chorea, dementia, and depression caused by progressive nerve cell degeneration, which is triggered by expanded CAG repeats in the huntingtin (Htt) gene. Currently, there is no cure for this disease, nor is there an effective medicine available to delay or improve the physical, mental, and behavioral severities caused by it. Areas covered: In this review, the authors describe the use of induced neural stem cells (iNSCs) by direct conversion technology, which offers great advantages as a therapeutic cell type to treat HD. Expert opinion: Cell conversion of somatic cells into a desired stem cell type is one of the most promising treatments for HD because it could be facilitated for the generation of patient-specific neural stem cells. The induced pluripotent stem cells (iPSCs) have a powerful potential for differentiation into neurons, but they may cause teratoma formation due to an undifferentiated pluripotent stem cell after transplantation Therefore, direct conversion of somatic cells into iNSCs is a promising alternative technology in regenerative medicine and the iNSCs may be provided as a therapeutic cell source for Huntington's disease.

Dystonia and Paroxysmal Dyskinesias: Under-Recognized Movement Disorders in Domestic Animals? A Comparison with Human Dystonia/Paroxysmal Dyskinesias.

PubMed

Richter, Angelika; Hamann, Melanie; Wissel, Jörg; Volk, Holger A

2015-01-01

Dystonia is defined as a neurological syndrome characterized by involuntary sustained or intermittent muscle contractions causing twisting, often repetitive movements, and postures. Paroxysmal dyskinesias are episodic movement disorders encompassing dystonia, chorea, athetosis, and ballism in conscious individuals. Several decades of research have enhanced the understanding of the etiology of human dystonia and dyskinesias that are associated with dystonia, but the pathophysiology remains largely unknown. The spontaneous occurrence of hereditary dystonia and paroxysmal dyskinesia is well documented in rodents used as animal models in basic dystonia research. Several hyperkinetic movement disorders, described in dogs, horses and cattle, show similarities to these human movement disorders. Although dystonia is regarded as the third most common movement disorder in humans, it is often misdiagnosed because of the heterogeneity of etiology and clinical presentation. Since these conditions are poorly known in veterinary practice, their prevalence may be underestimated in veterinary medicine. In order to attract attention to these movement disorders, i.e., dystonia and paroxysmal dyskinesias associated with dystonia, and to enhance interest in translational research, this review gives a brief overview of the current literature regarding dystonia/paroxysmal dyskinesia in humans and summarizes similar hereditary movement disorders reported in domestic animals.

Echolalia or functional repetition in conversation--a case study of an individual with Huntington's disease.

PubMed

Saldert, Charlotta; Hartelius, Lena

2011-01-01

In this case study, we investigated the use of repetition in an individual with a neurogenic communication disorder. We present an analysis of interaction in natural conversations between a woman with advanced Huntington's disease (HD), whose speech had been described as sometimes characterised by echolalia, and her personal assistant. The conversational interaction is analysed on a sequential level, and recurrent patterns are explored. Although the ability of the person with HD to interact is affected by chorea, word retrieval problems and reduced comprehension, she takes an active part in conversation. The conversational partner's contributions are often adapted to her communicative ability as they are formulated as questions or suggestions that can be elaborated on or responded to with a simple 'yes' or 'no'. The person with HD often repeats the words of her conversational partner in a way that extends her contributions and shows listenership, and this use of repetition is also frequent in ordinary conversations between non-brain-damaged individuals. The results show that the conversation partners in this case cooperate in making the conversation proceed and evolve, and that verbal repetition is used in a way that works as a strategy for compensating for the impairment.

Gilles de la Tourette and the discovery of Tourette syndrome. Includes a translation of his 1884 article.

PubMed

Lajonchere, C; Nortz, M; Finger, S

1996-06-01

In 1885, Gilles de la Tourette described 9 patients who suffered from a disorder characterized by involuntary movements, echolalia, echopraxia, coprolalia, and strange, uncontrollable sounds. In his article, Gilles de la Tourette presented some earlier descriptions of this disorder. To appreciate what first led Gilles de la Tourette to Tourette syndrome, however, it is necessary to turn to an article that he published a year earlier. In his 1884 article, Gilles de la Tourette cited several movement disorders that he thought were similar to each other, yet different from true chorea. After describing these disorders, namely, "jumping" of Maine, latah of Malaysia, and miryachit of Siberia, he briefly mentioned a boy in Charcot's ward in Paris, France, who seemed to exhibit the same condition. In an addendum, he then said that other cases were now surfacing in Paris and that he would write an additional article describing these individuals. To achieve a more thorough understanding of the events that led Gilles de la Tourette to his 1885 description of the disorder that now bears his name, we herein present an English-language translation of his 1884 article along with a commentary.

Focal expression of mutant huntingtin in the songbird basal ganglia disrupts cortico-basal ganglia networks and vocal sequences

PubMed Central

Tanaka, Masashi; Singh Alvarado, Jonnathan; Murugan, Malavika; Mooney, Richard

2016-01-01

The basal ganglia (BG) promote complex sequential movements by helping to select elementary motor gestures appropriate to a given behavioral context. Indeed, Huntington’s disease (HD), which causes striatal atrophy in the BG, is characterized by hyperkinesia and chorea. How striatal cell loss alters activity in the BG and downstream motor cortical regions to cause these disorganized movements remains unknown. Here, we show that expressing the genetic mutation that causes HD in a song-related region of the songbird BG destabilizes syllable sequences and increases overall vocal activity, but leave the structure of individual syllables intact. These behavioral changes are paralleled by the selective loss of striatal neurons and reduction of inhibitory synapses on pallidal neurons that serve as the BG output. Chronic recordings in singing birds revealed disrupted temporal patterns of activity in pallidal neurons and downstream cortical neurons. Moreover, reversible inactivation of the cortical neurons rescued the disorganized vocal sequences in transfected birds. These findings shed light on a key role of temporal patterns of cortico-BG activity in the regulation of complex motor sequences and show how a genetic mutation alters cortico-BG networks to cause disorganized movements. PMID:26951661

A clinical study of patients with genetically confirmed Huntington's disease from India.

PubMed

Murgod, U A; Saleem, Q; Anand, A; Brahmachari, S K; Jain, S; Muthane, U B

2001-09-15

Clinical data across the globe especially in genetic diseases like Huntington's disease (HD) is most helpful when collected using standardized formats. This helps in proper comparison of clinical and genetic data. Herein, we report clinical data on 26 genetically confirmed HD patients from 19 Indian families predominantly from South India. Clinical data and evaluation was performed using standardized formats used by the Huntington Disease Study Group. Adult onset HD was commonest while Juvenile HD (onset <20 years) was observed in approximately 15% of patients. Chorea was the commonest presenting symptom (n=23, 88.5%) while remaining presented with psychiatric symptoms (n=3, 11.5%). Impairment of saccades was observed in approximately 75% of patients. Mean (SD) CAG repeats in the abnormal allele was 48.4 (8.7). Total motor score but not the total behavioral score worsens with duration of symptoms. The functional checklist score correlates with total motor score rather than with duration of symptoms. We detail clinical characteristics in genetically confirmed HD patients from a predominantly South Indian cohort. We observed a slightly higher occurrence of Juvenile HD. Functional disabilities in our patients correlate with worsening of motor rather than behavioral symptoms.

[Anti-basal ganglia antibody].

PubMed

Hayashi, Masaharu

2013-04-01

Sydenham's chorea (SC) is a major manifestation of rheumatic fever, and the production of anti-basal ganglia antibodies (ABGA) has been proposed in SC. The pathogenesis is hypothesized as autoimmune targeting of the basal ganglia via molecular mimicry, triggered by streptococcal infection. The spectrum of diseases in which ABGA may be involved has been broadened to include other extrapyramidal movement disorders, such as tics, dystonia, and Parkinsonism, as well as other psychiatric disorders. The autoimmune hypothesis in the presence and absence of ABGA has been suggested in Tourette's syndrome (TS), early onset obsessive-compulsive disorders (OCD), and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Recently, the relationship between ABGA and dopamine neurons in the basal ganglia has been examined, and autoantibodies against dopamine receptors were detected in the sera from patients with basal ganglia encephalitis. In Japan, the occurrence of subacute encephalitis, where patients suffer from episodes of altered behavior and involuntary movements, has increased. Immune-modulating treatments are effective, indicating the involvement of an autoimmune mechanism. We aimed to detect the anti-neuronal autoantibodies in such encephalitis, using immunohistochemical assessment of patient sera. The sera from patients showing involuntary movements had immunoreactivity for basal ganglia neurons. Further epitopes for ABGA will be investigated in basal ganglia disorders other than SC, TS, OCD, and PANDAS.

Neurological implications and neuropsychological considerations on folk music and dance.

PubMed

Sironi, Vittorio A; Riva, Michele A

2015-01-01

Neurological and neuropsychological aspects of folk music and traditional dance have been poorly investigated by historical and scientific literature. Some of these performances could be indeed the manifestation of latent pathological conditions or the expression of liberation rituals. This chapter aimed at analyzing the relationships between traditional dance, folk music, and neurological and psychiatric disorders. Since ancient times, dance has been used in the individual or collective as treatment of some diseases, including epilepsy and movement disorders (dyskinesia, chorea, etc.). Dionysia in Ancient Greece, St. Vitus dance in the Middle Age, tarantism and other traditional dances of southern Italy and of non-Western countries might be credited as curative rituals of these neurological and psychiatric conditions. During the nineteenth century, dance was also used for the treatment of psychiatric patients; the relationship between dance and insanity could also be reflected in classical ballets and music of that period. Nowadays, neuropsychiatric manifestations could also be evidenced in modern dances (mass fainting at rock concerts, flash mobs); some ballroom dances are commonly used for the rehabilitation of patients suffering from neurodegenerative and psychiatric conditions. Interdisciplinary research on these subjects (ethnomusicology and cultural anthropology, clinical neurology and dynamic psychology, neuroradiology and neurophysiology, and socioneurology and neuromusicology) should be increased. © 2015 Elsevier B.V. All rights reserved.

Cannabis in the Treatment of Dystonia, Dyskinesias, and Tics.

PubMed

Koppel, Barbara S

2015-10-01

Cannabis has been used for many medicinal purposes, including management of spasms, dystonia, and dyskinesias, with variable success. Its use for tetanus was described in the second century BCE, but the literature continues to include more case reports and surveys of its beneficial effects in managing symptoms of hyperkinetic movement disorders than randomized controlled trials, making evidence-based recommendations difficult. This paper reviews clinical research using various formulations of cannabis (botanical products, oral preparations containing ∆(9)-tetrahydrocannabinol and/or cannabidiol) and currently available preparations in the USA (nabilone and dronabinol). This has been expanded from a recent systematic review of cannabis use in several neurologic conditions to include case reports and case series and results of anonymous surveys of patients using cannabis outside of medical settings, with the original evidence classifications marked for those papers that followed research protocols. Despite overlap in some patients, dyskinesias will be treated separately from dystonia and chorea; benefit was not established beyond individual patients for these conditions. Tics, usually due to Tourettes, did respond to cannabis preparations. Side effects reported in the trials will be reviewed but those due to recreational use, including the dystonia that can be secondary to synthetic marijuana preparations, are outside the scope of this paper.

Apolipoprotein E and presenilin-1 genotypes in Huntington's disease.

PubMed

Panas, M; Avramopoulos, D; Karadima, G; Petersen, M B; Vassilopoulos, D

1999-07-01

Huntington's disease (HD) is an autosomal dominant degenerative disease of the central nervous system manifested by involuntary movements (chorea), psychiatric manifestations, and cognitive impairment with a variable age at onset. This variability is mainly attributed to genetic factors. The so-called aging genes [e.g., those for apolipoprotein E (APOE) and presenilin-1 (PS-1) have been implicated in determining the age at onset of Alzheimer's disease, a disease sharing common clinical features with HD. In 60 unrelated patients suffering from HD (mean age at onset 40.1 years, range 20-65) we determined number of CAG repeats and the distribution of the APOE alleles (epsilon2, epsilon3, epsilon4) and PS-1 alleles. The results showed that: (a) The age at onset was higher in the group of patients with the epsilon4 allele (51.6 vs. 38.0 P<0.002), (b) The correlation between the age at onset and the number of CAG repeats was strong in patients with the epsilon3/epsilon3 genotype while it was not detected in patients with epsilon3/epsilon4 genotype. (c) No correlation was found between age at onset and PS-1 alleles. In conclusion, APOE seems to be a significant factor influencing the age at onset of Huntington's disease.

Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS): Experience at a Tertiary Referral Center.

PubMed

Helm, Caitlin E; Blackwood, R Alexander

2015-01-01

Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) is an autoimmune disorder presenting with obsessive compulsive disorder and/or tics. Like Sydenham's chorea, its presumed pathogenesis consists of autoantibodies cross-reacting with neurons in response to a group A beta-hemolytic streptococcal infection (GASI). There are currently no diagnostic laboratory findings and management ranges from antibiotic prophylaxis to intravenous immunoglobulin to plasmapheresis. The diagnosis remains controversial, resulting in inconsistent referrals and significant patient anxiety. A retrospective study was performed on all patients referred to the Pediatric Infectious Disease Division with a pre-referral diagnosis of PANDAS. Patients were analyzed by demographics, medical history, co-morbidities, symptoms, prior treatment, laboratory tests, management strategies, and treatment outcomes. From 2003 to 2013, there were 21 patients with a pre-referral diagnosis of PANDAS. Only five met the diagnostic criteria. No patient at referral had an objective scale to monitor symptoms. Eight referrals had a major psychiatric disorder, and none fulfilled diagnostic criteria (p<0.01). The majority of the patients referred with a pre-diagnosis of PANDAS do not fulfill diagnostic criteria nor do they have objective criteria for symptom monitoring. Major psychiatric disorders do not seem to be associated with PANDAS, and better physician education may prevent misdiagnoses. Multidisciplinary management is recommended.

Dystonia and Paroxysmal Dyskinesias: Under-Recognized Movement Disorders in Domestic Animals? A Comparison with Human Dystonia/Paroxysmal Dyskinesias

PubMed Central

Richter, Angelika; Hamann, Melanie; Wissel, Jörg; Volk, Holger A.

2015-01-01

Dystonia is defined as a neurological syndrome characterized by involuntary sustained or intermittent muscle contractions causing twisting, often repetitive movements, and postures. Paroxysmal dyskinesias are episodic movement disorders encompassing dystonia, chorea, athetosis, and ballism in conscious individuals. Several decades of research have enhanced the understanding of the etiology of human dystonia and dyskinesias that are associated with dystonia, but the pathophysiology remains largely unknown. The spontaneous occurrence of hereditary dystonia and paroxysmal dyskinesia is well documented in rodents used as animal models in basic dystonia research. Several hyperkinetic movement disorders, described in dogs, horses and cattle, show similarities to these human movement disorders. Although dystonia is regarded as the third most common movement disorder in humans, it is often misdiagnosed because of the heterogeneity of etiology and clinical presentation. Since these conditions are poorly known in veterinary practice, their prevalence may be underestimated in veterinary medicine. In order to attract attention to these movement disorders, i.e., dystonia and paroxysmal dyskinesias associated with dystonia, and to enhance interest in translational research, this review gives a brief overview of the current literature regarding dystonia/paroxysmal dyskinesia in humans and summarizes similar hereditary movement disorders reported in domestic animals. PMID:26664992

Relicts of dancing mania: the dancing procession of Echternach.

PubMed

Krack, P

1999-12-10

In the small town of Echternach in Luxembourg, remnants of chorea St. Vitii can be found every year when pilgrims gather at the grave of St. Willibrord (658-739) to take part in the so-called Dancing Procession on Whit Tuesday. Miracles and healings are reported to have taken place in front of Willibrord's sarcophagus in the late eighth century. News of the miraculous healings inspired the celebratory folkdances in Echternach. Willibrord became the patron saint of patients with movement disorders. Important annual pilgrimages to the grave of Saint Willibrord, with pilgrims from Gallic and Teutonic provinces, were reported around 1100. The Dancing Procession is first mentioned in the Echternach city archives in 1497. In 1900, Henri Meige, a neurologist with a special interest in movement disorders, visited Echternach to observe the annual Dancing Procession. Although Meige was disappointed with the lack of hysteria, he concluded that the Dancing Procession of Echternach was not without grandeur. Outbreaks of mass hysteria with a background of religious fervor, pagan traditions, or superstition are the most likely explanation for the medieval dancing mania. This view is supported by the religious motivation behind the present-day Dancing Procession in Echternach, a ritual with mixed pagan-Christian origins related to Saint Vitus' dance.

Agrypnia excitata in a patient with progeroid short stature and pigmented Nevi (Mulvihill-Smith syndrome).

PubMed

Ferri, Raffaele; Lanuzza, Bartolo; Cosentino, Filomena I I; Iero, Ivan; Russo, Noemi; Tripodi, Mariangela; Bosco, Paolo

2005-12-01

We report the video-polysomnographic sleep characteristics of a 25-year-old woman with the Mulvihill-Smith syndrome, a rare clinical condition characterized by progeria-like aspect, peculiar multiple pigmented nevi, low stature, and cognitive impairment. Among the various exams, two overnight video-polysomnographic recordings were carried out; moreover, cerebral MRI and molecular analysis of the prion protein gene (PRNP) were also performed. The video-polysomnographic recordings showed the absence of clear sleep episodes but the presence of periods during which the patient had poor contact with the environment, stereotyped afinalistic movements of the upper limbs and hands, irregular or periodic breathing (with central apnea episodes), heart rate arrhythmia, and rapid eye movements. Cerebral MRI showed only diffuse mild enlargement of the cortical sulci and the molecular genetics analysis of the PRNP was normal. Our clinical and neurophysiological study seems to indicate that a particular condition of severe sleep disruption, similar to some extent to that reported in the fatal familial insomnia and in the Morvan fibrillary chorea, which has been indicated as Agrypnia Excitata in recent literature, might be associated with the Mulvihill-Smith syndrome. The inclusion of a detailed study on the sleep characteristics of eventual additional patients will certainly help our understanding of this rare condition.

Methods to Quantify Cell Signaling and GPCR Receptor Ligand Bias: Characterization of Drugs that Target the Endocannabinoid Receptors in Huntington's Disease.

PubMed

Bagher, Amina M; Laprairie, Robert B; Kelly, Melanie E M; Denovan-Wright, Eileen M

2018-01-01

G protein-coupled receptors (GPCRs) interact with multiple intracellular effector proteins such that different ligands may preferentially activate one signal pathway over others, a phenomenon known as signaling bias. Signaling bias can be quantified to optimize drug selection for preclinical research. Here, we describe moderate-throughput methods to quantify signaling bias of known and novel compounds. In the example provided, we describe a method to define cannabinoid-signaling bias in a cell culture model of Huntington's disease (HD). Decreasing type 1 cannabinoid receptor (CB 1 ) levels is correlated with chorea and cognitive deficits in HD. There is evidence that elevating CB 1 levels and/or signaling may be beneficial for HD patients while decreasing CB 1 levels and/or signaling may be detrimental. Recent studies have found that Gα i/o -biased CB 1 agonists activate extracellular signal-regulated kinase (ERK), increase CB 1 protein levels, and improve viability of cells expressing mutant huntingtin. In contrast, CB 1 agonists that are β-arrestin1-biased were found to reduce CB 1 protein levels and cell viability. Measuring agonist bias of known and novel CB 1 agonists will provide important data that predict CB 1 -specific agonists that might be beneficial in animal models of HD and, following animal testing, in HD patients. This method can also be applied to study signaling bias for other GPCRs.

Epigenetics of Huntington's Disease.

PubMed

Bassi, Silvia; Tripathi, Takshashila; Monziani, Alan; Di Leva, Francesca; Biagioli, Marta

2017-01-01

Huntington's disease (HD) is a genetic, fatal autosomal dominant neurodegenerative disorder typically occurring in midlife with symptoms ranging from chorea, to dementia, to personality disturbances (Philos Trans R Soc Lond Ser B Biol Sci 354:957-961, 1999). HD is inherited in a dominant fashion, and the underlying mutation in all cases is a CAG trinucleotide repeat expansion within exon 1 of the HD gene (Cell 72:971-983, 1993). The expanded CAG repeat, translated into a lengthened glutamine tract at the amino terminus of the huntingtin protein, affects its structural properties and functional activities. The effects are pleiotropic, as huntingtin is broadly expressed in different cellular compartments (i.e., cytosol, nucleus, mitochondria) as well as in all cell types of the body at all developmental stages, such that HD pathogenesis likely starts at conception and is a lifelong process (Front Neurosci 9:509, 2015). The rate-limiting mechanism(s) of neurodegeneration in HD still remains elusive: many different processes are commonly disrupted in HD cell lines and animal models, as well as in HD patient cells (Eur J Neurosci 27:2803-2820, 2008); however, epigenetic-chromatin deregulation, as determined by the analysis of DNA methylation, histone modifications, and noncoding RNAs, has now become a prevailing feature. Thus, the overarching goal of this chapter is to discuss the current status of the literature, reviewing how an aberrant epigenetic landscape can contribute to altered gene expression and neuronal dysfunction in HD.

[Tonsillectomy for PANDAS?].

PubMed

Windfuhr, J P

2016-04-01

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is a disease attributed to children with obsessive compulsive or tic disorders associated with streptococcal infections. Because otolaryngologists evaluate a large number of pediatric patients with recurrent streptococcal infections, tonsillectomy (TE) is a common option of therapy. This study was undertaken to evaluate the efficacy of tonsillectomy in patients presenting with a verified PANDAS. A PubMed research was performed using search terms "tonsillectomy" and "PANDAS", "OCD", "compulsive", "pediatric autoimmune", "Chorea" and "Tic" limited by publication date January 1, 1995 to July 31, 2015. Reviews without patients were not included in the review. Nine papers matched our search terms, including 6 case reports with 8 patients and 3 case series. Most case reports were in favor for TE, but this was by far not supported by the findings in the case series. The follow-up ranged form 2-36 months (case reports) and 24-36 months (case series). establishing the diagnosis of PANDAS is complicated by underlying co-morbidities in the field of neurology-psychiatry and the lack of a reliable biomarker. The positive outcome after TE as reported in case studies may be influenced by the postoperative medication and is not supported by the results of large-scale studies. In the light of the considerable postoperative morbidity and unavoidable mortality rate it appears wise to indicate TE only in clinical studies with standardized inclusion criteria. © Georg Thieme Verlag KG Stuttgart · New York.

Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS): Experience at a Tertiary Referral Center

PubMed Central

Helm, Caitlin E.; Blackwood, R. Alexander

2015-01-01

Background Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) is an autoimmune disorder presenting with obsessive compulsive disorder and/or tics. Like Sydenham’s chorea, its presumed pathogenesis consists of autoantibodies cross-reacting with neurons in response to a group A beta-hemolytic streptococcal infection (GASI). There are currently no diagnostic laboratory findings and management ranges from antibiotic prophylaxis to intravenous immunoglobulin to plasmapheresis. The diagnosis remains controversial, resulting in inconsistent referrals and significant patient anxiety. Methods A retrospective study was performed on all patients referred to the Pediatric Infectious Disease Division with a pre-referral diagnosis of PANDAS. Patients were analyzed by demographics, medical history, co-morbidities, symptoms, prior treatment, laboratory tests, management strategies, and treatment outcomes. Results From 2003 to 2013, there were 21 patients with a pre-referral diagnosis of PANDAS. Only five met the diagnostic criteria. No patient at referral had an objective scale to monitor symptoms. Eight referrals had a major psychiatric disorder, and none fulfilled diagnostic criteria (p<0.01). Discussion The majority of the patients referred with a pre-diagnosis of PANDAS do not fulfill diagnostic criteria nor do they have objective criteria for symptom monitoring. Major psychiatric disorders do not seem to be associated with PANDAS, and better physician education may prevent misdiagnoses. Multidisciplinary management is recommended. PMID:26196024

Rules of meridians and acupoints selection in treatment of Parkinson's disease based on data mining techniques.

PubMed

Li, Zhe; Hu, Ying-Yu; Zheng, Chun-Ye; Su, Qiao-Zhen; An, Chang; Luo, Xiao-Dong; Liu, Mao-Cai

2018-01-15

To help selecting appropriate meridians and acupoints in clinical practice and experimental study for Parkinson's disease (PD), the rules of meridians and acupoints selection of acupuncture and moxibustion were analyzed in domestic and foreign clinical treatment for PD based on data mining techniques. Literature about PD treated by acupuncture and moxibustion in China and abroad was searched and selected from China National Knowledge Infrastructure and MEDLINE. Then the data from all eligible articles were extracted to establish the database of acupuncture-moxibustion for PD. The association rules of data mining techniques were used to analyze the rules of meridians and acupoints selection. Totally, 168 eligible articles were included and 184 acupoints were applied. The total frequency of acupoints application was 1,090 times. Those acupoints were mainly distributed in head and neck and extremities. Among all, Taichong (LR 3), Baihui (DU 20), Fengchi (GB 20), Hegu (LI 4) and Chorea-tremor Controlled Zone were the top five acupoints that had been used. Superior-inferior acupoints matching was utilized the most. As to involved meridians, Du Meridian, Dan (Gallbladder) Meridian, Dachang (Large Intestine) Meridian, and Gan (Liver) Meridian were the most popular meridians. The application of meridians and acupoints for PD treatment lay emphasis on the acupoints on the head, attach importance to extinguishing Gan wind, tonifying qi and blood, and nourishing sinews, and make good use of superior-inferior acupoints matching.

Pallidal neuronal discharge in Huntington's disease: support for selective loss of striatal cells originating the indirect pathway.

PubMed

Starr, Philip A; Kang, Gail A; Heath, Susan; Shimamoto, Shoichi; Turner, Robert S

2008-05-01

Chorea is the predominant motor manifestation in the early symptomatic phase of adult onset Huntington's disease (HD). Pathologically, this stage is marked by differential loss of striatal neurons contributing to the indirect pathway. This pattern of neuronal loss predicts decreased neuronal firing rates in GPi and increased firing rates in GPe, the opposite of the changes in firing rate known to occur in Parkinson's disease (PD). We present single-unit discharge characteristics (33 neurons) observed in an awake patient with HD (41 CAG repeats) undergoing microelectrode guided surgery for pallidal deep brain stimulation. Pallidal single-unit activity at "rest" and during voluntary movement was discriminated off line by principal component analysis and evaluated with respect to discharge rate, bursting, and oscillatory activity in the 0-200 Hz range. 24 GPi and 9 GPe units were studied, and compared with 132 GPi and 50 GPe units from 14 patients with PD. The mean (+/-SEM) spontaneous discharge rate for HD was 58+/-4 for GPi and 73+/-5 for GPe. This contrasted with discharge rates in PD of 95+/-2 for GPi and 57+/-3 for GPe. HD GPi units showed more bursting than PD GPi units but much less oscillatory activity in the 2-35 Hz frequency range at rest. These findings are consistent with selective early loss of striatal cells originating the indirect pathway.

Impact of tetrabenazine on gait and functional mobility in individuals with Huntington's disease.

PubMed

Kegelmeyer, Deb A; Kloos, Anne D; Fritz, Nora E; Fiumedora, Marianne M; White, Susan E; Kostyk, Sandra K

2014-12-15

Chorea may contribute to balance problems and walking difficulties that lead to higher fall rates in individuals with Huntington's disease (HD). Few studies have examined the effects of tetrabenazine (TBZ), an anti-choreic drug, on function and mobility in HD. The purpose of this study was to compare: 1) gait measures in forward walking, 2) balance and mobility measures, and 3) hand and forearm function measures on and off TBZ. We hypothesized that use of TBZ would improve gait, transfers and hand and forearm function. Eleven individuals with HD on stable doses of TBZ were evaluated while off medication and again following resumption of medication. Significant improvements were found on the Unified Huntington's Disease Rating Scale (UHDRS) motor scores, Tinetti Mobility Test (TMT) total (t=4.20, p=0.002) and balance subscale (t=-4.61, p=0.001) scores, and the Five Times Sit-to-Stand test (5TSST, t=3.20, p=.009) when on-TBZ compared to off-TBZ. Spatiotemporal gait measures, the Six Condition Romberg test, and UHDRS hand and forearm function items were not changed by TBZ use. Improved TMT and 5TSST performance when on drug indicates that TBZ use may improve balance and functional mobility in individuals with HD. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Informativeness of Early Huntington Disease Signs about Gene Status.

PubMed

Oster, Emily; Eberly, Shirley W; Dorsey, E Ray; Kayson-Rubin, Elise; Oakes, David; Shoulson, Ira

2015-01-01

The cohort-level risk of Huntington disease (HD) is related to the age and symptom level of the cohort, but this relationship has not been made precise. To predict the evolving likelihood of carrying the Huntington disease (HD) gene for at-risk adults using age and sign level. Using data from adults with early signs and symptoms of HD linked to information on genetic status, we use Bayes' theorem to calculate the probability that an undiagnosed individual of a certain age and sign level has an expanded CAG repeat. Both age and sign levels have substantial influence on the likelihood of HD onset, and the probability of eventual diagnosis changes as those at risk age and exhibit (or fail to exhibit) symptoms. For example, our data suggest that in a cohort of individuals age 26 with a Unified Huntington's Disease Rating Scale (UHDRS) motor score of 7-10 70% of them will carry the HD mutation. For individuals age 56, the same motor score suggests only a 40% chance of carrying the mutation. Early motor signs of HD, overall and the chorea subscore, were highly predictive of disease onset at any age. However, body mass index (BMI) and cognitive performance scores were not as highly predictive. These results suggest that if researchers or clinicians are looking for early clues of HD, it may be more foretelling to look at motor rather than cognitive signs. Application of similar approaches could be used with other adult-onset genetic conditions.

What do we know about Late Onset Huntington's Disease?

PubMed

Chaganti, Sai S; McCusker, Elizabeth A; Loy, Clement T

2017-01-01

Although the typical age of onset for Huntington's disease (HD) is in the fourth decade, between 4.4-11.5% of individuals with HD have a late onset (over 60 years of age). Diagnosis of Late onset HD (LoHD) can be missed, due to the perceived low likelihood of HD in the over 60-year-olds. To review the epidemiology, genotype and phenotype of LoHD. We systematically searched MEDLINE, EMBASE and Web of Science (inception-November 2016). Web of Science was then used to search for papers citing identified studies. Content experts were consulted for any additional studies. We included all studies reporting the clinical phenotype of LoHD for more than one participant. 20 studies were identified from a potential list of 1243. Among Caucasian HD cohorts, 4.4-11.5% of individuals have LoHD, and this proportion may be increasing. Proportion of LoHD without a positive family history ranges from 3-68%. 94.4% of reported cases of LoHD had CAG repeat lengths of ≤44. Motor manifestations are the commonest initial presentation, although 29.2% presented with non-motor manifestations as the first clinical feature in one case series. Individuals with LoHD may have slower progression of illness. Cognitive impairment rather than chorea may be the major source of disability in this group. LoHD represents a substantial proportion of new diagnoses of HD and has some unique features. Further characterization of this population will aid clinicians in diagnosis.

A novel ANO3 variant identified in a 53-year-old woman presenting with hyperkinetic dysarthria, blepharospasm, hyperkinesias, and complex motor tics.

PubMed

Blackburn, Patrick R; Zimmermann, Michael T; Gass, Jennifer M; Harris, Kimberly G; Cousin, Margot A; Boczek, Nicole J; Ross, Owen A; Klee, Eric W; Brazis, Paul W; Van Gerpen, Jay A; Atwal, Paldeep S

2016-12-05

Cervical dystonias have a variable presentation and underlying etiology, but collectively represent the most common form of focal dystonia. There are a number of known genetic forms of dystonia (DYT1-27); however the heterogeneity of disease presentation does not always make it easy to categorize the disease by phenotype-genotype comparison. In this report, we describe a 53-year-old female who presented initially with hand tremor following a total hip arthroplasty. The patient developed a mixed hyperkinetic disorder consisting of chorea, dystonia affecting the upper extremities, dysarthria, and blepharospasm. Whole exome sequencing of the patient revealed a novel heterozygous missense variant (Chr11(GRCh38): g.26525644C > G; NM_031418.2(ANO3): c.702C > G; NP_113606.2. p.C234W) in exon 7 in the ANO3 gene. ANO3 encodes anoctamin-3, a Ca +2 -dependent phospholipid scramblase expressed in striatal-neurons, that has been implicated in autosomal dominant craniocervical dystonia (Dystonia-24, DYT24, MIM# 615034). To date, only a handful of cases of DYT-24 have been described in the literature. The complex clinical presentation of the patient described includes hyperkinesias, complex motor movements, and vocal tics, which have not been reported in other patients with DYT24. This report highlights the utility of using clinical whole exome sequencing in patients with complex neurological phenotypes that would not normally fit a classical presentation of a defined genetic disease.

Positron emission tomography in neuropsychology.

PubMed

Heiss, W D; Herholz, K; Pawlik, G; Wagner, R; Wienhard, K

1986-01-01

By positron emission tomography (PET) of 18F-2-fluoro-2-deoxy-D-glucose (FDG) local cerebral metabolic rate for glucose (LCMRGl) can be measured in man. Normal values in cerebral cortex and basal ganglia range from 35 to 50 mumol/100 g/min, the values in gray matter structures of the posterior fossa were 25-30 mumol/100 g/min, the lowest LCMRGl was found in the white matter (15-20 mumol/100 g/min). During sensory stimulation by various modalities functional activation increases LCMRGl in the respective special areas, while sleep decreases metabolic rate in all cortical and basal gray matter structures. In many neurological disorders CMRGl is altered in a disease-specific pattern. In dementia of the Alzheimer type CMRGl is impaired even in early stages with accentuation in the parieto-temporal cortex, while in multi-infarct dementia glucose uptake is mainly reduced in the multifocal small infarcts. In Huntington's chorea the most conspicuous changes are found in the caudate nucleus and putamen. In cases of focal lesions (e.g. ischemic infarcts) metabolic disturbances extend far beyond the site of the primary lesion and inactivation of metabolism is found in intact brain structures far away from the anatomical lesion. Additional applications of PET include determination of the metabolism of various substrates, of protein synthesis, of function and distribution of receptors, of tumor growth and of the distribution of drugs as well as the measurement of oxygen consumption, blood flow and blood volume.

Genetic screening of Greek patients with Huntington’s disease phenocopies identifies an SCA8 expansion.

PubMed

Koutsis, G; Karadima, G; Pandraud, A; Sweeney, M G; Paudel, R; Houlden, H; Wood, N W; Panas, M

2012-09-01

Huntington’s disease (HD) is an autosomal dominant disorder characterized by a triad of chorea, psychiatric disturbance and cognitive decline. Around 1% of patients with HD-like symptoms lack the causative HD expansion and are considered HD phenocopies. Genetic diseases that can present as HD phenocopies include HD-like syndromes such as HDL1, HDL2 and HDL4 (SCA17), some spinocerebellar ataxias (SCAs) and dentatorubral-pallidoluysian atrophy (DRPLA). In this study we screened a cohort of 21 Greek patients with HD phenocopy syndromes formutations causing HDL2, SCA17, SCA1, SCA2, SCA3,SCA8, SCA12 and DRPLA. Fifteen patients (71%) had a positive family history. We identified one patient (4.8% of the total cohort) with an expansion of 81 combined CTA/CTG repeats at the SCA8 locus. This falls within what is believed to be the high-penetrance allele range. In addition to the classic HD triad, the patient had features of dystonia and oculomotor apraxia. There were no cases of HDL2, SCA17, SCA1, SCA2, SCA3, SCA12 or DRPLA. Given the controversy surrounding the SCA8 expansion, the present finding may be incidental. However, if pathogenic, it broadens the phenotype that may be associated with SCA8 expansions. The absence of any other mutations in our cohort is not surprising, given the low probability of reaching a genetic diagnosis in HD phenocopy patients.

Tonsillectomy remains a questionable option for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).

PubMed

Windfuhr, Jochen P

2016-01-01

Background: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is a disease attributed to children with obsessive compulsive disorders (OCD) or tic disorders associated with streptococcal infections. Because otolaryngologists examine a large number of pediatric patients with recurrent streptococcal infections, tonsillectomy (TE) is a common option of therapy. This study was conducted to evaluate the efficacy of TE in patients presenting with verified PANDAS. Material and methods: A PubMed review was performed using search terms "tonsillectomy" and "PANDAS", "OCD", "compulsive" "pediatric autoimmune", "chorea" and "tic" limited by publication date of January 1, 1995, to July 31, 2015. Reviews without patients were not included in the review. Results: Nine papers matched our search criteria, including 6 case reports with 8 patients and 3 case series. Most case reports were in favor of TE, but this was by far not supported by the findings in the case series. The follow-up ranged from 2 to 36 months in case reports and from 24 to 36 in case series. Conclusion: Establishing the diagnosis of PANDAS is complicated because of underlying comorbidities in the field of neurology-psychiatry and the lack of a reliable biomarker. The positive outcome after TE as reported in case studies may be influenced by the postoperative medication and is not supported by the results of large-scale studies. In the light of the considerable postoperative morbidity rate, it appears wise to indicate TE for PANDAS only in supervised clinical studies.

[Evaluation of a Neuropsychiatric Disorder: From PANDAS to PANS and CANS].

PubMed

Baytunca, Muharrem Burak; Donuk, Tuğba; Erermiş, Serpil

2016-01-01

PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections) syndrome is a disorder seen before adolescence that possesses an abrupt onset of obsessive-compulsive disorder symptoms and/or tics. Swedo and colleagues defined this disorder in 1998 as a syndrome related to Group A streptoccoccus (GAS) infection with neurological issues, such as motor hyperactivation and choreiform movements. The progress of the disorder may be described as wax-and-waning, apart from abrupt onset, and this relapse and remission course is associated with exacerbating infections, according to the creators of PANDAS syndrome. Ruling out of Rheumatoid Fever and Sydenham's Chorea was a necessity for making a proper diagnosis. Since the recognition of this syndrome, clinicians encountered many children who could not fulfill all 5 criteria, which must be met for PANDAS diagnosis. In addition, due to literature showing failure and lack of strong evidence of a major role of GAS, the newly-defined categories PANS (Pediatric Acute-onset Neuropsychiatric Syndrome) and CANS (Childhood Acute Neuropsychiatric Syndrome) were created to encompass those of "almost met" non-PANDAS cases. PANS and CANS include concurrent significant psychiatric symptoms with abrupt onset of OCD symptoms and/or tics but do not require identification of any infection agent, immune dysfunction, or enviromental precipitants. In this paper, we aimed to discuss PANS/ CANS, alterations of PANDAS, and diagnoses in which "almost met" PANDAS patients should be classified on the basis of a case who developed an abrupt onset of anxiety, obsessions, and vocal tics.

Genetic modifiers of Huntington's disease.

PubMed

Gusella, James F; MacDonald, Marcy E; Lee, Jong-Min

2014-09-15

Huntington's disease (HD) is a devastating neurodegenerative disorder that directly affects more than 1 in 10,000 persons in Western societies but, as a family disorder with a long, costly, debilitating course, it has an indirect impact on a far greater proportion of the population. Although some palliative treatments are used, no effective treatment exists for preventing clinical onset of the disorder or for delaying its inevitable progression toward premature death, approximately 15 years after diagnosis. Huntington's disease involves a movement disorder characterized by chorea, as well as a variety of psychiatric disturbances and intellectual decline, with a gradual loss of independence. A dire need exists for effective HD therapies to alleviate the suffering and costs to the individual, family, and health care system. In past decades, genetics, the study of DNA sequence variation and its consequences, provided the tools to map the HD gene to chromosome 4 and ultimately to identify its mutation as an expanded CAG trinucleotide repeat in the coding sequence of a large protein, dubbed huntingtin. Now, advances in genetic technology offer an unbiased route to the identification of genetic factors that are disease-modifying agents in human patients. Such genetic modifiers are expected to highlight processes capable of altering the course of HD and therefore to provide new, human-validated targets for traditional drug development, with the goal of developing rational treatments to delay or prevent onset of HD clinical signs. © 2014 International Parkinson and Movement Disorder Society.

Huntington disease in subjects from an Israeli Karaite community carrying alleles of intermediate and expanded CAG repeats in the HTT gene: Huntington disease or phenocopy?

PubMed

Herishanu, Yuval O; Parvari, Ruti; Pollack, Yaakov; Shelef, Ilan; Marom, Batia; Martino, Tiziana; Cannella, Milena; Squitieri, Ferdinando

2009-02-15

We report a cluster of patients from a Karaite Jew community with a movement disorder suggestive of Huntington disease (HD), in some cases associated with repeat lengths below the edge of 36 CAG repeats. The study describes the clinical and genetic features of four patients who were followed over several years. Patients belonged to an inbred family in whom progressive chorea, manifesting predominantly with dystonia and cerebellar features, developed during middle age. Although severe psychiatric symptoms ultimately developed in two of the four patients, cognitive function remained reasonably well preserved in all of them even after several disease years. Moderate cognitive deficits were limited to the visuomotor organization and abstract thinking subtests in three of the four patients. Qualitative brain imaging showed atrophy of brain predominantly involving cortex and cerebellum. Genetic testing revealed a variable mutation penetrance among family members, some affected members showing an upper allele size ranging from 34 to 49, whereas others remained unaffected despite the presence of the full mutation beyond 40 CAG repeats. Co-morbidity with recessive hereditary inclusion body myopathy was found in two subjects from one family. Although the main diagnosis of HD remains to be confirmed by further neuropathological studies, these cases may suggest that HD could manifest with as few as 34 CAG repeats, in some geographic areas, the disease phenotype most probably being influenced by additional, as yet unidentified, genes.

Takayasu arteritis in childhood: misdiagnoses at disease onset and associated diseases.

PubMed

Clemente, Gleice; Silva, Clovis A; Sacchetti, Silvana B; Ferriani, Virginia P L; Oliveira, Sheila K; Sztajnbok, Flavio; Bica, Blanca E R G; Cavalcanti, André; Robazzi, Teresa; Bandeira, Marcia; Terreri, Maria Teresa

2018-06-01

Juvenile-Takayasu arteritis (j-TA) is a difficult diagnosis and some patients develop uncommon manifestations and associated diseases that may contribute to the delayed diagnosis. Our aim was to identify the misdiagnoses, the associated diseases and the atypical manifestations observed in a j-TA Brazilian multicentre study. 71 children and adolescents who met the classification criteria for j-TA were included. The misdiagnoses, the associated diseases and the atypical manifestations were evaluated. 19 (26.8%) patients had misdiagnoses. The most common of them was aortic coarctation in six (8.4%) patients, followed by rheumatic fever in five (7.0%) and one patient presented with both former diagnoses. Limb pain (two patients), spondyloarthropathy, juvenile idiopathic arthritis (JIA), spinal arteriovenous malformation, polyarteritis nodosa (PAN) and fever of unknown origin (FUO) were other misdiagnoses. Patients who had misdiagnoses previously to j-TA diagnosis presented a trend to have a longer diagnosis delay. 11 (15.5%) patients had 14 TA-associated diseases, such as pulmonary tuberculosis (5 patients), rheumatic fever (2 patients), spondyloarthropathy, polyarticular JIA, Crohn's disease, Prader-Willi disease, diabetes mellitus, Moyamoya and primary immunodeficiency. 7 (9.9%) patients presented 10 atypical manifestations, such as pyoderma gangrenosum, erythema nodosum, myositis, chorea, enthesitis, episcleritis, uveitis, hepatomegaly, splenomegaly and necrosis of extremities. Our study emphasizes the main misdiagnoses, associated diseases and atypical manifestations that occur in patients with j-TA and warns of the features that may alert paediatricians to this diagnosis, such as constitutional symptoms and elevated inflammatory markers.

Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders

PubMed Central

Koppel, Barbara S.; Brust, John C.M.; Fife, Terry; Bronstein, Jeff; Youssof, Sarah; Gronseth, Gary; Gloss, David

2014-01-01

Objective: To determine the efficacy of medical marijuana in several neurologic conditions. Methods: We performed a systematic review of medical marijuana (1948–November 2013) to address treatment of symptoms of multiple sclerosis (MS), epilepsy, and movement disorders. We graded the studies according to the American Academy of Neurology classification scheme for therapeutic articles. Results: Thirty-four studies met inclusion criteria; 8 were rated as Class I. Conclusions: The following were studied in patients with MS: (1) Spasticity: oral cannabis extract (OCE) is effective, and nabiximols and tetrahydrocannabinol (THC) are probably effective, for reducing patient-centered measures; it is possible both OCE and THC are effective for reducing both patient-centered and objective measures at 1 year. (2) Central pain or painful spasms (including spasticity-related pain, excluding neuropathic pain): OCE is effective; THC and nabiximols are probably effective. (3) Urinary dysfunction: nabiximols is probably effective for reducing bladder voids/day; THC and OCE are probably ineffective for reducing bladder complaints. (4) Tremor: THC and OCE are probably ineffective; nabiximols is possibly ineffective. (5) Other neurologic conditions: OCE is probably ineffective for treating levodopa-induced dyskinesias in patients with Parkinson disease. Oral cannabinoids are of unknown efficacy in non–chorea-related symptoms of Huntington disease, Tourette syndrome, cervical dystonia, and epilepsy. The risks and benefits of medical marijuana should be weighed carefully. Risk of serious adverse psychopathologic effects was nearly 1%. Comparative effectiveness of medical marijuana vs other therapies is unknown for these indications. PMID:24778283

A clinical study of Gilles de la Tourette syndrome in the United Kingdom.

PubMed Central

Lees, A J; Robertson, M; Trimble, M R; Murray, N M

1984-01-01

The clinical features of 53 British-born patients with Gilles de la Tourette syndrome are described. The mean age at onset of body tics was seven years and for vocalisations 11 years. Coprolalia was present in 39%, copropraxia in 21%, echolalia in 46% and echopraxia in 21%. Complicated antics and mannerisms were also common, often involving the compulsive touching of objects or self-injurious behaviour. Forty-six per cent of cases had a family history of tics in a single close relative and in two individuals a further member of the family had Gilles de la Tourette syndrome. Focal dystonia was present in four patients who had never received neuroleptics drugs and chorea was seen in two other untreated patients. In three patients acoustic startle consistently induced brief eye blink followed by a whole body jerk or jump. Rapid repetitive movements of the hands increased the frequency and severity of tics in 13 patients, but the performance of mental arithmetic under time pressure had a much more unpredictable effect. Electroencephalographic abnormalities occurred in eight (13%) but no definite CT brain scan abnormalities were detected. The incidence of left handedness did not differ from that in the general population and no evidence to suggest organic impairment was found on neuropsychological testing. This study provides no support for the notion that Gilles de la Tourette syndrome is a degenerative disorder of the central nervous system but provides some evidence for heterogeneity. PMID:6582230

Catatonia After Cerebral Hypoxia: Do the Usual Treatments Apply?

PubMed Central

Quinn, Davin K.; Abbott, Christopher C.

2014-01-01

Introduction Neurologic deterioration occurring days to weeks after a cerebral hypoxic event accompanied by diffuse white matter demyelination is called delayed post-hypoxic leukoencephalopathy (DPHL). Manifestations of DPHL are diverse, and include dementia, gait disturbance, incontinence, pyramidal tract signs, parkinsonism, chorea, mood and thought disorders, akinetic mutism, and rarely catatonia. Methods The authors report a case of malignant catatonia in a patient diagnosed with DPHL that was refractory to electroconvulsive therapy (ECT), and review the literature on catatonia in DHPL. Results The patient was a 56 year-old female with schizoaffective disorder who was admitted with catatonia two weeks after hospitalization for drug overdose and respiratory failure. Her catatonic symptoms did not respond to lorazepam, amantadine, methylphenidate, or ten sessions of bilateral ECT at maximum energy. Repeat magnetic resonance imaging revealed extensive periventricular white matter lesions not present on admission scans, and she was diagnosed with DPHL. Discussion No treatment for DPHL has been proven to be widely effective. Hyperbaric oxygen treatments may reduce the rate of development, and symptom improvement has been reported with stimulants and other psychotropic agents. Review of the literature reveals rare success with GABAergic agents for catatonia after cerebral hypoxia, and no cases successfully treated with ECT. There are seven case reports of neurologic decompensation during ECT treatment after a cerebral hypoxic event. Conclusion Caution is advised when considering ECT for catatonia when delayed sequelae of cerebral hypoxia are on the differential diagnosis, as there is a dearth of evidence to support this treatment approach. PMID:25262046

Selection and ranking of patient video cases in paediatric neurology in relation to learner levels.

PubMed

Balslev, Thomas; Muijtjens, Arno M M; Maarbjerg, Sabine Frølich; de Grave, Willem

2018-05-01

Teaching and learning with patient video cases may add authenticity, enhance diagnostic accuracy and improve chances of early diagnosis. The aim of this study is firstly to identify selection criteria for key Patient video cases (PVCs), secondly to identify trends in relevance of PVCs for learner levels and thirdly, to rank PVCs for learner levels. Based on a literature review, we identified criteria for key PVCs for use in paediatric neurology. We then performed a multi-round Delphi analysis to obtain agreement between 28 expert clinician teachers concerning key PVCs for four learner levels. We identified two major criteria: key PVCs should demonstrate key movements, and these movements should be subtle and/or difficult to note. The expert clinician teachers subsequently assessed a list of 14 topics for key PVCs. We found a clear, increasing trend in relevance scores, from medical students to young residents to experienced residents and specialists. For medical students and residents, epileptic spasms, Down syndrome, developmental delay, cerebral palsy and absence epilepsy were highly ranked. For specialists, conditions like chorea, focal seizures or eye movement disorders topped the ranking list, although ranking was less clear for this group of advanced learners. Key PVCs should demonstrate movements that are difficult to note for learners. Ranked lists of key PVCs for teaching and learning at different learner levels are now available and may help institutions build validated local libraries of PVCs. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology.

PubMed

Koppel, Barbara S; Brust, John C M; Fife, Terry; Bronstein, Jeff; Youssof, Sarah; Gronseth, Gary; Gloss, David

2014-04-29

To determine the efficacy of medical marijuana in several neurologic conditions. We performed a systematic review of medical marijuana (1948-November 2013) to address treatment of symptoms of multiple sclerosis (MS), epilepsy, and movement disorders. We graded the studies according to the American Academy of Neurology classification scheme for therapeutic articles. Thirty-four studies met inclusion criteria; 8 were rated as Class I. The following were studied in patients with MS: (1) Spasticity: oral cannabis extract (OCE) is effective, and nabiximols and tetrahydrocannabinol (THC) are probably effective, for reducing patient-centered measures; it is possible both OCE and THC are effective for reducing both patient-centered and objective measures at 1 year. (2) Central pain or painful spasms (including spasticity-related pain, excluding neuropathic pain): OCE is effective; THC and nabiximols are probably effective. (3) Urinary dysfunction: nabiximols is probably effective for reducing bladder voids/day; THC and OCE are probably ineffective for reducing bladder complaints. (4) Tremor: THC and OCE are probably ineffective; nabiximols is possibly ineffective. (5) Other neurologic conditions: OCE is probably ineffective for treating levodopa-induced dyskinesias in patients with Parkinson disease. Oral cannabinoids are of unknown efficacy in non-chorea-related symptoms of Huntington disease, Tourette syndrome, cervical dystonia, and epilepsy. The risks and benefits of medical marijuana should be weighed carefully. Risk of serious adverse psychopathologic effects was nearly 1%. Comparative effectiveness of medical marijuana vs other therapies is unknown for these indications.

Longitudinal outcomes of children with pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS).

PubMed

Leon, Jill; Hommer, Rebecca; Grant, Paul; Farmer, Cristan; D'Souza, Precilla; Kessler, Riley; Williams, Kyle; Leckman, James F; Swedo, Susan

2018-05-01

Little is known about the natural history of children with pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). This study prospectively followed 33 children with PANDAS for up to 4.8 years (mean 3.3 ± 0.7 years) after enrollment in a 24-week randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin (IVIG) (N = 35). Fourteen of eighteen children randomized to placebo received open label IVIG 6 weeks after the blinded infusion, so follow-up results reported below largely reflect outcomes in a population of children who received at least one dose of IVIG. Telephone interviews with the parents of participants found that at the time of phone follow-up, 29 (88%) were not experiencing clinically significant obsessive-compulsive symptoms. During the interim period (6-57 months after entering the clinical trial), 24 (72%) had experienced at least one exacerbation of PANDAS symptoms, with a median of one exacerbation per child (range 1-12; interquartile range 0-3). A variety of treatment modalities, including antibiotics, IVIG, psychiatric medications, cognitive behavioral therapy, and others, were used to treat these exacerbations, and were often used in combination. The outcomes of this cohort are better than those previously reported for childhood-onset OCD, which may support conceptualization of PANDAS as a subacute illness similar to Sydenham chorea. However, some children developed a chronic course of illness, highlighting the need for research that identifies specific symptoms or biomarkers that can be used to predict the longitudinal course of symptoms in PANDAS.

Cross-cutting issues and future directions for the OCD spectrum.

PubMed

Hollander, Eric; Kim, Suah; Braun, Ashley; Simeon, Daphne; Zohar, Joseph

2009-11-30

The research planning agenda for DSM-V examined possible similarities in phenomenology, comorbidity, familial and genetic features, brain circuitry, and treatment response between obsessive-compulsive disorder (OCD) and several related disorders that are characterized by repetitive thoughts or behaviors. Such data support a re-examination of the DSM-IV-TR classification of OCD and the anxiety disorders, with possible inclusion of a group of obsessive-compulsive spectrum disorders (OCSDs) in DSM-V. Various disorders were systematically examined for inclusion in such a grouping, and later a smaller number were determined to meet threshold criteria for inclusion in the OCSDs. The disorders that were originally examined included OCD, obsessive-compulsive personality disorder (OCPD), Tourette's syndrome (TS) and other tic disorders, Sydenham's chorea, Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS), trichotillomania (TTM), body dysmorphic disorder (BDD), autism, eating disorders, Huntington's and Parkinson's disease, impulse control disorders, as well as substance and behavioral addictions. Certain disorders such as BDD, OCPD, TS, and TTM share many commonalities with OCD in phenomenology, comorbidity, familial and genetic features, brain circuitry, and treatment response. Other disorders, such as the impulse control disorders (ICDs) share some common features with OCD, but also differ in many ways as well. The articles presented in this issue of Psychiatry Research are a result of this international collaboration, which examined diagnostic and classification issues of OCSDs for DSM-V in a conference titled "The Future of Psychiatric Diagnosis: Refining the Research Agenda: Obsessive-Compulsive Behavior Spectrum" held in June 2006 at the American Psychiatric Association's headquarters in Arlington, VA.

Central nervous system involvement in pediatric rheumatic diseases: current concepts in treatment.

PubMed

Duzova, Ali; Bakkaloglu, Aysin

2008-01-01

Central nervous system (CNS) manifestations are not rare in pediatric rheumatic diseases. They may be a relatively common feature of the disease, as in systemic lupus erythematosus (SLE) and Behçet's disease. Direct CNS involvement of a systemic rheumatic disease, primary CNS vasculitis, indirect involvement secondary to hypertension, hypoxia and metabolic changes, and drug associated adverse events may all result in CNS involvement. We have reviewed the CNS manifestations of SLE, Behçet's disease, Henoch-Schönlein purpura, polyarteritis nodosa, juvenile idiopathic arthritis, juvenile ankylosing spondylitis, familial Mediterranean fever, scleroderma, sarcoidosis, Wegener's granulomatosis, Takayasu's arteritis, CINCA syndrome, Kawasaki disease, and primary CNS vasculitis; and adverse CNS effects of anti-rheumatic drugs in pediatric patients. The manifestations are diverse; ranging from headache, seizures, chorea, changes in personality, depression, memory and concentration problems, cognitive impairment, cerebrovascular accidents to coma, and death. The value of cerebrospinal fluid (CSF) examination (pleocytosis, high level of protein), auto-antibodies in serum and CSF, electroencephalography, neuroimaging with computerized tomography, magnetic resonance imaging, SPECT, PET, and angiography depends on the disease. Brain biopsy is gold standard for the diagnosis of CNS vasculitis, however it may be inconclusive in 25% of cases. A thorough knowledge of the rheumatic diseases and therapy-related adverse events is mandatory for the management of a patient with rheumatic disease and CNS involvement. Severe CNS involvement is associated with poor prognosis, and high mortality rate. High dose steroid and cyclophosphamide (oral or intravenous) are first choice drugs in the treatment; plasmapheresis, IVIG, thalidomide, and intratechal treatment may be valuable in treatment-resistant, and serious cases.

Delineating the spectrum of impairments, disabilities, and rehabilitation needs in methylmalonic acidemia (MMA).

PubMed

Ktena, Yiouli P; Paul, Scott M; Hauser, Natalie S; Sloan, Jennifer L; Gropman, Andrea; Manoli, Irini; Venditti, Charles P

2015-09-01

Methylmalonic acidemia patients have complex rehabilitation needs that can be targeted to optimize societal independence and quality of life. Thirty-seven individuals with isolated MMA (28 mut, 5 cblA, 4 cblB), aged 2-33 years, were enrolled in a natural history study, and underwent age-appropriate clinical assessments to characterize impairments and disabilities. Neurological examination and brain imaging studies were used to document movement disorders and the presence of basal ganglia injury. A range of impairments and disabilities were identified by a team of physical medicine experts. Movement disorders, such as chorea and tremor, were common (n = 31, 83%), even among patients without evidence of basal ganglia injury. Joint hypermobility (n = 24, 69%) and pes planus (n = 22, 60%) were frequent and, in many cases, under-recognized. 23 (62%) patients required gastrostomy feedings. 18/31 patients >4 years old (58%) had difficulties with bathing and dressing. 16 of 23 school-aged patients received various forms of educational support. Five of the 10 adult patients were employed or in college; three lived independently. Unmet needs were identified in access to rehabilitation services, such as physical therapy (unavailable to 14/31), and orthotics (unavailable to 15/22). We conclude that patients with MMA are challenged by a number of functional limitations in essential activities of mobility, self-care, and learning, in great part caused by movement disorders and ligamentous laxity. Early assessment, referral, and implementation of age-appropriate rehabilitation services should significantly improve independence and quality of life. © 2015 Wiley Periodicals, Inc.

Philadelphia Infirmary for Nervous Diseases: America's original model of institutional neurology.

PubMed

Pappert, E J

1998-06-01

The role and contributions of the Philadelphia Orthopedic Hospital and Infirmary for Nervous Diseases in the development of neurology in 19th-century America are described. American neurology was largely born during the Civil War through the work of S.W. Mitchell at Turner's Lane Hospital. With the closing of this military facility, the United States was left without an institution dedicated to neurologic research and the treatment of nervous system diseases. Nineteenth century archival data, including original Trustees' minutes, annual board of managers reports, patient case books, and published research from the Philadelphia Orthopedic Hospital and Infirmary for Nervous Diseases were studied. The Philadelphia Orthopedic Hospital and Infirmary for Nervous Diseases promoted the development of neurology in the United States through three main activities. First, it offered patients with primary nervous system diseases, arthritis, and orthopedic disorders specialized care that was unavailable at medical universities. Second, its medical staff, especially Mitchell, provided opportunities for advanced neurologic education. Postgraduate physicians interested in neurologic disease attended formal lectures and directly participated in the operation of outpatient clinics and inpatient rounds. Finally, its formalized record system in the form of case books facilitated neurologic research. These records formed the basis of landmark publications by Mitchell, Sinkler, Osler, and others on rest therapy, spastic palsies, chorea, and other topics. As America's first and comprehensive peacetime neurologic facility, the Philadelphia Orthopedic Hospital and Infirmary for Nervous Diseases fostered the evolution of neurology as a separate, viable specialty in the post-Civil War period and provided a particular focus for the study of interactions among orthopedic, nutritional, and neurologic disorders.

Toward a clinic of temporality?

PubMed

Rivasseau Jonveaux, Thérèse; Batt, Martine; Trognon, Alain

2017-12-01

The discovery of time cells has expanded our knowledge in the field of spatial and temporal information coding and the key role of the hippocampus. The internal clock model complemented with the attentional gate model allows a more in-depth understanding of the perception of time. The motor representation of duration is ensured by the basal ganglia, while the cerebellum synchronizes short duration for the movement. The right prefrontal cortex seemingly intervenes in the handling of temporal information in working memory. The temporal lobe ensures the comparison of durations, especially the right lobe for the reference durations and the medial lobe for the reproduction of durations in episodic memory. During normal aging, the hypothesis of slowing of the temporal processor is evoked when noting the perception of the acceleration of the passage of time that seemingly occurs with advancing age. The various studies pertaining specifically to time cognition, albeit heterogeneous in terms of methodology, attest to the wide-ranging disturbances of this cognitive field during the course of numerous disorders, whether psychiatric - depression and schizophrenia notably - or neurological. Hence, perturbations in temporality are observed in focal brain lesions and in subcortical disorders, such as Parkinson's disease or Huntington's chorea. Alzheimer's disease represents a particularly fertile field of exploration with regard to time cognition and temporality. The objectified deconstruction of temporal experience provides insights into the very processes of temporality and their nature: episodic, semantic and procedural. In addition to exploration based on elementary stimuli, one should also consider the time lived, i.e. that of the subject, to better understand cognition as it relates to time. While the temporal dimension permeates the whole cognitive field, it remains largely neglected: integration of a genuine time cognition and temporality clinic in daily practice remains to be implemented.

[Psychiatric Disorders in Pediatric Patients With Systemic Lupus Erythematosus in a Reference Hospital].

PubMed

Zuñiga Zambrano, Yenny Carolina; Vásquez, Rafael

2014-01-01

To describe the psychiatric manifestations in pediatric patients with systemic erythematous lupus seen in the Fundación Hospital de la Misericordia. Observational descriptive study. Medical charts and test results of inpatients and outpatients between 2007 and2013 were reviewed; 39 patients were selected. SPSS 19 was used for statistical analysis. Statistical significance was considered with P=.05. Mean age was 13.7 (2.33), with 78.9% female. The most frequent psychiatric manifestation was anxiety (52.6%), followed by adjustment disorder and depression (36.8% each one), psychosis (10%), conversion disorder (7.9%), and obsessive compulsive disorder (5.3%). The mean SLICC score was 2.76 (2.8), and the mean SLEDAI score was 20.81 (20.82). Antinuclear antibodies were positive in 81.25%. Neuropsychiatric lupus was diagnosed in 65.8% of patients; seizures were observed in 23.7%, headache in 36.8%, stroke in 13.2%, vasculitis, chorea 5.3%, and meningitis 5.3% of patients. The mean time from lupus diagnosis was 20.47 (22.2) months, with the shortest period for adjustment disorder and the longest period in patients with conversion disorder (pseudo-seizures) being 15 months and 31 months, respectively. The highest SLEDAI score was in patients with psychosis (35.5 [16.21] vs 19.08 [13.72]; P=.032), and also the highest disease damage (SLICC, 4.25 [4.03] vs 2.58 [2.67]; P=.27) in comparison with the other manifestations. The most frequent psychiatric manifestations were anxiety, depression, and adjustment disorder, with a higher frequency than other studies, and with lupus activity principally in patients with psychosis. Copyright © 2013 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Americo Negrette (1924 to 2003): diagnosing Huntington disease in Venezuela.

PubMed

Okun, Michael S; Thommi, Nia

2004-07-27

To elucidate the role of Dr. Americo Negrette in diagnosing and reclassifying the dancing mania in Maracaibo, Venezuela as Huntington disease (HD). All of the medical and nonmedical books and articles by Negrette were collected and reviewed. Personal interviews with Negrette were performed to confirm the details of his life and original work. His childhood, medical education, and contribution to HD, as well as contributions to medicine, art, and poetry, were covered in interview sessions. Excerpts from his autobiography, Ciudad de Fuego, were translated into English for publication. A complete bibliography of 70 books and research articles authored by Negrette was assembled. Negrette himself reviewed the compilation of this manuscript just days before his sudden death on September 14, 2003. Americo Negrette, a Venezuelan physician, biochemist, artist, and poet, observed a dancing epidemic in 1952. He acquired, through interviews with locals, the knowledge that there were two other small towns along Lake Maracaibo devastated by a syndrome called el mal (the bad). Negrette changed the diagnosis of these patients from a dancing mania to what he believed was Huntington chorea, later termed HD. He presented his findings at the Venezuelan Sixth Congress of Medical Science in 1955. He was met with reluctance in the local scientific community and a passive ear from government authorities. His description, written in Spanish, was not widely distributed beyond Venezuela, and its importance would have to wait until one of his students shared his observations (more than a decade later) with the HD research community and the rest of the world. The "dancing mania" of Maracaibo, because of the work of Americo Negrette, has been reclassified as Huntington disease.

An Item Response Analysis of the Motor and Behavioral Subscales of the Unified Huntington's Disease Rating Scale in Huntington Disease Gene Expansion Carriers

PubMed Central

Vaccarino, Anthony L.; Anderson, Karen; Borowsky, Beth; Duff, Kevin; Giuliano, Joseph; Guttman, Mark; Ho, Aileen K.; Orth, Michael; Paulsen, Jane S.; Sills, Terrence; van Kammen, Daniel P.; Evans, Kenneth R.

2011-01-01

Although the Unified Huntington's Disease Rating Scale (UHDRS) is widely used in the assessment of Huntington disease (HD), the ability of individual items to discriminate individual differences in motor or behavioral manifestations has not been extensively studied in HD gene expansion carriers without a motor-defined clinical diagnosis (i.e., prodromal-HD or prHD). To elucidate the relationship between scores on individual motor and behavioral UHDRS items and total score for each subscale, a non-parametric item response analysis was performed on retrospective data from two multicentre, longitudinal studies. Motor and Behavioral assessments were supplied for 737 prHD individuals with data from 2114 visits (PREDICT-HD) and 686 HD individuals with data from 1482 visits (REGISTRY). Option characteristic curves were generated for UHDRS subscale items in relation to their subscale score. In prHD, overall severity of motor signs was low and participants had scores of 2 or above on very few items. In HD, motor items that assessed ocular pursuit, saccade initiation, finger tapping, tandem walking, and to a lesser extent saccade velocity, dysarthia, tongue protrusion, pronation/supination, Luria, bradykinesia, choreas, gait and balance on the retropulsion test were found to discriminate individual differences across a broad range of motor severity. In prHD, depressed mood, anxiety, and irritable behavior demonstrated good discriminative properties. In HD, depressed mood demonstrated a good relationship with the overall behavioral score. These data suggest that at least some UHDRS items appear to have utility across a broad range of severity, although many items demonstrate problematic features. PMID:21370269

Rating Scales for Movement Disorders With Sleep Disturbances: A Narrative Review

PubMed Central

Rodríguez-Blázquez, Carmen; Forjaz, Maria João; Kurtis, Monica M.; Balestrino, Roberta; Martinez-Martin, Pablo

2018-01-01

Introduction: In recent years, a wide variety of rating scales and questionnaires for movement disorders have been developed and published, making reviews on their contents, and attributes convenient for the potential users. Sleep disorders are frequently present in movement disorders, and some movement disorders are accompanied by specific sleep difficulties. Aim: The aim of this study is to perform a narrative review of the most frequently used rating scales for movement disorders with sleep problems, with special attention to those recommended by the International Parkinson and Movement Disorders Society. Methods: Online databases (PubMed, SCOPUS, Web of Science, Google Scholar), related references from papers and websites and personal files were searched for information on comprehensive or global rating scales which assessed sleep disturbances in the following movement disorders: akathisia, chorea, dystonia, essential tremor, myoclonus, multiple system atrophy, Parkinson's disease, progressive supranuclear palsy, and tics and Tourette syndrome. For each rating scale, its objective and characteristics, as well as a summary of its psychometric properties and recommendations of use are described. Results: From 22 rating scales identified for the selected movement disorders, only 5 included specific questions on sleep problems. Movement Disorders Society-Unified Parkinson's Disease Rating scale (MDS-UPDRS), Non-Motor Symptoms Scale and Questionnaire (NMSS and NMSQuest), Scales for Outcomes in Parkinson's Disease (SCOPA)-Autonomic and Progressive Supranuclear Palsy Rating Scale (PSPRS) were the only rating scales that included items for assessing sleep disturbances. Conclusions: Despite sleep problems are frequent in movement disorders, very few of the rating scales addresses these specific symptoms. This may contribute to an infra diagnosis and mistreatment of the sleep problems in patients with movement disorders.

Executive dysfunction, obsessive-compulsive symptoms, and attention deficit and hyperactivity disorder in Systemic Lupus Erythematosus: Evidence for basal ganglia dysfunction?

PubMed

Maciel, Ricardo Oliveira Horta; Ferreira, Gilda Aparecida; Akemy, Bárbara; Cardoso, Francisco

2016-01-15

Chorea is well described in a group of patients with Systemic Lupus Erythematosus (SLE). There is less information, however, on other movement disorders as well as non-motor neuropsychiatric features such as obsessive-compulsive symptoms (OCS), executive dysfunction and attention deficit and hyperactivity disorder (ADHD) in subjects with SLE. Fifty-four subjects with SLE underwent a battery of neuropsychiatric tests that included the Mini Mental State Examination, the Montreal Cognitive Assessment, the Frontal Assessment Battery (FAB), the FAS verbal and the categorical (animals) semantic fluency tests, the Obsessive and Compulsive Inventory - Revised, the Yale-Brown Obsessive and Compulsive Scale and Beck's Anxiety and Depression Scales. ADHD was diagnosed according to DSM-IV criteria. SLE disease activity and cumulative damage were evaluated according to the modified SLE Disease Activity Index 2000 (mSLEDAI-2K) and the SLICC/ACR, respectively. Six (11.1%) and 33 (61.1%) patients had cognitive impairment according to the MMSE and MoCA, respectively. Eleven (20.4%) had abnormal FAB scores, and 5 (9.3%) had lower semantic fluency scores than expected. The overall frequency of cognitive dysfunction was 72.2% (39 patients) and of neuropsychiatric SLE was 77.8% (42 patients). Two patients (3.7%) had movement disorders. Fifteen (27.8%) had OCS and 17 (31.5%) met diagnostic criteria for ADHD. ADHD and OCS correlated with higher disease activity, p=0.003 and 0.006, respectively. Higher cumulative damage correlated with lower FAB scores (p 0.026). Executive dysfunction, ADHD, OCS, and movement disorders are common in SLE. Our finding suggests that there is frequent basal ganglia dysfunction in SLE. Copyright © 2015 Elsevier B.V. All rights reserved.

The expanding spectrum of neurological phenotypes in children with ATP1A3 mutations, Alternating Hemiplegia of Childhood, Rapid-onset Dystonia-Parkinsonism, CAPOS and beyond.

PubMed

Sweney, Matthew T; Newcomb, Tara M; Swoboda, Kathryn J

2015-01-01

ATP1A3 mutations have now been recognized in infants and children presenting with a diverse group of neurological phenotypes, including Rapid-onset Dystonia-Parkinsonism (RDP), Alternating Hemiplegia of Childhood (AHC), and most recently, Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss (CAPOS) syndrome. Existing literature on ATP1A3-related disorders in the pediatric population were reviewed, with attention to clinical features and associated genotypes among those with RDP, AHC, or CAPOS syndrome phenotypes. While classically defined phenotypes associated with AHC, RDP, and CAPOS syndromes are distinct, common elements among ATP1A3-related neurological disorders include characteristic episodic neurological symptoms and signs that vary in severity, duration, and frequency of occurrence. Affected children typically present in the context of an acute onset of paroxysmal, episodic neurological symptoms ranging from oculomotor abnormalities, hypotonia, paralysis, dystonia, ataxia, seizure-like episodes, or encephalopathy. Neurodevelopmental delays or persistence of dystonia, chorea, or ataxia after resolution of an initial episode are common, providing important clues for diagnosis. The phenotypic spectrum of ATP1A3-related neurological disorders continues to expand beyond the distinct yet overlapping phenotypes in patients with AHC, RDP, and CAPOS syndromes. ATP1A3 mutation analysis is appropriate to consider in the diagnostic algorithm for any child presenting with episodic or fluctuating ataxia, weakness or dystonia whether they manifest persistence of neurological symptoms between episodes. Additional work is needed to better identify and classify affected patients and develop targeted treatment approaches. Copyright © 2015 Elsevier Inc. All rights reserved.

[Images of gender and gender-specific therapies in German homoeopathic and naturopathic guidebooks (c. 1870-1930)].

PubMed

Weigl, Andreas

2011-01-01

In the second half of the nineteenth and early twentieth century sex and gender became crucial categories not only in the medical discourse of German speaking countries. At the very centre of this discourse was the idea of women as the weaker sex. Because of the paradigm shift in the history of medicine (due to the discovery of the cytopathology) the principle of a weaker sex seemed to be corroborated by scientific research, a fact which impacted on medical practice in many ways. "Nervous" disease evolved as the major threat "of our times," with urban girls, young women and "weak" young men being most at risk. At the same time homoeopaths and naturopaths challenged modern medicine, offering alternative health practices, cures and drugs for people who could not afford the help of physicians or distrusted them. An analysis of several alternative medical guidebooks printed between c. 1870 and 1930 showed that homoeopaths and naturopaths shared the "sexualization" of medical discourse and practice only to an extent. On the one hand they believed that disorders such as hysteria, masturbation, chorea Sydenham and anaemia were nervous in nature and that the chances of curing them were poor. With the exception of masturbation these "deadly" threats were considered to be typically female. The general approach of alternative physicians, on the other hand, was unisex. The cures they offered to the public used unisex scales of constitutional characters. They even ignored the gender specificity of sick headaches. Gender-specific problems such as difficult deliveries and childbed fever were treated as "natural" and mild cures were favoured. The conclusion is that the influences of upper and middle class discourse on common health practices should not be overestimated.

Decreased glycogen synthase kinase-3 levels and activity contribute to Huntington's disease.

PubMed

Fernández-Nogales, Marta; Hernández, Félix; Miguez, Andrés; Alberch, Jordi; Ginés, Silvia; Pérez-Navarro, Esther; Lucas, José J

2015-09-01

Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by brain atrophy particularly in striatum leading to personality changes, chorea and dementia. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase in the crossroad of many signaling pathways that is highly pleiotropic as it phosphorylates more than hundred substrates including structural, metabolic, and signaling proteins. Increased GSK-3 activity is believed to contribute to the pathogenesis of neurodegenerative diseases like Alzheimer's disease and GSK-3 inhibitors have been postulated as therapeutic agents for neurodegeneration. Regarding HD, GSK-3 inhibitors have shown beneficial effects in cell and invertebrate animal models but no evident efficacy in mouse models. Intriguingly, those studies were performed without interrogating GSK-3 level and activity in HD brain. Here we aim to explore the level and also the enzymatic activity of GSK-3 in the striatum and other less affected brain regions of HD patients and of the R6/1 mouse model to then elucidate the possible contribution of its alteration to HD pathogenesis by genetic manipulation in mice. We report a dramatic decrease in GSK-3 levels and activity in striatum and cortex of HD patients with similar results in the mouse model. Correction of the GSK-3 deficit in HD mice, by combining with transgenic mice with conditional GSK-3 expression, resulted in amelioration of their brain atrophy and behavioral motor and learning deficits. Thus, our results demonstrate that decreased brain GSK-3 contributes to HD neurological phenotype and open new therapeutic opportunities based on increasing GSK-3 activity or attenuating the harmful consequences of its decrease. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The social and economic origins of genetic determinism: a case history of the American Eugenics Movement, 1900-1940 and its lessons for today.

PubMed

Allen, G E

1997-01-01

Eugenics, the attempt to improve the genetic quality of the human species by 'better breeding', developed as a worldwide movement between 1900 and 1940. It was particularly prominent in the United States, Britain and Germany, and in those countries was based on the then-new science of Mendelian genetics. Eugenicists developed research programs to determine the degree in which traits such as Huntington's chorea, blindness, deafness, mental retardation (feeblemindedness), intelligence, alcoholism, schizophrenia, manic depression, rebelliousness, nomadism, prostitution and feeble inhibition were genetically determined. Eugenicists were also active in the political arena, lobbying in the United States for immigration restriction and compulsory sterilization laws for those deemed genetically unfit; in Britain they lobbied for incarceration of genetically unfit and in Germany for sterilization and eventually euthanasia. In all these countries one of the major arguments was that of efficiency: that it was inefficient to allow genetic defects to be multiplied and then have to try and deal with the consequences of state care for the offspring. National socialists called genetically defective individuals 'useless eaters' and argued for sterilization or euthanasia on economic grounds. Similar arguments appeared in the United States and Britain as well. At the present time (1997) much research and publicity is being given to claims about a genetic basis for all the same behaviors (alcoholism, manic depression, etc.), again in an economic context--care for people with such diseases is costing too much. There is an important lesson to learn from the past: genetic arguments are put forward to mask the true--social and economic--causes of human behavioral defects.

Movement disorders with neuronal antibodies: syndromic approach, genetic parallels and pathophysiology

PubMed Central

Balint, Bettina; Vincent, Angela; Meinck, Hans-Michael; Irani, Sarosh R; Bhatia, Kailash P

2018-01-01

Abstract Movement disorders are a prominent and common feature in many autoantibody-associated neurological diseases, a group of potentially treatable conditions that can mimic infectious, metabolic or neurodegenerative disease. Certain movement disorders are likely to associate with certain autoantibodies; for example, the characteristic dyskinesias, chorea and dystonia associated with NMDAR antibodies, stiff person spectrum disorders with GAD, glycine receptor, amphiphysin or DPPX antibodies, specific paroxysmal dystonias with LGI1 antibodies, and cerebellar ataxia with various anti-neuronal antibodies. There are also less-recognized movement disorder presentations of antibody-related disease, and a considerable overlap between the clinical phenotypes and the associated antibody spectra. In this review, we first describe the antibodies associated with each syndrome, highlight distinctive clinical or radiological ‘red flags’, and suggest a syndromic approach based on the predominant movement disorder presentation, age, and associated features. We then examine the underlying immunopathophysiology, which may guide treatment decisions in these neuroimmunological disorders, and highlight the exceptional interface between neuronal antibodies and neurodegeneration, such as the tauopathy associated with IgLON5 antibodies. Moreover, we elaborate the emerging pathophysiological parallels between genetic movement disorders and immunological conditions, with proteins being either affected by mutations or targeted by autoantibodies. Hereditary hyperekplexia, for example, is caused by mutations of the alpha subunit of the glycine receptor leading to an infantile-onset disorder with exaggerated startle and stiffness, whereas antibodies targeting glycine receptors can induce acquired hyperekplexia. The spectrum of such immunological and genetic analogies also includes cerebellar ataxias and some encephalopathies. Lastly, we discuss how these pathophysiological considerations could reflect on possible future directions regarding antigen-specific immunotherapies or targeting the pathophysiological cascades downstream of the antibody effects. PMID:29053777

Isolated and combined dystonia syndromes - an update on new genes and their phenotypes.

PubMed

Balint, B; Bhatia, K P

2015-04-01

Recent consensus on the definition, phenomenology and classification of dystonia centres around phenomenology and guides our diagnostic approach for the heterogeneous group of dystonias. Current terminology classifies conditions where dystonia is the sole motor feature (apart from tremor) as 'isolated dystonia', while 'combined dystonia' refers to dystonias with other accompanying movement disorders. This review highlights recent advances in the genetics of some isolated and combined dystonic syndromes. Some genes, such as ANO3, GNAL and CIZ1, have been discovered for isolated dystonia, but they are probably not a common cause of classic cervical dystonia. Conversely, the phenotype associated with TUBB4A mutations expanded from that of isolated dystonia to a syndrome of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC syndrome). Similarly, ATP1A3 mutations cause a wide phenotypic spectrum ranging from rapid-onset dystonia-parkinsonism to alternating hemiplegia of childhood. Other entities entailing dystonia-parkinsonism include dopamine transporter deficiency syndrome (SLC63 mutations); dopa-responsive dystonias; young-onset parkinsonism (PARKIN, PINK1 and DJ-1 mutations); PRKRA mutations; and X-linked TAF1 mutations, which rarely can also manifest in women. Clinical and genetic heterogeneity also characterizes myoclonus-dystonia, which includes not only the classical phenotype associated with epsilon-sarcoglycan mutations but rarely also presentation of ANO3 gene mutations, TITF1 gene mutations typically underlying benign hereditary chorea, and some dopamine synthesis pathway conditions due to GCH1 and TH mutations. Thus, new genes are being recognized for isolated dystonia, and the phenotype of known genes is broadening and now involves different combined dystonia syndromes. © 2015 EAN.

Effects of cyclooxygenase inhibitor pretreatment on nitric oxide production, nNOS and iNOS expression in rat cerebellum.

PubMed

Di Girolamo, G; Farina, M; Riberio, M L; Ogando, D; Aisemberg, J; de los Santos, A R; Martí, M L; Franchi, A M

2003-07-01

1. The therapeutic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is thought to be due mainly to its inhibition of cyclooxygenase (COX) enzymes, but there is a growing body of research that now demonstrates a variety of NSAIDs effects on cellular signal transduction pathways other than those involving prostaglandins. 2. Nitric oxide (NO) as a free radical and an agent that gives rise to highly toxic oxidants (peroxynitrile, nitric dioxide, nitron ion), becomes a cause of neuronal damage and death in some brain lesions such as Parkinson and Alzheimer disease, and Huntington's chorea. 3. In the present study, the in vivo effect of three NSAIDs (lysine clonixinate (LC), indomethacine (INDO) and meloxicam (MELO)) on NO production and nitric oxide synthase expression in rat cerebellar slices was analysed. Rats were treated with (a) saline, (b) lipopolysaccharide (LPS) (5 mg kg(-1), i.p.), (c) saline in combination with different doses of NSAIDs and (d) LPS in combination with different doses of NSAIDs and then killed 6 h after treatment. 4. NO synthesis, evaluated by Bred and Snyder technique, was increased by LPS. This augmentation was inhibited by coadministration of the three NSAIDs assayed. None of the NSAIDs tested was able to modify control NO synthesis. 5. Expression of iNOS and neural NOS (nNOS) was detected by Western blotting in control and LPS-treated rats. LC and INDO, but not MELO, were able to inhibit the expression of these enzymes. 6. Therefore, reduction of iNOS and nNOS levels in cerebellum may explain, in part, the anti-inflammatory effect of these NSAIDs and may also have importance in the prevention of NO-mediated neuronal injury.

Effects of cyclooxygenase inhibitor pretreatment on nitric oxide production, nNOS and iNOS expression in rat cerebellum

PubMed Central

DiGirolamo, G; Farina, M; Riberio, M L; Ogando, D; Aisemberg, J; de los Santos, A R; Martí, M L; Franchi, A M

2003-01-01

The therapeutic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is thought to be due mainly to its inhibition of cyclooxygenase (COX) enzymes, but there is a growing body of research that now demonstrates a variety of NSAIDs effects on cellular signal transduction pathways other than those involving prostaglandins. Nitric oxide (NO) as a free radical and an agent that gives rise to highly toxic oxidants (peroxynitrile, nitric dioxide, nitron ion), becomes a cause of neuronal damage and death in some brain lesions such as Parkinson and Alzheimer disease, and Huntington's chorea. In the present study, the in vivo effect of three NSAIDs (lysine clonixinate (LC), indomethacine (INDO) and meloxicam (MELO)) on NO production and nitric oxide synthase expression in rat cerebellar slices was analysed. Rats were treated with (a) saline, (b) lipopolysaccharide (LPS) (5 mg kg−1, i.p.), (c) saline in combination with different doses of NSAIDs and (d) LPS in combination with different doses of NSAIDs and then killed 6 h after treatment. NO synthesis, evaluated by Bred and Snyder technique, was increased by LPS. This augmentation was inhibited by coadministration of the three NSAIDs assayed. None of the NSAIDs tested was able to modify control NO synthesis. Expression of iNOS and neural NOS (nNOS) was detected by Western blotting in control and LPS-treated rats. LC and INDO, but not MELO, were able to inhibit the expression of these enzymes. Therefore, reduction of iNOS and nNOS levels in cerebellum may explain, in part, the anti-inflammatory effect of these NSAIDs and may also have importance in the prevention of NO-mediated neuronal injury. PMID:12871835

Glutamate as a neurotransmitter in the brain: review of physiology and pathology.

PubMed

Meldrum, B S

2000-04-01

Glutamate is the principal excitatory neurotransmitter in brain. Our knowledge of the glutamatergic synapse has advanced enormously in the last 10 years, primarily through application of molecular biological techniques to the study of glutamate receptors and transporters. There are three families of ionotropic receptors with intrinsic cation permeable channels [N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate]. There are three groups of metabotropic, G protein-coupled glutamate receptors (mGluR) that modify neuronal and glial excitability through G protein subunits acting on membrane ion channels and second messengers such as diacylglycerol and cAMP. There are also two glial glutamate transporters and three neuronal transporters in the brain. Glutamate is the most abundant amino acid in the diet. There is no evidence for brain damage in humans resulting from dietary glutamate. A kainate analog, domoate, is sometimes ingested accidentally in blue mussels; this potent toxin causes limbic seizures, which can lead to hippocampal and related pathology and amnesia. Endogenous glutamate, by activating NMDA, AMPA or mGluR1 receptors, may contribute to the brain damage occurring acutely after status epilepticus, cerebral ischemia or traumatic brain injury. It may also contribute to chronic neurodegeneration in such disorders as amyotrophic lateral sclerosis and Huntington's chorea. In animal models of cerebral ischemia and traumatic brain injury, NMDA and AMPA receptor antagonists protect against acute brain damage and delayed behavioral deficits. Such compounds are undergoing testing in humans, but therapeutic efficacy has yet to be established. Other clinical conditions that may respond to drugs acting on glutamatergic transmission include epilepsy, amnesia, anxiety, hyperalgesia and psychosis.

Human genome and philosophy: what ethical challenge will human genome studies bring to the medical practices in the 21st century?

PubMed

Renzong, Q

2001-12-01

A human being or person cannot be reduced to a set of human genes, or human genome. Genetic essentialism is wrong, because as a person the entity should have self-conscious and social interaction capacity which is grown in an interpersonal relationship. Genetic determinism is wrong too, the relationship between a gene and a trait is not a linear model of causation, but rather a non-linear one. Human genome is a complexity system and functions in a complexity system of human body and a complexity of systems of natural/social environment. Genetic determinism also caused the issue of how much responsibility an agent should take for her/his action, and how much degrees of freedom will a human being have. Human genome research caused several conceptual issues. Can we call a gene 'good' or 'bad', 'superior' of 'inferior'? Is a boy who is detected to have the gene of Huntington's chorea or Alzheimer disease a patient? What should the term 'eugenics' mean? What do the terms such as 'gene therapy', 'treatment' and 'enhancement' and 'human cloning' mean etc.? The research of human genome and its application caused and will cause ethical issues. Can human genome research and its application be used for eugenics, or only for the treatment and prevention of diseases? Must the principle of informed consent/choice be insisted in human genome research and its application? How to protecting gene privacy and combating the discrimination on the basis of genes? How to promote the quality between persons, harmony between ethnic groups and peace between countries? How to establish a fair, just, equal and equitable relationship between developing and developed countries in regarding to human genome research and its application?

Brain urea increase is an early Huntington's disease pathogenic event observed in a prodromal transgenic sheep model and HD cases.

PubMed

Handley, Renee R; Reid, Suzanne J; Brauning, Rudiger; Maclean, Paul; Mears, Emily R; Fourie, Imche; Patassini, Stefano; Cooper, Garth J S; Rudiger, Skye R; McLaughlan, Clive J; Verma, Paul J; Gusella, James F; MacDonald, Marcy E; Waldvogel, Henry J; Bawden, C Simon; Faull, Richard L M; Snell, Russell G

2017-12-26

The neurodegenerative disorder Huntington's disease (HD) is typically characterized by extensive loss of striatal neurons and the midlife onset of debilitating and progressive chorea, dementia, and psychological disturbance. HD is caused by a CAG repeat expansion in the Huntingtin ( HTT ) gene, translating to an elongated glutamine tract in the huntingtin protein. The pathogenic mechanism resulting in cell dysfunction and death beyond the causative mutation is not well defined. To further delineate the early molecular events in HD, we performed RNA-sequencing (RNA-seq) on striatal tissue from a cohort of 5-y-old OVT73 -line sheep expressing a human CAG-expansion HTT cDNA transgene. Our HD OVT73 sheep are a prodromal model and exhibit minimal pathology and no detectable neuronal loss. We identified significantly increased levels of the urea transporter SLC14A1 in the OVT73 striatum, along with other important osmotic regulators. Further investigation revealed elevated levels of the metabolite urea in the OVT73 striatum and cerebellum, consistent with our recently published observation of increased urea in postmortem human brain from HD cases. Extending that finding, we demonstrate that postmortem human brain urea levels are elevated in a larger cohort of HD cases, including those with low-level neuropathology (Vonsattel grade 0/1). This elevation indicates increased protein catabolism, possibly as an alternate energy source given the generalized metabolic defect in HD. Increased urea and ammonia levels due to dysregulation of the urea cycle are known to cause neurologic impairment. Taken together, our findings indicate that aberrant urea metabolism could be the primary biochemical disruption initiating neuropathogenesis in HD.

Behavioral and neurophysiological evidence for the enhancement of cognitive control under dorsal pallidal deep brain stimulation in Huntington's disease.

PubMed

Beste, Christian; Mückschel, Moritz; Elben, Saskia; J Hartmann, Christian; McIntyre, Cameron C; Saft, Carsten; Vesper, Jan; Schnitzler, Alfons; Wojtecki, Lars

2015-07-01

Deep brain stimulation of the dorsal pallidum (globus pallidus, GP) is increasingly considered as a surgical therapeutic option in Huntington's disease (HD), but there is need to identify outcome measures useful for clinical trials. Computational models consider the GP to be part of a basal ganglia network involved in cognitive processes related to the control of actions. We examined behavioural and event-related potential (ERP) correlates of action control (i.e., error monitoring) and evaluated the effects of deep brain stimulation (DBS). We did this using a standard flanker paradigm and evaluated error-related ERPs. Patients were recruited from a prospective pilot trial for pallidal DBS in HD (trial number NCT00902889). From the initial four patients with Huntington's chorea, two patients with chronic external dorsal pallidum stimulation were available for follow-up and able to perform the task. The results suggest that the external GP constitutes an important basal ganglia element not only for error processing and behavioural adaptation but for general response monitoring processes as well. Response monitoring functions were fully controllable by switching pallidal DBS stimulation on and off. When stimulation was switched off, no neurophysiological and behavioural signs of error and general performance monitoring, as reflected by the error-related negativity and post-error slowing in reaction times were evident. The modulation of response monitoring processes by GP-DBS reflects a side effect of efforts to alleviate motor symptoms in HD. From a clinical neurological perspective, the results suggest that DBS in the external GP segment can be regarded as a potentially beneficial treatment with respect to cognitive functions.

Severe Respiratory Acidosis in Status Epilepticus as a Possible Etiology of Sudden Death in Lesch-Nyhan Disease: A Case Report and Review of the Literature.

PubMed

Christy, Alison; Nyhan, William; Wilson, Jenny

2017-01-01

Lesch-Nyhan disease (LND) is an X-linked disorder of purine metabolism, associated with self-mutilation, dystonia, and chorea. Seizures are uncommon in LND. Patients with LND are at risk for sudden and unexpected death. The etiology of this is unknown, but appears to occur from a respiratory process. We propose that respiratory failure secondary to subclinical seizure may lead to sudden death in these patients. We report a case of an 11-year-old boy with LND who had two episodes of nocturnal gasping. The second event was immediately followed by a 10 min generalized seizure. Upon arrival at the hospital, an arterial blood gas test revealed a severe respiratory acidosis. Following aggressive treatment of his seizures, this patient did well, and was discharged home on oxcarbazepine with rectal diazepam. No further seizures have been noted in 1 year of follow-up. In this case report and review, we hypothesize that sudden death from respiratory failure in Lesch-Nyhan disease may in some cases be due to seizure-induced respiratory failure, akin to sudden unexpected death in epilepsy (SUDEP). We suggest screening for paroxysmal respiratory events; consideration of electroencephalography for patients with LND presenting in respiratory distress or failure; and consideration of more aggressive treatment of seizures in these patients. Brief Summary:We present an 11-year-old boy with Lesch-Nyhan disease (LND) who developed respiratory failure and severe respiratory acidosis from his first known seizure, which evolved to subclinical status epilepticus. We propose that patients with LND have a predisposition to respiratory failure and sudden death, which in some cases may be provoked by seizure (sudden unexpected death in epilepsy, or SUDEP).

Rheumatic fever & rheumatic heart disease: The last 50 years

PubMed Central

Kumar, R. Krishna; Tandon, R.

2013-01-01

Rheumatic fever (RF) and rheumatic heart disease (RHD) continue to be a major health hazard in most developing countries as well as sporadically in developed economies. Despite reservations about the utility, echocardiographic and Doppler (E&D) studies have identified a massive burden of RHD suggesting the inadequacy of the Jones’ criteria updated by the American Heart Association in 1992. Subclinical carditis has been recognized by E&D in patients with acute RF without clinical carditis as well as by follow up of RHD patients presenting as isolated chorea or those without clinical evidence of carditis. Over the years, the medical management of RF has not changed. Paediatric and juvenile mitral stenosis (MS), upto the age of 12 and 20 yr respectively, severe enough to require operative treatement was documented. These negate the belief that patients of RHD become symptomatic ≥20 years after RF as well as the fact that congestive cardiac failure in childhood indicates active carditis and RF. Non-surgical balloon mitral valvotomy for MS has been initiated. Mitral and/or aortic valve replacement during active RF in patients not responding to medical treatment has been found to be life saving as well as confirming that congestive heart failure in acute RF is due to an acute haemodynamic overload. Pathogenesis as well as susceptibility to RF continue to be elusive. Prevention of RF morbidity depends on secondary prophylaxis which cannot reduce the burden of diseases. Primary prophylaxis is not feasible in the absence of a suitable vaccine. Attempts to design an antistreptococcal vaccine utilizing the M-protein has not succeeded in the last 40 years. Besides pathogenesis many other questions remain unanswered. PMID:23703332

An item response analysis of the motor and behavioral subscales of the unified Huntington's disease rating scale in huntington disease gene expansion carriers.

PubMed

Vaccarino, Anthony L; Anderson, Karen; Borowsky, Beth; Duff, Kevin; Giuliano, Joseph; Guttman, Mark; Ho, Aileen K; Orth, Michael; Paulsen, Jane S; Sills, Terrence; van Kammen, Daniel P; Evans, Kenneth R

2011-04-01

Although the Unified Huntington's Disease Rating Scale (UHDRS) is widely used in the assessment of Huntington disease (HD), the ability of individual items to discriminate individual differences in motor or behavioral manifestations has not been extensively studied in HD gene expansion carriers without a motor-defined clinical diagnosis (ie, prodromal-HD or prHD). To elucidate the relationship between scores on individual motor and behavioral UHDRS items and total score for each subscale, a nonparametric item response analysis was performed on retrospective data from 2 multicenter longitudinal studies. Motor and behavioral assessments were supplied for 737 prHD individuals with data from 2114 visits (PREDICT-HD) and 686 HD individuals with data from 1482 visits (REGISTRY). Option characteristic curves were generated for UHDRS subscale items in relation to their subscale score. In prHD, overall severity of motor signs was low, and participants had scores of 2 or above on very few items. In HD, motor items that assessed ocular pursuit, saccade initiation, finger tapping, tandem walking, and to a lesser extent, saccade velocity, dysarthria, tongue protrusion, pronation/supination, Luria, bradykinesia, choreas, gait, and balance on the retropulsion test were found to discriminate individual differences across a broad range of motor severity. In prHD, depressed mood, anxiety, and irritable behavior demonstrated good discriminative properties. In HD, depressed mood demonstrated a good relationship with the overall behavioral score. These data suggest that at least some UHDRS items appear to have utility across a broad range of severity, although many items demonstrate problematic features. Copyright © 2011 Movement Disorder Society.

Atypical juvenile presentation of GM2 gangliosidosis AB in a patient compound-heterozygote for c.259G > T and c.164C > T mutations in the GM2A gene.

PubMed

Martins, Carla; Brunel-Guitton, Catherine; Lortie, Anne; Gauvin, France; Morales, Carlos R; Mitchell, Grant A; Pshezhetsky, Alexey V

2017-06-01

G M2 -gangliosidosis, AB variant is an extremely rare autosomal recessive inherited disorder caused by mutations in the GM2A gene that encodes G M2 ganglioside activator protein (GM2AP). GM2AP is necessary for solubilisation of G M2 ganglioside in endolysosomes and its presentation to β-hexosaminidase A. Conversely GM2AP deficiency impairs lysosomal catabolism of G M2 ganglioside, leading to its storage in cells and tissues. We describe a 9-year-old child with an unusual juvenile clinical onset of G M2 -gangliosidosis AB. At the age of 3 years he presented with global developmental delay, progressive epilepsy, intellectual disability, axial hypertonia, spasticity, seizures and ataxia, but without the macular cherry-red spots typical for G M2 gangliosidosis. Brain MRI detected a rapid onset of diffuse atrophy, whereas whole exome sequencing showed that the patient is a compound heterozygote for two mutations in GM2A : a novel nonsense mutation, c.259G > T (p.E87X) and a missense mutation c.164C > T (p.P55L) that was recently identified in homozygosity in patients of a Saudi family with a progressive chorea-dementia syndrome. Western blot analysis showed an absence of GM2AP in cultured fibroblasts from the patient, suggesting that both mutations interfere with the synthesis and/or folding of the protein. Finally, impaired catabolism of G M2 ganglioside in the patient's fibroblasts was demonstrated by metabolic labeling with fluorescently labeled G M1 ganglioside and by immunohistochemistry with anti-G M2 and anti-G M3 antibodies. Our observation expands the molecular and clinical spectrum of molecular defects linked to G M2 -gangliosidosis and suggests novel diagnostic approach by whole exome sequencing and perhaps ganglioside analysis in cultured patient's cells.

Biased Type 1 Cannabinoid Receptor Signaling Influences Neuronal Viability in a Cell Culture Model of Huntington Disease.

PubMed

Laprairie, Robert B; Bagher, Amina M; Kelly, Melanie E M; Denovan-Wright, Eileen M

2016-03-01

Huntington disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder with limited treatment options. Prior to motor symptom onset or neuronal cell loss in HD, levels of the type 1 cannabinoid receptor (CB1) decrease in the basal ganglia. Decreasing CB1 levels are strongly correlated with chorea and cognitive deficit. CB1 agonists are functionally selective (biased) for divergent signaling pathways. In this study, six cannabinoids were tested for signaling bias in in vitro models of medium spiny projection neurons expressing wild-type (STHdh(Q7/Q7)) or mutant huntingtin protein (STHdh(Q111/Q111)). Signaling bias was assessed using the Black and Leff operational model. Relative activity [ΔlogR (τ/KA)] and system bias (ΔΔlogR) were calculated relative to the reference compound WIN55,212-2 for Gαi/o, Gαs, Gαq, Gβγ, and β-arrestin1 signaling following treatment with 2-arachidonoylglycerol (2-AG), anandamide (AEA), CP55,940, Δ(9)-tetrahydrocannabinol (THC), cannabidiol (CBD), and THC+CBD (1:1), and compared between wild-type and HD cells. The Emax of Gαi/o-dependent extracellular signal-regulated kinase (ERK) signaling was 50% lower in HD cells compared with wild-type cells. 2-AG and AEA displayed Gαi/o/Gβγ bias and normalized CB1 protein levels and improved cell viability, whereas CP55,940 and THC displayed β-arrestin1 bias and reduced CB1 protein levels and cell viability in HD cells. CBD was not a CB1 agonist but inhibited THC-dependent signaling (THC+CBD). Therefore, enhancing Gαi/o-biased endocannabinoid signaling may be therapeutically beneficial in HD. In contrast, cannabinoids that are β-arrestin-biased--such as THC found at high levels in modern varieties of marijuana--may be detrimental to CB1 signaling, particularly in HD where CB1 levels are already reduced. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Influence of apolipoprotein E genotype on senile dementia of the Alzheimer and Lewy body types. Significance for etiological theories of Alzheimer's disease.

PubMed

Harrington, C R; Louwagie, J; Rossau, R; Vanmechelen, E; Perry, R H; Perry, E K; Xuereb, J H; Roth, M; Wischik, C M

1994-12-01

Alzheimer's disease (AD) is associated with an increased frequency of the apolipoprotein E type epsilon 4 allele. To address both the disease and the allele specificity of this association, we have examined the apolipoprotein E allele distribution in 255 elderly persons including those with autopsy-confirmed AD, senile dementia of the Lewy body type (SDLT), vascular dementia, Parkinson's disease (PD) or Huntington's disease and in nondemented controls either with or without coronary complications. The epsilon 4 allele frequency was increased in SDLT (0.365) and AD (0.328) as compared with controls (0.147), PD (0.098), or Huntington's chorea (0.171). Coronary disease and vascular dementia were associated with marginally higher epsilon 4 allele frequencies than in controls. In PD, amyloid beta-protein accumulated to a greater extent in those cases possessing an epsilon 4 allele than in those without. Those PD cases with dementia were not distinguished from either controls or PD cases without dementia, whether tested biochemically or by apolipoprotein E genotype. It is the comparison of the results in AD and SDLT that yielded the most significant findings. There was a 1.8-fold excess of amyloid beta-protein in AD as compared with controls, and the levels in SDLT were intermediate between those in AD and controls. In contrast, AD was discriminated from both controls and SDLT by the substantial accumulation of paired helical filament tau and phosphorylated tau (both increased more than 20-fold as compared with controls). SDLT was nevertheless characterized by an increased epsilon 4 allele frequency in the absence of significant tau pathology (at least 10-fold less than that in AD). These findings indicate that tau processing is more specifically associated with AD than is amyloid beta-protein accumulation and that presence of the epsilon 4 allele is not an etiological factor that accounts for tau pathology.

Influence of apolipoprotein E genotype on senile dementia of the Alzheimer and Lewy body types. Significance for etiological theories of Alzheimer's disease.

PubMed Central

Harrington, C. R.; Louwagie, J.; Rossau, R.; Vanmechelen, E.; Perry, R. H.; Perry, E. K.; Xuereb, J. H.; Roth, M.; Wischik, C. M.

1994-01-01

Alzheimer's disease (AD) is associated with an increased frequency of the apolipoprotein E type epsilon 4 allele. To address both the disease and the allele specificity of this association, we have examined the apolipoprotein E allele distribution in 255 elderly persons including those with autopsy-confirmed AD, senile dementia of the Lewy body type (SDLT), vascular dementia, Parkinson's disease (PD) or Huntington's disease and in nondemented controls either with or without coronary complications. The epsilon 4 allele frequency was increased in SDLT (0.365) and AD (0.328) as compared with controls (0.147), PD (0.098), or Huntington's chorea (0.171). Coronary disease and vascular dementia were associated with marginally higher epsilon 4 allele frequencies than in controls. In PD, amyloid beta-protein accumulated to a greater extent in those cases possessing an epsilon 4 allele than in those without. Those PD cases with dementia were not distinguished from either controls or PD cases without dementia, whether tested biochemically or by apolipoprotein E genotype. It is the comparison of the results in AD and SDLT that yielded the most significant findings. There was a 1.8-fold excess of amyloid beta-protein in AD as compared with controls, and the levels in SDLT were intermediate between those in AD and controls. In contrast, AD was discriminated from both controls and SDLT by the substantial accumulation of paired helical filament tau and phosphorylated tau (both increased more than 20-fold as compared with controls). SDLT was nevertheless characterized by an increased epsilon 4 allele frequency in the absence of significant tau pathology (at least 10-fold less than that in AD). These findings indicate that tau processing is more specifically associated with AD than is amyloid beta-protein accumulation and that presence of the epsilon 4 allele is not an etiological factor that accounts for tau pathology. PMID:7992850

'The Move', an innovative simulation-based medical education program using roleplay to teach neurological semiology: Students' and teachers' perceptions.

PubMed

Roze, E; Flamand-Roze, C; Méneret, A; Ruiz, M; Le Liepvre, H; Duguet, A; Renaud, M-C; Alamowitch, S; Steichen, O

2016-01-01

Neurological disorders are frequently being managed by general practitioners. It is therefore critical that future physicians become comfortable with neurological examination and physical diagnosis. Graduating medical students often consider neurological examination as one of the clinical skills they are least comfortable with, and they even tend to be neurophobic. One way to improve the learning of neurological semiology is to design innovative learner-friendly educational methods, including simulation training. The feasibility of mime-based roleplaying was tested by a simulation training program in neurological semiology called 'The Move'. The program was proposed to third-year medical students at Pierre and Marie Curie University in Paris during their neurology rotation. Students were trained to roleplay patients by miming various neurological syndromes (pyramidal, vestibular, cerebellar, parkinsonian) as well as distal axonopathy, chorea and tonic-clonic seizures. Using an anonymous self-administered questionnaire, the students' and teachers' emotional experience and views on the impact of the program were then investigated. A total of 223/365 students (61%) chose to participate in the study. Both students and teachers felt their participation was pleasant. Students stated that The Move increased their motivation to learn neurological semiology (78%), and improved both their understanding of the subject (77%) and their long-term memorization of the teaching content (86%). Although only a minority thought The Move was likely to improve their performance on their final medical examination (32%), a clear majority (77%) thought it would be useful for their future clinical practice. Both students (87%) and teachers (95%) thought The Move should be included in the medical curriculum. Mime-based roleplaying simulation may be a valuable tool for training medical students in neurological semiology, and may also help them to overcome neurophobia. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Behavioral characterization of mouse models of neuroferritinopathy.

PubMed

Capoccia, Sara; Maccarinelli, Federica; Buffoli, Barbara; Rodella, Luigi F; Cremona, Ottavio; Arosio, Paolo; Cirulli, Francesca

2015-01-01

Ferritin is the main intracellular protein of iron storage with a central role in the regulation of iron metabolism and detoxification. Nucleotide insertions in the last exon of the ferritin light chain cause a neurodegenerative disease known as Neuroferritinopathy, characterized by iron deposition in the brain, particularly in the cerebellum, basal ganglia and motor cortex. The disease progresses relentlessly, leading to dystonia, chorea, motor disability and neuropsychiatry features. The characterization of a good animal model is required to compare and contrast specific features with the human disease, in order to gain new insights on the consequences of chronic iron overload on brain function and behavior. To this aim we studied an animal model expressing the pathogenic human FTL mutant 498InsTC under the phosphoglycerate kinase (PGK) promoter. Transgenic (Tg) mice showed strong accumulation of the mutated protein in the brain, which increased with age, and this was accompanied by brain accumulation of ferritin/iron bodies, the main pathologic hallmark of human neuroferritinopathy. Tg-mice were tested throughout development and aging at 2-, 8- and 18-months for motor coordination and balance (Beam Walking and Footprint tests). The Tg-mice showed a significant decrease in motor coordination at 8 and 18 months of age, with a shorter latency to fall and abnormal gait. Furthermore, one group of aged naïve subjects was challenged with two herbicides (Paraquat and Maneb) known to cause oxidative damage. The treatment led to a paradoxical increase in behavioral activation in the transgenic mice, suggestive of altered functioning of the dopaminergic system. Overall, data indicate that mice carrying the pathogenic FTL498InsTC mutation show motor deficits with a developmental profile suggestive of a progressive pathology, as in the human disease. These mice could be a powerful tool to study the neurodegenerative mechanisms leading to the disease and help developing specific therapeutic targets.

Behavioral Characterization of Mouse Models of Neuroferritinopathy

PubMed Central

Buffoli, Barbara; Rodella, Luigi F.; Cremona, Ottavio; Arosio, Paolo; Cirulli, Francesca

2015-01-01

Ferritin is the main intracellular protein of iron storage with a central role in the regulation of iron metabolism and detoxification. Nucleotide insertions in the last exon of the ferritin light chain cause a neurodegenerative disease known as Neuroferritinopathy, characterized by iron deposition in the brain, particularly in the cerebellum, basal ganglia and motor cortex. The disease progresses relentlessly, leading to dystonia, chorea, motor disability and neuropsychiatry features. The characterization of a good animal model is required to compare and contrast specific features with the human disease, in order to gain new insights on the consequences of chronic iron overload on brain function and behavior. To this aim we studied an animal model expressing the pathogenic human FTL mutant 498InsTC under the phosphoglycerate kinase (PGK) promoter. Transgenic (Tg) mice showed strong accumulation of the mutated protein in the brain, which increased with age, and this was accompanied by brain accumulation of ferritin/iron bodies, the main pathologic hallmark of human neuroferritinopathy. Tg-mice were tested throughout development and aging at 2-, 8- and 18-months for motor coordination and balance (Beam Walking and Footprint tests). The Tg-mice showed a significant decrease in motor coordination at 8 and 18 months of age, with a shorter latency to fall and abnormal gait. Furthermore, one group of aged naïve subjects was challenged with two herbicides (Paraquat and Maneb) known to cause oxidative damage. The treatment led to a paradoxical increase in behavioral activation in the transgenic mice, suggestive of altered functioning of the dopaminergic system. Overall, data indicate that mice carrying the pathogenic FTL498InsTC mutation show motor deficits with a developmental profile suggestive of a progressive pathology, as in the human disease. These mice could be a powerful tool to study the neurodegenerative mechanisms leading to the disease and help developing specific therapeutic targets. PMID:25689865

Delayed-onset progressive movement disorders after static brain lesions.

PubMed

Scott, B L; Jankovic, J

1996-01-01

We studied 53 patients (64% females) with static brain lesions who developed progressive movement disorders. Of these, 50 (94%) had dystonia, 17 (32%) tremor, eight (15%) parkinsonism, seven (13%) myoclonus, and three (6%) chorea. The precipitating insults included perinatal hypoxia/ischemia in 22 (42%), stroke in 12 (23%), head injury in eight (15%), encephalitis in eight (15%), and carbon monoxide poisoning, kernicterus, and radiation necrosis in one patient (2%) each. Among the 30 patients with initial insult occurring at age 2 years or younger (Infant group), distribution of dystonia at follow-up was focal in three (10%), segmental in eight (27%), unilateral in 10 (33%), and generalized in nine (30%). The mean latency between the original injury and onset of movement disorder was 25.5 +/- 16.7 years. Among the nine patients who developed dystonia after an insult occurring between ages 6 and 17 (Childhood group), the distribution of dystonia at follow-up was segmental in two (33%) and unilateral in seven (78%); the mean latency of dystonia onset was 4.9 +/- 7.8 years. Of the 14 patients in the Adult group (injury at age 25 or older), 11 developed dystonia, two developed parkinsonism, and one had carbon monoxide encephalopathy and parkinsonism. The distribution of dystonia in the 11 patients at follow-up was segmental in three (27%) and unilateral in eight (73%). The mean latency of movement disorder onset in the 14 patients of the Adult group was 2.5 +/- 4.9 years. No individuals in the Childhood or Adult groups became left-hand dominant; by comparison, nine of the 30 individuals in the Infant group became left-handed. In conclusion, brain injury at a young age is associated with a longer latency to onset of subsequent movement disorder, a greater tendency to development of generalized dystonia, and a greater probability of altered handedness. These tendencies may result from differences in age-related neuroplasticity.

Reversal Learning and Associative Memory Impairments in a BACHD Rat Model for Huntington Disease

PubMed Central

Abada, Yah-se K.; Nguyen, Huu Phuc; Ellenbroek, Bart; Schreiber, Rudy

2013-01-01

Chorea and psychiatric symptoms are hallmarks of Huntington disease (HD), a neurodegenerative disorder, genetically characterized by the presence of expanded CAG repeats (>35) in the HUNTINGTIN (HTT) gene. HD patients present psychiatric symptoms prior to the onset of motor symptoms and we recently found a similar emergence of non motor and motor deficits in BACHD rats carrying the human full length mutated HTT (97 CAG-CAA repeats). We evaluated cognitive performance in reversal learning and associative memory tests in different age cohorts of BACHD rats. Male wild type (WT) and transgenic (TG) rats between 2 and 12 months of age were tested. Learning and strategy shifting were assessed in a cross-maze test. Associative memory was evaluated in different fear conditioning paradigms (context, delay and trace). The possible confound of a fear conditioning phenotype by altered sensitivity to a ‘painful’ stimulus was assessed in a flinch-jump test. In the cross maze, 6 months old TG rats showed a mild impairment in reversal learning. In the fear conditioning tasks, 4, 6 and 12 months old TG rats showed a marked reduction in contextual fear conditioning. In addition, TG rats showed impaired delay conditioning (9 months) and trace fear conditioning (3 months). This phenotype was unlikely to be affected by a change in ‘pain’ sensitivity as WT and TG rats showed no difference in their threshold response in the flinch-jump test. Our results suggest that BACHD rats have a profound associative memory deficit and, possibly, a deficit in reversal learning as assessed in a cross maze task. The time course for the emergence of these symptoms (i.e., before the occurrence of motor symptoms) in this rat model for HD appears similar to the time course in patients. These data suggest that BACHD rats may be a useful model for preclinical drug discovery. PMID:24223692

Novel mutations in PANK2 and PLA2G6 genes in patients with neurodegenerative disorders: two case reports.

PubMed

Dastsooz, Hassan; Nemati, Hamid; Fard, Mohammad Ali Farazi; Fardaei, Majid; Faghihi, Mohammad Ali

2017-08-18

Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous group of disorders associated with progressive impairment of movement, vision, and cognition. The disease is initially diagnosed on the basis of changes in brain magnetic resonance imaging which indicate an abnormal brain iron accumulation in the basal ganglia. However, the diagnosis of specific types should be based on both clinical findings and molecular genetic testing for genes associated with different types of NBIA, including PANK2, PLA2G6, C19orf12, FA2H, ATP13A2, WDR45, COASY, FTL, CP, and DCAF17. The purpose of this study was to investigate disease-causing mutations in two patients with distinct NBIA disorders. Whole Exome sequencing using Next Generation Illumina Sequencing was used to enrich all exons of protein-coding genes as well as some other important genomic regions in these two affected patients. A deleterious homozygous four-nucleotide deletion causing frameshift deletion in PANK2 gene (c.1426_1429delATGA, p.M476 fs) was identified in an 8 years old girl with dystonia, bone fracture, muscle rigidity, abnormal movement, lack of coordination and chorea. In addition, our study revealed a novel missense mutation in PLA2G6 gene (c.3G > T:p.M1I) in one and half-year-old boy with muscle weakness and neurodevelopmental regression (speech, motor and cognition). The novel mutations were also confirmed by Sanger sequencing in the proband and their parents. Current study uncovered two rare novel mutations in PANK2 and PLA2G6 genes in patients with NBIA disorder and such studies may help to conduct genetic counseling and prenatal diagnosis more accurately for individuals at the high risk of these types of disorders.

Enhanced retinal responses in Huntington's disease patients.

PubMed

Pearl, Jocelynn R; Heath, Laura M; Bergey, Dani E; Kelly, John P; Smith, Corrie; Laurino, Mercy Y; Weiss, Avery; Price, Nathan D; LaSpada, Albert; Bird, Thomas D; Jayadev, Suman

2017-01-01

Huntington's disease (HD) is a fatal progressive neurodegenerative disease characterized by chorea, cognitive impairment and psychiatric symptoms. Retinal examination of HD patients as well as in HD animal models have shown evidence of retinal dysfunction. However, a detailed retinal study employing clinically available measurement tools has not been reported to date in HD. The goal of this study was to assess retinal responses measured by electroretinogram (ERG) between HD patients and controls and evaluate any correlation between ERG measurements and stage of disease. Eighteen patients and 10 controls with inclusion criteria of ages 18-70 years (average age HD subjects: 52.1 yrs and control subjects: 51.9 yrs) were recruited for the study. Subjects with previous history of retinal or ophthalmologic disease were excluded. Retinal function was examined by full-field ERG in both eyes of each subject. Amplitudes and latencies to increasing flash intensities in both light- and dark-adaptation were measured in all subjects. Statistical analyses employed generalized estimating equations, which account for repeated measures per subject. We analyzed the b-wave amplitudes of ERG response in all flash intensities and with 30 Hz flicker stimulation. We found statistically significant increased amplitudes in HD patients compared to controls at light-adapted (photopic) 24.2 and 60.9 cd.sec/m2 intensities, dark-adapted (scotopic, red flash) 0.22 cd.sec/m2 intensity, and a trend toward significance at light-adapted 30 Hz flicker. Furthermore, we found a significant increase in light-adapted ERG response from female compared to male HD patients, but no significant difference between gender amongst controls. We also noted a positive association between number of CAG repeats and ERG response at the smallest light adapted intensity (3.1 cd.sec/m2). ERG studies revealed significantly altered retinal responses at multiple flash intensities in subjects with an HD expansion allele compared to controls. Significant differences were observed with either light-adapted tests or the dark-adapted red flash which suggests that the enhanced responses in HD patients is specific to the cone photoreceptor pathway.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): An Evolving Concept

PubMed Central

Macerollo, Antonella; Martino, Davide

2013-01-01

Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS) originated from the observational work of Swedo and collaborators, who formalized their definition in 1998 in a set of operational criteria. The application of these criteria, which focuses on tics and obsessive-compulsive symptoms as core symptoms, has encountered difficulties, eventually leading to a high rate of misdiagnosis. In particular, the core feature represented by the association between newly diagnosed infections and neuropsychiatric symptom relapses in youths with this diagnosis could not be demonstrated by longitudinal studies. Exploratory studies aiming to identify clinical or cognitive features that could discriminate PANDAS from other pediatric obsessive-compulsive and tic disorders present methodological limitations, and therefore are not conclusive. Other behavioral features, in addition to obsessive-compulsive symptoms and tics, have been included in pediatric acute-onset neuropsychiatric syndromes (PANS) and childhood acute neuropsychiatric syndromes (CANS), two new concepts recently proposed in order to define a much broader clinical spectrum encompassing etiologically diverse entities. Given the uncertainties on the clinical definition of PANDAS, it is not surprising that evidence in support of a post-infectious, immune-mediated pathophysiology is also insufficient. Anti-dopamine receptor antibodies might be relevant to both Sydenham’s chorea (SC)—the prototypical post-streptococcal neuropsychiatric disorder—and some rare forms of encephalitis targeting the basal ganglia specifically, but studies exploring their association with children fulfilling Swedo’s criteria for PANDAS have been inconclusive. Moreover, we lack evidence in favor of the efficacy of antibiotic prophylaxis or tonsillectomy in patients fulfilling Swedo’s criteria for PANDAS, whereas a response to immune-mediated treatments like intravenous immunoglobulins has been documented by one study, but needs replication in larger trials. Overall, the available evidence does not convincingly support the concept that PANDAS are a well-defined, isolated clinical entity subdued by definite pathophysiological mechanisms; larger, prospective studies are necessary to reshape the nosography and disease mechanisms of post-streptococcal acute neuropsychiatric disorders other than SC. Research is also under way to shed further light on a possible relationship between streptococcal infections, other biological and psychosocial stressors, and the complex pathobiology of chronic tic disorders. PMID:24106651

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): An Evolving Concept.

PubMed

Macerollo, Antonella; Martino, Davide

2013-01-01

Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS) originated from the observational work of Swedo and collaborators, who formalized their definition in 1998 in a set of operational criteria. The application of these criteria, which focuses on tics and obsessive-compulsive symptoms as core symptoms, has encountered difficulties, eventually leading to a high rate of misdiagnosis. In particular, the core feature represented by the association between newly diagnosed infections and neuropsychiatric symptom relapses in youths with this diagnosis could not be demonstrated by longitudinal studies. Exploratory studies aiming to identify clinical or cognitive features that could discriminate PANDAS from other pediatric obsessive-compulsive and tic disorders present methodological limitations, and therefore are not conclusive. Other behavioral features, in addition to obsessive-compulsive symptoms and tics, have been included in pediatric acute-onset neuropsychiatric syndromes (PANS) and childhood acute neuropsychiatric syndromes (CANS), two new concepts recently proposed in order to define a much broader clinical spectrum encompassing etiologically diverse entities. Given the uncertainties on the clinical definition of PANDAS, it is not surprising that evidence in support of a post-infectious, immune-mediated pathophysiology is also insufficient. Anti-dopamine receptor antibodies might be relevant to both Sydenham's chorea (SC)-the prototypical post-streptococcal neuropsychiatric disorder-and some rare forms of encephalitis targeting the basal ganglia specifically, but studies exploring their association with children fulfilling Swedo's criteria for PANDAS have been inconclusive. Moreover, we lack evidence in favor of the efficacy of antibiotic prophylaxis or tonsillectomy in patients fulfilling Swedo's criteria for PANDAS, whereas a response to immune-mediated treatments like intravenous immunoglobulins has been documented by one study, but needs replication in larger trials. Overall, the available evidence does not convincingly support the concept that PANDAS are a well-defined, isolated clinical entity subdued by definite pathophysiological mechanisms; larger, prospective studies are necessary to reshape the nosography and disease mechanisms of post-streptococcal acute neuropsychiatric disorders other than SC. Research is also under way to shed further light on a possible relationship between streptococcal infections, other biological and psychosocial stressors, and the complex pathobiology of chronic tic disorders.

Cannabinoids: novel medicines for the treatment of Huntington's disease.

PubMed

Sagredo, Onintza; Pazos, M Ruth; Valdeolivas, Sara; Fernandez-Ruiz, Javier

2012-04-01

Cannabinoid pharmacology has experienced a notable increase in the last 3 decades which is allowing the development of novel cannabinoid-based medicines for the treatment of different human pathologies, for example, Cesamet® (nabilone) or Marinol® (synthetic Δ9-tetrahydrocannabinol for oral administration) that were approved in 80s for the treatment of nausea and vomiting associated with chemotherapy treatment in cancer patients and in 90s for anorexiacachexia associated with AIDS therapy. Recently, the british company GW Pharmaceuticals plc has developed an oromucosal spray called Sativex®, which is constituted by an equimolecular combination of Δ9-tetrahydrocannabinol- and cannabidiol- enriched botanical extracts. Sativex® has been approved for the treatment of specific symptoms (i.e. spasticity and pain) of multiple sclerosis patients in various countries (i.e. Canada, UK, Spain, New Zealand). However, this cannabis- based medicine has been also proposed to be useful in other neurological disorders given the analgesic, antitumoral, anti-inflammatory, and neuroprotective properties of their components demonstrated in preclinical models. Numerous clinical trials are presently being conducted to confirm this potential in patients. We are particularly interested in the case of Huntington's disease (HD), an autosomal-dominant inherited disorder caused by an excess of CAG repeats in the genomic allele resulting in a polyQ expansion in the encoded protein called huntingtin, and that affects primarily striatal and cortical neurons thus producing motor abnormalities (i.e. chorea) and dementia. Cannabinoids have been studied for alleviation of hyperkinetic symptoms, given their inhibitory effects on movement, and, in particular, as disease-modifying agents due to their anti-inflammatory, neuroprotective and neuroregenerative properties. This potential has been corroborated in different experimental models of HD and using different types of cannabinoid agonists, including the phytocannabinoids present in Sativex®, and we are close to initiate a clinical trial with this cannabis-based medicine to evaluate its capability as a disease-modifying agent in a population of HD patients. The present review will address all preclinical evidence supporting the potential of Sativex® for the treatment of disease progression in HD patients. The article presents some promising patents on the cannabinoids.

Molecular Imaging Markers to Track Huntington's Disease Pathology.

PubMed

Wilson, Heather; De Micco, Rosa; Niccolini, Flavia; Politis, Marios

2017-01-01

Huntington's disease (HD) is a progressive, monogenic dominant neurodegenerative disorder caused by repeat expansion mutation in the huntingtin gene. The accumulation of mutant huntingtin protein, forming intranuclear inclusions, subsequently leads to degeneration of medium spiny neurons in the striatum and cortical areas. Genetic testing can identify HD gene carriers before individuals develop overt cognitive, psychiatric, and chorea symptoms. Thus, HD gene carriers can be studied in premanifest stages to understand and track the evolution of HD pathology. While advances have been made, the precise pathophysiological mechanisms underlying HD are unclear. Magnetic resonance imaging (MRI) and positron emission tomography (PET) have been employed to understand HD pathology in presymptomatic and symptomatic disease stages. PET imaging uses radioactive tracers to detect specific changes, at a molecular level, which could be used as markers of HD progression and to monitor response to therapeutic treatments for HD gene expansion carriers (HDGECs). This review focuses on available PET techniques, employed in cross-sectional and longitudinal human studies, as biomarkers for HD, and highlights future potential PET targets. PET studies have assessed changes in postsynaptic dopaminergic receptors, brain metabolism, microglial activation, and recently phosphodiesterase 10A (PDE10A) as markers to track HD progression. Alterations in PDE10A expression are the earliest biochemical change identified in HD gene carriers up to 43 years before predicted symptomatic onset. Thus, PDE10A expression could be a promising marker to track HD progression from early premanifest disease stages. Other PET targets which have been less well investigated as biomarkers include cannabinoid, adenosine, and GABA receptors. Future longitudinal studies are required to fully validate these PET biomarkers for use to track disease progression from far-onset premanifest to manifest HD stages. PET imaging is a crucial neuroimaging tool, with the potential to detect early changes and validate sensitivity of biomarkers for tracking HD pathology. Moreover, continued development of novel PET tracers provides exciting opportunities to investigate new molecular targets, such as histamine and serotonin receptors, to further understand the mechanisms underlying HD pathology.

Survey of the Huntington's Disease Patient and Caregiver Community Reveals Most Impactful Symptoms and Treatment Needs.

PubMed

Simpson, Jennifer A; Lovecky, Debra; Kogan, Jane; Vetter, Louise A; Yohrling, George J

2016-12-15

In preparation for a meeting with the U.S. Food and Drug Administration (FDA) on Patient-Focused Drug Development in Huntington's disease, the Huntington's Disease Society of America (HDSA) created and distributed two comprehensive surveys on the symptom experience and treatment approaches for Huntington's disease. The objective of these surveys was to identify the specific symptoms that most impact the daily lives of individuals with Huntington's disease/Juvenile Huntington's disease (HD/JHD) and their caregivers and to solicit input on the types of treatments desired by HD affected families. The data were shared with the FDA to offer background and insight in preparation for the patient-focused meeting, as well as to ensure representation by the community in a manner that would complement those who attended in person. Two distinct surveys were created using SurveyMonkey to capture patient and caregiver perspectives on HD symptoms and current treatments. HDSA distributed the surveys to the HD community in August and September 2014 and collected responses through January 2015. More than 3,600 responses to the two surveys were received. The data showed that both caregivers and individuals with HD were severely impacted by the cognitive and behavioral symptoms of HD with HD patients reporting problems with executive functioning and cognitive decline as most impactful to them. However, 30 percent of caregivers reported that chorea was the most impactful symptom compared to 17 percent of people with HD. Across all the symptom categories, patients reported a lower occurrence of symptoms than were reported by their caregivers. With only one drug approved for treatment of a symptom of Huntington's disease and no disease modifying treatments available, there is a critical need for new medicines to treat the cognitive, psychiatric and motor symptoms associated with HD. While the surveys did not capture risk/benefit data, the data collected do provide new insights around the different perspectives of patients and caregivers. We believe that industry development of treatments would be well-informed by incorporating the patient community, which is more knowledgeable and engaged than given credit, in consideration of treatment regimens, risk-benefit and priorities for therapeutic development.

Alliteration in medicine: a puzzling profusion of p's

PubMed Central

Hayden, Gregory F

1999-01-01

Problem Puzzling, progressive profusion of alliterative “p's” in published papers. Purpose To depict this particular “p” predominance with pinpoint precision. Plan Periodic, painstaking perusal of periodicals by a professor of paediatrics. Proposal The “p” plethora is positively perplexing and potentially perturbing. Alliteration is a literary device consisting of repetition of the same starting sound in several words in a sentence.1 Consider, for example, Shakespeare's playful parody of alliteration in Peter Quince's prologue in A Midsummer Night's Dream: “Whereat with blade, with bloody blameful blade, He bravely broach'd his boiling bloody breast.” Alliteration has appeared frequently in the medical literature—for example: “Respiratory syncytial virus—from chimps with colds to conundrums and cures;”2 “The choreas: of faints, fevers, and families;”3 “Coronary artery stents—gauging, gorging, and gouging;”4 “Moschcowitz, multimers, and metalloprotease;”5 “Alagille syndrome: a nutritional niche for Notch;”6 “Theodor Billroth: success with sutures and strings.”7 Perusing the medical literature with alliteration in mind, I have become perplexed by a peculiar propensity for the letter “p” to be placed in prominent positions. Consider for a moment the alliterative content of the BMJ, a prestigious periodical also published in Pakistani, Polish, and Portuguese. Perhaps the prime example is a piece entitled “A potpourri of parasites in poetry and proverb,”8 but the journal has presented articles addressing such topics as paracetamol poisoning,9 practitioners' pressure to prescribe,10 physicians' partnerships with patients,11 partnerships for prevention in public playgrounds,12 and pregnancy outcomes which have been persistently poor.13 Other topics have included patients' priorities,14 the political process of puzzling out private versus public priorities,15 and the ponderous problem of whether the priorities in apportioning resources should be primarily pragmatic or principally principled.16 In pursuing this plethora of “p” further, it becomes apparent that this predominance extends past paper titles to many other aspects of medicine. The purpose of this paper is to point this puzzling phenomenon of “p” profusion to the attention of practising physicians. PMID:10600957

Antineuronal antibodies in a heterogeneous group of youth and young adults with tics and obsessive-compulsive disorder.

PubMed

Cox, Carol J; Zuccolo, Amir J; Edwards, Erica V; Mascaro-Blanco, Adita; Alvarez, Kathy; Stoner, Julie; Chang, Kiki; Cunningham, Madeleine W

2015-02-01

Antineuronal antibodies have been implicated in tic and obsessive compulsive disorders (OCD) associated with group A streptococcal infections. We investigated antineuronal autoantibody levels as well as antibody-mediated neuronal cell signaling activity, as previously reported for Sydenham chorea and pediatric autoimmune neuropsychiatric disorder associated with streptococci (PANDAS), to determine immunological profiles for a large cohort of children with tics and/or OCD. Study participants (n=311; ages 4-27 years, 66% male) were selected from a larger group of individuals with self-reported neuropsychiatric symptoms (n=742) and included only those with accurate knowledge of group A streptococcal infection status, except for four individuals in whom streptococcal infection status was unknown. Healthy control samples (n=16; ages 5-14 years, 81% male), came from the National Institute of Mental Health and Yale University. In addition to serum donations, participants and/or legal guardians provided neuropsychiatric and related medical histories of symptoms that had lasted >1 year. Antineuronal immunoglobulin G (IgG) titers were measured by standard enzyme-linked immunosorbent assay (ELISA) and compared with mean titers of normal age-matched sera against lysoganglioside, tubulin, and dopamine receptors (D1R and D2R). Antibody-mediated signaling of calcium calmodulin dependent protein kinase II (CaMKII) activity in a human neuronal cell line (SK-N-SH) was tested in serum. Of 311 individuals, 222 (71%) had evidence of group A streptococcal infection, which was associated with tics and/or OCD status (p=0.0087). Sera from individuals with tics and/or OCD (n=261) had evidence of elevated serum IgG antibodies against human D1R (p<0.0001) and lysoganglioside (p=0.0001), and higher serum activation of CaMKII activity (p<0.0001) in a human neuronal cell line compared with healthy controls (n=16). Furthermore, patients with tics and OCD had significantly increased activation of CaMKII activity compared with patients with only tics or only OCD (p<0.033 for each). Our study suggested a significant correlation of streptococcal-associated tics and OCD with elevated anti-D1R and antilysoganglioside antineuronal antibodies in serum concomitant with higher activation of CaMKII in human neuronal cells. Youth and young adults with chronic tics and OCD may have underlying infectious/immunologic etiology.

Antineuronal Antibodies in a Heterogeneous Group of Youth and Young Adults with Tics and Obsessive-Compulsive Disorder

PubMed Central

Cox, Carol J.; Zuccolo, Amir J.; Edwards, Erica V.; Mascaro-Blanco, Adita; Alvarez, Kathy; Stoner, Julie; Chang, Kiki

2015-01-01

Abstract Background and objective: Antineuronal antibodies have been implicated in tic and obsessive compulsive disorders (OCD) associated with group A streptococcal infections. We investigated antineuronal autoantibody levels as well as antibody-mediated neuronal cell signaling activity, as previously reported for Sydenham chorea and pediatric autoimmune neuropsychiatric disorder associated with streptococci (PANDAS), to determine immunological profiles for a large cohort of children with tics and/or OCD. Methods: Study participants (n=311; ages 4–27 years, 66% male) were selected from a larger group of individuals with self-reported neuropsychiatric symptoms (n=742) and included only those with accurate knowledge of group A streptococcal infection status, except for four individuals in whom streptococcal infection status was unknown. Healthy control samples (n=16; ages 5–14 years, 81% male), came from the National Institute of Mental Health and Yale University. In addition to serum donations, participants and/or legal guardians provided neuropsychiatric and related medical histories of symptoms that had lasted >1 year. Antineuronal immunoglobulin G (IgG) titers were measured by standard enzyme-linked immunosorbent assay (ELISA) and compared with mean titers of normal age-matched sera against lysoganglioside, tubulin, and dopamine receptors (D1R and D2R). Antibody-mediated signaling of calcium calmodulin dependent protein kinase II (CaMKII) activity in a human neuronal cell line (SK-N-SH) was tested in serum. Results: Of 311 individuals, 222 (71%) had evidence of group A streptococcal infection, which was associated with tics and/or OCD status (p=0.0087). Sera from individuals with tics and/or OCD (n=261) had evidence of elevated serum IgG antibodies against human D1R (p<0.0001) and lysoganglioside (p=0.0001), and higher serum activation of CaMKII activity (p<0.0001) in a human neuronal cell line compared with healthy controls (n=16). Furthermore, patients with tics and OCD had significantly increased activation of CaMKII activity compared with patients with only tics or only OCD (p<0.033 for each). Conclusion: Our study suggested a significant correlation of streptococcal-associated tics and OCD with elevated anti-D1R and antilysoganglioside antineuronal antibodies in serum concomitant with higher activation of CaMKII in human neuronal cells. Youth and young adults with chronic tics and OCD may have underlying infectious/immunologic etiology. PMID:25658702

Therapeutic Plasma Apheresis as a Treatment for 35 Severely Ill Children and Adolescents with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections

PubMed Central

Latimer, M. Elizabeth; L'Etoile, Nathan; Seidlitz, Jakob

2015-01-01

Abstract Background: Because of its reported similarities to Sydenham chorea, therapeutic plasma apheresis (TPA) has been proposed as a potential treatment of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). To date, support for the use of TPA has been limited to a few anecdotal reports and a small placebo-controlled trial demonstrating dramatic symptom improvements at 1 month and 1 year follow-up. To evaluate the safety and efficacy of TPA further, we undertook a retrospective review of all PANDAS patients treated with TPA at Georgetown University Hospital between August 2009 and October 2013. Methods: Forty patients were identified, and sufficient information was available from medical records and telephone interview for 35 cases (88%). All 35 (23 boys; 12 girls) met diagnostic criteria for PANDAS (Swedo et al. 1998) and had severe symptoms. The TPA procedures were performed at Georgetown University Hospital using a protocol that processes a total of 4.5 blood volumes over 3–5 days (three treatments of 1.5 volumes each). Overall symptom improvements at 6 months post-TPA and long-term follow-up were estimated by parents, who also rated changes in individual symptoms to provide information about patterns of improvement. Results: All patients were reported to have received at least some benefit from TPA, with average improvement of 65% at 6 months post-TPA and 78% at longer-term follow-up. A decrease in the number of reported symptoms also occurred, with particular improvements in obsessive-compulsive disorder (OCD), anxiety, tics, and somatic symptoms, including dysgraphia, sleep difficulties, and urinary urgency or frequency. Contrary to expectations, preceding duration of illness was not correlated with degree of improvement following TPA, suggesting that acuity of illness is not a factor affecting response. Only two adverse events were reported: both involved reopening of the site where the central line had been placed and resolved immediately following application of pressure and re-dressing of the puncture site. Conclusions: Therapeutic plasma apheresis is an invasive medical intervention that should be reserved for treatment of children and adolescents who are severely affected by PANDAS. In such patients, it appears to be a safe, well-tolerated, and beneficial treatment option. PMID:25658452

Therapeutic plasma apheresis as a treatment for 35 severely ill children and adolescents with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.

PubMed

Latimer, M Elizabeth; L'Etoile, Nathan; Seidlitz, Jakob; Swedo, Susan E

2015-02-01

Because of its reported similarities to Sydenham chorea, therapeutic plasma apheresis (TPA) has been proposed as a potential treatment of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). To date, support for the use of TPA has been limited to a few anecdotal reports and a small placebo-controlled trial demonstrating dramatic symptom improvements at 1 month and 1 year follow-up. To evaluate the safety and efficacy of TPA further, we undertook a retrospective review of all PANDAS patients treated with TPA at Georgetown University Hospital between August 2009 and October 2013. Forty patients were identified, and sufficient information was available from medical records and telephone interview for 35 cases (88%). All 35 (23 boys; 12 girls) met diagnostic criteria for PANDAS (Swedo et al. 1998 ) and had severe symptoms. The TPA procedures were performed at Georgetown University Hospital using a protocol that processes a total of 4.5 blood volumes over 3-5 days (three treatments of 1.5 volumes each). Overall symptom improvements at 6 months post-TPA and long-term follow-up were estimated by parents, who also rated changes in individual symptoms to provide information about patterns of improvement. All patients were reported to have received at least some benefit from TPA, with average improvement of 65% at 6 months post-TPA and 78% at longer-term follow-up. A decrease in the number of reported symptoms also occurred, with particular improvements in obsessive-compulsive disorder (OCD), anxiety, tics, and somatic symptoms, including dysgraphia, sleep difficulties, and urinary urgency or frequency. Contrary to expectations, preceding duration of illness was not correlated with degree of improvement following TPA, suggesting that acuity of illness is not a factor affecting response. Only two adverse events were reported: both involved reopening of the site where the central line had been placed and resolved immediately following application of pressure and re-dressing of the puncture site. Therapeutic plasma apheresis is an invasive medical intervention that should be reserved for treatment of children and adolescents who are severely affected by PANDAS. In such patients, it appears to be a safe, well-tolerated, and beneficial treatment option.

Editing for an AMPA receptor subunit RNA in prefrontal cortex and striatum in Alzheimer's disease, Huntington's disease and schizophrenia

NASA Technical Reports Server (NTRS)

Akbarian, S.; Smith, M. A.; Jones, E. G.; Bloom, F. E. (Principal Investigator)

1995-01-01

Animal studies and cell culture experiments demonstrated that posttranscriptional editing of the transcript of the GluR-2 gene, resulting in substitution of an arginine for glutamine in the second transmembrane region (TM II) of the expressed protein, is associated with a reduction in Ca2+ permeability of the receptor channel. Thus, disturbances in GluR-2 RNA editing with alteration of intracellular Ca2+ homeostasis could lead to neuronal dysfunction and even neuronal degeneration. The present study determined the proportions of edited and unedited GluR-2 RNA in the prefrontal cortex of brains from patients with Alzheimer's disease, in the striatum of brains from patients with Huntington's disease, and in the same areas of brains from age-matched schizophrenics and controls, by using reverse transcriptase-polymerase chain reaction, restriction endonuclease digestion, gel electrophoresis and scintillation radiometry. In the prefrontal cortex of controls, < 0.1% of all GluR-2 RNA molecules were unedited and > 99.9% were edited; in the prefrontal cortex both of schizophrenics and of Alzheimer's patients approximately 1.0% of all GluR-2 RNA molecules were unedited and 99% were edited. In the striatum of controls and of schizophrenics, approximately 0.5% of GluR-2 RNA molecules were unedited and 99.5% were edited; in the striatum of Huntington's patients nearly 5.0% of GluR-2 RNA was unedited. In the prefrontal white matter of controls, approximately 7.0% of GluR-2 RNA was unedited. In the normal human prefrontal cortex and striatum, the large majority of GluR-2 RNA molecules contains a CGG codon for arginine in the TMII coding region; this implies that the corresponding AMPA receptors have a low Ca2+ permeability, as previously demonstrated for the rat brain. The process of GluR-2 RNA editing is compromised in a region-specific manner in schizophrenia, in Alzheimer's disease and Huntington's Chorea although in each of these disorders there is still a large excess of edited GluR-2 RNA molecules. Disturbances of GluR-2 RNA editing leading to excessive Ca2+ permeability, may contribute to neuronal dysfunction in schizophrenia and to neuronal death in Alzheimer's disease and Huntington's disease.

Clinical, Genetic, and Radiological Features of Extrapyramidal Movement Disorders in Mitochondrial Disease.

PubMed

Martikainen, Mika H; Ng, Yi Shiau; Gorman, Gráinne S; Alston, Charlotte L; Blakely, Emma L; Schaefer, Andrew M; Chinnery, Patrick F; Burn, David J; Taylor, Robert W; McFarland, Robert; Turnbull, Doug M

2016-06-01

Extrapyramidal movement disorders associated with mitochondrial disease are difficult to treat and can lead to considerable disability. Moreover, potential new treatment trials on the horizon highlight the importance of genotype-phenotype associations and deep phenotyping of the movement disorders related to mitochondrial disease. To describe the phenotype, genetic etiology, and investigation of extrapyramidal movement disorders in a large and well-defined mitochondrial disease cohort. An observational cohort study at a single national referral center. Among 678 patients (87% adults) followed up at the Newcastle mitochondrial disease specialized referral center between January 1, 2000, and January 31, 2015, 42 patients (12 pediatric, 30 adult) with genetic or biochemical evidence of mitochondrial disease and with 1 or more predefined extrapyramidal movement disorders (parkinsonism, dystonia, tremor, chorea, and restless legs syndrome) were included. We investigated the prevalence and genetic causes of dystonia and parkinsonism as well as radiological findings in the context of movement disorders in mitochondrial disease. All patients were interviewed and examined. All available medical notes and clinical, radiological, and genetic investigations were reviewed. Forty-two patients (mean [SD] age, 37 [25] years; 38% female) with mitochondrial disease (12 pediatric [age range, 4-14 years], 30 adult [age range, 20-81 years]) with extrapyramidal movement disorders were identified. Dystonia manifested in 11 pediatric patients (92%), often in the context of Leigh syndrome; parkinsonism predominated in 13 adult patients (43%), among whom 5 (38%) harbored either dominant (n = 1) or recessive (n = 4) mutations in POLG. Eleven adult patients (37%) manifested with either generalized or multifocal dystonia related to mutations in mitochondrial DNA, among which the most common were the m.11778G>A mutation and mutations in MT-ATP6 (3 of 11 patients [27%] each). Bilateral basal ganglia lesions were the most common finding in brain magnetic resonance imaging, usually associated with generalized dystonia or Leigh syndrome. Dystonia, often associated with Leigh syndrome, was the most common extrapyramidal movement disorder among pediatric patients with mitochondrial disease. Parkinsonism was the most prevalent extrapyramidal movement disorder in adults and was commonly associated with POLG mutations; dystonia was predominantly associated with mitochondrial DNA mutations. These findings may help direct genetic screening in a busy neurology outpatient setting.

Proximal movements compensate for distal forelimb movement impairments in a reach-to-eat task in Huntington's disease: new insights into motor impairments in a real-world skill.

PubMed

Klein, Alexander; Sacrey, Lori-Ann R; Dunnett, Stephen B; Whishaw, Ian Q; Nikkhah, Guido

2011-02-01

Huntington's disease (HD) causes severe motor impairments that are characterized by chorea, dystonia, and impaired fine motor control. The motor deficits include deficits in the control of the forelimb, but as yet there has been no comprehensive assessment of the impairments in arm, hand and digit movements as they are used in every-day tasks. The present study investigated the reaching of twelve HD subjects and twelve age-matched control subjects on a reach-to-eat task. The subjects were asked to reach for a small food item, with the left or the right hand, and then bring it to the mouth for eating. The task assesses the major features of skilled forelimb use, including orienting to a target, transport of the hand to a target, use of a precision grasp of the target, limb withdrawal to the mouth, and release of the food item into the mouth, and the integration of the movements into a smooth act. The movements were analyzed frame-by-frame by scoring the video record using an established movement element rating scale and by biometric analysis to describe limb trajectory. All HD subjects displayed greater reliance on more proximal movements in reaching. They also displayed overall jerkiness, a significant impairment in end point error correction (i.e. no smooth trajectories), deficits in timing and terminating motion (overshooting the target), impairments in rotation of the hand, abnormalities in grasping, and impairments in releasing the food item to the mouth. Although impairment in the control of the distal segments of the limb was common to all subjects, the intrusion of choreatic movements produced a pattern of highly variable performance between subjects. The quantification of reaching performance as measured by this analysis provides new insights into the impairments of HD subjects, allows an easily administered and inexpensive way to document the many skilled limb movement abnormalities, and relates the impairments to a real-world context. The protocol can serve as a useful clinical tool to evaluate innovative therapeutic interventions in HD such as physiotherapy, drug therapy, or functional neurosurgical procedures. Copyright © 2010 Elsevier Inc. All rights reserved.

Paleoneurology: neurodegenerative diseases are age-related diseases of specific brain regions recently developed by Homo sapiens.

PubMed

Ghika, J

2008-11-01

Bipedal locomotion and fine motility of hand and larynx of humans introduced musculoskeletal adaptations, new pyramidal, corticostriatal, corticobulbar, nigrostriatal, and cerebellar pathways and expansions of prefrontal, cingular, parieto-temporal and occipital cortices with derived new brain capabilities. All selectively degenerate in aged homo sapiens following 16 syndromic presentations: (1) Parkinsonism: nigrostriatal control for fast automatic movements of hand, larynx, bipedal posture and gait ("simian gait and hand"). (2) Frontal (highest level) gait disorders (lower body parkinsonism, gait apraxia, retropulsion): prefrontostriatal executive control of bipedal locomotion. (3) ataxia: new synergistic coordination of bipedal gait and fine motility. (4) Dyskinesias (chorea, dystonia, tremor...): intrusions of simian basal ganglia motor subroutines. (5) motoneuron diseases: new proximo-distal and bulbar motoneurones, preserving older ones (oculomotor, abdominal...). (6) Archaic reflexes: prefrontal disinhibition of old mother/tree-climbing-oriented reflexes (sucking, grasping, Babinski/triple retraction, gegenhalten), group alarms (laughter, crying, yawning, grunting...) or grooming (tremor=scratching). (7) Dysautonomia: contextual regulation (orthostatism...). (8) REM sleep disorders of new cortical functions. (9) Corticobasal syndrome: melokinetic control of hand prehension-manipulation and language (retrocession to simian patterns). (10) Frontal/temporal lobe degeneration: medial-orbitofrontal behavioural variant: self monitoring of internal needs and social context: apathy, loss of personal hygiene, stereotypia, disinhibition, loss of concern for consequences of acts, social rules, danger and empathy; dorsolateral executive variant: inadequacy to the context of action (goal, environmental changes...); progressive non-fluent aphasia: executive and praxic processing of speech; temporal variant: abstract concepts for speech, gestures and vision (semantic dementia, progressive nonfluent aphasia) (11) Temporomesial-limbic-paralimbic-associative cortical dementias (Alzheimer's disease, Lewy body, progressive amnesia): processing of explicit cognition: amnesic syndrome, processing of hand, larynx and eye: disorientation, ideomotor apraxia, agnosia, visuospatial processing, transcortical aphasia. (12) Focal posterior atrophy (Benson, progressive apraxia): visuomotor processing of what and where. (13) Macular degeneration: retinal "spot" for explicit symbols. (14) "Psychiatric syndromes": metacognition, self monitoring and regulation of hierarchical processing of metacognition: hallucinations, delusions, magic and mystic logic, delusions, confabulations; drive: impulsivity, obsessive-compulsive disorders, mental automatisms; social interactions: theory of mind, autism, Asperger. (15) Mood disorders: control on emotions: anxio-depressive and bipolar disorders, moria, emotional lability. (16) Musculoskeletal: inclusion body myositis: muscles for bipedal gait and fine motility. Paget's disease: bones for bipedal gait and cranium. Understanding of the genetic mechanisms underlying the evolution of these recent human brain regions and paleoneurology my be the key to the focal, asymmetrical or systemic character of neurodegeneration, the pathologic heterogeneity/overlap of syndromic presentations associating gait, hand, language, cognition, mood and behaviour disorders.

A novel NREM and REM parasomnia with sleep breathing disorder associated with antibodies against IgLON5: a case series, pathological features, and characterization of the antigen

PubMed Central

Sabater, Lidia; Gaig, Carles; Gelpi, Ellen; Bataller, Luis; Lewerenz, Jan; Torres-Vega, Estefanía; Contreras, Angeles; Giometto, Bruno; Compta, Yaroslau; Embid, Cristina; Vilaseca, Isabel; Iranzo, Alex; Santamaría, Joan; Dalmau, Josep; Graus, Francesc

2014-01-01

Summary Background Autoimmunity may be involved in sleep and neurodegenerative disorders. We aimed to describe a neurological syndrome with prominent sleep dysfunction and antibodies to a previously unknown neuronal antigen. Methods In this observational study, clinical and video-polysomnography (V- PSG) investigations identified a novel sleep disorder in three patients referred to the Sleep Unit of Hospital Clinic University of Barcelona for abnormal sleep behaviors and obstructive sleep apnea(OSA). They had antibodies against a neuronal surface antigen also present in five additional patients referred to our laboratory for antibody studies. These five patients had been evaluated with PSG and in two, the study was done or reviewed in our Sleep Unit. Two patients underwent postmortem brain examination. Immunoprecipitation and mass spectrometry were used to characterize the antigen and to develop a diagnostic test. Serum or CSF from 285 patients with neurodegenerative, sleep, or autoimmune disorders served as controls. Findings All eight patients (five women; range: 52–76 years, median 59) had abnormal sleep movements and behaviors and OSA confirmed by PSG. Six patients had a chronic evolution (range 2–12 years, median 5.5); in four the sleep disorder was the initial and most prominent feature, and in two it was preceded by gait instability, and followed by dysarthria, dysphagia, ataxia, or chorea. Two patients had a rapid evolution with disequilibrium, dysarthria, dysphagia, and central hypoventilation, and died two and six months after symptom onset. In 5/5 patients, the V-PSG reviewed in our Unit disclosed OSA, stridor, and abnormal sleep architecture with undifferentiated NREM sleep or poorly structured stage N2 with simple movements and finalistic behaviors, normalization of NREM sleep by the end of the night, and REM sleep behavior disorder. Four/4 patients carried the HLA-DRB1*1001 and HLA-DQB1*0501 alleles. All patients had antibodies (mainly IgG4) against IgLON5, member of a family of neuronal cell adhesion molecules. Only 1/285 controls (with progressive supranuclear palsy) had IgLON5 antibodies. Neuropathology showed neuronal loss and extensive deposits of hyperphosphorylated tau mainly involving the tegmentum of the brainstem and hypothalamus. Interpretation IgLON5-antibodies identify a unique NREM and REM parasomnia with sleep breathing dysfunction and pathological features suggesting a tauopathy. Funding Fondo de Investigaciones Sanitarias. Centros de Investigación Biomédica en Red de enfermedades neurodegenerativas (CIBERNED) and Respiratorias (CIBERES), Ministerio de Economía y Competitividad, Fundació la Marató TV3 and the National Institutes of Health. PMID:24703753

[Do the glutamate excitotoxicity theory and potential free radicals implication in schizophrenia aetiopathogenesis provide a new enlightenment to links between: genome, environment and biology in the determinism of that disorder?].

PubMed

Nguimfack Mbodie, P C

2002-01-01

The aetiopathogenesis of schizophrenia constitutes nowadays one of the major points of interest for researchers on this cosmopolitan disorder which involves about 1% of the world population and which significantly alters the social functioning of the individual. Numerous studies have focused on the role played by genome, environmental factors and biology in the development of symptoms. The neurodevelopmental theory is an illustration with the perinatal period considered as the main provider of environmental factors (hypertension, infections, bleedings during pregnancy, acute and chronic fetal distress.). Many authors found significant associations between such factors, the occurrence of brain lesions and finally schizophrenic symptoms. Although no convincing genetic model had been established to date for schizophrenia, nevertheless it appears that a predisposition not inheritable under the mendelian mode exists and authors showed that disease gets more and more severe over schizophrenic descendants. The risk to be schizophrenic being a first degree relative of the schizophrenic person is about ten time superior than in general population. Indeed, this risk is also about ten time superior in biological parents of schizophrenic adoptees than in biological parents of healthy adoptees. Studies done in monozygotic comparing to dizygotic twins are in favour of an important role played by genetic factors more than socioeducational or psychological factors. Concerning biology, the dopaminergic hypothesis remains shared by numerous authors although direct links with incriminated factors are not well established. Now is suspected the glutamate excitotoxicity with implication of free radicals in schizophrenia. These free radicals are products of various enzymatic activations led by overstimulation of post synaptic receptors (NMDA and AMPA) by the excess glutamate. Therefore, according to that concept, some amino acids as glutamate and derivatives could have through free radicals a noxious effect on neuronal synapses. This could be due to a failing of their recapture at the presynaptic level in addition to a dysfunctioning of the antioxidizing system (glutathion, carnosine, superoxide dismutase, aspartate) to which dopamine and other monoamines might participate. The question is whether or not this theory contributes to shed light on links between: genome, environmental factors and biology in schizophrenia. Through the review and discussion of genetical aspects of schizophrenia, environmental factors and the biological aspect, we intend to revive debate on that question. The articles and authors were selected with regard to the aptness of their publications on that subject, their evolving ideas and finally the interest of their works for neurosciences. This new approach perhaps is opening the way to new therapeutic perspectives in the treatment of schizophrenia based on the antioxidizing substances as shown for some neurological diseases (amyotrophic lateral sclerosis, Parkinson's disease and Huntington's chorea) for which experiments are going on.

A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study.

PubMed

Sabater, Lidia; Gaig, Carles; Gelpi, Ellen; Bataller, Luis; Lewerenz, Jan; Torres-Vega, Estefanía; Contreras, Angeles; Giometto, Bruno; Compta, Yaroslau; Embid, Cristina; Vilaseca, Isabel; Iranzo, Alex; Santamaría, Joan; Dalmau, Josep; Graus, Francesc

2014-06-01

Autoimmunity might be associated with or implicated in sleep and neurodegenerative disorders. We aimed to describe the features of a novel neurological syndrome associated with prominent sleep dysfunction and antibodies to a neuronal antigen. In this observational study, we used clinical and video polysomnography to identify a novel sleep disorder in three patients referred to the Sleep Unit of Hospital Clinic, University of Barcelona, Spain, for abnormal sleep behaviours and obstructive sleep apnoea. These patients had antibodies against a neuronal surface antigen, which were also present in five additional patients referred to our laboratory for antibody studies. These five patients had been assessed with polysomnography, which was done in our sleep unit in one patient and the recording reviewed in a second patient. Two patients underwent post-mortem brain examination. Immunoprecipitation and mass spectrometry were used to characterise the antigen and develop an assay for antibody testing. Serum or CSF from 298 patients with neurodegenerative, sleep, or autoimmune disorders served as control samples. All eight patients (five women; median age at disease onset 59 years [range 52-76]) had abnormal sleep movements and behaviours and obstructive sleep apnoea, as confirmed by polysomnography. Six patients had chronic progression with a median duration from symptom onset to death or last visit of 5 years (range 2-12); in four the sleep disorder was the initial and most prominent feature, and in two it was preceded by gait instability followed by dysarthria, dysphagia, ataxia, or chorea. Two patients had a rapid progression with disequilibrium, dysarthria, dysphagia, and central hypoventilation, and died 2 months and 6 months, respectively, after symptom onset. In five of five patients, video polysomnography showed features of obstructive sleep apnoea, stridor, and abnormal sleep architecture (undifferentiated non-rapid-eye-movement [non-REM] sleep or poorly structured stage N2, simple movements and finalistic behaviours, normalisation of non-REM sleep by the end of the night, and, in the four patients with REM sleep recorded, REM sleep behaviour disorder). Four of four patients had HLA-DRB1*1001 and HLA-DQB1*0501 alleles. All patients had antibodies (mainly IgG4) against IgLON5, a neuronal cell adhesion molecule. Only one of the 298 controls, who had progressive supranuclear palsy, had IgLON5 antibodies. Neuropathology showed neuronal loss and extensive deposits of hyperphosphorylated tau mainly involving the tegmentum of the brainstem and hypothalamus in the two patients studied. IgLON5 antibodies identify a unique non-REM and REM parasomnia with sleep breathing dysfunction and pathological features suggesting a tauopathy. Fondo de Investigaciones Sanitarias, Centros de Investigación Biomédica en Red de enfermedades neurodegenerativas (CIBERNED) and Respiratorias (CIBERES), Ministerio de Economía y Competitividad, Fundació la Marató TV3, and the National Institutes of Health. Copyright © 2014 Elsevier Ltd. All rights reserved.