Severe Chorea Research Articles

Identifying and verifying Huntington's disease subtypes: Clinical features, neuroimaging, and cytokine changes.

Huntington's disease (HD) is a progressive neurodegenerative disorder with heterogeneous clinical manifestations. Identifying distinct clinical clusters and their relevant biomarkers could elucidate the underlying disease pathophysiology. Following the Enroll-HD program initiated in 2018.09, we have recruited 104 HD patients (including 21 premanifest) and 31 health controls at Beijing Tiantan Hospital. Principal components analysis and k-means cluster analysis were performed to determine HD clusters. Chi-square test, one-way ANOVA, and covariance were used to identify features among these clusters. Furthermore, plasma cytokines levels and brain structural imaging were used as biomarkers to delineate the clinical features of each cluster. Three clusters were identified. Cluster 1 demonstrated the most severe motor and nonmotor symptoms except for chorea, the lowest whole brain volume, the plasma levels of IL-2 were higher and significantly associated with cluster 1. Cluster 2 was characterized with the most severe chorea and the largest pallidum volume. Cluster 3 had the most benign motor symptoms but moderate psychiatric problems. We have identified three HD clusters via clinical manifestations with distinct biomarkers. Our data shed light on better understanding about the pathophysiology of HD.

Symptomatic treatment options for Huntington’s disease (guidelines of the German Neurological Society)

IntroductionAmeliorating symptoms and signs of Huntington’s disease (HD) is essential to care but can be challenging and hard to achieve. The pharmacological treatment of motor signs (e.g. chorea) may favorably or unfavorably impact other facets of the disease phenotype (such as mood and cognition). Similarly, pharmacotherapy for behavioral issues may modify the motor phenotype. Sometimes synergistic effects can be achieved. In patients undergoing pragmatic polypharmacological therapy, emerging complaints may stem from the employed medications' side effects, a possibility that needs to be considered. It is recommended to clearly and precisely delineate the targeted signs and symptoms (e.g., chorea, myoclonus, bradykinesia, Parkinsonism, or dystonia). Evidence from randomized controlled trials (RCTs) is limited.Summary or definition of the topicTherefore, the guidelines prepared for the German Neurological Society (DGN) for German-speaking countries intentionally extend beyond evidence from RCTs and aim to synthesize evidence from RCTs and recommendations of experienced clinicians.RecommendationsFirst-line treatment for chorea is critically discussed, and a preference in prescription practice for using tiapride instead of tetrabenazine is noted. In severe chorea, combining two antidopaminergic drugs with a postsynaptic (e.g., tiapride) and presynaptic mode of action (e.g., tetrabenazine) is discussed as a potentially helpful strategy. Sedative side effects of both classes of compounds can be used to improve sleep if the highest dosage of the day is given at night. Risperidone, in some cases, may ameliorate irritability but also chorea and sleep disorders. Olanzapine can be helpful in the treatment of weight loss and chorea, and quetiapine as a mood stabilizer with an antidepressant effect.ConclusionsSince most HD patients simultaneously suffer from distinct motor signs and distinct psychiatric/behavioral symptoms, treatment should be individually adapted.

Defining Utility Values for Chorea Health States in Patients with Huntington's Disease.

IntroductionChorea is characterized by sudden, involuntary movements that interfere with quality of life (QOL). Utility values measure preferences for different health states and reflect societal perceived disease severity. To date, no studies have reported utility values specifically for Huntington’s disease (HD) chorea. We estimated impact on QOL of HD chorea severity using utility values from the general population.MethodsParticipants were enrolled using computer-assisted telephone interviews. Participants read vignettes describing four health states for varying levels of chorea severity, with the same underlying HD severity. Time trade-off (TTO) methods were used to estimate utility values, which range from −1 (worse than death) to +1 (perfect health) and represent the number of years in an imperfect health state an individual is willing to give up to live in full health. TTO utilities were augmented with visual analog scale (VAS) participant responses. The primary outcome was HD chorea utility estimated by TTO.ResultsMean ± SD TTO-derived utility values were 0.07 ± 0.52, 0.26 ± 0.50, 0.48 ± 0.47, and 0.64 ± 0.41 for severe, moderate/severe, moderate/mild, and mild chorea severity, respectively. Differences between each health state and its adjacent less severe health state were statistically significant (all P < 0.0001). Respondents were willing to give up 3.6, 5.2, 7.4, and 9.3 years during a 10-year life span to avoid living with mild, mild/moderate, moderate/severe, and severe chorea, respectively. VAS and TTO results were consistent.ConclusionsSignificant decreases in utility values were seen as HD chorea severity increased. These data can be leveraged for cost-effectiveness modeling to better understand the value of treatments for chorea.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02046-z.

Electroconvulsive therapy for severe depression, psychosis and chorea in a patient with Huntington's disease: case report and review of the literature.

The psychiatric manifestations of Huntington's disease are myriad and difficult to control. The use of electroconvulsive therapy (ECT) is not commonly considered for this condition. We describe a patient with severe depression, psychomotor retardation, delusions and weight loss who responded to ECT with good control of her symptoms. Both our case and the literature appear to confirm the efficacy of ECT in the treatment of depression in Huntington's disease and suggest that other psychiatric manifestations of Huntington's are also responsive. ECT is an effective and safe treatment that should be considered earlier in the course of the disease in cases that show limited response to pharmacological therapy. It should also be considered as an adjunct to medical therapy that may simplify polypharmacy and allow better control in patients with debilitating psychiatric manifestations of the disease. There is limited and conflicting evidence for its efficacy in chorea.

N-Methyl-D-Aspartate Encephalitis our Experience with Diagnostic Dilemmas, Clinical Features, and Outcome.

Introduction:A neuropsychiatric syndrome characterized by a wide spectrum of clinical manifestations. It is seen in patients with antibodies against NR1-NR2 heteromers of the NMDA receptor. As the spectrum is mainly psychiatric most patients are treated as psychiatric disease resulting in huge diagnostic delay.Patient and methods:Here we describe 29 patients with NMDA encephalitis seen by the authors in the last five years. Percentage of Transfected cells showing granular cytoplasmic florescence was considered for positivity and severity both in CSF and serum. Their presenting diagnosis, clinical features and the dilemmas, alarming gaps, laboratory data, response to treatment and relapses are discussed.Observations:All patients presented with a spectrum of psychiatric symptoms varying from panic to severe aggression, seizures, chorea, hemiplegia, catatonia, mitgehen, mutism, delirium, mania and memory problems. EEG is invariably abnormal as against imaging.Conclusion:NMDA receptor mediated encephalitis should be suspected in all children and females of adolescent age with refractory neuropsychiatric syndrome. Both CSF and serum should be tested and regular follow up for relapses and neoplasms is mandatory.

Severe chorea revealing a large precerebral vessels vasculopathy with Moyamoya syndrome

Severe chorea revealing a large precerebral vessels vasculopathy with Moyamoya syndrome

EP 34. Effects of deep brain stimulation of the globus pallidus interna on Huntington’s disease at 1 year

Introduction Huntington’s disease (HD) is an autosomal dominant and progressive neurodegenerative disorder. The disease is caused by a strongly increased number of trinucleotide CAG repeats in the Huntingtin gene and characterized by a progressive loss of striatal neurons. Phenotypically, patients present with severe motor symptoms, such as chorea, dystonia, and bradykinesia. Deep brain stimulation (DBS) of the globus pallidus interna (GPi) has been proposed to treat abnormal movements in HD. Here, we report the clinical outcomes of DBS of the GPi in three HD patients followed for 1 year respectively. Objectives Our main objective was to assess the efficacy and safety of DBS of the GPi in alleviating motor symptoms, particularly chorea. Materials and methods Patients with major functional disability due to pharmacoresistant chorea, preserved or mildly altered cognitive function and no severe psychiatric disorder were selected. Due to the severity of chorea, DBS of the GPi were performed under general anesthesia. Microelectrode recording were also used in the preoperative period in all patients. They were followed for 1 year respectively. Outcome measure were scored by the change of the chorea and total motor scores of the Unified Huntington’s Disease Rating Scale (UHDRS) between pre- and last postoperative assessments. Results Chorea improved in all patients (13%, 86% and 29%) and total motor score decreased in 1 patient (%24) postoperatively. 1 patient had a transient dysarthria because of frontal cerebral contusion after operation. Conclusion Based on these results and previous published reports, DBS of the GPi may be considered as an alternative treatment in non-demented HD patients with severe chorea.

Autoimmune chorea in adults

To determine the characteristics of adult-onset autoimmune chorea, and compare paraneoplastic and idiopathic subgroups. Thirty-six adults with autoimmune chorea were identified at Mayo Clinic (Rochester, MN) from 1997 to 2012. Medical record and laboratory data were recorded. Nonparaneoplastic (n = 22) and paraneoplastic cases (n = 14) were compared. Women accounted for 21 patients (58%). Median age at symptom onset was 67 years (range 18-87 years). We estimated the incidence for Olmsted County was 1.5 per million person-years. Symptom onset was subacute in all. Chorea was focal (20 patients) or generalized (16 patients). Although chorea predominated, other neurologic disorders frequently coexisted (29 patients); abnormal eye movements were uncommon (4 patients). No patient had NMDA receptor antibody or any immunoglobulin (Ig)G yielding a detectable immunofluorescence binding pattern restricted to basal ganglia. Two had synaptic IgG antibodies novel to the context of chorea (GAD65, 1; CASPR2, 1). In the paraneoplastic group, 14 patients had evidence of cancer. Of 13 with a histopathologically confirmed neoplasm, small-cell carcinoma and adenocarcinoma were most common; 6 patients had a cancer-predictive paraneoplastic autoantibody, with CRMP-5-IgG and ANNA-1 being most common. In the idiopathic group, 19 of the 22 patients had a coexisting autoimmune disorder (most frequently systemic lupus erythematosus and antiphospholipid syndrome); autoantibodies were detected in 21 patients, most frequently lupus and phospholipid specificities (19 patients). The paraneoplastic group was older (p = 0.001), more frequently male (p = 0.006), had more frequent weight loss (p = 0.02), and frequently had peripheral neuropathy (p = 0.008). Autoimmune chorea is a rare disorder with rapid onset. Male sex, older age, severe chorea, coexisting peripheral neuropathy, and weight loss increase the likelihood of cancer.

Adult-Onset Autoimmune Chorea (S08.003)

Objective: To describe adults consecutively evaluated with autoimmune chorea (Mayo Clinic, 1997-2011). Background Data regarding adult-onset autoimmune chorea is limited. Design/Methods: Inclusion criteria: 1) chorea as the predominant complaint; 2) an autoimmune cause was suspected based on: presence of a paraneoplastic antibody or cancer (Paraneoplastic Group) or clinical/serological evidence of autoimmunity without cancer (Non-paraneoplastic Group). The Groups were statistically compared (Fisher or Wilcoxon tests). Results: Chorea-onset was acute/subacute in 36/38 patients (median-age 68 years; range, 18-87 [women, 22]) and affected whole-body (28 patients), hemi-body (5), or extremities only (5; upper, 4; lower, 1); median follow-up, 13 months (range, 1-228). Paraneoplastic Group: 17/38 patients; 16 had ≥1 cancer (small-cell lung, 4; hematological, 4; adenocarcinoma [2 each of breast, colon, prostate]; other, 3) and 5 had ≥1 paraneoplastic antibody (CRMP-5 IgG, 4; ANNA-1, 2; other, 2). Male sex (p=0.02), older age (p=0.001), severe chorea (p=0.04), and weight loss (p=0.04) were more common. Non-paraneoplastic Group: 21/38 patients; antiphospholipid syndrome, SLE (6 patients each) and spontaneous remissions were more common (p=0.02). Both groups were similar in respect of: coexisting neurological disorders (cognitive/personality change, 11; neuropathy, 9; other, 4), MRI findings (irrelevant to chorea), other coexisting autoimmune diseases (thyroid, 5; Sjogren disease, 4; other, 12), other antibody findings (antinuclear antibody, 20; phospholipid antibody, 16; SS-A/SS-B, 7; other, 9) and physician-reported treatment responses (p>0.05). Immunotherapy-responsiveness was documented in 18/21 patients (median treatment-duration, 1.5 months [range 0.25-228]): corticosteroids, 18; plasmapheresis, cyclophosphamide, chemotherapy, 2 each. Complementary steroid-sparing strategies employed included: hydroxychloroquine, azathioprine, 5 each; cyclophosphamide, mycophenolate, 1 each. Effective symptomatic therapies (13/24 patients) were: risperidone, 6; benzodiazepines, 3; fluphenazine, reserpine, divalproex, gabapentin, 2 each. Final outcomes (30 patients) were: remission, 14 (including 4 untreated patients); improved, 11; unchanged, 3; worsened, 2. Conclusions: Autoimmune chorea is usually rapid-onset and frequently remits. Male sex, older age and severe symptoms should strengthen the suspicion for cancer. Disclosure: Dr. O9Toole has nothing to disclose. Dr. Ahlskog has nothing to disclose. Dr. Matsumoto has nothing to disclose. Dr. Pittock has received research support from Alexion Pharmaceuticals, Inc. Dr. Bower has received personal compensation for activities with Teva Neuroscience and Merck & Co., Inc. as a consultant. Dr. Lennon has nothing to disclose. Dr. Lachance has nothing to disclose. Dr. Fealey has nothing to disclose. Dr. McKeon has nothing to disclose.

An International Survey-based Algorithm for the Pharmacologic Treatment of Chorea in Huntington’s Disease

It is generally believed that treatments are available to manage chorea in Huntington’s disease (HD). However, lack of evidence prevents the establishment of treatment guidelines. The HD chorea research literature fails to address the indications for drug treatment, drug selection, drug dosing and side effect profiles, management of inadequate response to a single drug, and preferred drug when behavioral symptoms comorbid to chorea are present. Because there is lack of an evidence base to inform clinical decision-making, we surveyed an international group of experts to address these points. Survey results showed that patient stigma, physical injury, gait instability, work interference, and disturbed sleep were indications for a drug treatment trial. However, the experts did not agree on first choice of chorea drug, with the majority of experts in Europe favoring an antipsychotic drug (APD), and a near equal split in first choice between an APD and tetrabenazine (TBZ) among experts from North America and Australia. All experts chose an APD when comorbid psychotic or aggressive behaviors were present, or when active depression prevented the use of TBZ. However, there was agreement from all geographic regions that both APDs and TBZ were acceptable as monotherapy in other situations. Perceived efficacy and side effect profiles were similar for APDs and TBZ, except for depression as a significant side effect of TBZ. Experts used a combination of an APD and TBZ when treatment required both drugs for control of chorea and a concurrent comorbid symptom, or when severe chorea was inadequately controlled by either drug alone. The benzodiazepines (BZDs) were judged ineffective as monotherapy but useful as adjunctive therapy, particularly when chorea was exacerbated by anxiety. There was broad disagreement about the use of amantadine for chorea. Experts who had used amantadine described its benefit as small and transient. In addition to survey results, this report reviews available chorea studies, and lastly presents an algorithm for the treatment of chorea in HD which is based on expert preferences obtained through this international survey.

Reply: Mutations of TSEN and CASK genes are prevalent in pontocerebellar hypoplasias type 2 and 4

Sir, Pontocerebellar hypoplasia (PCH) type 2 caused by missense mutations in TSEN54 is a distinct phenotype encompassing progressive microcephaly, swallowing problems and severe mental and motor impairments. None of the patients with PCH2 with missense mutations in TSEN54 achieved unsupported walking or sitting, voluntary hand control was absent in almost all and higher visual functioning was absent or very limited. A common characteristic of PCH2 is the extrapyramidal dyskinesia, which often presents as severe chorea. In the more severe subtype PCH type 4 (due to compound heterozygosity of missense mutations plus nonsense or splice site mutations in TSEN54 ), the early lethality and prenatal symptoms like polyhydramnios, congenital contractures and the necessity for mechanical ventilation signify a more profound involvement. In both subtypes, MRI shows hypoplasia of the cerebellar hemispheres with relative sparing of the vermis and hypoplasia and atrophy of the ventral pons. Additionally, in PCH2 cases there is variable progressive atrophy of the cerebral cortex, delayed myelination and attenuation of the corpus callosum. In PCH4, impaired growth and maturation of the supratentorial parts of the brain results in increased pericerebral space and an immature aspect of the cerebral cortex. There is a remarkable coherence in the clinical presentation of cases with TSEN54 mutations, resulting in either a PCH2 or …

Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN

BackgroundThis study reports on a hitherto undescribed autosomal recessive syndrome characterised by dysmorphic features and multiple congenital anomalies together with severe neurological impairment, chorea and seizures leading to early death,...

Juvenile Huntington disease in an 18-month-old boy revealed by global developmental delay and reduced cerebellar volume

Juvenile Huntington disease (JHD) is a rare clinical entity characterized by disease onset before the age of 21. JHD accounts for <10% of Huntington disease patients. Transmission of JHD is paternal in 80-90% of cases. Patients with JHD usually carry more than 60 CAG repeats within the HTT gene. We report here on a 23-month-old boy presenting with global developmental delay first noted at 18 months of age. Clinical examination showed truncal hypotonia, postural and intentional tremor, limb rigidity, and ataxia. Cerebral magnetic resonance imagery (MRI) showed reduced cerebellar volume. Six months later, his 47-year-old father was seen for a 4-year history of progressive dementia with severe behavioral disturbance and chorea. Cerebral MRI showed discrete global and caudate atrophy. DNA analysis revealed a very large and heterogeneous expansion (210-250 CAG) in the child and a 43 CAG expansion of the HTT gene in the father. This unusual case demonstrates that very early onset JHD due to large CAG expansions should be considered in cases of global developmental delay associated with reduced cerebellar volume, including cases without known HD family history.

Deficiencia cerebral de creatina: primeros pacientes españoles con mutaciones en el gen GAMT

Background and objetive Brain creatine (Cr) deficiencies are a group of inborn errors of metabolism that are characterized by an absence or severe reduction of brain Cr. Clinically, these patients can display psychomotor/mental retardation and language disorders, commonly associated with epilepsy or movement disorders. Three metabolic defects are known: two affect synthesis – guanidinoacetate metiltransferase (GAMT) and glycine amidinotransferase (AGAT) deficiencies– and one affect the Cr transporter (CRTR). We present the first three Spanish patients with GAMT deficiency, and we compare their clinical phenotype and treatment response with other published cases. Patients and method The three patients presented mental retardation, epilepsy and autistic behaviour. Patient 1 also had severe chorea. Diagnosis was done by biochemical and genetic procedures (guanidinoacetate quantification, determination of GAMT activity and mutation analysis in the GAMT gene). Results An increase of guanidinoacetate was detected in urine and plasma. Brain magnetic resonance spectroscopy revealed low Cr levels. Enzymatic studies revealed a decreased GAMT activity in fibroblasts. Molecular analysis detected pathogenic mutations in the GAMT gene. After the deficiency was confirmed, the patients started treatment with Cr. In addition, patient 2 and 3 received an arginine-restricted diet and ornithine supplements. All them showed a partial improvement. Conclusions Patients with GAMT deficiency have an unspecific but relatively constant clinical presentation. Brain Cr deficiency should be considered in patients with mental retardation of unknown aetiology, specially in those with movement disorders or epilepsy. Early diagnosis is important in cases with known treatment such as GAMT deficiency.

Severe reversible chorea complicating non‐ketotic hyperglycaemia

AbstractMovement disorders can manifest as initial presentations in a variety of metabolic and endocrine disorders. Chorea, though rare, has been documented to occur in patients with non‐ketotic hyperglycaemia and usually has a good prognosis once the causal association is recognised and the hyperglycaemia treated. We report the case of an 87‐year‐old lady who presented with chorea complicating non‐ketotic hyperglycaemia, and this was confirmed with MRI brain imaging demonstrating the classical feature of this condition. A high T1‐weighted signal in the putamen is quite characteristic of this condition. Copyright © 2009 John Wiley &amp; Sons.

Chorée aiguë post-streptococcique : une étrange réaction après chirurgie d’une insuffisance mitrale rhumatismale

We report on a 12-year-old patient from Congo who presented acute chorea following cardiac surgery for poststreptococcal mitral valvulopathy. She showed severe and asymmetrical chorea, associated with motor impersistence and agitation. Biological investigations disclosed inflammatory signs and brain MRI was normal. Due to the negative results of the biological and morphological investigations, the diagnosis of Sydenham chorea was suspected. High doses of oral steroids resulted in a dramatic improvement of the chorea as well as the behavior disturbance within 1 month. Sydenham chorea is not an unusual complication of rheumatic fever. Usually, patients develop chorea a few weeks after beta-hemolytic streptococcal pharyngitis. Details on its pathophysiology remain to be determined. Our case highlights its possible onset in the postoperative period if alternative etiologies of infantile chorea have been excluded.

Sydenham’s chorea

Sydenham's chorea (SC) is a manifestation of acute rheumatic fever (ARF). Although the incidence of SC has declined significantly, particularly in developed areas, it remains the most common cause of acute chorea in children worldwide. Recent data show that SC accounts for almost all cases of chorea in children in the United States. As there is no specific laboratory marker of this condition, the diagnosis relies on a careful clinical history and laboratory assessment to rule out alternative causes. Morbidity is primarily related to cardiac lesions in ARF. It is recommended that all patients with suspected SC submit to a cardiologic evaluation. Neurologic features encompass motor signs, among which chorea is the most prominent, and nonmotor symptoms such as obsessive-compulsive behavior and attention-deficit/hyperactivity disorder. The first-line treatment of SC is valproic acid. Patients who do not respond to this drug or who present with severe chorea (particularly chorea paralytica, in which the muscle tone is so decreased that patients are bedridden) should be treated with risperidone. Other dopamine receptor-blocking drugs, such as haloperidol, may also be useful. There is growing evidence that immunosuppressive treatment, such as intravenous methylprednisolone followed by a tapering course of oral prednisone, is effective. This option has been used in patients who failed to respond to (or did not tolerate) the previously mentioned therapies. Plasmapheresis and intravenous immunoglobulin are regarded as experimental treatments. Obsessive-compulsive behavior associated with SC is not usually as severe as in other conditions such as Tourette's syndrome. Finally, because at least 20% of patients with SC experience recurrent attacks of ARF, they carry a high risk of developing severe cardiac lesions. These patients require prophylaxis against streptococcus infection, using penicillin or sulfa drugs.

Huntington's Disease

Huntington's disease may present at any age, but most typically manifests between the ages of 35 and 45 years as a slowly progressive neurodegenerative movement disorder with cognitive and behavioral impairment. It is an autosomal-dominant disorder that has a substantial impact on family structure and dynamics in terms of providing care for affected family members and, for the offspring of an affected parent, dealing with at-risk status. Therapy that slows the progressive neuronal dysfunction or degeneration is unavailable, so pharmacotherapy is currently aimed primarily at managing behavioral and psychiatric symptoms, and, in selected cases, controlling severe chorea. Effective intervention by clinicians is possible, however, in terms of providing patients and families with accurate information about the disease, counseling them about availability of genetic testing at specialized centers, and in giving them sound advice regarding work, driving, relationships, finances, research participation, and support groups.

Sydenham's chorea: Clinical observations from a Brazilian movement disorder clinic

We retrospectively evaluated the clinical and epidemiological characteristics of 100 patients suffering from Sydenham's chorea (SC). Our analysis revealed a recent, progressive decline in the number of new cases. Onset of SC was frequently reported between 7 and 12 years of age, being more frequent in females. Patients with generalized or severe chorea showed a higher risk of presenting gait abnormalities and behavioral symptoms. Chorea was transitory and remitted within the first 6 months in about 50% of patients but was persistent in 40%. Almost all patients with persistent chorea remitted after a protracted course of the disease.

Severe autoimmune chorea with positive antibasalganglia antibodies (ABGA) following herpesencephalitis: Treatment with plasmapheresis and corticosteroids

Severe autoimmune chorea with positive antibasalganglia antibodies (ABGA) following herpesencephalitis: Treatment with plasmapheresis and corticosteroids