Choreic Movements Research Articles

Atypical presentation of anti-N-methyl-D-aspartate receptor encephalitis: two case reports

BackgroundAnti-N-methyl-D-aspartate receptor encephalitis is a rare autoimmune disease characterized by severe neurological and psychiatric symptoms and a difficult diagnosis.The disease is often secondary to a neoplastic lesion, seldom diagnosed years later. Psychiatric symptoms are prevalent in adults; neurologic symptoms are more evident in children, who typically present primarily with neurological symptoms. To the best of our knowledge, the association with juvenile idiopathic arthritis has not been described.Case presentationWe report the cases of two caucasian girls with an atypical presentation.The first patient was an 8-year-old girl with normal psychomotor development. Over a 4-month period she developed behavioral problems, speech impairment, and deterioration in academic skills. Within 8 months from the onset of symptoms, choreic movements gradually appeared. Hematological, neuroradiological, and neurophysiological examinations were negative; however, her symptoms worsened and treatment with prednisone was started. Although her choreic movements improved within 1 month, her neuropsychological and behavioral symptoms continued. Anti-N-methyl-D-aspartate receptor antibodies in cerebrospinal fluid and in blood were detected. Therapy with intravenously administered immunoglobulins was administered, without improvement of symptoms. After 2 months of steroid treatment, she suddenly started to pronounce some words with a progressive improvement in language and behavior.The second patient was a 14-year-old girl with classic anti-N-methyl-D-aspartate receptor encephalitis, treated successfully with intravenously administered immunoglobulins and methylprednisolone, followed by orally administered prednisone, who developed chronic arthritis of the hip. The arthritis was confirmed by magnetic resonance imaging and associated to antinuclear antigen antibody positivity.One year after the encephalitis presentation, an ovarian cystic mass was identified as a teratoma. The surgical resection of the mass was followed by the resolution of the psychotic spectrum and arthritis.ConclusionsAnti-N-methyl-D-aspartate receptor encephalitis in pediatric patients can present initially with neuropsychological and behavioral symptoms.In the literature, the association of anti-N-methyl-D-aspartate receptor encephalitis with juvenile idiopathic arthritis is not yet described: to the best of our knowledge, this is the first case reported. The link to a neoplastic lesion can explain the favorable course of encephalitis and arthritis, after the surgical resection of the mass. Early diagnosis and treatment can improve the patient’s outcome.

Clozapine efficiency in tardive syndromes induced by anti-psychotic treatment

IntroductionTardive syndromes (TS) resulting from prolonged exposure to dopamine receptor blocking agents are frequent. Clozapine is considered to have a low risk of causing new onset TS and accounts therefore as an interesting option in patients with invalidating TS.ObjectivesOur study aims to describe clozapine indications in patients experiencing TS.MethodsPresentation of the clinical cases of five patients, who experienced different kinds of TS secondary to 1st and 2nd generation anti-psychotic treatment.ResultsWe present the cases of AB aged 41, MJ aged 40, HM aged 31 and AS aged 30, diagnosed with schizophrenia; and FB aged 24,diagnosed with schizoaffective disorder. Adverse side effects to conventional anti-psychotics such as limb and trunk tremors were described for AB, choreic limb movements, axial and segmental dystonia for MJ, AS, FB and oculogyration for FB. All patients were switched to atypical anti-psychotics without improvement of the TS. The switch to clozapine, associated with abotulinum injection for MJ, led to regression of the TS and improvement of clinical signs. In fact, according to several studies, clozapine seems to be an interesting option when invalidating TS occurs. The low prevalence of TS under clozapine can be explained by its low affinity for striatal-D2 receptors, its anti-serotonin and anti-cholinergic effects.ConclusionsClozapine should be considered in symptomatic patients who develop TS while receiving other anti-psychotics. Further research on mechanism of TS and clozapine effect on TS is needed.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Miljokazi progresije Huntingtonove bolesti

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease which is characterized by the presence of involuntary choreatic movements, cognitive impoverishment and behavioral disorders. The objectives of this research were: analysis of the clinical specifics of people with HD and definition of chronology in the occurrence of milestone disease progression. 56 patients with HD were interviewed by telephone about their age, family history, age at onset of the disease, first symptoms, current symptoms and their beginning. Also, the number of trinucleotide (CAG) repeats was determined by PCR method. In group of 50 alive patients the average age was 54.5 years, age at the beginning of disease 46.7 years, disease duration 7.8 years and latency to diagnosis 2 years, approximately. Family history was positive for 22 patients. Most frequently first symptoms were involuntary movements as isolated symptom (24 patients). In a progression of the disease swallowing difficulty and choking were first problem in everyday life for patients and they occurred 4.5 years after the first symptoms. Talking difficulty, falls, dependence on the assistance of another person during bathing and eating and walking difficulty happened after 4.6, 5.2, 6.2, 7.5 and 7.5 years, respectively. The average number of trinucleotide repeats was 43.8, in range from 40 to 51 repeats. HD in short term leads to significant disability with the emergence of problems with swallowing, speaking and walking, leading thus to complete depending on the physical assistance of another person.

Children with Mild CAG Repeat Expansion in HTT Gene Showing Psychiatric but not Neurological Presentation: Is It One More Shade of Huntington Disease?

Objective: Huntington disease (HD) generally manifests in adulthood. Large mutations with CAG repeat expansion in HTT gene may rarely cause juvenile Huntington disease (JHD) in early childhood or adolescence with atypical clinical features, i.e., atypical parkinsonism, if compared to adult patients. Our objective is to characterize the rare occurrence of clinical manifestations in children carrying mutations in the low-mild size, generally causing adult HD with typical choreic movements. Methods: We are following up a subgroup of young subjects with HD mutation who manifested with disabling psychiatric condition since early childhood or adolescence. We are collecting data by the observational studies Registry and ENROLL-HD since 2004. Among 60 JHD patients we are currently following-up, we selected people who carry a mutation in the mild range of CAG expansions (i.e., expected to manifest in adulthood), psychiatric manifestations and no neurological signs or movement disorders suggestive of HD. All patients were genetically (i.e., CAG size analysis) and clinically (i.e., total motor score within the Unified HD Rating Scale) characterized. Results: We found four subjects who showed the characteristics for this analysis. All four subjects presented a CAG expansion size <45 repeats. Two patients manifested a schizophrenia-like disturbance during their adolescence, with the later appearance of motor signs after age 20. In the other two cases, patients presented symptoms of autistic spectrum disorder, since infancy. One of them showed also a schizophrenia-like disturbance and, later, HD onset with motor signs after 20. A 45 year old patient is currently manifesting an autistic disorder in absence of others neurological signs. Conclusion: The description of JHD includes sometimes children with psychiatric manifestations associated with adult motor onset. We advise to pay careful attention to such rare conditions that might represent either psychiatric conditions erroneously classified as JHD or prodromic adult HD cases.

Réponse spectaculaire au valproate de sodium d’une chorée de Sydenham récurrente

La chorée du Sydenham est la première cause de chorée acquise dans le tiers monde. Nous rapportons le cas d'une Chorée récurrente traitée avec succès par le valproate du sodium. Mlle A.C âgée de 16 ans ayant comme antécédents des angines à répétition et un épisode de mouvement choréique il y a 2 ans, pour lequel elle a été mise sous Halopéridol et sous prévention du rhumatisme articulaire aigu. La patiente a interrompue le traitement et quelques mois plus tard elle a présenté le même tableau neurologique. L'IRM cérébrale et l'échographie transthoracique étaient normales. La prévention par Extencilline a été réinstaurée ainsi que l'halopéridol sans aucune amélioration, d'où la mise en route sous valproate de sodium. La réponse était spectaculaire après 2 mois de traitement sans récidive après 3ans de recul. Le traitement de la chorée du Sydenham était les neuroleptiques. Des études récentes préconisent d'autres molécules efficaces et mieux tolérées.

Experience of experimental modelling of Huntington’s disease

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by choreic involuntary movements, decline in cognitive functions, behavioral disturbances, and progressive neuronal death affecting primarily the striatum. The fatal nature of HD makes it important to search for new effective methods of its treatment, which requires the development of experimental models of the disease. These models can be created using 3-nitropropionic acid (3-NPA), which is a neurotoxin causing typical changes in motor skills and memory impairment in animals due to induction of oxidative stress, impaired glutathione defense, and destruction of striatal cells. We modeled HD in rats by chronic daily intraperitoneal administration of 3-NPA for 17 days. Systemic administration of a low dose of 3-NPA (10 mg/kg) induced hyperactivity of animals in the open field test (including movement redundancy as a hyperkinesia analogue) and had no effect on the behavior of the animals in the X-maze test. On the contrary, rats administered with a toxic dose of 3-NPA (20 mg/kg) exhibited a significant decrease in their motor activity and a cognitive decline in behavioral tests. A histopathological analysis revealed damage and loss of neurons and a decrease in expression of dopaminergic markers (tyrosine hydroxylase and plasma membrane dopamine transporter) in the striatum. The gliotoxic effect of 3-NPA was also found in the striatum, which was confirmed by immunohistochemical staining for astrocytic proteins: GFAP, glutamine synthetase, and aquaporin-4. This HD model may be helpful for testing new experimental therapies at different stages of HD-like neurodegeneration, including therapies based on cell neurotransplantation.

Maladie de Huntington : données actuelles sur la prise en charge thérapeutique des troubles psychiatriques

ObjectiveHuntington's disease is a neurodegenerative genetic, autosomal dominant disease. George Huntington describes this trouble in 1872. In 1993, scientist founded mutation on IT15 gene on 4th chromosome. Prevalence in France is 1/10 000 without sex predominance or race. The main symptoms are: choreic movements, axial impairment, psychiatric disorders and the presence of cognitive impairment. The diagnostic is clinic, genetic and radiologic. Despite the absence of curative treatment, symptomatic care supports deficit symptoms of the pathology, thus improves the quality of life of patients. In the context of a comprehensive and optimal therapy, health professionals provide recommendations for guidelines like Huntington's disease national reference center in August 2015. We will define diagnostic and clinical aspects of Huntington's disease, and then we will focus our analysis on the psychiatric aspect. Material and methodFirst, we will illustrate management provided by our teams. Patient A had positive diagnostic of Huntington's disease and personal psychiatric antecedent of depression. She was hospitalized in neurological unit for a panic attack in August 2015. They give tetrabenazine and to prevent depressive effect we prescribed antidepressant first (serotonin–norepinephrine reuptake inhibitor), then antipsychotic (risperidone, then haloperidol) and benzodiazepine. Patient B had Huntington's disease in family and personal diagnostic of Huntington's disease and personal psychiatric antecedent of depression. She was admitted in psychiatric unit for psychotic symptom. She received antipsychotic (risperidone) and antidepressant (venlafaxine) with benzodiazepine. Both of them had clinical improvement. Patient A, went to reeducation care, patient B went home with nurse. When we analyzed literature on the psychiatric therapeutic in Huntington's disease with review, we found that apathy is the most psychiatric symptom in Huntington's disease (50–80% Inserm). Benzodiazepine had good result for anxiety. We must search and treat psychiatric disorder like depression and mood disorder. Irritability and anxiety are symptoms of mood disorder and can be treated with antidepressive and mood stabilizer. Suicide is an emergency because of the mortality rate. The guideline is the same of suicide in psychiatric emergency. Antipsychotics are not avoided and used for choreic and psychotic symptoms (delirium, hallucination…) but second generation antipsychotics are generally preferable because of the lesser presence of adverse event. ResultsThe use of selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitor (SNRI) for moods sign are the most frequently used therapy reference. Electroconvulsive therapy (ECT) and mood stabilizer have similar results to those obtained in mood disorders without neurodegenerative pathology. Antipsychotic like risperidone or olanzapine are good requirements. Guidelines of Huntington's disease national reference center and literature give these therapeutic choices. With our two patients, we can see clinical improvement and the main objective was return home. Literature explain important role of psychotherapy, social, diet and hygiene habits. We must have global care like other psychiatric patient and more because of neurological reach. ConclusionThe implementation of classical specific therapeutic in psychiatry improves these symptoms and optimizes the quality of life for our patients. A comprehensive and multidisciplinary support involving medical and paramedical rehabilitation is a necessity to take into account.

EP 15. Choreatic side effects of deep brain stimulation of the subthalamic nucleus for treatment resistant OCD: A case history

Introduction Patients with severe treatment resistant obsessive-compulsive disorder (OCD) are potential candidates for deep brain stimulation (DBS). The anteromedial limbic part of the subthalamic nucleus (STN) and the ventral capsule/ventral striatum (VC/VS) are among the most commonly used targets. Objective To report a side effect of anteromedial STN-DBS in an OCD patient that has not been described before. Method Case report. Results A 49-year old female patient with a 30-year history of treatment-resistant obsessive-compulsive disorder was indicated for anteromedial STN-DBS. Correct target identification was done using electrophysiological recordings preoperatively and confirmed with CT scanning post-operatively. Already after the first days of STN stimulation, there was a clear mood-enhancing effect. However, the patient developed compulsive behavior towards the operation wounds (scratching and itching), which may have been the cause of a subsequent hardware infection. The infection resolved after surgery and antibiotic therapy. In the outpatient period, the programming was limited by the fact that STN-DBS caused motor symptoms at voltages above circa 2.5 V. These consisted of bilateral hyperkinesia and dyskinesias, as well as sudden large amplitude choreatic movements of the arms and legs. With lower stimulation amplitude (and 90 ms and 130 Hz) there was no effect on compulsions. Due to this programming limitation, we decided to re-operate and target the VC/VS, with the deepest electrode contact point in the area of the nucleus accumbens. After programming, the patient now experiences a substantial reduction (50%) of the key symptoms and obtained an acceptable quality of life. Conclusion In this 49-year old patient with OCD, anteromedial STN-DBS induced hyperkinetic movements in the lower extremities that limited the programming possibilities. Choreatic movements and (contralateral) hemiballismus have since long been associated with damage to the subthalamic nucleus ( Hawley and Weiner, 2012) , and have been described as a side-effect of STN-DBS in Parkinson’s disease ( Baizabal-Carvalla and Jankovic, 2016) . However, the emergence of such motor symptoms as a side-effect of STN-DBS in OCD has to our knowledge not been described before. Reimplantation to the VC/VS successfully overcame this limitation and resulted in adequate therapeutic response.

Paroxysmal movement disorders: An update

Paroxysmal movement disorders comprise both paroxysmal dyskinesia, characterized by attacks of dystonic and/or choreic movements, and episodic ataxia, defined by attacks of cerebellar ataxia. They may be primary (familial or sporadic) or secondary to an underlying cause. They can be classified according to their phenomenology (kinesigenic, non-kinesigenic or exercise-induced) or their genetic cause. The main genes involved in primary paroxysmal movement disorders include PRRT2, PNKD, SLC2A1, ATP1A3, GCH1, PARK2, ADCY5, CACNA1A and KCNA1. Many cases remain genetically undiagnosed, thereby suggesting that additional culprit genes remain to be discovered. The present report is a general overview that aims to help clinicians diagnose and treat patients with paroxysmal movement disorders.

HEMICHOREA ASSOCIATED WITH NON-KETOTIC HYPERGLICEMIA: REPORT OF TWO CASES AND BRIEF REVIEW OF THE LITERATURE

Introduction: Chorea is characterized as a hyperkinetic movement disorder that is caused by lesions on the basal ganglia. Many etiological factors have been described, including ischemia, infection, neoplasm and neurodegenerative disorders, such as Hun-tington’s disease. Non-ketotic hyperglycemia induced chorea is a rare, but reversible, condition usually associated with contralat-eral striatal radiological abnormalities. Case Report: Case 1: A 64 year-old Brazilian woman was admitted concerning about a 4-day history of involuntary, erratic and continuous movements with sudden onset affecting the left arm, leg and, partially, the left hemiface. Her past medical history was remarkable for arterial hypertension and type 2 diabetes mellitus. Neurologic examina-tion revealed the presence of choreic movements of the left hemiface, arm and leg. Case 2: A 63 year-old Brazilian woman was admitted concerning about an 1-day history of involuntary, without purpose, assymmetric, irregular and abrupt movements of the upper limbs and face associated with difficulty of speaking and swallowing. Her past medical history was remarkable for arterial hypertension and coronariopathy with two episodes of acute myocardial infarction four months before. There was no history of diabetes mellitus. On neurological examination, she presented severe dysartry and difficulty of swallowing associated with choreic movements of the upper limbs and face. Conclusion: In the present study, we describe two cases of chorea as a complication of non-ketotic hyperglycemia. A high index of clinical awareness and early suspicion of this possible association are extremely important, once the correct management and normalization of glycemia may result in complete recovery of neurologic symptoms.

Brain stimulation in Huntington's disease.

Huntington's disease (HD) is a hereditary neurodegenerative disorder which is associated with severe disturbances of motor function, especially choreatic movements, cognitive decline and psychiatric symptoms. Various brain stimulation methods have been used to study brain function in patients with HD. Moreover, brain stimulation has evolved as an alternative or additive treatment option, besides current symptomatic medical treatment. This article summarizes the results of brain stimulation to better understand the characteristics of cortical excitability and plasticity in HD and gives a perspective on the therapeutic role for noninvasive and invasive neuromodulatory brain stimulation methods.

Cotard syndrome in a young man?

IntroductionAnti-NMDA encephalitis normally appears as a characteristic syndrome with typical symptoms that undergoes with multiphase evolution. However, it sometimes develops atypical symptoms so we must perform a careful differential diagnosis.ObjectivesTo conduct a current review of detection and management of anti-NMDAr encephalitis, and psychiatric manifestations.MethodSystematic review of the literature in English (PubMed), with the following keywords: “Autoimmune encephalitis”, “psychosis”, and “NMDA receptor”.ResultsWe present the case of a 15-year-old boy referred to evaluation for a first psychotic episode. He had no past history of psychiatric illness or substance abuse. The only relevant antecedent is multiple sclerosis in a first degree relative. For the last months, he presented high levels of anxiety symptoms apparently related to college stressful events and fluctuating hypoesthesia of left cranial side. Days later, it appeared autolimited gastrointestinal symptoms, headache and fever. During the next days it appeared psychomotor retardation, choreic movements, suicide ideation and mood-congruent paranoid and nihilistic ideation, auditory and visual hallucinations, perplexity and catatonic symptoms so he was hospitalized. We observed cognitive functions impairment, unsteady gait, dysartria, dysphasia, clonus and left babinsky sign. EEG showed slow waves on right frontal area. CFS showed protein elevation and immunologic study revealed positive anti-NMDA antibodies. Treatment with methylprednisolone and gammaglobuline was started with partial response, needing addition of rituximab.ConclusionsIn this case, we highlight the importance of early detection and a detailed differential diagnosis, to determine whether the etiology of psychiatric symptoms in order to achieve an accurate and early treatment.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Tardive dyskinesia: When one should suspect of another diagnosis?

IntroductionTardive dyskinesia is a collection of symptoms related to the side effects of neuroleptic medications that can mimic other types of disorders. Accurate diagnosis can be challenging, as there is no single test for tardive dyskinesia.Case reportFemale patient, 64 years old, with personal history of Chronic Myeloid Leukaemia and psychosis since forth decade, currently medicated with quetiapine 350 mg/day, risperidone IM 50 mg 15/15 days and trazodone 150 mg/day (previously medicated with haloperidol, amisulpride and olanzapine). She started with involuntary movements interpreted as tardive dyskinesia after 2 years on neuroleptic treatment. The difficult control of involuntary movements motivated the reference to ambulatory Neurology department. The review of personal history suggested a family history of involuntary movements and psychiatric illness. Physical examination showed generalized choreic movements. The analytical and imagiologic study was unremarkable. The presence of family history and involuntary movements atypical to be classified as tardive dyskinesia supported a genetic test for Huntington's disease who detected a CAG expansion with 43 repetitions in HTT gene. Despite treatment with amantadine and riluzole she maintains disease progression and evident cognitive deterioration.ConclusionThe diagnostic process of involuntary movements may involve more than one physician and requires the review of a detailed medical history, a physical examination and a neuropsychological evaluation in order to determine whether one is indeed suffering from tardive dyskinesia or a different neurological disorder.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Movement Disorders: A Complication of Chronic Hyperglycemia? A Case Report

Abstract Introduction The association of chorea with a specific lesion on brain imaging is described as an atypical manifestation of chronic hyperglycemia. Case report Patient of 77 years, hospitalized for bilateral choreic movements predominant on the right with dystonic movements, appeared a month ago. At admission Hyperglycemia at 2.4 g/L, without ketosis, a type 2 diabetes (HbA1c 17.3%) on oral antidiabetic agents. CT scan shows hyperdensity of putamen and lenticular nucleus that eliminates an ischemic attack. Evolution after glycemic reequilibration and treatment by haloperidol is favorable, with regression of chorea. Discussion This is a rare syndrome, affecting more elderly, presenting a diabetes poorly controlled. There is hyperglycemia without ketosis and moderate hyperosmolarity. The symptoms usually regress after glycemic control and neuroleptic treatment (recurrence in 13% of cases). The appearance of this syndrome seems to be related to the achievement of the control system GABAergic of the basal ganglia leading to an excitation of the cerebral cortex, causing involuntary movements. The etiopathogenic hypotheses advanced are multiple: impaired striatal neurotransmission associated with metabolic disturbances of hyperglycemia, dysfunction of the hematoencephalic barrier and abnormalities of the cerebral vascularization. Conclusion Chorea secondary to nonketotic hyperglycemia is a rare complication and little known of type 2 diabetes. Transitional neuroleptic treatment and glycemic control make the symptoms regress in most cases with the disappearance of the lesion imaging.

Hemiballismus That Develops upon Thalamic Hemorrhage: A Case Report

Hemichorea is characterized by sudden, spasmodic, irregular, short-term finger, hand, arm, face, tongue or head movements including one half of body. Ballismus concept defines the high-amplitude, violent, centrifugal or throwing motions. Hemichorea-hemiballismus are the most frequently reported movement disorders in patients with acute stroke. Even if it is believed to occur depending on the effect on contralateral subthalamic nucleus; it has been reported that in the following years there have been choreic and ballistic movements in various lesions intersecting the afferent and efferent subtalamopalidal paths of basal ganglion. In this article; hemiballismus, which has developed after thalamic hemorrhage, of an 63 year old female patient is presented.

Acute Chorea Onset after Hot Food Consumption in a Patient with Moyamoya Disease.

Acute Chorea Onset after Hot Food Consumption in a Patient with Moyamoya Disease.

Impact of Caryolanemagnolol on Gait and Functional Mobility on Individuals with Huntington’s Disease

Purpose: To highlight the impact of caryolanemagnolol on gait measures in forward walking, balance and mobility measures, as well as in hand and forearm function measures.Methods: Twenty patients with Huntington’s disease (HD) on stable doses of caryolanemagnolol were evaluated after medication and again following resumption of medication. The improvement in spatiotemporal gait parameters was measured by GAITRite, balance and/or mobility using Tinetti mobility test (TMT), five times sit-to-stand test (5TSST), and six-condition Romberg tests, as well as the function of the hand and forearm by finger tapping and Luria tests on Huntington's disease rating scale (UHDRS) motor scale.Results: The results demonstrated significant improvement in the unified UHDRS motor scores, Tinetti mobility test (TMT) total and balance subscale scores, and the five times sit-to-stand test when oncaryolanemagnolol compared to off-caryolanemagnolol. Spatiotemporal gait measures, the six condition Romberg test, and UHDRS hand and forearm function items remained unaffected on caryolanemagnolol treatment. Improved TMT and 5TSST performance when on drug indicates that caryolanemagnolol use may improve balance and functional mobility in individuals with HD.Conclusions: Caryolanemagnolol improves chorea and functional mobility by improving dynamic balance in individuals without any negative impact on motor function in walking and transfers.Keywords: Huntington's disease, Caryolanemagnolol, Gait measures, Choreic movements, Mobility tests

Losing sleep

In 1939, in a letter to The Lancet, the link between anxiety and sleeplessness was suggested on the basis of experiences from the Spanish Civil War and the early days of the Second World War.1AnonymousInsomnia.Lancet. 1939; 234: 1123Google Scholar Insomnia was depicted as the result of life-threatening living conditions, and supposedly cured by calming the patient with relaxation techniques or sedative substances. These assumptions prevailed until recently, and may have contributed to a view of insomnia not as a brain disorder, but merely as a reflection of stressful life conditions or a symptom of other disorders. Review articles on insomnia usually emphasise epidemiology, diagnosis, pharmacological and psychological treatment and, more recently, the neurobiological aspects.2Riemann D Nissen C Palagini L Otte A Perlis ML Spiegelhalder K The neurobiology, investigation, and treatment of chronic insomnia.Lancet Neurol. 2015; 14: 547-558Summary Full Text Full Text PDF PubMed Scopus (288) Google Scholar Current psychological theories emphasise the role of stressful life experiences, maladaptive behaviours, cognitive factors, and learned negative associations from a top-down perspective.3Spielman AJ Caruso LS Glovinsky PB Behavioral perspective on insomnia.Psychiatr Clin North Am. 1987; 10: 541-553PubMed Google Scholar, 4Harvey AG A cognitive model of insomnia.Behav Res Ther. 2002; 40: 869-893Crossref PubMed Scopus (1024) Google Scholar, 5Espie CA Broomfield NM MacMahon KM Macphee LM Taylor LM The attention-inattention-effort pathway in the development of psychophysiologic insomnia: an invited theoretical review.Sleep Med Rev. 2006; 10: 215-245Summary Full Text Full Text PDF PubMed Scopus (317) Google Scholar This perspective has served as the basis for cognitive-behavioural therapy as the first-line treatment for insomnia (CBT-I).6Riemann D Perlis ML The treatments of chronic insomnia: a review of benzodiazepine receptor agonists and psychological and behavioral therapies.Sleep Med Rev. 2009; 13: 205-214Summary Full Text Full Text PDF PubMed Scopus (336) Google Scholar In addition, psychophysiological research has suggested the concept of central nervous system hyperarousal as a core pathophysiological pathway.7Riemann D Spiegelhalder K Feige B et al.The hyperarousal model of insomnia: A review of the concept and its evidence.Sleep Med Rev. 2010; 14: 19-31Summary Full Text Full Text PDF PubMed Scopus (976) Google Scholar This echoes the first neurobiological description of insomnia by von Economo,8Von Economo C Der Schlaf als Lokalisationsproblem.in: Pötzl O Der schlaf. Mitteilungen und stellungnahme zum derzeitigen stand des schlafproblems. JF Lehmans Verlag, München1929: 38-53Google Scholar based on his neuropathological work in encephalitis lethargica. He reported that a minority of affected individuals did not show symptoms of fatigue or hypersomnia, but developed choreatic movements accompanied by severe insomnia. He suggested that specific CNS lesions, especially in the midbrain, are relevant for sleep, thus proposing the concept of a localisable sleep center in the brain.

A randomized, placebo-controlled trial of AFQ056 for the treatment of chorea in Huntington's disease.

This study investigated the hypothesis that AFQ056 (mavoglurant), a selective metabotropic glutamate receptor 5 antagonist, reduces chorea in Huntington's disease (HD). This 32-day randomized, double-blind, parallel-group, proof-of-concept study investigated AFQ056 (25-150 mg [incremental doses], twice-daily) versus placebo in patients with HD. Primary efficacy assessments were the chorea-sum score and orientation index (nondominant hand) from the quantitative motor (Q-Motor) grasping task at day 28. Key secondary efficacy assessments included finger-tapping in the Unified Huntington's Disease Rating Scale-Total Motor Score and Q-Motor measures. Safety and tolerability were assessed. Overall, 42 patients were randomized. At day 28, no improvement was observed on the primary efficacy assessments (P > 0.10) with AFQ056 versus placebo. The Q-Motor speeded-tapping interonset interval variability was reduced with AFQ056 versus placebo for the nondominant hand (P = 0.01). The incidence of adverse events was 66.7% with AFQ056 and 57.1% with placebo. AFQ056 did not reduce choreatic movements in HD, but was well tolerated. The clinical relevance of the Q-Motor findings (speeded-tapping) are unknown and may warrant further investigation.

Haplotype analysis of the 4p16.3 region in Portuguese families with Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder characterized by involuntary choreic movements, cognitive impairment, and behavioral changes, caused by the expansion of an unstable CAG repeat in HTT. We characterized the genetic diversity of the HD mutation by performing an extensive haplotype analysis of ∼1Mb region flanking HTT in over 300 HD families of Portuguese origin. We observed that haplotype A, marked by HTT delta2642, was enriched in HD chromosomes and carried the two largest expansions reported in the Portuguese population. However, the most frequent HD haplotype B carried one of the largest (+12 CAGs) expansions, which resulted in an allele class change to full penetrance. Despite having a normal CAG distribution skewed to the higher end of the range, these two core haplotypes had similar expanded CAG repeat sizes compared to the other major core haplotypes (C and D) and there was no statistical difference in transmitted repeat instability across haplotypes. We observed a diversity of HTT region haplotypes in both normal and expanded chromosomes, representative of more than one ancestral chromosome underlying HD in Portugal, where multiple independent events on distinct chromosome 4 haplotypes have given rise to expansion into the pathogenic range. © 2015 Wiley Periodicals, Inc.