The Neuropsychiatry of Huntington Disease-Like 2: A Comparison with Huntington's Disease.

BACKGROUND: Huntington Disease-Like 2 (HDL2) is a rare autosomal dominant disorder caused by an abnormal CAG/CTG triplet repeat expansion on chromosome 16q24. The symptoms of progressive decline in motor, cognitive and psychiatric functioning are similar to those of Huntington's disease (HD). The psychiatric features of the HDL2 have been poorly characterized. OBJECTIVE: To describe the neuropsychiatric features of HDL2 and compare them with those of HD. METHODS: A blinded cross-sectional design was used to compare the behavioural component of the Unified Huntington's Disease Rating Scale (UHDRS) in participants with HDL2 (n = 15) and HD (n = 13) with African ancestry. RESULTS: HDL2 patients presented with psychiatric symptoms involving mood disturbances and behavioural changes that were not significantly different from those in the HD group. Duration of disease and motor performance correlated (p < 0.001) with the Functional Capacity score and the Independence score of the UHDRS. HD patients reported movement dysfunction as the first symptom more frequently than HDL2 Patients (p < 0.001). CONCLUSION: The psychiatric phenotype of HDL2 is similar to that of HD and linked to motor decline and disease duration. Psychiatric symptoms seem more severe for HDL2 patients in the early stages of the disease.

Discriminating chorea-acanthocytosis from Huntington's disease with single-case voxel-based morphometry analysis.

BACKGROUND AND PURPOSE: Chorea-acanthocytosis is clinically difficult to distinguish from Huntington's disease because these disorders have similar symptoms and MR imaging findings. We evaluated the usefulness of single-case voxel-based morphometry (VBM) analysis for differentiating the two diseases as well as VBM analysis. MATERIALS AND METHODS: We examined five genetically proven chorea-acanthocytosis patients and 11 Huntington's disease patients to detect differences in the gray and white matter atrophic pattern by using single-case VBM analysis in each patient and their clinical findings. We also evaluated VBM analysis for a group comparison in both disease and control groups. RESULTS: The single-case VBM analysis results demonstrated a gray matter volume loss in caudate nucleus in all 16 patients. A characteristic symmetrical white matter volume loss was detected in globus pallidus, putamen, and thalamus on both sides in all the chorea-acanthocytosis patients, but this pattern of atrophy was not seen in any of the Huntington's disease patients. With the VBM analysis, a significant gray matter volume loss was noted in caudate nucleus on both sides in chorea-acanthocytosis patients compared with Huntington's disease patients, and a more extensive white matter volume loss around the basal ganglia and thalamus was observed in chorea-acanthocytosis patients compared to Huntington's disease patients, consistent with the single-case VBM analysis results. Genetic testing identified two novel pathogenic mutations, exon 1 c.16_22delGTGGTCG and exon 55 c.7736-7739delGAGA in a chorea-acanthocytosis patient. CONCLUSIONS: Single-case VBM analysis may be useful to differentiate chorea-acanthocytosis from Huntington's disease with a focus on white matter atrophy.

The "sick dancers": The construction of medical knowledge about the "epidemic of dance" in Itapagipe, Salvador, Bahia (1882-1901).

The goal of this paper is to analyze a little-known set of documents referring to a "Dancing Epidemic" that took place in Itapagipe, a suburb of Salvador, capital of the province of Bahia, Brazil, in 1882. Through the studies of a group of physicians, especially Raimundo Nina Rodrigues (1862-1906), a psychiatrist and anthropologist from the Bahia School of Medicine, the medical knowledge built on this unique phenomenon in Brazilian history is examined. The case in particular involved a crowd that spread through the streets of Itapagipe, attracting the interest of the medical classes, who were intrigued by the symptoms of motor incoordination the patients manifested. Inspired by foreign literature, but developing their own theories, Rodrigues and colleagues created a unique body of knowledge about the infirmity.

Understanding How Chorea Affects Health-Related Quality of Life in Huntington Disease: An Online Survey of Patients and Caregivers in the United States.

BACKGROUND: Chorea is the hallmark motor feature of Huntington disease (HD) and can negatively impact daily functioning and health-related quality of life (HRQoL). OBJECTIVE: The objective of this study was to evaluate how chorea impacts HRQoL and overall functioning among HD patients participating on the PatientsLikeMe website ( www.PatientsLikeMe.com ). METHODS: A survey was provided to HD participants and/or their caregivers via PatientsLikeMe (9 February 2017-22 March 2017), comprising multiple-choice and open-ended questions designed to assess how chorea impacts HRQoL and overall functioning, and the importance of treating chorea. The HDQLIFE measurement system was used to evaluate patient-reported outcomes of chorea and compare Anxiety and Stigma scores in participants with high chorea versus those with low chorea [HDQLIFE Chorea scores ≥ 60 (n = 45) vs. < 60 (n = 38)]. RESULTS: A total of 115 participants (n = 35 caregivers; n = 80 individuals with HD) were included in this study. Among those experiencing chorea (n = 83, 74% of respondents), 66% indicated it was 'Very Important' to manage chorea; however, only 47% agreed that their current medication regimen helped manage their movements. In general, respondents reported that chorea negatively affected HRQoL [HDQLIFE Chorea mean score (standard deviation): 59.3 (6.1)]. Consistent with this, significantly higher Anxiety (P = 0.0423) and stigma (P < 0.0001) scores were observed among respondents with high chorea than in those with low chorea. CONCLUSIONS: These results highlight the negative impact of chorea on HRQoL and overall functioning in individuals with HD. Better chorea treatment options are needed to successfully manage symptoms and to help improve HRQoL in these individuals, and patient experiences of anxiety and stigma should be considered in treatment plans.

The relationship of dystonia and choreoathetosis with activity, participation and quality of life in children and youth with dyskinetic cerebral palsy.

AIM: To relate dystonia and choreoathetosis with activity, participation and quality of life (QOL) in children and youth with dyskinetic Cerebral Palsy (CP). METHODS: Fifty-four participants with dyskinetic CP (mean age 14y6m, SD 4y2m, range 6-22y) were included. The Dyskinesia Impairment Scale (DIS) was used to evaluate dystonia and choreoathetosis. Activity, participation and quality of life (QOL) were assessed with the Gross Motor Function Measure (GMFM), the Functional Mobility Scale (FMS), the Jebsen-Taylor Hand Function Test (JTT), the ABILHAND-Kids Questionnaire (ABIL-K), the Life Habits Kids (LIFE-H) and the Quality of Life Questionnaire for children with CP (CP-QOL). Spearman's rank correlation coefficient (rs) was used to assess the relationship between the movement disorders and activity, participation and QOL measures. RESULTS: Significant negative correlations were found between dystonia and the activity scales with Spearman's rank correlation coefficient (rs) varying between -0.65 (95% CI = -0.78 to -0.46) and -0.71 (95% CI = -0,82 to -0.55). Correlations were also found with the LIFE-H (rs = -0.43; 95%CI = -0.64 to -0.17) and the CP-QOL (rs = -0.32; 95%CI = -0.56 to -0.03). As far as choreoathetosis is concerned, no or only weak relationships were found with the activity, participation and quality of life scales. INTERPRETATION: This cross-sectional study is the first to examine the relationship of dystonia and choreoathetosis in dyskinetic CP with the level of activity, participation and QOL. The results revealed dystonia has a higher impact on activity, participation and quality of life than choreoathetosis. These findings seem to suggest it is necessary to first focus on dystonia reducing intervention strategies and secondly on choreoathetosis.

The development of a new computer adaptive test to evaluate chorea in Huntington disease: HDQLIFE Chorea.

PURPOSE: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease associated with motor, behavioral, and cognitive deficits. The hallmark symptom of HD, chorea, is often the focus of HD clinical trials. Unfortunately, there are no self-reported measures of chorea. To address this shortcoming, we developed a new measure of chorea for use in HD, HDQLIFE Chorea. METHODS: Qualitative data and literature reviews were conducted to develop an initial item pool of 141 chorea items. An iterative process, including cognitive interviews, expert review, translatability review, and literacy review, was used to refine this item pool to 64 items. These 64 items were field tested in 507 individuals with prodromal and/or manifest HD. Exploratory and confirmatory factor analyses (EFA and CFA, respectively) were conducted to identify a unidimensional set of items. Then, an item response theory graded response model (GRM) and differential item functioning analyses were conducted to select the final items for inclusion in this measure. RESULTS: EFA and CFA supported the retention of 34 chorea items. GRM and DIF supported the retention of all of these items in the final measure. GRM calibration data were used to inform the selection of a 6-item, static short form and to program the HDQLIFE Chorea computer adaptive test (CAT). CAT simulation analyses indicated a 0.99 correlation between the CAT scores and the full item bank. CONCLUSIONS: The new HDQLIFE Chorea CAT and corresponding 6-item short form were developed using established rigorous measurement development standards; this is the first self-reported measure developed to evaluate the impact of chorea on HRQOL in HD. This development work indicates that these measures have strong psychometric properties; future work is needed to establish test-retest reliability and responsiveness to change.

Autoimmunity against dopamine receptors in neuropsychiatric and movement disorders: a review of Sydenham chorea and beyond.

Antineuronal autoantibodies are associated with the involuntary movement disorder Sydenham chorea (SC) and paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) which are characterized by the acute onset of tics and/or obsessive compulsive disorder (OCD). In SC and PANDAS, autoantibodies signal human neuronal cells and activate calcium calmodulin-dependent protein kinase II (CaMKII). Animal models immunized with group A streptococcal antigens demonstrate autoantibodies against dopamine receptors and concomitantly altered behaviours. Human monoclonal antibodies (mAbs) derived from SC target and signal the dopamine D2L (long) receptor (D2R). Antibodies against D2R were elevated over normal levels in SC and acute-onset PANDAS with small choreiform movements, but were not elevated over normal levels in PANDAS-like chronic tics and OCD. The expression of human SC-derived anti-D2R autoantibody V gene in B cells and serum of transgenic mice demonstrated that the human autoantibody targets dopaminergic neurones in the basal ganglia and other types of neurones in the cortex. Here, we review current evidence supporting the hypothesis that antineuronal antibodies, specifically against dopamine receptors, follow streptococcal exposures and may target dopamine receptors and alter central dopamine pathways leading to movement and neuropsychiatric disorders.

Neuropsychological manifestations in children with Sydenham's chorea after adjunct intravenous immunoglobulin and standard treatment.

This was an exploratory study comparing neuropsychological manifestations of Sydenham's chorea (SC), 6 months after initiation of treatment, in children who had received intravenous immunoglobulins as an adjunct to standard treatment, with those who had received standard treatment. We included a non-SC control group for comparison. We hypothesized that compared to controls, children with SC who had received prior intravenous immunoglobulins would demonstrate less pronounced impairments compared to those who had received standard care. We conducted a cross-sectional analysis of 17 children with -SC who had received treatment 6 months previously (9 treated with standard of care and 8 augmented with intravenous immunoglobulins) and 17 non-SC, medically well controls. The standard treatment group (n = 9) exhibited significant behavioral difficulties, including significantly poorer co-operation (p = 0.009) compared with the other augmented immunoglobulins and non-SC control groups, and increased impulsivity (p = 0.016) compared with non-SC controls. The standard treatment group scored significantly lower than the other two groups on a measure of executive functioning (p = 0.03). Children with SC may be more at risk for neuropsychological difficulties than non-SC, medically well children. Intravenous immunoglobulins may mitigate some of these impairments.

Language Impairment in Adolescents With Sydenham Chorea.

BACKGROUND: Neuropsychiatric comorbidities are frequent in Sydenham chorea. However, cognitive impairment in Sydenham chorea has not been sufficiently described. The objective of this study was to evaluate expressive and receptive language deficits in adolescents with Sydenham chorea. METHODS: Twenty patients with Sydenham chorea were compared with 20 patients with rheumatic fever without chorea and 20 healthy controls. Participants were matched for age and gender. Participants were assessed with verbal fluency tasks (phonemic and semantic) and with verbal comprehension tasks (Token Test). Patients with Sydenham chorea were also assessed with the Universidade Federal de Minas Gerais Sydenham Chorea Rating Scale. RESULTS: Performance in verbal fluency and in verbal comprehension tasks differed significantly (P < 0.01) among the three groups. Patients with Sydenham chorea performed significantly worse than healthy control group in phonemic and semantic verbal fluency tasks as well as in the Token Test. The group with rheumatic fever also performed worse than healthy controls in phonemic verbal fluency. Severity of motor signs in Sydenham chorea inversely correlated with performance in phonemic verbal fluency (words beginning with letter S, and total sum of words beginning with letters F, A, and S). CONCLUSIONS: Adolescents with Sydenham chorea show difficulties in verbal fluency and in verbal comprehension. Patients with rheumatic fever also have some degree of language impairment. Future studies must investigate language impairment in difference stages of Sydenham chorea (acute, persistent, and remission) and putative biological markers.

The neuropsychological profile of patients with 3-methylglutaconic aciduria type III, Costeff syndrome.

Costeff syndrome is a rare genetic neuro-ophthalmological syndrome consisting of early-onset bilateral optic atrophy along with a progressive complex motor disorder with elevated levels of urinary 3-methylglutaconic acid and 3-methylglutaric acid. While borderline to mild cognitive deficits have been considered to be common in patients with this syndrome, a comprehensive cognitive assessment has never been performed. The aim of the current study was to explore the cognitive profile associated with Costeff syndrome. Sixteen adult patients diagnosed with Costeff syndrome were administered a neuropsychological test battery that was composed of standardized verbal tests adapted for the blind. General intelligence ranged from average to borderline, with a group mean consistent with intact general cognitive functioning (VIQmean = 85, z = -1) in the low-average range of the general population. The auditory immediate and delayed memory indexes were in the average range and were significantly higher than the general cognitive functioning, whereas the working memory index was significantly lower than the general cognitive functioning. Adult patients with Costeff syndrome have intact global cognition and learning abilities and strong auditory memory performance. © 2015 Wiley Periodicals, Inc.

Benign hereditary chorea as an experimental model to investigate the role of medium spiny neurons for response adaptation.

Processing errors is a major requirement for behavioral adaptation. While it has been assumed that the basal ganglia play an important role in initiating these processes, the role of the striatal microstructure for these processes remains to be uncovered. Previous studies in basal ganglia diseases could not elucidate the relevance of the striatal medium spiny neuron (MSN) microstructure unambiguously because structural alterations occur together with alterations in various neurotransmitter systems. We present and examine a possible model that allows the examination of MSN dysfunction unbiased by other modulations, i.e. a case of 'benign hereditary chorea' (BHC) in comparison to healthy controls. We apply event-related potentials (ERPs) to uncover the underlying neurophysiological mechanisms underlying post-error behavioral adaptation. The BHC patient revealed a smaller error-related negativity (ERN) together with almost absent behavioral adaptation after an error and generally more error-prone behavior. Performance monitoring processes unrelated to errors, as well as response inhibition processes, were not affected in the BHC patient. The results suggest that the striatal MSN microstructural integrity is more important for error-related behavioral adaptation than for other response monitoring processes unrelated to errors.

Psychiatric disorders in persistent and remitted Sydenham's chorea.

BACKGROUND: Sydenham's chorea (SC) has been associated with increased frequency of psychiatric disorders. The objective of the present study was to determine whether there is any difference in the frequency of psychiatric disorders between SC patients in remission and patients with persistent chorea. METHODS: Fifty consecutive patients with SC (mean age ± SD, years; 21.5 ± 6.7; M/F; 10/40) were subjected to a comprehensive and structured psychiatric evaluation. RESULTS: The most frequent psychiatric disorders observed in SC patients were: major depression (14%); generalized anxiety disorder (16%), social phobia (24%) and obsessive-compulsive disorder (24%). The frequency of psychiatric disorders did not differ between SC patients in remission in comparison with patients with persistent chorea, except for depressive disorders which were more frequent in the later CONCLUSIONS: Psychiatric disorders are common among young adults with SC regardless of the status of motor symptoms.

Síntomas psiquiátricos en una enferma de corea-acantocitosis / Psychiatric symptoms in a woman with chorea-acanthocytosis

La corea-acantocitosis es un raro trastorno neurodegenerativo de curso lentamente progresivo, caracterizado por movimientos involuntarios semejantes a la corea de Hungtinton, deterioro cognitivo, cambios en la conducta, crisis convulsivas y polineuropatía. Pertenece al grupo de las neuroacantocitosis, enfermedad es genéticamente definidas, en las que se asocia la degeneración progresiva de los ganglios de la base y la presencia de acantocitos en sangre periférica. La forma de inicio es heterogénea pudiendo ser los síntomas psiquiátricos su primera manifestación. Caso clínico: mujer de 48 años que comenzó con crisis convulsivas a los 35 años y aparición posterior de cambios de conducta y afectivos que motivaron la consulta en salud mental. Presentaba alteración en la marcha, torpeza motora, inestabilidad emocional e impulsividad y fue diagnosticada de cambio de personalidad debido a enfermedad médica, aunque los primeros estudios neurológicos resultaron negativos.La evolución posterior con aparición de movimientos coreicos, atrofia del núcleo estriado en RMN y detección de acantocitos en sangre periférica posibilitaron el diagnóstico. Se discute el papel de los ganglios basales en las manifestaciones psiquiátricas y la fisiopatología de la enfermedad (AU)

Chorea-acanthocytosis is an uncommon neurodegenerative disorder, usually with a low rate of progression. It is characterized by Huntington disease-like involuntary movements, cognitive decline, behavioral changes, seizures and polyneuropathy. Chorea-acanthocytosis belongs to the group of neuroacanthocytosis syndromes, a group of genetically defined diseases associated with progressive degeneration of the basal ganglia and peripheral red blood cellacanthocytes. The onset of the disease is variable in its manifestations and psychiatric symptoms may dominate the clinical picture. Case report: A 48-year-old woman with a history of seizures since age 35 developed behavioral and affective changes that led to her referral to our mental health unit. She had an unsteady gait, motor clumsiness, emotional instability and impulsivity. Personality changes related with medical illness were diagnosed despite a normal neurological survey. Subsequent development of choreic involuntary movements, evidence of striatal atrophy on MRI and detection of acanthocytes in a peripheral blood smear allowed diagnosis. The role of the basal ganglia in psychiatric manifestations and the pathophysiology of chorea-acanthocytosis are discussed (AU)

Is non-recognition of choreic movements in Huntington disease always pathological?

Clinical experience and prior studies suggest that Huntington disease (HD) patients have low insight into their motor disturbances and poor real-time awareness (concurrent awareness) of chorea. This has been attributed to sensory deficits but, until now, concurrent awareness of choreic movements has not been compared to the degree of insight that presymptomatic carriers of the HD gene and healthy control subjects have into non-pathological involuntary movements. To further investigate loss of insight into motor dysfunction in HD patients, we administered a video-recorded interview and 4 experimental tasks to 68 subjects from the TRACK-HD cohort, including 28 high-functioning patients in early stages of HD, 28 premanifest mutation carriers and 12 controls. All underwent full neurological and neuropsychological evaluations and 3T MRI examinations. Subjects were asked to assess the presence, body location, frequency, practical consequences and probable causes of motor impairments, as well as the presence and body location of involuntary movements during 4 experimental tasks. The accuracy of their judgments, assessed by comparison with objective criteria, was used as a measure of their insight into motor disturbances and of their concurrent awareness of involuntary movements. Insight was poor in early HD patients: motor symptoms were nearly always underestimated. In contrast, concurrent awareness of involuntary movements, although also poor, was essentially indistinguishable across the 3 groups of subjects: non-pathological involuntary movements were as difficult to perceive by controls and premanifest carriers as was chorea for early HD patients. GLM analysis suggested that both concurrent awareness and perception of practical consequences of movement disorder had a positive effect on intellectual insight, and that mental flexibility is involved in concurrent awareness. Our results suggest that low insight into motor dysfunction in early HD, although marginally modulated by cognitive factors, is mainly non-pathological, and parallels a general tendency, shared by healthy subjects, to neglect self-generated involuntary movements in real time. This tendency, combined with the paucity of functional consequences of incipient chorea, could explain the difficulty of its discovery by the patients.

The neuropsychiatric manifestations of Huntington's disease-like 2.

Huntington's disease-like 2 (HDL2) is a rare neuropsychiatric disorder that resembles HD but results from a distinct mutation. The authors present a patient with HDL2, hospitalized for psychiatric management, and they review the neuropsychiatric manifestations of this disorder. Depression, irritability/aggression, and frontal lobe personality changes are common presentations of HDL2 and are comparable to classic HD. Patients with HDL2 may differ from those with HD in having a lower incidence of obsessive-compulsive acts, known suicides, antisocial acts, and changes in sexuality. Clinicians should be aware of the psychiatric presentations of this disorder, when to obtain genetic testing, and how to manage problematic behaviors.

Use of electroconvulsive therapy in a patient with chorea neuroacanthocytosis and prominent delusions.

A middle-aged white man with a diagnosis of chorea neuroacanthocytosis developed progressive and distressing persecutory delusions with an obsessional component. Pharmacotherapy was ineffective in controlling the symptoms or halting their progression. Electroconvulsive therapy was attempted with very limited success but had to be discontinued owing to mild elation and increased irritability. The patient's distress was only improved after his transfer to a nursing home specializing in Huntington disease.

Behavioral, pharmacological, and immunological abnormalities after streptococcal exposure: a novel rat model of Sydenham chorea and related neuropsychiatric disorders.

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.

Acute and chronic corticosteroid treatment of ten patients with paralytic form of Sydenham's chorea.

AIMS: To determine efficacy and safety of corticosteroid treatment in patients with severe Sydenham's chorea paralytic form. METHODS: This is a 4 years observational study on ten patient with severe paralytic form of Sydenham's chorea unresponsive to neuroleptics and antiepileptics agents, treated with intravenous methylprednisolone followed by oral deflazacort therapy. Chorea paralytica patients were bedridden, unable to take independent steps, showed severe generalized hypotonia and were hospitalized for 3-4 weeks. Additional clinical evaluations were undertaken at 1, 3 and 6 months and 1, 2 and 4 years from onset of chorea. Severity chorea at the onset and during follow up was rated according to Universidade Federal de Minas Gerais (UFMG) Sydenham's Chorea Rating Scale (USCRS). In all children video-recording was performing at onset and during clinical follow-up. RESULTS: We reported a significant improvement in swallowing and chewing with partial recovery of language 2-3 days after starting intravenous methylprednisolone treatment and complete disappearance of movement disorders after 3-4 weeks of treatment. All our patients were followed for 4 years from onset and none experienced relapse of chorea, other movement disorders or psychiatric disturbances. The treatment with deflazacort was well-tolerated in all children with no significant side effects reported. CONCLUSION: Our data showed that high dose of methylprednisolone intravenously followed by deflazacort therapy may be effective and well-tolerated in children with severe paralytic form of Sydenham's chorea.