Raphael M. Bonelli

Neuroprotection in Huntington's disease: a 2-year study on minocycline.

Huntingtons disease (HD), a relentlessly progressive neurodegenerative disorder, is characterized by a clinical triad of psychiatric, cognitive and motor disturbances. The antibiotic minocycline, a caspase inhibitor exhibiting antiapoptotic properties, has been shown to prolong survival in the transgenic mouse model of HD. We administrated minocycline to 14 patients with genetically confirmed HD. The patients were psychiatrically, neurologically and neuropsychologically evaluated at baseline, and after 6 and 24 months of treatment, using the Unified HD Rating Scale and a neuropsychological test battery. After 12 months, three patients were lost to follow-up so that 11 patients were analysed at the endpoint. Minocycline was well tolerated. Unlike the expected natural course of HD, patients exhibited stabilization in general motor and neuropsychological function at endpoint, after improving in the first 6 months. Moreover, we found a significant amelioration of psychiatric symptoms that was not apparent after the first 6 months. In detail, the Mini-Mental State Examination, the Total Motor Score, the Total Functional Capacity Scale and the Independence Scale, as the most prominent scales in HD, were stabilized after 3 years of treatment. Our results confirm previous animal studies and indicate a neuroprotective effect of this agent in HD. A long-term, double-blind, placebo-controlled trial appears highly warranted for definitively establishing the value of minocycline in HD.

Huntington's disease: present treatments and future therapeutic modalities.

Huntingtons disease (HD) is a devastating neuropsychiatric disorder for which therapeutic interventions have been rather fruitless to date, except in a slight symptomatic relief. Even the discovery of the gene related to HD in 1993 has not effectively advanced treatments. This article is essentially a review of available double-blind, placebo-controlled trials of therapy for this condition which also includes relevant open label trials. Unfortunately, HD research has tended to concentrate on the motor aspects of the disorder, whereas the major problems are behavioural (e.g. dementia, depression, psychosis), and the chorea is often least relevant in terms of management. We conclude that there is definitely poor evidence in management of HD. The analysis of the 24 best studies fails to result in a treatment recommendation of clinical relevance. Based on data of open-label studies, or even case reports, we recommend riluzole, olanzapine and amantadine for the treatment of the movement disorders associated with HD, selective serotonin reuptake inhibitors and mirtazapine for the treatment of depression, and atypical antipsychotic drugs for HD psychosis and behavioural problems. Moreover, adjuvant psychotherapy, physiotherapy and speech therapy should be applied to supply the optimal management. Finally, some cellular mechanisms are discussed in this paper because they are essential for future neuroprotective modalities, such as minocycline, unsaturated fatty acids or riluzole.

Minocycline for Huntington’s disease: An open label study

Despite advances in understanding the pathogenesis of Huntington’s disease (HD), there is no effective treatment. In the HD transgenic mouse, expression of a dominant-negative caspase-1 mutant extended survival and delayed the onset of symptoms, suggesting that caspase-1 is crucial in HD pathogenesis.1 In fact, the caspase inhibitor minocycline delayed disease progression and extended survival by 14% in the HD mouse model.2 Minocycline is a second-generation tetracycline commonly used for a prolonged period to treat acne. Minocycline crosses the blood–brain barrier and inhibits caspase-1 in acute stroke and decreases infarct size in a mouse stroke model.2 Minocycline protects neurons in mixed spinal cord cultures …

Neuropsychiatric symptoms in a European Huntington's disease cohort (REGISTRY)

Background The majority of Huntingtons disease (HD) mutation carriers experience some psychopathology during their lifetime, varying from irritability to psychosis, but prevalences of particular symptoms vary widely due to diverse study populations in different stages of HD and the use of different assessment methods. Methods The study population consisted of 1993 HD mutation carriers from 15 European countries, all participating in the observational REGISTRY study. The behavioural section of the Unified HD Rating Scale was used to examine the prevalence and correlates of five neuropsychiatric features: depression, irritability/aggression, obsessive/compulsive behaviours, apathy and psychosis. Results Twenty-seven per cent of the participants did not have any neuropsychiatric symptom in the last month. Moderate to severe apathy occurred in 28.1% of the participants, whereas moderate to severe depression was found in 12.7%. Irritable/aggressive symptoms were present in 13.9% of the participants, and 13.2% showed obsessive/compulsive behaviours. Moderate to severe psychotic symptoms were found in only 1.2%. Only 54.9% of all participants with moderate to severe depression used antidepressants, suggesting undertreatment of depression. Obsessive/compulsive behaviours and irritability/aggression were inversely correlated with the Total Functional Capacity score, but with apathy showing the strongest inverse association. Conclusions A variety of neuropsychiatric symptoms are highly prevalent in different stages of HD in this European HD population, with apathy as the most frequent symptom. Depression, irritability/aggression and OCBs are prevalent in all stages of HD. Apathy was the key neuropsychiatric symptom occurring most often in advanced HD stages. Due to possible selection of relatively healthy participants, prevalences reported in this study might be an underestimation of prevalence in the entire HD population.

A systematic review of the treatment studies in Huntington’s disease since 1990

Huntington’s disease (HD) is an autosomal dominant, inherited, neuropsychiatric disease that gives rise to progressive motor, cognitive and behavioural symptoms. Current drug therapy has no effect on the progression of disability, and the need for any pharmacological treatment should be carefully considered. Hyperkinesias and psychiatric symptoms may respond well to pharmacotherapy, but neuropsychological deficits and dementia remain untreatable. Pharmacological intervention in the treatment of the movement disorder of HD is aimed at restoring the balance of neurotransmitters in the basal ganglia. A surprising amount of current drug therapy of HD in clinical practice is based on studies published before 1990. The authors conducted a systematic review of pharmacological therapy in HD using the available papers that were published between 1990 and 2006.

Frontal-subcortical dementias.

Frontal-subcortical dementias are a heterogeneous group of disorders that share primary pathology in subcortical structure and a characteristic pattern of neuropsychologic impairment. Their clinical presentation is characterized by memory disorders, an impaired ability to manipulate acquired knowledge, important changes of personality (apathy, inertia, or depression), and slowed thought processes (or bradyphrenia). It also has marked frontal dysfunction. Classic frontal-subcortical dementias include Huntington chorea, Parkinson disease dementia, progressive supranuclear palsy, thalamic degeneration, subcortical vascular dementia, multiple sclerosis, the acquired immunodeficiency syndrome dementia complex, depressive pseudodementia, and some other rare dementias like spinocerebellar degenerative syndromes, Hallervorden-Spatz disease, choreoacanthocytosis, idiopathic basal ganglia calcification, Guamanian parkinsonism-dementia complex, corticobasal degeneration multiple system atrophy, Wilson disease, metachromatic leukodystrophy, adrenoleukodystrophy, hypoparathyroidism, sarcoidosis, and other CNS inflammatory disorders. Anatomic data suggest that the frontal signs result from a disconnection of the frontal cortex from the basal ganglia. However, most frontal-subcortical dementias show cortical atrophy in later stages, and cortical dementias have subcortical pathology at some point. In fact, the concept might be seen as a continuum, and only the 2 extremes would be represented by pure cortical or subcortical pathology. Anyway, subcortical disorders may still be more similar to one another than they are to AD. Possibly, frontal-subcortical and cortical dementias are the description of the prior main target of the disease process, ending up in both cases in a global dementia. Although the dichotomy cortical versus frontal-subcortical dementia is not strict, the 2 concepts still seem to have advantages.

Sexuality in multiple sclerosis.

Summary.Sexuality and partnership have an important influence on the quality of life of every person and also on people with chronic disorders such as multiple sclerosis. The findings in literature show high evidence that people with multiple sclerosis experience high levels of sexual dysfunction, most of them with hypoactive sexual behaviour often associated with dissatisfaction in relationship, and also the partners seem to show lower sexual and partnership satisfaction. The most common problems in women are lack of sexual interest and decreased libido, often with problems in orgasmic capacity, while men report erectile dysfunction and also lack of sexual interest. The impact of the level of disability and duration of the illness remains unclear. Positive familial support can often help the patient in coping with the illness, nonetheless problems with changing roles and multiple-sclerosis-minimizing can improve the need of contacts to outstanding persons.

Normal striatal D2 receptor binding in idiopathic restless legs syndrome with periodic leg movements in sleep.

Dopaminergic treatment is very effective in restless legs syndrome (RLS) and periodic leg movements in sleep (PLMS). However, neuroreceptor imaging studies that addressed altered striatal dopaminergic function have given controversial results. In this present study, 14 patients with idiopathic RLS (iRLS) and PLMS with a good response to dopaminergic and non-dopaminergic treatment and ten healthy sex- and age-matched controls were investigated off-medication by using 123I-IBZM and SPECT. RLS symptoms and sleep disturbances were evaluated using three nights of polysomnography, the Pittsburgh Sleep Quality Index, and the International RLS Study Group (IRLSSG) rating scale. The patients presented with sleep disturbances, a high PLMS index (56.2±33.1 per h), and severe RLS symptoms during SPECT (IRLSSG rating scale 23.1±8.0), and showed no significant differences in striatal to frontal IBZM binding to D2 receptors compared to controls (ratio striatum/frontal cortex, right side 1.60±0.10 vs 1.63±0.08, P = 0.35, NS; left side 1.61±0.11 vs 1.63±0.08, P = 0.51, NS). These findings show normal function of striatal D2 receptors in successfully treated patients with iRLS and PLMS. Dopaminergic and non-dopaminergic pretreatment does not appear to change striatal D2 receptor binding as compared to healthy controls. Structures other than striatal D2 receptors are discussed as possible causes of the treatment effects in RLS.

Structural neuroimaging of the basal ganglia in schizophrenic patients: a review

ZusammenfassungVerschiedene Gründe sprechen für eine wichtige Rolle der Basalganglien in der Schizophrenie-forschung: So findet sich in diesen Strukturen eine hohe Dichte an Dopaminrezeptoren, an welchen viele Neuroleptika wirken, mit denen die Schizophrenie seit Jahren erfolgreich behandelt wird. Andererseits haben die Basalganglien eine wichtige Funktion bei der Ausübung höherer kognitiver Funktionen wie Aufmerksamkeit, Merkfähigkeit und zielgerichtetes Verhalten, die allesamt bei Schizophrenie-kranken Störungen unterliegen. Die Magnetresonanztomographie erlaubt eine nicht-invasive Darstellung und Messung dieser Strukturen in Vivo. Ziel dieser Arbeit war daher die Erfassung aller verfügbaren Studien zur Magnetresonanztomographie von Basalganglien bei Schizophrenie. Zusammenfassen zeigten sich in den Ergebnissen Hinweise auf verminderte Nucleus Caudatus-Volumina bei Erstmanifestation der Erkrankung, wohingegen Untersuchungen chronisch erkrankter Schizophrener überwiegend Volumsvergrößerungen von Caudatus, Putamen und Pallidum zeigen. Die Ergebnisse von Verlaufsstudien zeigen, dass atypische und typische Neuroleptika unterschiedliche morphologische Veränderungen hervorrufen und, dass diese Veränderungen dynamisch und reversibel sind. Zum besseren Verständnis jener Mechanismen, welche strukturelle Veränderungen der Basalganglien bei Schizophrenie bewirken, werden weitere Untersuchungen erforderlich sein, in denen insbesondre Medikamenteneffekte eine verstärkte Beachtung finden sollten.SummaryThe basal ganglia structures have quickened interests in schizophrenia research for several reasons: On the one hand, schizophrenic patients are successfully treated with neuroleptics acting on dopamine receptors, which are highly concentrated in the basal ganglia structures. On the other hand, basal ganglia play an important role in higher cognitive functions such as attention, working memory and goal-directed behavior, which are impaired in schizophrenia. Magnetic resonance imaging allows non-invasive in vivo volumetric measurement of these brain structures. In this review, we studied all available papers on MRI research of the basal ganglia in schizophrenic patients. We found a possibly decreased caudate volume in first-episode schizophrenic patients, whereas studies on chronic patients mostly reveal volume increases in caudate, putamen and pallidum. Data from longitudinal studies suggest on the one hand that typical and atypical neuroleptics may produce different effects on brain morphology and on the other hand, that these changes are dynamic and might be reversible. Further studies are warranted for a better understanding of the mechanisms, which may lead to structural basal ganglia abnormalities, with medication effects demanding particular attention.

Prevalence of autoimmune thyroiditis and non-immune thyroid disease in multiple sclerosis.

Abstract. Since multiple sclerosis (MS) and autoimmune thyroiditis (AIT) are presumed to be of autoimmune origin the correlation of these two diseases is of special interest. The aim of this study was to determine whether there are differences in the prevalence of thyroid disease with special emphasis on AIT compared with MS and normal subjects and whether the presence of thyroid disease correlates with disability, disease course, age, and disease duration. 353 consecutive patients with clinically definite MS, without interferon-beta treatment and 308 patients with low back pain or headache were extensively examined for the presence of non-immune or autoimmune thyroid disease. We found a significantly higher prevalence of AIT in male MS patients (9.4 %) than in male controls (1.9 %; p = 0.03). The prevalence of AIT in female MS patients (8.7 %) did not differ from female controls (9.2 %). Hypothyroidism, caused by AIT in almost all cases, showed a tendency to be more severe and more often present in patients with MS. There was no association between relapsing-remitting and secondary progressive disease course of MS and the prevalence of AIT. MS patients with AIT were significantly older but did not differ in disease duration and expanded disability status scale (EDSS). Further studies are warranted, to see if there is a difference in sex-hormone levels between MS patients with and without AIT and healthy controls. Longitudinal studies comparing MS patients with or without AIT could show whether there is an influence of AIT on the disease course or progression.