Showing papers by "Klaus Seppi published in 2001"

Riluzole in Huntington's disease (HD) : an open label study with one year follow up

Abstract: In an open label study, we administered riluzole (50 mg twice a day) to nine patients with genetically confirmed Huntington's disease (HD) (clinical stages 1-3; mean age 46.4 (SD 9.3) years; mean disease duration 8 (SD 3.3) years). The study was designed to evaluate (1) safety and tolerability of riluzole and (2) effects of riluzole on motor impairment, functional disability, cognitive impairment, and behavioral abnormalities using the Unified HD Rating Scale. Patients were evaluated at baseline and after three and twelve months of riluzole therapy. Laboratory tests (hematology and liver enzymes) were repeated monthly. All adverse experiences, reported spontaneously or observed directly by the investigator, were recorded. Riluzole was well tolerated. No increase of serum liver enzymes was seen throughout the study in all but one patient showing a mild elevation. At three months, mean total motor scale (TMS), mean TMS chorea subscore, and mean total functional capacity scale were significantly improved compared with baseline. At twelve months, however, this beneficial effect on motor status and overall function was not sustained. In contrast, severity and frequency of behavioral dysfunction as well as psychomotor speed assessed by the symbol digit modalities test were improved compared with baseline. Our data suggest that there are transient antichoreatic effects and more sustained effects of riluzole on psychomotor speed and behavior in patients with HD. A double-blind, placebo-controlled trial appears highly warranted to establish definitely the symptomatic versus neuroprotective actions of riluzole in HD.

Striatal dopamine transporter function in dementia with Lewy bodies and Parkinson's disease

Abstract: The aim of this study was to compare parkinsonian features and loss of striatal dopamine transporter (DAT) function in patients with dementia with Lewy bodies (DLB) and Parkinson's disease (PD), matched for age and disease duration. Twenty patients with DLB, 24 PD patients and 10 matched controls were examined with SPET using a dual-head camera and the dopamine-transporter ligand 123I-β-CIT (148 MBq). Moreover, in a subgroup of patients (16 DLB and 20 PD patients), subscores of the Unified Parkinson's Disease Rating Scale (UPDRS) – motor examination (ME) subscale were obtained during "practical off", i.e. 12 h following withdrawal of antiparkinsonian therapy. Compared with controls, striatal/cerebellar (S/C) ratios of DAT binding were significantly reduced in both DLB and PD, deficits being more marked in DLB patients (controls 7.2±1.2, DLB 3.3±1, PD 4.2±1.4; means±SD). The side-to-side differences in the S/C ratios were lower in the DLB group and the controls than in PD patients (0.4±0.4, 0.2±0.2 and 0.6±0.3, respectively, P<0.05). The total UPDRS-ME scores during practical-off were significantly higher in the DLB than in the PD group (41.2±12.7 vs 26.6±15.3, P<0.01). The side-to-side differences of the summed UPDRS extremity subscores were smaller in the DLB than in the PD group (2.2±2.3 vs 7.4±3.9, P<0.0001). Our findings suggest that parkinsonism evolves largely symmetrically and progresses more rapidly with more severe loss of striatal dopamine transporter function in DLB compared to PD. Whether these findings are helpful in the differential diagnosis of DLB and PD needs to be examined in further studies.

Multiple system atrophy.

Abstract: Multiple system atrophy (MSA) is an adult-onset sporadic progressive neurodegenerative disorder of unknown etiology. It is clinically characterized by the variable combination of autonomic failure, parkinsonism, cerebellar ataxia, and pyramidal signs. The present review summarizes up-to-date knowledge on the clinical diagnosis and molecular pathology of MSA. We also review the role of additional investigations that may support a clinical diagnosis of MSA. Finally, we briefly discuss the management of MSA, focusing on possible future therapeutic strategies.

Irresistible onset of sleep during acute levodopa challenge in a patient with multiple system atrophy (MSA): placebo-controlled, polysomnographic case report.

Abstract: A 67-year-old male patient with clinically probable multiple system atrophy developed severe reproducible sleepiness and irresistible onset of sleep during an acute levodopa (L-dopa) challenge. In a placebo-controlled, double-blind study of acute L-dopa challenge, videopolysomnography revealed multiple episodes of non-rapid eye movement sleep 60 minutes after L-dopa and none following placebo. These observations suggest the irresistible sleep can also be induced by L-dopa and also in patients with atypical parkinsonism.

Overstimulation of the alpha1B-adrenergic receptor causes a "seizure plus" syndrome.

Abstract: To the editor—Zuscik and colleagues report transgenic mice with overexpression of the α1B-adrenergic receptor (α1BAR) leading to apoptotic neurodegeneration in α1B-expressing domains including cerebral cortex, hypothalamus, thalamus and cerebellum. Moreover, their model showed a reduction of tyrosine hydroxylase immunoreactivity in the substantia nigra with a loss of neuronal cell bodies and axonal projections. Transgenic mice exhibited a terazosineand L-DOPA–responsive parkinson-like motor disorder predominantly affecting gait in association with recurrent grand mal seizures and some degree of autonomic failure. The authors propose that both the behavioural and neuropathological phenotype displayed by α1BAR transgenic mice are consistent with the autonomic (Shy–Drager) presentation of multiple system atrophy (MSA). We disagree with this conclusion. MSA is a neurodegenerative disorder that is dominated clinically by autonomic dysfunction and L-DOPA–unresponsive parkinsonism, or less commonly, cerebellar ataxia. The term ‘Shy–Drager syndrome’ has been misused in the past to encompass not only MSA, but also Parkinson disease (PD) with autonomic failure. It was therefore abandoned by a recent consensus conference on the clinical diagnosis of MSA (ref. 5). A seizure disorder, one of the key features of the transgenic mice model described by Zuscik and colleagues, does not occur in MSA (ref. 3). Furthermore, the pattern of brain lesions present in the transgenic mouse model (beginning in cortex, hypothalamus and cerebellum, then progressing with age to encompass all brain areas) is only partially consistent with the neuropathology of MSA that is characterized by neuronal cell loss and gliosis particularly involving putamen and substantia nigra (striatonigral degeneration) as well as pons, inferior olives and cerebellar cortex (olivopontocerebellar atrophy), and preganglionic sympathetic centres in the intermediolateral cell column of the spinal cord. In contrast, cortex and hypothalamus are relatively spared. In addition, in MSA there is prominent subcellular pathology comprising αsynuclein–positive glial and neuronal cytoplasmic and nuclear inclusions, with a distribution selectively involving basal ganglia, supplementary and primary motor cortex, reticular formation, basis pontis, middle cerebellar peduncles and cerebellar white matter. Together with Parkinson Disease and dementia with Lewy bodies, MSA is increasingly conceived as α-synucleinopathy. Although Zuscik et al. briefly mention the presence of cytoplasmic inclusions in the discussion, they do not state whether MSA-like glial and/or neuronal α-synuclein inclusions were present in the transgenic brains. We therefore conclude that Zuscik et al. provide no convincing evidence for a transgenic mouse model of MSA and instead report an unusual ‘seizure-plus’ syndrome based on a neuronal multisystem degeneration with prominent cortical degeneration.

Diagnosis and therapy of multiple system atrophy

Abstract: Numerous studies of the past years have established the clinical features, course and neuropathology characterizing multiple system atrophy (MSA). Clinically, two motor subtypes can be classified based on the predominance of a parkinsonian syndrome refractory to L-dopa and cerebellar ataxia. 80% of the cases involve MSA-P (the parkinsonian variant of MSA) and 20% MSA-C (cerebellar variant of MSA). Virtually all of these patients show disturbances of autonomic and urogenital function, half of the patients also exhibit pyramidal signs. Neuropathologically, MSA-C is based on an olivopontocerebellar atrophy (OPCA) and MSA-P on striatonigral degeneration (SND). However, a combination of OPCA and SND pathologies is observed in most cases. Recent evidence suggests that a key pathogenetic role may be played by glial alpha synuclein-containing inclusion bodies, which might lead to neuronal dysfunction and ultimately to cell loss. There is no therapy known to be effective in treating the motor disorders of MSA-C. By contrast, L-dopa replacement is at least transiently effective in about 30% of patients with MSA-P. Currently, initial efforts are being undertaken throughout Europe to develop neuroprotective solutions. Experiments are underway to test whether neurotransplantation by striatal grafting is a suitable method for inducing a clinically relevant response to L-dopa. Neurologically, the options for treating orthostatic hypertension and urogenital disorders are often overlooked.