Michael Abele

Magnetic resonance imaging-based volumetry differentiates idiopathic Parkinson's syndrome from multiple system atrophy and progressive supranuclear palsy.

By using three‐dimensional magnetic resonance imaging–based volumetry, we studied atrophy of the caudate nucleus, putamen, brainstem, and cerebellum in patients with idiopathic Parkinsons syndrome (IPS, n = 11), progressive supranuclear palsy (PSP, n = 6), and multiple system atrophy with predominant parkinsonism (MSA‐P, n = 12) or ataxia (MSA‐C, n = 17). Patients were compared with a total of 46 controls, of whom 16 were age matched. Mean striatal, cerebellar, and brainstem volumes were normal in patients with IPS. We found significant reductions in mean striatal and brainstem volumes in patients with MSA‐P, MSA‐C, and PSP, whereas patients with MSA‐C and MSA‐P also showed a reduction in cerebellar volume. On an individual basis, volumes of structures in patients with MSA and PSP showed an extensive overlap with the normal range with the exception of brainstem volumes in patients with MSA‐C. Therefore, groups could not be discriminated on the basis of individual structure volumetry. Application of stepwise discriminant analysis, however, allowed discrimination of all 12 patients with MSA‐P, 15 of 17 patients with MSA‐C, and 5 of 6 patients with PSP from the normal and IPS cohorts. However, patients with IPS could not be separated from controls and patients with MSA‐P could not be separated from patients with PSP. In conclusion, total intracranial volume–normalized magnetic resonance imaging–based volumetric measurements provide a sensitive marker to discriminate typical and atypical parkinsonism. Ann Neurol 1999;45:65–74

Autosomal dominant cerebellar ataxia type I : oculomotor abnormalities in families with SCA1, SCA2, and SCA3

Abstract Forty-six patients suffering from autosomal dominant cerebellar ataxia type I (ADCA I) underwent to a genotype-phenotype correlation analysis by molecular genetic assignment to the spinocerebellar ataxia type 1, 2, or 3 (SCA1, SCA2, SCA3) genetic locus and electro-oculography. Oculomotor deficits that are attributed to dysfunction of cerebellar structures occurred in all three mutations without major differences between the groups. Gaze-evoked nystagmus, however, was not found to be associated with SCA2. Square wave jerks were exclusively observed in SCA3. The gain in vestibulo-ocular reflex was significantly impaired in SCA3 and SCA1. In SCA3 the severity of vestibular impairment increased with CAG repeat length. Severe saccade slowing was a highly characteristic feature of SCA2. In SCA3 saccade velocity was normal to mildly reduced while SCA1 fell into an intermediate range. The present data show that each mutation is associated with a distinct syndrome of oculomotor deficits. Reduced saccade velocity and the absence of both square-wave jerks and gaze-evoked nystagmus allow one SCA2 to be distinguished from SCA3 patients in almost all cases. The eye movement disorder of SCA1 patients, however, overlaps with both SCA2 and SCA3.

Presentation, diagnosis, and management of multiple system atrophy in Europe: Final analysis of the European multiple system atrophy registry†

Multiple system atrophy (MSA) is a Parkinsons Disease (PD)‐like α‐synucleinopathy clinically characterized by dysautonomia, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. We aimed to determine whether the clinical presentation of MSA as well as diagnostic and therapeutic strategies differ across Europe and Israel. In 19 European MSA Study Group centres all consecutive patients with a clinical diagnosis of MSA were recruited from 2001 to 2005. A standardized minimal data set was obtained from all patients. Four‐hundred thirty‐seven MSA patients from 19 centres in 10 countries were included. Mean age at onset was 57.8 years; mean disease duration at inclusion was 5.8 years. According to the consensus criteria 68% were classified as parkinsonian type (MSA‐P) and 32% as cerebellar type (MSA‐C) (probable MSA: 72%, possible MSA: 28%). Symptomatic dysautonomia was present in almost all patients, and urinary dysfunction (83%) more common than symptomatic orthostatic hypotension (75%). Cerebellar ataxia was present in 64%, and parkinsonism in 87%, of all cases. No significant differences in the clinical presentation were observed between the participating countries. In contrast, diagnostic work up and therapeutic strategies were heterogeneous. Less than a third of patients with documented orthostatic hypotension or neurogenic bladder disturbance were receiving treatment. This largest clinical series of MSA patients reported so far shows that the disease presents uniformly across Europe. The observed differences in diagnostic and therapeutic management including lack of therapy for dysautonomia emphasize the need for future guidelines in these areas.

Red Flags for Multiple System Atrophy

The clinical diagnosis of multiple system atrophy (MSA) is fraught with difficulty and there are no pathognomonic features to discriminate the parkinsonian variant (MSA‐P) from Parkinsons disease (PD). Besides the poor response to levodopa, and the additional presence of pyramidal or cerebellar signs (ataxia) or autonomic failure as major diagnostic criteria, certain other clinical features known as “red flags” or warning signs may raise the clinical suspicion of MSA. To study the diagnostic role of these features in MSA‐P versus PD patients, a standardized red flag check list (RFCL) developed by the European MSA Study Group (EMSA‐SG) was administered to 57 patients with probable MSA‐P and 116 patients with probable PD diagnosed according to established criteria. Those red flags with a specifity over 95% were selected for further analysis. Factor analysis was applied to reduce the number of red flags. The resulting set was then applied to 17 patients with possible MSA‐P who on follow‐up fulfilled criteria of probable MSA‐P. Red flags were grouped into related categories. With two or more of six red flag categories present specificity was 98.3% and sensitivity was 84.2% in our cohort. When applying these criteria to patients with possible MSA‐P, 76.5% of them would have been correctly diagnosed as probable MSA‐P 15.9 (±7.0) months earlier than with the Consensus criteria alone. We propose a combination of two out of six red flag categories as additional diagnostic criteria for probable MSA‐P.

Restless legs syndrome in spinocerebellar ataxia types 1, 2, and 3.

Abstract To identify the prevalence and determinants of restless legs syndrome (RLS) in spinocerebellar ataxia (SCA) we studied 58 patients with a molecular diagnosis of SCA1, SCA2 and SCA3. Data on the symptoms of RLS were collected by a standardized questionnaire, and RLS was diagnosed when patients met the four minimal criteria of the syndrome as recently defined by an international study group. In addition, we studied the relationship between RLS and age, age at ataxia onset, CAG repeat length, and nerve conduction and evoked potentials data. RLS was significantly more frequent in SCA patients than in controls (28 % vs. 10 %). Age at RLS onset in SCA was 49.0 ± 10.9 years. There were no significant differences in nerve conduction or evoked potentials between RLS and non-RLS SCA patients. The probability of developing RLS increased with age but not with CAG repeat length or higher age of ataxia onset. The data provide evidence that patients with SCA1, SCA2 and SCA3 are per se more susceptible to RLS than non-affected individuals. The probability of developing RLS is related principally to the period over which the CAG repeat mutation exerts its effect and not to CAG repeat length or age of ataxia onset.

Progression of multiple system atrophy (MSA): A prospective natural history study by the European MSA study group (EMSA SG)

The disease‐specific Unified Multiple System Atrophy Rating Scale (UMSARS) has been developed recently and validated for assessing disease severity in multiple system atrophy (MSA). Here, we aimed at (1) assessing rates of disease progression in MSA and (2) validating UMSARS for sensitivity to change over time. Impairment was assessed at two time points 12 months apart using UMSARS Part I (historical review), UMSARS Part II (motor examination), as well as measures of global disease severity, including UMSARS Part IV, Hoehn and Yahr (HY) Parkinsons disease staging, Schwab England Activities of Daily Living (SE ADL), and a three‐point global Severity Scale (SS3). Fifty patients (male:female ratio, 1:0.9; possible MSA, 16%; probable MSA, 84%; MSA‐parkinsonian, 58%; MSA‐cerebellar, 42%) were assessed twice with an interval of 12.3 months. UMSARS II scores progressed by 57.3% (P < 0.0001) and UMSARS I scores by 35.6% (P < 0.0001) in relation to the respective baseline scores with no differences between motor subtypes, diagnostic categories and gender. Significant inverse correlations between (1) UMSARS I or UMSARS II progression and (2) baseline disability measures (i.e., the respective UMSARS or SS3 scores) and disease duration were found. Furthermore, the increases in HY staging, SE ADL and SS3 correlated significantly with UMSARS I, UMSARS II, and UMSARS IV progression. This report is the first prospective study showing rapid annual UMSARS rates of decline in MSA. Our data contribute to the ongoing validation process of UMSARS, and they facilitate the planning and implementation of future neuroprotective intervention trials.

Reliability and validity of the scale for the assessment and rating of ataxia: a study in 64 ataxia patients.

The objective of this study was to test the reliability and validity of the Scale for the Assessment and Rating of Ataxia (SARA) in ataxia patients not suffering from autosomal dominant spinocerebellar ataxia (SCA). To this end, 64 patients with various ataxia disorders or stable cerebellar lesions were rated independently by two investigators. In addition to SARA, the following assessment instruments were applied: ataxia disease stage, Barthel index and part IV (functional assessment) of the Unified Huntingtons Disease Rating scale (UHDRS‐IV). Eighteen patients were rated twice. Inter‐rater and intrarater reliability were very high with ICCs of 0.98 and 0.99. Internal consistency was high indicated by Cronbachs α of 0.97. Factorial analysis revealed that the rating results were mainly determined by one major factor with an eigenvalue of 6.34 which explained 52.8% of the variance. SARA score increased with disease stage (P < 0.0001) and was closely correlated with Barthel index (r = −0.63, P < 0.0001) and UHDRS‐IV (r = −0.62, P < 0.0001), but only weakly correlated with disease duration (r = 0.44, P < 0.001). The results suggest that SARA is a reliable and valid measure of ataxia in non‐SCA ataxia patients.

Bright light therapy in Parkinson's disease: a pilot study.

Several observations suggest a beneficial effect of melatonin antagonism for Parkinsons disease (PD). Although bright light therapy (BLT) suppresses melatonin release and is an established treatment for depression and sleep disturbances, it has not been evaluated in PD. We examined effects of BLT on motor symptoms, depression, and sleep in PD in a randomized placebo‐controlled double‐blind study in 36 PD patients, using Parkinsons Disease Rating Scale (UPDRS) I–IV, Becks Depression Inventory, and Epworth Sleepiness Scale. All patients received BLT for 15 days in the morning, 30 min daily. Illuminance was 7.500 lux in the active treatment group and 950 lux in the placebo group. Although group differences were small, BLT led to significant improvement of tremor, UPDRS I, II, and IV, and depression in the active treatment group but not in the placebo group. It was very well tolerated. Follow up studies in more advanced patient populations employing longer treatment durations are warranted.

Voxel-based morphometry and voxel-based relaxometry in multiple system atrophy-a comparison between clinical subtypes and correlations with clinical parameters.

Multiple system atrophy (MSA) is a neurodegenerative disease affecting basal ganglia, brainstem, cerebellum, and intermediolateral cell columns of the spinal cord. Clinically, a cerebellar (MSA-C) and a parkinsonian variant of MSA (MSA-P) are distinguished. We used voxel-based morphometry (VBM) and voxel-based relaxometry (VBR) in 48 MSA patients (32 MSA-C, 16 MSA-P) and 46 controls. In MSA-C, VBM revealed gray matter loss in cerebellum, right thalamus, both putamina and several cortical regions including insular cortex. Gray matter loss in the cerebellum and insular cortex was correlated with disease duration and severity. There was white matter loss in the brainstem, which was correlated with disease duration and severity. VBR analysis in MSA-C showed decreased relaxation rate R2 in cerebellum, pontine brainstem and cortical regions including insular cortex. In MSA-P, gray matter was reduced in cerebellum, dorsal midbrain, both putamina, and several cortical regions including insular cortex. A correlation with disease duration and severity was detected only for some small cortical areas. Direct comparison of MSA-C and MSA-P showed differences only in infratentorial brain regions where structural abnormalities were more pronounced in MSA-C than in MSA-P. In MSA-C, there was a stronger reduction of gray matter in the basal parts of the cerebellum, of white matter in the brainstem and of the relaxation rate R2 in the cerebellum and brainstem.

Cerebellar ataxia with glutamic acid decarboxylase autoantibodies

Article abstract Degenerative cerebellar ataxia with autoantibodies against glutamic acid decarboxylase (GAD) is a rare disorder and may represent a subset of ataxias previously classified as idiopathic. The authors report a patient with progressive cerebellar ataxia, insulin-dependent diabetes mellitus, and GAD antibodies who responded to IV immunoglobulins.