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Netherlands Society of Neurology
Clinical Neurology and Neurosurgery 101 (1999) 280 – 283 www.elsevier.com/locate/clineuro
Society Proceedings
Netherlands Society of Neurology SecretariatNetherlands Society of Neurology c/o Dr P.J. Koehler, Netherlands Society of Neurology, P.O. Box 20050, 3502 LB Utrecht, The Netherlands Abstracts from the scientific meeting held on the 10 and 11 December 1998
1 White matter changes after radiotherapy for primary cerebral nonHodgkin’s lymphoma —J.E.C. Bromberga, M.W.M. Wassenberga, Th.D. Witkampb, M.J.B. Taphoorna, aUni6ersity Department of Neurology, Utrecht, bUni6ersity Department of Radiology, Utrecht Aim: To investigate the frequency of white matter changes after radiotherapy for primary cerebral non-Hodgkin’s lymphoma (PCNL) and to assess the incidence of clinical symptoms of leucoencephalopathy in these patients. Furthermore to assess which factors predisposed for white matter changes and how long after treatment these changes developed. Methods: Using regional cancer registry data, charts of all patients diagnosed with PCNL between 1986 and 1996 were reviewed. For patients treated with radiotherapy, cranial imaging was retrieved. The presence or absence of leukoencephalopathy was assessed from the charts according to predefined criteria. All scans were assessed for white matter lesions before and after treatment but before tumor recurrence, whenever possible. Results: We found 44 patients with PCNL treated with radiotherapy. White matter lesions were found in patients surviving at least 8 months. For 20 patients who survived more than 8 months scans were retrieved and reassessed. In 14 of these (70%) white matter lesions developed or increased significantly: in patients aged 60 or over an increase was seen in 86%. For 12 patients with increased white matter lesions, data on clinical symptoms could be retrieved: at least six had symptoms of leukoencephalopathy. The number of treated patients was too small to determine the effect of radiotherapy dose and the addition of chemotherapy. Conclusion: The risk of white matter lesions on cranial imaging is high in patients surviving more than 8 months after treatment with radiotherapy for PCNL and a significant proportion of patients with white matter lesions have symptoms of leukoencephalopathy. 2 Epilepsy, risks and insurances: preliminary results —M.C.T.F.M. de Kroma, A.E.H. Sonnenb, J. Grie¨ta, J. vd Heijdena, E. Beghic also on behalf of the rest-group, aMaastricht Uni6ersity Hospital, Maastricht, The Netherlands, bHans Bergerkliniek, Breda, The Netherlands, cInstituto di Ricerche Farmacologiche ‘Mario Negri’, Milan, Italy Although reliable data are lacking, people with epilepsy are considered to be at a higher risk for accidents and illnesses. A European multicentre patient control study was started to obtain data regarding illnesses, accidents and social conditions of patients with epilepsy. Patients were recruited if their epilepsy was diagnosed
within 5 years or less (80% of the cases) or within 10 years or less (20% of the cases). Acute symptomatic seizures (i.e. occuring within 30 days after a cerebral insult) and seizures due to a progressive neurological disease were excluded. Control persons were recruited among family members, colleagues or friends of the people with epilepsy. Follow up was 12 months at least. At intake demographic variables, current and best occupation, and (in case of epilepsy only) details regarding epileptic seizures and syndrome were collected. Patients and controls recorded prospectively illnesses, accidents, medication and (patients only) seizures using a calender which was checked every month by the center’s study coordinator. Preliminary results: data of 1037 patients and 993 controls are processed at this moment. Patients have a lower number of illnesses and more accidents compared to their controls, but if seizure related accidents are left out, patients and controls have the same number of accidents. Furthermore if only data of adults are considered, people with epilepsy have an odds ratio for driving, sport, better education, better occupation and insurance of 0.27, 0.59, 1.30, 0.60 and 1.49, respectively. 3 PCV chemotherapy in recurrent glioblastoma multiforme —A.C. Kappellea, T.J. Postmaa, M.J.B. Taphoornb, C.J. v Groeningena, J.J. Heimansa, aUni6ersity Hospital Vrije Uni6ersiteit Amsterdam, b Uni6ersity Hospital Utrecht, The Netherlands Objecti6e: To evaluate the efficacy and toxicity of PCV chemotherapy (a combination of procarbazine, CCNU and vincristine) in patients with a recurrent glioblastoma multiforme (GBM). Methods: A total of 24 patients with a recurrent GBM were treated with PCV chemotherapy. In all, 18 patients had a recurrence of a primary GBM, whereas six patients had former histology of a lower grade tumor. Response was evaluated according to Macdonald’s criteria. Toxicity was scored according to NCIC-CTC criteria. Results: A total of 24 patients, median age 48 years were evaluated. The patients received 1 – 7 cycles (median 2) of PCV. Dose-limiting toxicity was not encountered. Complete response (CR) was observed in one, partial response (PR) in two, stable disease (SD) in four and progressive disease (PD) in 17 patients. Median time to tumor progression (TTP) and median survival for all patients were 3 and 8 months, respectively, 3 and 6 months for those patients with PD, and 9 and 11 months for patients with CR, PR or SD. Conclusions: In a minority of patients (29%) with a recurrent GBM, PCV chemotherapy induces an effect (CR, PR or SD) which results in a prolongation of TTP and survival. Toxicity due to PCV chemotherapy is acceptable.
0303-8467/99/$ - see front matter © 1999 Elsevier Science B.V. All rights reserved. PII: S 0 3 0 3 - 8 4 6 7 ( 9 9 ) 0 0 0 2 9 - 3
Society Proceedings / Clinical Neurology and Neurosurgery 101 (1999) 280–283 4 Clinical features and diagnosis of degenerative ataxias at a Hereditary Brain Disease clinic —H.P.H. Kremer, N.V.A.M. Knoers, Polikliniek Erfelijke Hersenziekten, St. Radboud Ziekenhuis Nijmegen Between May 1 1994 and October 1 1998 we examined a consecutive series of 144 subjects suffering from, or at risk of hereditary or degenerative ataxia. Setting: the Hereditary Brain Disease clinic, a tertiary referral center. The first group of 59 individuals from 35 families were diagnosed as Autosomal Dominant Cerebellar Ataxia (ADCA). In 35 affected patients from 26 ADCA families, genotyping revealed the following distribution ( c patients/c families): 3/2 SCA1; 4/4 SCA2; 4/4 SCA3; 7/4 SCA6; 5/4 SCA7; 12 affected patients from eight families could not be genotyped. A second group of 57 patients from 44 families was classified as recessive ataxia. Of those, eight (six families) turned out to have Friedreich’s Ataxia, with homozygosity for GAA expansion in intron 1 of the frataxin gene. Three had onset around age 30, with retained tendon reflexes at ages 38, 38 and 40, respectively. A ninth patient turned out to be a compound heterozygote. Eight patients presented with Friedreich-like progressive spinocerebellar disease (oculomotor abnormalities, dysarthria, limb ataxia, and lower limb pyramidal tract abnormalities) without GAA expansion. A third group consisted of 28 patients with sporadic late onset ataxia, after age 45. The majority (n = 21) was diagnosed as Multiple Systems Atrophy. 5 CADASIL: survey and Dutch research results—S.A.J. Lesnik Obersteina, M.H. Breuninga, J. Haanb, aDepartment of Clinical Genetics, Leiden Uni6ersity Medical Centre, bRijnland Hospital and L.U.M.C. (For the Dutch CADASIL research group) CADASIL is a late-onset hereditary disease characterised by recurrent strokes, vascular dementia, migraine with aura ( 9 35%) and mood disorders ( 930%). Cerebral MRI in symptomatic, but also in many presymptomatic individuals, shows a confluent leukoencephalopathy and small subcortical infarcts. Pathognomonic for CADASIL is electron-dense granular material in the media of small cerebral arteries. These non-amyloid, non-atherosclerotic deposits can also be found in arteries of other organs, such as skin arterioles. Recently, mutations have been found in the Notch3 gene on chromosome 19, introducing mutation analysis as an important diagnostic tool in CADASIL families. Until now, 15 Dutch families have been referred to our research group. For most of these we have been able to confirm the diagnosis by detecting a mutation in exon 4 of the Notch3 gene. Considering more than 120 families have been described worldwide, it is reasonable to assume that CADASIL is not a rare disease. Therefore, we expect that there may be more Dutch CADASIL families. We present a clinical survey of CADASIL, as well as results of mutation analysis in Dutch CADASIL families. 6 Early immune activation in muscle biopsies from patients with Critical Illness Polyneuromyopathy —M.A.C.J. Megens-de Letter a,b , P.A. van Doornb, H.F.J. Savelkoulc, P.I.M. Schmitzd, A.A.W. Op de Coula, L.H. Vissera, M. Krossb, J.L.J.M. Teepena, F.G.A. van der Meche´b, aDepartment of Neurology, St. Elisabeth Hospital, Tilburg, The Netherlands, bDepartment of Neurology, Uni6ersity Hospital and Erasmus Uni6ersity Rotterdam, cDepartment of Immunology, Uni6ersity Hospital and Erasmus Uni6ersity Rotterdam, d Department of Statistics, Uni6ersity Hospital Daniel den Hoed and Erasmus Uni6ersity Rotterdam In a longitudinal prospective study we included 98 patients, who needed artificial respiration and followed them for the development of Critical Illness Polyneuromyopathy (CIPNM). We evaluated signs of local immune activation using routine lightmicroscopic and im-
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munohistochemical studies in muscle biopsies of all 30 patients who developed CIPNM. Neuropathic changes were found in 33%, myopathic in 37% and both neuropathic and myopathic changes in 27%. Immunohistochemical analysis comprised: CD4, CD8, CD20, CD68, E-selectin, ICAM1, VCAM, Membrane Attack Complex (MAC), HLA-I and HLA-DR. CD4 positive T-cells were seen in 60% (18/30). Small infiltrates with macrophages (CD68) and Th1-cells (CD4) were present in 27% (8/30). Overall macrophages were present in 33% (10/30) of the biopsies. Expression of E-selectin was negative, but that of ICAM-1 was found in 54% (14/26) and VCAM in 57% (17/30). MAC stained on the vascular endothelium in 72% (21/29) of the biopsies. In all cases HLA-I and HLA-DR were upregulated. We analysed the muscle tissue for the expression of proinflammatory cytokines, because the results thus far showed signs of early immune activation. Immunohistochemical staining was found for IL-1b in 83% (24/29), IFN-g in 43% (12/28), IL-12 in 69% (20/29) and TNF-aR75 in 90% (27/30) of the biopsies. The increased number of macrophages is associated with the release of proinflammatory cytokines that may result in temporary Th1-cell activation (amplified by an HLA-1 and HLA-DR upregulation). Expression of ICAM-1, VCAM and MAC suggests increased vascular permeability that can damage the muscle fibers. This shows that early local immune activation may be of importance in the pathophysiology of muscle weakness in patients with CIPNM. 7 The diagnostic value of electrophysiological studies in the diagnostic work-up of patients with a peripheral neuropathy— N.R. Rosenberg, M. de Visser, P. Portegies, M. Vermeulen, Academic Medical Centre, Amsterdam Background: We investigated whether electrophysiological studies direct the clinician in a focused search for an aetiology in patients with peripheral neuropathy of at least 6 weeks. Methods: We reviewed medical records of 209 patients referred with a possible peripheral neuropathy. Excluded were patients who were sent for a second opinion. Results: Final diagnoses were diabetic neuropathy (n = 52), chronic idiopathic axonal neuropathy (26), neuropathy caused by HIV (20), alcoholism (12), uraemia (7) or medication (7), and miscellaneous (57). Twenty eight patients had no neuropathy. Electrodiagnostic studies were performed in 168 patients of which 48% (80/168) was not contributing, since there was a plausible explanation for the distal symmetrical polyneuropathy (diabetes mellitus, alcoholism, HIV, uraemia or medication) and the diagnosis had not changed after these studies. In patients with electrophysiological studies, 12/168 (7%) fulfilled the criteria of a demyelinating neuropathy. There was only one unexpected electrophysiological result. Conclusions: (1) Electrophysiological studies do not contribute to the diagnosis if a patient with symmetrical distal polyneuropathy is known with diabetes, alcohol abuse, HIV, uraemia or neurotoxic drugs. (2) The distinction between demyelinating and axonal neuropathies does rarely direct the clinician in a focused search of a definitive aetiology, since a demyelinating neuropathy occurred in only 7%. 8 Rhizotomy in primary cervical dystonia — J.D. Speelman, D.A. Bosch, J.W.M. Brans, AMC Uni6ersity of Amsterdam The treatment of first choice in primary cervical dystonia (CD) is botulinum toxin (BTX). Surgical therapy is considered in cases of non-responders. Since 1987 selective peripheral denervation (rhizotomy) is the surgical treatment of choice. The surgical results of 11 patients are discussed. Two patients were excluded from surgery because of primary non-responsiveness to BTX, and depressive state. Of the 11 patients ten had a favourable outcome. Four improved 30 – 60%, and six more than 60%. Two
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Society Proceedings / Clinical Neurology and Neurosurgery 101 (1999) 280–283
patients had a unilateral upper trapezius muscle paresis due to accessory nerve lesion with impaired abduction of the arm. Two other patients had transient adverse events, one fatigue and orthostatic hypotension, and the other impairment of speech and swallowing. Conclusions: (1) Parameters for a favourable outcome are: secondary non-responsiveness to BTX; retro or rotational type of CD; longterm physiotherapy postoperative. (2) Unfavourable outcome parameters: primary non-responders of BTX; fixed posturing of the head; tremor or antecollis type of CD; mainly involvement of lateral neck muscles; severe depression. 9 The role of vascular disease in the development of chronic idiopathic axonal polyneuropathy—L.L. Teunissena, N.C. Notermansa, Y. van der Graafa, H. Franssena, W.H.J.P. Linssenb, J.D. Bangaa, B.C. Eikelbooma, D. Lamanb, J.H.J. Wokkea, aUni6ersity Hospital Utrecht, bSt Lucas-Andreas Ziekenhuis Amsterdam The cause of chronic idiopathic axonal polyneuropathy (CIAP) is unknown. CIAP shows male predominance and onset in older age. In this age group vascular disease is common. In patients with peripheral arterial disease (PAD), neuropathic changes have been described. To evaluate if vascular disease plays a role in the development of CIAP, we compared the prevalence of vascular disease and risk factors in 97 patients with CIAP and the prevalence of polyneuropathy in 96 patients with PAD with 97 age and sex matched controls. Electrophysiologic examination was performed in 43 patients with PAD and 48 controls. Manifest vascular disease (i.e. stroke or myocard infarction) was present in 40 patients with CIAP and 18 controls, OR 3.0, 95% confidence interval 1.6–5.8. Risk factors for vascular disease were more often present in CIAP in comparison with controls. Clinical signs of a polyneuropathy were present in 22 patients with PAD and eight controls (OR 2.2, CI 1.1–8.5). Electrophysiological examination was abnormal in 14 patients with PAD and 1 control (OR 3.2, CI 1.4–7.7). Since vascular disease is more common in CIAP and neuropathy is more common in patients with PAD, we conclude that vascular disease may play a role in the development of CIAP. 10 EMG frequency analysis in patients with movement disorders — M.A.J. Tijssena,b, J.G. van Dijka, J. Marsdenb, P. Brownb, aAfd. Neurologie en Klinische neurofysiologie, LUMC, Leiden, Netherlands, bMRC Human Mo6ement and Balance Unit, The Institute of Neurology, Queen Square, London, UK Voluntary muscle activity is characterised by a tendency for motor units in the muscle to discharge synchronously and rhythmically. Such oscillations are occasionally evident in raw records of electromyographic (EMG) activity, and usually require special analysis techniques. There are three main frequency bands of interest. Firstly, activity around 10 Hz is dependent on activity in the cerebellar-olivary loop. Secondly, rhythmic muscle discharge in the 15– 30 Hz band has a cortical origin. Thirdly, at higher frequency, 35– 50 Hz, Piper rhythms also have a cortical origin. All three rhythmicities may be recorded during the same muscle contraction. There has been little quantitative analysis of the rhythmic elements in involuntary muscle contractions. Coherence (frequency domain) and time domain analysis of EMG signals can afford insight into the responsible levels of these motor control disturbances in the nervous system. Coherence can be measured between EMG activities in muscles from different parts of the body. Under normal circumstances during weak voluntary isometric contractions there is synchronisation and coherence at certain frequencies within the same muscle or between synergistic muscles which are closely related (Farmer SF, Halliday DM, Conway BA, Stephens, JA, Rosenberg JR. A review of recent applications of cross-correlation methodologies to human motor unit recording. J Neurosci Methods 1997;74(2):175– 87). Needle EMG recordings in the sternocleidomastoid and splenius
muscles during involuntary muscle activity in patients with torticollis will be shown. Synchronisation between pairs of motor units and a common drive to motor neurons from presynaptic inputs is hypothesised with coherence at different frequency bands. Coherence between these muscles and thus departures from the normal pattern of rhythmicity can afford further insight into the areas or levels of the nervous system responsible for oscillations of different frequencies and might prove of diagnostic value. 11 Interphase cytogenetics improves the cytodiagnosis and evaluation of therapy for leptomeningeal metastases — R.J. van Oostenbruggea, A.H.N. Hopmanb, J.W. Arendsc, F.C.S. Ramaekersb, A. Twijnstraa, aDepartment of Neurology, Uni6ersity Hospital Maastricht, bDepartment of Molecular Cell Biology & Genetics, Uni6ersity of Maastricht, cDepartment of Pathology, Uni6ersity Hospital Maastricht Objecti6e: To improve cytodiagnostic efficiency and evaluation of therapy for leptomeningeal metastases (LMM) by detection of chromosome aberrations using in situ hybridization (ISH). Background: The demonstration of malignant cells in cerebrospinal fluid (CSF) is required for a definitive diagnosis of LMM. However, this method is moderately sensitive and becomes even less sensitive during therapy. ISH enables the detection of numerical chromosomal aberrations in interphase nuclei and can thus be used to detect malignant cells. Methods: CSF samples of 45 patients clinically suspected of LMM were analyzed with ISH using a probe for chromosome 1 ( c1). The results were compared with the results of the first CSF cytology. Furthermore, the known numerical aberration for c1 was used to detect residual malignancy in 76 CSF samples of seven patients treated for LMM. Results: Cytology classified 27 samples as malignant, eight as atypical, and ten as normal in the clinically suspected cases. ISH detected an aberrant copy number for c1 in three of the eight samples with atypical cells. All three could be classified as being malignant after repeated cytology. Furthermore, compared with routine CSF cytology alone 32 CSF samples obtained during therapy could be additionally classified as malignant by the use of ISH. Consequently, response to therapy was monitored more accurately in six of the seven patients. Conclusion: We demonstrated that ISH is a valuable additional diagnostic test to CSF cytology. Furthermore, ISH is a more accurate method to monitor response to therapy for LMM. This study was financially supported by the Dutch Cancer Society. 12 A locus for Mo¨bius syndrome on the long arm of chromosome 10 — H.T.F.M. Verzijla, B. van den Helma, B. Veldmana, L.P. Kuytc, B.C.J. Hamelb, H. Kremerb, G.W. Padberga, aDepartment of Neurology, Uni6ersity Hospital Nijmegen, bDepartment of Human Genetics, Uni6ersity Hospital Nijmegen, cDepartment of Human Genetics, Free Uni6ersity, Amsterdam, The Netherlands Mo¨bius syndrome (MIM 157900) consists of congenital paresis of the seventh cranial nerve, frequently accompanied by dysfunction of other cranial nerves. The abducens nerve is regularly affected and often also the hypoglossal nerve. In addition, orofacial and limb malformations, defects of the musculoskeletal system and mental retardation are seen. Most patients are sporadic, but familial cases occur. Different modes of inheritance are suggested by different pedigrees. Genetic heterogeneity of Mo¨bius syndrome has been suggested by cytogenetic studies and linkage analysis. Previously, we identified a locus on chromosome 3q21 – q22 in a large Dutch family with autosomal dominant Mo¨bius syndrome consisting essentially of asymmetric bilateral facial paresis.
Society Proceedings / Clinical Neurology and Neurosurgery 101 (1999) 280–283 Here, we performed linkage analysis in a second large Dutch family with autosomal dominant facial palsy. After exclusion of more than 90% of the genome, we identified the locus in this family on the long arm of chromosome 10. The maximum lod score in a two-point analysis is 4.47 at a recombination fraction of 0.05. Herewith, we have proven genetic heterogeneity for autosomal dominant Mo¨bius syndrome. After proving linkage in this family the penetrance is recalculated leading to a value of 60%. The high non-penetrance in the present family suggests that at least part of the seemingly sporadic cases might be members of a family with a low penetrance of Mo¨bius syndrome and might be caused by a mutation in a gene of 10q. 13 Neuropsychological assessment for the evaluation of dementia: standard, option or not at all? —H.C. Weinstein, D. Broere, J.F.M. de Jonghe, E. Jansen, C.S. van der Reijden, Department of Neurology, St Lucas Andreas Ziekenhuis, The Netherlands The first Dutch consensus conference (1988) for the evaluation of dementia recommended neuropsychological assessment as a standard procedure. However, in 1997 a revision of this recommendation suggested a neuropsychological assessment as an option, although no clinical study justified this alteration. We carried out a prospective study with the aim of assessing the
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degree of agreement between a neurologist or a resident and a neuropsychologist with regard to the diagnosis of (1) dementia and (2) the type of dementia. Methods: All patients referred between 1993 and 1997 for the evaluation of memory impairment or behavioral changes were examined by a neurologist or trained resident and a neuropsychologist. Both assessors categorized the patients’ diagnosis: no dementia, cognitive deficits but no dementia, dementia. If a diagnosis of dementia was made the type of dementia had to be determined: cortical, subcortical, fronto-temporal, or mixed dementia. The degree of agreement was calculated with kappa statistics. Results: Sixty eight of the 100 patients were women. The mean age of the women was 79.5 96.2 years and of the thirty two men 75.5 9 6.1 years. Duration of disease: 31 926.4 months; MMSE: mean 21.59 5.6. In 92 patients, there was agreement between the two examinations with regard to the diagnosis (kappa: 0.82). In eight patients of the group of 81 patients with a diagnosis of dementia there was no agreement with regard to the type of dementia (kappa: 0.86). Conclusion: Our findings support the revised version of the Dutch consensus recommendations for the evaluation of dementia. A standard neuropsychological assessment will not alter the clinical diagnosis of an experienced neurologist or trained resident.
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Society Proceedings
Netherlands Society of Neurology SecretariatNetherlands Society of Neurology c/o Dr P.J. Koehler, Netherlands Society of Neurology, P.O. Box 20050, 3502 LB Utrecht, The Netherlands Abstracts from the scientific meeting held on the 10 and 11 December 1998
1 White matter changes after radiotherapy for primary cerebral nonHodgkin’s lymphoma —J.E.C. Bromberga, M.W.M. Wassenberga, Th.D. Witkampb, M.J.B. Taphoorna, aUni6ersity Department of Neurology, Utrecht, bUni6ersity Department of Radiology, Utrecht Aim: To investigate the frequency of white matter changes after radiotherapy for primary cerebral non-Hodgkin’s lymphoma (PCNL) and to assess the incidence of clinical symptoms of leucoencephalopathy in these patients. Furthermore to assess which factors predisposed for white matter changes and how long after treatment these changes developed. Methods: Using regional cancer registry data, charts of all patients diagnosed with PCNL between 1986 and 1996 were reviewed. For patients treated with radiotherapy, cranial imaging was retrieved. The presence or absence of leukoencephalopathy was assessed from the charts according to predefined criteria. All scans were assessed for white matter lesions before and after treatment but before tumor recurrence, whenever possible. Results: We found 44 patients with PCNL treated with radiotherapy. White matter lesions were found in patients surviving at least 8 months. For 20 patients who survived more than 8 months scans were retrieved and reassessed. In 14 of these (70%) white matter lesions developed or increased significantly: in patients aged 60 or over an increase was seen in 86%. For 12 patients with increased white matter lesions, data on clinical symptoms could be retrieved: at least six had symptoms of leukoencephalopathy. The number of treated patients was too small to determine the effect of radiotherapy dose and the addition of chemotherapy. Conclusion: The risk of white matter lesions on cranial imaging is high in patients surviving more than 8 months after treatment with radiotherapy for PCNL and a significant proportion of patients with white matter lesions have symptoms of leukoencephalopathy. 2 Epilepsy, risks and insurances: preliminary results —M.C.T.F.M. de Kroma, A.E.H. Sonnenb, J. Grie¨ta, J. vd Heijdena, E. Beghic also on behalf of the rest-group, aMaastricht Uni6ersity Hospital, Maastricht, The Netherlands, bHans Bergerkliniek, Breda, The Netherlands, cInstituto di Ricerche Farmacologiche ‘Mario Negri’, Milan, Italy Although reliable data are lacking, people with epilepsy are considered to be at a higher risk for accidents and illnesses. A European multicentre patient control study was started to obtain data regarding illnesses, accidents and social conditions of patients with epilepsy. Patients were recruited if their epilepsy was diagnosed
within 5 years or less (80% of the cases) or within 10 years or less (20% of the cases). Acute symptomatic seizures (i.e. occuring within 30 days after a cerebral insult) and seizures due to a progressive neurological disease were excluded. Control persons were recruited among family members, colleagues or friends of the people with epilepsy. Follow up was 12 months at least. At intake demographic variables, current and best occupation, and (in case of epilepsy only) details regarding epileptic seizures and syndrome were collected. Patients and controls recorded prospectively illnesses, accidents, medication and (patients only) seizures using a calender which was checked every month by the center’s study coordinator. Preliminary results: data of 1037 patients and 993 controls are processed at this moment. Patients have a lower number of illnesses and more accidents compared to their controls, but if seizure related accidents are left out, patients and controls have the same number of accidents. Furthermore if only data of adults are considered, people with epilepsy have an odds ratio for driving, sport, better education, better occupation and insurance of 0.27, 0.59, 1.30, 0.60 and 1.49, respectively. 3 PCV chemotherapy in recurrent glioblastoma multiforme —A.C. Kappellea, T.J. Postmaa, M.J.B. Taphoornb, C.J. v Groeningena, J.J. Heimansa, aUni6ersity Hospital Vrije Uni6ersiteit Amsterdam, b Uni6ersity Hospital Utrecht, The Netherlands Objecti6e: To evaluate the efficacy and toxicity of PCV chemotherapy (a combination of procarbazine, CCNU and vincristine) in patients with a recurrent glioblastoma multiforme (GBM). Methods: A total of 24 patients with a recurrent GBM were treated with PCV chemotherapy. In all, 18 patients had a recurrence of a primary GBM, whereas six patients had former histology of a lower grade tumor. Response was evaluated according to Macdonald’s criteria. Toxicity was scored according to NCIC-CTC criteria. Results: A total of 24 patients, median age 48 years were evaluated. The patients received 1 – 7 cycles (median 2) of PCV. Dose-limiting toxicity was not encountered. Complete response (CR) was observed in one, partial response (PR) in two, stable disease (SD) in four and progressive disease (PD) in 17 patients. Median time to tumor progression (TTP) and median survival for all patients were 3 and 8 months, respectively, 3 and 6 months for those patients with PD, and 9 and 11 months for patients with CR, PR or SD. Conclusions: In a minority of patients (29%) with a recurrent GBM, PCV chemotherapy induces an effect (CR, PR or SD) which results in a prolongation of TTP and survival. Toxicity due to PCV chemotherapy is acceptable.
0303-8467/99/$ - see front matter © 1999 Elsevier Science B.V. All rights reserved. PII: S 0 3 0 3 - 8 4 6 7 ( 9 9 ) 0 0 0 2 9 - 3
Society Proceedings / Clinical Neurology and Neurosurgery 101 (1999) 280–283 4 Clinical features and diagnosis of degenerative ataxias at a Hereditary Brain Disease clinic —H.P.H. Kremer, N.V.A.M. Knoers, Polikliniek Erfelijke Hersenziekten, St. Radboud Ziekenhuis Nijmegen Between May 1 1994 and October 1 1998 we examined a consecutive series of 144 subjects suffering from, or at risk of hereditary or degenerative ataxia. Setting: the Hereditary Brain Disease clinic, a tertiary referral center. The first group of 59 individuals from 35 families were diagnosed as Autosomal Dominant Cerebellar Ataxia (ADCA). In 35 affected patients from 26 ADCA families, genotyping revealed the following distribution ( c patients/c families): 3/2 SCA1; 4/4 SCA2; 4/4 SCA3; 7/4 SCA6; 5/4 SCA7; 12 affected patients from eight families could not be genotyped. A second group of 57 patients from 44 families was classified as recessive ataxia. Of those, eight (six families) turned out to have Friedreich’s Ataxia, with homozygosity for GAA expansion in intron 1 of the frataxin gene. Three had onset around age 30, with retained tendon reflexes at ages 38, 38 and 40, respectively. A ninth patient turned out to be a compound heterozygote. Eight patients presented with Friedreich-like progressive spinocerebellar disease (oculomotor abnormalities, dysarthria, limb ataxia, and lower limb pyramidal tract abnormalities) without GAA expansion. A third group consisted of 28 patients with sporadic late onset ataxia, after age 45. The majority (n = 21) was diagnosed as Multiple Systems Atrophy. 5 CADASIL: survey and Dutch research results—S.A.J. Lesnik Obersteina, M.H. Breuninga, J. Haanb, aDepartment of Clinical Genetics, Leiden Uni6ersity Medical Centre, bRijnland Hospital and L.U.M.C. (For the Dutch CADASIL research group) CADASIL is a late-onset hereditary disease characterised by recurrent strokes, vascular dementia, migraine with aura ( 9 35%) and mood disorders ( 930%). Cerebral MRI in symptomatic, but also in many presymptomatic individuals, shows a confluent leukoencephalopathy and small subcortical infarcts. Pathognomonic for CADASIL is electron-dense granular material in the media of small cerebral arteries. These non-amyloid, non-atherosclerotic deposits can also be found in arteries of other organs, such as skin arterioles. Recently, mutations have been found in the Notch3 gene on chromosome 19, introducing mutation analysis as an important diagnostic tool in CADASIL families. Until now, 15 Dutch families have been referred to our research group. For most of these we have been able to confirm the diagnosis by detecting a mutation in exon 4 of the Notch3 gene. Considering more than 120 families have been described worldwide, it is reasonable to assume that CADASIL is not a rare disease. Therefore, we expect that there may be more Dutch CADASIL families. We present a clinical survey of CADASIL, as well as results of mutation analysis in Dutch CADASIL families. 6 Early immune activation in muscle biopsies from patients with Critical Illness Polyneuromyopathy —M.A.C.J. Megens-de Letter a,b , P.A. van Doornb, H.F.J. Savelkoulc, P.I.M. Schmitzd, A.A.W. Op de Coula, L.H. Vissera, M. Krossb, J.L.J.M. Teepena, F.G.A. van der Meche´b, aDepartment of Neurology, St. Elisabeth Hospital, Tilburg, The Netherlands, bDepartment of Neurology, Uni6ersity Hospital and Erasmus Uni6ersity Rotterdam, cDepartment of Immunology, Uni6ersity Hospital and Erasmus Uni6ersity Rotterdam, d Department of Statistics, Uni6ersity Hospital Daniel den Hoed and Erasmus Uni6ersity Rotterdam In a longitudinal prospective study we included 98 patients, who needed artificial respiration and followed them for the development of Critical Illness Polyneuromyopathy (CIPNM). We evaluated signs of local immune activation using routine lightmicroscopic and im-
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munohistochemical studies in muscle biopsies of all 30 patients who developed CIPNM. Neuropathic changes were found in 33%, myopathic in 37% and both neuropathic and myopathic changes in 27%. Immunohistochemical analysis comprised: CD4, CD8, CD20, CD68, E-selectin, ICAM1, VCAM, Membrane Attack Complex (MAC), HLA-I and HLA-DR. CD4 positive T-cells were seen in 60% (18/30). Small infiltrates with macrophages (CD68) and Th1-cells (CD4) were present in 27% (8/30). Overall macrophages were present in 33% (10/30) of the biopsies. Expression of E-selectin was negative, but that of ICAM-1 was found in 54% (14/26) and VCAM in 57% (17/30). MAC stained on the vascular endothelium in 72% (21/29) of the biopsies. In all cases HLA-I and HLA-DR were upregulated. We analysed the muscle tissue for the expression of proinflammatory cytokines, because the results thus far showed signs of early immune activation. Immunohistochemical staining was found for IL-1b in 83% (24/29), IFN-g in 43% (12/28), IL-12 in 69% (20/29) and TNF-aR75 in 90% (27/30) of the biopsies. The increased number of macrophages is associated with the release of proinflammatory cytokines that may result in temporary Th1-cell activation (amplified by an HLA-1 and HLA-DR upregulation). Expression of ICAM-1, VCAM and MAC suggests increased vascular permeability that can damage the muscle fibers. This shows that early local immune activation may be of importance in the pathophysiology of muscle weakness in patients with CIPNM. 7 The diagnostic value of electrophysiological studies in the diagnostic work-up of patients with a peripheral neuropathy— N.R. Rosenberg, M. de Visser, P. Portegies, M. Vermeulen, Academic Medical Centre, Amsterdam Background: We investigated whether electrophysiological studies direct the clinician in a focused search for an aetiology in patients with peripheral neuropathy of at least 6 weeks. Methods: We reviewed medical records of 209 patients referred with a possible peripheral neuropathy. Excluded were patients who were sent for a second opinion. Results: Final diagnoses were diabetic neuropathy (n = 52), chronic idiopathic axonal neuropathy (26), neuropathy caused by HIV (20), alcoholism (12), uraemia (7) or medication (7), and miscellaneous (57). Twenty eight patients had no neuropathy. Electrodiagnostic studies were performed in 168 patients of which 48% (80/168) was not contributing, since there was a plausible explanation for the distal symmetrical polyneuropathy (diabetes mellitus, alcoholism, HIV, uraemia or medication) and the diagnosis had not changed after these studies. In patients with electrophysiological studies, 12/168 (7%) fulfilled the criteria of a demyelinating neuropathy. There was only one unexpected electrophysiological result. Conclusions: (1) Electrophysiological studies do not contribute to the diagnosis if a patient with symmetrical distal polyneuropathy is known with diabetes, alcohol abuse, HIV, uraemia or neurotoxic drugs. (2) The distinction between demyelinating and axonal neuropathies does rarely direct the clinician in a focused search of a definitive aetiology, since a demyelinating neuropathy occurred in only 7%. 8 Rhizotomy in primary cervical dystonia — J.D. Speelman, D.A. Bosch, J.W.M. Brans, AMC Uni6ersity of Amsterdam The treatment of first choice in primary cervical dystonia (CD) is botulinum toxin (BTX). Surgical therapy is considered in cases of non-responders. Since 1987 selective peripheral denervation (rhizotomy) is the surgical treatment of choice. The surgical results of 11 patients are discussed. Two patients were excluded from surgery because of primary non-responsiveness to BTX, and depressive state. Of the 11 patients ten had a favourable outcome. Four improved 30 – 60%, and six more than 60%. Two
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patients had a unilateral upper trapezius muscle paresis due to accessory nerve lesion with impaired abduction of the arm. Two other patients had transient adverse events, one fatigue and orthostatic hypotension, and the other impairment of speech and swallowing. Conclusions: (1) Parameters for a favourable outcome are: secondary non-responsiveness to BTX; retro or rotational type of CD; longterm physiotherapy postoperative. (2) Unfavourable outcome parameters: primary non-responders of BTX; fixed posturing of the head; tremor or antecollis type of CD; mainly involvement of lateral neck muscles; severe depression. 9 The role of vascular disease in the development of chronic idiopathic axonal polyneuropathy—L.L. Teunissena, N.C. Notermansa, Y. van der Graafa, H. Franssena, W.H.J.P. Linssenb, J.D. Bangaa, B.C. Eikelbooma, D. Lamanb, J.H.J. Wokkea, aUni6ersity Hospital Utrecht, bSt Lucas-Andreas Ziekenhuis Amsterdam The cause of chronic idiopathic axonal polyneuropathy (CIAP) is unknown. CIAP shows male predominance and onset in older age. In this age group vascular disease is common. In patients with peripheral arterial disease (PAD), neuropathic changes have been described. To evaluate if vascular disease plays a role in the development of CIAP, we compared the prevalence of vascular disease and risk factors in 97 patients with CIAP and the prevalence of polyneuropathy in 96 patients with PAD with 97 age and sex matched controls. Electrophysiologic examination was performed in 43 patients with PAD and 48 controls. Manifest vascular disease (i.e. stroke or myocard infarction) was present in 40 patients with CIAP and 18 controls, OR 3.0, 95% confidence interval 1.6–5.8. Risk factors for vascular disease were more often present in CIAP in comparison with controls. Clinical signs of a polyneuropathy were present in 22 patients with PAD and eight controls (OR 2.2, CI 1.1–8.5). Electrophysiological examination was abnormal in 14 patients with PAD and 1 control (OR 3.2, CI 1.4–7.7). Since vascular disease is more common in CIAP and neuropathy is more common in patients with PAD, we conclude that vascular disease may play a role in the development of CIAP. 10 EMG frequency analysis in patients with movement disorders — M.A.J. Tijssena,b, J.G. van Dijka, J. Marsdenb, P. Brownb, aAfd. Neurologie en Klinische neurofysiologie, LUMC, Leiden, Netherlands, bMRC Human Mo6ement and Balance Unit, The Institute of Neurology, Queen Square, London, UK Voluntary muscle activity is characterised by a tendency for motor units in the muscle to discharge synchronously and rhythmically. Such oscillations are occasionally evident in raw records of electromyographic (EMG) activity, and usually require special analysis techniques. There are three main frequency bands of interest. Firstly, activity around 10 Hz is dependent on activity in the cerebellar-olivary loop. Secondly, rhythmic muscle discharge in the 15– 30 Hz band has a cortical origin. Thirdly, at higher frequency, 35– 50 Hz, Piper rhythms also have a cortical origin. All three rhythmicities may be recorded during the same muscle contraction. There has been little quantitative analysis of the rhythmic elements in involuntary muscle contractions. Coherence (frequency domain) and time domain analysis of EMG signals can afford insight into the responsible levels of these motor control disturbances in the nervous system. Coherence can be measured between EMG activities in muscles from different parts of the body. Under normal circumstances during weak voluntary isometric contractions there is synchronisation and coherence at certain frequencies within the same muscle or between synergistic muscles which are closely related (Farmer SF, Halliday DM, Conway BA, Stephens, JA, Rosenberg JR. A review of recent applications of cross-correlation methodologies to human motor unit recording. J Neurosci Methods 1997;74(2):175– 87). Needle EMG recordings in the sternocleidomastoid and splenius
muscles during involuntary muscle activity in patients with torticollis will be shown. Synchronisation between pairs of motor units and a common drive to motor neurons from presynaptic inputs is hypothesised with coherence at different frequency bands. Coherence between these muscles and thus departures from the normal pattern of rhythmicity can afford further insight into the areas or levels of the nervous system responsible for oscillations of different frequencies and might prove of diagnostic value. 11 Interphase cytogenetics improves the cytodiagnosis and evaluation of therapy for leptomeningeal metastases — R.J. van Oostenbruggea, A.H.N. Hopmanb, J.W. Arendsc, F.C.S. Ramaekersb, A. Twijnstraa, aDepartment of Neurology, Uni6ersity Hospital Maastricht, bDepartment of Molecular Cell Biology & Genetics, Uni6ersity of Maastricht, cDepartment of Pathology, Uni6ersity Hospital Maastricht Objecti6e: To improve cytodiagnostic efficiency and evaluation of therapy for leptomeningeal metastases (LMM) by detection of chromosome aberrations using in situ hybridization (ISH). Background: The demonstration of malignant cells in cerebrospinal fluid (CSF) is required for a definitive diagnosis of LMM. However, this method is moderately sensitive and becomes even less sensitive during therapy. ISH enables the detection of numerical chromosomal aberrations in interphase nuclei and can thus be used to detect malignant cells. Methods: CSF samples of 45 patients clinically suspected of LMM were analyzed with ISH using a probe for chromosome 1 ( c1). The results were compared with the results of the first CSF cytology. Furthermore, the known numerical aberration for c1 was used to detect residual malignancy in 76 CSF samples of seven patients treated for LMM. Results: Cytology classified 27 samples as malignant, eight as atypical, and ten as normal in the clinically suspected cases. ISH detected an aberrant copy number for c1 in three of the eight samples with atypical cells. All three could be classified as being malignant after repeated cytology. Furthermore, compared with routine CSF cytology alone 32 CSF samples obtained during therapy could be additionally classified as malignant by the use of ISH. Consequently, response to therapy was monitored more accurately in six of the seven patients. Conclusion: We demonstrated that ISH is a valuable additional diagnostic test to CSF cytology. Furthermore, ISH is a more accurate method to monitor response to therapy for LMM. This study was financially supported by the Dutch Cancer Society. 12 A locus for Mo¨bius syndrome on the long arm of chromosome 10 — H.T.F.M. Verzijla, B. van den Helma, B. Veldmana, L.P. Kuytc, B.C.J. Hamelb, H. Kremerb, G.W. Padberga, aDepartment of Neurology, Uni6ersity Hospital Nijmegen, bDepartment of Human Genetics, Uni6ersity Hospital Nijmegen, cDepartment of Human Genetics, Free Uni6ersity, Amsterdam, The Netherlands Mo¨bius syndrome (MIM 157900) consists of congenital paresis of the seventh cranial nerve, frequently accompanied by dysfunction of other cranial nerves. The abducens nerve is regularly affected and often also the hypoglossal nerve. In addition, orofacial and limb malformations, defects of the musculoskeletal system and mental retardation are seen. Most patients are sporadic, but familial cases occur. Different modes of inheritance are suggested by different pedigrees. Genetic heterogeneity of Mo¨bius syndrome has been suggested by cytogenetic studies and linkage analysis. Previously, we identified a locus on chromosome 3q21 – q22 in a large Dutch family with autosomal dominant Mo¨bius syndrome consisting essentially of asymmetric bilateral facial paresis.
Society Proceedings / Clinical Neurology and Neurosurgery 101 (1999) 280–283 Here, we performed linkage analysis in a second large Dutch family with autosomal dominant facial palsy. After exclusion of more than 90% of the genome, we identified the locus in this family on the long arm of chromosome 10. The maximum lod score in a two-point analysis is 4.47 at a recombination fraction of 0.05. Herewith, we have proven genetic heterogeneity for autosomal dominant Mo¨bius syndrome. After proving linkage in this family the penetrance is recalculated leading to a value of 60%. The high non-penetrance in the present family suggests that at least part of the seemingly sporadic cases might be members of a family with a low penetrance of Mo¨bius syndrome and might be caused by a mutation in a gene of 10q. 13 Neuropsychological assessment for the evaluation of dementia: standard, option or not at all? —H.C. Weinstein, D. Broere, J.F.M. de Jonghe, E. Jansen, C.S. van der Reijden, Department of Neurology, St Lucas Andreas Ziekenhuis, The Netherlands The first Dutch consensus conference (1988) for the evaluation of dementia recommended neuropsychological assessment as a standard procedure. However, in 1997 a revision of this recommendation suggested a neuropsychological assessment as an option, although no clinical study justified this alteration. We carried out a prospective study with the aim of assessing the
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degree of agreement between a neurologist or a resident and a neuropsychologist with regard to the diagnosis of (1) dementia and (2) the type of dementia. Methods: All patients referred between 1993 and 1997 for the evaluation of memory impairment or behavioral changes were examined by a neurologist or trained resident and a neuropsychologist. Both assessors categorized the patients’ diagnosis: no dementia, cognitive deficits but no dementia, dementia. If a diagnosis of dementia was made the type of dementia had to be determined: cortical, subcortical, fronto-temporal, or mixed dementia. The degree of agreement was calculated with kappa statistics. Results: Sixty eight of the 100 patients were women. The mean age of the women was 79.5 96.2 years and of the thirty two men 75.5 9 6.1 years. Duration of disease: 31 926.4 months; MMSE: mean 21.59 5.6. In 92 patients, there was agreement between the two examinations with regard to the diagnosis (kappa: 0.82). In eight patients of the group of 81 patients with a diagnosis of dementia there was no agreement with regard to the type of dementia (kappa: 0.86). Conclusion: Our findings support the revised version of the Dutch consensus recommendations for the evaluation of dementia. A standard neuropsychological assessment will not alter the clinical diagnosis of an experienced neurologist or trained resident.
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