Catharina G Faber

Abstract: BACKGROUND: Pulsed high-dose dexamethasone induced long-lasting remission in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in a pilot study. The PREDICT study aimed to compare remission rates in patients with CIDP treated with high-dose dexamethasone with rates in patients treated with standard oral prednisolone. METHODS: In eight neuromuscular centres in the Netherlands and one in the UK, patients aged 18 years or older who had newly diagnosed definite or probable CIDP were randomly assigned to a treatment regimen of either pulsed high-dose dexamethasone or standard oral prednisolone. Randomisation was done with a random number generator. The primary outcome measure was remission at 12 months, defined as improvement of at least three points on the Rivermead mobility index and improvement of at least one point on the inflammatory neuropathy cause and treatment disability scale. Analysis was by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN07779236. FINDINGS: Between December, 2003, and December, 2008, 40 patients were treated: 24 received dexamethasone and 16 received prednisolone. At 12 months, 16 patients were in remission: ten in the dexamethasone group and six in the prednisolone group (odds ratio [OR] 1.2, 95% CI 0.3-4.4). Most adverse events were minor and did not differ substantially between treatment groups; however, sleeplessness and Cushing's face occurred more often in the prednisolone group. INTERPRETATION: Pulsed high-dose dexamethasone treatment did not induce remission more often than prednisolone treatment. A substantial proportion of patients were in remission at 12 months in both treatment groups. High-dose dexamethasone could be considered as induction therapy in CIDP, but comparison with intravenous immunoglobulin treatment is needed. FUNDING: The Prinses Beatrix Fonds (MAR01-0213) and the Department of Neurology, Academic Medical Center.

Abstract: Myotonic dystrophy type 1 (DM1) is one of the most variable inherited human disorders. It is characterized by the involvement of multiple tissues and is caused by the expansion of a highly unstable CTG repeat. Variation in disease severity is partially accounted for by the number of CTG repeats inherited. However, the basis of the variable tissue-specific symptoms is unknown. We have determined that an unusual Dutch family co-segregating DM1, Charcot-Marie-Tooth neuropathy, encephalopathic attacks and early hearing loss, carries a complex variant repeat at the DM1 locus. The mutation comprises an expanded CTG tract at the 5'-end and a complex array of CTG repeats interspersed with multiple GGC and CCG repeats at the 3'-end. The complex variant repeat tract at the 3'-end of the array is relatively stable in both blood DNA and the maternal germ line, although the 5'-CTG tract remains genetically unstable and prone to expansion. Surprisingly though, even the pure 5'-CTG tract is more stable in blood DNA and the maternal germ line than archetypal DM1 alleles of a similar size. Complex variant repeats were also identified at the 3'-end of the CTG array of approximately 3-4% of unrelated DM1 patients. The observed polarity and the stabilizing effect of the variant repeats implicate a cis-acting modifier of mutational dynamics in the 3'-flanking DNA. The presence of such variant repeats very likely contributes toward the unusual symptoms in the Dutch family and additional symptomatic variation in DM1 via affects on both RNA toxicity and somatic instability.

Abstract: BACKGROUND: Spinal cord stimulation (SCS) has proven to be an effective however an invasive and relatively expensive treatment of chronic Complex Regional Pain Syndrome type 1(CRPS-1). Furthermore, in one third of CRPS-1 patients, SCS treatment fails to give significant pain relief and 32-38% of treated patients experience complications. The aim of the current study was to develop effective prognostic factors for prediction of successful outcome of SCS. METHODS AND RESULTS: The study population consisted of 36 chronic CRPS patients enrolled in a randomized controlled trial of SCS efficacy. We analyzed various prognostic factors in the group of patients treated with SCS and compared baseline values of possible predictors of outcome in the successfully treated and the not successfully treated group. Success was defined as Patient Global Perceived Impression of Change score of at least "much improved" and pain reduction of at least 2.5 on a visual-analogue scale (VAS score 0-10). Univariate analyses showed that patient age, duration of the disease, localization of the disease, intensity of the pain, and the presence of mechanical hypoesthesia did not predict SCS success. The mean and maximum value of brush-evoked allodynia proved to be statistically significant predictors of outcome. Using Receiver-Operating Characteristic (ROC) curve analyses of maximum allodynia values, the diagnostic sensitivity for successful SCS was 0.75 and the specificity 0.81. CONCLUSION: Brush-evoked allodynia may be a significant negative prognostic factor of SCS treatment outcome after 1 year in chronic CRPS-1.

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Abstract: Anti-myelin associated glycoprotein (MAG) neuropathy is a chronic disorder in which IgM antibodies react with Schwann cell glycoproteins, including MAG and peripheral myelin protein 22 (PMP22). Nerve conduction studies show features of axon loss and predominantly distal slowing consistent with demyelination. Because a genetic loss of PMP22 function yields hereditary neuropathy with liability to pressure palsies (HNPP), loss of PMP22 function due to anti- MAG antibodies may result in increased sensitivity to entrapment. We investigated this by performing standardized electrophysiological studies in 16 patients with anti-MAG neuropathy and 16 disease controls with genetically confirmed HNPP. Disproportionate slowing relative to adjacent segments occurred in similar proportions of patients with anti-MAG neuropathy and HNPP, and was of the same magnitude in each group. Affected were the elbow, carpal tunnel and the wrist-hand segments of the median and ulnar nerves. However, in anti-MAG neuropathy as compared to HNPP, absolute values of distal motor latencies and conduction velocities outside entrapment sites were slower and amplitudes were lower. In conclusion, increased sensitivity for entrapment may occur in anti-MAG neuropathy and contribute to part of the nerve damage.

Abstract: BACKGROUND: Intraepidermal nerve fiber density (IENFD) is considered a good diagnostic tool for small fiber neuropathy (SFN). OBJECTIVES: To assess stratified normative values for IENFD and determine the reliability and validity of IENFD in sarcoidosis. METHODS: IENFD was assessed in 188 healthy volunteers and 72 patients with sarcoidosis (n = 58 with SFN symptoms, n = 14 without SFN symptoms). Healthy controls were stratified (for age and sex), resulting in 6 age groups (20-29, 30-39, ... up to > or = 70 years) containing at least 15 men and 15 women. A skin biopsy was taken in each participant 10 cm above the lateral malleolus and analyzed in accordance with the international guidelines using bright-field microscopy. Interobserver/intraobserver reliability of IENFD was examined. In the patients, a symptoms inventory questionnaire (SIQ; assessing SFN symptoms) and the Vickrey Peripheral Neuropathy Quality-of-Life Instrument-97 (PNQoL-97) were assessed to examine the discriminative ability of normative IENFD values. RESULTS: There was a significant age-dependent decrease of IENFD values in healthy controls, with lower densities in men compared with women. Good interobserver/intraobserver reliability scores were obtained (kappa values > or = 0.90). A total of 21 patients with sarcoidosis had a reduced IENFD score (< 5th percentile; 19 [32.8%] in patients with SFN symptoms, 2 [14.3%] in patients without SFN symptoms). The validity of the normative IENFD values was demonstrated by distinguishing between the SIQ scores and various PNQoL-97 values for the different patient groups. CONCLUSION: This study provides clinically applicable distal intraepidermal nerve fiber density normative values, showing age- and sex-related differences.

Abstract: OBJECTIVE: To report new disease components in a unique myotonic dystrophy type 1 (DM1) family previously described by us in which all affected members also had a sensorimotor neuropathy that co-segregated with markers flanking the DM1 locus. METHODS: Clinical observations, electrophysiology, audiometry, DNA studies. RESULTS: During a follow-up period of over 25 years, the following were observed: (i) co-segregation of a striking new encephalopathic phenotype. In middle age, five patients were admitted on multiple occasions with attacks of impaired consciousness, psychomotor agitation, fever and, in about half of the cases, focal neurological signs, including unilateral weakness, sensory deficits and dysphasia. Reported onset phenomena consisted of confusion, headache, focal neurological symptoms and nausea; (ii) many patients show an early and severe sensorineural hearing loss; (iii) although they have mothers with the adult onset type, the four affected subjects from the youngest generation do not show any signs or symptoms of childhood or congenital myotonic dystrophy; (iv) the neuropathy meets the criteria of an intermediate type Charcot-Marie-Tooth (CMT), and is more severe in males; and (v) patients presented with an expanded fragment at the DM1 CTG repeat but this allele was refractory to PCR amplification and triplet repeat primed PCR at the 3' end of the array, indicating the existence of an additional lesion at the 3' end. CONCLUSIONS: The phenotype in this unique family extends beyond myotonic dystrophy and CMT to include encephalopathic attacks and early hearing loss, and is associated with an atypical mutation at the DM1 locus.

Abstract: Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of hereditary disorders affecting neuromuscular transmission. We have identified mutations within the acetylcholine receptor (AChR) epsilon-subunit gene underlying congenital myasthenic syndromes in nine patients (seven kinships) of Dutch origin. Previously reported mutations epsilon1369delG and epsilonR311Q were found to be common; epsilon1369delG was present on at least one allele in seven of the nine patients, and epsilonR311Q in six. Phenotypes ranged from relatively mild ptosis and external ophthalmoplegia to generalized myasthenia. The common occurrence of epsilonR311Q and epsilon1369delG suggests a possible founder for each of these mutations originating in North Western Europe, possibly in Holland. Knowledge of the ethnic or geographic origin within Europe of AChR deficiency patients can help in targeting genetic screening and it may be possible to provide a rapid genetic diagnosis for patients of Dutch origin by screening first for epsilonR311Q and epsilon1369delG.

Abstract: OBJECTIVE: To study whether clinical characteristics can differentiate sporadic presentations of hereditary spastic paraparesis (HSP) from primary lateral sclerosis (PLS). Differentiation between these diseases is important for genetic counseling and prognostication. DESIGN: Case series. SETTING: Tertiary referral center. PATIENTS: One hundred four Dutch patients with an adult-onset, sporadic upper motor neuron syndrome of at least 3 years' duration. Hereditary spastic paraparesis was genetically confirmed in 14 patients (7 with SPG4 and 7 with SPG7 mutations). RESULTS: All 14 patients with the SPG4 or SPG7 mutation had symptom onset in the legs, and 1 of the patients with the SPG7 mutation also developed symptoms in the arms. Of the other 90 patients, 78 (87%) had symptom onset in the legs. Thirty-six patients developed a PLS phenotype (bulbar region involvement), 15 had a phenotype that was difficult to classify as similar to HSP or PLS (involvement of legs and arms only), and 39 continued to have a phenotype similar to typical HSP (involvement of the legs only). Median age at onset was lower in patients with the SPG4 or SPG7 mutation (39 [range, 29-69] years), but there was considerable overlap with patients with the PLS phenotype (52 [range, 32-76] years). No differences were found in the features used by previous studies to distinguish HSP from PLS, including evidence of mild dorsal column impairment (decreased vibratory sense or abnormal leg somatosensory evoked potentials), symptoms of urinary urgency, or mild electromyographic abnormalities. CONCLUSIONS: In most patients with a sporadic adult-onset upper motor neuron syndrome, differentiation of sporadic presentations of HSP from PLS based on clinical characteristics is unreliable and therefore depends on results of genetic testing.

Abstract: Patients with non-dystrophic myotonias, including chloride (myotonia congenita) and sodium channelopathies (paramyotonia congenita/potassium aggravated myotonias), may show muscular hypertrophy in combination with some histopathological abnormalities. However, the extent of muscle changes has never been assessed objectively in a large group genetically confirmed patients. This study quantitatively determines echo intensities, thicknesses, ranges-of-motion and force of four skeletal muscles in 63 genetically confirmed patients. The main findings revealed elevated echo intensities in all muscles except the rectus femoris (+1.3-2.2SD, p<0.0001), and hypertrophy in the arms (+0.5-0.9SD, p<0.01). Muscle echo intensities were inversely correlated to the corresponding ranges-of-motion (biceps brachii: r= -0.43; p<0.001, forearm flexors: r= -0.47; p<0.001, rectus femoris: r= -0.40; p=0.001, and tibial anterior: r= -0.27; p=0.04) and correlated positively to age (r=0.22; p=0.05). The echo intensity of the forearm flexors was inversely correlated to their muscles' force (r= -0.30; p=0.02). Together, these data suggest that non-dystrophic myotonias may lead to structural muscle changes.

Abstract: Sodium channelopathies (NaCh), as part of the non-dystrophic myotonic syndromes (NDMs), reflect a heterogeneous group of clinical phenotypes accompanied by a generalized myotonia. Because of recent availability of diagnostic genetic testing in NDM, there is a need for identification of clear clinical genotype-phenotype correlations. This will enable clinicians to distinguish NDMs from myotonic dystrophy, thus allowing them to inform patients promptly about the disease, perform genetic counseling, and orient therapy (Vicart et al. Neurol Sci 26:194-202, 2005). We describe the first distinctive clinical genotype-phenotype correlation within NaCh: a strictly isolated eyelid closure myotonia associated with the L250P mutation in SCN4A. Using clinical assessment and needle EMG, we identified this genotype-phenotype correlation in six L250P patients from one NaCh family and confirmed this finding in another, unrelated NaCh family with three L250P patients.

Abstract: Fatigue is a major disabling complaint in patients with immune-mediated neuropathies (IN). The 9-item fatigue severity scale (FSS) has been used to assess fatigue in these conditions, despite having limitations due to its classic ordinal construct. The aim was to improve fatigue assessment in IN through evaluation of the FSS using a modern clinimetric approach [Rasch unidimensional measurement model (RUMM2020)]. Included were 192 stable patients with Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) or polyneuropathy associated with monoclonal gammopathy of undetermined significance (MGUSP). The obtained FSS data were exposed to RUMM2020 model to investigate whether this scale would meet its expectations. Also, reliability and validity studies were performed. The original FSS did not meet the Rasch model expectations, primarily based on two misfitting items, one of these also showing bias towards the factor 'walking independent.' After removing these two items and collapsing the original 7-point Likert options to 4-point response categories for the remaining items, we succeeded in constructing a 7-item Rasch-built scale that fulfilled all requirements of unidimensionality, linearity, and rating scale model. Good reliability and validity were also obtained for the modified FSS scale. In conclusion, a 7-item linearly weighted Rasch-built modified FSS is presented for more proper assessment of fatigue in future studies in patients with immune-mediated neuropathies.

Abstract: OBJECTIVE: To redefine phenotypical characteristics for both chloride (ClCh) and sodium channelopathies (NaCh) in non-dystrophic myotonic syndromes (NDM). METHODS: In a cross-sectional, nationwide study, standardised interviews and clinical bedside tests were performed in 62 genetically confirmed NDM patients, 32 ClCh and 30 NaCh. RESULTS: Standardised interviews revealed that ClCh reported a higher frequency of muscle weakness (75 vs 36.7%; p<0.01), the warm-up phenomenon (100 vs 46.7%; p<0.001), and difficulties in standing up quickly (90.6 vs 50.0%; p<0.001), running (90.6% vs 66.7; p<0.05) and climbing stairs (90.6 vs 63.3%; p = 0.01). Patients with NaCh reported an earlier onset (4.4 vs 9.6 years; p<0.001), and higher frequencies of paradoxical (50.0 vs 0%; p<0.001) and painful myotonia (56.7 vs 28.1%; p<0.05). Standardised clinical bedside tests showed a higher incidence and longer relaxation times of myotonia in the leg muscles for ClCh (100 vs 60%; mean duration of chair tests 12.5 vs 6.3 s; p<0.001), and in eyelid muscles for NaCh (96.7 vs 46.9%; mean relaxation time of 19.2 vs 4.3 s; p<0.001). Transient paresis was only observed in ClCh (62.5%) and paradoxical myotonia only in NaCh (30.0%). Multivariate logistic regression analyses allowed clinical guidelines to be proposed for genetic testing. CONCLUSION: This study redefined the phenotypical characteristics of NDM in both ClCh and NaCh. The clinical guidelines proposed may help clinicians working in outpatient clinics to perform a focused genetic analysis of either CLCN1 or SCN4A.

Abstract: To determine self-reported health status in non-dystrophic myotonias (NDM) and its relationship to painful myotonia and fatigue. In a cross-sectional study, 32 NDM patients with chloride and 30 with sodium channelopathies, all off treatment, completed a standardised interview, the fatigue assessment scale (FAS), and the 36-item Short-Form Health Survey (SF-36). Beside formal assessment of pain, assessment of painful or painless myotonia was determined. The domain scores of the SF-36 were compared with Dutch community scores. Apart from the relationship among SF-36 scores and (1) painful myotonia and (2) fatigue, regression analyses in both NDM groups were conducted to determine the strongest determinants of the SF-36 domains general health perception, physical component (PCS) and mental component summary (MCS). All physically oriented SF-36 domains in both NDM groups (P <or= 0.01) and social functioning in the patients with sodium channelopathies (P = 0.048) were substantially lower relative to the Dutch community scores. The patients with painful myotonia (41.9%) scored substantially (P < 0.05) lower on most SF-36 domains than the patients without painful myotonia (58.1%). Fatigued patients (53.2%) scored substantially lower (P <or= 0.01) on all SF-36 domains than their non-fatigued counterparts (46.8%). The regression analysis showed that fatigue was the strongest predictor for the general-health perception and painful myotonia for the physical-component summary. None of the patients showed below-norm scores on the domain mental-component summary. The impact of NDM on the physical domains of patients' health status is substantial, and particularly painful myotonia and fatigue tend to impede their physical functioning.

Abstract: BACKGROUND: Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron (SMN)1 gene. The nearly identical SMN2 gene plays a disease modifying role. SMA is classified into four different subtypes based on age of onset and clinical course (SMA types 1-4). The natural history of early onset SMA types 1-3a has been studied extensively. Late onset SMA is rare and disease course has not been studied in detail. OBJECTIVE: To perform a prospective study on the clinical course and the correlation with SMN2 copy numbers of late onset SMA. METHODS: Patients fulfilling the diagnostic criteria for late onset SMA (types 3b and 4) were included in the study. At inclusion and follow-up, muscle strength, respiratory function, functional status and quality of life were assessed. SMN2 copy number was determined in all patients. RESULTS: Twelve patients were identified and included. Six patients were siblings from one family, two patients were brothers from a second family and four patients were sporadic cases. All patients carried four copies of the SMN2 gene. Median age of disease onset was 22.2 years (10-37). Age of disease onset in patients from family one was lower as compared to the other patients. None of the outcome measures changed after a follow-up of 2.5 years. Five patients reported an increase in fatigue and muscle weakness. None of the patients showed symptoms of respiratory insufficiency. CONCLUSIONS: This study indicates that late onset SMA is not characterized by disease progression and that alternative or surrogate disease markers are required for the design of future trials. This study confirms the finding that SMN2 copy number is a SMA disease course modifier.

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Abstract: BACKGROUND: The aim of this study was to evaluate the uptake and -washout of I-123 meta-iodobenzylguanidine (MIBG), reflecting norepinephrine metabolism, in the lungs in patients with sarcoidosis. METHODS: Lung I-123 MIBG kinetics was assessed in 43 patients with sarcoidosis. The range of disease duration was 1-16 years (median: 3 years). Thirteen patients had radiographic stage 0-I, 30 patients had radiographic stage II-IV. Serological clinical parameters and small fibre neuropathy, as assessed by temperature threshold testing (TTT) were measured in 39/43 patients. 31/39 patients had an abnormal TTT. Eleven healthy controls participated in this study. Both dual head planar and dual headed SPECT images of the thoracic regions were made. The uptake of I-123 MIBG and the washout percentage were calculated in sarcoidosis patients and compared with the healthy persons. RESULTS: Lung I-123 MIBG uptake in patients with sarcoidosis did not differ from controls. The lung washout of I-123 MIBG was significantly (p<or=0.01) decreased in sarcoidosis. Remarkably this was most clearly seen in patients with an abnormal TTT and in patients with more advanced radiographic pulmonary involvement (radiographic stages II-IV) but not in patients with decreased lung function (FVC<80% or DLCO<80%). CONCLUSION: The inflammatory process of the lungs in sarcoidosis seems not to affect pulmonary vasculature. In sarcoidosis decreased lung washout of I-123 MIBG might, at least partly, be explained by sympathetic autonomic nerve dysfunction. Future studies are needed to explore the clinical relevance of this observation.

Abstract: BACKGROUND: Neuromuscular symptoms in patients with Lambert-Eaton myasthenic syndrome (LEMS) and a small cell lung cancer (SCLC) develop more rapidly than in LEMS patients without a SCLC. We studied how this clinical information, which is readily available at the first consultation, can be used to predict the presence of SCLC. PATIENTS AND METHODS: In our study we included 52 LEMS patients with SCLC and 45 non-tumor patients (NT-LEMS). We interviewed patients using a structured checklist and reviewed their clinical records. We compared frequency and onset of symptoms during the course of LEMS. RESULTS: In the first six months, over half the SCLC-LEMS patients had developed seven separate symptoms, while NT-LEMS patients developed only two symptoms. Proximal leg weakness and dry mouth were early symptoms in both groups. Rapid involvement of proximal arm muscles (p=0.0001), distal arm muscles (p=0.0037), distal leg muscles (p=0.0002), dysartria (p=0.0091) and the presence of erectile dysfunction (p=0.007) were found significantly more often in SCLC-LEMS patients in both cohorts. Cerebellar symptoms, although present in 9% of LEMS patients, were almost exclusively related to SCLC-LEMS. CONCLUSION: A rapidly progressive course of disease from onset in LEMS patients should raise a high suspicion of SCLC. Special attention should be paid to involvement of upper extremities, involvement of distal arm and distal leg muscles, to erectile dysfunction and probably ataxia in order to discriminate between SCLC-LEMS and NT-LEMS.

Abstract: Non-dystrophic myotonias (NDMs) are caused by mutations in CLCN1 or SCN4A. The purpose of the present study was to optimize the genetic characterization of NDM in The Netherlands by analysing CLCN1 and SCN4A in tandem. All Dutch consultant neurologists and the Dutch Patient Association for Neuromuscular Diseases (Vereniging Spierziekten Nederland) were requested to refer patients with an initial diagnosis of NDM for clinical assessment and subsequent genetic analysis over a full year. Based on clinical criteria, sequencing of either CLCN1 or SCN4A was performed. When previously described mutations or novel mutations were identified in the first gene under study, the second gene was not sequenced. If no mutations were detected in the first gene, the second gene was subsequently also analysed. Underlying NDM mutations were explored in 54 families. In total, 20% (8 of 40) of our probands with suspected chloride channel myotonia showed no CLCN1 mutations but subsequent SCN4A screening revealed mutations in all of them. All 14 probands in whom SCN4A was primarily sequenced showed a mutation. In total, CLCN1 mutations were identified in 32 families (59%) and SCN4A in 22 (41%), resulting in a diagnostic yield of 100%. The yield of mutation detection was 93% with three recessive and three sporadic cases not yielding a second mutation. Among these mutations, 13 in CLCN1 and 3 in SCN4A were novel. In conclusion, the current results show that in tandem analysis of CLCN1 and SCN4A affords high-level mutation ascertainment in families with NDM.

Abstract: Peripheral neurological disorders like neuropathies may cause impairments (such as weakness and sensory deficits), which may lead to problems in daily life and social functioning with a possible decrement in quality of life expectations. Choosing the proper outcome measure to evaluate the therapeutic efficacy of an intervention at one of these levels of outcome should therefore be considered as fundamental to the design of randomized trials in peripheral neurological disorders. However, these choices are dependent not only on the proposed research purposes but also, and perhaps more importantly, on the fulfillment of the scientific needs of these measures. With an increasing demand for accuracy, a thorough and comprehensive evaluation of an outcome measure is needed to determine its simplicity, communicability, validity, reliability, and responsiveness before being clinically applicable, techniques that are being captured by the science of clinimetrics. Most neurologists are still unfamiliar with these rigorous methodological essentials or overlook some of them in their trial preparations because these are considered time consuming and mind numbing. This review will highlight, against the background of the international classification framework and clinimetric needs for outcome measures, the selected scales applied in published randomized controlled trials in patients with Guillain-Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and gammopathy-related neuropathies. The need for comparison responsiveness studies between equally valid and reliable measures and to standardize their use is emphasized in these conditions. Finally, specific recommendations are given to move from classic to modern clinimetric approach when constructing, evaluating, and selecting outcome measures using new methods like Rasch analysis, accentuating the need of shifting toward a more modern era.

Abstract: OBJECTIVES: To revise the static and dynamic normative values for the two-point discrimination test and to examine its applicability and validity in patients with a polyneuropathy. METHODS: Two-point discrimination threshold values were assessed in 427 healthy controls and 99 patients mildly affected by a polyneuropathy. The controls were divided into seven age groups ranging from 20-29, 30-39,..., up to 80 years and older; each group consisted of at least 30 men and 30 women. Two-point discrimination examination took place under standardised conditions on the index finger. Correlation studies were performed between the scores obtained and the values derived from the Weinstein Enhanced Sensory Test (WEST) and the arm grade of the Overall Disability SumScore (ODSS) in the patients' group (validity studies). Finally, the sensitivity to detect patients mildly affected by a polyneuropathy was evaluated for static and dynamic assessments. RESULTS: There was a significant age-dependent increase in the two-point discrimination values. No significant gender difference was found. The dynamic threshold values were lower than the static scores. The two-point discrimination values obtained correlated significantly with the arm grade of the ODSS (static values: r = 0.33, p = 0.04; dynamic values: r = 0.37, p = 0.02) and the scores of the WEST in patients (static values: r = 0.58, p = 0.0001; dynamic values: r = 0.55, p = 0.0002). The sensitivity for the static and dynamic threshold values was 28% and 33%, respectively. CONCLUSION: This study provides age-related normative two-point discrimination threshold values using a two-point discriminator (an aesthesiometer). This easily applicable instrument could be used as part of a more extensive neurological sensory evaluation.

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Abstract: In addition to the review by van Alfen et al., which has been published in 2000, we would like to report a seven-week-old boy with bilateral idiopathic brachial plexus neuropathy that did not show any signs of osteomyelitis on repeated scintigraphy. To our knowledge this is the first child reported with bilateral plexus involvement.

Abstract: Each of the various neuromuscular diseases is rare. Consequently, solid epidemiological data are not available and it is often difficult to find sufficient patients for studies. For this reason, the Dutch neuromuscular database, CRAMP (Computer Registry of All Myopathies and Polyneuropathies), was developed in 2004 by the Dutch Neuromuscular Research Support Centre, to store information on patient characteristics and diagnoses (based on Rowland and McLeod's classification) in a uniform and easily retrievable manner. Care was taken to preserve data confidentiality. It is envisaged that CRAMP will prove particularly useful for studies in which multicentre collaboration is needed to recruit a sufficiently large number of patients. More than 10,000 patients with neuromuscular diseases (4,837 female, 5,476 male) have been registered since 2004, half of whom (n=5059) have peripheral nerve disorders.

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Abstract: We describe a case of dynamic scapular winging due to trapezius muscle paresis following a sport-related injury of the accessory nerve. The typical clinical findings related to the peripheral nerve involved, the importance of neurophysiologic work-up, and possibilities for treatment are discussed.

Abstract: We describe a patient with severe small fiber neuropathy (SFN) accompanied by autonomic involvement, who was experimentally treated with infliximab, an anti-tumour necrosis factor-alpha (TNF-alpha) therapy. Six months after this treatment was started his symptoms completely resolved. Until now they did not return. Repeated temperature threshold testing (TTT) as well as cardiovascular autonomic function test clearly improved after one year therapy. This case reveals two important issues. First, it shows that SFN seems not an irreversible disorder, even in severe cases. Second, TNF-alpha may be a crucial cytokine in the pathogenesis of SFN in sarcoidosis and eventually also in other immune mediated inflammatory diseases.

Abstract: A late onset axonal Charcot-Marie-Tooth phenotype is described, resulting from a novel mutation in the myelin protein zero (MPZ) gene. Comparative computer modelling of the three dimensional structure of the MPZ protein predicts that this mutation does not cause a significant structural change. The primary axonal disease process in these patients points to a function of MPZ in maintenance of the myelinated axons, apart from securing stability of the myelin layer.

Abstract: BACKGROUND: Abnormal delayed relaxation of skeletal muscles, known as myotonia, can cause disability in myotonic disorders. Sodium channel blockers, tricyclic antidepressive drugs, benzodiazepines, calcium-antagonists, taurine and prednisone may be of use in reducing myotonia. OBJECTIVES: To consider the evidence from randomised controlled trials on the efficacy and tolerability of drug treatment in patients with clinical myotonia due to a myotonic disorder. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (April 2004), MEDLINE (January 1966 to December 2003) and EMBASE (January 1980 to December 2003). Grey literature was handsearched and reference lists of identified studies and reviews were examined. Authors, disease experts and manufacturers of anti-myotonic drugs were contacted. SELECTION CRITERIA: We considered all (quasi) randomised trials of participants with myotonia treated with any drug treatment versus no therapy, placebo or any other active drug treatment. The primary outcome measure was:reduced clinical myotonia using two categories: (1) no residual myotonia or improvement of myotonia or (2) No change or worsening of myotonia. Secondary outcome measures were:(1) clinical relaxation time; (2) electromyographic relaxation time; (3) stair test; (4) presence of percussion myotonia; and (5) proportion of adverse events. DATA COLLECTION AND ANALYSIS: Two authors extracted the data independently onto standardised extraction forms and disagreements were resolved by discussion. MAIN RESULTS: Nine randomised controlled trials were found comparing active drug treatment versus placebo or another active drug treatment in patients with myotonia due to a myotonic disorder. Included trials were double-blind or single-blind crossover studies involving a total of 137 patients of which 109 had myotonic dystrophy type 1 and 28 had myotonia congenita. The studies were of poor quality. Therefore, we were not able to analyse the results of all identified studies. Two small crossover studies without a washout period demonstrated a significant effect of imipramine and taurine in myotonic dystrophy. One small crossover study with a washout period demonstrated a significant effect of clomipramine in myotonic dystrophy. Meta-analysis was not possible. AUTHORS' CONCLUSIONS: Due to insufficient good quality data and lack of randomised studies, it is impossible to determine whether drug treatment is safe and effective in the treatment of myotonia. Small single studies give an indication that clomipramine and imipramine have a short-term beneficial effect and that taurine has a long-term beneficial effect on myotonia. Larger, well-designed randomised controlled trials are needed to assess the efficacy and tolerability of drug treatment for myotonia.

Abstract: Primary lateral sclerosis (PLS) is a diagnosis of exclusion in patients with progressive spinobulbar spasticity and could be part of the clinical spectrum of ALS. Unlike ALS, which is familial in 5 to 10% of the cases, PLS has been described as a sporadic disorder in adults. The authors report two patients with PLS from unrelated SOD1-negative familial ALS families. These observations provide further evidence that PLS can be linked pathophysiologically to ALS.

Abstract: The clinical features of inclusion body myositis (IBM) were of minor importance in the design of consensus diagnostic criteria, mainly because of controversial views on the specificity of signs and symptoms, although some authors reported "typical" signs. To re-assess the clinical spectrum of IBM, a single investigator using a standard protocol studied a cohort of 64 patients cross-sectionally. Symptom onset was before the age of 50 years in 20% of cases. Only a few patients (14 %) started with weakness other than that of quadriceps, finger flexor or pharyngeal muscles. The sequence of power loss was erratic, but onset of symptoms with quadriceps weakness predicted an earlier onset of dysphagia in older patients (> or = 56 years) compared with younger ones (< 56 years) (p = 0.02). Despite widespread weakness patients had favourable scores on three commonly used function scales and they kept their employment. Complete wheel-chair dependency was rare (3 %). A dominant characteristic was the anatomical distribution of afflicted muscles: ventral extremity muscle groups were more affected than dorsal muscle groups and girdle muscles were least affected, the latter preserving postural stability. Ankylosis, especially in extension of the fingers,was frequently present. Together with the sparing of intrinsic hand muscles it was helpful in the preservation of many skillful movements. IBM has a unique distribution of muscle weakness. Ankylotic contractures are common. We feel that their joint impact on daily functioning is characteristic for the disease.

Abstract: Myotonic dystrophy type 1 is the most common muscular dystrophy in adults. Clinical features are variable and include myotonia, a slowly progressive muscle weakness and organ complications. Inheritance is autosomal dominant and characterised by anticipation, i.e. an earlier age of onset and more severe clinical course in subsequent generations, and exclusively maternal transmission of the most severe congenital type. The myotonic dystrophy type 1 mutation is an untranslated cytosine-thymine-guanine (CTG) expansion in the 'dystrophia myotonica-protein kinase' (DMPK) gene. The repeat expansion alters RNA processing, including alternative splicing of several genes and the expression of several transcription factors. Furthermore, reduced DMPK protein levels are present and it is proposed that the expanded CTG repeat has a local effect on genes in the myotonic dystrophy type 1 region by altering the chromatin structure.

Abstract: BACKGROUND AND AIM: Recently we found that small fiber neuropathy (SFN) occurs frequently in sarcoidosis. Autonomic dysfunction may be a feature of SFN. Since cardiac autonomic dysfunction has been identified as a strong predictor of morbidity and mortality, recognition of cardiac autonomic involvement is of clinical relevance. It was hypothesised that SFN might be related to cardiac sympathetic denervation in sarcoidosis. METHODS: In the present study 45 consecutive sarcoidosis patients (13 without SFN assessed by thermal threshold testing (TTT), 32 with SFN (abnormal TTT) were enrolled. To rule out bias due to myocardial ischemia, cases with abnormal Thallium (201Tl) perfusion scintigraphy were excluded (n = 2). Cardiovascular autonomic function testing (Ewing tests) and 123I-MIBG (metaiodobenzylguanidine) scintigraphy were used to assess cardiac autonomic function. Further cardiac diagnostic work-up included ECG, Holter recording and echo Doppler cardiography. RESULTS: Mild to moderate heterogeneity of 123I-MIBG uptake regional in the myocardium was demonstrated in a substantial number of the studied sarcoidosis population, especially in those with SFN (abnormal TTT). Mean inferior-anterior ratios were 0.85+/-0.17 (SFN) and 1.0+/-0.17 (no SFN; p = 0.003), respectively. Four out of the 14 cases with abnormal MIBG scintigraphy and SFN showed an abnormal Ewing test. CONCLUSION: Cardiac sympathetic dysfunction assessed by use of 123I-MIBG myocardial scanning appeared to be heterogeneous in sarcoidosis patients and dependent on the presence or absence of SFN. MIBG scintigraphy may be of additional value in the management and follow-up of sarcoidosis patients. Future study is warranted to explore possible prognostic and therapeutic implications of these findings in sarcoidosis.

Abstract: BACKGROUND AND AIM: Sarcoidosis has been reported to be associated with the HLA genes, in particular DQB1. METHODS: High resolution DQB 1 of 103 sarcoidosis patients was obtained by sequence-based typing; low resolution HLA-A/B/DRB 1 typing was performed by serological and molecular methods. Small fiber neuropathy (SFN) was established by thermal threshold testing. RESULTS: Sixty-seven patients suffered from SFN (SFN+), in 36 patients SFN was absent (SFN-). Comparing HLA DQB 1 typings of SFN+ patients, SFN- patients and control individuals revealed a significant increase of the allele DQB 1 0602 in SFN+ patients compared to controls. CONCLUSION: This association might be correlated with a severe course of the disease.

Abstract: Channelopathies are a heterogeneous group of genetic diseases in which a defective ion channel is responsible for the symptoms. They manifest as diseases of the heart, brain or skeletal muscle. Hereditary skeletal-muscle channelopathies are characterised by myotonia, periodic paralysis or a combination of both and can be categorised as chloride, sodium and calcium channelopathies. When there is myotonia, the skeletal-muscle membrane is overexcited. In cases of periodic paralysis, the skeletal-muscle membrane is inactive. It is difficult to classify hereditary muscle channelopathies on the basis of clinical criteria only. A more reliable diagnosis is made using DNA analysis. Scientific research should focus on genotype-phenotype relationships.

Abstract: Anti-Hu syndrome is a paraneoplastic neurological syndrome, most frequently associated with small cell carcinoma of the lung. Subacute sensory neuronopathy is thought to be the most frequent presentation of the anti-Hu syndrome, but it seems that sensory-motor neuropathy is the most common form in the anti-Hu neuropathy. Neurological symptoms often appear before the associated cancer has been identified. Sometimes the tumor is discovered months or even a few years after the appearance of the neurological syndrome. FDG-PET scan seems a better method for finding the tumor in patients with paraneoplastic neurological syndrome and anti-Hu antibodies who had negative test results after an initial workup using radiological methods. In this case report we present a patient with the anti-Hu syndrome associated with an unclassified rhabdomyosarcoma with epitheloid cellular morphology and neuroendocrine differentiation.

Abstract: Whether autoimmune mechanisms play a role in the pathogenesis of inclusion body myositis (IBM) is unknown. Human leukocyte antigen (HLA) analysis in 52 patients, including 17 with autoimmune disorders (AIDs), showed that patients were more likely to have antigens from the autoimmune-prone HLA-B8-DR3 ancestral haplotype than healthy control subjects, irrespective of the presence of AIDs. Patients lacked the apparently protective HLA-DR53 antigen. The results provide further support for an autoimmune basis in IBM.

Abstract: A 35-year-old patient had persistent, refractory symptomatic pulmonary sarcoidosis, complicated by a rare congenital muscular disease: McArdle's disease (a glycogen storage disease caused by myophosphorylase deficiency). As the desaturations during mild exercise caused by the sarcoidosis aggravated the negative consequences of his muscle disease and he failed to respond adequately to corticosteroids and methotrexateimmunosuppressive agents, the patient was successfully treated experimentally with infliximab, a monoclonal antibody and specific tumour necrosis factor alpha (TNF-alpha) inhibitor. The results were favourable: after 17, 21 and 36 months there was an improvement in various lung function parameters, his fatigue was reduced and the patient had been able to resume his work as a taxi driver. TNF-alpha appears to be an important mediator of clinical disease in sarcoidosis and infliximab could be a promising therapy for patients with refractory sarcoidosis.

Abstract: Small fiber neuropathy (SFN) is a neuropathy selectively involving small diameter myelinated and unmyelinated nerve fibers. Interest in this disorder has considerably increased during the past few years. It is often idiopathic and typically presents with peripheral pain and/or symptoms of autonomic dysfunction. Diagnosis is made on the basis of the clinical features, normal nerve conduction studies (NCS) and abnormal specialized tests of small nerve fibers. Among others, these tests include assessment of epidermal nerve fiber density, temperature sensation tests for sensory fibers and sudomotor and cardiovagal testing (QSART) for autonomic fibers. Unless an underlying disease is identified, treatment is usually symptomatic and directed towards alleviation of neuropathic pain.

Abstract: Sarcoidosis is an inflammatory multisystem disorder of unknown cause. Practically no organ is immune to sarcoidosis; most commonly, in up to 90% of patients, it affects the lungs. The nervous system is involved in 5-15% of patients. Neurosarcoidosis is a serious and commonly devastating complication of sarcoidosis. Clinical diagnosis of neurosarcoidosis depends on the finding of neurological disease in multisystem sarcoidosis. As the disease can present in many different ways without biopsy evidence, solitary nervous-system sarcoidosis is difficult to diagnose. Corticosteroids are the drug of first choice. In addition, several cytotoxic drugs, including methotrexate, have been used to treat sarcoidosis. The value of new drugs such as anti-tumour necrosis factor alpha will be assessed. In this review we describe the clinical manifestations of neurosarcoidosis, diagnostic dilemmas and considerations, and therapy.

Abstract: Recently, Chlamydia pneumoniae has been identified as a risk factor for atherosclerosis, cardiovascular disease, and stroke. In young patients the causes of stroke are more diverse, and remain unknown in about 30% of cases, despite thorough investigations. To find a possible relationship between C. pneumoniae infection and stroke at young age, we investigated C. pneumoniae antibody titers in 41 patients with ischemic stroke who were younger than 50 years old and in 55 healthy control subjects. A positive IgA antibody titer to C. pneumoniae was significantly associated with stroke (crude odds ratio 2.1; 90% confidence interval 1.1-9.5; P = .04). After adjusting for hypertension, smoking, and hypercholesterolemia, positive Chlamydia antibodies remained associated with stroke (adjusted odds ratio 2.8; 90% confidence interval 1.1-7.1; P = .04). No significant association between positive IgG antibodies and stroke was found. Because a positive IgA antibody titer may reflect a persistent infection, these data indicate that persistent C. pneumoniae infection may be an independent risk factor for stroke at young age.

Abstract: The time course of the concentration of active thrombin in clotting plasma (the thrombogram) was measured by subsampling from platelet-rich plasma (PRP) and continuous chromogenic measurement of platelet-poor plasma (PPP) in 41 stroke patients under the age of 50, in whom stroke could not be attributed to cardioembolic disease, arterial dissection or vasculitis. A significant increase in the area under the thrombogram (endogenous thrombin potential, ETP) was seen in 23 patients. In 9 of them, ETP was increased in PRP but normal in PPP. High ETP in PRP was significantly associated with stroke, both in the middle and in the highest tercile of the ETP (odds ratio 5.1, range 1.8-15.1, and 3.7, range 1.3-10.3, respectively). A decreased sensitivity to the inhibitory action of thrombomodulin (TM) on thrombin generation was observed in 5 of 37 cases. No further definition of the cause of increased thrombin generation or TM resistance was attempted, except for the role of von Willebrand factor (vWF). ETP in PRP, platelet-derived procoagulant activity and vWF were correlated and higher in patients than in controls (p=0.002, p=0.045 and p=0.0006, respectively). This confirms the correlation between vWF level and stroke at young age found in epidemiological studies. It suggests that the role of vWF in thrombin generation, which has been demonstrated in vitro, may be the underlying mechanism of this correlation. In summary, hypercoagulability, defined as an increased capacity of the platelet plasma system to form thrombin, is found in over half of the patients under 50 years with an otherwise unexplained stroke. Sometimes it is due to increased plasma factor activity, sometimes to an increased procoagulant activity of the platelets.

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Abstract: BACKGROUND AND AIM: Although pain is prevalent in sarcoidosis, this has never been studied systematically. The aim of the present study was to evaluate the presence and impact of pain in sarcoidosis. METHODS: Members from the Dutch Sarcoidosis Society without co-morbidity (n = 821) participated in this study. The World Health Organisation Quality of Life assessment instrument (WHOQOL-100) was completed, as well as a symptom inventory questionnaire addressing the presence of various categories of pain, i.e., muscle pain, chest pain, abdominal pain, arthralgia, and/or headache. RESULTS: Pain was reported by 594 patients (72.4%). Arthralgia was experienced most frequently (53.8%), followed by muscle pain (40.2%), headache (28.0%) and chest pain (26.9%). The number of types of pain a patient was suffering from (ranging from 0-5) was related to the WHOQOL- 100 Pain and Discomfort scale (r = 0.49, p < 0.001). Patients with more types of pain had lower quality of life (QOL). In addition, the total amount of experienced pain categories was associated with the WHOQOL-100 domain Level of Independence (r = -O.43, p < 0.001), and the facet Energy and Fatigue (r = -0.38, p < 0.001). The number of types of pain was predicted by using analgesics, psychological/neurological medication, NSAIDs, being female, indicating to feel tired, more negative feelings and less energy (F(7.635) = 35.2, p < 0.001; R2 = 27.9%). CONCLUSIONS: Pain appeared to be a major problem in sarcoidosis, especially arthralgia. Although negative feelings and fatigue were related to pain, it could not fully explain pain. Future studies are needed to address mechanisms of pain, pain behaviour, and the best therapeutic approach to pain in sarcoidosis.

Abstract: OBJECTIVE: A substantial number of sarcoidosis patients report apparently non-specific symptoms such as pain, for which no organic substrate has yet been found. Recently we observed symptoms suggestive of small-fibre neuropathy in a group of sarcoidosis patients. The aim of the present study was to verify this observation using various electrophysiological tests. METHODS: In 74 sarcoidosis patients complaining of symptoms suggestive of small-fibre neuropathy, thresholds for warm (WS) and cold sensation (CS) as well as for heat pain were determined at the thenar eminence and the foot dorsum. Furthermore, sympathetic skin responses (SSR), nerve conduction studies and concentric needle electromyography were performed. In 31 patients, cardiovascular autonomic testing was carried out. RESULTS: Thermal threshold testing (TTT) revealed abnormalities in 51 of the 74 patients. Abnormalities showed an asymmetrical distribution. WS was affected more often than CS and feet more often than hands. Nerve conduction studies in the legs showed slightly abnormal results in 6 patients; all of these had abnormal TTT results. The SSR was absent at the foot in 7 patients. Cardiovascular autonomic testing was abnormal in only a single patient. CONCLUSIONS: In a subgroup of sarcoidosis patients we found TTT abnormalities suggestive of small-fibre neuropathy. SSR and cardiovascular autonomic testing appeared to be of little diagnostic value. Small-fibre neuropathy may be the cause of a number of hitherto unexplained symptoms in sarcoidosis.

Abstract: Three patients, one woman aged 22 and two men aged 54 and 28, presented with scapular winging. In the first patient amyotrophic plexus neuralgia was diagnosed. The second patient most probably suffered from a stretch injury of the long thoracic nerve. The third patient had scapular winging due to an isolated paresis of the trapezius muscle, which was caused by an idiopathic lesion of the accessory nerve. In the first and second patient an improvement was noticeable after 9 months and 1.5 years respectively. There was no improvement in the third patient after 11 years. Paresis of the M. serratus anterior occurs due to paralysis of the N. thoracicus longus, as a result of direct compression, stump trauma, interventions such as thoracic operations, (repeated) stretch injuries or neuralgic brachial plexus amyotrophy; in these cases the scapular winging increases as the arm is lifted forwards. Paresis of the M. trapezius occurs due to the paralysis of the N. accessorius, due to trauma, interventions such as in the neck area, a space-occupying abnormality or an idiopathic abnormality; in these cases the scapular winging increases upon the arm being lifted sideways. Another possible cause of scapular winging is muscular dystrophy, especially fascioscapulohumeral muscular dystrophy (FSHD). Usually the prognosis for recovery from a neuropraxia and an idiopathic lesion of the N. thoracicus longus within a two-year period is good. The prognosis for an isolated lesion of the N. accessorius is much less favourable. An EMG is essential for establishing a diagnosis.

Abstract: Some patients with sarcoidosis have unexplained pain and dysaesthesia. We did quantitative sensory testing in 31 sarcoidosis patients with pain or autonomic dysfunction. 25 patients had reduced warmth sensitivity, cold sensitivity, or both. Intraepidermal nerve fibre density (IENFD) was measured in punch biopsy skin samples in seven consecutive patients. All seven patients had reduced IENFD compared with controls, which confirmed the presence of small fibre neuropathy in these patients. Some patients with sarcoidosis may have small fibre neuropathy with autonomic involvement.

Abstract: In a series of 171 consecutive survivors of acute myocardial infarction, the predictive value of late potentials and QTc prolongation was prospectively assessed. QT intervals were measured in lead V2, corrected QT (QTc) was calculated using Bazett's equation (cut-off value 440 ms). Late potentials were considered to be present when all of the three signal-averaged electrocardiographic variables were abnormal (i.e. QRS > 114 ms, D40 > 38 ms, and V40 < 20 microV). Complete follow-up was obtained (mean 13 +/- 6 months, range 6-24 months). Six percent of the patients had an arrhythmic event (i.e. sustained ventricular tachycardia or sudden death). The relative risk of late potentials for arrhythmic events was 7.7 (P < 0.02). The relative risk of QTc > 440 ms was 1.1 (NS). In a multivariate analysis, the addition of QTc prolongation did not significantly improve the prognostic value of late potentials alone. It is concluded that late potentials are predictive of arrhythmic events after myocardial infarction, but the presence of concomitant QTc prolongation does not worsen the prognosis.

Abstract: Although a number of studies have shown that the incidence of late potentials is lower after thrombolytic therapy, it is not known whether this is paralleled by fewer arrhythmic events during long-term follow-up. In patients with first acute myocardial infarction, filtered QRS duration was significantly shorter when treated with streptokinase (95 +/- 11 ms, n = 53) than when treated with conventional therapy (99 +/- 12 ms, n = 77, p < 0.05). The low-amplitude signal (D40) was shorter after thrombolysis (28 +/- 11 vs 33 +/- 12 ms, p < 0.02). Terminal root-mean-square voltage did not differ significantly (41 +/- 24 vs 35 +/- 23 microV). Irrespective of treatment, late potentials were predictive in the complete group (n = 171) for arrhythmic events during follow-up (13 +/- 6 months, range 6 to 24) (hazard ratio 7.7, p < 0.02, Cox proportional-hazards survival analysis), but treatment (streptokinase vs conventional) did not significantly affect outcome when added to the model. It is concluded that thrombolysis prevents the development of late potentials. However, this study does not confirm the hypothesis that prevention of late potentials leads to a decrease in arrhythmic events.