Long-term follow-up study on patients with Miyoshi phenotype of distal muscular dystrophy.

BACKGROUND AND PURPOSE: To describe the long-term follow-up of a cohort of 22 patients with the Miyoshi phenotype of distal muscular dystrophy (MMD). METHODS: A long-term clinical follow-up study was conducted. Patients were genotyped for dysferlin (MMD1) or anoctamin 5 (MMD3) mutations. Patients also underwent cardiological evaluation. RESULTS: There were 10 patients with MMD1, eight patients with MMD3 and four patients with linkage to chromosome 10 (MMD2). All patients deteriorated over 5.7 (range: 4.2-6.6) years of follow-up. Weakness increased significantly (P < 0.035) in all but the neck extensor, serratus anterior, and wrist flexor and extensor muscles. The decrease of strength was most pronounced in the iliopsoas (15%), toe extensors (15%), anterior tibial and peroneal muscles (10%). Patients with MMD1 showed early onset of the disease (mean 22 years) with typically symmetrical distribution of weakness starting in the calf muscles. Patients with MMD1 had a worse clinical course compared with patients with MMD3. Ninety percent of the former had to make use of a wheelchair within 15 years after onset of the disease, whereas patients with MMD3, who have a significantly later onset (mean 35 years) of asymmetrical calf muscle weakness and atrophy, remained ambulant during the first 15 years of their disease. None of the patients with MMD2 became fully confined to the wheelchair. None of the 22 MMD phenotype patients had heart disease. CONCLUSIONS: Patients with MMD1 have a worse clinical course compared with patients with MMD3. There are no cardiological abnormalities in all MMD categories.

Rate of disease progression during long-term follow-up of patients with late-onset Pompe disease.

To determine the rate of disease progression in patients with late-onset Pompe disease, we collected longitudinal data on pulmonary function and skeletal muscle strength in 16 patients whose symptoms had started in childhood or adulthood. The mean duration of follow-up was 16 years (range 4-29 years). During the follow-up period, eight patients (50%) became wheelchair bound and three (19%) became ventilator dependent. At a group level, pulmonary function deteriorated by 1.6% per year, and proximal muscle weakness progressed gradually. At the individual level, however, the rate and extent of progression varied highly between patients. In two thirds of patients, pulmonary function and muscle strength declined simultaneously and to the same extent. The remaining one third of patients showed a variable, sometimes rapidly progressive course, leading to early respirator or wheelchair dependency. These individual differences, especially in pulmonary dysfunction, indicate the need for regular monitoring every 6-12 months depending on the rate of disease progression.

Rituximab for polyneuropathy with IgM monoclonal gammopathy.

BACKGROUND: Polyneuropathy with IgM monoclonal gammopathy can be a disabling disorder necessitating treatment. METHODS: In a prospective open label trial, 17 patients with disabling IgM MGUS polyneuropathy were treated with rituximab, a chimeric anti-CD-20 monoclonal antibody. RESULTS: Rituximab induced an improvement of >or=1 point on the Overall Disability Sum Score in 2/17 patients, an improvement of >or=5% of the distal MRC sum score in 4/17 and the sensory sum score in 9/17 patients. Bone marrow investigations showed CD 20 B cell depletion in all patients. There were no serious adverse events. Compared with treatment with intermittent cyclophosphamide with prednisone or treatment with fludarabine, it shows a comparable response percentages but fewer side effects. The presence of anti-MAG and a disease duration shorter than 10 years may predict treatment response. CONCLUSION: Rituximab is a candidate for treatment of IgM MGUS polyneuropathy and should be further investigated in a double-blind randomised trial.

The realistic yield of lower leg SNAP amplitudes and SRAR in the routine evaluation of chronic axonal polyneuropathies.

OBJECTIVE: To assess the realistic yield of lower leg sensory nerve action potential amplitudes (SNAP) and the sural/radial nerve amplitude ratio (SRAR) in the routine evaluation of suspected distal axonal polyneuropathy. METHODS: Investigated were 721 people. In 393 referents without and 328 patients with chronic distal symmetrical polyneuropathy the SRAR, sural, superficial peroneal and dorsal sural SNAP were determined. RESULTS: The dorsal sural SNAP could not be elicited in 26 % of referents. Axonal polyneuropathy was confirmed by an abnormally low value of the sural or superficial peroneal SNAP or SRAR in 70 % of patients, and most often (68 %) by an absent sural or superficial peroneal SNAP. In 9 % of patients there was a normal sural but abnormal superficial peroneal SNAP, and 11 % had an abnormal sural but normal superficial peroneal SNAP. ROC curve analysis demonstrated equal accuracy of the sural and superficial peroneal SNAP. CONCLUSIONS: To confirm distal axonal polyneuropathy in routine clinical practice the sural and superficial peroneal SNAP had equal and complementary yield, whereas the SRAR and dorsal sural SNAP had limited additional yield.

Interpretation of electrodiagnostic findings in sporadic progressive muscular atrophy.

OBJECTIVE: We present the electrophysiologic data at baseline of 37 patients who were included in our prospective study on sporadic adult-onset progressive muscular atrophy (PMA). The aim was to correlate electrophysiological signs of lower motor neuron (LMN) loss with clinical signs of LMN loss, and to determine the prognostic value of the distribution of electrophysiological abnormalities in patients who presented clinically with only lower motor neuron signs. METHODS: Thirty-seven patients, who met our inclusion criteria for a prospective study on sporadic adult-onset PMA, underwent extensive standardized electrophysiological examination at baseline, consisting of concentric needle EMG in three regions (cervical, thoracic and lumbosacral) and standardized nerve conduction studies. RESULTS: Denervation on needle EMG was found in 88 % of clinically affected and in 40 % of clinically unaffected limb regions. All patients with a segmental or distal phenotype at baseline who developed generalized weakness had denervation in the thoracic region. Motor nerve conduction abnormalities were found in a substantial number of nerves and included reduced CMAP amplitude, increased distal motor latency, decreased motor conduction velocity, and F-wave abnormalities. Signs of demyelination and sensory nerve conduction abnormalities were rare. CONCLUSIONS: Our electrophysiological data in patients recently diagnosed with sporadic progressive muscular atrophy are consistent with widespread LMN loss. Progression in patients with a segmental or distal onset of PMA may be likely if denervation is found in clinically unaffected regions, including the thoracic region.

A natural history study of late onset spinal muscular atrophy types 3b and 4.

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.

Intake of polyunsaturated fatty acids and vitamin E reduces the risk of developing amyotrophic lateral sclerosis.

BACKGROUND: To assess whether the premorbid dietary intake of fatty acids, cholesterol, glutamate or antioxidants was associated with the risk of developing amyotrophic lateral sclerosis (ALS). METHODS: Patients referred to our clinic during 2001-2002, who had definite, probable or possible ALS according to El Escorial criteria, without a familial history of ALS, were asked to participate in a case-control study (132 patients and 220 healthy controls). A food-frequency questionnaire was used to assess dietary intake for the nutrients of interest. Multivariate logistic regression analysis was performed with adjustment for confounding factors (sex, age, level of education, energy intake, body mass index and smoking). RESULTS: A high intake of polyunsaturated fatty acid (PUFA) and vitamin E was significantly associated with a reduced risk of developing ALS (PUFA: odds ratio (OR) = 0.4, 95% confidence interval (CI) = 0.2 to 0.7, p = 0.001; vitamin E: OR = 0.4, 95% CI = 0.2 to 0.7, p = 0.001). PUFA and vitamin E appeared to act synergistically, because in a combined analysis the trend OR for vitamin E was further reduced from 0.67 to 0.37 (p = 0.02), and that for PUFA from 0.60 to 0.26 (p = 0.005), with a significant interaction term (p = 0.03). The intake of flavonols, lycopene, vitamin C, vitamin B2, glutamate, calcium or phytoestrogens was not associated with the risk of developing ALS. CONCLUSION: A high intake of PUFAs and vitamin E is associated with a 50-60% decreased risk of developing ALS, and these nutrients appear to act synergistically.

Criteria for conduction block based on computer simulation studies of nerve conduction with human data obtained in the forearm segment of the median nerve.

The finding of conduction block (CB) on nerve conduction studies supports the diagnosis of potentially treatable immune-mediated neuropathies. CB in a number of axons may result in reduction of the compound muscle action potential (CMAP) on proximal versus distal stimulation (decrement). Decrement may also result from increased temporal dispersion (TD) as this leads to desynchronization and phase cancellation of the motor unit action potentials (MUAPs) out of which the CMAP is built up; polyphasia of MUAPs possibly yields additional decrement. To prove the occurrence of CB, decrement has to be larger than can be explained by increased TD or increased phase cancellation. This was established previously by simulations using MUAPs recorded in rats assuming maximal TD. Unfortunately, criteria based on human data and criteria for nerves with limited TD are not available. In the present study, criteria for CB were derived using simulations with thenar surface recorded MUAPs affected by collateral reinnervation that were obtained in patients with lower motor neurone disease (LMND). The effect of TD on decrement was determined for a wide range of TDs in the forearm segment of the median nerve and the segment distal to this. Our criteria for CB were based on area decrement because this was less influenced by TD and more by CB than amplitude decrement. The maximal area decrement in the forearm segment increased as TD in the forearm segment increased but decreased as TD in the distal segment increased. This suggests that, when desynchronization and phase cancellation occur in the distal segment due to TD, less phase cancellation and, therefore, less decrement can occur due to TD in the forearm. The finding that duration prolongation on proximal versus distal stimulation reflected TD within the forearm segment and that distal duration reflected TD in the distal segment allowed proposal of a more flexible set of criteria for forearm segments when TD in the forearm segment is limited or TD in the distal segment is pronounced. A separate investigation showed that the maximal TD in chronic inflammatory demyelinating polyneuropathy was within the range of our simulations, indicating that these were realistic. Our criteria were validated retrospectively in patients with multifocal motor neuropathy and patients with LMND. In the forearm segment of the median nerve, our criteria were more sensitive and equally specific for CB as compared with criteria for CB based on the study using rats. Our criteria have to be evaluated prospectively.

Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease.

BACKGROUND: Trophic factors, including recombinant human insulin-like growth factor I (rhIGF-I) are possible disease modifying therapies for amyotrophic lateral sclerosis. OBJECTIVES: To examine the efficacy of recombinant human insulin-like growth factor I in amyotrophic lateral sclerosis. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register (March 2006), MEDLINE (January 1966 to March 2006) and EMBASE (January 1980 to March 2006) and asked the authors of randomised clinical trials and manufacturers of recombinant human insulin-like growth factor I. SELECTION CRITERIA: We considered all randomised controlled clinical trials involving rhIGF-I treatment of amyotrophic lateral sclerosis in adults with a clinical diagnosis of definite or probable amyotrophic lateral sclerosis according to the El Escorial Criteria. The primary outcome measure was change in Appel Amyotrophic Lateral Sclerosis Rating Scale (AALSRS) total score after nine months treatment and secondary outcome measures were change in AALSRS at 1, 2, 3, 4, 5, 6, 7, 8, 9 months, change in quality of life (Sickness Impact Profile scale), survival and adverse events. DATA COLLECTION AND ANALYSIS: We identified three randomised clinical trials. Only two were included in the analysis. Each author graded the studies for methodological quality. Data were extracted and entered by the lead author and checked by the other two. Some missing data had to be regenerated by calculations based on ruler measurements of data presented in published graphs. MAIN RESULTS: In a European trial with 59 participants on placebo and 124 on rhIGF-I, 0.1 mg/kg/day the mean difference (MD) in change in AALSRS total score after nine months was -3.30 (95% confidence interval (CI) -8.68 to 2.08), non-significantly less in the treated than the placebo group. In a North American trial, in which 90 participants on placebo were compared with 89 on recombinant human insulin-like growth factor I 0.05 mg/kg/day, and 87 participants on 0.1 mg/kg/day, the MD after nine months was -6.00 (95%CI -10.99 to -1.01), significantly less on treatment. The combined analysis from both randomised clinical trials showed a weighted mean difference after nine months of -4.75 (95% CI -8.41 to -1.09), a significant difference in favour of the treated group. The secondary outcome measures showed non-significant trends favouring rhIGF-I. Similarly the data with the 0.05 mg/kg/day dose showed trends favouring rhIGF-I at all time points but did not reach significance at the five per cent level at any point. There was an increased risk of injection site reactions with rhIGF-I (relative risk 2.53, 95% CI 1.40 to 4.59). AUTHORS' CONCLUSIONS: The available randomised placebo controlled trials do not permit a definitive assessment of the clinical efficacy of rhIGF-I on ALS. More research is needed and one trial is in progress. Future trials should include survival as an outcome measure.

Immunosuppressive treatment for non-systemic vasculitic neuropathy.

BACKGROUND: Non-systemic vasculitic neuropathy is a rare disabling disease that usually has a subacute onset of progressive or relapsing-remitting sensory or sensorimotor deficits. Asymmetry, pain and weakness are key features. The diagnosis can only be made by exclusion of other causes, the absence of systemic vasculitis or other rheumatic diseases, and the demonstration of vasculitis in a nerve or a combined nerve and muscle biopsy. There is a need for efficacious therapy to prevent disease progression and to improve prognosis. OBJECTIVES: To assess if immunosuppressive treatment in non-systemic vasculitic neuropathy reduces disability, and ameliorates neurological symptoms, and if such therapy can be given safely. SEARCH STRATEGY: The Cochrane Neuromuscular Disease Group Trials Register (March 2006), The Cochrane Library (Issue 1, 2006), MEDLINE, EMBASE, LILACS, and ISI were searched from January 1980 until April 2006. In addition, the reference lists of relevant articles, reviews and textbooks were handsearched. SELECTION CRITERIA: All randomised or quasi-randomised trials that examined the efficacy of immunosuppressive treatment for non-systemic vasculitic neuropathy at least one year after the onset of therapy were sought. Participants had to fulfill the following criteria: absence of systemic or neurological disease, exclusion of any recognised cause of the neuropathy by appropriate clinical or laboratory investigations, electrophysiological studies in agreement with axonal neuropathy, confirmation of vasculitis in a nerve or a combined nerve and muscle biopsy. The primary outcome measure was to be improvement in disability. Secondary outcome measures were to be change in the mean disability score, change in muscle strength measured with the Medical Research Council sum score, change in pain or other positive sensory symptoms, number of relapses, and adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed and extracted details of all potentially relevant trials. For included studies pooled relative risks and pooled weighted standardised mean differences were to be calculated to assess treatment efficacy. MAIN RESULTS: Fifty-nine studies were identified and assessed for possible inclusion in the review, but all were excluded because of insufficient quality or lack of relevance. AUTHORS' CONCLUSIONS: No adequate randomised or quasi-randomised controlled clinical trials have been performed on which to base treatment for non-systemic vasculitic neuropathy. Randomised trials of corticosteroids and other immunosuppressive agents are needed.

Axon loss is an important determinant of weakness in multifocal motor neuropathy.

BACKGROUND: Multifocal motor neuropathy (MMN) is characterised by asymmetrical weakness and muscle atrophy, in the arms more than the legs, without sensory loss. Despite a beneficial response to treatment with intravenous immunoglobulins (IVIg), weakness is slowly progressive. Histopathological studies in MMN revealed features of demyelination and axon loss. It is unknown to what extent demyelination and axon loss contribute to weakness. Unlike demyelination, axon loss has not been studied systematically in MMN. Aims/ METHODS: To assess the independent determinants of weakness in MMN, 20 patients with MMN on IVIg treatment were investigated. Using a standardised examination in each patient, muscle strength was determined in 10 muscles. In the innervating nerve of each muscle, axon loss was assessed by concentric needle electromyography, and conduction block or demyelinative slowing by motor nerve conduction studies. Multivariate analysis was used to assess independent determinants of weakness. RESULTS: Needle electromyography abnormalities compatible with axon loss were found in 61% of all muscles. Axon loss, and not conduction block or demyelinative slowing, was the most significant independent determinant of weakness in corresponding muscles. Furthermore, axon loss and conduction block were independently associated with each other. CONCLUSION: Axon loss occurs frequently in MMN and pathogenic mechanisms leading to axonal degeneration may play an important role in the outcome of the neurological deficit in patients with MMN. Therapeutic strategies aimed at prevention and reduction of axon loss, such as early initiation of treatment or additional (neuroprotective) agents, should be considered in the treatment of patients with MMN.

Criteria for demyelination based on the maximum slowing due to axonal degeneration, determined after warming in water at 37 degrees C: diagnostic yield in chronic inflammatory demyelinating polyneuropathy.

The diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) is based on clinical and laboratory results and on features of demyelination found in nerve conduction studies. The criteria that are currently used to reveal demyelinative slowing in CIDP have several limitations. These criteria were only determined in lower arm and lower leg nerve segments, were not defined with respect to nerve temperature, and the relationship with distal compound muscle action potential (CMAP) amplitudes is unclear. The aim of our study was to determine criteria for demyelinative slowing for lower arm and leg segments as well as for upper arm and shoulder segments at a temperature of 37 degrees C, and to assess whether criteria have to be modified when the distal CMAP is decreased. Included were 73 patients with lower motor neuron disease (LMND), 45 patients with CIDP and 36 healthy controls. The arms and legs were warmed in water at 37 degrees C for at least 30 min prior to an investigation and thereafter kept warm with infrared heaters. The proposed criteria for demyelinative slowing were based on the maximum conduction slowing that may occur as a consequence of axonal degeneration and consisted of the upper boundary (99%) or the lower boundary (1%) of conduction values in LMND. In LMND, the maximum conduction slowing was different for arm and leg nerves and for segments within the arm nerves. Moreover, distal motor latency and motor conduction velocity were slower in nerves with distal CMAP amplitudes below 1 mV than in nerves with distal CMAP amplitudes above 1 mV. For these reasons, separate criteria were proposed for arm nerves, for leg nerves and for different segments within arm nerves, and more stringent criteria were proposed for distal motor latency and motor conduction velocity when the distal CMAP amplitude was below 1 mV. The diagnostic yield in CIDP was assessed using the nerve, and not the patient, as the unit of measurement. Thus, whether demyelinative slowing was present was determined for each nerve. Compared with other criteria, our criteria increased the specificity without affecting sensitivity. We conclude that the present criteria, based on the maximum slowing that may occur as a result of axonal degeneration, allow more accurate detection of demyelinative slowing in CIDP compared with other criteria. It should be emphasized that the proposed criteria can only be applied if the method of warming in water at 37 degrees C for at least 30 min is adopted.

[Clinical reasoning and decision-making in practice. A patient with loss of vision and painful legs]. / Klinisch denken en beslissen in de praktijk. Een patiënt met visusdaling en pijnlijke benen.

A 69-year-old man was admitted to the Department of Ophthalmology with bilateral loss of vision. For a few months he had also had shooting pains in both legs and instability of gait. Neurological examination showed loss of vision bilaterally and minor sensory disturbances of the legs with diminished tendon reflexes. As extensive further examination showed no specific abnormalities, the tentative diagnosis 'arteriitis temporalis' was made. Despite treatment with corticosteroids his condition deteriorated. Only after a repeat medical history had been taken did it become clear that in the past he had had homosexual contact with a number of partners. This increased the likelihood of a sexually transmitted disease in the differential diagnosis. In the meantime the results from serological tests became known: there were strongly elevated titres for syphilis in both serum and cerebral spinal fluid. Eventually the patient was diagnosed with neurosyphilis with ocular involvement and tabes dorsalis. He recovered almost completely in a few months after treatment with doxycycline.

Mimic syndromes in sporadic cases of progressive spinal muscular atrophy.

Described are patients initially diagnosed with progressive spinal muscular atrophy (PSMA), in whom further evaluation established another diagnosis. The authors prospectively investigated incident and prevalent cases of PSMA. Seventeen of 89 patients, after initial registration, were later excluded because reassessment revealed a diagnosis other than PSMA. In 11 of the 17 patients with a revised diagnosis, a potential treatment was available: multifocal motor neuropathy (7), chronic inflammatory demyelinating polyneuropathy (2), inflammatory myopathy (1), and MG (1). Other misdiagnoses included myopathy, syringomyelia, ALS, idiopathic chronic axonal polyneuropathy, and idiopathic brachial plexus neuropathy. One patient with a possible herniated lumbar disk recovered spontaneously.

Sexual differences in onset of disease and response to exercise in a transgenic model of ALS.

Transgenic mice that overexpress the mutant human SOD1 gene (hSOD1) serve as an animal model for amyotrophic lateral sclerosis (ALS). Age and sex are recognized as risk factors for ALS, but physical activity remains controversial. Therefore, we investigated the effect of exercise on the phenotype of male and female hSOD1 mice. Onset of disease, progression of disease and survival were measured in low-copy and high-copy hSOD1 mice that were randomized to an exercise or sedentary group. We found that onset of disease was different for the two sexes: significantly earlier in male than in female hSOD1 mice. Exercise delayed the onset of disease in female but not in male hSOD1 mice. Also, exercise delayed the total survival time in female high-copy hSOD1 mice. Muscle morphometry and motor neuron counts were similar in all experimental groups at the end of training. Sedentary female hSOD1 mice showed more frequently irregular estrous cycles suggesting a higher estrogen exposure in exercising female mice. These results suggest a possible neuroprotective effect of female sex hormones and support the view that ALS patients should not avoid regular exercise.

Comparison of maximal voluntary isometric contraction and hand-held dynamometry in measuring muscle strength of patients with progressive lower motor neuron syndrome.

Context. Maximal voluntary isometric contraction, a method quantitatively assessing muscle strength, has proven to be reliable, accurate and sensitive in amyotrophic lateral sclerosis. Hand-held dynamometry is less expensive and more quickly applicable than maximal voluntary isometric contraction. Objective. To investigate if hand-held dynamometry is as reliable and valid as maximal voluntary isometric contraction in measuring muscle strength in patients with an adult-onset, non-hereditary progressive lower motor neuron syndrome. Design. Two testers performed maximal voluntary isometric contraction and hand-held dynamometry measurements in six muscle groups bilaterally in patients with progressive lower motor neuron syndrome to assess reliability and validity of both the methods. Setting. Outpatient units of an academic medical center. Patients. A consecutive sample of 19 patients with non-hereditary progressive lower motor neuron syndrome (median disease duration 32.5 months, range 10-84) was tested. Outcome measures. Comparison between maximal voluntary strength contractions as measured by hand-held dynamometry and maximal voluntary isometric contraction. Results. Low intra- and interrater variation in all muscle groups were found, intraclass correlation coefficients vary between 0.86 and 0.99 for both methods. Both methods correlated well in all muscle groups with Pearson's correlation coefficients ranged between 0.78 and 0.98. Scatter plots indicated a trend to under-estimate muscle strength above 250 N by hand-held dynamometry as compared with maximal voluntary isometric contraction. Conclusions. For longitudinal evaluation of muscle strength in patients with progressive lower motor neuron syndrome (i.e. between 0 and 250 N), muscle strength can be accurate quantified with both hand-held dynamometry and maximal voluntary isometric contraction. Hand-held dynamometry has the advantage of being cheap and quickly applicable. However, our results indicate that hand-held dynamometry is less sensitive than maximal voluntary isometric contraction in detecting subnormal muscle strength in strong muscle groups (i.e. >250 N), due to limited strength of the tester.

Evidence for heterogeneity of T cell expansion in polymyositis and inclusion body myositis.

Vbeta usage of muscle-infiltrating T lymphocytes in polymyositis (PM) and sporadic inclusion body myositis (s-IBM) was correlated with clinical and histopathological features. Immunohistochemical analysis was combined with complementarity-determining region 3 (CDR3) length analysis in nine muscle biopsies of eight PM patients and six biopsies of five s-IBM patients. Vbeta usage was heterogeneous in seven patients. Four of these patients had definite PM with endomysial located T cell infiltrates, but T cells specifically surrounding and invading individual non-necrotic fibers were not found. In two s-IBM patients, Vbeta 2 usage was increased. In one of them, a repeat biopsy showed a heterogeneous Vbeta usage. We conclude that clonal expansion of muscle-infiltrating T cells could only be detected in part of the patients. Explanations may be that clonal expansion does not take place in all disease phases and that PM is a heterogeneous disease with respect to pathogenesis.

Association of the Fc gamma receptor IIA-R/R131 genotype with myasthenia gravis in Dutch patients.

Myasthenia gravis (MG) susceptibility is partially determined by allelic heterogeneity of immune-modulatory genes. IgG receptors (FcgammaR) link the humoral and cellular branches of the immune system, and regulate immune responses and inflammation. Three FcgammaR subclasses (FcgammaRIIa, FcgammaRIIIa, and FcgammaRIIIb) exhibit functional polymorphisms, which affect efficiency of FcgammaR-mediated functions. FcgammaRIIa genotypes, but not FcgammaRIIIa and FcgammaRIIIb genotypes, were differentially distributed among 107 MG patients as compared to 239 healthy controls (Pz.Lt;0.01), with a relative increase of the FcgammaRIIa-R/R131 genotype (Odds ratio 2.4, 95% confidence interval 1.4-3.9). These data suggest that the FcgammaRIIa-R/R131 genotype is a marker for susceptibility to MG.

Ovariectomy and 17beta-estradiol modulate disease progression of a mouse model of ALS.

The incidence of amyotrophic lateral sclerosis (ALS) is higher among men than women but rises in women after the menopause. Estrogens may play a protective role. Treatment with estrogens has been shown to be neuroprotective in models of several neurodegenerative diseases. We therefore determined the effect of ovariectomy on female G93A mSOD1 transgenic mice, and the effect of subsequent treatment with 17beta-estradiol (E2). Ovariectomy led to a significant acceleration of disease progression of the mice, and high-dose E2 treatment significantly delayed disease progression of ovariectomized G93A mSOD1 transgenic mice. We conclude that treatment with E2 may also delay disease progression of post-menopausal women with ALS.

The spectrum of lower motor neuron syndromes.

This review discusses the most important lower motor neuron syndromes. This relatively rare group of syndromes has not been well described clinically. Two subgroups can be distinguished: patients in whom motor neurons (lower motor neuron disease (LMND)) are primarily affected or motor axons and their surrounding myelin (multifocal motor neuropathy (MMN)), both leading to muscle atrophy and weakness. Both hereditary and sporadic forms of LMND have been described. The discussion of recent advances in the genetic knowledge of several hereditary forms of LMND may lead to a better understanding of the pathophysiology and the development of therapeutic strategies. By contrast, the pathogenesis of sporadic LMND is largely unknown. It is, therefore, difficult to consider the various sporadic forms of LMND, discussed in this review, as separate diseases. Because the diagnostic and therapeutic options may differ, it would seem rational to consider sporadic LMND as a spectrum of syndromes which can be distinguished from each other on the basis of clinical presentation.MMN is a lower motor neuron syndrome with presumed immunemediated pathogenesis. Evidence of motor conduction block on nerve conduction studies and a positive response to treatment with intravenous immunoglobulins (IVIg) are considered the most relevant criteria for the diagnosis of MMN. As it is treatable, it is important to distinguish MMN from LMND. Careful electrophysiological analysis in the search for conduction block is, therefore, required in all adult patients with pure lower motor neuron syndromes. For the individual patient, distinction between the various lower motor neuron syndromes is important as it enables the physician to provide adequate information over the disease course in LMND and to facilitate early treatment in MMN.