Search

The Polyneuropathy And Treatment with Hizentra (PATH) study required subjects with chronic inflammatory demyelinating polyneuropathy (CIDP) to show dependency on immunoglobulin G (IgG) and then be restabilized on IgG before being randomized to placebo or one of two doses of subcutaneous immunoglobulin (SCIG). Nineteen of the 51 subjects (37%) randomized to placebo did not relapse over the next 24 weeks. This article explores the reasons for this effect. A post‐hoc analysis of the PATH placebo group was undertaken. A literature search identified other placebo‐controlled CIDP trials for review and comparison. In PATH, subjects randomized to placebo who did not relapse were significantly older, had more severe disease, and took longer to deteriorate in the IgG dependency period compared with those who relapsed. Published trials in CIDP, whose primary endpoint was stability or deterioration, had a mean non‐deterioration (placebo effect) of 43%, while trials with a primary endpoint of improvement had a placebo response of only 11%. Placebo is an important variable in the design of CIDP trials. Trials designed to show clinical improvement will have a significantly lower effect of this phenomenon than those designed to show stability or deterioration.

Mika Saarela työryhmän jäsenenä. Background Approximately two-thirds of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) need long-term intravenous immunoglobulin. Subcutaneous immunoglobulin (SCIg) is an alternative option for immunoglobulin delivery, but has not previously been investigated in a large trial of CIDP. The PATH study compared relapse rates in patients given SCIg versus placebo. Methods Between March 12, 2012, and Sept 20, 2016, we studied patients from 69 neuromuscular centres in North America, Europe, Israel, Australia, and Japan. Adults with definite or probable CIDP who responded to intravenous immunoglobulin treatment were eligible. We randomly allocated participants to 0.2 g/kg or 0.4 g/kg of a 20% SCIg solution (IgPro20) weekly versus placebo (2% human albumin solution) for maintenance treatment for 24 weeks. We did randomisation in a 1: 1:1 ratio with an interactive voice and web response system with a block size of six, stratified by region (Japan or non-Japan). The primary outcome was the proportion of patients with a CIDP relapse or who were withdrawn for any other reason during 24 weeks of treatment. Patients, caregivers, and study personnel, including those assessing outcomes, were masked to treatment assignment. Analyses were done in the intention-to-treat and per-protocol sets. This trial is registered with ClinicalTrials. gov, number NCT01545076. Findings In this randomised, double-blind, placebo-controlled trial, we randomly allocated 172 patients: 57 (33%) to the placebo group, 57 (33%) to the low-dose group, and 58 (34%) to the high-dose group. In the intention-to-treat set, 36 (63% [95% CI 50-74]) patients on placebo, 22 (39% [27-52]) on low-dose SCIg, and 19 (33% [22-46]) on high-dose SCIg had a relapse or were withdrawn from the study for other reasons (p=0.0007). Absolute risk reductions were 25% (95% CI 6-41) for low-dose versus placebo (p=0.007), 30% (12-46) for high-dose versus placebo (p=0.001), and 6% (-11 to 23) for high-dose versus low-dose (p=0.32). Causally related adverse events occurred in 47 (27%) patients (ten [18%] in the placebo group, 17 [30%] in the low-dose group, and 20 [34%] in the high-dose group). Six (3%) patients had 11 serious adverse events: one (2%) patient in the placebo group, three (5%) in the low-dose group, and two (3%) in the high-dose group; only one (an acute allergic skin reaction in the low-dose group) was assessed to be causally related. Interpretation This study, which is to our knowledge, the largest trial of CIDP to date and the first to study two administrations of immunoglobulins and two doses, showed that both doses of SCIg IgPro20 were efficacious and well tolerated, suggesting that SCIg can be used as a maintenance treatment for CIDP.

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 image groups (20-29, 30-39, ... up to >= 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 >= 0.90). A total of 21 patients with sarcoidosis had a reduced IENFD score (

Contains fulltext : 69798.pdf (Publisher’s version ) (Closed access) 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.

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

Contains fulltext : 51646.pdf (Publisher’s version ) (Closed access) 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.

Contains fulltext : 48412.pdf (Publisher’s version ) (Closed access) 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 (>/= 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 skilful 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.

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.

Recent suppressive subtractive hybridization analysis on human atherosclerotic plaque-derived RNA revealed genes upregulated in plaques with a thrombus versus stable plaques. Clone SSH6, containing part of a putative open reading frame of an unknown protein, was further investigated. Full-length cDNA, coding for a 473–amino acid (aa) protein, was identified in a vascular smooth muscle cell (SMC) cDNA library. Bioinformatics suggested the presence of multiple SSH6 variants due to alternative splicing of exon 3. Multiple-tissue Northern blot analysis demonstrated a differential expression pattern of these variants, as a ubiquitously expressed SSH6 mRNA missing exon 3, was detected apart from a putative vascular SMC–specific form containing exon 3. Western blot analysis indicated a ubiquitous 35-kDa protein (SSH6-β), in addition to a 45-kDa protein (vasculin), detected in the vascular wall and in plasma. Analysis of arteries displaying various stages of atherosclerosis indicated that the vasculin/SSH6-β ratio increases throughout atherogenesis. Immunohistochemical analysis demonstrated cytoplasmic expression of SSH6 gene products in macrophages, endothelial cells, and SMCs. In summary, we identified a novel mRNA/protein, vasculin, in the arterial wall and plasma. The regulated expression of vasculin in plaques suggests a role in atherogenesis. Moreover, its presence in plasma opens perspectives for vasculin as a marker for atherosclerosis.

The availability of antibodies against the protein-gene product 9.5, since the early 1990s, opened the way to the use of skin biopsy for detecting morphometry and structural damages of somatic small nerve fibers, a subgroup of sensory nerves that was traditionally considered invisible. Epidermal nerve fibers are unmyelinated axons with exclusive somatic functions and the most distal nociceptors of our body. They can be examined by skin biopsy, which is a safe, minimally invasive, painless, and a cheap technique. The quantification of epidermal nerve fibers is reliable, reproducible, and unaffected by the severity of neuropathy. It allows to confirm the diagnosis of small fiber neuropathy, a distinct clinical syndrome characterized by burning feet and neuropathic pain. This article reviews the techniques that have been used to investigate the innervation of the epidermis and the correlation between degeneration and regeneration of epidermal nerve fibers and neuropathic pain.

Small fiber neuropathy (SFN) is a disorder typically dominated by neuropathic pain and autonomic dysfunction, in which the thinly myelinated Aδ-fibers and unmyelinated C-fibers are selectively injured. The diagnosis SFN is based on a reduced intraepidermal nerve fiber density and/or abnormal thermal thresholds in quantitative sensory testing. The etiologies of SFN are diverse, although no apparent cause is frequently seen. Recently, SCN9A-gene variants (single amino acid substitutions) have been found in ∼30% of a cohort of idiopathic SFN patients, producing gain-of-function changes in sodium channel Na(V)1.7, which is preferentially expressed in small diameter peripheral axons. Functional testing showed that these variants altered fast inactivation, slow inactivation or resurgent current and rendered dorsal root ganglion neurons hyperexcitable. In this review, we discuss the role of Na(V)1.7 in pain and highlight the molecular genetics and pathophysiology of SCN9A-gene variants in SFN. With increasing knowledge regarding the underlying pathophysiology in SFN, the development of specific treatment in these patients seems a logical target for future studies.

Objectives: Although small fiber neuropathy (SFN) often occurs without apparent cause, the molecular etiology of idiopathic SFN (I-SFN) has remained enigmatic. Sodium channel Na(v)1.7 is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons and their small-diameter peripheral axons. We recently reported the presence of Na(v)1.7 variants that produce gain-of-function changes in channel properties in 28% of patients with painful I-SFN and demonstrated impaired slow-inactivation in one of these mutations after expression within HEK293 cells. Here we show that the I739V Na(v)1.7 variant in a patient with biopsy-confirmed I-SFN impairs slow-inactivation within DRG neurons and increases their excitability. Methods: A patient with SFN symptoms including pain, and no identifiable underlying cause, was evaluated by skin biopsy, quantitative sensory testing, nerve conduction studies, screening of genomic DNA for variants in SCN9A, and functional analysis. Results: Voltage-clamp analysis following expression within DRG neurons revealed that the Na(v)1.7/I739V substitution impairs slow-inactivation, depolarizing the midpoint (V-1/2) by 5.6 mV, and increasing the noninactivating component at 10 mV from 16.5% to 22.2%. Expression of I739V channels within DRG neurons rendered these cells hyperexcitable, reducing current threshold and increasing the frequency of firing evoked by graded suprathreshold stimuli. Conclusions: These observations provide support, from a patient with biopsy-confirmed SFN, for the suggestion that functional variants of Na(v)1.7 that impair slow-inactivation can produce DRG neuron hyperexcitability that contributes to pain in SFN. Na(v)1.7 channelopathy-associated SFN should be considered in the differential diagnosis of cases of SFN in which no other cause is found. Neurology (R) 2012;78:1635-1643

Contains fulltext : 81752.pdf (Publisher’s version ) (Closed access) 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

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.

Contains fulltext : 70850.pdf (Publisher’s version ) (Closed access) 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.

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.

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.

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.

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.

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.

Dystrophinopathy patient registries are very useful for improvement of standard care and planning of clinical trials. The Dutch Dystrophinopathy Database contains information of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients in the Netherlands. The historical incidence of DMD is estimated at 20 boys per year and unknown for BMD. DMD and BMD patients received information through patient organisations, treating physicians, the genetic test centre or a website ( www.lumc.nl/duchenne ). Included patients gave consent for registration in the national patient registry and the international TREAT-NMD database, permission to contact their physician and filled out a questionnaire about their disease course. On January 2013 the database contained disease milestones of 420 DMD and 140 BMD patients, including data from 78 deceased DMD and 16 deceased BMD males. 324 DMD and 104 BMD patients have a DNA confirmed diagnosis. The mean yearly incidence for DMD was 18 between 1980 and 2000. Given a mean life expectancy of 27 years this would suggest a prevalence of 486 DMD patients, and thus an inclusion rate in the database of 70%. The mean yearly incidence for BMD was 4 between 1960 and 2000. The mean life expectancy was 55 years suggesting a prevalence of 220 BMD patients, and thus an inclusion rate in the database of 56%. In the DNA confirmed DMD cohort mean age at diagnosis decreased from 5.6 years before 1970 to 4.0 years more recently. The mean age at loss of ambulation increased to 9.8 years and for scoliosis surgery to 14 years. Age at start of mechanical ventilation ranged from 14 to 28 years. Close collaboration during five years between patient organisations, physicians and researchers resulted in a patient registry covering three quarters of all Dutch DMD patients. The yearly update is a constant challenge, but the advantage is one national registry representative for the whole population, limiting selection bias to a minimum.

Contains fulltext : 58576.pdf (Publisher’s version ) (Closed access) 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.

Summary 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 dugs, including methotrexate, have been used to treat sarcoidosis. The value of new drugs such as anti-tumour necrosis factor α will be assessed. In this review we describe the clinical manifestations of neurosarcoidosis, diagnostic dilemmas and considerations, and therapy.

Mevrouw Verhoeven is voor de tweede maal zwanger. Haar eerste kind, een zoon, is gezond, hoewel zijn ontwikkeling wat traag verloopt. Hij is nu 6 jaar oud en kon in het gewone basisonderwijs niet meekomen; sinds kort volgt hij speciaal onderwijs. Hij is onderzocht door een kinderarts en een kinderneuroloog, maar beiden konden geen oorzaak vinden voor zijn leerproblemen. De huidige zwangerschap verloopt naar wens, hoewel de moeder de baby minder goed voelt dan haar eerste kind.

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.

Sirs: Myotonia is a clinical phenomenon consisting of uncontrolled temporary muscle stiffness after voluntary or evoked muscle contractions [1]. It is a cardinal symptom in non-dystrophic myotonias, including chloride and sodium channelopathies. Myotonia typically occurs after a period of rest and decreases with continuing exercise, commonly referred to as the warm-up phenomenon. This is in contrast with what occurs in paradoxical myotonia, where muscle stiffness increases as a result of continuing exercise. The warm-up phenomenon is an established clinical feature in chloride channelopathies, both in recessive myotonia congenita (Becker’s disease) as well as in dominant myotonia congenita (Thomsen’s disease). It has also been shown to occur in limb muscles of patients with a sodium channelopathy [1, 4]. By contrast, paradoxical myotonia has been established by others as the characteristic feature of sodium channel myotonias [3]. Thus, unlike the phenotypic homogeneity of chloride channelopathies, sodium channel mutations are associated with a broad spectrum of clinical phenotypes [5]. Here we report three patients with a predominant and generalised warm-up phenomenon associated with the V445M missense mutation of the SCN4A gene encoding the alpha-subunit of the voltage gated sodium channel. Three patients, from two families, with an autosomal dominant non-dystrophic myotonia and a predominant warm-up phenomenon were referred to our clinic. All patients had complaints of generalised muscle stiffness since birth and had earlier been diagnosed as Thomsen’s disease, but recent chloride channel gene (CLCN1) mutation screening was negative. Clinical myotonia was generalised, severe and painful. All patients noticed aggravation of myotonia at cold temperatures and only one patient reported aggravation after eating potassium rich food. They all used sodium channel blockers (mexiletine 200 mg three times a day, procainamide 1000 mg three times a day and quinine 200 mg three times a day respectively) with a good subjective effect. Needle EMG of all patients revealed myotonic discharges in all muscles investigated (left biceps muscle, right first interosseus muscle, right rectus femoris muscle, left tibialis anterior muscle and left orbicularis oculi muscle). We measured the warm-up phenomenon in three different muscle groups during a drug free period. The warm-up phenomenon of eyelid muscles and right hand flexor muscles was quantified by measuring the difference between two relaxation times - timed with a stopwatch - , i.e. after maximum voluntary contraction of three seconds following ten minutes of rest and after ten successive contractions. For leg muscles we compared the first and tenth trial on a ‘chair test’ in which the time required to rise from a standardised chair, to move around it and to sit down again was measured. DNA extracted from 20 ml of blood was screened for mutations in SCN4A by direct nucleotide sequence analysis. All patients showed a marked generalised warm-up phenomenon (Table 1). Direct nucleotide sequence analysis of all three patients showed the same missense mutation (c.1333G>A; p.V445M) in SCN4A. Table 1 Clinical relaxation times (in seconds) of three patients after the first (1st) and tenth (10th) maximum voluntary contraction of eyelid muscles (eyes), right hand flexor muscles (hand) and leg muscles (legs) The V445M sodium channel mutation was first reported by Rosenfeld et al. causing a painful myotonia congenita [4]. The warm-up phenomenon was mentioned in one patient. Here we report three patients with a predominant and generalised (eyelid muscles, right hand flexor muscles and leg muscles) warm-up phenomenon in association with the same V445M sodium channel mutation. Although quantitative computer analysis for the warm-up phenomenon of a single muscle group has already been developed, we used clinical tests in order to be able to measure this phenomenon in three various muscle groups [2]. For a definite molecular diagnosis clinicians should be aware that a predominant and generalised warm-up phenomenon may be found in chloride channelopathies but also in sodium channelopathies. A definite diagnosis is important for informing patients about their disease, orienting therapy and genetic counselling [5]. Thus, in patients with severe, painful myotonia in combination with a clear warm-up phenomenon, we recommend screening of SCN4A with particular attention for the V445M mutation.

Contains fulltext : 51361.pdf (Publisher’s version ) (Open Access) 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.