Impact of contractures on daily functioning in adolescents with spinal muscular atrophy: a qualitative study.

PURPOSE: Exploring the impact of contractures in adolescents and young adults (AYA) with spinal muscular atrophy (SMA) on daily functioning and participation and the impact of received contracture management. METHODS: We included 14, non-ambulant AYA with SMA types 2/3 (10 females and 4 males), aged 16-30 years. Interviews focused on two topics: perceived impact of contractures on daily functioning and of previous contracture management. We used inductive thematic analysis for interview analysis. RESULTS: In general, participants experienced muscle weakness to be more of a hindrance than contractures; they had adapted to their contractures over time. Participants considered contracture treatment useful when goals were meaningful and realistic. Participants mentioned that their perspective on contracture management would change in light of a promise of improved motor function due to disease-modifying treatment. CONCLUSION: Despite the relatively low impact of contractures in comparison to the loss of muscle strength, non-ambulant AYA with SMA should be informed on the potential impact of contractures and benefits and potential adverse effects of their management. This information can support the shared decision-making process. While respecting individual choices, allows for incorporating interventions into daily life and the promotion of daily functioning and participation when children with SMA are growing up.

The variability of the perceived impact of contractures in non-ambulant adolescents and young adults with spinal muscular atrophy (SMA) underscores the need for individualized assessment and contracture management based on discussions about challenges, benefits and burden.In the treatment plan for contracture management in SMA it is important to take into account: 1) that adolescents often experienced physiotherapy as additional comfort, with less feeling of stiffness, and 2) that most perceived orthosis and standers as unnecessary and burdensome as contracture management.Clinicians should consider postural management in an early stage given the improved prognosis on motor development of children with SMA.Clinicians should monitor and revisit treatment goals, benefits and adverse effects on a regular basis as part of the shared goal-setting and decision-making in contracture management for children with SMA.

Swallowing Problems in Spinal Muscular Atrophy Types 2 and 3: A Clinical, Videofluoroscopic and Ultrasound Study.

BACKGROUND: Spinal muscular atrophy (SMA) is a hereditary motor neuron disorder, characterized by the degeneration of motor neurons and progressive muscle weakness. There is a large variability of disease severity, reflected by the classification of SMA types 1-4. OBJECTIVE: The aim of this cross-sectional study was to determine the nature of swallowing problems and underlying mechanisms in patients with SMA types 2 and 3, and the relationship between swallowing and mastication problems. METHODS: We enrolled patients (aged 13-67 years) with self-reported swallowing and/or mastication problems. We used a questionnaire, the functional oral intake scale, clinical tests (dysphagia limit, and timed test swallowing, the test of mastication and swallowing solids), a videofluoroscopic swallowing study (VFSS), and muscle ultrasound of the bulbar muscles (i.e. digastric, geniohyoid and tongue muscles). RESULTS: Non-ambulant patients (n = 24) had a reduced dysphagia limit (median 13 ml (3-45), and a swallowing rate at the limit of normal (median 10 ml/sec (range 4-25 ml). VFSS revealed piecemeal deglutition and pharyngeal residue. We found pharyngo-oral regurgitation in fourteen patients (58%), i.e. they transported the residue from the hypopharynx back into the oral cavity and re-swallowed it. Six patients (25%) demonstrated impaired swallowing safety (i.e. penetration aspiration scale > 3). Muscle ultrasound revealed an abnormal muscle structure of the submental and tongue muscles. Ambulant patients (n = 3), had a normal dysphagia limit and swallowing rate, but VFSS showed pharyngeal residue, and muscle ultrasound demonstrated an abnormal echogenicity of the tongue. Swallowing problems were associated with mastication problems (p = 0.001).

Inflammatory markers in cerebrospinal fluid of paediatric spinal muscular atrophy patients receiving nusinersen treatment.

Spinal muscular atrophy (SMA) is a progressive motor neuron disease with onset during infancy or early childhood. Recent therapeutic advances targeting the genetic defect that underlies SMA improved survival in patients with infantile onset SMA (type 1) and improved motor function in SMA type 1-3. The most commonly used therapy for SMA, the antisense oligonucleotide nusinersen, is delivered by repeated intrathecal injections. The long-term safety effects of this procedure, however, have not yet been investigated in detail. We here present case reports of three children with SMA in which routine laboratory investigation revealed increased leukocyte counts in cerebrospinal fluid (CSF) collected during the course of nusinersen treatment. To further characterize this observation, we used a multiplex method to analyse a broad spectrum of inflammatory markers in the CSF of these patients. We found that interleukin-10 (IL10) was consistently elevated in CSF with increased leukocyte counts, but other inflammatory markers were not. Based on this analysis we selected 7 markers for further analysis in a cohort of 38 children with SMA and determined their expression during the course of nusinersen therapy. No consistent association was found between levels of inflammatory markers and the duration of nusinersen therapy in individual patients. However, monocyte chemoactive protein 1 (MCP1/CCL2) -a neuroprotective protein secreted by astrocytes and previously associated with SMA- levels increased over the course of nusinersen treatment, indicating a possible neuroprotective mechanism associated with nusinersen therapy. In summary, our findings confirm that repeated intrathecal injections are safe and do not trigger unwanted immune responses.

Mastication in Patients with Spinal Muscular Atrophy Types 2 and 3 is Characterized by Abnormal Efficiency, Reduced Endurance, and Fatigue.

Mastication problems can have a negative impact on the intake of food and quality of life. This cross-sectional study characterizes mastication problems using clinical and instrumental assessments in patients with spinal muscular atrophy (SMA) types 2 and 3 with self-reported bulbar problems. We included 27 patients (aged 13-67 years), 18 with SMA type 2 and 9 patients with SMA type 3 (of whom three were still ambulant) and applied a questionnaire, clinical mastication tests (TOMASS and 6-min mastication test), and muscle ultrasound of the mastication muscles. Non-ambulant patients demonstrated inefficient mastication as reflected by median z scores for masticatory cycles (z = 1.8), number of swallows (z = 4.3) and time needed to finish the cracker (z = 3.4), and limited endurance of continuous mastication as demonstrated by the median z scores of the 6-min mastication test (z = - 1.5). Patients reported increased fatigue directly after the 6-min mastication test as well as 5 min after completing the test (p < 0.001; p = 0.003). Reduced maximal mouth opening was associated with mastication problems (p < 0.001). Muscle ultrasound of the mastication muscles showed an abnormal muscle structure in 90% of both ambulant and non-ambulant patients. This study aims to understand the nature and underlying mechanisms of mastication problems in patients with SMA types 2 and 3 with reported bulbar problems.

Clinical outcome of CIDP one year after start of treatment: a prospective cohort study.

OBJECTIVE: To assess clinical outcome in treatment-naive patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: We included adult treatment-naive patients participating in the prospective International CIDP Outcome Study (ICOS) that fulfilled the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) diagnostic criteria for CIDP. Patients were grouped based on initial treatment with (1) intravenous immunoglobulin (IVIg), (2) corticosteroid monotherapy or (3) IVIg and corticosteroids (combination treatment). Outcome measures included the inflammatory Rasch-built overall disability scale (I-RODS), grip strength, and Medical Research Council (MRC) sum score. Treatment response, treatment status, remissions (improved and untreated), treatment changes, and residual symptoms or deficits were assessed at 1 year. RESULTS: Forty patients were included of whom 18 (45%) initially received IVIg, 6 (15%) corticosteroids, and 16 (40%) combination treatment. Improvement on ≥ 1 of the outcome measures was seen in 31 (78%) patients. At 1 year, 19 (48%) patients were still treated and fourteen (36%) patients were in remission. Improvement was seen most frequently in patients started on IVIg (94%) and remission in those started on combination treatment (44%). Differences between groups did not reach statistical significance. Residual symptoms or deficits ranged from 25% for neuropathic pain to 96% for any sensory deficit. CONCLUSIONS: Improvement was seen in most patients. One year after the start of treatment, more than half of the patients were untreated and around one-third in remission. Residual symptoms and deficits were common regardless of treatment.

Feeding and Swallowing Problems in Infants with Spinal Muscular Atrophy Type 1: an Observational Study.

BACKGROUND: Infantile hereditary proximal spinal muscular atrophy (SMA) type 1 is characterized by onset in the first 6 months of life and severe and progressive muscle weakness. Dysphagia is a common complication but has not been studied in detail. OBJECTIVE: To study feeding and swallowing problems in infants with SMA type 1, and to explore the relation between these problems and functional motor scores. METHODS: We prospectively included 16 infants with SMA type 1 between September 2016 and October 2018. Eleven infants received palliative care and five infants best supportive care in combination with nusinersen. We compiled and used an observation list with feeding related issues and observed feeding sessions during inpatient and outpatient visits. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) was used as a measure of motor function. RESULTS: All infants in the palliative care group (median onset of disease 14 days (range 1-56); median inclusion in the study 52 days (range 16-252) demonstrated symptoms of fatigue during feeding and unsafe swallowing. Symptoms were short nursing sessions (10-15 minutes), and not being able to finish the recommended feeding volumes (72%); increased frequency of feeding sessions (55%); coughing when drinking or eating (91%), and wet breathing during and after feeding (64%).Two out of five infants in the nusinersen group (median onset of disease 38 days (range 21-90); inclusion in the study at 63 days (range 3-218) were clinically pre-symptomatic at the start of treatment. The other three infants showed symptoms of fatigue and unsafe swallowing at inclusion in the study. These symptoms initially decreased after the start of the treatment, but (re)appeared in all five infants between the ages of 8 to 12 months, requiring the start tube of feeding. In the same period motor function scores significantly improved (median increase CHOP INTEND 16 points). CONCLUSION: Impaired feeding and swallowing remain important complications in infants with SMA type 1 after the start of nusinersen. Improvement of motor function does not imply similar gains in bulbar function.

Bulbar Problems Self-Reported by Children and Adults with Spinal Muscular Atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) is hereditary motor neuron disorder, characterised by the degeneration of motor neurons and progressive muscle weakness. It is caused by the homozygous loss of function of the survival motor neuron (SMN) 1 gene. SMA shows a wide variability of disease severity. OBJECTIVE: To investigate self-reported bulbar problems in patients with SMA, and their relationship to age, functional motor scores and active maximum mouth opening. METHODS: We used the Diagnostic List of Dysphagia and Dysarthria in (pediatric) patients and relevant recent clinical data from the national SMA database. RESULTS: The 118 included patients with SMA frequently reported jaw problems (34%), fatigue associated with mastication (44%), choking (56%) and intelligibility problems (27%). Jaw, mastication and swallowing problems frequently occurred in combination with each other. There was an increase of reported bulbar problems in patients with SMA type 3a, older than 30 years of age, compared to younger patients of this SMA type.The Hammersmith Functional Motor Scale Expanded scores showed a negligible correlation with jaw and mastication problems, a low negative correlation with swallowing problems and a moderate negative correlation with intelligibility problems. Reduced mouth opening showed a significant, but low correlation with bulbar complaints in patients with SMA type 2. CONCLUSIONS: Fatigue associated with mastication and swallowing problems were frequently reported complaints. Patients 30 years and older with milder forms of SMA showed an increase of self-reported bulbar problems.

Participation and mental well-being of mothers of home-living patients with spinal muscular atrophy.

Proximal spinal muscular atrophy (SMA) causes severe physical limitations but also has a major impact on the lives of parents. The aim of this study was to investigate participation and mental well-being (burden, emotional distress and satisfaction with participation) of parents of home-living patients with SMA. Caregiver burden was assessed with the Caregiver Strain Index, emotional distress with the Hospital Anxiety and Depression Scale and satisfaction with participation with the Utrecht Scale for Evaluation of Rehabilitation-Participation. Because the majority of parents were mothers of home-living SMA patients (76%), further analyses were restricted to mothers. Seventy-seven percent of mothers of patients with SMA had paid work. A substantial proportion of mothers (76%) perceived high caregiver burden. Burden, emotional distress and satisfaction with participation were comparable between mothers of children and mothers of adults with SMA. Caregivers' participation in leisure activities was significantly related to their perceived level of caregiver burden, emotional distress and satisfaction with participation. Mothers engaging in more social and leisure activities reported lower emotional distress and caregiver burden. Considering the high level of burden attention should be paid to mental well-being of primary caregivers of patients with SMA. Caregivers should be motivated to keep participating in social/leisure activities.

The POWER-tool: Recommendations for involving patient representatives in choosing relevant outcome measures during rare disease clinical trial design.

In clinical trials, it is relevant to ask patients and/or their caregivers which aspects concerning their disease they consider important to measure when a new intervention is being investigated. Those aspects, useful as outcome measures in a trial, are of pivotal importance for the result of the trial and the subsequent decision-making. In rare diseases the choice of outcome measures may be even more important, due to the small numbers and heterogeneity of the patients that are included. We have developed a tool to involve patients in the determination of outcome measures and the choice of measurement instruments. This tool was developed together with a patient think tank, consisting of a group of rare disease patient representatives, and by interviewing end users. We have road-tested our tool in an ongoing trial, and evaluated it during a focus group meeting. The tool consists of three steps: 1) Preparation, 2) Consultation of patients, 3) Follow-up during which the consultation results are implemented in the trial design. The tool provides guidelines for researchers to include the patient's opinion in the choice of outcome measures in the trial design stage. We describe the development of the POWER-tool (Patient participation in Outcome measure WEighing for Rare diseases), and first experiences of the tool in an ongoing trial.

Muscle strength and motor function throughout life in a cross-sectional cohort of 180 patients with spinal muscular atrophy types 1c-4.

BACKGROUND AND PURPOSE: Natural history studies in spinal muscular atrophy (SMA) have primarily focused on infants and children. Natural history studies encompassing all age groups and SMA types are important for the interpretation of treatment effects of recently introduced survival motor neuron gene-augmenting therapies. METHODS: We conducted a cross-sectional study to investigate muscle strength, Hammersmith Functional Motor Scale (Expanded) score and the patterns of muscle weakness in relation to age and SMA type. RESULTS: We included 180 patients with SMA types 1-4 in the age range 1-77.5 years with median disease duration of 18 (range 0-65.8) years. With the exception of the early phases of disease in which children with SMA types 2 and 3 may achieve new motor skills and show a temporary increase in muscle strength, cross-sectional data suggested that declining muscle strength and loss of motor skills over time are characteristic of all SMA types. Mean loss of strength was at least 1 point on the Medical Research Council score and 0.5 point on the Hammersmith Functional Motor Scale (Expanded) score per year. Trend lines compatible with deterioration of motor function and muscle strength started in childhood and continued into adulthood. The age at loss of specific motor skills was associated with disease severity. Triceps, deltoid, iliopsoas and quadriceps were the weakest muscles in all patients. Hierarchical cluster analysis did not show a segmental distribution of muscle weakness as suggested previously. CONCLUSIONS: Progressive muscle weakness and loss of motor function are characteristic of all SMA types and all ages.

A comparative study of brachial plexus sonography and magnetic resonance imaging in chronic inflammatory demyelinating neuropathy and multifocal motor neuropathy.

BACKGROUND AND PURPOSE: To compare the performance of neuroimaging techniques, i.e. high-resolution ultrasound (HRUS) and magnetic resonance imaging (MRI), when applied to the brachial plexus, as part of the diagnostic work-up of chronic inflammatory demyelinating neuropathy (CIDP) and multifocal motor neuropathy (MMN). METHODS: Fifty-one incident, treatment-naive patients with CIDP (n = 23) or MMN (n = 28) underwent imaging of the brachial plexus using (i) a standardized MRI protocol to assess enlargement or T2 hyperintensity and (ii) bilateral HRUS to determine the extent of nerve (root) enlargement. RESULTS: We found enlargement of the brachial plexus in 19/51 (37%) and T2 hyperintensity in 29/51 (57%) patients with MRI and enlargement in 37/51 (73%) patients with HRUS. Abnormal results were only found in 6/51 (12%) patients with MRI and 12/51 (24%) patients with HRUS. A combination of the two imaging techniques identified 42/51 (83%) patients. We found no association between age, disease duration or Medical Research Council sum-score and sonographic nerve size, MRI enlargement or presence of T2 hyperintensity. CONCLUSIONS: Brachial plexus sonography could complement MRI in the diagnostic work-up of patients with suspected CIDP and MMN. Our results indicate that combined imaging studies may add value to the current diagnostic consensus criteria for chronic inflammatory neuropathies.

Cardiac pathology in spinal muscular atrophy: a systematic review.

BACKGROUND: Hereditary proximal spinal muscular atrophy (SMA) is a severe neuromuscular disease of childhood caused by homozygous loss of function of the survival motor neuron (SMN) 1 gene. The presence of a second, nearly identical SMN gene (SMN2) in the human genome ensures production of residual levels of the ubiquitously expressed SMN protein. Alpha-motor neurons in the ventral horns of the spinal cord are most vulnerable to reduced SMN concentrations but the development or function of other tissues may also be affected, and cardiovascular abnormalities have frequently been reported both in patients and SMA mouse models. METHODS: We systematically reviewed reported cardiac pathology in relation to SMN deficiency. To investigate the relevance of the possible association in more detail, we used clinical classification systems to characterize structural cardiac defects and arrhythmias. CONCLUSIONS: Seventy-two studies with a total of 264 SMA patients with reported cardiac pathology were identified, along with 14 publications on SMA mouse models with abnormalities of the heart. Structural cardiac pathology, mainly septal defects and abnormalities of the cardiac outflow tract, was reported predominantly in the most severely affected patients (i.e. SMA type 1). Cardiac rhythm disorders were most frequently reported in patients with milder SMA types (e.g. SMA type 3). All included studies lacked control groups and a standardized approach for cardiac evaluation. The convergence to specific abnormalities of cardiac structure and function may indicate vulnerability of specific cell types or developmental processes relevant for cardiogenesis. Future studies would benefit from a controlled and standardized approach for cardiac evaluation in patients with SMA.

Altered Energetics of Exercise Explain Risk of Rhabdomyolysis in Very Long-Chain Acyl-CoA Dehydrogenase Deficiency.

Rhabdomyolysis is common in very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and other metabolic myopathies, but its pathogenic basis is poorly understood. Here, we show that prolonged bicycling exercise against a standardized moderate workload in VLCADD patients is associated with threefold bigger changes in phosphocreatine (PCr) and inorganic phosphate (Pi) concentrations in quadriceps muscle and twofold lower changes in plasma acetyl-carnitine levels than in healthy subjects. This result is consistent with the hypothesis that muscle ATP homeostasis during exercise is compromised in VLCADD. However, the measured rates of PCr and Pi recovery post-exercise showed that the mitochondrial capacity for ATP synthesis in VLCADD muscle was normal. Mathematical modeling of oxidative ATP metabolism in muscle composed of three different fiber types indicated that the observed altered energy balance during submaximal exercise in VLCADD patients may be explained by a slow-to-fast shift in quadriceps fiber-type composition corresponding to 30% of the slow-twitch fiber-type pool in healthy quadriceps muscle. This study demonstrates for the first time that quadriceps energy balance during exercise in VLCADD patients is altered but not because of failing mitochondrial function. Our findings provide new clues to understanding the risk of rhabdomyolysis following exercise in human VLCADD.

Cytokine profiles in multifocal motor neuropathy and progressive muscular atrophy.

Multifocal motor neuropathy (MMN) and progressive muscular atrophy (PMA) are associated with IgM monoclonal gammopathy or the presence IgM anti-GM1-antibodies. To further investigate the pathophysiology of MMN and PMA we determined concentrations of 16 mainly B-cell associated inflammatory markers in serum from 25 patients with MMN, 55 patients with PMA, 25 patients with amyotrophic lateral sclerosis (ALS) and 50 healthy controls. Median serum concentrations of the 16 tested cytokines and chemokines were not significantly increased in patients with MMN or patients with PMA, irrespective of the presence of IgM monoclonal gammopathy or high IgM anti-GM1 antibodies. These results argue against a systemic B-cell mediated immune response underlying the pathogenesis of MMN and PMA.

RYR1-related myopathies: a wide spectrum of phenotypes throughout life.

BACKGROUND AND PURPOSE: Although several recent studies have implicated RYR1 mutations as a common cause of various myopathies and the malignant hyperthermia susceptibility (MHS) trait, many of these studies have been limited to certain age groups, confined geographical regions or specific conditions. The aim of the present study was to investigate the full spectrum of RYR1-related disorders throughout life and to use this knowledge to increase vigilance concerning malignant hyperthermia. METHODS: A retrospective cohort study was performed on the clinical, genetic and histopathological features of all paediatric and adult patients in whom an RYR1 mutation was detected in a national referral centre for both malignant hyperthermia and inherited myopathies (2008-2012). RESULTS: The cohort of 77 non-related patients (detection rate 28%) included both congenital myopathies with permanent weakness and 'induced' myopathies such as MHS and non-anaesthesia-related episodes of rhabdomyolysis or hyperCKemia, manifested throughout life and triggered by various stimuli. Sixty-one different mutations were detected, of which 24 were novel. Some mutations are present in both dominant (MHS) and recessive modes (congenital myopathy) of inheritance, even within families. Histopathological features included an equally wide spectrum, ranging from only subtle abnormalities to prominent cores. CONCLUSIONS: This broad range of RYR1-related disorders often presents to the general paediatric and adult neurologist. Its recognition is essential for genetic counselling and improving patients' safety during anaesthesia. Future research should focus on in vitro testing by the in vitro contracture test and functional characterization of the large number of RYR1 variants whose precise effects currently remain uncertain.

Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis.

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of neuromuscular disease, ranging from various congenital myopathies to the malignant hyperthermia (MH) susceptibility trait without associated weakness. We sequenced RYR1 in 39 unrelated families with rhabdomyolysis and/or exertional myalgia, frequent presentations in the neuromuscular clinic that often remain unexplained despite extensive investigations. We identified 9 heterozygous RYR1 mutations/variants in 14 families, 5 of them (p.Lys1393Arg; p.Gly2434Arg; p.Thr4288_Ala4290dup; p.Ala4295Val; and p.Arg4737Gln) previously associated with MH. Index cases presented from 3 to 45 years with rhabdomyolysis, with or without exertional myalgia (n=12), or isolated exertional myalgia (n=2). Rhabdomyolysis was commonly triggered by exercise and heat and, less frequently, viral infections, alcohol and drugs. Most cases were normally strong and had no personal MH history. Inconsistent additional features included heat intolerance, and cold-induced muscle stiffness. Muscle biopsies showed mainly subtle changes. Familial RYR1 mutations were confirmed in relatives with similar or no symptoms. These findings suggest that RYR1 mutations may account for a substantial proportion of patients presenting with unexplained rhabdomyolysis and/or exertional myalgia. Associated clinico-pathological features may be subtle and require a high degree of suspicion. Additional family studies are paramount in order to identify potentially MH susceptible relatives.

Effect of stem cell transplantation for B-cell malignancies on disease course of associated polyneuropathy.

B cell dyscrasias are often refractory to medical treatments, and hematological stem cell therapy (SCT) may be warranted. It is not clear whether an associated polyneuropathy may also profit from SCT. In exceptional cases SCT has been tried in patients with monoclonal gammopathy and progressive polyneuropathy refractory to medical treatments. In a cohort of 225 patients with monoclonal gammopathy and polyneuropathy, we selected the six patients who underwent SCT and retrospectively examined the effects of SCT on the disease course of the associated polyneuropathy. In all patients except one, the indication for SCT was hemato-oncological (multiple myeloma in 4 patients and primary AL amyloidosis in 1). The remaining patient had an IgG monoclonal gammopathy of undetermined significance and a progressive and painful polyneuropathy for which she was treated with SCT. SCT led to improvement of motor scores and autonomic symptoms in one patient; three patients experienced improvement of neuropathic pain or sensory deficits but showed further progression of weakness. One patient showed no improvement at all. One patient died within 100 days after SCT. In conclusion, SCT as a treatment of refractory hematological malignancy may occasionally have a positive effect on the associated progressive polyneuropathy, although the benefits are very limited and the treatment-related mortality is high.

Multifocal motor neuropathy: association of anti-GM1 IgM antibodies with clinical features.

OBJECTIVE: To determine the prevalence and specificity of antibodies against single gangliosides and ganglioside complexes in serum from 88 patients with multifocal motor neuropathy (MMN) and to study the association with clinical features. METHODS: ELISA was used to detect immunoglobulin (Ig)M, IgG, and IgA antibodies against GM1, GM2, GD1a, GD1b, GM1b, GT1a, GT1b, GQ1b, GalNAc-GD1a, and the glycolipid SGPG; absorption studies were performed to study cross-reactivity. Presence of antibodies against ganglioside complexes consisting of any of combinations of GM1, GM2, GD1a, GD1b, GT1b, and GQ1b was also tested. RESULTS: Anti-GM1 IgM, IgG, and IgA antibodies were detected in serum from 43%, 1%, and 5% of patients with MMN. Anti-GM2 IgM antibodies were detected in 6% and anti-GD1b IgM antibodies in 9% of patients. Patients with MMN with anti-GM1 IgM antibodies had more severe weakness (p < 0.01), more disability (p < 0.01), and more axon loss (p = 0.05) than patients without anti-GM1 IgM antibodies. Anti-GM1 IgM antibody titers correlated with Medical Research Council scores (correlation coefficient = 0.43; p < 0.0001). Anti-GD1b IgM antibody activity was associated with reduced vibration sense (p < 0.01). Absorption studies showed that anti-GD1b and anti-GM2 IgM antibodies cross-reacted with GM1. Antibodies against ganglioside complexes were not detected. Complexes containing GD1a, GD1b, GT1b, or GQ1b with GM1 lowered antibody activity against GM1. CONCLUSION: Anti-ganglioside IgM antibodies in MMN display limited specificity and are associated with severity and clinical characteristics. Results of this study suggest that anti-GM1 IgM antibodies may play a role in MMN pathogenesis.

Correlates of outcome and response to IVIg in 88 patients with multifocal motor neuropathy.

OBJECTIVE: Identification and examination of all patients with multifocal motor neuropathy (MMN) in the Netherlands to document the clinical spectrum and response to IV immunoglobulin (IVIg) and to determine correlates of outcome. METHODS: A national cross-sectional descriptive study was performed. Ninety-seven patients were identified; 88 participated. Logistic regression analysis was used to study determinants of outcome. RESULTS: Age at onset was younger in men than in women (38 vs 45 years, p = 0.05). Onset of weakness was in distal arm (61%) or distal leg (34%), and occasionally in the upper arm (5%). Initial diagnosis was motor neuron disease in one-third of patients. Brisk, but not pathologic, reflexes in weakened muscles were found in 8%. Conduction blocks were most frequently detected in the ulnar (80%) and median (77%) nerves, but occasionally only between Erb and axilla (6%), or in the musculocutaneous nerve (1%). Ninety-four percent responded to IVIg therapy: nonresponders had longer disease duration before the first treatment (p = 0.03). Seventy-six percent received IVIg maintenance treatment at the time of this study (median duration 6 years; range 0-17): the median dose increased over the years from 12 to 17 g per week (p < 0.01). Independent determinants of more severe weakness and disability were axon loss (p < 0.001; p < 0.0001) and longer disease duration without IVIg (p = 0.03; p = 0.07). CONCLUSION: The results of this study may help aid recognition the clinical picture of MMN. Early IVIg treatment may help to postpone axonal degeneration and permanent deficits. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that IVIg improves muscle strength of patients with MMN and disability (defined as an increase of >or=1 Medical Research Council grade in at least 2 muscle groups without decrease in other muscle groups) in 94% (95% confidence interval, 86.8%-97.4%) of patients.