Diagnostic accuracy of nerve excitability and compound muscle action potential scan derived biomarkers in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: The lack of reliable early biomarkers still causes substantial diagnostic delays in amyotrophic lateral sclerosis (ALS). The aim was to assess the diagnostic accuracy of a novel electrophysiological protocol in patients with suspected motor neuron disease (MND). METHODS: Consecutive patients with suspected MND were prospectively recruited at our tertiary referral centre for MND in Utrecht, The Netherlands. Procedures were performed in accordance with the Standards for Reporting of Diagnostic Accuracy. In addition to the standard diagnostic workup, an electrophysiological protocol of compound muscle action potential (CMAP) scans and nerve excitability tests was performed on patients' thenar muscles. The combined diagnostic yield of nerve excitability and CMAP scan based motor unit number estimation was compared to the Awaji and Gold Coast criteria and their added value was determined. RESULTS: In all, 153 ALS or progressive muscular atrophy patients, 63 disease controls and 43 healthy controls were included. Our electrophysiological protocol had high diagnostic accuracy (area under the curve [AUC] 0.85, 95% confidence interval [95% CI] 0.80-0.90), even in muscles with undetectable axon loss (AUC 0.78, 95% CI 0.70-0.85) and in bulbar-onset patients (AUC 0.85, 95% CI 0.73-0.95). Twenty-four of 33 (73%) ALS patients who could not be diagnosed during the same visit were correctly identified, as well as 8/13 (62%) ALS patients not meeting the Gold Coast criteria and 49/59 (83%) ALS patients not meeting the Awaji criteria during this first visit. CONCLUSIONS: Our practical and non-invasive electrophysiological protocol may improve early diagnosis in clinically challenging patients with suspected ALS. Routine incorporation may boost early diagnosis, enhance patient selection and generate baseline measures for clinical trials.

Composite endpoint for ALS clinical trials based on patient preference: Patient-Ranked Order of Function (PROOF).

BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) show considerable variation in symptoms. Treatments targeting an overall improvement in symptomatology may not address what the majority of patients consider to be most important. Here, we propose a composite endpoint for ALS clinical trials that weighs the improvement in symptoms compared with what the patient population actually wants. METHODS: An online questionnaire was sent out to a population-based registry in The Netherlands. Patients with ALS were asked to score functional domains with a validated self-reported questionnaire, and rank the order of importance of each domain. This information was used to estimate variability in patient preferences and to develop the Patient-Ranked Order of Function (PROOF) endpoint. RESULTS: There was extensive variability in patient preferences among the 433 responders. The majority of the patients (62.1%) preferred to prioritise certain symptoms over others when evaluating treatments. The PROOF endpoint was established by comparing each patient in the treatment arm to each patient in the placebo arm, based on their preferred order of functional domains. PROOF averages all pairwise comparisons, and reflects the probability that a patient receiving treatment has a better outcome on domains that are most important to them, compared with a patient receiving placebo. By means of simulation we illustrate how incorporating patient preference may upgrade or downgrade trial results. CONCLUSIONS: The PROOF endpoint provides a balanced patient-focused analysis of the improvement in function and may help to refine the risk-benefit assessment of new treatments for ALS.

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.

No association between Borrelia burgdorferi antibodies and amyotrophic lateral sclerosis in a case-control study.

BACKGROUND AND PURPOSE: Previous studies, mostly case reports and uncontrolled studies, provide a low level of evidence for the hypothesized link between Lyme disease and amyotrophic lateral sclerosis (ALS). In order to make evidence-based recommendations regarding testing for Borrelia burgdorferi antibodies in the diagnostic work-up for ALS, the objective of this study was to explore the evidence for an association between these antibodies and ALS in a case-control design including age-, gender- and residency-matched controls. METHODS: A total of 491 patients with ALS were matched to 982 controls. IgG titers against B. burgdorferi were determined by an enzyme-linked immunosorbent assay and, in the case of positivity or borderline results, a western blot was performed. Conditional logistic regression and Fisher's exact tests were used to compare the antibody titers or positivity between patients and controls. RESULTS: No difference in seroprevalence of Borrelia was found between patients (4.1%) and controls (5.9%). Clinical characteristics and survival were similar between seropositive and seronegative patients. Moreover, patients with a spinal onset were not more frequently seropositive compared with patients with a bulbar onset (P = 0.47), and neither were patients with a short diagnostic delay of <6 months compared with controls (P = 0.69). None of the 20 patients with a diagnostic delay of <3 months tested positive for IgM antibodies, suggestive of a recent infection. CONCLUSION: This large case-control study provides evidence for a lack of association between B. burgdorferi antibodies and ALS, and therefore does not support the inclusion of routine testing for these antibodies in the diagnostic work-up in patients with classical ALS.

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.

Susceptibility loci for sporadic brain arteriovenous malformation; a replication study and meta-analysis.

BACKGROUND: Case-control studies have reported multiple genetic loci to be associated with sporadic brain arteriovenous malformations (AVMs) but most of these have not been replicated in independent populations. The aim of this study was to find additional evidence for these reported associations and perform a meta-analysis including all previously published results. METHODS: We included 167 Dutch patients and 1038 Dutch controls. Case genotyping was performed by KASPar assays. Controls had been previously genotyped with a genome wide single nucleotide polymorphisms (SNP) array. Differences in genotype frequencies between cases and controls were estimated by χ(2) testing in Plink V.1.07. Meta-analysis was performed in RevMan V.5.3. RESULTS: In our case-control study we found no significant association with brain AVM (BAVM) for previously discovered SNPs near ANGPTL4, IL-1ß, GPR124, VEGFA and MMP-3. The meta-analysis revealed a statistically significant association with BAVMs for the polymorphism rs11672433 near ANGPTL4 (OR 1.39; 95% CI 1.10 to 1.75, p value 0.005). CONCLUSIONS: The results of this study support a role for the previously identified SNP near ANGPTL4 in the pathogenesis of AVMs. Previously found associations with SNPs near IL-1ß, GPR124, VEGFA and MMP-3 genes could not be substantiated in our replication cohort or in the meta-analysis.

Correlation of the patient's reported outcome Inflammatory-RODS with an objective metric in immune-mediated neuropathies.

BACKGROUND AND PURPOSE: There is increasing interest in using patient-reported outcome measures (PROMs) in clinical studies to capture individual changes over time. However, PROMs have also been criticized because they are entirely subjective. Our objective was to examine the relationship between a subjective PROM and an objective outcome tool in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and gammopathy-related polyneuropathy (MGUSP). METHODS: The Inflammatory Rasch-built Overall Disability Scale (I-RODS©, a multi-item scale that examines functionality) was completed by 137 patients with newly diagnosed (or relapsing) GBS (55), CIDP (59) and MGUSP (23) who were serially examined (GBS/CIDP, T0/T1/T3/T6/T12 months; MGUSP, T0/T3/T12). Possible association between the I-RODS findings and the vigorimeter scores, an objective linear instrument to assess grip strength, was examined. RESULTS: A significant correlating trend was found between the I-RODS and grip strength scores for the overall group and in each illness, independently. CONCLUSION: The objectivity of patients' subjective report on their functional state based on a strong correlation between the I-RODS and grip strength in patients with GBS, CIDP and MGUSP has been demonstrated. These findings provide further support to use the I-RODS and grip strength in future clinical studies in these conditions.

Evaluation of genetic risk loci for intracranial aneurysms in sporadic arteriovenous malformations of the brain.

BACKGROUND: In genome-wide association studies (GWAS) five putative risk loci are associated with intracranial aneurysm. As brain arteriovenous malformations (AVM) and intracranial aneurysms are both intracranial vascular diseases and AVMs often have associated aneurysms, we investigated whether these loci are also associated with sporadic brain AVM. METHODS: We included 506 patients (168 Dutch, 338 American) and 1548 controls, all Caucasians. Controls had been recruited as part of previous GWAS. Dutch patients were genotyped by KASPar assay and US patients by Affymetrix SNP 6.0 array. Associations in each cohort were tested by univariable logistic regression modelling, with subgroup analysis in 205 American cases with aneurysm data. Meta-analysis was performed by a Mantel-Haenszel fixed-effect method. RESULTS: In the Dutch cohort none of the single nucleotide polymorphisms (SNPs) were associated with AVMs. In the American cohort, genotyped SNPs near SOX-17 (OR 0.74; 95% CI 0.56-0.98), RBBP8 (OR 0.76; 95% CI 0.62-0.94) and an imputed SNP near CDKN2B-AS1 (OR 0.79; 95% CI 0.64-0.98) were significantly associated with AVM. The association with SNPs near SOX-17 and CDKN2B-AS1 but not RBBP8 were strongest in patients with AVM with associated aneurysms. In the meta-analysis we found no significant associations between allele frequencies and AVM occurrence, but rs9298506, near SOX-17 approached statistical significance (OR 0.77; 95% CI 0.57-1.03, p=0.08). CONCLUSIONS: Our meta-analysis of two Caucasian cohorts did not show an association between five aneurysm-associated loci and sporadic brain AVM. Possible involvement of SOX-17 and RBBP8, genes involved in cell cycle progression, deserves further investigation.

Prose memory impairment in amyotrophic lateral sclerosis patients is related to hippocampus volume.

BACKGROUND AND PURPOSE: Thirty per cent of amyotrophic lateral sclerosis (ALS) patients have non-motor symptoms, including executive and memory deficits. The in vivo anatomical basis of memory deficits in ALS has not been elucidated. In this observational study, brain atrophy in relation to memory function was investigated in ALS patients and controls. METHODS: Twenty-six ALS patients without dementia and 21 healthy volunteers matched for gender, age and education level underwent comprehensive neuropsychological evaluation and T1- and T2-weighted 3 T magnetic resonance imaging scanning of the brain. Grey and white matter brain volumes were analysed using voxel-based morphometry and age related white matter changes were assessed. The most frequently abnormal memory test (<2 SD below normative data corrected for age, gender and education) was correlated with regional brain volume variations by multiple regression analyses with age, gender and total grey matter volumes as covariates. RESULTS: Immediate and delayed story recall scores were abnormal in 23% of ALS patients and correlated to bilateral hippocampus grey matter volume (r = 0.52 for both memory tests; P < 0.05; corrected for age, gender and total grey matter volume). This correlation was not found in healthy controls with similar age, education, anxiety and depression levels and white matter changes. CONCLUSIONS: Prose memory impairment is a frequent finding in this cohort and is associated with hippocampus volume in ALS patients without dementia. These findings complement previous hippocampus changes in imaging studies in ALS and suggest involvement of the hippocampus in cognitive dysfunction of ALS.

Treatment of respiratory impairment in patients with motor neuron disease in the Netherlands: patient preference and timing of referral.

BACKGROUND AND PURPOSE: We assessed the first evaluation at a large ventilation clinic in the Netherlands to: (i) determine what proportion of patients with motor neuron disease would benefit from earlier referral; and (ii) examine the patient preferences regarding ventilatory support. METHODS: Observational study at a single centre with a catchment area of 7.6 million inhabitants. Data on disease status, the referral process and patients' preferences regarding ventilatory support were collected during the first home ventilation services (HVS) assessment and analysed for correlation with the presence of daytime hypercapnia and suspected nocturnal hypoventilation. The latter conditions require immediate (within 48 h) or subacute (within 3 weeks) initiation of ventilatory support. RESULTS: Vital capacity (in percentage of predicted value, VC%pred) was assessed by referring physicians in 84% of the 217 referred patients; the mean VC%pred was 69% (SD 16). One-hundred and ninety-one patients attended the first HVS assessment without ventilatory support, at a median of 21 days following referral: 18% had respiratory failure (daytime hypercapnia), 19% had normocapnia but were suspected of nocturnal hypoventilation, and 63% had normocapnia without symptoms. Following the HVS assessment, 25 patients (13%) declined home mechanical ventilation; this occurred more often in patients with (14/70) compared with patients without respiratory impairment (11/121; P < 0.05). CONCLUSION: A meaningful proportion of patients who desire ventilatory support are referred to a ventilation clinic after already developing respiratory failure. Future studies could examine means, including more sensitive respiratory measures, to detect those patients who could benefit from earlier referral.

Beneficial vascular risk profile is associated with amyotrophic lateral sclerosis.

OBJECTIVES: Reports of increased amyotrophic lateral sclerosis (ALS) with hyperlipidaemia and elevated plasma homocysteine levels as well as cigarette-smoking and polymorphisms in angiogenic genes suggest a role for altered vascular homeostasis in ALS pathogenesis. The authors assessed the association between vascular risk factors and ALS. METHODS: Traditional cardiovascular risk factors (smoking, hypertension, hypercholesterolaemia, diabetes and body mass index (BMI)) and cardiovascular disease prior to ALS onset established by a questionnaire were compared in 334 patients and 538 age- and sex-matched controls. Biochemical assessments (total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), hs-CRP, and homocysteine) at diagnosis were measured in blood samples of 303 patients with ALS and compared with prospectively collected data from 2100 population-based controls. RESULTS: Patients with ALS used cholesterol-lowering agents less frequently (OR=0.6, p=0.008) and had a lower BMI (OR=0.9, p=0.001), a lower LDL/HDL ratio (women: OR=0.5, p<0.001; men: OR=0.4, p<0.001) and lower homocysteine levels (women: OR=0.9, p=0.02; men: OR=0.9, p<0.001). The mean LDL and TC levels were significantly lower among patients with a lower functional vital capacity percentage of predicted (FVC). In the univariate analysis, a higher LDL/HDL ratio correlated with increased survival (HR=0.9, p=0.04); after adjusting for the confounders age, site and FVC, no difference was observed. CONCLUSIONS: Vascular risk factors, measured clinically and biochemically, were not associated with increased ALS. Instead, patients reported less use of cholesterol-lowering medication and had a lower premorbid BMI and favourable lipid profile-all findings consistent with the hypothesis that a higher metabolic rate plays a role in ALS.

Inhibition of HERV-K (HML-2) in amyotrophic lateral sclerosis patients on antiretroviral therapy.

Reactivation of Human Endogenous Retrovirus K (HERV-K), subtype HML-2, has been associated with pathophysiology of amyotrophic lateral sclerosis (ALS). We aimed to assess the efficacy of antiretroviral therapy in inhibiting HML-2 in patients with ALS and a possible association between the change in HML-2 levels and clinical outcomes. We studied the effect of 24-weeks antiretroviral combination therapy with abacavir, lamivudine, and dolutegravir on HML-2 levels in 29 ALS patients. HML-2 levels decreased progressively over 24 weeks (P = 0.001) and rebounded within a week of stopping medications (P = 0.02). The majority of participants (82%), defined as "responders", experienced a decrease in HML-2 at week 24 of treatment compared to the pre-treatment levels. Differences in the evolution of some of the clinical outcomes could be seen between responders and non-responders: FVC decreased 23.69% (SE = 11.34) in non-responders and 12.71% (SE = 8.28) in responders. NPI score decreased 91.95% (SE = 6.32) in non-responders and 53.05% (SE = 10.06) in responders (P = 0.01). Thus, participants with a virological response to treatment showed a trend for slower progression of the illness. These findings further support the possible involvement of HML-2 in the clinical course of the disease.

Randomised controlled trial comparing two different intravenous immunoglobulins in chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND: Different preparations of intravenous immunoglobulin (IVIg) are considered to have comparable clinical efficacy but this has never been formally investigated. Some patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) report that some IVIg brands are more effective than others. A liquid IVIg preparation is more user friendly and potentially can be infused at a faster rate. OBJECTIVES: The primary objective was to compare the efficacy of two different IVIg brands in CIDP. The secondary objective was to compare their safety. METHODS: This was an investigator-initiated multi-centre randomised controlled double-blind trial. Twenty-seven patients with active but stable CIDP treated with their individual stable IVIg (Gammagard S/D) maintenance dose and interval were randomised to receive four infusions of freeze-dried 5% IVIg (Gammagard S/D) or the new liquid 10% IVIg (Kiovig). The overall disability sum score (ODSS) was used as the primary outcome scale. The equivalence margin was defined as a difference of ≤1 point in mean ΔODSS between treatment groups. Main secondary outcome scales were the MRC sum score and the Vigorimeter. RESULTS: Repeated measurements analysis of variance, adjusted for baseline ODSS, showed a clinically insignificant treatment difference of 0.004 (95% CI -0.4 to 0.4). We also found no significant differences in any of the other outcome measures. Besides a lower occurrence of cold shivers in patients randomised to Kiovig (p=0.03), no significant differences were found in the occurrence of adverse events. CONCLUSIONS: This trial demonstrated equal clinical efficacy between a freeze-dried and a liquid IVIg preparation for maintenance treatment of CIDP.

Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the -2578AA genotype.

BACKGROUND: Targeted delivery of the angiogenic factor, vascular endothelial growth factor (VEGF), to motor neurons prolongs survival in rodent models of amyotrophic lateral sclerosis (ALS), while mice expressing reduced VEGF concentrations develop motor neuron degeneration reminiscent of ALS, raising the question whether VEGF contributes to the pathogenesis of ALS. An initial association study reported that VEGF haplotypes conferred increased susceptibility to ALS in humans, but later studies challenged this initial finding. METHODS AND FINDINGS: A meta-analysis was undertaken to critically reappraise whether any of the three common VEGF gene variations (-2578C/A, -1154G/A and -634G/C) increase the risk of ALS. Over 7000 subjects from eight European and three American populations were included in the analysis. Pooled odds ratios were calculated using fixed-effects and random-effects models, and four potential sources of heterogeneity (location of disease onset, gender, age at disease onset and disease duration) were assessed. After correction, none of the genotypes or haplotypes was significantly associated with ALS. Subgroup analysis by gender revealed, however, that the -2578AA genotype, which lowers VEGF expression, increased the risk of ALS in males (OR = 1.46 males vs females; 95% CI = 1.19 to 1.80; p = 7.8 10E-5), even after correction for publication bias and multiple testing. CONCLUSIONS: This meta-analysis does not support the original conclusion that VEGF haplotypes increase the risk of ALS in humans, but the significant association of the low-VEGF -2578AA genotype with increased susceptibility to ALS in males reappraises the link between reduced VEGF concentrations and ALS, as originally revealed by the fortuitous mouse genetic studies.

[Amyotrophic lateral sclerosis]. / Amyotrofische laterale sclerose.

Amyotrophic lateral sclerosis is one of the most severe and disabling diseases of the nervous system. Amyotrophic lateral sclerosis leads to the progressive weakening of the muscles in the arms, legs, face, mouth and trunk. The onset of the disease is insidious, starting with weakness in the hands or feet or with slurred speech. The weakness worsens and patients pass away as a result of weakness of the respiratory muscles on average within 3 years of the onset of the disease. In the Netherlands, approximately 400 patients are diagnosed with amyotrophic lateral sclerosis every year. There is no diagnostic test for this neuro-muscular disease; the diagnosis is established by excluding other disorders that resemble amyotrophic lateral sclerosis. Only one drug is able to inhibit the progression of the disease to any extent: riluzole. Treatment, therefore, is mainly focused on supportive measures and those which enhance the quality of life optimally.

Associations between illness cognitions and health-related quality of life in the first year after diagnosis of amyotrophic lateral sclerosis.

OBJECTIVE: To describe illness cognitions among patients with amyotrophic lateral sclerosis (ALS), to study cross-sectional associations between illness cognitions and health-related quality of life (HRQoL) and to study the predictive value of illness cognitions measured shortly after the diagnosis for HRQoL at follow-up. METHODS: Prospective longitudinal design. We administered Self-report questionnaires at study onset (n = 72) and follow-up (n = 48). Median follow-up period was 10.0 months. At baseline median ALS Functional Rating Scale-Revised was 43, median time since onset of symptoms was 13.6 months, 79% of patients presented with spinal onset. Illness cognitions Helplessness, Acceptance and Disease Benefits were measured with the Illness Cognitions Questionnaire (ICQ) and HRQoL with the ALS Assessment Questionnaire (ALSAQ-40). Correlational and regression analyses were used. RESULTS: Patients experienced more Helplessness at follow-up. We found no significant changes in Acceptance or Disease Benefits at follow-up. In cross-sectional analyses, Helplessness was independently related to worse HRQoL at baseline (ß = 0.44; p = .001) and Acceptance and Disease Benefits were independently related to worse HRQoL at follow-up (ß = -0.17, p = .045) and (ß = -0.186, p = .03 respectively). Longitudinal analyses showed that, adjusted for disease severity at baseline, Helplessness at baseline was a predictor of worse HRQoL at follow-up (ß = 0.43; p = .006). None of the illness cognitions were a significant predictor of HRQoL with adjustment for baseline HRQoL. CONCLUSION: Helplessness was independently associated with HRQoL in the cross-sectional and longitudinal analyses. These results can help us identify patients shortly after diagnosis who might benefit from psychological interventions.

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.

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.