Small and large fiber neuropathy in adults with myotonic dystrophy type 1.

Introduction: Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disorder that affects multiple organs. In this study, we investigated symptoms of pain and presence of small and large fiber neuropathy in the juvenile and adult form of DM1. Method: Twenty genetically verified DM1 patients were included. Pain was assessed, and neurological examination and investigations of the peripheral nervous system by quantification of small nerve fibers in skin biopsy, quantitative sensory testing and nerve conduction studies were performed. Results from skin biopsies were compared to healthy controls. Result: Seventeen patients reported chronic pain. Large and/or small fiber abnormalities were present in 50% of the patients. The intraepidermal nerve fiber density was significantly lower in the whole group of patients compared to healthy controls. Conclusion: Small-fiber neuropathy might be an important cause of pain in DM1.

Cutaneous nerve biopsy in patients with symptoms of small fiber neuropathy: a retrospective study.

OBJECTIVES: We aimed to investigate to what extent small fiber tests were abnormal in an unselected retrospective patient material with symptoms suggesting that small fiber neuropathy (SFN) could be present, and to evaluate possible gender differences. METHODS: Nerve conduction studies (NCS), skin biopsy for determination of intraepidermal nerve fiber density (IENFD) and quantitative sensory testing (QST) were performed. Z-scores were calculated from reference materials to adjust for the effects of age and gender/height. RESULTS: Two hundred and three patients, 148 females and 55 males had normal NCS and were considered to have possible SFN. 45.3 % had reduced IENFD, 43.2 % of the females and 50.9 % of the males. Mean IENFD was 7.3 ± 2.6 fibers/mm in females and 6.1 ± 2.3 in males (p<0.001), but the difference was not significant when adopting Z-scores. Comparison of gender differences between those with normal and abnormal IENFD were not significant when Z-scores were applied. QST was abnormal in 50 % of the patients (48.9 % in females and 52.9 % in males). In the low IENFD group 45 cases out of 90 (50 %) were recorded with abnormal QST. In those with normal IENFD 51 of 102 (50 %) showed abnormal QST. CONCLUSIONS: Less than half of these patients had reduced IENFD, and 50 % had abnormal QST. There were no gender differences. A more strict selection of patients might have increased the sensitivity, but functional changes in unmyelinated nerve fibers are also known to occur with normal IENFD. Approval to collect data was given by the Norwegian data protection authority at University Hospital of North Norway (Project no. 02028).

Diagnostic accuracy of the 5.07 monofilament test for diabetes polyneuropathy: influence of age, sex, neuropathic pain and neuropathy severity.

INTRODUCTION: There is a need for simple and cheap diagnostic tools for diabetic polyneuropathy (DPN). We aimed to assess the diagnostic accuracy of the 5.07/10 g monofilament test in patients referred to polyneuropathy assessments, as well as to examine how disease severity, age, sex and neuropathic pain (NP) impact diagnostic accuracy. RESEARCH DESIGN AND METHODS: Five Norwegian university hospitals recruited patients with diabetes aged 18-70 referred to neurological outpatient clinics for polyneuropathy assessments. The 5.07/10 g Semmes-Weinstein monofilament examination (SWME) was validated against the Toronto consensus for diagnosing diabetic neuropathies; the results were stratified by age, sex and NP. Disease severity was graded by a combined nerve conduction study (NCS) Z-score, and logistic regression was applied to assess whether disease severity was a predictor of diagnostic accuracy. RESULTS: In total, 506 patients were included in the study. Global sensitivity was 0.60 (95% CI 0.55, 0.66), specificity 0.82 (95% CI 0.75, 0.87), positive and negative predictive values were 0.86 (95% CI 0.81, 0.90) and 0.52 (95% CI 0.46, 0.58), respectively, positive and negative likelihood ratios were 3.28 (95% CI 2.37, 4.53) and 0.49 (95% CI 0.42, 0.57), respectively. The SWME was less sensitive in females (0.43), had lower specificity in patients with NP (0.56), and performed worse in patients ≥50 years. NCS-based disease severity did not affect diagnostic accuracy (OR 1.15, 95% CI 0.95, 1.40). CONCLUSIONS: This multicenter study demonstrates poor diagnostic performance for the 5.07/10 g SWME in patients with diabetes referred to polyneuropathy assessments; it is particularly unsuited for female patients and those with NP. The diagnostic accuracy of the SWME was not influenced by NCS-based disease severity, demonstrating that it does not perform better in patients with later stages of DPN. We do not recommend the use of the 5.07/10 g monofilament in the evaluation of patients with diabetes referred to polyneuropathy assessments.

Late-onset sensory-motor axonal neuropathy, a novel SLC12A6-related phenotype.

We describe five families from different regions in Norway with a late-onset autosomal-dominant hereditary polyneuropathy sharing a heterozygous variant in the SLC12A6 gene. Mutations in the same gene have previously been described in infants with autosomal-recessive hereditary motor and sensory neuropathy with corpus callosum agenesis and mental retardation (Andermann syndrome), and in a few case reports describing dominantly acting de novo mutations, most of them with onset in childhood. The phenotypes in our families demonstrated heterogeneity. Some of our patients only had subtle to moderate symptoms and some individuals even no complaints. None had CNS manifestations. Clinical and neurophysiological evaluations revealed a predominant sensory axonal polyneuropathy with slight to moderate motor components. In all 10 patients the identical SLC12A6 missense variant, NM_001365088.1 c.1655G>A p.(Gly552Asp), was identified. For functional characterization, the mutant potassium chloride cotransporter 3 was modelled in Xenopus oocytes. This revealed a significant reduction in potassium influx for the p.(Gly552Asp) substitution. Our findings further expand the spectrum of SLC12A6 disease, from biallelic hereditary motor and sensory neuropathy with corpus callosum agenesis and mental retardation and monoallelic early-onset hereditary motor and sensory neuropathy caused by de novo mutations, to late-onset autosomal-dominant axonal neuropathy with predominant sensory deficits.

Accuracy of neuropathic pain measurements in patients with symptoms of polyneuropathy: validation of painDETECT, Self-Completed Leeds Assessment of Neuropathic Symptoms and Signs, and Douleur Neuropathique 4.

ABSTRACT: Pain is a common symptom in patients referred to polyneuropathy assessment. Diagnostic evaluation and choice of treatment may depend on whether the pain is likely to be neuropathic or not. This study aimed to investigate the diagnostic accuracy of 3 tools commonly used to differentiate between neuropathic and nonneuropathic pain. To accomplish this, we included patients with bilateral distal lower extremity pain, referred to neurological outpatient clinics at 5 Norwegian University hospitals for polyneuropathy assessment. The patients filled in Norwegian versions of painDETECT, the Self-Completed Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS), and the clinician-rated Douleur Neuropathique 4 (DN4). All patients underwent a clinical examination and nerve conduction measurements and were classified according to the NeuPSIG neuropathic pain criteria (reference standard). In total, 729 patients were included, of which 63% had neuropathic pain by the reference standard. Only DN4 demonstrated high sensitivity (0.87), whereas all 3 tools had low specificity (≤0.65). Importantly, the tools' predictive ability was unsatisfactory; The probability of getting a correct test result was 3 quarters at best, and at worst, no better than two fifths. Consequently, we show that neither DN4, painDETECT, nor S-LANSS can be confidently used to assess neuropathic pain in a neurological outpatient population with symptoms of polyneuropathy.

Kennedy disease in two sisters with biallelic CAG expansions of the androgen receptor gene.

We present a retrospective 21-year follow-up of two sisters with X-linked biallelic CAG expansions in the androgen receptor (AR) gene causing Kennedy disease. Two sisters inherited CAG expansions from their mother who was a carrier and their father who had Kennedy disease. Genetic testing revealed alleles comprising 43/45, and 43/43 CAG repeats in the younger and older sister, respectively. They were referred to a neurologist for further evaluation. Both reported similar symptoms with chronic backache, pain and cramps in upper- and lower extremities, and fasciculations in their faces and extremities. Neurological examination demonstrated postural hand tremor in both and EMG revealed chronic neurogenic changes. Reevaluation of the patients at ages 74 and 83 showed slight progression of clinical manifestations. As opposed to male patients, these two females showed minimal disease progression and have maintained normal level of function into old age.

Pain in adult myotonic dystrophy type 1: relation to function and gender.

BACKGROUND: Pain is prevalent in myotonic dystrophy 1 (DM1). This study investigated whether CTG repeat size, disease duration, BMI and motor and psychological function were related to pain in adult patients with DM1, and if there were gender differences regarding intensity and location of pain. METHOD: Cross-sectional design. Pain was investigated in 50 genetically confirmed DM1 patients by combining clinical assessment and self-reports of pain intensity and locations. Pain scoring results were related to CTG size, disease duration, muscle strength, walking capacity measured by 6-min walk test, activity of daily life by Katz ADL Index, respiratory function by Forced Vital Capacity and BMI. In addition, the degree of reported pain was related to Quality of life measured by WHOQOL-BREF; fatigue was measured by Fatigue severity scale; psychological functions were measured by Beck Depression Inventory, Beck Anxiety Inventory, IQ and Autism spectrum Quotient. RESULTS: Pain was reported in 84% of the patients and was significantly correlated with CTG size (r = 0.28 p = 0.050), disease duration (r = 0.38 p = 0.007), quality of life (r = - 0.37 p = 0.009), fatigue (r = 0.33 p = 0.02) and forced vital capacity (r = - 0.51, p = 0.005). Significant gender differences, with higher scores for females, were documented. In male subjects the number of pain locations was significantly correlated with quality of life and the autism quotient. In females, pain intensity was significantly correlated with activity, respiratory function and BMI. CONCLUSIONS: Pain in DM1 was prevalent, with a strong association to lung function and other aspects of the disease. Significant gender differences were present for pain intensity and number of pain locations. How pain was related to other symptoms differed between male and female subjects. Our findings highlight the importance of assessments of pain in DM1 patients.

[Myasthenia gravis - optimal treatment and accurate diagnosis]. / Myasthenia gravis - diagnostikk og behandling.

Around 700 people in Norway have myasthenia gravis, an autoimmune disease that affects neuromuscular transmission and results in fluctuating weakness in some muscles as its sole symptom. The diagnosis is based on typical symptoms and findings, detection of antibodies and neurophysiological examination. Symptomatic treatment with acetylcholinesterase inhibitors is generally effective, but most patients also require immunosuppressive drug treatment. Antigen-specific therapy is being tested in experimental disease models.

Reference values for jitter recorded by concentric needle electrodes in healthy controls: A multicenter study.

INTRODUCTION: The aim of this study was to create reference values for jitter measured with concentric needle electrodes. METHODS: Operators worldwide contributed recordings from orbicularis oculi (OO), frontalis (FR), and extensor digitorum (ED) muscles in healthy controls. Criteria for acceptable signal quality were agreed upon in advance. Fifteen or 20 recordings of acceptable quality from each muscle were required for voluntary and electrical stimulation recordings, respectively. RESULTS: Recordings from 59 to 92 subjects were obtained for each muscle and activation type. Outlier limits for mean consecutive difference and individual jitter data for voluntary activation were: OO, 31 and 45 µs; FR, 28 and 38 µs; ED, 30 and 43 µs; and for electrical stimulation they were: OO, 27 and 36 µs; FR, 21 and 28 µs; ED, 24 and 35 µs. CONCLUSION: Reference jitter values from concentric needle electrode recordings were developed from signals of defined quality while seeking to avoid creating supernormal values.

Small and large fiber neuropathy in those with type 1 and type 2 diabetes: a 5-year follow-up study.

The purpose of this study was to evaluate progression of diabetic polyneuropathy and differences in the spectrum and evolution of large- and small-fiber involvement in patients with diabetes type 1 and 2 over 5 years. Fifty-nine patients (35 type 1 and 24 type 2) were included. Nerve conduction studies (NCS), quantitative sensory testing, skin biopsy for quantification of intraepidermal nerve fiber density (IENFD), symptom scoring and clinical evaluations were performed. Z-scores were calculated to adjust for the physiologic effects of age and height/gender. Neuropathic symptoms were not significantly more frequent in type 2 than in type 1 diabetic patients at follow-up (54% vs. 37%). The overall mean NCS Z-score remained within the normal range, but there was a small significant decline after 5 years in both groups: type 1 (p = 0.004) and type 2 (p = 0.02). Mean IENFD Z-scores changed from normal to abnormal in both groups, but only significantly in those with type 2 diabetes (reduction from 7.9 ± 4.8 to 4.3 ± 2.8 fibers/mm, p = 0.006). Cold perception threshold became more abnormal only in those with type 2 diabetes (p = 0.049). There was a minimal progression of large fiber neuropathy in both groups. Reduction of small fibers predominated and progressed more rapidly in those with type 2 diabetes.

Painful cramps and giant myotonic discharges in a family with the Nav1.4-G1306A mutation.

INTRODUCTION: Two previously reported Norwegian patients with painful muscle cramps and giant myotonic discharges were genotyped and compared with those of members of 21 families harboring the same mutation. METHODS: Using primers specific for SCN4A and CLCN1, the DNA of the Norwegian family members was amplified and bidirectionally sequenced. Clinical and neurophysiological features of other families harboring the same mutation were studied. RESULTS: A G1306A mutation in the Nav1.4 voltage-gated sodium channel of skeletal muscle was identified. This mutation is known to cause myotonia fluctuans. No giant myotonic discharges or painful muscle cramps were found in the other G1306A families. CONCLUSIONS: Ephaptic transmission between neighboring muscle fibers may not only cause the unusual size of the myotonic discharges in this family, but also a more severe type of potassium-aggravated myotonia than myotonia fluctuans.

Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy.

Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of rare diseases resulting from impaired neuromuscular transmission. Their clinical hallmark is fatigable muscle weakness associated with a decremental muscle response to repetitive nerve stimulation and frequently related to postsynaptic defects. Distal myopathies form another clinically and genetically heterogeneous group of primary muscle disorders where weakness and atrophy are restricted to distal muscles, at least initially. In both congenital myasthenic syndromes and distal myopathies, a significant number of patients remain genetically undiagnosed. Here, we report five patients from three unrelated families with a strikingly homogenous clinical entity combining congenital myasthenia with distal muscle weakness and atrophy reminiscent of a distal myopathy. MRI and neurophysiological studies were compatible with mild myopathy restricted to distal limb muscles, but decrement (up to 72%) in response to 3 Hz repetitive nerve stimulation pointed towards a neuromuscular transmission defect. Post-exercise increment (up to 285%) was observed in the distal limb muscles in all cases suggesting presynaptic congenital myasthenic syndrome. Immunofluorescence and ultrastructural analyses of muscle end-plate regions showed synaptic remodelling with denervation-reinnervation events. We performed whole-exome sequencing in two kinships and Sanger sequencing in one isolated case and identified five new recessive mutations in the gene encoding agrin. This synaptic proteoglycan with critical function at the neuromuscular junction was previously found mutated in more typical forms of congenital myasthenic syndrome. In our patients, we found two missense mutations residing in the N-terminal agrin domain, which reduced acetylcholine receptors clustering activity of agrin in vitro. Our findings expand the spectrum of congenital myasthenic syndromes due to agrin mutations and show an unexpected correlation between the mutated gene and the associated phenotype. This provides a good rationale for examining patients with apparent distal myopathy for a neuromuscular transmission disorder and agrin mutations.

[Electromyography (EMG) and neurography in patients with severe neuromuscular diseases]. / Elektromyografi og nevrografi ved alvorlig nevromuskulær sykdom.

BACKGROUND: Many neuromuscular diseases are potentially severe, and EMG and neurography are methods used in the assessment of these conditions. METHOD: The article is based on the authors' knowledge and experience, with special emphasis on the use of these methods in the assessment of severe diseases affecting striated muscle and peripheral nerves. A PubMed search was performed with the cut-off fifteen years back in time, and in addition a discretionary selection was made of articles known to the authors. RESULTS: EMG is the most valuable method for assessing myopathy, and neurography provides most information about neuropathy, but the methods are complementary. These examinations are the most sensitive for diagnosing some conditions (for example myasthaenia) A high level of expertise is necessary for diagnosing these conditions. INTERPRETATION: EMG and neurography are important and often necessary means of assessing patients with severe neuromuscular disease.

A novel late-onset axial myopathy associated with mutations in the skeletal muscle ryanodine receptor (RYR1) gene.

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of inherited neuromuscular disorders and have been associated with a wide clinical spectrum, ranging from various congenital myopathies to the malignant hyperthermia susceptibility (MHS) trait without any associated weakness. RYR1-related myopathies are usually of early-childhood onset. Here we present 11 patients from 8 families with a late-onset axial myopathy associated with RYR1 variants. Patients presented between the third and seventh decade of life to neuromuscular centres in Norway, the Netherlands and the United Kingdom with predominant axial muscle involvement, comprising variable degrees of lumbar hyperlordosis, scapular winging and/or camptocormia. Marked myalgia was commonly associated. Serum creatine kinase levels were normal or moderately elevated. Muscle imaging showed consistent involvement of the lower paravertebral muscles and the posterior thigh. Muscle biopsy findings were often discrete, featuring variability in fibre size, increased internal nuclei and unevenness of oxidative enzyme staining, but only rarely overt cores. RYR1 sequencing revealed heterozygous missense variants, either previously associated with the MHS trait or localizing to known MHS mutational hotspots. These findings indicate that MHS-related RYR1 mutations may present later in life with prominent axial weakness but not always typical histopathological features. We propose a combined effect of RyR1 dysfunction, aging and particular vulnerability of axial muscle groups as a possible pathogenic mechanism. RYR1 is a candidate for cases with "idiopathic" camptocormia or bent spine syndrome (BSS).

Clinical impact of persistent hyperCKemia in a Norwegian general population: a case-control study.

In this case-control study we assessed the clinical impact of persistent hyperCKemia in a Norwegian general population. HyperCKemia was defined according to the NORIP- references (women 35-210 U/L, men <50 years 50-400 U/L, and men ≥50 years 40-280 U/L). We compared the frequency of muscular symptoms and function, neuromuscular diseases and risk factors between 120 cases with persistent hyperCKemia and 130 age- and sex-matched controls with normal CK values, all recruited from the single-centre, population-based prospective Tromsø Study. The participants underwent a standardized interview assessing muscle symptoms, physical activity, use of statins and presence of other CK risk factors, prior to clinical neurological and neurophysiological examination. Knee extensor muscle strength (Cybex NORM dynamometer) and dominant hand grip strength (Martin Vigorimeter) was assessed. A total of 85 cases (71%) reported either muscle pain, muscle stiffness or cramps, compared to 70 controls (54%) (p=0.017) There were no differences in muscle strength between the groups. In men, weight, Body Mass Index and muscle symptoms were significantly higher in the group with persistent hyperCKemia. In women, no differences between the groups were detected. Use of statins was similar in cases and controls. We diagnosed 3 women with previously unknown myopathy, all in the group with persistent hyperCKemia. This study support that CK may be used as a marker of muscular symptoms in the general population.

Variation of serum creatine kinase (CK) levels and prevalence of persistent hyperCKemia in a Norwegian normal population. The Tromsø Study.

In this cross-sectional study we assessed the prevalence of hyperCKemia, defined as persistent CK values ≥210 U/L in women, ≥400 U/L in men <50 years and ≥280 U/L in men ≥50 years (reference values according to the Nordic Reference Interval Project). Blood samples were obtained from 12,828 participants in the 6th survey of The Tromsø Study. We identified 686 (5.3%) individuals with incidentally elevated CK. After a standardized control test, 169 persons (1.3%) had persistent hyperCKemia, i.e. 69.9% normalization. Use of statins or other causes of hyperCKemia were detected in 78 individuals (46.2%), giving a prevalence of "idiopathic hyperCKemia" of 0.71%. CK variation was highest in younger men and in females between 60 and 69 years. This study has identified persistent hyperCKemia in 1.3% of the normal population, and demonstrates the importance of performing controlled CK analyses, also in those with identified risk factors.

Polyneuropathy in type 1 and type 2 diabetes: comparison of nerve conduction studies, thermal perception thresholds and intraepidermal nerve fibre densities.

BACKGROUND: To evaluate possible differences in distal polyneuropathy (PN) characteristics and degree of abnormalities for various small and large fibre parameters in diabetes type 1 (DM1) and type 2 (DM2). METHODS: Sixty-six DM1 and 57 DM2 patients with or without PN symptoms were included. Nerve conduction studies (NCS), quantitative sensory testing (QST) and quantification of intraepidermal nerve fibres (IENFs) were performed. Z-scores were calculated from reference materials. RESULTS: In both groups, 42% had abnormal NCS classification, 42% (DM1) and 39% (DM2) abnormal QST, as well as 40% (DM1) and 32% (DM2) abnormal IENF density. Seventy percent (DM1) and 65% (DM2) had one of the three tests abnormal (differences not significant). Correlations were found between most Z-score parameters and disease duration and HbA1c in DM1, but fewer in DM2. In multivariate analysis, some NCS and QST Z-scores were more abnormal in DM2. Symptom scoring correlated better with NCS and QST parameters in DM1. CONCLUSIONS: The differences could be referred to disease duration, glycaemic control and possibly patient age. The various parameters from NCS, QST and IENF analysis contribute differently in the assessment of polyneuropathy.

The value of skin biopsy with recording of intraepidermal nerve fiber density and quantitative sensory testing in the assessment of small fiber involvement in patients with different causes of polyneuropathy.

The primary aim of our study was to demonstrate how the diagnostic characteristics of skin biopsy used to evaluate small fiber involvement in patients with different causes of polyneuropathy are intrinsically related to the method used to establish the reference values (cut-off values). We also investigated intraepidermal nerve fiber (IENF) density and abnormalities in quantitative sensory testing (QST) in patients with different causes of polyneuropathy and signs of small fiber involvement. A total of 210 patients with symptoms and signs of polyneuropathy were entered into the study. All patients underwent neurological examination, nerve conduction studies, QST on the thigh and distal part of the calf with detection of warm and cold perception thresholds, and skin biopsy with assessment of IENF density. Cut-off values for IENF density were established from our reference material using Z-scores (calculated from multiple regression analysis), fifth percentile, and receiver operating characteristic (ROC) analysis. Of the patients participating in the study, 65 had an established diagnosis of diabetes mellitus, 70 were classified with idiopathic polyneuropathy, and 75 had other possible causes of polyneuropathy. Forty-five patients met the criteria for small fiber polyneuropathy (SFN), and the remaining 165 had also involvement of large nerve fibers. Of the total patient cohort, 84 (40%) had reduced IENF density based on the Z-score, and 106 patients (50%) had at least one abnormality based on QST. In the SFN group, skin biopsy showed a sensitivity of 31% and a specificity of 98% when reference values were presented with Z-scores. When the fifth percentile was used as the cut-off value (6.7 fibers/mm), sensitivity was 35% and specificity 95%. Applying the ROC analysis with a chosen sensitivity of 78% and specificity of 64%, we had a cut-off point of 10.3 fibers/mm. We conclude that skin biopsy with assessment of IENF is a useful method for investigating patients with SFN. The diagnostic value of the test, however, depends upon on the approach used to estimate the reference values.