Sissel Løseth

Early diabetic neuropathy: thermal thresholds and intraepidermal nerve fibre density in patients with normal nerve conduction studies

ObjectivesTo determine whether neuropathy in diabetic patients with normal nerve conduction studies could be detected by measurements of thermal thresholds and quantification of intraepidermal nerve fibre (IENF) density, and to evaluate differences in parameters between patients with and without neuropathic symptoms.MethodsA total of 22 patients with and 37 patients without sensory symptoms suggesting distal neuropathy were included. Measurements of warm and cold perception thresholds and skin biopsy for quantification of IENFs were performed distally on the leg. Reference data were used to normalize test results for age and height or gender of individual patients by calculating the Z-scores.ResultsIENF density was significantly reduced in both symptomatic and asymptomatic patients compared to controls (p < 0.001), and in patients with symptoms compared to those without (p = 0.01). Thermal thresholds were significantly elevated (more abnormal) in patients with symptoms compared to controls (p < 0.01), but only for cold perception threshold (CPT) (p < 0.001) in the asymptomatic group. When comparing symptomatic and asymptomatic patients, there was no statistically significant difference in thermal thresholds. Depletion of IENFs in skin biopsy was the most frequent abnormal finding in the subgroup of patients with neuropathic symptoms (36 %) followed by abnormal CPT (27 %).ConclusionPatients with diabetes and normal nerve conduction studies had significantly lower IENF density and higher CPT than controls, whether they had symptoms of polyneuropathy or not. In patients with neuropathic symptoms, abnormal IENF density predominated and seemed thus to be the most sensitive tool of detecting small diameter nerve fibre involvement.

Intraepidermal nerve fibre density, quantitative sensory testing and nerve conduction studies in a patient material with symptoms and signs of sensory polyneuropathy

Small diameter nerve fibre (SDNF) neuropathy is an axonal sensory neuropathy affecting unmyelinated (C) and thin myelinated (A‐delta) fibres. We have evaluated 75 patients with symptoms and signs suggesting SDNF dysfunction with or without symptoms and signs of co‐existing large diameter nerve fibre involvement. The patients were examined clinically and underwent skin biopsy, quantitative sensory testing (QST) and nerve conduction studies (NCS). The purpose of this study was to compare the relationship between the different methods and in particular measurements of thermal thresholds and intraepidermal nerve fibre (IENF) density in the same site of the distal leg. The main subdivision of the patient material was made according to the overall NCS pattern. Patients with normal NCS (38) had 6.4 ± 3.8 and patients with abnormal NCS (37) had 4.4 ± 3.4 IENF per mm (P = 0.02). Limen (difference between warm and cold perception thresholds) was significantly higher (more abnormal) in those with abnormal than in those with normal NCS (22.1 ± 9.1 vs. 13.4 ± 5.6, P < 0.0001). Cold perception threshold was more abnormal (P < 0.0001) than warm perception threshold (P = 0.002). Correlation between IENF and QST was statistically significant only when NCS was abnormal, and thus dependent of a more severe neuropathic process in SDNFs.

Peripheral neuropathy in systemic lupus erythematosus – a longitudinal study

Objective– Peripheral neuropathy (PN) is reported to occur in 5–27% of patients with systemic lupus erythematosus (SLE) mostly as a length‐dependent sensorimotor axonopathy. Studies over time have not been performed. Design– Longitudinal study. Subjects and methods– Thirty‐three Caucasian SLE patients consented to participate in the study and were subjected to clinical examination, laboratory tests, and nerve conduction velocity (NCV) studies. At the follow‐up 7 years later, 7 patients (21%) were dead, 4 refused to participate, and 2 did not want to perform NCV studies. Twenty patients were thus available for longitudinal study. Results– When all SLE patients were considered on a group basis at follow‐up, 8 (33%) out of 24 NCV parameters showed significant deterioration despite correction for time, while 16 (67%) were unchanged. Analysis of change from baseline showed that, except for F‐responses, several NCV changes were highly dependent (negative regression coefficients) on baseline levels at start of study. No demographic, laboratory, or disease associated quantitative factor was associated with these changes in NCV parameters over time. Nor was a consistent effect on NCV parameters from any qualitative demographic or disease associated factor confirmed by Repeated Measures ANOVA analyses. Conclusions– A modest progressive neuropathic process exists in patients with SLE. Important is also the finding that, over time, the abnormalities of NCV parameters fluctuate in the individual patients, and the impairments are not necessarily irreversible. This study also shows no association to medication, demographic‐, or other disease associated factors.

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).

Idiopathic polyneuropathy and impaired glucose metabolism in a Norwegian patient series.

Background and purpose:  North American studies have indicated a high prevalence of impaired glucose tolerance (IGT) in patients with sensory polyneuropathy. We searched for the occurrence of IGT in a Norwegian patient material with polyneuropathy.

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.

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

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).

Aspects of peripheral nerve involvement in patients with treated hypothyroidism

Background:  We studied involvement of large and small nerve fibres in patients with hypothyroidism and symptoms and signs of polyneuropathy.

Organic Brain Disease in Psychogeriatric Patients: Impact of Symptoms and Screening Methods on the Diagnostic Process

Psychogeriatric patients are mentally affected by a heterogeneous group of diseases, traditionally classified as func tional or organic brain disorders (OBDs). Here, we evaluate screening procedures with respect to revelation of underlying OBD. Fifty consecutive patients admitted to a psychogeriatric unit dedicated to late-onset psychiatric disease were included. Diagnosis at admission, symptoms, and time of onset of disease were determined blindly by an independent, experienced psychiatrist on the basis of referral documents and the interview written at admis sion. Subsequently, consensus established a clinical diagnosis (after psychiatric and neurologic evaluations) and a final diagnosis after the screening procedures (Cognistat and MMS-tests, electroencephalograms, computed tomog raphy, and SPECT). Conventional criteria (ICD-10, ICPC) were used for diagnostic classification. Only 10 of the 50 patients were diagnosed with OBD at admission and an additional 7 patients following full clinical evaluations. At final diagnosis, 34 (of 46) patients were diagnosed with significant OBD. The Cognistat test had the largest diag nostic impact, with sensitivity/specificity values of 81%/60% for OBD. (J Geriatr Psychiatry Neurol 1999; 12:16-20).

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. Muscle Nerve 53: 351–362, 2016