The minimum clinically important difference: which direction to take.

Over the past decades in modern medicine, there has been a shift from statistical significance to clinical relevance when it comes to interpreting results from clinical trials. A concept that is increasingly being used as a surrogate for clinical relevance and effect size calculation is the minimum clinically important difference (MCID). In this paper, an overview is presented of the most important aspects of the MCID concept used in research trials and a discussion of what this means for the neurological patient in clinical trials and daily practice is given. Is the MCID the best outcome measure cut-off to be implemented?

Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands.

Few reliable data exist on the prevalence of skeletal muscle channelopathies. We determined the minimum point prevalence of genetically-defined skeletal muscle channelopathies in the Netherlands and report their mutation spectrum. Minimum point prevalence rates were calculated as number of genetically-confirmed skeletal muscle channelopathy patients (CLCN1, SCN4A, CACNA1S and KCNJ2 gene mutations) in the Netherlands (1990-2015) divided by the total number of at-risk individuals. Rates were expressed as cases/100.000 and 95% confidence intervals were calculated based on Poisson distribution. Results of standardized genetic diagnostic procedures were used to analyze mutation spectra. We identified 405 patients from 234 unrelated pedigrees, resulting in a minimum point prevalence of 2.38/100.000 (95% CI 2.16-2.63) for skeletal muscle channelopathies in the Netherlands. Minimum point prevalence rates for the disease groups, non-dystrophic myotonia and periodic paralysis, were 1.70/100.000 and 0.69/100.000 respectively. Sixty-one different CLCN1 mutations (including 12 novel mutations) were detected in myotonia congenita. Twenty-eight different SCN4A missense mutations (including three novel mutations) were identified in paramyotonia congenita/sodium channel myotonia, hypokalemic periodic paralysis and hyperkalemic periodic paralysis. Four different CACNA1S missense mutations were detected in hypokalemic periodic paralysis and five KCNJ2 missense mutations in Andersen-Tawil syndrome. The minimum point prevalence rates for genetically-defined skeletal muscle channelopathies confirm their rare disease status in the Netherlands. Rates are almost twice as high as in the UK and more in line with pre-genetic prevalence estimates in parts of Scandinavia. Future diagnostic and therapeutic studies may benefit from knowledge of the mutation spectrum of skeletal muscle channelopathies.

Associated conditions in small fiber neuropathy - a large cohort study and review of the literature.

BACKGROUND AND PURPOSE: Small fiber neuropathy (SFN) is a common disorder leading to neuropathic pain and autonomic symptoms. The objective of this study was to investigate associated conditions in a large cohort of SFN patients and compare the prevalence to healthy individuals. METHODS: A total of 921 patients with pure SFN were screened according to a standardized comprehensive diagnostic algorithm and compared with literature findings. RESULTS: No associated condition could be found in 53% of the patients. Autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiencies were more prevalent than reported literature findings, followed by alcohol abuse, chemotherapy, monoclonal gammopathy of undetermined significance, and haemochromatosis. In patients who were already known with a possible underlying condition at screening, additional underlying conditions were still found in another 26.7% of patients. CONCLUSIONS: Based on these results, it is recommended that patients with pure SFN are screened at least for autoimmune diseases, sodium channel gene mutations, diabetes mellitus including glucose intolerance, and vitamin B12 deficiency, even when they already have a potential underlying condition at referral.

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.

Ca2+ toxicity due to reverse Na+/Ca2+ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation.

Gain-of-function missense mutations in voltage-gated sodium channel Nav1.7 have been linked to small-fiber neuropathy, which is characterized by burning pain, dysautonomia and a loss of intraepidermal nerve fibers. However, the mechanistic cascades linking Nav1.7 mutations to axonal degeneration are incompletely understood. The G856D mutation in Nav1.7 produces robust changes in channel biophysical properties, including hyperpolarized activation, depolarized inactivation, and enhanced ramp and persistent currents, which contribute to the hyperexcitability exhibited by neurons containing Nav1.8. We report here that cell bodies and neurites of dorsal root ganglion (DRG) neurons transfected with G856D display increased levels of intracellular Na(+) concentration ([Na(+)]) and intracellular [Ca(2+)] following stimulation with high [K(+)] compared with wild-type (WT) Nav1.7-expressing neurons. Blockade of reverse mode of the sodium/calcium exchanger (NCX) or of sodium channels attenuates [Ca(2+)] transients evoked by high [K(+)] in G856D-expressing DRG cell bodies and neurites. We also show that treatment of WT or G856D-expressing neurites with high [K(+)] or 2-deoxyglucose (2-DG) does not elicit degeneration of these neurites, but that high [K(+)] and 2-DG in combination evokes degeneration of G856D neurites but not WT neurites. Our results also demonstrate that 0 Ca(2+) or blockade of reverse mode of NCX protects G856D-expressing neurites from degeneration when exposed to high [K(+)] and 2-DG. These results point to [Na(+)] overload in DRG neurons expressing mutant G856D Nav1.7, which triggers reverse mode of NCX and contributes to Ca(2+) toxicity, and suggest subtype-specific blockade of Nav1.7 or inhibition of reverse NCX as strategies that might slow or prevent axon degeneration in small-fiber neuropathy.

Physician-assessed and patient-reported outcome measures in chemotherapy-induced sensory peripheral neurotoxicity: two sides of the same coin.

BACKGROUND: The different perception and assessment of chemotherapy-induced peripheral neurotoxicity (CIPN) between healthcare providers and patients has not yet been fully addressed, although these two approaches might eventually lead to inconsistent, possibly conflicting interpretation, especially regarding sensory impairment. PATIENTS AND METHODS: A cohort of 281 subjects with stable CIPN was evaluated with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC v. 2.0) sensory scale, the clinical Total Neuropathy Score (TNSc©), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sumscore (mISS) and the European Organization for Research and Treatment of Cancer CIPN specific self-report questionnaire (EORTC QOL-CIPN20). RESULTS: Patients' probability estimates showed that the EORTC QLQ-CIPN20 sensory score was overall more highly related to the NCI-CTC sensory score. However, the vibration perception item of the TNSc had a higher probability to be scored 0 for EORTC QLQ-CIPN20 scores lower than 35, as vibration score 2 for EORTC QLQ-CIPN20 scores between 35 and 50 and as grade 3 or 4 for EORTC QLQ-CIPN20 scores higher than 50. The linear models showed a significant trend between each mISS item and increasing EORTC QLQ-CIPN20 sensory scores. CONCLUSION: None of the clinical items had a perfect relationship with patients' perception, and most of the discrepancies stood in the intermediate levels of CIPN severity. Our data indicate that to achieve a comprehensive knowledge of CIPN including a reliable assessment of both the severity and the quality of CIPN-related sensory impairment, clinical and PRO measures should be always combined.

Rasch-built Overall Disability Scale for patients with chemotherapy-induced peripheral neuropathy (CIPN-R-ODS).

Chemotherapy-induced peripheral neuropathy (CIPN) is a common neurological side-effect of cancer treatment and may lead to declines in patients' daily functioning and quality of life. To date, there are no modern clinimetrically well-evaluated outcome measures available to assess disability in CIPN patients. The objective of the study was to develop an interval-weighted scale to capture activity limitations and participation restrictions in CIPN patients using the Rasch methodology and to determine its validity and reliability properties. A preliminary Rasch-built Overall Disability Scale (pre-R-ODS) comprising 146 items was assessed twice (interval: 2-3 weeks; test-retest reliability) in 281 CIPN patients with a stable clinical condition. The obtained data were subjected to Rasch analyses to determine whether model expectations would be met, and if necessarily, adaptations were made to obtain proper model fit (internal validity). External validity was obtained by correlating the CIPN-R-ODS with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) neuropathy scales and the Pain-Intensity Numeric-Rating-Scale (PI-NRS). The preliminary R-ODS did not meet Rasch model's expectations. Items displaying misfit statistics, disordered thresholds, item bias or local dependency were systematically removed. The final CIPN-R-ODS consisting of 28 items fulfilled all the model's expectations with proper validity and reliability, and was unidimensional. The final CIPN-R-ODS is a Rasch-built disease-specific, interval measure suitable to detect disability in CIPN patients and bypasses the shortcomings of classical test theory ordinal-based measures. Its use is recommended in future clinical trials in CIPN.

The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study. PATIENTS AND METHODS: After literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out. RESULTS: Good inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test-retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures. CONCLUSION: Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.

Pain relief and quality-of-life improvement after spinal cord stimulation in painful diabetic polyneuropathy: a pilot study.

BACKGROUND: Painful diabetic polyneuropathy (PDP) is associated with high pain scores and is difficult to treat. Therefore, spinal cord stimulation (SCS) has been suggested as second-line treatment. In this study, the feasibility and efficacy of SCS in PDP were investigated, as well as the predictive value of clinical sensory testing for the treatment outcome. METHODS: Fifteen patients with intractable PDP in the lower limbs were recruited. During lead implantation, the feasibility of achieving adequate paraesthesia coverage using one stimulation lead was investigated. If trial stimulation was successful, a definitive neurostimulator was implanted. Pain intensity was scored using an 11-point numeric rating scale and patients' global impression of change scale. Additionally, neuropathic pain characteristics, quality of life, sleep quality and mood were assessed. The predictive value of clinical sensory testing for the treatment outcome was analysed. RESULTS: Adequate paraesthesia coverage was achieved in 14 out of 15 patients. Clinically relevant pain relief was present in 11 patients after trial stimulation and 10 patients at 12 months. The quality of life was significantly increased at 2 weeks and 3 months in patients with successful SCS treatment. Several neuropathic pain characteristics and quality of sleep were improved at 2 weeks and 12 months. Preoperative clinical sensory testing did not differentiate between treatment responders from non-responders. CONCLUSIONS: SCS seems to be an efficacious and feasible treatment for intractable PDP. In this exploratory study, it was not possible to predict the treatment outcome using clinical sensory testing. These results justify performing a randomized clinical trial.

Genetic aspects of sodium channelopathy in small fiber neuropathy.

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

Nav1.7-related small fiber neuropathy: impaired slow-inactivation and DRG neuron hyperexcitability.

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

Morphometry of dermal nerve fibers in human skin.

OBJECTIVE: We aimed to assess the innervation density of dermal nerves in human skin biopsies by bright-field immunohistochemistry. METHODS: The size of dermal area where nerve length was quantified was validated in 30 skin biopsy sections (5 controls and 5 patients with small-fiber neuropathy [SFN]). It was obtained dividing an area of 200-µm depth from the dermal-epidermal junction into 4 equal portions. The length of dermal nerves (DNFL) was measured into 150 sections (25 controls and 25 patients with SFN) and values per millimeter of epidermis (DNFL/mm) and dermal area (DNFL/mm2) were obtained. Age- and gender-matched normative values of intraepidermal nerve fiber (IENF) density were used as gold standard to calculate the performance of dermal nerve morphometry. RESULTS: Patients showed significantly lower DNFL (1.96 mm ± 0.96 SD), DNFL/mm (0.65 ± 0.29 SD), and DNFL/mm2 (3.75 ± 1.7 SD) than controls (DNFL 3.52 mm ± 1.31 SD, 5th percentile 2.05; DNFL/mm 1.25 ± 0.39, 5th percentile 0.71; DNFL/mm2 7.07 ± 2.41 SD, 5th percentile 3.95). Sensitivity, specificity, and percentage of individuals correctly classified were 75.8%, 73.9%, and 74.8% for DNFL, 75%, 80%, and 77.7% for DNFL/mm, and 75.8%, 80.2%, and 78.1% for DNFL/mm2. Receiver operator characteristic area analysis confirmed the excellent discrimination (0.8-0.9) between patients and controls. Dermal nerve morphometry significantly correlated with IENF density. Spearman rank correlation demonstrated good agreement for interobserver analysis (0.87-0.89), and between DNFL and IENF densities (0.71-0.73; p < 0.0001). CONCLUSIONS: We provided a reliable method to quantify the innervation density of dermal nerves that might improve the diagnostic yield of skin biopsy.

Rasch-built Overall Disability Scale (R-ODS) for immune-mediated peripheral neuropathies.

OBJECTIVE: To develop a patient-based, linearly weighted scale that captures activity and social participation limitations in patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and gammopathy-related polyneuropathy (MGUSP). METHODS: A preliminary Rasch-built Overall Disability Scale (R-ODS) containing 146 activity and participation items was constructed, based on the WHO International Classification of Functioning, Disability and Health, literature search, and patient interviews. The preliminary R-ODS was assessed twice (interval: 2-4 weeks; test-retest reliability studies) in 294 patients who experienced GBS in the past (n = 174) or currently have stable CIDP (n = 80) or MGUSP (n = 40). Data were analyzed using the Rasch unidimensional measurement model (RUMM2020). RESULTS: The preliminary R-ODS did not meet the Rasch model expectations. Based on disordered thresholds, misfit statistics, item bias, and local dependency, items were systematically removed to improve the model fit, regularly controlling the class intervals and model statistics. Finally, we succeeded in constructing a 24-item scale that fulfilled all Rasch requirements. "Reading a newspaper/book" and "eating" were the 2 easiest items; "standing for hours" and "running" were the most difficult ones. Good validity and reliability were obtained. CONCLUSION: The R-ODS is a linearly weighted scale that specifically captures activity and social participation limitations in patients with GBS, CIDP, and MGUSP. Compared to the Overall Disability Sum Score, the R-ODS represents a wider range of item difficulties, thereby better targeting patients with different ability levels. If responsive, the R-ODS will be valuable for future clinical trials and follow-up studies in these conditions.

Hereditary muscular dystrophies and the heart.

Cardiac disease is a common clinical manifestation of neuromuscular disorders, particularly of muscular dystrophies. Heart muscle cells as well as specialized conducting myocardial fibres may be affected by the dystrophic process. The incidence and nature of cardiac involvement vary with different types of muscular dystrophies. Some mainly lead to myocardial disease, resulting in cardiomyopathy and heart failure, while others particularly affect the conduction system, leading to arrhythmias and sudden death. As prognosis of muscular dystrophy patients may be directly related to cardiac status, surveillance and timely management of cardiac complications are important. However, recognition of cardiac involvement requires active investigation and remains challenging since typical signs and symptoms of cardiac dysfunction may not be present and progression is unpredictable. In this review, we present a comprehensive overview of hereditary muscular dystrophies associated with cardiac disease to provide an efficient strategy for the expertise and management of these diseases.

Pain and autonomic dysfunction in patients with sarcoidosis and small fibre neuropathy.

Small fibre neuropathy (SFN) has been demonstrated in sarcoidosis. However, a systematic analysis of neuropathic pain and autonomic symptoms, key features of SFN, has not been performed. Clinimetric evaluation of pain and autonomic symptoms using the neuropathic pain scale (NPS) and the modified Composite Autonomic Symptoms Scale (mCOMPASS) was used in sarcoidosis patients for this study. A total of 91 sarcoidosis patients (n = 23 without SFN symptoms, n = 43 with SFN symptoms but normal intraepidermal nerve fibre density (IENFD), n = 25 with SFN symptoms and reduced IENFD) were examined. NPS and mCOMPASS were assessed twice (reliability studies). Severity of pain was compared between the subgroups. Correlation between NPS and a visual analogue pain scale (VAS) was assessed (validity studies). Healthy controls (n = 105) completed the mCOMPASS for comparison with patients' scores. Patients with sarcoidosis, SFN complaints, and reduced IENFD demonstrated more severe pain scores on the NPS. The mCOMPASS differentiated between subjects with and without SFN symptoms. A significant correlation was obtained between the NPS and VAS, indicating good construct validity. Good reliability values were obtained for all scales. The use of the NPS to evaluate SFN symptoms is suggested, as it shows differences between patients with SFN symptoms with normal or reduced IENFD values. The mCOMPASS might be used to select patients for further testing.

Isolated eyelid closure myotonia in two families with sodium channel myotonia.

Sodium channelopathies (NaCh), as part of the non-dystrophic myotonic syndromes (NDMs), reflect a heterogeneous group of clinical phenotypes accompanied by a generalized myotonia. Because of recent availability of diagnostic genetic testing in NDM, there is a need for identification of clear clinical genotype-phenotype correlations. This will enable clinicians to distinguish NDMs from myotonic dystrophy, thus allowing them to inform patients promptly about the disease, perform genetic counseling, and orient therapy (Vicart et al. Neurol Sci 26:194-202, 2005). We describe the first distinctive clinical genotype-phenotype correlation within NaCh: a strictly isolated eyelid closure myotonia associated with the L250P mutation in SCN4A. Using clinical assessment and needle EMG, we identified this genotype-phenotype correlation in six L250P patients from one NaCh family and confirmed this finding in another, unrelated NaCh family with three L250P patients.

Intraepidermal nerve fiber density and its application in sarcoidosis.

BACKGROUND: Intraepidermal nerve fiber density (IENFD) is considered a good diagnostic tool for small fiber neuropathy (SFN). OBJECTIVES: To assess stratified normative values for IENFD and determine the reliability and validity of IENFD in sarcoidosis. METHODS: IENFD was assessed in 188 healthy volunteers and 72 patients with sarcoidosis (n = 58 with SFN symptoms, n = 14 without SFN symptoms). Healthy controls were stratified (for age and sex), resulting in 6 age groups (20-29, 30-39, ... up to > or = 70 years) containing at least 15 men and 15 women. A skin biopsy was taken in each participant 10 cm above the lateral malleolus and analyzed in accordance with the international guidelines using bright-field microscopy. Interobserver/intraobserver reliability of IENFD was examined. In the patients, a symptoms inventory questionnaire (SIQ; assessing SFN symptoms) and the Vickrey Peripheral Neuropathy Quality-of-Life Instrument-97 (PNQoL-97) were assessed to examine the discriminative ability of normative IENFD values. RESULTS: There was a significant age-dependent decrease of IENFD values in healthy controls, with lower densities in men compared with women. Good interobserver/intraobserver reliability scores were obtained (kappa values > or = 0.90). A total of 21 patients with sarcoidosis had a reduced IENFD score (< 5th percentile; 19 [32.8%] in patients with SFN symptoms, 2 [14.3%] in patients without SFN symptoms). The validity of the normative IENFD values was demonstrated by distinguishing between the SIQ scores and various PNQoL-97 values for the different patient groups. CONCLUSION: This study provides clinically applicable distal intraepidermal nerve fiber density normative values, showing age- and sex-related differences.

Muscle ultrasound measurements and functional muscle parameters in non-dystrophic myotonias suggest structural muscle changes.

Patients with non-dystrophic myotonias, including chloride (myotonia congenita) and sodium channelopathies (paramyotonia congenita/potassium aggravated myotonias), may show muscular hypertrophy in combination with some histopathological abnormalities. However, the extent of muscle changes has never been assessed objectively in a large group genetically confirmed patients. This study quantitatively determines echo intensities, thicknesses, ranges-of-motion and force of four skeletal muscles in 63 genetically confirmed patients. The main findings revealed elevated echo intensities in all muscles except the rectus femoris (+1.3-2.2SD, p<0.0001), and hypertrophy in the arms (+0.5-0.9SD, p<0.01). Muscle echo intensities were inversely correlated to the corresponding ranges-of-motion (biceps brachii: r= -0.43; p<0.001, forearm flexors: r= -0.47; p<0.001, rectus femoris: r= -0.40; p=0.001, and tibial anterior: r= -0.27; p=0.04) and correlated positively to age (r=0.22; p=0.05). The echo intensity of the forearm flexors was inversely correlated to their muscles' force (r= -0.30; p=0.02). Together, these data suggest that non-dystrophic myotonias may lead to structural muscle changes.

Encephalopathic attacks in a family co-segregating myotonic dystrophy type 1, an intermediate Charcot-Marie-Tooth neuropathy and early hearing loss.

OBJECTIVE: To report new disease components in a unique myotonic dystrophy type 1 (DM1) family previously described by us in which all affected members also had a sensorimotor neuropathy that co-segregated with markers flanking the DM1 locus. METHODS: Clinical observations, electrophysiology, audiometry, DNA studies. RESULTS: During a follow-up period of over 25 years, the following were observed: (i) co-segregation of a striking new encephalopathic phenotype. In middle age, five patients were admitted on multiple occasions with attacks of impaired consciousness, psychomotor agitation, fever and, in about half of the cases, focal neurological signs, including unilateral weakness, sensory deficits and dysphasia. Reported onset phenomena consisted of confusion, headache, focal neurological symptoms and nausea; (ii) many patients show an early and severe sensorineural hearing loss; (iii) although they have mothers with the adult onset type, the four affected subjects from the youngest generation do not show any signs or symptoms of childhood or congenital myotonic dystrophy; (iv) the neuropathy meets the criteria of an intermediate type Charcot-Marie-Tooth (CMT), and is more severe in males; and (v) patients presented with an expanded fragment at the DM1 CTG repeat but this allele was refractory to PCR amplification and triplet repeat primed PCR at the 3' end of the array, indicating the existence of an additional lesion at the 3' end. CONCLUSIONS: The phenotype in this unique family extends beyond myotonic dystrophy and CMT to include encephalopathic attacks and early hearing loss, and is associated with an atypical mutation at the DM1 locus.