Ari Breiner

Does the Prevailing Hypothesis That Small-Fiber Dysfunction Precedes Large-Fiber Dysfunction Apply to Type 1 Diabetic Patients?

OBJECTIVE The prevailing hypothesis that early subclinical small-fiber injury precedes large-fiber damage in diabetic sensorimotor polyneuropathy (DSP) is based on lower intraepithelial nerve fiber density in type 2 prediabetic patients despite normal nerve conduction studies (NCSs). We aimed to confirm the same hypothesis in type 1 diabetic patients by examining whether: 1) subjects without DSP include a spectrum with both normal and abnormal small-fiber measures and 2) subjects with DSP have concurrent evidence of abnormal small-fiber measures. RESEARCH DESIGN AND METHODS A healthy control population (n = 53) was used to generate threshold values for four small-fiber tests: cooling detection thresholds (CDTs), laser Doppler imaging of heat-evoked flare (LDIflare), heart rate variability (HRV), and corneal confocal microscopy. Based on NCS results, type 1 diabetic patients (n = 131) were dichotomized according to the presence or absence of DSP. RESULTS Threshold values derived from healthy control subjects were 26.5°C, 1.4 cm2, 13%, and 12.9 mm/mm2 for CDT, LDIflare, HRV, and corneal nerve fiber length, respectively. Among type 1 diabetic patients, 57 of 131 had evidence of DSP, and 74 of 133 did not. Using abnormality of any small-fiber test to define small-fiber dysfunction, 55 of 57 (96.5%) DSP patients and 39 of 74 (52.7%) control subjects without DSP had concurrent small-fiber damage. The severity of small-fiber abnormalities worsened with an increasing number of NCS abnormalities (ANOVA, P < 0.01). CONCLUSIONS Our findings in type 1 diabetes support the prevailing hypothesis that small-fiber dysfunction occurs early in DSP. However, further research is required to determine which combination of small-fiber tests is most suitable as a surrogate marker in clinical trials.

Epidemiology of myasthenia gravis in Ontario, Canada.

Incidence and prevalence estimates in myasthenia gravis have varied widely. Recent studies based on administrative health data have large sample sizes but lack rigorous validation of MG cases, and have not examined the North American population. Our aim was to explore trends in MG incidence and prevalence for the years 1996-2013 in the province of Ontario, Canada (population 13.5 million). We employed a previously validated algorithm to identify MG cases. Linking with census data allowed for the calculation of crude- and age/sex-standardized incidence and prevalence rates for the years 1996-2013. The regional distribution of MG cases throughout the province was examined. Mean age at the first myasthenia gravis encounter was 60.2u2009±u200917.1 years. In 2013, there were 3611 prevalent cases in Ontario, and the crude prevalence rate was 32.0/100,000 population. Age- and sex-standardized prevalence rates rose consistently over time from 16.3/100,000 (15.4-17.1) in 1996 to 26.3/100,000 (25.4-27.3) in 2013. Standardized incidence rates remained stable between 1996 (2.7/100,000; 95% CL 2.3-3.0) and 2013 (2.3/100,000; 2.1-2.6). Incidence was highest in younger women and older men, and geographic variation was evident throughout the province. In conclusion, this large epidemiological study shows rising myasthenia gravis prevalence with stable incidence over time, which is likely reflective of patients living longer, possibly due to improved disease treatment. Our findings provide accurate information on the Canadian epidemiology of myasthenia gravis and burden for health care resources planning for the province, respectively.

The Characteristics of Chronic Inflammatory Demyelinating Polyneuropathy in Patients with and without Diabetes – An Observational Study

Introduction We aimed to determine whether the clinical characteristics and electrodiagnostic classification of nerve injury, and response to treatment differed in patients diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) with and without diabetes. Methods CIDP patients with diabetes (CIDP+DM) (nu200a=u200a67) and without diabetes (CIDP-DM) (nu200a=u200a67) underwent clinical examination and nerve conduction studies (NCS). CIDP-DM patients were selected using age and gender matching with the existing CIDP+DM cohort. Patients treated with immunotherapies were classified as responders (R) (nu200a=u200a46) or non-responders (NR) (nu200a=u200a54) based on clinical response to treatment. The groups were compared using analysis of variance, contingency tables and Kruskal-Wallis analyses. Results CIDP+DM subjects had more severe neuropathy based on higher lower limb vibration potential thresholds (VPT)(pu200a=u200a0.004), higher Toronto Clinical Neuropathy Score (TCNS) (pu200a=u200a0.0009), more proximal weakness (pu200a=u200a0.03), more gait abnormality (pu200a=u200a0.03) and more abnormal NCS. CIDP+DM subjects had more abnormal sural NCS with lower sural sensory nerve action potential amplitudes (2.4±3.0 µV, 6.6±6.0 µV, p<0.0001) and slower sural nerve conduction velocities (38.6±5.4 m/s, 41.0±5.3 m/s, pu200a=u200a0.04). CIDP-DM subjects were more likely to receive immune therapies (93% vs 57%, pu200a=u200a<0.0001), despite no significant differences in treatment responder rates (pu200a=u200a0.71). Patients who responded to therapy had shorter duration of CIDP than non-responders (8.0±6.0 y vs 11.9±7.6 y, pu200a=u200a0.004). Discussion The clinical phenotype and electrophysiological profile of CIDP patients differs according to the presence or absence of diabetes. Despite CIDP+DM patients having more severe clinical and electrophysiological neuropathy, they are less likely to receive disease-modifying/specific therapy, yet have similar response rates to treatment as those without diabetes. Specifically, the duration of neuropathy - not diabetes status - was associated with treatment response.

Laser Doppler Flare Imaging and Quantitative Thermal Thresholds Testing Performance in Small and Mixed Fiber Neuropathies

Introduction Small fiber neuropathy might be a part of typical mixed small and large fiber neuropathy, or a distinct entity, affecting exclusively small nerve fibers. Objectives Explore the utility of small nerve fiber testing in patients with clinical presentation suggesting small fiber neuropathy, with and without evidence for concomitant large fiber neuropathy. Methods Patients attending the neuromuscular clinic from 2012 to 2015 with a clinical presentation suggesting small nerve fiber impairment, who had Laser Doppler flare imaging (LDIFlare) and quantitative thermal testing (QTT) were evaluated for this study. Patients with clinical or electrophysiological evidence for concomitant large fiber neuropathy were not excluded. Results The sensitivities of LDIFlare, cooling and heat threshold testing were 64%, 36%, and 0% respectively for clinically highly suggestive small fiber neuropathy, 64%, 56%, and 19% respectively for mixed fiber neuropathy, and 86%, 79%, and 29% respectively for diabetic mixed fiber neuropathy. Discussion LDIFlare and cooling thresholds testing are non-invasive small nerve fiber testing modalities, with moderate performance in patients with small and mixed fiber neuropathy, and excellent performance in diabetic mixed fiber neuropathy.

Incat disability score: A critical analysis of its measurement properties

Background: The INCAT (Inflammatory Neuropathy Cause and Treatment) disability score is a measure of activity limitation. It is used frequently as a primary endpoint in inflammatory polyneuropathy clinical trials. A comprehensive critical analysis of its measurement properties has not been performed. Methods: Critical analysis of measurement properties. Results: The INCAT disability score was derived based on items from Guys Neurological Disability Scale (GNDS), a disability measure intended for application in multiple sclerosis. Strengths of the INCAT score include evaluation of upper and lower limb dysfunction, ease of administration (feasibility), high face validity, and high reliability. Weaknesses of the scale include concerns about methodological quality of validation studies; failure to properly capture activity limitations due to proximal arm weakness, or fatigue; heavy individual item weighting; and poor sensitivity for detection of clinically important change. Conclusions: Although the INCAT scale has been an effective tool in inflammatory polyneuropathy studies, its limitations may warrant development of new scales. Muscle Nerve 50:164–169, 2014

Comparison of diabetes patients with “demyelinating” diabetic sensorimotor polyneuropathy to those diagnosed with CIDP

We have previously identified a subset of diabetic sensorimotor polyneuropathy (DSP) patients with probable demyelination related to poor glycemic control. We aimed to determine whether the clinical characteristics and electrodiagnostic classification of nerve injury in diabetes patients with “demyelinating” DSP (D‐DSP) differed from those diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) (CIDP + diabetes mellitus [DM]).

Treatment responsiveness in CIDP patients with diabetes is associated with unique electrophysiological characteristics, and not with common criteria for CIDP.

Objectives: Characterize treatment responsiveness in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients with diabetes mellitus (DM). Methods: We performed a retrospective chart review of CIDP subjects assessed between 1997 and 2013 and compared treatment response rates in those with and without DM, using different sets of criteria. Results: 99 CIDP patients were included, 34 CIDP+DM and 65 CIDP−DM patients, both having similar treatment response rates. CIDP patients fulfilling European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria had higher treatment response rates. Responders fulfilled a higher number of American Academy of Neurology (AAN) and EFNS/PNS criteria and had a higher number of demyelinating features in the total cohort and in CIDP−DM but not in CIDP+DM patients. CIDP+DM responders, however, had unique electrophysiologic characteristics. Conclusion: Fulfilling EFNS/PNS and AAN criteria, and higher number of demyelinating features, are associated with higher treatment response rates in CIDP−DM but not in CIDP+DM patients, implying the need for adjusting current criteria to predict treatment response rates in CIDP−DM patients.

Peripheral Nerve Ultrasound in Small Fiber Polyneuropathy.

Routine nerve conduction studies are normal in patients with small fiber neuropathy (SFN), and a definitive diagnosis is based on skin biopsy revealing reduced intra-epidermal nerve fiber density (IENFD). In large fiber polyneuropathy, ultrasound (US) parameters indicate enlargement in cross-sectional area (CSA). This study was aimed at determining if similar changes in large fibers on US are apparent in patients with SFN. Twenty-five patients with SFN diagnosed by reduced IENFD and 25 age- and body mass index (BMI)-matched healthy controls underwent US studies of sural and superficial peroneal sensory nerves. The mean CSA of the sural nerve in SFN patients was 3.2 ± 0.8 mm(2), and in controls, 2.7 ± 0.6 mm(2) (p < 0.0070), and this was independent of sex. There was no difference in the thickness-to-width ratio or echogenicity of the nerves. US of the sural nerve in patients diagnosed with small fiber neuropathy reveals an enlarged cross-sectional area similar to that in large fiber polyneuropathy.

Peripheral nerve ultrasound imaging shows enlargement of peripheral nerves outside the brachial plexus in neuralgic amyotrophy.

Purpose: Neuralgic amyotrophy is characterized by acute or subacute onset of shoulder and arm pain, followed by muscle atrophy and weakness, and variable sensory abnormalities. Historically, the site of inflammation has been localized to the brachial plexus, although the involvement of individual nerve branches has been well recognized. Methods: We describe ultrasound findings in two cases with a clinical presentation suggestive of neuralgic amyotrophy, involving individual peripheral nerves, correlating with clinical and electrophysiological findings. Results: In the first case, selective fusiform enlargement of the left radial nerve in the proximal forearm is shown, whereas in the second case, fusiform enlargement of the left median nerve in the antecubital fossa is shown. Discussion: These cases confirm that the site of nerve inflammation may lie outside the brachial plexus, keeping with previous reports, and suggests that peripheral nerve ultrasound imaging might aid in the diagnosis of neuralgic amyotrophy and exclude mimicking conditions.

Measurement of Cooling Detection Thresholds for Identification of Diabetic Sensorimotor Polyneuropathy in Type 1 Diabetes

Objective Compared to recently-studied novel morphological measures, conventional small nerve fiber functional tests have not been systematically studied for identification of diabetic sensorimotor polyneuropathy (DSP). We aimed to determine and compare the diagnostic performance of cooling detection thresholds (CDT) in a cross-sectional type 1 diabetes cohort. Research Design and Methods 136 subjects with type 1 diabetes and 52 healthy volunteers underwent clinical and electrophysiological examination for DSP classification concomitantly with the Toronto Clinical Neuropathy Score (TCNS) and three small fiber function tests: CDT, heart rate variability (HRV), and laser doppler imaging of axon-mediated neurogenic flare responses to cutaneous heating (LDIFLARE). Area under the curve (AUC) and optimal thresholds were determined by receiver operating characteristic (ROC) curves in the type 1 diabetes cohort. Results Type 1 diabetes subjects were 42±17 years of age with mean HbA1c 7.9±1.7%. Fifty-nine (45%) met the case definition for DSP. CDT values were lowest in cases with DSP (18.3±8.4°C) compared to controls without DSP (28.4±3.5°C) and to healthy volunteers (29.6±1.8°C; p-value for both comparisons<0.0001). AUCCDT was 0.863 which was similar to AUCTCNS (0.858, pu200a=u200a0.24) and AUCHRV (0.788, pu200a=u200a0.05), but exceeded AUCLDIFLARE (0.750, pu200a=u200a0.001). The threshold of <25.1°C was equivalent to the lower bound of the healthy volunteer 95% distribution [25.1, 30.8°C] and performed with 83% sensitivity and 82% specificity. Conclusions Akin to novel small fiber morphological measures, CDT is a functional test that identifies DSP with very good diagnostic performance. These findings support further research that revisits the role of CDT in early DSP detection.