Epilepsy in neurofibromatosis type 1: Prevalence, phenotype, and genotype in adults.

PURPOSE: Studies have shown an increased risk of epilepsy in patients with neurofibromatosis type 1 (NF1). However, most reports focus on the pediatric population. In this study, we describe the trajectory of patients with NF1 and epilepsy beyond childhood. METHODS: Patients with NF1 ≥18 years-old consecutively seen at a multidisciplinary neurofibromatosis clinic during a four-year period were prospectively enrolled and offered routine EEG, MRI, and genetic testing. The lifelong and point prevalence of epilepsy in patients with NF1 were calculated. Demographic, genetic, radiological, and clinical features found to be statistically associated with having received a diagnosis of epilepsy were incorporated into a logistic regression model. RESULTS: Among 113 patients with NF1 included in this study (median age at study inclusion: 33 years), the lifelong prevalence of epilepsy was 11% (CI95%=6-18%) and point prevalence 7% (CI95%= 3-13%). Most patients (73%) were diagnosed with epilepsy before the age of 18 and achieved seizure-freedom by adulthood. At study inclusion, three-quarters of patients with a diagnosis of epilepsy had been seizure-free for more than one year and a third had resolved epilepsy. A routine EEG with epileptiform discharges had a sensitivity of 25% (CI95%=3-65) and specificity of 99% (CI95%=93-100) for identifying adult patients with NF1 and unresolved epilepsy. A history of epilepsy was associated with having a low-grade glioma (OR: 38.2; CI95%=2.2-674.7; p<0.01), learning disability (OR: 5.7; CI95%=1.0-31.5; p<0.05), and no plexiform neurofibroma (OR: 0.05; CI95%=0.0-0.8; p=0.04). No single mutation type was associated with the development of epilepsy. CONCLUSIONS: In patients with NF1, although resolution of epilepsy over time was observed in many cases, the prevalence of epilepsy was higher among adults with NF1 than that reported in the general population. Epileptogenesis in NF1 likely requires the combination of multiple genetic and environmental factors and suggests involvement of a network that spreads beyond the borders of a well-defined parenchymal lesion.

Efficacy and safety of high infusion rate IVIG in CIDP.

BACKGROUND: We aimed to determine the safety and tolerance of higher rates of infusion of intravenous immunoglobulin (IVIG) in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: Patients began infusions with 10% IVIG at the standard rate of 0.08 mL/kg/min. If tolerated, infusion rates were incrementally increased to 0.14 mL/kg/min. We considered the frequency of infusions with adverse events (AEs) as the primary outcome. RESULTS: Nineteen of 25 patients safely tolerated the maximum rate of 0.14 mL/kg/min. We observed 25 treatment-related AEs (TAEs) over 13 infusions at standard or transitional rates, across seven patients. We observed no TAEs associated with the maximum infusion rate. CONCLUSIONS: We found that 10% IVIG can be safely administered at a high infusion rate (0.14 ml/kg/min) in most CIDP patients, reducing the treatment time and burden on healthcare resources.

Prospective study of stress, depression and personality in myasthenia gravis relapses.

BACKGROUND: Psychopathology and personality traits may influence the course of autoimmune disorders. With this prospective longitudinal cohort study, we aimed to assess personality, stress and depression in myasthenia patients who relapse and those who remain stable or improve (non-relapsers). METHOD: We collected data from 155 consecutive adult patients with confirmed MG attending the Neuromuscular Clinic, Toronto General Hospital, between March 2017 and July 2018, for this study. Patients were assessed at baseline and 6 months, or at the time of MG relapse. At both visits, the patients were assessed clinically and were asked to complete self-administered questionnaires for disease severity, chronic stress and depression. Personality type was assessed at baseline only. Relapsing patients were defined as those patients with MGII score increasing by more than 5.5 points from visit 1 to visit 2. RESULTS: Relapsers had higher baseline scores for depression (p = 0.01) and the change in disease severity correlated with the change in depression score (r = 0.2534, p = 0.0015, 95% CI: 0.098 0.3961). Higher levels of stress at baseline and neuroticism predicted higher relapse rates (p = 0.01 and p < .0001, respectively). In the linear regression model, with change of the MGII score as the dependent variable, change in depression scores (p = 0.0004) and age (p = 0.03) predicted change in disease severity. CONCLUSIONS: Since emotional factors and personality type may influence MG, attention to these factors might improve care in MG patients.

Agreement between automated and manual quantification of corneal nerve fiber length: Implications for diabetic neuropathy research.

AIMS: Quantification of corneal nerve fiber length (CNFL) by in vivo corneal confocal microscopy represents a promising diabetic neuropathy biomarker, but applicability is limited by resource-intensive image analysis. We aimed to evaluate, in cross-sectional analysis of non-diabetic controls and patients with type 1 and type 2 diabetes with and without neuropathy, the agreement between manual and automated analysis protocols. METHODS: Sixty-eight controls, 139 type 1 diabetes, and 249 type 2 diabetes participants underwent CNFL measurement (N=456). Neuropathy status was determined by clinical and electrophysiological criteria. CNFL was determined by manual (CNFLManual, reference standard) and automated (CNFLAuto) protocols, and results were compared for correlation and agreement using Spearman coefficients and the method of Bland and Altman (CNFLManual subtracted from CNFLAuto). RESULTS: Participants demonstrated broad variability in clinical characteristics associated with neuropathy. The mean age, diabetes duration, and HbA1c were 53±18years, 15.9±12.6years, and 7.4±1.7%, respectively, and 218 (56%) individuals with diabetes had neuropathy. Mean CNFLManual was 15.1±4.9mm/mm2, and mean CNFLAuto was 10.5±3.7mm/mm2 (CNFLAuto underestimation bias, -4.6±2.6mm/mm2 corresponding to -29±17%). Percent bias was similar across non-diabetic controls (-33±12%), type 1 (-30±20%), and type 2 diabetes (-28±16%) subgroups (ANOVA, p=0.068), and similarly in diabetes participants with and without neuropathy. Levels of CNFLAuto and CNFLManual were both inversely associated with neuropathy status. CONCLUSIONS: Although CNFLAuto substantially underestimated CNFLManual, its bias was non-differential between diverse patient groups and its relationship with neuropathy status was preserved. Determination of diagnostic thresholds specific to CNFLAuto should be pursued in diagnostic studies of diabetic neuropathy.

Validation of cooling detection threshold as a marker of sensorimotor polyneuropathy in type 2 diabetes.

AIM: We aimed to validate the performance cooling detection thresholds (CDT) to detect diabetic sensorimotor polyneuropathy (DSP) in type 2 diabetes. METHODS: Two hundred and twenty participants with type 2 diabetes underwent clinical and electrophysiological examinations including 3 small fiber function tests: CDT, heart rate variability (HRV) and LDIFLARE. Clinical DSP was defined by consensus criteria whereas preclinical DSP was defined by presence of at least one electrophysiological abnormality. Area under the curve (AUC) and optimal thresholds were determined by receiver operating characteristic curves. RESULTS: Participants were aged 63 ± 11 years with mean HbA1c of 7.5 ± 1.6%. The 139 (63%) clinical DSP cases had mean CDT values of 18.3 ± 8.9°C; the 52 (24%) preclinical DSP cases had 25.3 ± 3.5°C; and the 29 (13%) controls had 27.1 ± 3.8°C; (p-value<0.02 for all comparisons). For identification of clinical DSP cases, AUCCDT was 0.79 which exceeded AUCHRV (0.60, p=<0.0001) and AUCLDI FLARE (0.69, p=0.0003), optimal threshold <22.8°C (64% sensitivity, 83% specificity). Preclinical DSP AUCCDT was 0.80, also exceeding the other 2 measures (p<0.02 for both comparisons), optimal threshold ≤27.5°C (83% sensitivity, 72% specificity). CONCLUSIONS: CDT had good diagnostic performance for identification of both clinical and preclinical neuropathy in type 2 diabetes. Its use as a non-invasive screening tool should be considered for research and clinical practice.

Construction and validation of the chronic acquired polyneuropathy patient-reported index (CAP-PRI): A disease-specific, health-related quality-of-life instrument.

INTRODUCTION: Generic health-related quality-of-life (HRQOL) patient-reported outcome measures have been used in patients with chronic immune-mediated polyneuropathies. We have created a disease-specific HRQOL instrument. METHODS: The chronic acquired polyneuropathy patient-reported index (CAP-PRI) was developed and validated in multiple steps. Items were initially generated through patient and specialist input. The performance of the preliminary 20 items was analyzed via a prospective, 5-center study involving chronic immune-mediated polyneuropathy patients. RESULTS: Data analysis suggested modification to a 15-item scale with 3 response categories rather than 5. The final CAP-PRI was validated in another prospective, 5-center study. The CAP-PRI appeared to be a unidimensional outcome measure that fit the Rasch model in our multicenter cohort. It correlated appropriately with outcome measures commonly used in this patient population. CONCLUSIONS: The CAP-PRI is a simple disease-specific HRQOL measure that appears to be useful for clinical care and possibly also for clinical trials. Muscle Nerve 54: 9-17, 2016.

Reproducibility of In Vivo Corneal Confocal Microscopy Using an Automated Analysis Program for Detection of Diabetic Sensorimotor Polyneuropathy.

OBJECTIVE: In vivo Corneal Confocal Microscopy (IVCCM) is a validated, non-invasive test for diabetic sensorimotor polyneuropathy (DSP) detection, but its utility is limited by the image analysis time and expertise required. We aimed to determine the inter- and intra-observer reproducibility of a novel automated analysis program compared to manual analysis. METHODS: In a cross-sectional diagnostic study, 20 non-diabetes controls (mean age 41.4±17.3y, HbA1c 5.5±0.4%) and 26 participants with type 1 diabetes (42.8±16.9y, 8.0±1.9%) underwent two separate IVCCM examinations by one observer and a third by an independent observer. Along with nerve density and branch density, corneal nerve fibre length (CNFL) was obtained by manual analysis (CNFLMANUAL), a protocol in which images were manually selected for automated analysis (CNFLSEMI-AUTOMATED), and one in which selection and analysis were performed electronically (CNFLFULLY-AUTOMATED). Reproducibility of each protocol was determined using intraclass correlation coefficients (ICC) and, as a secondary objective, the method of Bland and Altman was used to explore agreement between protocols. RESULTS: Mean CNFLManual was 16.7±4.0, 13.9±4.2 mm/mm2 for non-diabetes controls and diabetes participants, while CNFLSemi-Automated was 10.2±3.3, 8.6±3.0 mm/mm2 and CNFLFully-Automated was 12.5±2.8, 10.9 ± 2.9 mm/mm2. Inter-observer ICC and 95% confidence intervals (95%CI) were 0.73(0.56, 0.84), 0.75(0.59, 0.85), and 0.78(0.63, 0.87), respectively (p = NS for all comparisons). Intra-observer ICC and 95%CI were 0.72(0.55, 0.83), 0.74(0.57, 0.85), and 0.84(0.73, 0.91), respectively (p<0.05 for CNFLFully-Automated compared to others). The other IVCCM parameters had substantially lower ICC compared to those for CNFL. CNFLSemi-Automated and CNFLFully-Automated underestimated CNFLManual by mean and 95%CI of 35.1(-4.5, 67.5)% and 21.0(-21.6, 46.1)%, respectively. CONCLUSIONS: Despite an apparent measurement (underestimation) bias in comparison to the manual strategy of image analysis, fully-automated analysis preserves CNFL reproducibility. Future work must determine the diagnostic thresholds specific to the fully-automated measure of CNFL.

In vivo corneal confocal microscopy and prediction of future-incident neuropathy in type 1 diabetes: a preliminary longitudinal analysis.

OBJECTIVE: In vivo corneal confocal microscopy (IVCCM) has been established in cross-sectional studies as a valid measure for the identification of diabetic sensorimotor polyneuropathy (DSP). We aimed to determine the predictive validity of a baseline IVCCM measure in identifying future DSP onset in patients with type 1 diabetes. METHODS: We followed 65 patients with type 1 diabetes without DSP at baseline. They were followed longitudinally for a mean of 3.5±0.9 years and underwent IVCCM, clinical and electrophysiologic examinations at baseline and follow up. At the end of follow up, participants were assigned as new-onset cases of DSP or as controls. Predictive validity was assessed using receiver operating characteristic curves. RESULTS: At baseline, participants were 34±15 years of age with mean diabetes duration of 18±12 years. The 11 (17%) new-onset cases of DSP were similar to the 54 (83%) controls in baseline age, diabetes duration, gender, glycated hemoglobin levels and electrophysiologic parameters (p≥0.20). However, cases of new onset had significantly lower baseline corneal nerve fibre length (CNFL) and branch density (p<0.05). For identification of new-onset cases, area under the receiver operating characteristic curve for CNFL was 0.78 with an optimal threshold of 14.9 mm/mm(2) (sensitivity=0.82, specificity=0.69). CONCLUSIONS: Despite similar clinical and electrophysiologic parameters, participants with type 1 diabetes at risk for future DSP had significantly lower baseline IVCCM measures. CNFL may have applicability in identifying high-risk patients for therapeutic intervention in clinical research and practice.

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, p = 0.24) and AUCHRV (0.788, p = 0.05), but exceeded AUCLDIFLARE (0.750, p = 0.001). 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.

Diabetic neuropathy and axon reflex-mediated neurogenic vasodilatation in type 1 diabetes.

OBJECTIVE: Axon reflex-mediated neurogenic vasodilatation in response to cutaneous heating may reflect early, pre-clinical small fibre dysfunction. We aimed to evaluate the distribution of the vascular flare area measured by laser doppler imaging ("LDI(FLARE) area") in type 1 diabetes and in healthy volunteers. RESEARCH AND METHODS: Concurrent with clinical and electrophysiological examination to classify diabetic sensorimotor polyneuropathy (DSP), LDI(FLARE) area (cm(2)) was determined in 89 type 1 diabetes subjects matched to 64 healthy volunteers. We examined the association and diagnostic performance of LDI with clinical and subclinical measures of DSP and its severity. RESULTS: Compared to the 64 healthy volunteers, the 56 diabetes controls without DSP had significantly lower LDI(FLARE) area (p = 0.006). The 33 diabetes cases with DSP had substantially lower LDI(FLARE) area as compared to controls without DSP (p = 0.002). There was considerable overlap in LDI(FLARE) area between all groups such that the ROC curve had an AUC of 0.72 and optimal sensitivity of 70% for the detection of clinical DSP. Use of a subclinical definition for DSP, according to subclinical sural nerve impairment, was associated with improved AUC of 0.75 and sensitivity of 79%. In multivariate analysis higher HbA1c and body mass index had independent associations with smaller LDI(FLARE) area. CONCLUSIONS: Axon reflex-mediated neurogenic vasodilatation in response to cutaneous heating is a biomarker of early nerve dysfunction in DSP. Its independent association with glycemic exposure in diabetes subjects and both glycemic exposure and BMI in healthy volunteers highlights the existence of small-fibre dysfunction in the natural history of DSP.

Prediction of incident diabetic neuropathy using the monofilament examination: a 4-year prospective study.

OBJECTIVE: To determine the specific monofilament examination score that predicts the subsequent 4-year incidence of diabetic neuropathy with the highest degree of diagnostic accuracy. RESEARCH DESIGN AND METHODS: Longitudinal follow-up of 175 of 197 (89%) participants in the Toronto Diabetic Neuropathy Cohort without baseline neuropathy for incident neuropathy. We examined the baseline monofilament examination score (and other simple sensory screening tests) by receiver operating characteristic (ROC) curve analysis. RESULTS: Incident diabetic neuropathy developed in 50 (29%) participants over a mean follow-up of 4.1 years (interquartile range 2.6-7.1 years). Although male sex, longer diabetes duration, taller height, and higher blood pressure at baseline were associated with incident neuropathy, the strongest association was with a lower baseline monofilament score (score out of 8 was 3.7 +/- 2.5 for incident neuropathy vs. 5.7 +/- 2.3 for those who did not develop neuropathy; P < 0.001). The optimal threshold score for risk of incident neuropathy was

Multi-site testing with a point-of-care nerve conduction device can be used in an algorithm to diagnose diabetic sensorimotor polyneuropathy.

OBJECTIVE: We aimed to establish whether multi-nerve testing with a point-of-care nerve conduction device could be used to diagnose diabetic sensorimotor polyneuropathy. RESEARCH DESIGN AND METHODS: A total of 72 consecutive patients with diabetes underwent a full neurological examination and a concurrent evaluation for nine standard electrophysiological parameters using conventional nerve conduction studies (the reference standard) and a point-of-care device. RESULTS: Spearman coefficients for correlation of point-of-care and conventional parameters ranged between 0.76 and 0.91 (P < 0.001 in all comparisons). Agreement by the method of Bland and Altman was acceptable despite small systematic biases. Fifty subjects (69%) had neuropathy according to conventional criteria. The sensitivity and specificity for the point-of-care device to identify such neuropathy was 88 and 82%, respectively. CONCLUSIONS: A novel point-of-care device has reasonable diagnostic accuracy and thus may represent a sufficiently accurate alternative for detecting the diffuse electrophysiological criteria necessary to make the diagnosis of diabetic sensorimotor polyneuropathy.

IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial.

OBJECTIVE: We aimed to determine the effectiveness of IV immunoglobulin (IVIG) in the treatment of patients with myasthenia gravis (MG) and worsening weakness in a randomized, placebo-controlled, masked study. METHODS: Fifty-one patients with worsening weakness due to MG were randomized to infusion with 2 g/kg of IVIG or an equivalent volume of IV dextrose 5% in water. The Quantitative Myasthenia Gravis (QMG) Score for Disease Severity, a validated clinical composite scale, was calculated by a masked observer at baseline and days 14 and 28. RESULTS: In IVIG-treated patients, a clinically meaningful improvement in QMG Score for Disease Severity was observed at day 14 and persisted at day 28. The greatest improvement occurred in patients with more severe disease as defined by a QMG Score for Disease Severity greater than 10.5. CONCLUSION: This study provides level 1 evidence for the effectiveness of IV immunoglobulin in patients with worsening weakness due to myasthenia gravis.

Validation of a novel point-of-care nerve conduction device for the detection of diabetic sensorimotor polyneuropathy.

OBJECTIVE: The diagnosis of diabetic sensorimotor polyneuropathy using objective electrophysiological tests is hindered by limited access to the specialized laboratories and technicians that perform and interpret them. We evaluated the performance characteristics of a novel portable and automated point-of-care nerve conduction study device, which can be operated by nontechnical personnel, and compared it with conventional nerve conduction studies performed in a specialist setting. RESEARCH DESIGN AND METHODS: Seventy-two consecutive patients with diabetes (8 type 1, 64 type 2) from a diabetes and a neuropathy outpatient clinic were evaluated concurrently with conventional nerve conduction studies (the reference standard) and the point-of-care device for sural nerve function (sural nerve amplitude potentials in microvolts [microV]). RESULTS: Sural nerve amplitude potentials measured by the point-of-care device shared very strong correlation with the reference standard (Spearman's correlation coefficient 0.95, P < 0.001). The Bland and Altman method yielded agreement despite a small systematic underestimation by the point-of-care device of 1.2 +/- 3.4 microV. Despite this small systematic bias, the sensitivity and specificity of normal and abnormal sural nerve amplitude potentials measured by the point-of-care device for the detection of diabetic sensorimotor polyneuropathy defined by standard clinical and electrophysiological criteria were 92 and 82%, respectively. CONCLUSIONS: A novel point-of-care device has excellent diagnostic accuracy for detecting electrophysiological abnormality in the sural nerve of patients who have diabetes. This automated device represents an alternative to conventional nerve conduction studies for the diagnosis of diabetic sensorimotor polyneuropathy.

Low-intensity laser therapy for painful symptoms of diabetic sensorimotor polyneuropathy: a controlled trial.

OBJECTIVE: Low-intensity laser therapy (LILT) has been advocated for treatment of chronic pain disorders. Although the mechanism of pain relief is uncertain, this therapy has been suggested for relief of painful symptoms of diabetic sensorimotor polyneuropathy (DSP). The objective of this study was to determine whether LILT relieves the pain of DSP. RESEARCH DESIGN AND METHODS: We conducted a randomized, double-masked, sham therapy-controlled clinical trial in 50 patients with painful DSP diagnosed with the Toronto Clinical Neuropathy Score. All patients received sham therapy over a 2-week baseline period and were then randomized to receive biweekly sessions of either sham or LILT for 4 weeks. The primary efficacy parameter was the difference in the weekly mean pain scores on a visual analog scale (VAS). RESULTS: The patients had similar baseline characteristics for pain intensity, HbA(1c), and duration of DSP. Both groups noted a decrease in weekly mean pain scores during sham treatment. After the 4-week intervention, the LILT group had an additional reduction in weekly mean pain scores of -1.0 +/- 0.4 compared with -0.0 +/- 0.4 for the sham group (P = 0.07). LILT had no effect on the Toronto Clinical Neuropathy Score, nerve conduction studies, sympathetic skin response, or quantitative sensory testing. CONCLUSIONS: Although an encouraging trend was observed with LILT, the study results do not provide sufficient evidence to recommend this treatment for painful symptoms of DSP.