Genomic testing and counseling: The contribution of next-generation sequencing to epilepsy genetics.

INTRODUCTION: Currently, next-generation sequencing (NGS) technology is more accessible and available to detect the genetic causation of diseases. Though NGS technology benefited some clinical phenotypes, for some clinical diagnoses such as seizures and epileptic disorders, adaptation occurred slowly. The genetic diagnosis was mainly based on epilepsy gene panels and not on whole exome and/or genome sequencing. METHOD: We retrospectively analyzed 420 index cases, referred for NGS over a period of 18 months, to investigate the challenges in diagnosing epilepsy. RESULT: Of the 420 cases, 65 (15%) were referred due to epilepsy with one third having a positive family history. The result of the NGS was 14 positive cases (21.5%), 16 inconclusive cases (24%), and 35 (53%) negative cases. No gene has been detected twice in the inconclusive and positive groups. Comparative genomic hybridization has been performed for all 30 NGS negative cases and four cases with pathogenic variants (deletion in 15q11.213.1, deletion of 2p16.3, deletion in Xq22.1, and deletion in 17p13.3) were identified. CONCLUSION: These findings have implications for our understanding of the approach to genetic testing and counseling of patients affected with seizures and epilepsy disorders. The overall diagnostic yield of exome/genome sequencing in our cohort was 23%. The main characteristic is genetic heterogeneity, supporting NGS technology as a suitable testing approach for seizures and epilepsy disorders. Genetic counseling for newly identified disease-causing variants depends on the pedigree interpretation, within the context of disease penetrance and variable expressivity.

Peripheral nerve high-resolution ultrasound in diabetes.

INTRODUCTION: High-resolution ultrasound (HRU) is used in the diagnosis of peripheral neuropathies. There are conflicting data regarding HRU findings in patients with diabetic sensorimotor polyneuropathy (DSP). Our purpose in this study was to measure nerve cross-sectional areas (CSAs) in patients with diabetes, with and without DSP. METHODS: We performed a prospective peripheral nerve HRU study of 100 diabetic subjects, assessed the CSA at predefined sites, and compared the results with those of 100 normal subjects. We evaluated the use of individual CSA values and various summary scores for diagnosis of DSP. RESULTS: Diabetic subjects had higher CSA values than healthy volunteers, and those with DSP had higher CSA values. Three or more enlarged CSA sites predicted DSP with 64% sensitivity and 77% specificity. CONCLUSIONS: Peripheral nerves are enlarged diffusely in diabetic patients, including sites not susceptible to bony compression. The number of enlarged CSA values can help predict the presence of DSP. Muscle Nerve, 2016 Muscle Nerve 55: 171-178, 2017.

Frequent laboratory abnormalities in CIDP patients.

INTRODUCTION: The role of screening laboratory tests in chronic inflammatory demyelinating polyneuropathy (CIDP) is currently unknown. The objectives of this study are to explore common laboratory test abnormalities in CIDP patients. METHODS: CIDP subjects attending the Neuromuscular Clinic between 01/2013 and 12/2014 were evaluated. Demographic data, clinical history, physical examination, and laboratory test results were extracted from their charts. RESULTS: Seventy-nine charts were reviewed. Mean age was 61 ± 11 years. Most (84%) CIDP patients had laboratory test abnormalities; the most frequent were paraproteinemia (29%) and elevated HbA1C (28%) and creatine kinase (27%). Additional abnormalities included anemia in 19%, and elevated anti-neutrophil cytoplasmic antibody, erythrocyte sedimentation rate, and urate in 17%, elevated antinuclear antibodies, rheumatoid factor, and thyroid-stimulating hormone in 11%, and abnormal C3 in 10%. CONCLUSIONS: Laboratory test abnormalities were found in most CIDP patients. The most common were paraproteinemia, higher than expected frequency of diabetes, and unexpected CK elevation. Additional abnormalities included anemia, high urate levels, and common biomarkers for vasculitic neuropathies. Muscle Nerve 53: 862-865, 2016.

Reference values for ultrasonograpy of peripheral nerves.

INTRODUCTION: High-resolution ultrasonography (HRU) is a novel method that provides morphological information about peripheral nerves. We aimed to determine reference values for nerve cross-sectional area (CSA) on HRU. METHODS: One hundred healthy volunteers had HRU of median, radial, ulnar, fibular, tibial, sural, and superficial fibular nerves at defined sites. The CSA was measured and the effects of age, gender, and body mass index (BMI) were evaluated. RESULTS: CSA values in healthy subjects are described. CSA is larger in lower limb motor nerves than in sensory nerves at similar sites, and the CSA tends to be symmetrical. The strongest effect on CSA was for age, although gender and BMI had some effects. CONCLUSIONS: This study provides normative values for HRU, and it suggests that further research with age- and gender-specific distributions must be a key priority in the development of HRU for use as a diagnostic test for peripheral nerve diseases.

Elevated Vibration Perception Thresholds in CIDP Patients Indicate More Severe Neuropathy and Lower Treatment Response Rates.

INTRODUCTION: Vibration perception threshold (VPT) examination using a neurothesiometer provides objective, sensitive and specific information, and has been utilized mainly in patients with diabetic polyneropathy. OBJECTIVES: Explore the utility of VPT examination in CIDP patients. METHODS: CIDP subjects attending the Neuromuscular clinic between 01/2013 and 12/2014 were evaluated. Demographic data, clinical history, physical examination, VPT values, and electrophysiologic data from their charts were extracted. RESULTS: 70 charts were reviewed. 55 CIDP patients had elevated VPT, associated with higher frequency of abnormal sensory testing for various modalities (92.7% vs. 46.7%, p<0.0001), lower sensory and motor amplitudes and reduced conduction velocities on nerve conduction studies, and lower treatment response rates (54% vs. 93%, p = 0.01). CONCLUSION: VPT examination is a simple tool, which is a reliable and sensitive measure not only for diabetic neuropathy, but also for CIDP. Moreover, in CIDP, elevated VPT values are also associated with lower treatment response rates.

Treatment Responsiveness in CIDP Patients with Diabetes Is Associated with Higher Degrees of Demyelination.

INTRODUCTION: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is one of several chronic treatable acquired demyelinating neuropathies. OBJECTIVES: To explore the association between the degree of demyelination in CIDP, and treatment responsiveness. METHODS: A retrospective chart review of CIDP subjects assessed between 1997 and 2013 was performed to compare treatment responsiveness using different sets of criteria. RESULTS: 99 CIDP patients were included, 34 with diabetes mellitus (DM). Treatment responsiveness was higher in CIDP-DM fulfilling 1 or more EFNS/PNS criteria, (63% vs. 31%, p = 0.03), and in CIDP+DM fulfilling 2 or more criteria (89% vs. 36%, p = 0.01). Nonetheless, treatment responsiveness in CIDP+DM had the highest odds ratio (3.73, p = 0.01). Similar results were also shown in simplified uniform study criteria, with 10% cut off values for CIDP-DM, compared to 30% for CIDP+DM. CONCLUSION: In CIDP+DM, higher degrees of demyelination are associated with treatment responsiveness, implying the need to adjust current criteria in these patients.

Choosing drugs for the treatment of diabetic neuropathy.

INTRODUCTION: Diabetic sensorimotor polyneuropathy (DSP) affects 50% of diabetes patients and is painful in about 26%. Although disease-modifying therapies are not available for DSP, symptomatic treatments for painful diabetic neuropathy (PDN) are effective. AREAS COVERED: We performed a MEDLINE search on PubMed using the search terms: treatment diabetic neuropathy and treatment PDN. This review outlines the problem posed by DSP, the clinical presentation and the characterization of PDN. A discussion of disease-modifying interventions, including the benefits of strict glycemic control, is followed by a focus on interventions for PDN including antidepressants, anticonvulsants and other treatments. EXPERT OPINION: Disease modification in DSP remains an unmet need in clinical medicine affecting a large percentage of the population with concomitant healthcare costs. Strict glycemic control and attention to potential risk factors such as hypertension, hyperlipidemia and obesity may minimize DSP. Many patients benefit from treatment of their painful symptoms with anticonvulsants or antidepressants, but all are associated with significant side effects that limit their usefulness. There is a need for treatments of PDN with fewer side effects and more effective pain relief.