Spinal charcot‐marie‐tooth disease: A reappraisal

Introduction: Distal hereditary motor neuropathy (dHMN) is characterized by isolated distal muscle atrophy without sensory deficit. Nevertheless, clinical sensory loss has been reported despite preserved sensory nerve conduction in a few patients, thus differentiating these cases from the classical type 2 Charcot‐Marie‐Tooth disease (CMT2). Methods: We report 4 patients who presented with clinical sensory and motor neuropathy and normal peripheral sensory nerve conduction studies and were investigated with complete electrophysiological studies, including somatosensory evoked potentials (SEP). Results: These patients had a clinical presentation of classical CMT with isolated axonal motor neuropathy suggestive of dHMN. Interestingly, tibial nerve SEPs showed abnormalities suggestive of proximal involvement of dorsal roots that may explain the clinical somatosensory disturbances. Conclusions: These cases support the concept of spinal CMT that should be recognized as an intermediate form between dHMN and CMT2. SEP recording was helpful in defining a more precise phenotype of spinal CMT. Muscle Nerve 46: 603–607, 2012     

Long‐term course of oxaliplatin‐induced polyneuropathy: a prospective 2‐year follow‐up study

This prospective study sought to identify the potential reversibility of oxaliplatin‐induced peripheral neuropathy (OXAIPN) by following‐up its long‐term course 2 years after discontinuation of oxaliplatin (OXA)‐based chemotherapy. Participants were 91 colorectal cancer patients treated with OXA‐based chemotherapy. Neurological assessment, clinical Total Neuropathy Score© (TNSc©) and nerve conduction studies were performed at baseline (T0), the end of chemotherapy (T1) and 2 years (T2) after discontinuation of chemotherapy. A total of 73 of 91 (80%) patients experienced OXAIPN at T1. At a median follow‐up of 25 months, persistence of chronic OXAIPN was present in 61 of 73 patients (84%) and complete resolution was present in 12 patients (17%). Longitudinal comparison of TNSc© values between T1 and T2 revealed that the overall severity of OXAIPN in those 61 patients significantly decreased over time. Median TNSc© values were nine (range: 2–15) at T1 vs. four (range: 2–12) at T2 (P < 0.001). Likewise, sensory nerve conduction measures at T2 significantly improved in all sensory nerves tested, compared with T1. Severity of OXAIPN at T2 was significantly associated (P < 0.001) with high severity of OXAIPN at T1. In conclusion, persistence of OXAIPN beyond 2 years after finishing chemotherapy is common. Clinical and neurophysiological improvement is observed, although recovery is often incomplete.     

Early, progressive, and sustained dysfunction of sensory axons underlies paclitaxel-induced neuropathy

Paclitaxel is used in the adjuvant treatment of breast cancer. It induces disabling and potentially long-lasting sensory neuropathy. This study systematically and prospectively investigated sensory function, using clinical grading scales, quantitative sensory testing, and neurophysiological and nerve excitability studies in 28 patients with early-stage breast cancer. After administration of 529 ± 41 mg/m(2) paclitaxel, 71% of patients developed neuropathic symptoms by 6 weeks of treatment. Early and progressive increases in stimulus threshold (P < 0.05) and reduction in sensory amplitudes from 47.0 ± 3.3 μV to 42.4 ± 3.4 μV (P < 0.05) occurred by 4 weeks, with a further reduction by final treatment (33.7 ± 3.0 μV, P < 0.001). The majority of patients (63%) did not experience recovery of neuropathic symptoms at follow-up. Axonal disruption did not relate to membrane conductance dysfunction. We found that paclitaxel produces early sensory dysfunction and leads to persistent neuropathy. Importantly, significant axonal dysfunction within the first month of treatment predated symptom onset, suggesting a window for neuroprotective therapies.     

糖尿病周围神经病97例临床特征与神经电生理分析

目的:探讨糖尿病周围神经病(DPN)患者的临床特征与神经电生理变化。方法:分析97例DPN患者的临床特征,比较DPN组和对照组的神经传导速度(NCV)、远端潜伏期、远端波幅3个参数。结果:①临床特征以肢体麻木(59%)最多见、其次为疼痛(42%)。②患者组NCV、远端波幅值低于对照组,远端潜伏期比对照组延长;两组3个参数比较,除腓总神经远端波幅、尺神经感觉传导速度和正中、尺、腓肠神经远端潜伏期外,差异均有统计学意义(P<0.05)。结论:①DPN患者临床特征以肢体麻木和疼痛最多见;②检测NCV、远端潜伏期、远端波幅,能较早发现临床患者。     

Invited review: peripheral neuropathy in Sjogren's syndrome

Our experience and review of the literature reveal that Sjogren's syndrome (SS) is an important, poorly recognized cause of peripheral neuropathy. Several forms of peripheral nerve dysfunction occur in SS including trigeminal sensory neuropathy, mononeuropathy multiplex, distal sensory neuropathy, distal sensorimotor peripheral neuropathy and a pure sensory neuronopathy syndrome. Rarely, chronic relapsing inflammatory polyneuropathy and multiple cranial neuropathies appear. Clinical evidence of glandular involvement is often minimal or absent when patients with SS develop peripheral neuropathy; and the diagnosis of the underlying condition is elusive. We review clinical and laboratory features of this disorder and suggest appropriate evaluation of patients with neuropathy and suspected SS.     

Multifocal motor neuropathy with high titers of anti‐MAG antibodies

Multifocal motor neuropathy (MMN) and anti‐myelin‐associated glycoprotein (anti‐MAG)‐associated neuropathy are clinically and electrophysiologically distinct entities. We describe a patient with characteristic features of both neuropathies, raising the possibility of an overlap syndrome. A 49‐year‐old patient reported a history of slowly progressive predominantly distal tetraparesis, with mild sensory deficits. Nerve conduction studies demonstrated persistent motor conduction blocks outside compression sites, typical of MMN. Laboratory findings revealed persistently high titers of anti‐MAG immunoglobulin Mλ (IgMλ) paraprotein in the context of a monoclonal gammapathy of unknown significance. Skin biopsy of distal lower limb revealed IgM positive terminal nerve perineurium deposits. This case suggests that the distinction between subtypes of chronic inflammatory neuropathies may not be as clear as initially thought, and that the pattern of pathogenicity of anti‐MAG antibodies may vary.     

Cutaneous silent period in human immunodeficiency virus-related peripheral neuropathy

The aim of this work was first to determine whether the cutaneous silent period (CSP), a marker of small-nerve-fibre function, was altered in human immunodeficiency virus (HIV)-positive subjects with predominantly sensory symmetrical polyneuropathy and, second, to assess whether such alterations were predictive of an impairment in the largest calibre sensory and motor nerve fibres of the upper limb (UL) peripheral nerves. CSP was assessed in three groups of subjects: healthy control subjects, HIV-positive subjects with peripheral neuropathy (PN) of the lower limbs, and HIV-positive patients with clinical and neurophysiological involvement of the four limbs. CSP study showed a significant increase of the latency compared to the controls both in HIV-positive cases with no impairment in the UL (p=0.006) and in patients with four-limb neuropathy (p=0.002). CSP study in HIV-positive patients with mild lower limb distal sensory polyneuropathy can detect an early involvement of the UL peripheral nerves. CSP latency increase could therefore be addressed as the first sign of PN spreading to the UL.     

Prediabetes/early diabetes-associated neuropathy predominantly involves sensory small fibres

The aim of this study was to investigate the characteristics of prediabetes (preDM) and early (<3 years) diabetes mellitus type 2 (eDM2)-associated neuropathy and the value of recently proposed diagnostic criteria for diabetic sensorimotor polyneuropathy (DSPN). A prospective case-control study in a group of 48 consecutive patients with eDM2, 16 preDM patients and 40 age- and sex-matched normoglycaemic controls was performed. Clinical and laboratory diagnostic tests were used to detect neuropathic abnormalities; these were further classified in terms of recent diagnostic criteria. Criteria for confirmed DSPN based on abnormal nerve conduction (NC) studies were met in 7 (14.6%) eDM2 patients compared to no control (p < 0.05), and the proportion significantly increased to 37.5% compared to 2.5% controls (p < 0.001), if intraepidermal nerve fibre density (IENFD) was used as an alternative criterion in addition to NC. The subclinical DSPN criteria based on NC abnormalities were met in 4.2% eDM2 patients, while the proportion of preDM and eDM2 cases with subclinical sensory small-fibre involvement documented by IENFD reached 12.5% and 22.9% compared with 2.5% controls (p = 0.005 for eDM2). The absolute IENFD values from distal leg were significantly lower in both eDM2 (p < 0.0001) and preDM patients (p = 0.005) compared to controls. Neuropathy associated with preDM/eDM2 predominantly involves sensory small fibres.     

Peripheral neuropathy in glycogen storage disease type III: Fact or myth?

Introduction: The aim of this study was to assess whether peripheral neuropathy is a feature of glycogen storage disease type IIIa (GSD IIIa) in adult patients. Methods: Medical records of a cohort of adult GSD IIIa patients who underwent electromyography (EMG) and nerve conduction studies (NCS) were reviewed, and the results were correlated with physical examination findings. Results: Sixteen patients underwent EMG and NCS; 4 complained of exercise intolerance, 1 of foot paresthesia, and 11 of muscle weakness (3 proximal, 8 distal). None of the patients had sensory deficits on clinical examination. All motor and sensory conduction velocities and sensory amplitudes were within reference ranges. EMG showed myopathic motor unit potentials in 15 of the 16 patients. Conclusions: Based on the clinical examination and the NCS and EMG results, we did not identify any peripheral nerve involvement in our adult patients diagnosed with GSD III. Muscle Nerve 53: 310–312, 2016     

Neuropathy and levodopa in Parkinson's disease: Evidence from a multicenter study

The objectives of this study were to evaluate the risk of neuropathy in patients with Parkinson's disease (PD) and to evaluate the role of levodopa exposure as a potential risk factor. A multicenter study of 330 patients with PD and 137 healthy controls with a comparable age distribution was performed. With respect to levodopa exposure, 144 patients had long exposure (≥3 years) to levodopa (LELD), 103 patients had short exposure (<3 years) to levodopa (SELD), and 83 patients had no exposure to levodopa (NOLD). Nerve function was evaluated using the reduced total neuropathy score. Right sural sensory antidromic and peroneal motor nerve conduction studies were performed by neurophysiologists who were blinded to the existence of neuropathy clinical features or PD treatment. Overall, 19.40% of patients in the LELD group, 6.80% in the SELD group, 4.82% in the NOLD group, and 8.76% in the control group were diagnosed with neuropathy (axonal, predominantly sensory). Multivariate logistic analysis indicated that the risk of neuropathy was not influenced by disease duration, severity, or sex. The risk of neuropathy increased by approximately 8% for each year of age (P < 0.001; odds ratio [OR], 1.08; 95% confidence interval [CI], 1.037‐1.128). The risk of neuropathy was 2.38 higher in the LELD group than in the control group (P = 0.022; OR, 2.38; 95% CI, 1.130‐5.014). In a comparison between patients with and without neuropathy (Student's t test), the levodopa dose was higher (P < 0.0001), serum vitamin B12 levels were lower (P = 0.0102), and homocysteine levels were higher (P < 0.001) in the patients with neuropathy. Our results demonstrate that the duration of exposure to levodopa, along with age, is the main risk factor for the development of neuropathy. Screening for homocysteine and vitamin B12 levels and clinical‐neurophysiological monitoring for neuropathy may be advisable in patients with PD who are receiving treatment with levodopa. © 2013 International Parkinson and Movement Disorder Society     

Prevalence and characteristics of peripheral neuropathy in hepatitis C virus population

OBJECTIVE: To assess the prevalence of peripheral neuropathy (PN) and its correlation with cryoglobulinemia (CG) in an unselected, untreated referral hepatitis C virus (HCV) population. PATIENTS AND METHODS: Two hundred and thirty four patients (120 women and 114 men) with untreated HCV infection were consecutively enrolled by seven Italian centres. Clinical neuropathy was diagnosed when symptoms and signs of peripheral sensory or motor involvement were present. Median, ulnar, peroneal, and sural nerves were explored in all patients and distal symmetric polyneuropathy was diagnosed when all explored nerves or both lower limb nerves were affected. Mononeuropathy and mononeuropathy multiplex were diagnosed when one nerve or two non-contiguous nerves with asymmetrical distribution were affected. Screening for CG was done in 191 unselected patients. RESULTS: Clinical signs of PN were observed in 25 of the 234 patients (10.6%). Electrophysiological PN was found in 36 (15.3%). CG was present in 56/191 patients (29.3%). The prevalence of CG increased significantly with age (p<0.001) and disease duration (p<0.05). PN was present in 12/56 (21%) patients with CG and 18/135 (13%) without CG (p=NS). PN increased significantly with age (p<0.001) and logistic regression analysis confirmed age as the only independent predictor of PN (OR 1.10 for each year; 95% CI 1.04 to 1.15; p<0.001). CONCLUSIONS: Electrophysiological examination detected subclinical neuropathy in 11 patients (4.7%). Statistical analysis showed that CG was not a risk factor for PN whereas PN prevalence increased significantly with age.     

Neurophysiological recovery 5 years after carpal tunnel release in patients with diabetes

Introduction: The long‐term results of neurophysiological recovery after carpal tunnel release in patients with diabetes have not been studied. Methods: Thirty‐five patients with diabetes and carpal tunnel syndrome (CTS) were matched with 31 patients without diabetes who had idiopathic CTS, and 27 and 30 patients, respectively, participated in this follow‐up study. Nerve conduction results at 5 years were compared with previously published results at baseline and 1 year. Results: Significant neurophysiological improvement continued from 1 to 5 years after carpal tunnel release for patients with and without diabetes. However, wrist–palm sensory conduction velocity was still abnormal for 85% and 43% of patients with and without diabetes, respectively. Although diabetes had an impact on 4 of 10 measured neurophysiological parameters, the influence of peripheral neuropathy seemed insignificant. Discussion: After carpal tunnel release, significant long‐term neurophysiological improvement is possible for patients with diabetes, and it is not influenced by the presence of peripheral neuropathy. Muscle Nerve 56 : E59–E64, 2017     

Celiac disease presenting with motor neuropathy: effect of gluten free-diet

Celiac disease is a rare cause of neuropathy that most commonly presents with symmetric distal sensory disturbances. We describe two patients with celiac disease in whom neuropathy presented unusually with progressive weakness of the limbs. In both patients a gluten-free diet induced a significant improvement of muscle strength and neurophysiological abnormalities, suggesting a direct pathogenetic role of sensitivity to gluten. Celiac disease should be considered in patients with idiopathic neuropathy even when gastrointestinal symptoms are absent.     

Mitochondrial trifunctional protein deficiency: A rare cause of adult‐onset rhabdomyolysis

Introduction: Mitochondrial trifunctional protein deficiency is a rare autosomal recessive disorder of mitochondrial fatty acid β‐oxidation that may be due to mutations in 2 different nuclear genes, HADHA and HADHB. Perturbation of this multienzyme complex compromises the oxidation of long‐chain fatty acids, which leads to multiorgan dysfunction. Childhood‐ or adolescent‐onset recurrent rhabdomyolysis is a common muscular manifestation and is preceded frequently by clinically overt peripheral neuropathy. Methods: In this report we describe a patient with late adult‐onset recurrent rhabdomyolysis. Results: Despite normal sensory examination, nerve conduction studies showed a mild axonal peripheral neuropathy. The acylcarnitine profile showed elevated long‐chain and 3‐hydroxy long‐chain acylcarnitine species. HADHA sequencing revealed known compound heterozygous mutations c.180+3A>G (p.Thr37SerfsX6) and c.1528G>C (p.Glu510Gln). During a 10‐month follow‐up period, he had no further episodes of rhabdomyolysis after appropriate dietary modifications. Conclusions: Mitochondrial trifunctional protein deficiency should be considered in patients with adult‐onset recurrent rhabdomyolysis, especially in those with either clinically overt or subclinical peripheral neuropathy. Muscle Nerve 48 : 989–991, 2013     

Subclinical diabetic neuropathy with normal conventional electrophysiological study

Background For early detection and prevention of diabetic neuropathy, it is important to identify subclinical diabetic neuropathy. Routine nerve conduction study often fails to detect early stage of neuropathy. Objectives The purpose of this study is to evaluate the clinical usefulness of electrophysiological indexes in detecting early diabetic neuropathy with no objective clinical or electrophysiological abnormalities. Materials and Methods Nerve conduction study of upper/lower limbs was investigated in 31 subclinical diabetic neuropathy patients with normal nerve conduction studies(group I), 38 clinical diabetic neuropathy patients with normal nerve conduction studies(group II) and 31 normal controls. Residual latency (RL), terminal latency index (TLI) and modified F raito (MFR) were calculated and compared among groups. Results Compared with controls, MFR of lower limbs and TLI of both upper/lower limbs were significantly decreased in both group I and II (p<0.05). RL was increased in both groups, but the difference was not statistically significant. Comparing the indexes between group I and II, there was no significant difference. Conclusions RL, TLI and MFR, which reflect distal conduction slowing, may be useful indexes to identify subclinical diabetic neuropathy. The results also suggest that electrophysiological changes that are obscured in routine nerve conduction study are present before the clinical manifestation. Presented at the American Academy of Neurology annual meeting, Miami, Florida, April 13, 2005. Received in revised form: 22 March 2006     

Peripheral neuropathy in CADASIL

Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a hereditary cerebral microangiopathy associated with mutations in the Notch 3 gene. The clinical phenotype is characterized by cerebral impairment even though typical microvascular changes are diffuse. Objective To assess peripheral neuropathy in patients with CADASIL. Patients and Methods We enrolled eleven CADASIL patients with variable phenotype including clinical signs of peripheral nerve involvement. In all patients electromyography and nerve conduction velocities were performed. Peripheral nerve biopsy was performed in three cases. Results We found sensory motor neuropathy in 7/11 patients. Nerve biopsy revealed axonal and demyelinated findings. Conclusion Our findings suggest that peripheral neuropathy may be part of the CADASIL phenotype.     

Hereditary sensory autonomic neuropathy type II: Report of two novel mutations in the FAM134B gene

Hereditary sensory autonomic neuropathy (HSAN) type II is a rare, autosomal recessive, and early onset sensory neuropathy, characterized by severe and progressive sensation impairment, leading to ulcero‐mutilating complications. FAM134B gene, also known as RETREG1 gene, mutations have been reported to be associated to HSAN‐IIB. We report four patients from two unrelated families who developed during childhood a sensory axonal neuropathy with variable severity and pronounced nociception impairment. Complications such as recurrent ulcerations, osteomyelitis, and osteonecrosis leading to distal amputation were noticed. Dysautonomia was mild or even absent in our group of patients. Additionally, either clinical or neurophysiological motor impairment was not uncommon. Presence of upper motor neuron signs was also a distinctive feature in two related patients. After extensive workup, two novel homozygous mutations in the FAM134B gene were identified. This report expands the clinical and genetic spectrum of HSAN type II and emphasizes the phenotype variability even within the same family.     

Paclitaxel plus carboplatin–induced peripheral neuropathy

Objective The current study intended to determine the incidence, severity and reversibility of paclitaxel plus carboplatin (CP)–induced peripheral neuropathy (CPPN) and to describe its clinical and electrophysiological features. Patients and methods We prospectively studied 21 adult patients scheduled to be treated with 6 courses of cumulative carboplatin plus paclitaxel (CP) regimens for a non–myeloid malignancy. They were followed–up by neurological examination and electrophysiological study during chemotherapy and 3 months after its discontinuation. The severity of neurotoxicity was assessed by means of a modified peripheral neuropathy (PNP) score. Results Evidence of CPPN was recorded in 14 of the 21 patients (66.6 %). The sensory symptoms were present in the lower limbs first and then involved the upper limbs. No statistical significance, concerning the changes from baseline to subsequent mean scores in all motor conduction parameters examined,was revealed. By contrast, comparisons of the mean changes at baseline and each of the follow–up studies showed significant decrease in all sensory action potentials examined. The mean PNP scores for patients that manifested some grade of neurotoxicity were 17.9 ± 9.8. The followup data 3 months after the discontinuation of chemotherapy showed that the CP–induced neuropathy was at least partially reversed. Conclusions CP–induced neuropathy was symmetrical, distal and predominately sensory in character, though minor to moderate motor signs were only evident in severely affected patients. Reversibility of CPinduced neuropathy was partially observed after the suspension of chemotherapy.     

Hallazgos clínico-neurofisiológicos en neuropatías hereditarias sensibles a la presión con deleción del cromosoma 17p11.2

IntroductionHereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant disorder, typically presenting with recurrent episodes of mononeuropathy in nerves susceptible to compression, with similar neurophysiological characteristics. However, other clinical and neurophysiological presentations have been reported.MethodsWe retrospectively analysed the clinical and neurophysiological characteristics of 20 patients with genetically confirmed HNPP. Sixteen patients were studied in our department between 1996 and 2016.ResultsIn addition to the typical characteristics of HNPP, we found atypical forms including recurrent positional sensory symptoms in 3 patients, chronic sensorimotor polyneuropathy in one, and non-progressive mononeuropathy in one. Onset was early in 2 patients: one at the age of 7 years, with common peroneal nerve injury, and another at birth, with brachial plexus involvement. By frequency, the main pathological findings in the nerve conduction study were: decreased sensory nerve conduction velocity in the sural (84%) and the median and superficial peroneal nerves (94%); decreased motor nerve conduction velocity in the ulnar nerve through the elbow (97%), and increased motor distal latency of the median and deep peroneal nerves (74%).ConclusionOur results confirm the clinical variability of HNPP, with the most frequent nerve conduction study findings being the generalised decrease in sensory nerve conduction velocity, in addition to motor involvement, mainly in locations susceptible to nerve compression. The nerve conduction study can detect typical, atypical, and asymptomatic cases of HNPP.     

Pilot phenotype and natural history study of hereditary neuropathies caused by mutations in the HSPB1 gene

Mutations in HSPB1 are one of the commonest causes of distal Hereditary Motor Neuropathy (dHMN). Transgenic mouse models of the disease have identified HDAC6 inhibitors as promising treatments for the condition paving the way for human trials. A detailed phenotype and natural history study of HSPB1 neuropathy is therefore required in order to inform the duration and outcome measures of any future trials. Clinical and neurophysiological data and lower limb muscle MRI were collected both prospectively and retrospectively from patients with mutations in HSPB1. The natural history was assessed by recording the weighted Charcot–Marie–Tooth Examination Score (CMTES) at annual intervals in a subset of patients. 20 patients from 14 families were recruited into the study. The average age of onset was in the 4th decade. Patients presented with a length dependent neuropathy but with early ankle plantar flexion weakness. Neurophysiology confirmed a motor neuropathy but also showed sensory nerve involvement in most patients. Cross sectional muscle MRI revealed soleus and medial gastrocnemius fat infiltration as an early signature of mutant HSPB1 disease. In this study neither semi quantitative muscle MRI, the CMTES nor neurophysiology were able to detect disease progression in HSPB1 neuropathy over 1 or 2 years. Further studies are therefore required to identify a suitable biomarker before clinical trials in HSPB1 neuropathy can be undertaken.