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Toxic neuropathies result from exogenous substances damaging the peripheral nerves. There are numerous causes, including prescribed and recreational drugs, heavy metals, industrial agents and biological toxins. Timely recognition of these neuropathies gives better outcomes, as they usually improve or stabilise once the toxin is removed. Most toxic neuropathies are axonal, length-dependent and sensory predominant, although some have significant motor involvement or can present acutely or subacutely. Here, we outline our clinical approach and discuss the major causes of toxic neuropathy, while emphasising the clinical and neurophysiological features and the neuropathy phenotype. We also include an update on newer medications that can cause neuropathy, including immune checkpoint inhibitors and BRAF/MEK inhibitors.

BackgroundA 22-year-old woman was initially assessed in the context of a family history of distal wasting and weakness, typically with upper limb onset, then lower limb involvement. When assessed as a child her phenotype was recognised to be atypical compared to her sister, but she was thought to be affected. Ultimately the family was diagnosed with distal hereditary motor neuropathy due to a GARS mutation. However, this patient did not carry the mutation, prompting further evaluation.CaseAt age 11 the left foot was smaller with some toe clawing and cavus deformity. Left sided wasting of tibialis anterior and the posterior compartment was seen, ankle dorsiflexors were grade 3.ResultsNerve conduction studies and EMG were normal in the right leg and arms. Chronic denervation was identified in L4, L5 and S1. MRI of lumbar spine was normal. However, 2 areas of marked thickening and enhancement were seen in the left sciatic nerve in the upper thigh and a further lesion in the mid- thigh. Fascicular preservation of the nerve was felt to be strongly suggestive of a perineurioma.DiscussionThis case highlights the importance of careful phenotyping when validating novel variants in potentially causative genes.c.doherty@ucl.ac.uk

ImportanceDisease modifying treatments in Guillain-Barré syndrome (GBS) are not tailored to the different pathological subtypes. Strategies to prospectively identify sub-sets of patients with specific disease mecha- nisms and inform the use of non-standard therapies may lead to improved outcomes. We present a case series of seven patients with IgG1 subclass pan-neurofascin antibodies.ResultsAll seven patients presented with a severe, acute or sub-acute onset, predominantly motor, autoimmune neuropathy. In all but one case the neuropathy was severe enough to warrant mechanical ventilation and intensive care support. Cranial nerve deficits were universally present and autonomic dysfunction was common. Although clinically resembling GBS, the response to standard GBS therapies was poor. Four patients received the B-cell depleting therapy rituximab and showed significant and sustained functional improvement within weeks of treatment. The three remaining patients who did not receive rituximab died.Conclusions and RelevanceThese observations should lead to a re-evaluation of the benefit of nodal/paranodal antibody testing in neuropathies with acute onset, GBS-like presentations. We believe that such testing should form part of the routine diagnostic work up of such patients, and that the identifica- tion of a distinct, serologically-defined disease sub-type should prompt consideration of more targeted immunotherapy. The apparent benefit of rituximab reported here should be evaluated in a well-conduc- ted clinical trial, the design of which must consider the potentially grave outcome in pan-neurofascin antibody-positive patients receiving only standard therapies.simon.rinaldi@nhs.net

BackgroundA problem frequently faced by neurologists is the interpretation of genetic variants of unknown significance(VUS). Unlike in many muscle diseases, specific patterns of muscle involvement are not typically demonstrated on muscle MRI of inherited neuropathy patients. Imaging muscle involvement can be of assistance when assessing VUS.Case ExamplesTwo unrelated individuals with axonal CMT were identified to have a novel p.Lys554Glu DNM2 mutation. Neuromuscular MRI was consistent with the clinical findings and similar to literature descriptions, supporting the pathogenicity of this variant.Spinal Muscular Atrophy Lower Extremity Dominant (SMA-LED) due to DYNC1H1 mutations can be associ- ated with sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, with diffuse involvement at the calf level, sparing the anterior-medial muscles1 on MRI. These features were demonstrated in the imaging of a proband with SMA-LED has two mutations in DYNC1H1, one of which is novel. The novel p.His75Pro mutation was also found in his mother who has normal clinical examination and neuromuscular MRI, suggesting that the previously described p.Arg251His mutation2 was the cause of the neuromuscular phenotype in the proband.DiscussionMRI has a role supporting the diagnosis of inherited neuropathies, and in evaluating VUS.Scoto et al. Novel mutations expand the clinical spectrum of DYNC1H1-associated SMA. Neurology.2015Feb17;84:668–679Antoniadi et al. Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides high diagnostic yield.BMCMedGenet.2015Sep21;16:84.c.doherty@ucl.ac.uk

IntroductionSORD is a newly described autosomal recessive gene that is emerging as the commonest cause of autosomal recessive CMT (Charcot-Marie-Tooth disease) and hereditary motor neuropathy (HMN).MethodsWe present nine cases of SORD-related neuropathy.ResultsNine unrelated patients were found to have biallelic mutations in SORD. Eight were male (89%) and median age of assessment was 34 years (range 18–55 years). Median age of symptom onset was 15 years (range 12–18 years) and all patients initially presented with difficulty walking and/or problems involving distal lower limbs. Only one patient (11%) had sensory symptoms. 5/9 (56%) had distal upper limb weakness and all had distal lower limb weakness. Sensory examination was abnormal to at least one modality in 7/9 cases (78%). The median CMT Examination and CMT Neuropathy Scores were 6 (range 2–12) and 7.5 (range 3–14) respectively. Neurophysiology showed conduction velocities in the axonal or intermediate ranges in all cases. Clinical diagnosis was distal HMN in 5/9 (56%), CMT2 in 2/9 (22%) and CMT intermediate in 2/9 (22%).ConclusionsThe SORD phenotype is typically a slowly progressive, length-dependent motor neuropathy of onset during the second decade. Sensory symptoms are rare and sensory signs minimal.chris.record@ucl.ac.uk

Systemic amyloidosis can be hereditary or acquired. The autosomal dominant hereditary transthyretin amyloidosis and the acquired light-chain amyloidosis, the result of a plasma cell dyscrasia, are multisystem disorders with cardiovascular, autonomic and peripheral nerve involvement. There are numerous investigational modalities available to diagnose systemic amyloidosis and to assess the extent of organ involvement, but it is frequently misdiagnosed due to its heterogeneous clinical presentations and misleading investigation findings. An accurate and timely diagnosis of amyloid neuropathy can greatly impact on the outcomes for patients, especially as there will soon be new gene-silencing treatments for hereditary transthyretin amyloidosis.

Many genetic neurological diseases result from the dysfunction of single proteins. Genetic therapies aim to modify these disease-associated proteins by targeting the RNA and DNA precursors. This review provides a brief overview of the main types of genetic therapies, with a focus on antisense oligonucleotides (ASOs) and RNA interference (RNAi). We use examples of new genetic therapies for spinal muscular atrophy, Duchenne muscular dystrophy and familial amyloid polyneuropathy to highlight the different mechanisms of action of ASOs and RNAi.

A 26-year-old man was referred with facial weakness, dysarthria, dysphagia, ophthalmoparesis and severely weak and wasted legs. His symptoms had begun when aged 20 with electric shock pains and paraesthesia in both feet progressing over 6 months to the lower calves. He then developed buttock numbness and occasional faecal incontinence. By age 22, he had diffuse lower limb weakness and wasting, with difficulty standing from a seated position and frequent tripping. He became wheelchair-dependent within 3 years. Over the same time period, he developed progressive facial weakness, bilateral ptosis, slurred speech, difficulty chewing and swallowing and lost 10 kg of weight. He reported hearing difficulty, and an audiogram showed high-frequency hearing loss. Important negatives included absence of upper limb symptoms, autonomic, cardiac, respiratory or cognitive dysfunction. He was from a non-consanguineous, Lithuanian background and the eldest of three siblings. He was born following a normal pregnancy and delivery, and motor development was normal. He had sustained a left corneal abrasion with visual impairment following an accidental chemical injury aged 14. During the initial investigation of his symptoms (age 23), he was found to have a choroid plexus lesion in the fourth ventricle. It was completely resected and histology confirmed benign choroid plexus papilloma WHO grade I. Postoperative neuro-oncology discussion deemed the lesion cured. He had bilateral ptosis, bilateral facial wasting and could not close his mouth against gravity (figure 1A). Visual acuity was reduced to perception of light on the left, 6/9 on the right. There was almost complete, complex ophthalmoplegia (figure 1B) without fatiguability. Trigeminal sensation was reduced. He could not achieve eyelid closure; frontalis, buccinator and orbicularis oris were symmetrically weak. His speech was dysarthric and his tongue was weak. His uvula was central with symmetrical palatal movement, but the gag reflex was reduced. Figure 1 Clinical examination at age 26. …

A 60-year-old Nigerian man, who had lived in Europe for 30 years but had returned home frequently, presented with right frontalis muscle weakness and right ulnar nerve palsy, without skin lesions. Neurophysiology showed a generalised neuropathy with demyelinating features. Blood tests were positive for HIV, with a normal CD4 count. There was nerve thickening both clinically and on MRI. Nerve biopsy showed chronic endoneuritis and perineuritis (indicating leprosy) without visible mycobacteria. His neuropathy continued to deteriorate (lepra reaction) before starting treatment with WHO multidrug therapy, highly active antiretroviral therapy and corticosteroids. There are 10 new cases of leprosy diagnosed annually in the UK. Coinfection with HIV is rare but paradoxically does not usually adversely affect the outcome of leprosy or change treatment. However, permanent nerve damage in leprosy is common despite optimal therapy. Leprosy should be considered in patients from endemic areas who present with mononeuritis multiplex.

Immune checkpoint inhibitors (ICI), monoclonal antibodies enhancing T cell responses against tumour cells, have revolutionised the treatment of cancers such as advanced melanoma, leading to enhanced survival. Their action, however, is not tumour-specific, and patients can develop multisystem immune related adverse events (irAE). Neurological irAEs have been reported in 1–14% of patients, depending upon the ICI used, and can affect any part of the neuro-axis. A recent case series from the Royal Marsden Hospital (RMH) identified 10 patients with neurotoxicity following ICI for advanced melanoma between 2010–15, specifically neuropathy (6), plexopathy (1) and aseptic meningitis (3). Exactly how neurological injury occurs, whether cell-, cytokine- or antibody-mediated, is unknown.We present early data from a newly established collaboration with RMH, aiming to clinically characterize these patients, and identify the cause of neurological injury. To date, we have advised on patients (age range 53–80) with myositis, Guillain-Barré (GBS)-like neuropathy, plexopathy, aseptic meningitis, and encephalitis following ICI (ipilimumab and/or nivolumab) for advanced melanoma. Features common to these patients include their subacute onset, time from ICI administration, and steroid responsiveness (including in GBS-like cases). The incidence of neurological irAEs following ICI will rise with increasing use, and is therefore of concern to practicing neurologists.

CaseA 20-year-old female had symptom onset age 7 of bilateral foot drop and distal lower limb atrophy. Nerve conduction studies demonstrated a length dependent axonal motor and sensory neuropathy. At 16 her vision deteriorated to 3/36 right, 6/60 left. Visual evoked potentials were borderline compatible with bilateral optic atrophy. Metabolic and structural causes were excluded.ExaminationAt age 18 examination demonstrated bilateral foot drop and a positive knee bob sign. There was asymmetrical distal limb atrophy. Fundi were pale. Reflexes were brisk in upper limbs and knees with absent ankles and mute plantars.ResultsThe 56-gene Bristol axonal neuropathy panel revealed a non-pathogenic TRPV4 mutation. Mutations in OPA1, OPA3, POLG, ATPase 6 and 8 were not identified. Exome sequencing in the research setting demonstrated compound heterozygous SLC25A46 mutations. One mutation was confirmed in each of her parents.DiscussionMutations in SLC25A46 are associated with spectrum of disorders encompassing pontocerebellar hypoplasia (including lethal congenital cases), Leigh Syndrome, Progressive myoclonic ataxia with optic atrophy and neuropathy, and hereditary motor and sensory neuropathy type 6B, sometimes with associated features such as cerebellar ataxia and spasticity. We present a case of CMT2 with optic atrophy due to heterozygous mutations and discuss the literature.

Charcot-Marie-Tooth (CMT) disease and related disorders encompass a phenotypically and genetically heterogeneous group of disorders. Our diagnostic approach to CMT has been revolutionised by the advent and use of next-generation sequencing (NGS) technologies with applications in CMT gene panels, whole exome and whole genome sequencing, mitochondrial sequencing and high-throughput transcriptome sequencing.We present the up to date evidence pertaining to the application of these technologies in CMT diagnostics and also discuss what challenges they bring in relation to variant interpretation. Phenotypic, genetic and bioinformatic evidence should be used to overcome these challenges, and we discuss how setting a maximum credible population allele frequency for pathogenic variants in dominant and recessive CMT genes is crucial in filtering efficiently NGS-derived variants.Whole genome sequencing as a single molecular genetic test is very appealing and, in the context of the 100,000 Genome Project, we suggest how its application into CMT clinical practice can happen with a balance between improved diagnostic yield and burden of variant analysis.

Background Charcot–Marie–Tooth disease (CMT) is a clinically and genetically heterogeneous group of diseases with approximately 45 different causative genes described. The aims of this study were to determine the frequency of different genes in a large cohort of patients with CMT and devise guidelines for genetic testing in practice. Methods The genes known to cause CMT were sequenced in 1607 patients with CMT (425 patients attending an inherited neuropathy clinic and 1182 patients whose DNA was sent to the authors for genetic testing) to determine the proportion of different subtypes in a UK population. Results A molecular diagnosis was achieved in 62.6% of patients with CMT attending the inherited neuropathy clinic; in 80.4% of patients with CMT1 (demyelinating CMT) and in 25.2% of those with CMT2 (axonal CMT). Mutations or rearrangements in PMP22 , GJB1 , MPZ and MFN2 accounted for over 90% of the molecular diagnoses while mutations in all other genes tested were rare. Conclusion Four commonly available genes account for over 90% of all CMT molecular diagnoses; a diagnostic algorithm is proposed based on these results for use in clinical practice. Any patient with CMT without a mutation in these four genes or with an unusual phenotype should be considered for referral for an expert opinion to maximise the chance of reaching a molecular diagnosis.

BackgroundABN immunoglobulin (Ig) guidelines advise routine FBC and U and E monitoring with every treatment episode and screening for IgA deficiency. AimsWe audited compliance in inflammatory neuropathy patients on longterm treatment in two UK Neurology departments. We looked for evidence of clinically relevant haematological or AKI Ig-related events.MethodsData was collected from Nov 2015 to Nov 2017. Accepted definitions for clinically and/or biochemically significant haemolysis, neutropenia, thrombocytopenia and AKI were used.Results1919 treatment episodes in 90 patients were analysed. Mean age (SD)=57.6 (14.4)years, 69.1% male, 74% CIDP (26% MMN), 94% IVIg (6% SCIg). Mean dose=1.57 (0.74) g/kg/month or 97.1 (37.3) g/infusion. No clinically significant episodes of haemolysis, neutropenia, thrombocytopenia or AKI occurred in relation to Ig treatment. An asymptomatic drop of >10 g/L Hb occurred in 68/1919 episodes in 38 individuals (3.5%); mean reduction 17.7 g/L, lowest Hb 99 g/L. Two patients with CRF (stage 3) received 28 (IV) and 104 (SC) infusions respectively without impact on eGFR. Two individuals with relative IgA deficiency (0.38 g/L, 0.4 g/L) received 16 infusions over 1.5 years without complications.ConclusionsNo clinically significant Ig-related events were identified in this representative cohort. We suggest annual screening or clinically indicated testing as safe and more appropriate in longterm IVIg use.

Background Observational data suggest intravenous immunoglobulin (IVIg) increases risk of thromboembolic events (TEE). Traditional vascular risk factors influence individual risk but the pro-coagulant mechanism of IVIg is not understood. Aims To ascertain frequency of and risk factors for arterial (ATE) and venous thromboembolic events (VTE) in neuromuscular patients receiving regular IVIg. Methods Diagnosis, dose, frequency, vascular risk factors, pre and post-treatment IgG levels and plasma viscosity were recorded by retrospective casenote review. Results 112 patients received a mean (S.D) dose of 1.6 (1.2)g/kg/month, range:0.2–6.5 g/kg/month; at a mean (S.D.) interval of 4.4 (3.0) weeks, range:1–18 weeks for CIDP (58.9%), MMN (36.6%), sensory neuropathy/neuronopathy (3.7%) and myositis (0.9%). Twelve TEEs were documented during the 30 month study period (January ‘14-June ‘16); 6 MIs, 2 CVAs, and individual occurrences of TIA, DVT, PE, SVC obstruction due to central line thrombosis. TEE incidence (95% C.I.)=53.6 (30.9, 91.3)/1000 patient-years; ATE incidence=35.7 (18.2, 68.9)/1000 patient-years; VTE=22.3 (9.6–51.2)/1000 patient-years. Age (p=0.005) and QRISK2 score (p=0.01) were higher in those who had an event. There was no difference in dose/kg/month (p=0.66), or dose/g/day (p=0.28). Conclusions TEE incidence in this cohort was higher than population-based rates (TEE=7.6–7.7/1000; ATE=4.4–6.5/1000 and VTE=1.2/1000 patient-years). This analysis suggests reduction of daily dose or rate of infusion does little to mediate risk.

A 60 year old Nigerian man with diabetes who has lived in Europe for 30 years but regularly revisits Nigeria, presented with 6 months of numbness and weakness in all four limbs and recent right facial weakness. Examination revealed partial right facial and left ulnar nerve palsies with areflexia but no skin lesions. Neurophysiology showed multifocal mixed sensory-motor neuropathy with demyelinating features and prominent facial nerve involvement. He was found to be HIV positive. Subsequent examination revealed peripheral nerve thickening confirmed on limb MRI. Nerve biopsy showed chronic endoneuritis and perineuritis, but no organisms were seen or cultured. He was diagnosed with pure neural borderline tuberculoid leprosy and treated with WHO leprosy multidrug therapy and HAART. This case illustrates the complexities of HIV-leprosy coinfection. Perhaps surprisingly leprosy infection is only subtly affected by HIV coinfection. Both HIV and leprosy cause neuropathies but coinfection is fortunately rare particularly in the UK. Here clinically grossly thickened nerves and neuropathological inflammatory changes in a patient from prevalent area strongly favoured the diagnosis of leprosy. It is not clear why HIV has such differing interactions between M.leprae and M.tuberculosis. Leprosy remains a major treatable diagnosis we need to keep reminding ourselves about.

We report the case of a 62 year old gentleman with sensorineuronal hearing loss beginning in the second decade. At the age of 40 he collapsed and was unable to walk more than a few metres. He was admitted to hospital and diagnosed with a motor neuron disease on the basis of an EMG. Examination at the time revealed bilateral deafness, facial weakness, dysphagia, dysphonia and both proximal and distal weakness.The family history was remarkable for two sisters who died of a similar condition in the second decade. In view of the combination of sensory neuronal deafness and a motor neuronopathy, a diagnosis of Brown Violetta Van Laera (BVVL) syndrome was made.A PEG tube was inserted and the patient was discharged to a nursing home for palliation. After several months, our patient discharged himself, reintroduced thickened fluids resulting in removal of the PEG tube. His clinical condition has continued to improve although he intermittently requires a wheelchair.Genetic testing of the SLC52A3 gene revealed two missense mutations (p.Glu36Lys and p.Val413Ala) confirming the clinical diagnosis of BVVL. SLC52A3 encodes a riboflavin transporter and in case series, riboflavin supplementation has halted or reversed the disease.

Patients with Charcot-Marie-Tooth (CMT) disease most commonly have a slowly progressive neuropathy where ankle dorsiflexion weakness is much more prominent than ankle plantar flexion weakness. The eventual involvement of the ankle plantar flexors has major functional consequences for patients as they lose the ability to stand still. We have found the knee bob sign whereby both knees bob up and down when standing still to be a reliable marker of ankle plantar flexion weakness in CMT.

We present the case of a 47-year-old woman with encephalopathy, ataxia and oscillopsia diagnosed with opsoclonus myoclonus syndrome (OMS). In adults, OMS in the context of encephalopathy is commonly paraneoplastic. A CT of the chest, abdomen and pelvis and a gastroscopy were performed and were normal. A fluorodeoxyglucose positron emission tomography CT scan demonstrated increased uptake in the mid-oesophagus and an endoscopic ultrasound examination demonstrated intramural thickening of 5 mm with no epithelial lesion. The patient was treated with three courses of intravenous immunoglobulin (IvIg) with improvement in her symptoms. A year following the initial presentation a repeat endoscopic examination demonstrated an ulcerated oesophageal carcinoma with regional lymph node involvement. The patient was treated with neo adjuvant chemotherapy prior to oesophagectomy. The patient's symptoms resolved within 6 months of tumour resection without the need for further IvIg. Unfortunately, after a further 6 months the patient developed liver metastases and died.

During the last decade, mutations in three small heat shock proteins (Hsps) HSPB1, HSPB3 and HSPB8 have been identified as causative of distal hereditary motor neuropathy (dHMN). Hsps are a ubiquitously expressed family of molecular chaperones with versatile functions that include refolding of misfolded proteins. Hsp70, the archetypal ATP-dependent Hsp, binds misfolded proteins with weak affinity. J domain (HSP40) proteins bind to HSP70, thereby increasing its protein binding and refolding capacity. In 2008, an autosomal recessive form of dHMN was described due to homozygous mutations in the Hsp40 gene, HSJ1. We have preliminary evidence that HSJ1 knockout mice develop de novo motor neuron (MN) degeneration, providing a model for this new form of dHMN. In this study, MNs from HSJ1 +/+ and HSJ1 −/− mice have been examined in vitro in primary MN cultures. We examined the effects of HSJ1 ablation on the stress response in MNs. We found that HSJ−/− MNs display an enhanced ER stress response compared to +/+ MNs in response to heat shock. Thus, HSJ−/− cells upregulate the expression of ER stress markers, such as the ER resident heat shock protein BiP. We also examined functional markers of MN function including axonal transport but found that the transport of mitochondria in HSJ −/− cells was unaffected. Thus, HSJ −/− primary motoneurons display some of the pathological hallmarks of dHMN and therefore can be a suitable model to study the mechanism of disease.