Toxic neuropathies.

PURPOSE OF REVIEW: Immunotherapy has had a significant impact on the treatment of an increasing number of cancers as well as in inflammatory, rheumatological and gastroenterological conditions.Recreational nitrous oxide use is now a global epidemic. Linezolid is now recommended for the treatment of drug-resistant tuberculosis (TB); neuropathy is a significant cause of morbidity.Global warming will result in increasing toxin exposure, such as ciguatera, in previously unaffected areas. RECENT FINDINGS: With increasing experience, the pathophysiology underlying the neuropathic complications of these drugs has become clear with guidelines now available, for the complications of immune check-point inhibitors and nitrous oxide toxicity. The optimum dose and duration of treatment for resistant TB with regimens, including linezolid, has been ascertained. SUMMARY: Although neuropathic complications with immunotherapy are relatively rare, it is essential that they are recognized and treated early. Nitrous oxide toxicity should be in the differential diagnosis for all patients, particularly those of younger age, presenting with a neuropathy or myleo-neuropathy. Ciguatera toxicity is under recognized and its geographical spread will increase due to global warming. Further research is necessary on the mechanisms and treatment of both acute and chronic effects, which at present, are only symptomatic.

RFC1 expansions are a common cause of idiopathic sensory neuropathy.

After extensive evaluation, one-third of patients affected by polyneuropathy remain undiagnosed and are labelled as having chronic idiopathic axonal polyneuropathy, which refers to a sensory or sensory-motor, axonal, slowly progressive neuropathy of unknown origin. Since a sensory neuropathy/neuronopathy is identified in all patients with genetically confirmed RFC1 cerebellar ataxia, neuropathy, vestibular areflexia syndrome, we speculated that RFC1 expansions could underlie a fraction of idiopathic sensory neuropathies also diagnosed as chronic idiopathic axonal polyneuropathy. We retrospectively identified 225 patients diagnosed with chronic idiopathic axonal polyneuropathy (125 sensory neuropathy, 100 sensory-motor neuropathy) from our general neuropathy clinics in Italy and the UK. All patients underwent full neurological evaluation and a blood sample was collected for RFC1 testing. Biallelic RFC1 expansions were identified in 43 patients (34%) with sensory neuropathy and in none with sensory-motor neuropathy. Forty-two per cent of RFC1-positive patients had isolated sensory neuropathy or sensory neuropathy with chronic cough, while vestibular and/or cerebellar involvement, often subclinical, were identified at examination in 58%. Although the sensory ganglia are the primary pathological target of the disease, the sensory impairment was typically worse distally and symmetric, while gait and limb ataxia were absent in two-thirds of the cases. Sensory amplitudes were either globally absent (26%) or reduced in a length-dependent (30%) or non-length dependent pattern (44%). A quarter of RFC1-positive patients had previously received an alternative diagnosis, including Sjögren's syndrome, sensory chronic inflammatory demyelinating polyneuropathy and paraneoplastic neuropathy, while three cases had been treated with immune therapies.

Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome.

Reports of Guillain-Barré syndrome (GBS) have emerged during the Coronavirus disease 2019 (COVID-19) pandemic. This epidemiological and cohort study sought to investigate any causative association between COVID-19 infection and GBS. The epidemiology of GBS cases reported to the UK National Immunoglobulin Database was studied from 2016 to 2019 and compared to cases reported during the COVID-19 pandemic. Data were stratified by hospital trust and region, with numbers of reported cases per month. UK population data for COVID-19 infection were collated from UK public health bodies. In parallel, but separately, members of the British Peripheral Nerve Society prospectively reported incident cases of GBS during the pandemic at their hospitals to a central register. The clinical features, investigation findings and outcomes of COVID-19 (definite or probable) and non-COVID-19 associated GBS cases in this cohort were compared. The incidence of GBS treated in UK hospitals from 2016 to 2019 was 1.65-1.88 per 100 000 individuals per year. GBS incidence fell between March and May 2020 compared to the same months of 2016-19. GBS and COVID-19 incidences during the pandemic also varied between regions and did not correlate with one another (r = 0.06, 95% confidence interval: -0.56 to 0.63, P = 0.86). In the independent cohort study, 47 GBS cases were reported (COVID-19 status: 13 definite, 12 probable, 22 non-COVID-19). There were no significant differences in the pattern of weakness, time to nadir, neurophysiology, CSF findings or outcome between these groups. Intubation was more frequent in the COVID-19 affected cohort (7/13, 54% versus 5/22, 23% in COVID-19-negative) attributed to COVID-19 pulmonary involvement. Although it is not possible to entirely rule out the possibility of a link, this study finds no epidemiological or phenotypic clues of SARS-CoV-2 being causative of GBS. GBS incidence has fallen during the pandemic, which may be the influence of lockdown measures reducing transmission of GBS inducing pathogens such as Campylobacter jejuni and respiratory viruses.

Dramatic clinical response to ultra-high dose IVIg in otherwise treatment resistant inflammatory neuropathies.

BACKGROUND: Intravenous immunoglobulin (IVIg) has short and long-term efficacy in both chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy with conduction block (MMNCB). There is potential for under and over-treatment if trial regimens are strictly adhered to in clinical practice where titrating dose to clinical response is recommended. METHODS: We report the response to high-dose IVIg (>2 g/kg/6 weeks) in a subgroup of patients with definite CIDP or MMNCB who were unresponsive to 'usual' dosing. IVIg frequency and dosing was determined for each individual by subjective and objective outcome measures for impairment, grip strength, and activity and participation. RESULTS: Six patients (three with chronic inflammatory demyelinating polyneuropathy (CIDP), three with MMN) were included. Two patients (one CIDP and one MMNCB) returned to full-time work on fractionated IVIg doses of 5 g/kg/month and 9 g/kg/month. Patient three (CIDP) failed numerous other immunosuppressants but responded to short-term fractionated 4 g/kg/month of IVIg. Patient four has severe, refractory, childhood-onset CIDP, remains stable but dependent currently on 6.9 g/kg/month of IVIg. Patients five and six, both with MMNCB, required short term 4.5-5 g/kg/month to recover significant bilateral hand strength. No IVIg-related adverse events occurred in any individual. CONCLUSIONS: These six cases demonstrate the safety and effectiveness of a treatment approach that includes individualised but evidence-based clinical assessment and, when necessary, high-doses of IVIg to restore patients' strength and ability to participate in activities of daily activities. Careful patient selection is important.

An approach to assessing immunoglobulin dependence in chronic inflammatory demyelinating inflammatory polyneuropathy.

Regular immunoglobulin treatment maintains strength and prevents disability in chronic inflammatory demyelinating polyneuropathy (CIDP). Discrimination between active disease, with optimum symptom control on treatment, and disease in remission not requiring treatment is essential for therapeutic decision-making and clinical trial design. To compare treatment cessation versus gradual dose reduction in assessment of disease activity (immunoglobulin dependence) in a cohort of stable CIDP patients on maintenance immunoglobulin treatment. An approach to restabilization of immunoglobulin-dependent individuals is also described. Retrospective review of IVIg cessation or gradual reduction in 33 patients with stable CIDP on maintenance IVIg. Demographic, clinical and treatment data were collected; clinical monitoring data were recorded prospectively as part of routine clinical practice. A total of 21/33 patients (62.6%) were immunoglobulin dependent, (gradual dose reduction:11, cessation:10). Mean change in Inflammatory Rasch-built Overall Disability Scale (I-RODS) (-15, standard deviation [SD] 16) and Medical Research Council Sum Score (MRC-SS) (-4, SD: 4) was clinically and statistically meaningful (>75% exceeded minimum clinically important differences). Mean time to deterioration was 5.0 (SD: 4.6) months, shorter in cessation group (3.5 months) than gradual reduction group (8.8 months). All patients were restabilized to previous baseline (M: 2.3, SD: 4.3 months), half within 1 week of retreatment. A total of 12 patients (37.4%) remained stable without treatment for ≥2 years (remission). A total of 50% were identified rapidly by cessation and 50% by gradual dose reduction requiring mean 4.8 (SD: 2.8) years follow-up and costing £113 623 per person Ig spend. No predictors of disease activity were identified. A treatment cessation trial with close clinical monitoring is an efficient, cost-effective and safe approach to assessing disease activity in CIDP.

Peripheral nerve neurolymphomatosis: Clinical features, treatment, and outcomes.

This series characterises nine patients with neurohistopathologically proven peripheral nerve neurolymphomatosis. A search of the hospital neuropathology database from 2002 to 2019 identified biopsy proven cases. Clinical data, investigation modalities, treatments, and outcomes were collated. Median age at neuropathy onset was 47 y, the neuropathy commonly as the initial lymphoma disease manifestation. Most (8/9) presented with painful asymmetrical sensory disturbance, with additional cranial nerve involvement in three. Neurophysiology typically demonstrated multiple axonal mononeuropathies. Cerebrospinal fluid protein was often raised (6/8). Magnetic resonance imaging suggested peripheral nerve infiltration in 6/9 and positron emission tomography CT in 4/9. Bone marrow biopsy was abnormal in 6/8. Treatment involved systemic or intrathecal chemotherapy and radiotherapy. Median survival was 23 mo. Neurolymphomatosis is a rare but important cause of neuropathy, particularly in those lacking systemic evidence of lymphoma as correct aggressive treatment can prolong survival. Nerve biopsy is essential to classify lymphoma type and rule out alternatives.

Optical coherence tomography in autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a rare neurodegenerative disorder caused by mutations in the SACS gene. Thickened retinal nerve fibres visible on fundoscopy have previously been described in these patients; however, thickening of the retinal nerve fibre layer as demonstrated by optical coherence tomography appears to be a more sensitive and specific feature. To test this observation, we assessed 292 individuals (191 patients with ataxia and 101 control subjects) by peripapillary time-domain optical coherence tomography. The patients included 146 with a genetic diagnosis of ataxia (17 autosomal spastic ataxia of Charlevoix-Saguenay, 59 Friedreich's ataxia, 53 spinocerebellar ataxias, 17 other genetically confirmed ataxias) and 45 with cerebellar ataxia of unknown cause. The controls included 13 asymptomatic heterozygotes for SACS mutations and 88 unaffected controls. The cases with autosomal recessive spastic ataxia of Charlevoix-Saguenay included 11 previously unpublished SACS mutations, of which seven were nonsense and four missense mutations. Most patients were visually asymptomatic and had no previous history of ophthalmic complaints and normal or near normal visual test results. None had visual symptoms directly attributable to the retinal changes. Twelve of the 17 cases (70.6%) had thickened retinal nerve fibres visible on fundoscopy. All patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay had thickening of the peripapillary retinal nerve fibre layer on optical coherence tomography, whereas all the remaining cases and controls except one showed normal or reduced average peripapillary retinal nerve fibre layer thickness on optical coherence tomography. We propose a cut-off value of 119 µm in average peripapillary retinal nerve fibre layer thickness, which provides a sensitivity of 100% and specificity of 99.4% amongst patients affected with ataxia. This is the largest cohort of patients with this condition to undergo systematic evaluation by optical coherence tomography. This is a useful tool in identifying cases of autosomal recessive spastic ataxia of Charlevoix-Saguenay from other causes of ataxia. Visualization of thickened retinal fibres by direct fundoscopy is less sensitive. We therefore advocate the use of this technique in the assessment of possible cases of this condition.

Can compressive thoracic cord lesions cause a pure lower motor neurone syndrome?

Compressive lesions of the spinal cord usually cause a syndrome of upper motor neurone weakness, spasticity and sensory loss below the level of the lesion. It has long been recognised that compressive cervical cord lesions may present as isolated lower motor neurone weakness of the upper limbs, a syndrome termed cervical spondylotic amyotrophy. We describe two patients presenting with isolated lower motor neurone weakness of the lower limbs in association with a compressive cord lesion at T11/12, a condition we have termed thoracic spondylotic amyotrophy.

'Montezuma's revenge': neurological disorders in the returning traveller.

'The world is a book and those who do not travel read only one page'.Augustine of Hippo - Latin philosopher and theologian.Neurological presentations are seen in about 1.5%-2.0% of returning travellers seeking medical attention, and may pose a particular challenge to diagnose and treat. These may be severe and life threatening, such as meningoencephalitic illnesses or inflammatory radiculoneuropathy (Guillain-Barré-like) syndromes requiring intensive care support. It is essential not to miss the potentially treatable and common diseases such as malaria, which can be lethal if undiagnosed. Herpes simplex virus remains the most common cause of encephalitis in returning travellers to the UK. Furthermore, common bacterial conditions such as pneumococcal meningitis may be associated with different resistance patterns globally, and this must be taken into account in treatment decisio.ns. This review provides a clinical approach, illustrated with a range of cases, and suggestions where to get further management advice.

AL amyloidosis presenting with limb girdle myopathy.

An elderly Caucasian man presented with a 10-month history of proximal myopathy and dysphagia. His serum creatine kinase (CK) was elevated at 877 U/L (normal 40-320) and electromyography confirmed a myopathic process. Blood and urine tests suggested myeloma; bone marrow examination showed 30% plasma cells and stained positive for amyloid. The muscle biopsy was initially reported as normal but in the light of the bone marrow report, the biopsy specimen was stained for amyloid, which was positive. We diagnosed systemic amyloidosis causing a myopathy and have started treatment for myeloma.

Genetic and clinical characteristics of NEFL-related Charcot-Marie-Tooth disease.

OBJECTIVES: To analyse and describe the clinical and genetic spectrum of Charcot-Marie-Tooth disease (CMT) caused by mutations in the neurofilament light polypeptide gene (NEFL). METHODS: Combined analysis of newly identified patients with NEFL-related CMT and all previously reported cases from the literature. RESULTS: Five new unrelated patients with CMT carrying the NEFL mutations P8R and N98S and the novel variant L311P were identified. Combined data from these cases and 62 kindreds from the literature revealed four common mutations (P8R, P22S, N98S and E396K) and three mutational hotspots accounting for 37 (55%) and 50 (75%) kindreds, respectively. Eight patients had de novo mutations. Loss of large-myelinated fibres was a uniform feature in a total of 21 sural nerve biopsies and 'onion bulb' formations and/or thin myelin sheaths were observed in 14 (67%) of them. The neurophysiological phenotype was broad but most patients with E90K and N98S had upper limb motor conduction velocities <38 m/s. Age of onset was ≤3 years in 25 cases. Pyramidal tract signs were described in 13 patients and 7 patients were initially diagnosed with or tested for inherited ataxia. Patients with E90K and N98S frequently presented before age 3 years and developed hearing loss or other neurological features including ataxia and/or cerebellar atrophy on brain MRI. CONCLUSIONS: NEFL-related CMT is clinically and genetically heterogeneous. Based on this study, however, we propose mutational hotspots and relevant clinical-genetic associations that may be helpful in the evaluation of NEFL sequence variants and the differential diagnosis with other forms of CMT.

Leprosy in a patient infected with HIV.

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.

Progressive weakness and intermittent low-grade fever in a Libyan man.

We present a diagnostically challenging case of a 61-year-old man presenting with progressive weakness and intermittent low-grade fever.

Pathologic RFC1 repeat expansions do not contribute to the development of inflammatory neuropathies.

Biallelic expansions of the AAGGG repeat in the replication factor C subunit 1 (RFC1) have recently been described to be responsible for cerebellar ataxia, peripheral neuropathy and vestibular areflexia syndrome. This genetic alteration has also allowed genetic classification in up to one-third of cases with idiopathic sensory neuropathy. Here, we screened a well-characterized cohort of inflammatory neuropathy patients for RFC1 repeat expansions to explore whether RFC1 was increased from background rates and possibly involved in the pathogenesis of inflammatory neuropathy. A total of 259 individuals with inflammatory neuropathy and 243 healthy controls were screened for the AAGGG repeat expansion using short-range flanking PCR and repeat-primed PCR. Cases without amplifiable PCR product on flanking PCR and positive repeat-primed PCR were also tested for the mostly non-pathogenic expansions of the AAAGG and AAAAG repeat units. None of the patients showed biallelic AAGGG expansion of RFC1, and their carrier frequency for AAGGG was comparable with controls [n = 27 (5.2%) and n = 23 (4.7%), respectively; P > 0.5]. Data suggest that the pathologic expansions of AAGGG repeats do not contribute to the development of inflammatory neuropathies nor lead to misdiagnosed cases. Accordingly, routine genetic screening for RFC1 repeat expansion is not indicated in this patient population.