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.

Delayed diagnosis of spinal cord schistosomiasis in a non-endemic country: A tertiary referral centre experience.

BACKGROUND: Neuroschistosomiasis is a severe complication of schistosomiasis, triggered by the local immune reaction to egg deposition, with spinal cord involvement the most well recognised form. Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae. The rarity of this condition in returning travellers to high income countries can result in delayed diagnosis and treatment. We aimed to evaluate the diagnosis and management of neuroschistosomiasis in a UK national referral centre. MATERIALS/METHODS: A retrospective review of confirmed clinical cases of spinal schistosomiasis referred to the Hospital for Tropical Diseases, UK, between January 2016 and January 2020 was undertaken. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data collected. RESULTS: Four cases of neuroschistosomiasis were identified. The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. All patients presented with features of transverse myelitis including back pain, leg weakness, paraesthesia and urinary dysfunction. The mean time from presentation to health services to definitive treatment was 42.5 days (range 16-74 days). Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiological features on MRI spine included enhancement focused predominantly in the lower thoracic spinal cord in three cases and the conus in one patient. All patients received a minimum of three days of oral praziquantel and high dose steroids. At three-month follow-up, one patient had complete resolution of symptoms and three had residual deficit; one patient was left with urinary and faecal incontinence, another had urinary retention, and the final patient has persistent leg pains and constipation. CONCLUSION: We observed a marked delay in diagnosis of neuroschistosomiasis in a non-endemic country. We advocate undertaking a thorough travel history, early use of imaging and CSF schistosomal serology to ensure early diagnosis of neuroschistosomiasis in patients presenting with consistent symptoms. If schistosomal diagnostics are not immediately available, presumptive treatment under the guidance of a tropical medicine specialist should be considered to minimize the risk of residual disability. We advocate for consensus guidelines to be produced and reporting to be performed in a uniform way for patients with spinal schistosomiasis.

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.

Clinical characteristics, risk factors, and outcomes of POEMS syndrome: A longitudinal cohort study.

OBJECTIVE: POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin lesions) is a paraneoplastic disorder resulting in severe neurologic disability. Understanding the clinical, laboratory, neurophysiologic, and histopathologic features as well as treatment responses of POEMS will assist in more accurate and timely diagnosis, risk stratification, and effective management. METHODS: This was a retrospective longitudinal cohort study from 1998 to March 2019, with 7,184 person-months of follow-up time. Hospital databases were used to collate presenting features, investigations, therapies, and response. RESULTS: One hundred patients were included with a median follow-up time of 59 months (range, 1-252). Mean symptom onset to diagnosis was 15 months (range, 1-77), with 54% of patients initially misdiagnosed with chronic inflammatory demyelinating polyneuropathy. Median number of multisystem features at diagnosis was 7. Ninety-six (96%) presented with neuropathy, which was length-dependent in 93 (93%) and painful in 75 (75%). At diagnosis, 35% of patients were wheelchair or bedbound, with median Overall Neuropathy Limitation Score of 6, improving to 3 following treatment (p < 0.05). Five-year survival was 90% and 82% at 10 years, with 5- and 10-year progression-free survival of 65% and 53%. Nontreatment with autologous stem cell transplantation, nonhematologic response, and non-vascular endothelial growth factor response are significant risk factors in multivariate analysis to predict progression or death. Risk factors are incorporated to develop a risk score enabling stratification of high- and low-risk cases. CONCLUSIONS: POEMS syndrome is a rare multisystem condition with delayed diagnosis and poor neurologic function at presentation. Therapy has favorable outcomes. Patients at high risk of death or progression can be identified, which may allow for more active monitoring and influence management.

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.

Active neurocysticercosis at the Hospital for Tropical Diseases, London: a clinical case series.

Background: Neurocysticercosis is the commonest infectious cause of epilepsy in endemic countries, and accounts for a greater number of cases worldwide than any other single pathology. Infection is associated with long-term exposure in low-income countries, although acquisition after travel has been recognized. The standard of care in the UK is inpatient treatment with anti-helminthic drugs and steroids. Methods: The authors reviewed all cases of neurocysticercosis managed at the Hospital for Tropical Diseases in London, England, between 2001 and 2015. Active disease was defined as evidence of either viable cysts or involuting cysts with associated parenchymal inflammation. Results: Of 26 active cases, 65.4% were migrants from nine different countries; 34.6% were UK-born travellers who had visited 19 countries across South and Central America, sub-Saharan Africa, South and South-east Asia; India was the commonest country of exposure in both groups. Only 73.1% presented with seizures; two diagnoses were made through brain imaging of patients with peripheral cysticerci; 53.8% had a single cyst. Migrants were more likely to be seropositive than travellers (p=0.033). Only two patients had seizures during admission, one of whom had multiple seizures prior to diagnosis. Conclusions: Neurocysticercosis presents in a non-endemic setting in both migrants and travellers. Travellers are less likely to be sero-positive. Not all cases of neurocysticercosis present with seizures. Outpatient management could be considered for selected patients.

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.

Drug-induced neuropathies.

Although drug-induced neuropathies account for only 2-4% of referrals, their identification is important. Numerically, chemotherapy and antiretroviral drugs are the most important worldwide. Research is currently focused on elucidating pathogenic mechanisms and the earliest presymptomatic changes using neurophysiological and pharmacogenetic techniques in order to avoid the drug or make dosage changes before irreversible damage occurs. Chemoprotectants against chemotherapy-induced neuropathy are also an active area of research. This chapter focuses on the pathophysiology of drug-induced neuropathies in general, followed by detailed reviews of neuropathy due to; newer compounds such as TNF (tumor necrosis factor) α antagonists and antibiotics such as linezolid; chemotherapeutic agents, old and new, where significant progress has been made; antiretroviral drugs; and amiodarone, which is unusual in that it causes a demyelinating neuropathy. The controversial issue of statin-induced neuropathy is also reviewed.

Toxic neuropathy.

PURPOSE OF REVIEW: The aim is to review the recent publications highlighting current areas of research on the subject of toxic and drug-related neuropathies. RECENT FINDINGS: The emphasis in chemotherapy-induced peripheral neuropathy is on trying to elucidate underlying mechanisms using neurophysiological techniques, such as excitability studies. These data are also being used to identify the earliest presymptomatic changes. A large number of papers have been published on chemoprotectants, both in animal models and patients. According to the Cochrane criteria, none of the clinical trials have been shown to be effective. Pharmacogenetic techniques used on tumour and host tissue are now in the embryonic stages of trying to identify genes which may help in predicting individuals at high risk of developing drug-induced neuropathies. A review of alcohol-induced neuropathy provides evidence to suggest reclassification from a nutritional to a toxic neuropathy. Nitrous oxide, which causes myeloneuropathy, is increasingly used as a recreational drug. A red flag has been raised with the triazole antifungal agents, itraconazole and voriconazole, causing neuropathy. SUMMARY: The introduction of new neurophysiological techniques, such as excitability studies and pharmacogenetics, holds promise in elucidating the underlying mechanisms of drug-induced neuropathies. Furthermore, they will help identify the patients at highest risk of developing drug-induced neuropathies. The hope still remains of identifying chemoprotective agents - the results of animal and human studies suggest there are reasons to be optimistic. Clinicians need to aware of nitrous oxide myeloneuropathy and triazole-induced neuropathy.