Climate change and disorders of the nervous system.

Anthropogenic climate change is affecting people's health, including those with neurological and psychiatric diseases. Currently, making inferences about the effect of climate change on neurological and psychiatric diseases is challenging because of an overall sparsity of data, differing study methods, paucity of detail regarding disease subtypes, little consideration of the effect of individual and population genetics, and widely differing geographical locations with the potential for regional influences. However, evidence suggests that the incidence, prevalence, and severity of many nervous system conditions (eg, stroke, neurological infections, and some mental health disorders) can be affected by climate change. The data show broad and complex adverse effects, especially of temperature extremes to which people are unaccustomed and wide diurnal temperature fluctuations. Protective measures might be possible through local forecasting. Few studies project the future effects of climate change on brain health, hindering policy developments. Robust studies on the threats from changing climate for people who have, or are at risk of developing, disorders of the nervous system are urgently needed.

The Queen Square Encephalitis Multidisciplinary Team Meeting - experience over three years, pre and post the COVID-19 pandemic.

BACKGROUND: Patients with suspected encephalitis continue to represent a diagnostic and therapeutic challenge, even in highly resourced centres. In February 2018, we set up a monthly in-person multidisciplinary team meeting (MDT). We describe the experience and outcomes of the MDT over three years. METHODS: A retrospective analysis was performed to summarise patient demographics, MDT outcomes and final diagnoses. RESULTS: Over the three-year period, 324 discussions of 238 patients took place. Cases were diverse; approximately 40% related to COVID-19 or brain infection, 40% autoimmune or other inflammatory disorders and 20% encephalitis mimics or uncertain aetiologies. Feedback from an online survey sent to referring teams and attendees highlighted the value of the MDT; 94% reported the discussion was useful and 69% reported resulting change in patient management. CONCLUSIONS: Multidisciplinary input is crucial in this challenging area, ensuring that all diagnostic avenues are explored and opening doors to novel diagnostics and therapeutics. It also supports clinicians dealing with unwell patients, including in centres where less specialist input is available, and when decisions have to be made where there is little or no evidence base.

Pathophysiology, diagnosis, and management of neuroinflammation in covid-19.

Although neurological complications of SARS-CoV-2 infection are relatively rare, their potential long term morbidity and mortality have a significant impact, given the large numbers of infected patients. Covid-19 is now in the differential diagnosis of a number of common neurological syndromes including encephalopathy, encephalitis, acute demyelinating encephalomyelitis, stroke, and Guillain-Barré syndrome. Physicians should be aware of the pathophysiology underlying these presentations to diagnose and treat patients rapidly and appropriately. Although good evidence has been found for neurovirulence, the neuroinvasive and neurotropic potential of SARS-CoV-2 is limited. The pathophysiology of most complications is immune mediated and vascular, or both. A significant proportion of patients have developed long covid, which can include neuropsychiatric presentations. The mechanisms of long covid remain unclear. The longer term consequences of infection with covid-19 on the brain, particularly in terms of neurodegeneration, will only become apparent with time and long term follow-up.

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.

Clinical Reasoning: Progressive Hemiparesis and White Matter Abnormalities in an HIV-Negative Patient.

A 61-year-old man from India was admitted to hospital after being found unresponsive by the roadside. He was treated with dual-antiplatelet therapy for an acute coronary syndrome. Ten days into admission, he had mild left-sided face, arm, and leg weakness, which progressed significantly over the next 2 months in association with progressive white matter abnormalities on brain MRI. In this case study, we outline our clinical reasoning, which led to the detection of a rare underlying cause of a devastating neurologic disease. We also present our approach to treatment, which achieved a sustained clinical and radiologic response.

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.

Serum and cerebrospinal fluid biomarker profiles in acute SARS-CoV-2-associated neurological syndromes.

Preliminary pathological and biomarker data suggest that SARS-CoV-2 infection can damage the nervous system. To understand what, where and how damage occurs, we collected serum and CSF from patients with COVID-19 and characterized neurological syndromes involving the PNS and CNS (n = 34). We measured biomarkers of neuronal damage and neuroinflammation, and compared these with non-neurological control groups, which included patients with (n = 94) and without (n = 24) COVID-19. We detected increased concentrations of neurofilament light, a dynamic biomarker of neuronal damage, in the CSF of those with CNS inflammation (encephalitis and acute disseminated encephalomyelitis) [14 800 pg/ml (400, 32 400)], compared to those with encephalopathy [1410 pg/ml (756, 1446)], peripheral syndromes (Guillain-Barré syndrome) [740 pg/ml (507, 881)] and controls [872 pg/ml (654, 1200)]. Serum neurofilament light levels were elevated across patients hospitalized with COVID-19, irrespective of neurological manifestations. There was not the usual close correlation between CSF and serum neurofilament light, suggesting serum neurofilament light elevation in the non-neurological patients may reflect peripheral nerve damage in response to severe illness. We did not find significantly elevated levels of serum neurofilament light in community cases of COVID-19 arguing against significant neurological damage. Glial fibrillary acidic protein, a marker of astrocytic activation, was not elevated in the CSF or serum of any group, suggesting astrocytic activation is not a major mediator of neuronal damage in COVID-19.

Spectrum, risk factors and outcomes of neurological and psychiatric complications of COVID-19: a UK-wide cross-sectional surveillance study.

SARS-CoV-2 is associated with new-onset neurological and psychiatric conditions. Detailed clinical data, including factors associated with recovery, are lacking, hampering prediction modelling and targeted therapeutic interventions. In a UK-wide cross-sectional surveillance study of adult hospitalized patients during the first COVID-19 wave, with multi-professional input from general and sub-specialty neurologists, psychiatrists, stroke physicians, and intensivists, we captured detailed data on demographics, risk factors, pre-COVID-19 Rockwood frailty score, comorbidities, neurological presentation and outcome. A priori clinical case definitions were used, with cross-specialty independent adjudication for discrepant cases. Multivariable logistic regression was performed using demographic and clinical variables, to determine the factors associated with outcome. A total of 267 cases were included. Cerebrovascular events were most frequently reported (131, 49%), followed by other central disorders (95, 36%) including delirium (28, 11%), central inflammatory (25, 9%), psychiatric (25, 9%), and other encephalopathies (17, 7%), including a severe encephalopathy (n = 13) not meeting delirium criteria; and peripheral nerve disorders (41, 15%). Those with the severe encephalopathy, in comparison to delirium, were younger, had higher rates of admission to intensive care and a longer duration of ventilation. Compared to normative data during the equivalent time period prior to the pandemic, cases of stroke in association with COVID-19 were younger and had a greater number of conventional, modifiable cerebrovascular risk factors. Twenty-seven per cent of strokes occurred in patients <60 years. Relative to those >60 years old, the younger stroke patients presented with delayed onset from respiratory symptoms, higher rates of multi-vessel occlusion (31%) and systemic thrombotic events. Clinical outcomes varied between disease groups, with cerebrovascular disease conferring the worst prognosis, but this effect was less marked than the pre-morbid factors of older age and a higher pre-COVID-19 frailty score, and a high admission white cell count, which were independently associated with a poor outcome. In summary, this study describes the spectrum of neurological and psychiatric conditions associated with COVID-19. In addition, we identify a severe COVID-19 encephalopathy atypical for delirium, and a phenotype of COVID-19 associated stroke in younger adults with a tendency for multiple infarcts and systemic thromboses. These clinical data will be useful to inform mechanistic studies and stratification of patients in clinical trials.

Emerging potential mechanisms and predispositions to the neurological manifestations of COVID-19.

A spectrum of neurological disease associated with COVID-19 is becoming increasingly apparent. However, the mechanisms behind these manifestations remain poorly understood, significantly hindering their management. The present review subsequently attempts to address the evolving molecular, cellular and systemic mechanisms of NeuroCOVID, which we have classified as the acute and long-term neurological effects of COVID-19. We place particular emphasis on cerebrovascular, demyelinating and encephalitic presentations, which have been reported. Several mechanisms are presented, especially the involvement of a "cytokine storm". We explore the genetic and demographic factors that may predispose individuals to NeuroCOVID. The increasingly evident long-term neurological effects are also presented, including the impact of the virus on cognition, autonomic function and mental wellbeing, which represent an impending burden on already stretched healthcare services. We subsequently reinforce the need for cautious surveillance, especially for those with predisposing factors, with effective clinical phenotyping, appropriate investigation and, if possible, prompt treatment. This will be imperative to prevent downstream neurological sequelae, including those related to the long COVID phenotypes that are being increasingly recognised.

Antiphospholipid antibodies and neurological manifestations in acute COVID-19: A single-centre cross-sectional study.

BACKGROUND: A high prevalence of antiphospholipid antibodies has been reported in case series of patients with neurological manifestations and COVID-19; however, the pathogenicity of antiphospholipid antibodies in COVID-19 neurology remains unclear. METHODS: This single-centre cross-sectional study included 106 adult patients: 30 hospitalised COVID-neurological cases, 47 non-neurological COVID-hospitalised controls, and 29 COVID-non-hospitalised controls, recruited between March and July 2020. We evaluated nine antiphospholipid antibodies: anticardiolipin antibodies [aCL] IgA, IgM, IgG; anti-beta-2 glycoprotein-1 [aß2GPI] IgA, IgM, IgG; anti-phosphatidylserine/prothrombin [aPS/PT] IgM, IgG; and anti-domain I ß2GPI (aD1ß2GPI) IgG. FINDINGS: There was a high prevalence of antiphospholipid antibodies in the COVID-neurological (73.3%) and non-neurological COVID-hospitalised controls (76.6%) in contrast to the COVID-non-hospitalised controls (48.2%). aPS/PT IgG titres were significantly higher in the COVID-neurological group compared to both control groups (p < 0.001). Moderate-high titre of aPS/PT IgG was found in 2 out of 3 (67%) patients with acute disseminated encephalomyelitis [ADEM]. aPS/PT IgG titres negatively correlated with oxygen requirement (FiO2 R=-0.15 p = 0.040) and was associated with venous thromboembolism (p = 0.043). In contrast, aCL IgA (p < 0.001) and IgG (p < 0.001) was associated with non-neurological COVID-hospitalised controls compared to the other groups and correlated positively with d-dimer and creatinine but negatively with FiO2. INTERPRETATION: Our findings show that aPS/PT IgG is associated with COVID-19-associated ADEM. In contrast, aCL IgA and IgG are seen much more frequently in non-neurological hospitalised patients with COVID-19. Characterisation of antiphospholipid antibody persistence and potential longitudinal clinical impact are required to guide appropriate management. FUNDING: This work is supported by UCL Queen Square Biomedical Research Centre (BRC) and Moorfields BRC grants (#560441 and #557595). LB is supported by a Wellcome Trust Fellowship (222102/Z/20/Z). RWP is supported by an Alzheimer's Association Clinician Scientist Fellowship (AACSF-20-685780) and the UK Dementia Research Institute. KB is supported by the Swedish Research Council (#2017-00915) and the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and theUK Dementia Research Institute at UCL. BDM is supported by grants from the MRC/UKRI (MR/V007181/1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3). MSZ, MH and RS are supported by the UCL/UCLH NIHR Biomedical Research Centre and MSZ is supported by Queen Square National Brain Appeal.

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.

Subcutaneous immunoglobulin dose titration to clinical response in inflammatory neuropathy.

INTRODUCTION: Individualized dosing is an established approach in intravenous immunoglobulin (IVIg) treatment for inflammatory neuropathies. There is less experience in effective dosing strategies for subcutaneous (SC) immunoglobulin. METHODS: We conducted a retrospective cohort study of patients with inflammatory neuropathies transferring from IVIg to SCIg in two UK peripheral nerve services. I-RODS and grip strength were used to measure outcome. Dose and clinical progress were documented at 1 year and at last review. RESULTS: 44/56 patients remained on maintenance SCIg beyond 1 year (mean 3.3 years, range 1-9 years) with stable clinical outcomes. Clinical deteriorations were corrected by small increases in SCIg dose in 20 patients at 1 year, a further 9 requiring subsequent further up-titrations. Sixteen tolerated dose reduction. Mean dose change was + 2.4% from baseline. Two patients required IVIg bolus rescue (2 g/kg). Three patients successfully discontinued Ig therapy. Nine patients returned to IVIg due to clinical relapse or patient preference. Overall tolerance was good. DISCUSSION: Dose titration to clinical response is an effective approach in SCIg maintenance therapy.

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.

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.

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.