Michael P. Lunn

Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study

BACKGROUND Encephalitis has many causes, but for most patients the cause is unknown. We aimed to establish the cause and identify the clinical differences between causes in patients with encephalitis in England. METHODS Patients of all ages and with symptoms suggestive of encephalitis were actively recruited for 2 years (staged start between October, 2005, and November, 2006) from 24 hospitals by clinical staff. Systematic laboratory testing included PCR and antibody assays for all commonly recognised causes of infectious encephalitis, investigation for less commonly recognised causes in immunocompromised patients, and testing for travel-related causes if indicated. We also tested for non-infectious causes for acute encephalitis including autoimmunity. A multidisciplinary expert team reviewed clinical presentation and hospital tests and directed further investigations. Patients were followed up for 6 months after discharge from hospital. FINDINGS We identified 203 patients with encephalitis. Median age was 30 years (range 0-87). 86 patients (42%, 95% CI 35-49) had infectious causes, including 38 (19%, 14-25) herpes simplex virus, ten (5%, 2-9) varicella zoster virus, and ten (5%, 2-9) Mycobacterium tuberculosis; 75 (37%, 30-44) had unknown causes. 42 patients (21%, 15-27) had acute immune-mediated encephalitis. 24 patients (12%, 8-17) died, with higher case fatality for infections from M tuberculosis (three patients; 30%, 7-65) and varicella zoster virus (two patients; 20%, 2-56). The 16 patients with antibody-associated encephalitis had the worst outcome of all groups-nine (56%, 30-80) either died or had severe disabilities. Patients who died were more likely to be immunocompromised than were those who survived (OR = 3·44). INTERPRETATION Early diagnosis of encephalitis is crucial to ensure that the right treatment is given on time. Extensive testing substantially reduced the proportion with unknown cause, but the proportion of cases with unknown cause was higher than that for any specific identified cause. FUNDING The Policy Research Programme, Department of Health, UK.

Chronic inflammatory demyelinating polyradiculoneuropathy: a prevalence study in south east England

Although there are now widely accepted diagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) there are few epidemiological data. A prevalence study was performed in the four Thames health regions, population 14 049 850. The prevalence date was 1 January 1995. Data were from a national consultant neurologist surveillance programme and the personal case series of two investigators. A diagnosis of CIDP was made according to definite, probable, possible, or suggestive diagnostic criteria. A wide difference in prevalence rates between the four health regions was noted, probably due to reporting bias. In the South East Thames Region, from which the data were most comprehensive the prevalence for definite and probable cases was 1.00/100 000; the highest total prevalence (if possible and suggestive cases were included) would have been 1.24/100 000. On the prevalence date 13% of patients required aid to walk and 54% were still receiving treatment.

Charcot–Marie–Tooth disease: frequency of genetic subtypes and guidelines for genetic testing

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.

Diagnosis of Neuroinvasive Astrovirus Infection in an Immunocompromised Adult With Encephalitis by Unbiased Next-Generation Sequencing

Metagenomic next-generation sequencing (NGS) was used to diagnose an unusual and fatal case of progressive encephalitis in an immunocompromised adult presenting at disease onset as bilateral hearing loss. The sequencing and confirmatory studies revealed neuroinvasive infection of the brain by an astrovirus belonging to a recently discovered VA/HMO clade.

High-affinity anti-ganglioside IgG antibodies raised in complex ganglioside knockout mice: reexamination of GD1a immunolocalization.

Abstract : Gangliosides, sialic acid‐bearing glycosphingolipids, are highly enriched in the vertebrate nervous system. Anti‐ganglioside antibodies are associated with various human neuropathies, although the pathogenicity of these antibodies remains unproven. Testing the pathogenic role of anti‐ganglioside antibodies will be facilitated by developing high‐affinity IgG‐class complement‐fixing monoclonal anti‐bodies against major brain gangliosides, a goal that has been difficult to achieve. In this study, mice lacking complex gangliosides were used as immune‐naive hosts to raise anti‐ganglioside antibodies. Wild‐type mice and knockout mice with a disrupted gene for GM2/GD2 synthase (UDP‐N‐acetyl‐D‐galactosamine : GM3/GD3 N‐acetyl‐D‐glactosaminyltransferase) were immunized with GD1a conjugated to keyhole limpet hemocyanin. The knockout mice produced a vigorous anti‐GD1a IgG response, whereas wildtype littermates failed to do so. Fusion of spleen cells from an immunized knockout mouse with myeloma cells yielded numerous IgG anti‐GD1a antibody‐producing colonies. Ganglioside binding studies revealed two specificity classes ; one colony representing each class was cloned and characterized. High‐affinity monoclonal antibody was produced by each hybridoma : an IgG1 that bound nearly exclusively to GD1a and an IgG2b that bound GD1a, GT1b, and GT1aα. Both antibodies readily readily detected gangliosides via ELISA, TLC immune overlay, immunohistochemistry, and immunocytochemistry. In contrast to prior reports using anti‐GD1a and anti‐GT1b IgM class monoclonal antibodies, the new antibodies bound avidly to granule neurons in brain tissue sections and cell cultures. Mice lacking complex gangliosides are improved hosts for raising high‐affinity, high‐titer anti‐ganglioside IgG antibodies for probing for the distribution and physiology of gangliosides and the pathophysiology of anti‐ganglioside antibodies.

Successful treatment of IgM paraproteinaemic neuropathy with fludarabine

OBJECTIVES To evaluate the response of four patients with IgM paraproteinaemic neuropathy to a novel therapy—pulsed intravenous fludarabine. BACKGROUND The peripheral neuropathy associated with IgM paraproteinaemia usually runs a chronic, slowly progressive course which may eventually cause severe disability. Treatment with conventional immunosuppressive regimens has been unsatisfactory. Fludarabine is a novel purine analogue which has recently been shown to be effective in low grade lymphoid malignancies. METHODS Four patients were treated with IgM paraproteinaemic neuropathy with intravenous pulses of fludarabine. Two of the four patients had antibodies to MAG and characteristic widely spaced myelin on nerve biopsy and a third had characteristic widely spaced myelin only. The fourth had an endoneurial lymphocytic infiltrate on nerve biopsy and a diagnosis of Waldenström’s macroglobulinaemia. RESULTS In all cases subjective and objective clinical improvement occurred associated with a significant fall in the IgM paraprotein concentration in three cases. Neurophysiological parameters improved in the three patients examined. The treatment was well tolerated. All patients developed mild, reversible lymphopenia and 50% mild generalised myelosuppression, but there were no febrile episodes. CONCLUSION Fludarabine should be considered as a possible treatment for patients with IgM MGUS paraproteinaemic neuropathy.

Causality in acute encephalitis: defining aetiologies

Defining the causal relationship between a microbe and encephalitis is complex. Over 100 different infectious agents may cause encephalitis, often as one of the rarer manifestations of infection. The gold-standard techniques to detect causative infectious agents in encephalitis in life depend on the study of brain biopsy material; however, in most cases this is not possible. We present the UK perspective on aetiological case definitions for acute encephalitis and extend them to include immune-mediated causes. Expert opinion was primarily used and was supplemented by literature-based methods. Wide usage of these definitions will facilitate comparison between studies and result in a better understanding of the causes of this devastating condition. They provide a framework for regular review and updating as the knowledge base increases both clinically and through improvements in diagnostic methods. The importance of new and emerging pathogens as causes of encephalitis can be assessed against the principles laid out here.

Reference measurement procedures for Alzheimer’s disease cerebrospinal fluid biomarkers: definitions and approaches with focus on amyloid β42

Cerebrospinal fluid (CSF) biomarkers for Alzheimers disease (AD) are increasingly used in clinical settings, research and drug trials. However, their broad-scale use on different technology platforms is hampered by the lack of standardization at the level of sample handling, determination of concentrations of analytes and the absence of well-defined performance criteria for in vitro diagnostic or companion diagnostic assays, which influences the apparent concentration of the analytes measured and the subsequent interpretation of the data. There is a need for harmonization of CSF AD biomarker assays that can reliably, across centers, quantitate CSF biomarkers with high analytical precision, selectivity and stability over long time periods. In this position paper, we discuss reference procedures for the measurement of CSF AD biomarkers, especially amyloid β42 and tau. We describe possible technical approaches, focusing on a selected reaction monitoring mass spectrometry assay as a candidate reference method for quantification of CSF amyloid β42.

Primary sciatic nerve lymphoma: a case report and review of the literature

A patient with primary B cell non-Hodgkin’s lymphoma of the sciatic nerve is described. He presented with neuropathic symptoms in the left leg, initially diagnosed as tarsal tunnel syndrome. Magnetic resonance imaging (MRI) identified the abnormality in the sciatic nerve. A fascicular biopsy of the sciatic nerve showed a diffuse large B cell non-Hodgkin’s lymphoma. The patient was treated with chemotherapy and rituximab (anti-CD20 monoclonal antibody). Four months later he was in remission, and remains so 48 months from presentation. Primary lymphoma of single peripheral nerves may be a unique subtype of extranodal lymphoma, which usually follows an aggressive course and has a variable response to current therapeutic strategies. MRI is useful, alongside electrophysiological studies, in patients with atypical peripheral nerve symptoms.

Neurological Manifestations of Influenza Infection in Children and Adults: Results of a National British Surveillance Study

BACKGROUND The emergence of influenza A(H1N1) 2009 was met with increased reports of associated neurological manifestations. We aimed to describe neurological manifestations of influenza in adults and children in the United Kingdom that presented at this time. METHODS A 2-year surveillance study was undertaken through the British adult and pediatric neurological surveillance units from February 2011. Patients were included if they met clinical case definitions within 1 month of proven influenza infection. RESULTS Twenty-five cases were identified: 21 (84%) in children and 4 (16%) in adults. Six (29%) children had preexisting neurological disorders. Polymerase chain reaction of respiratory secretions identified influenza A in 21 (81%; 20 of which [95%] were H1N1) and influenza B in 4 (15%). Twelve children had encephalopathy (1 with movement disorder), 8 had encephalitis, and 1 had meningoencephalitis. Two adults had encephalopathy with movement disorder, 1 had encephalitis, and 1 had Guillain-Barré syndrome. Seven individuals (6 children) had specific acute encephalopathy syndromes (4 acute necrotizing encephalopathy, 1 acute infantile encephalopathy predominantly affecting the frontal lobes, 1 hemorrhagic shock and encephalopathy, 1 acute hemorrhagic leukoencephalopathy). Twenty (80%) required intensive care, 17 (68%) had poor outcome, and 4 (16%) died. CONCLUSIONS This surveillance study described a cohort of adults and children with neurological manifestations of influenza. The majority were due to H1N1. More children than adults were identified; many children had specific encephalopathy syndromes with poor outcomes. None had been vaccinated, although 8 (32%) had indications for this. A modified classification system is proposed based on our data and the increasing spectrum of recognized acute encephalopathy syndromes.