R. D. M. Hadden

European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of paraproteinaemic demyelinating neuropathies: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society*

Background. Paraprotein‐associated neuropathies have heterogeneous clinical, neurophysiological, neuropathological and haematological features. Objectives. To prepare evidence‐based and consensus guidelines on the clinical management of patients with both a demyelinating neuropathy and a paraprotein (paraproteinaemic demyelinating neuropathy, PDN). Methods. Search of MEDLINE and the Cochrane library, review of evidence and consensus agreement of an expert panel. Recommendations. In the absence of adequate data, evidence based recommendations were not possible but the panel agreed the following good practice points: (1) Patients with PDN should be investigated for a malignant plasma cell dyscrasia. (2) The paraprotein is more likely to be causing the neuropathy if the paraprotein is immunoglobulin (Ig)M, antibodies are present in serum or on biopsy, or the clinical phenotype is chronic distal sensory neuropathy. (3) Patients with IgM PDN usually have predominantly distal and sensory impairment, with prolonged distal motor latencies, and often anti‐myelin associated glycoprotein antibodies. (4) IgM PDN sometimes responds to immune therapies. Their potential benefit should be balanced against their possible side‐effects and the usually slow disease progression. (5) IgG and IgA PDN may be indistinguishable from chronic inflammatory demyelinating polyradiculoneuropathy, clinically, electrophysiologically, and in response to treatment. (6) For POEMS syndrome, local irradiation or resection of an isolated plasmacytoma, or melphalan with or without corticosteroids, should be considered, with haemato‐oncology advice.

MPV17 mutation causes neuropathy and leukoencephalopathy with multiple mtDNA deletions in muscle

Disorders of mitochondrial DNA (mtDNA) maintenance are clinically and genetically heterogeneous, embracing recessive mtDNA depletion syndromes affecting children and adult-onset multiple mtDNA deletion disorders. Here we show that mutation of MPV17 – a gene implicated in severe, infantile hepatocerebral mtDNA depletion disorders characterised by a loss of mtDNA copies – can also cause clonally-expanded mtDNA deletion and focal cytochrome c oxidase (COX) deficiency in skeletal muscle associated with an adult presentation of neuropathy and leukoencephalopathy. The mpv17 protein is therefore intimately involved in both the mtDNA replication and repair processes and associated with both quantitative and qualitative mtDNA abnormalities.

Switch from intravenous to subcutaneous immunoglobulin in CIDP and MMN: improved tolerability and patient satisfaction

Objectives: To assess clinical outcomes and patient satisfaction in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) or multifocal motor neuropathy (MMN) who were switched from intravenous immunoglobulin (IVIG) to subcutaneous immunoglobulin (SCIG). Methods: Eight consecutive patients, four with MMN and four with CIDP, already on long-term, hospital-based IVIG were switched to home-based SCIG. These patients were selected on the basis of their requirement for relatively low treatment doses, problems experienced with IVIG, and their willingness to switch to SCIG. Results: After a mean 33 [standard deviation (SD) 19] months receiving SCIG, 7 patients remained neurologically stable and 6 remained on a similar mean weekly immunoglobulin dose relative to their original intravenous dose. A good outcome was reported by 7 of the 8 patients: there were improvements in nausea and headache (n = 4), need to travel to hospital (n = 4), venous access problems (n = 3), immunoglobulin-induced neutropenia (n = 3), treatment wearing-off fluctuations (n = 2), IVIG-induced allergy requiring antihistamine/hydrocortisone (n = 1) and time taken off work (n = 1). The eighth patient required increasing doses of immunoglobulin to maintain strength but still wanted to continue SCIG. Seven patients completed a questionnaire: there was a very high overall satisfaction level with immunoglobulin treatment [mean 96 (SD 5), visual analogue scale (VAS) where 0 = very unsatisfied, 100 = very satisfied]; and very strong preference for subcutaneous over intravenous immunoglobulin (VAS mean 93 [SD 12] where 0 = prefer IVIG, 100 = prefer SCIG). Conclusions: In seven of the eight patients, SCIG gave improved tolerability and patient satisfaction with similar efficacy compared with IVIG.

Vasculitis as an adverse event following immunization - Systematic literature review.

BACKGROUND Several types of vasculitis have been observed and reported in temporal association with the administration of various vaccines. A systematic review of current evidence is lacking. OBJECTIVE This systematic literature review aimed to assess available evidence and current reporting practice of vasculitides as adverse events following immunization (AEFI). METHODS We reviewed the literature from 1st January 1994 to 30th June 2014. This review comprises randomized controlled trials, observational studies, case series, case reports, reviews and comments regardless of vaccine and target population. RESULTS The initial search resulted in the identification of 6656 articles. Of these, 157 articles were assessed for eligibility and 75 studies were considered for analysis, including 6 retrospective/observational studies, 2 randomized controlled trials, 7 reviews, 11 case series, 46 case reports and 3 comments. Most of the larger, higher quality studies found no causal association between vaccination and subsequent development of vasculitis, including several studies on Kawasaki disease and Henoch-Schönlein purpura (IgA vasculitis). Smaller case series reported a few cases of vasculitis following BCG and vaccines against influenza and hepatitis. Only 24% of the articles reported using a case definition of vasculitis. CONCLUSIONS Existing literature does not allow establishing a causative link between vaccination and vasculitides. Further investigations were strengthened by the use of standardized case definitions and methods for data collection, analysis and presentation to improve data comparability and interpretation of vasculitis cases following immunization.

A proposed dosing algorithm for the individualized dosing of human immunoglobulin in chronic inflammatory neuropathies

Dosing guidelines for immunoglobulin (Ig) treatment in neurological disorders do not consider variations in Ig half‐life or between patients. Individualization of therapy could optimize clinical outcomes and help control costs. We developed an algorithm to optimize Ig dose based on patients response and present this here as an example of how dosing might be individualized in a pharmacokinetically rational way and how this achieves potential dose and cost savings. Patients are “normalized” with no more than two initial doses of 2 g/kg, identifying responders. A third dose is not administered until the patients condition deteriorates, allowing a “dose interval” to be set. The dose is then reduced until relapse allowing dose optimization. Using this algorithm, we have individualized Ig doses for 71 chronic inflammatory neuropathy patients. The majority of patients had chronic inflammatory demyelinating polyradiculoneuropathy (n = 39) or multifocal motor neuropathy (n = 24). The mean (standard deviation) dose of Ig administered was 1.4 (0.6) g/kg, with a mean dosing interval of 4.3 weeks (median 4 weeks, range 0.5–10). Use of our standardized algorithm has allowed us to quickly optimize Ig dosing.

Vasculitic peripheral neuropathy: Case definition and guidelines for collection, analysis, and presentation of immunisation safety data.

Department of Neurology, King’s College Hospital, London, UK Department of Neurology, Medical College of Wisconsin, USA Department of Neurology, University of Pittsburgh Medical Center, USA Department of Neurology, National Taiwan University Hospital, Taiwan Italian Medicines Agency (AIFA), Italy Brighton Collaboration Foundation, Basel, Switzerland University of Basel Children’s Hospital, Basel, Switzerland

Individualized immunoglobulin therapy in chronic immune-mediated peripheral neuropathies*

Despite the well‐recognized importance of immunoglobulin therapy individualization during the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP), the pathway to best achieve optimization is unknown. There are many pharmacokinetic and immunobiologic variables that can potentially influence the appropriateness of any individual therapy. Although identification of specific autoantibodies and their targets has only been accomplished in a minority of patients with CIDP, already the diagnostic and treatment implications of specific autoantibody detection are being realized. Individual variability in IgG pharmacokinetic properties including IgG catabolic rates and distribution, as well as the IgG level necessary for disease control also require consideration during the optimization process. For optimization to be successful there must be a measure of treatment response that has a clinically meaningful interpretation. There are currently available well‐defined and validated clinical assessment tools and outcome measures that are well suited for this purpose. While there remains much to learn on how best to manipulate immunopathology and immunoglobulin pharmacokinetics in the most favorable way, there currently exists an understanding of these principles to a degree sufficient to begin to develop rational and evidence‐based treatment optimization strategies.