Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg

Objective: To describe the frequency of antibodies against neurofascin in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and the associated clinical features.

Methods: Immunocytochemistry was used to identify antibodies to neurofascin 155 (NF155) and 186. Serum reactivity with paranodes and brain tissue was tested with immunohistochemistry of teased-nerve fibers and rat brain. Antibody titers and immunoglobulin (Ig) G isotypes were determined using ELISA. Clinical information was obtained retrospectively.

Results: Two of 53 patients, but none of 204 controls, had antibodies to NF155 (p = 0.041). The 2 patients with NF155 antibodies developed severe polyradiculoneuropathy with predominant distal weakness that was refractory to IVIg. Eight additional patients with IVIg-refractory CIDP were then identified from a national database; 2 of them with the same clinical features also had NF155 antibodies. Overall, 3 of the 4 patients with NF155 antibodies had a disabling and characteristic tremor (high amplitude, low frequency, postural, and intention). Patients' antibodies reacted with the paranodes in teased-nerve fibers and with the neuropil of rat cerebellum, brain, and brainstem. Anti-NF155 antibodies were predominantly of the IgG4 isotype in all patients.

Conclusion: Patients with CIDP positive for IgG4 NF155 antibodies constitute a specific subgroup with a severe phenotype, poor response to IVIg, and disabling tremor. Autoantibodies against paranodal structures associate with distinct clinical features in CIDP and their identification has diagnostic, prognostic, and therapeutic implications.

Classification of evidence: This study provides Class IV evidence that autoantibodies to NF155 identify a CIDP subtype characterized by severe neuropathy, poor response to IVIg, and disabling tremor.

Neurology 2014

Daclizumab-induced adverse events in multiple organ systems in multiple sclerosis

Objective: To report 3 patients with multiple sclerosis (MS) who presented with daclizumab-related adverse events (AEs) in multiple organ systems.

Methods: A retrospective chart review was performed of patients with MS who had clinical and histopathologic findings suggestive of daclizumab-induced AEs between 2004 and 2010 at the Johns Hopkins MS Clinic. This study met criteria for exemption from review from the institutional review board.

Results: Of 20 total patients with MS who had been treated with daclizumab, 3 patients with clinical and histopathologic findings suggestive of daclizumab-induced AEs were identified. All patients were treated with Zenapax (1 mg/kg monthly IV infusions) outside of a clinical trial setting. Clinical manifestations after a mean treatment duration of 20 months consisted of diffuse rash and alopecia, diffuse lymphadenopathy, and breast nodules. Tissue histopathology demonstrated lymphocytic infiltrates with CD56-expressing cells in 2 patients (lymph node, breast nodule). On daclizumab discontinuation, the rash/alopecia and diffuse lymphadenopathy resolved, while the breast nodules stabilized.

Conclusions: Daclizumab-induced AEs can occur in various organ systems after a relatively prolonged duration of exposure and require clinician awareness. Future studies are needed to better understand the relationship between natural killer cells and daclizumab-related AEs.

Neurology 2014

Genetics of essential tremor

Objective: To provide a comprehensive meta-analysis and review of the clinical and molecular genetics of essential tremor (ET).

Methods: Studies were reviewed from the literature. Linkage studies were analyzed applying criteria used for monogenic disorders. For association studies, allele counts were extracted and allelic association calculated whenever possible. A meta-analysis was performed for genetic markers investigated in more than 3 studies.

Results: Linkage studies have shown conclusive results in a single family only for the locus ETM2 (essential tremor monogenetic locus 2, logarithm of odds score [lod] > 3.3). None of the 3 ETM loci has been confirmed independently with a lod score >2.0 in a single family. A mutation in the FUS gene (fused in sarcoma) was found in one ET family by exome sequencing. Two genome-wide association studies demonstrated association between variants in the LINGO1gene (leucine-rich repeat and Ig domain containing 1) and the SLC1A2 gene (solute carrier family 1 member 2) and ET, respectively. Our meta-analysis confirmed the association of rs9652490 in LINGO1 with ET. Candidate gene mutation analysis and association studies have not identified reproducible associations.

Conclusion: Problems of genetic studies of ET are caused by the lack of stringent diagnostic criteria, small sample sizes, lack of biomarkers, a high phenocopy rate, evidence for nonmendelian inheritance, and high locus heterogeneity in presumably monogenic ET. These issues could be resolved by better worldwide cooperation and the use of novel genetic techniques.

Neurology 2014

Acute and chronic ataxic neuropathies with disialosyl antibodies: A continuous clinical spectrum and a common pathophysiological mechanism

Acute ataxic neuropathies with disialosyl antibodies include Fisher syndrome, ataxic Guillain-Barré syndrome (GBS), and acute sensory ataxic neuropathy. Fisher syndrome and ataxic GBS are more strongly associated with IgG anti-GQ1b and -GT1a than with anti-GD1b antibodies, whereas the association is reversed in the case of acute sensory ataxic neuropathy. Chronic ataxic neuropathy with disialosyl antibodies is associated with IgM paraprotein to GD1b and GQ1b, which occasionally reacts with GT1a. The clinical, electrophysiological, and pathological features, along with experimental findings, suggest that acute and chronic ataxic neuropathies with disialosyl antibodies form a continuous clinical and pathophysiological spectrum characterized by a complement-mediated disruption at the nodal region and are better classified in the new category of nodo-paranodopathies.

Muscle e Nerve 2014

Genetic heterogeneity of ALS: implications for clinical practice and research

Genetic insights into the pathophysiology of amyotrophic lateral sclerosis (ALS) are untangling the clinical heterogeneity that may contribute to poor clinical trial outcomes and thus to a lack of effective treatments. Mutations in a large number of genes, including SOD1,C9ORF72, TARDBP, FUS, VAPB, VCP, UBQLN2, ALS2, SETX, OPTN, ANG, and SPG11, are thought to cause ALS, whereas others, including ATAXN2, GRN, HFE, NEFH, UNC13A, and VEGF, appear to be disease-modifying genes. Epigenetic influences may also play important roles. An improved understanding of ALS genetics should lead to better trial designs, insights into common molecular pathways, and better characterization of preclinical models. New genetic sequencing techniques, which use high-throughput methods to assess variants across the genome or exome, may facilitate rational patient stratification for clinical trials and permit more individualized prognostic information and treatment decisions in clinical care. 

Muscle e Nerve 2014

Delayed gastric emptying in Parkinson's disease

Gastrointestinal symptoms are evident in all stages of Parkinson's disease (PD). Most of the gastrointestinal abnormalities associated with PD are attributable to impaired motility. At the level of the stomach, this results in delayed gastric emptying. The etiology of delayed gastric emptying in PD is probably multifactorial but is at least partly related to Lewy pathology in the enteric nervous system and discrete brainstem nuclei. Delayed gastric emptying occurs in both early and advanced PD but is underdetected in routine clinical practice. Recognition of delayed gastric emptying is important because it can cause an array of upper gastrointestinal symptoms, but additionally it has important implications for the absorption and action of levodopa. Delayed gastric emptying contributes significantly to response fluctuations seen in people on long-term l-dopa therapy. Neurohormonal aspects of the brain-gut axis are pertinent to discussions regarding the pathophysiology of delayed gastric emptying in PD and are also hypothesized to contribute to the pathogenesis of PD itself. Ghrelin is a gastric-derived hormone with potential as a therapeutic agent for delayed gastric emptying and also as a novel neuroprotective agent in PD. Recent findings relating to ghrelin in the context of PD and gastric emptying are considered. This article highlights the pathological abnormalities that may account for delayed gastric emptying in PD. It also considers the wider relevance of abnormal gastric pathology to our current understanding of the etiology of PD

Movement Disorders 2014

Venturing into the no-man's land of the retina in Parkinson's disease

The development of optical coherence tomography (OCT) has led to increasing interest in the retina in Parkinson's disease (PD). The retina is a multilayered tissue: looking into the eye from the outside, these layers comprise the nerve fiber layer (NFL); the ganglion cell layer (GCL); the inner plexiform layer (IPL), which contains the interconnecting plexus, including tyrosine hydroxylase-positive (dopaminergic) fibers of amacrine cells; the inner nuclear layer; and several outer retinal layers. Commercial spectral-domain OCT has a specific program for detecting peripapillary NFL defects and a different macular program for diabetic retinopathy. Specific programs for PD are not commercially available. Taking all studies together, it seems that macular programs have a higher diagnostic yield than NFL programs, but the numbers of studies and examined patients are relatively small. It is not certain that all retinal thinning in PD is due to dopaminergic neuronal loss. When applying OCT, the where (region of interest) and the what of the focus of automated programs must be considered. With these caveats, one could take advantage of the power of OCT for looking in-depth into the terra incognita of individual retinal layers at the fovea and perhaps at other appropriate retinal locations

Movement Disorders 2014