Mauermann, Michelle L.

AbstractIntroduction/AimsWe aimed to describe the clinical phenotype, histopathological findings and overall survival (OS) of the immune‐mediated neuromuscular complications of graft‐versus‐host disease (GVHD).MethodsWe conducted a retrospective chart review of adult patients presenting with immune‐mediated neuromuscular complications of GVHD to Mayo Clinic, between April 2013 and July 2018.We collected clinical and laboratory characteristics, histopathological findings, response to treatment and survival data.ResultsWe identified 20 patients with a mean age at presentation of 55 y. Mean time from transplant to neurological presentation was 14 mo. Myositis was the most common complication seen in 17 patients, manifesting with predominantly axial and/or proximal weakness. Eleven patients had a muscle biopsy showing diffuse perimysial, predominantly macrophagic infiltration in 10, 3 of them with perimysial perivascular lymphocytic collections, and endomysial and perimysial lymphocytic infiltration in 1. Only two patients had a neuropathic complication: one each with acute inflammatory demyelinating polyradiculoneuropathy and neuralgic amyotrophy. A single patient had a myasthenic syndrome presenting with fluctuating foot drop. Nineteen patients were treated and all responded to immunosuppressive agents; however, 11 had further GVHD flares requiring escalation of therapy. After a median follow‐up of 83 mo, seven (35%) patients died: five from progressive GVHD and two from infections. The 5‐y OS from time of transplant was 68%.DiscussionMyositis is the most common immune‐mediated neuromuscular complication of GVHD while peripheral neuropathy and myasthenic syndromes appear less common. The macrophage‐predominant infiltration on muscle biopsy deserves further study to better clarify the role of macrophages in GVHD pathogenesis.

Abstract Systemic amyloidosis is a rare protein misfolding and deposition disorder leading to progressive organ failure. There are over 15 types of systemic amyloidosis, each caused by a different precursor protein which promotes amyloid formation and tissue deposition. Amyloidosis can be acquired or hereditary and can affect various organs, including the heart, kidneys, liver, nerves, gastrointestinal tract, lungs, muscles, skin and soft tissues. Symptoms are usually insidious and nonspecific resulting in diagnostic delay. The field of amyloidosis has seen significant improvements over the past decade in diagnostic accuracy, prognosis prediction and management. The advent of mass spectrometry‐based shotgun proteomics has revolutionized amyloid typing and has led to the discovery of new amyloid types. Accurate typing of the precursor protein is of paramount importance as the type dictates a specific management approach. In this article, we review each type of systemic amyloidosis to provide the practitioner with practical tools to improve diagnosis and management of these rare disorders.

Abstract Objectives: The objective of the study is to distinguish the mechanisms of disease for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN), which we believe to be fundamentally different. However, distinguishing the mechanisms is more difficult when the presentation of CIDP is motor-predominant, focal, or asymmetric. Methods: We describe 3 focal, motor-predominant, representative cases that could be interpreted on clinical and/or electrophysiological grounds as either MMN or focal CIDP, and present pathological findings. Results: We highlight pathological differences in these cases, and provide an argument that CIDP and MMN are distinct entities with different pathophysiological mechanisms—chronic demyelination for CIDP, and an immune-mediated attack on paranodal motor axons for MMN. Conclusions: Based on clinical evaluation, electrophysiology, and nerve biopsy pathology, we can divide the conditions into inflammatory demyelinating neuropathy (focal CIDP) versus chronic axonal neuropathy (MMN). The divergent pathological findings provide further evidence that CIDP and MMN are fundamentally different disorders.

AbstractIntroductionInotersen, an antisense oligonucleotide inhibitor of transthyretin (TTR) protein production, demonstrated significant benefit versus placebo in the modified Neuropathy Impairment Score (NIS) +7 neurophysiologic tests (mNIS+7) in patients with hereditary TTR‐mediated amyloidosis (hATTR) with polyneuropathy. This analysis assessed the mNIS+7 components by anatomic location and the lower limb function (LLF) test.MethodsAdults with hATTR in the NEURO‐TTR trial (NCT01737398) were randomly assigned to receive weekly doses of subcutaneous inotersen 300 mg or placebo for 65 weeks. The mNIS+7 and LLF were assessed at 35 and 66 weeks.ResultsAll major mNIS+7 components (muscle weakness, muscle stretch reflexes, sensation) and the LLF showed significant efficacy in patients receiving inotersen versus placebo; however, NIS‐reflexes (upper limb), touch pressure (upper and lower limbs), and heart rate during deep breathing did not show significant effects.DiscussionThe results of this analysis reinforce the beneficial effect of inotersen on slowing neuropathy progression in patients with hATTR polyneuropathy.

AbstractIntroductionHereditary transthyretin‐mediated amyloidosis (hATTR) manifests as multisystem dysfunction, including progressive polyneuropathy. Inotersen, an antisense oligonucleotide, improved the course of neuropathic impairment in patients with hATTR in the pivotal NEURO‐TTR study (NCT01737398). To determine inotersen's impact on symptoms and patients’ neuropathy experience, we performed a post hoc analysis of the Neuropathy Symptoms and Change (NSC) score.MethodsStage 1 or 2 hATTR patients were randomized to receive weekly subcutaneous inotersen or placebo for 65 weeks. NSC score was assessed at baseline and 35 and 66 weeks.ResultsAt 66 weeks, inotersen‐treated patients had symptom stabilization as compared with worsening in patients receiving placebo, based on total NSC score. There were also improvements in the subdomains of muscle weakness, sensory, pain, and autonomic symptoms, and for various individual items.DiscussionInotersen treatment stabilized neuropathy symptoms, including autonomic symptoms, in patients with hATTR according to NSC score. Thus, the NSC may be an effective measure to assess neuropathy progression and patients’ neuropathy experience in clinical practice.