Elie Naddaf

Neurological Complications Associated With Anti–Programmed Death 1 (PD-1) Antibodies

Importance Neurological complications are an increasingly recognized consequence of the use of anti–programmed death 1 (PD-1) antibodies in the treatment of solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical spectrum and optimum treatment approach are not established. Objective To investigate the frequency, clinical spectrum, and optimum treatment approach to neurological complications associated with anti–PD-1 therapy. Design, Setting, and Participants This single-center, retrospective cohort study was conducted from either September or December 2014 (the approval dates of the study drugs by the US Food and Drug Administration) to May 19, 2016. All patients receiving anti–PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy Database. Patients with development of neurological symptoms within 12 months of anti–PD-1 therapy were included. Patients with neurological complications directly attributable to metastatic disease or other concurrent cancer-related treatments were excluded. Main Outcomes and Measures Clinical and pathological characteristics, time to development of neurological symptoms, and modified Rankin Scale (mRS) score. Results Among 347 patients treated with anti–PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti–PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti–PD-1 antibodies was discontinued in 7 patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died. Conclusions and Relevance Neurological adverse events associated with anti–PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti–PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti–PD-1 therapy is recommended. In some cases, immune rescue treatment may be required.

Thrombocytosis distinguishes POEMS syndrome from chronic inflammatory demyelinating polyneuropathy

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) syndrome may be mistaken for chronic inflammatory demyelinating polyneuropathy (CIDP). Differentiating the 2 entities is crucial, as there are major treatment implications.

Clinical spectrum of Castleman disease–associated neuropathy

Objective: To define the peripheral neuropathy phenotypes associated with Castleman disease. Methods: We conducted a retrospective chart review for patients with biopsy-proven Castleman disease evaluated between January 2003 and December 2014. Patients with associated peripheral neuropathy were identified and divided into 2 groups: those with Castleman disease without POEMS syndrome (CD-PN) and those with Castleman disease with POEMS syndrome (CD-POEMS). We used a cohort of patients with POEMS as controls. Clinical, electrodiagnostic, and laboratory characteristics were collected and compared among patient subgroups. Results: There were 7 patients with CD-PN, 20 with CD-POEMS, and 122 with POEMS. Patients with CD-PN had the mildest neuropathy characterized by predominant sensory symptoms with no pain and mild distal sensory deficits (median Neuropathy Impairment Score of 7 points). Although both patients with CD-POEMS and patients with POEMS had a severe sensory and motor neuropathy, patients with CD-POEMS were less affected (median Neuropathy Impairment Score of 33 and 66 points, respectively). The degree of severity was also reflected on electrodiagnostic testing in which patients with CD-PN demonstrated a mild degree of axonal loss, followed by patients with CD-POEMS and then those with POEMS. Demyelinating features, defined by European Federation of Neurologic Societies/Peripheral Nerve Society criteria, were present in 43% of the CD-PN, 78% of the CD-POEMS, and 86% of the POEMS group. Conclusion: There is a spectrum of demyelinating peripheral neuropathies associated with Castleman disease. CD-PN is sensory predominant and is the mildest phenotype, whereas CD-POEMS is a more severe sensory and motor neuropathy. Compared to the POEMS cohort, those with CD-POEMS neuropathy have a similar but less severe phenotype. Whether these patients respond differently to treatment deserves further study.

Hereditary myopathies with early respiratory insufficiency in adults

Introduction: Hereditary myopathies with early respiratory insufficiency as a predominant feature of the clinical phenotype are uncommon and underestimated in adults. Methods: We reviewed the clinical and laboratory data of patients with hereditary myopathies who demonstrated early respiratory insufficiency before the need for ambulatory assistance. Only patients with disease‐causing mutations or a specific histopathological diagnosis were included. Patients with cardiomyopathy were excluded. Results: We identified 22 patients; half had isolated respiratory symptoms at onset. The diagnosis of the myopathy was often delayed, resulting in delayed ventilatory support. The most common myopathies were adult‐onset Pompe disease, myofibrillar myopathy, multi‐minicore disease, and myotonic dystrophy type 1. Single cases of laminopathy, MELAS (mitochondrial encephalomyopathy with lactic acidosis and strokelike events), centronuclear myopathy, and cytoplasmic body myopathy were identified. Conclusion: We highlighted the most common hereditary myopathies associated with early respiratory insufficiency as the predominant clinical feature, and underscored the importance of a timely diagnosis for patient care. Muscle Nerve 56: 881–886, 2017

Myopathy With SQSTM1 and TIA1 Variants: Clinical and Pathological Features

Objective The aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies. Patients and methods Clinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy. Results Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in SQSTM1 (c.1175C>T, p.Pro392Leu) and a heterozygous variant in TIA1 (c.1070A>G, p.Asn357Ser). The affected fraternal twin of one proband also carries both variants, while the unaffected family members harbor one or none. Two unrelated probands (family 1, II.3, and family 3, II.1) have a distal myopathy with rimmed vacuoles that manifested with index extensor weakness; the other proband (family 2, I.1) has myofibrillar myopathy manifesting with hypercapnic respiratory insufficiency and distal weakness. Conclusion The findings indicate that all the affected individuals have a myopathy associated with both variants in SQSTM1 and TIA1, respectively, suggesting that the two variants determine the phenotype and likely functionally interact. We speculate that the TIA1 variant is a modifier of the SQSTM1 mutation. We identify the combination of SQSTM1 and TIA1 variants as a novel genetic defect associated with myofibrillar myopathy and suggest to consider sequencing both genes in the molecular investigation of myopathy with rimmed vacuoles and myofibrillar myopathy although additional studies are needed to investigate the digenic nature of the disease.

Adult polyglucosan body disease presenting as a unilateral progressive plexopathy

Adult polyglucosan body disease (APBD) usually presents with progressive spastic paraparesis, neurogenic bladder, and distal lower limb sensory abnormalities. It is caused by mutations in the glycogen branching enzyme gene (GBE1).

Neurologic Complications of Plasma Cell Dyscrasias

Plasma cell dyscrasias are commonly associated with peripheral nervous system involvement and rarely affect the central nervous system. They are often associated with significant morbidity affecting patient’s function and quality of life. In this chapter, we discuss different plasma cell dyscrasias including monoclonal gammopathy of undetermined significance, Waldenstrom macroglobulinemia, primary amyloidosis, multiple myeloma and POEMS syndrome as well as their neurologic complications. We will emphasize the different neuropathy phenotypes associated with each hematologic disorder and discuss the various treatment options.

Inclusion Body Myositis: Update on Pathogenesis and Treatment

Inclusion body myositis is the most common acquired myopathy after the age of 50. It is characterized by progressive asymmetric weakness predominantly affecting the quadriceps and/or finger flexors. Loss of ambulation and dysphagia are major complications of the disease. Inclusion body myositis can be associated with cytosolic 5′-nucleotidase 1A antibodies. Muscle biopsy usually shows inflammatory cells surrounding and invading non-necrotic muscle fibers, rimmed vacuoles, congophilic inclusions, and protein aggregates. Disease pathogenesis remains poorly understood and consists of an interplay between inflammatory and degenerative pathways. Antigen-driven, clonally restricted, cytotoxic T cells represent a main feature of the inflammatory component, whereas abnormal protein homeostasis with protein misfolding, aggregation, and dysfunctional protein disposal is the hallmark of the degenerative component. Inclusion body myositis remains refractory to treatment. Better understanding of the disease pathogenesis led to the identification of novel therapeutic targets, addressing both the inflammatory and degenerative pathways.

Muscle Biopsy and Electromyography Correlation

Introduction: In myopathies, the correlation of individual electromyographic and histopathologic findings remains poorly explored, as most previous studies have focused on the ability of muscle biopsy and electromyography to distinguish the neuropathic vs. myopathic nature of the underlying neuromuscular disease. Methods: We identified 100 patients who had a muscle biopsy and electromyography performed on identical muscles. We used a detailed grading system ranging from 0- normal to 4- severe; and graded 16 histopathologic findings in each biopsy. Electromyography findings were also graded from 0 to 4 according to the standard protocol in our EMG laboratory. We used Kendalls tau for non-parametric ordinal correlation analysis. Results: Fibrillation potentials correlated with atrophic, necrotic, and regenerating fibers, fibers harboring vacuoles, fiber splitting, fibers reacting for non-specific esterase, fibers with congophilic inclusions, inflammation (endoymysial and perimysial), and increased endomysial connective tissue. Short-duration motor unit potentials correlated with atrophic, necrotic, and regenerating fibers, increased endomysial connective tissue, and perimysial inflammation. Long-duration motor unit potentials correlated with fiber-type grouping. Increased phases of motor unit potentials correlated with atrophic fibers, increased endomysial connective tissue, and fibers reacting for non-specific esterase; while increased turns correlated with atrophic and regenerating fibers, increased endomysial connective tissue and target formations. Rapid recruitment correlated with regenerating fibers, perimysial inflammation, and increased endomysial connective tissue. Discussion: By demonstrating a clear correlation of various electromyographic and histopathologic findings, this study improves interpreting electrodiagnostic testing in myopathies, and serves as the basis to further assess the correlation between clinical, electromyographic, and histopathologic findings.

Systemic vasculitis with dermatomyositis, hearing loss, neuropathy, and multiorgan dysfunction

A 39-year-old woman presented with 10 months of steadily progressive weakness, myalgia, weight loss, and intermittent feet tingling. During the course of her illness, she developed refractory atrial fibrillation, left followed by right-sided hearing loss, amenorrhea, and hematuria. She had been on rituximab for years for “polyarthralgias,” which was stopped at symptom onset. Examination showed severe proximal weakness and mildly decreased toe proprioception. Deltoid biopsy (figure) was diagnostic of dermatomyositis. Liver and enteric biopsies showed lymphocytosis. Suspicion for vasculitis led to sural nerve biopsy (figure), showing large-arteriole vasculitis. Despite treatment with high-dose prednisone and cyclophosphamide, the patient died. This is a unique case of systemic vasculitis associated with dermatomyositis, hearing loss, neuropathy, and multiorgan dysfunction. The histologic findings and the relentless progression despite stopping rituximab argue against a role for rituximab in the pathogenesis.