Jayashri Srinivasan

Immune-mediated necrotizing myopathy associated with statins.

We report patients from two neuromuscular centers who were evaluated between the years 2000 and 2008 and met the following criteria: (1) proximal muscle weakness occurring during or after treatment with statins; (2) elevated serum creatine kinase (CK); (3) persistence of weakness and elevated CK despite discontinuation of the statin; (4) improvement with immunosuppressive agents; and (5) muscle biopsy showing necrotizing myopathy without significant inflammation. Twenty‐five patients fulfilled our inclusion criteria. Twenty‐four patients required multiple immunosuppressive agents. Fifteen patients relapsed after being tapered off immunosuppressive therapy. Exposure to statins prior to onset was significantly higher in patients with necrotizing myopathy (82%) as compared to those with dermatomyositis (18%), polymyositis (24%), and inclusion‐body myositis (38%) seen in the same time period. The lack of improvement following discontinuation of statins, the need for immunosuppressive therapy, and frequent relapse when treatment was tapered suggest an immune‐mediated etiology for this rare, statin‐associated necrotizing myopathy. Muscle Nerve, 2010

Leprosy and the peripheral nervous system: Basic and clinical aspects

Leprosy is one of the most common causes of nontraumatic peripheral neuropathy in the developing world. The causative agent, Mycobacterium leprae, has a predilection for Schwann cells, where the organism multiplies unimpeded by organism‐specific host immunity, resulting in destruction of myelin, secondary inflammatory changes, and destruction of the nerve architecture. The cardinal diagnostic features of leprosy are anesthetic skin lesions, neuropathy, and positive skin smears for the bacilli. However, patients may rarely present without skin lesions in pure neuritic leprosy. Electrodiagnostic findings early in the disease reveal demyelinating features, such as slowing of conduction velocity and prolongation of latencies, but as the disease progresses secondary axonal damage commonly ensues. Electrodiagnostic studies are also useful to monitor for toxicity secondary to therapy, particularly thalidomide‐associated neuropathy. Nerve biopsy of a sensory cutaneous nerve is sometimes essential to confirm a diagnosis of leprosy. Significant advances in understanding of the pathogenesis, mapping of the genome, and other advances in molecular biology may result in better preventive and therapeutic modalities, and the goal of eradicating leprosy as a global problem may yet be realized. Muscle Nerve 30: 393–409, 2004

Inappropriate surgeries resulting from misdiagnosis of early amyotrophic lateral sclerosis

Initial symptoms of amyotrophic lateral sclerosis (ALS) may mimic radiculopathy, myelopathy, mononeuropathy, or arthropathy. A retrospective review of 260 consecutive patients with ALS evaluated between 1996 and 2004 revealed that 55 (21%) had had surgery within the 5 years prior to ALS diagnosis. Thirty‐four of these 55 (61%) had surgery for symptoms and signs that retrospectively were attributable to early manifestations of ALS. Misdiagnosis of early ALS may lead to unnecessary surgeries with their attendant potential complications. Muscle Nerve, 2006

Pediatric sciatic neuropathies: a 30-year prospective study.

Objective: The incidence, cause, and prognosis of sciatic neuropathy in children is not well understood. We report our 30-year experience of 53 patients with pediatric sciatic neuropathies (SN). Methods: Prospective review of the history, physical examination, electrophysiologic findings, and clinical course of children with SN. Results: The etiology of SN injury was varied and included trauma (13), iatrogenic causes (13) (8 orthopedic surgeries and 5 miscellaneous surgeries), prolonged extrinsic compression and immobilization (6), tumors (7), vascular (5), idiopathic and progressive (4), infantile and nonprogressive (2), and unknown, presumed postviral (3). Electrophysiologic studies demonstrated abnormalities in motor conduction studies of the peroneal nerve in 44/53 (83%) or tibial nerve in 35/51 (67%). Sensory conduction studies were abnormal in sural nerve in 34 of 43 cases (79%), and superficial peroneal nerves in 15/25 (60%). Needle EMG was abnormal in peroneal innervated muscles in all subjects, in tibial nerve innervated muscles in 43/51 (84%), and in the hamstrings in 18/29 (62%). Prognosis for recovery was variable and depended on the etiology and the severity of the nerve injury. Conclusions: SN is an uncommon mononeuropathy in children. The causes of SN are varied in children compared to adults. Electrophysiologic studies in children may be limited by poor tolerance but play an important role in establishing the diagnosis.

Lambert-Eaton Syndrome, an Unrecognized Treatable Pediatric Neuromuscular Disorder: Three Patients and Literature Review

BACKGROUND Lambert-Eaton myasthenic syndrome, a presynaptic neuromuscular junction autoimmune disorder, rarely occurs in children. Patients typically present with proximal lower extremity weakness with areflexia. METHODS We report three children presenting between ages 9 and 10 years diagnosed with Lambert-Eaton myasthenic syndrome 2 years, 1 year, and 5 months later, respectively. Their clinical attributes are correlated with nine other pediatric Lambert-Eaton myasthenic syndrome patients found in our literature review. RESULTS These patients were identified as having Lambert-Eaton myasthenic syndrome during their evaluation for proximal weakness. Low-amplitude compound muscle action potentials classically facilitating >100% with voluntary exercise and/or 50 Hz stimulation were essential to diagnosis. Three of the 12 children had associated malignancies, two of them had lymphoproliferative disorders with onset of symptoms more rapid than the rest, and the third had neuroblastoma. The nine nonparaneoplastic Lambert-Eaton myasthenic syndrome patients responded to immunomodulatory therapy with close return to their baseline function. Complete remission no longer necessitating medication was reported in two patients. Follow-up up to 17 years was available on two patients previously reported. CONCLUSION Lambert-Eaton myasthenic syndrome is a diagnosis that must be considered in children presenting with unidentified proximal muscle weakness. In most children, Lambert-Eaton myasthenic syndrome is a primary autoimmune disorder that is treatable. Nevertheless, a search for malignancy is recommended.

Pediatric sciatic neuropathy associated with neoplasms

Seven children with sciatic neuropathy associated with an underlying neoplasm are reported. Clinical presentation, electrophysiological data, imaging, pathology, and/or autopsy results are described. Pain and weakness, primarily foot drop, were the most common presenting symptoms. The mechanism of sciatic neuropathy was varied and included: nerve infiltration by the adjacent neoplasm (neuroblastoma, rhabdomyosarcoma, and leukemic or lymphomatous infiltration); an expanding, intrinsic neurogenic tumor (perineurioma); or intraoperative stretch injury (osteosarcoma resection). The prognosis for sciatic nerve recovery was good among children who survived their associated cancer. Three children died from the cancer or complications of treatment. One child with perineurioma remained clinically stable, and two children improved after treatment of their neoplasm. Muscle Nerve 43: 183–188, 2011

Pediatric sciatic neuropathies due to unusual vascular causes

Four cases of pediatric sciatic neuropathies due to unusual vascular mechanisms are reported. Pediatric sciatic neuropathies were seen after umbilical artery catheterization, embolization of arteriovenous malformation, meningococcemia, and hypereosinophilic vasculitis. Electrophysiologic studies demonstrated abnormalities in motor studies of peroneal and tibial nerves. Sensory studies demonstrated abnormalities of sural and superficial peroneal nerves. Results of needle electromyography were abnormal in sciatic-innervated muscles. Prognosis was variable and depended on the severity of the initial nerve injury.

Rituximab and mycophenolate combination therapy in refractory dermatomyositis with multiple autoimmune disorders.

We report a case of dermatomyositis associated with rheumatoid arthritis, Hashimoto thyroiditis, and diabetes mellitus responsive only to combination of rituximab with mycophenolate. A 42-year-old woman presented with proximal muscle weakness, myalgias, fever, night sweats, and shortness of breath. Creatinine kinase was 8155 IU/L, and muscle biopsy was diagnostic of dermatomyositis. She was started on glucocorticoids; her systemic symptoms improved, but her muscle weakness persisted. She was serially treated with intravenous immunoglobulin, azathioprine, and mycophenolate mofetil without improvement in her weakness. She responded dramatically to combination therapy with rituximab and mycophenolate, with improvement in strength and normalization of creatinine kinase. She has been well controlled on rituximab infusion every 6 months and maintenance mycophenolate mofetil.

Facial onset sensory and motor neuronopathy (FOSMN) of childhood onset

A 53-year-old right-handed Syrian man with hypertension, hyperlipidemia, and no pertinent family history first noticed painless right facial weakness at age 7 years. As a teenager, he developed progressive weakness of right grip which spread slowly to the whole right arm. Within a decade, he noticed progressive right facial numbness, and most recently numbness of the left face. Examination revealed prominent weakness and atrophy of his right temporalis and masseter muscles (Fig. 1). The right corneal reflex and the jaw jerk were absent. Sensation was decreased in the right more than left V1–V3 dermatomes. There was mild right peripheral facial weakness. There was atrophy and weakness (Medical Research Council grade 4-) in the right C7–T1 myotomes. Deep tendon reflexes were absent in the right arm. A small area of alopecia was noted on his thigh suggestive of alopecia areata. The remainder of the examination was unremarkable. Laboratory testing for complete blood count, comprehensive metabolic profile, thyroid stimulating hormone, creatine kinase, glycated hemoglobin, erythrocyte sedimentation rate, C-reactive protein, double stranded DNA/anti-neutrophil cytoplasmic/ribonucleoprotein/ Ro/La/Scl 70/Jo1/rheumatoid factor antibodies, varicella zoster/herpes simplex/human immunodeficiency viruses/Lyme serology, rapid plasma reagin, immunofixation, GM1 and myelin-associated glycoprotein antibodies, lipid profile, apolipoprotein, cholestanol levels, vitamins B1/B6/B12/E, and gelsolin amyloidosis gene sequencing was negative except for antinuclear antibodies (1:160), which in isolation had unclear significance. Cerebrospinal fluid analysis for cell count, protein, glucose, oligoclonal bands, and cytology was unremarkable. Magnetic resonance imaging of the brain and whole spine were unremarkable. Electrodiagnostic testing disclosed a normal right median motor study, reduced ulnar and radial motor amplitudes, and chronic neurogenic changes on needle examination of muscles innervated by the right facial nerve and C5–T1 roots. On blink reflex testing, R1 and R2 responses were absent with stimulation of the right supraorbital nerve, but latencies were normal with stimulation of the left supraorbital nerve. Sensory nerve conduction studies of bilateral median, ulnar, radial, and medial and lateral antebrachial cutaneous nerves were normal. Abdominal fat, alopecic skin, and lower lip biopsies did not reveal evidence of amyloidosis, leprosy, or Sjogren syndrome, respectively. The clinical and electrodiagnostic findings in conjunction with multiple other negative studies were most consistent with facial onset sensory and motor neuronopathy (FOSMN). Because of the relatively well-preserved function and slow progression, additional biopsies were not performed, and treatment was not undertaken. FOSMN is characterized by facial onset sensory deficits and slowly evolving sensory and motor deficits in a rostral– caudal direction. Of interest, our patient recalled facial weakness preceding the sensory deficits. Twenty-four patients with FOSMN have been reported, with a mean age of disease onset of 53 years (range, 38–72 years) and a mean disease duration of 8 years (range, 1.2–29 years). Neuroinflammatory, neurodegenerative, or mixed pathophysiological mechanisms have been proposed. Our patient’s Middle Eastern ancestry may be associated with a more benign variant with earlier onset, but this is admittedly speculative. This case incorporates FOSMN in the spectrum of pediatric neuromuscular disorders, extends the disease course to more indolent variations, and provides indirect support for a neurodegenerative, rather than an inflammatory, process.

Inflammatory myopathy associated with imatinib mesylate therapy.

We report a patient with chronic myelogenous leukemia (CML) who developed an inflammatory myopathy while being treated with imatinib mesylate. We found serum antibodies directed against a component of the human exosome. Similar antibodies have been demonstrated in patients with CML following immune-induced remission and also are occasionally found in patients with polymyositis. It is known that the previous use of alpha-interferon followed by imatinib leads to rapid apoptosis of leukemic cells. We speculate that the subsequent release of a large bolus of leukemia antigens could have crossreactivity with muscle antigens and generate an autoimmune response.