Anti-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibody in necrotizing myopathy: treatment outcomes, cancer risk, and role of autoantibody level.

Objective: To evaluate clinical associations of anti-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibody (Ab) and statin exposure in necrotizing myopathy (NM) patients. Methods: NM without a known myositis-specific autoantibody (MSA) was ascertained from a large single-centre myositis database between 1985 and 2012. A comparison NM cohort included 32 anti-SRP+ autoantibody patients, and other control groups included 74 non-NM myositis patients and 21 non-myositis controls. Sera from all cases and controls were tested using a validated anti-HMGCR enzyme-linked immunosorbent assay. Clinical features including statin use and anti-HMGCR Ab status were compared between cases and controls. Results: Of the 256 NM muscle biopsies reviewed, only 48 subjects with available sera were identified as traditional MSA-negative NM. Anti-HMGCR positivity was significantly (p < 0.001) associated with MSA-negative NM [48% (23/48)] compared to all of the myositis and non-myositis controls [5% (6/127)]. Most anti-HMGCR Ab-positive NM patients had high titres of anti-HMGCR (83%) and a history of statin exposure (78%), along with severe muscle weakness, high creatine kinase (CK) levels (90% ≥ 5000 IU/L), a paucity of other organ manifestations, and the need for immunosuppression with prednisone and methotrexate, but generally favourable outcomes. Anti-HMGCR serum levels were associated with baseline CK levels but not muscle weakness. Conclusion: HMGCR Ab-positive NM patients are associated with statin exposure, have severe muscle weakness and high CK at presentation, lack other organ manifestations, and generally have favourable outcomes from immunosuppression. Anti-HMGCR Abs should be assessed in MSA-negative NM patients, particularly those with a history of statin exposure.

Vasculitic neuropathy--electrodiagnostic findings and association with malignancies.

BACKGROUND: Vasculitic neuropathies occur in the context of systemic disorders or in isolation. Histopathologic evaluation remains the gold standard for diagnosis, but certain electrodiagnostic findings may heighten suspicion of vasculitic neuropathy and improve the yield of nerve and muscle biopsy. AIM OF THE STUDY: Description of electrodiagnostic patterns associated with vasculitic neuropathies, and a report of a possible association with malignancies. METHODS: Retrospective review of medical records of patients with histopathologically proven vasculitic and non-vasculitic axonal neuropathies evaluated at the University of Pittsburgh Medical Center from November 1995 to November 2003. RESULTS: The most distinctive electrodiagnostic patterns associated with vasculitic neuropathy were mononeuritis multiplex (27.5% vs 4% in controls; P = 0.003) and axonal sensorimotor polyneuropathy with side-to-side amplitude asymmetry (50% vs 32%, P > 0.05). Additionally, six patients (15% vs 2%; P = 0.034) developed various malignancies within 2 years of onset of vasculitic neuropathy. CONCLUSIONS: While generalized polyneuropathy was the most common presentation of nerve vasculitis, our study affirms side-to-side amplitude asymmetry and mononeuritis multiplex as the most distinctive electrodiagnostic features. The frequent occurrence of malignancies suggests a possible association with the vasculitic neuropathy and warrants additional investigation.

Sensory neuropathy associated with metronidazole: report of four cases and review of the literature.

OBJECTIVE: To better characterize sensory neuropathy associated with metronidazole. METHODS: We report four patients who developed dysesthesias after metronidazole treatment. One received topical metronidazole only. All four underwent electrodiagnostic studies, including nerve conduction studies (NCS), quantitative sensory testing (QST), and quantitative sudomotor axon reflex testing (QSART). One underwent nerve biopsy. RESULTS: NCS were normal in all patients. QST showed impaired vibration thresholds in three patients. Three of four patients had abnormal tests of small fiber function. Cooling thresholds were abnormal in one; QSART was abnormal in one and borderline in another. The nerve biopsy specimen showed mild loss of small myelinated axons. CONCLUSIONS: This study shows that paresthesias associated with metronidazole exposure may be the result of a relatively mild sensory neuropathy with predominant involvement of small fibers and milder, mostly subclinical involvement of large fibers.

The use of percutaneous needle muscle biopsy in the diagnosis of myopathy.

Less invasive, inexpensive, and minimally time-consuming muscle biopsy techniques are desirable if their diagnostic yield is similar to that of open muscle biopsy. This article reviews the technique of semi-automated percutaneous needle muscle biopsy and its utility in diagnosis of neuromuscular diseases. Although direct comparisons with open biopsy are not available, the data indicate that percutaneous needle biopsy is quite useful for diagnosis of inflammatory as well as other forms of myopathy. The specimens can also be utilized for molecular diagnostic studies and cell culture.

Histological effects of trigeminal nerve radiosurgery in a primate model: implications for trigeminal neuralgia radiosurgery.

OBJECTIVE: Stereotactic radiosurgical treatment of the proximal trigeminal nerve is used to relieve the pain of trigeminal neuralgia. The mechanism of the radiosurgical effect is not understood. METHODS: Two adult baboons underwent stereotactic magnetic resonance imaging-guided radiosurgery, using a gamma knife. A single 4-mm isocenter was targeted to each proximal trigeminal nerve, just anterior to the pons, to deliver a maximal dose of 80 or 100 Gy (total of four nerves). A nonirradiated baboon brain and nerves served as control specimens. Six months after treatment, magnetic resonance imaging was again performed and the brains and nerves were studied using light and electron microscopy. RESULTS: Magnetic resonance imaging indicated a 4-mm-diameter area of contrast enhancement at the target site in each nerve. All irradiated nerves exhibited axonal degeneration and mild edema at the target, with remnants of some myelinated axons. Large and small myelinated and unmyelinated fibers were affected. No inflammation was observed. Nerve necrosis was identified after 100-Gy treatment. The trigeminal ganglion appeared normal. CONCLUSION: Radiosurgery at 80 Gy causes focal axonal degeneration of the trigeminal nerve. At higher doses, partial nerve necrosis is observed. We think that these effects influence the physiological features of trigeminal neuralgia.

Rapidly progressive, acute polyradiculopathies and cranial neuropathies resulting from leptomeningeal nasal-type NK cell lymphoma.

Lymphomas may cause polyradiculopathies by several pathogenic mechanisms. However, such a presentation of a nasal-type NK (natural killer) cell lymphoma is rare. We report a previously healthy man who developed acute, axon-loss radiculopathies and cranial neuropathies. Despite the lack of a nasal or midline facial mass, cerebrospinal fluid cytologic and flow cytometric immurtophenotypic studies disclosed that the patient's rapid demise was the result of a nasal-type NK cell lymphoma with leptomeningeal involvement.

Sensory Neuropathy With Sjögren's Syndrome, Thymoma, and Hypogammaglobulinemia.

We report a 63-year-old woman with common variable immunodeficiency (CVID) and an indolent distal sensory neuropathy. Despite having negative serologic tests for Sjögren's syndrome, evaluation of the neuropathy led to a new diagnosis of Sjögren's syndrome based on the presence of sicca symptoms, an abnormal Schirmer's test, and histologic evidence of sialadenitis. In addition, a thymoma was discovered. We conclude that the occurrence of thymoma, CVID, and Sjogren's syndrome reflect a state of systemic autoimmune dysregulation in this patient. We also reiterate the diagnostic importance of salivary gland biopsy in patients with sicca symptoms and sensory neuropathy.

Acute myopathy after liver transplantation.

Acute myopathy is a cause of weakness and additional morbidity in a variety of critically ill patients, including transplant recipients. We report the incidence of and risk factors associated with acute myopathy after orthotopic liver transplantation (OLTx). One hundred consecutive adult patients were prospectively assessed for muscle weakness after OLTx. Electrodiagnostic studies and muscle biopsies were performed on consenting affected patients. Potential risk factors for myopathy were evaluated in patients with myopathy versus control subjects. Seven patients developed acute persistent weakness after OLTx. Electrodiagnostic studies were consistent with a necrotizing myopathy. Histopathologic evaluation in five revealed a necrotizing myopathy with loss of myosin thick filaments. A higher initial index of illness severity, dialysis requirement, and higher doses of glucocorticoids were associated with development of myopathy. Patients with myopathy subsequently remained in the intensive care unit (ICU) longer than unaffected patients. In conclusion, acute substantial weakness was a source of additional morbidity in 7% of patients after OLTx. Most had myopathy with loss of myosin thick filaments. Patients with greater severity of illnesses and renal failure requiring dialysis were more likely to be affected. The effect of reducing exposure to corticosteroids in high-risk patients warrants further investigation.

Percutaneous needle muscle biopsy in the evaluation of patients with suspected inflammatory myopathy.

OBJECTIVE: To determine the usefulness of a unique method of percutaneous needle muscle biopsy (NMB) in patients with suspected idiopathic inflammatory myopathy (IIM). METHODS: The yield of percutaneous NMB was studied in 55 patients who were found to have a combination of clinical, laboratory, or electromyographic features of IIM. RESULTS: A diagnosis of IIM was confirmed histopathologically in 29 patients (53%), other specific myopathies were found in 5 (9%), nonspecific myopathic changes were present in 11 (20%), and a neurogenic process was diagnosed in 3 (5%). Nonspecific changes or no abnormalities were present in 7 patients (13%). Followup of the 18 patients with nonspecific histopathologic findings disclosed that only 3 had a subsequent disease course compatible with IIM. CONCLUSION: Percutaneous NMB is a safe, convenient, and relatively inexpensive method of muscle biopsy, with a high diagnostic yield for the pathologic confirmation of IIM. It should be considered as a primary method of acquiring muscle for histopathologic examination in the evaluation of suspected IIM.

Acute onset of colchicine myoneuropathy in cardiac transplant recipients: case studies of three patients.

Colchicine causes both muscle and peripheral nerve toxicity of subacute onset in patients with renal insufficiency. We report three cardiac transplant recipients, treated with colchicine for cyclosporin A (CyA)-induced gout, who developed acute weakness due to colchicine myoneuropathy. The onset of disabling weakness occurred over a 1-2 week period. All three patients had concomitant renal insufficiency and an elevated serum creatine kinase and two elevated CyA levels at the time of presentation. Electromyography revealed features of myopathy and motor axonal neuropathy in all three patients. Two underwent muscle biopsy which confirmed the presence of sarcoplasmic vacuoles characteristic of colchicine-induced myopathy. All patients rapidly improved with either colchicine dose reduction or drug discontinuation. In conclusion, cardiac transplant recipients treated with CyA and colchicine may be at increased risk of developing colchicine-induced myoneuropathy especially in the setting of concurrent renal insufficiency. In patients with post-transplantation gouty arthritis, other treatment modalities are suggested; and if colchicine is administered, the dose should be reduced, CyA levels should be monitored closely and patients should be assessed for signs of neuromuscular toxicity.

Acute myopathy of intensive care: clinical, electromyographic, and pathological aspects.

An acute myopathy of intensive care occurs in critically ill patients treated with intravenous corticosteroids and neuromuscular junction-blocking agents. The full clinicopathological spectrum is uncertain. We evaluated the clinical, electrodiagnostic, and histopathological features of 14 patients who developed acute myopathy of intensive care after organ transplantation or during treatment of severe pulmonary disorders and sepsis. Patients received high-dose intravenous corticosteroids, usually in conjunction with relatively low to moderate doses of neuromuscular junction-blocking agents. After discontinuation of the latter drugs, most had diffuse, flaccid weakness with failure to wean from mechanical ventilation. Electrodiagnostic findings were consistent with a necrotizing myopathy. Muscle histopathology revealed myopathy with loss of thick filaments in 79%, mild myopathic changes in 14%, and atrophy of type 1 and type 2 fibers in 7%. Loss of thick filaments was identified in muscle biopsy specimens obtained 30 +/- 11 days (mean +/- standard deviation) after intravenous corticosteroid treatment but not in those obtained earlier (12 +/- 2 days). Critically ill patients, including those receiving organ transplants, may develop acute myopathy of intensive care after exposure to intravenous corticosteroids and neuromuscular junction-blocking agents, although the exposure to the latter drugs may be minimal. Selective loss of thick filaments is common in acute myopathy of intensive care, especially if the muscle biopsy specimen is obtained 2 weeks or more after intravenous corticosteroid exposure.

Case of the month. June 1996--anorexia nervosa.

A 32 year old woman with a history of anorexia nervosa began experiencing severe muscle weakness. Proximal weakness was worse than distal and she became unable to walk. Serum creatine kinase was elevated 15-fold and EMG was consistent with a myopathic process. Muscle biopsy showed focal areas of absent staining using NADH and ATPase enzyme histochemistry. Gomori trichrome revealed many positive inclusions which were positive using immunohistochemistry for actin. Electron microscopy revealed these areas to contain cytoid bodies with Z-band streaming and disorganization of the myofibrillar network. These findings are consistent with the myopathy associated with ipecac (emetine) toxicity. A urine toxicology screen demonstrated evidence of emetine abuse, which was later admitted by the patient. Following discontinuation of the drug, the patient recovered normal muscle strength.

Disseminated histoplasmosis presenting as myositis and fasciitis in a patient with dermatomyositis.

A 54-year-old man with dermatomyositis initially responsive to corticosteroids and methotrexate developed severe myalgias, increasing weakness, and fevers. Laboratory studies were suggestive of disseminated histoplasmosis, and muscle biopsy revealed myositis, fasciitis, and yeast in the perimysial connective tissue. Histoplasma capsulatum was cultured from skeletal muscle. Despite antifungal therapy, necrotizing fasciitis progressed to gluteal abscess formation. Disseminated histoplasmosis may present atypically in immunocompromised hosts as fasciitis and myositis. Patients with dermatomyositis could be particularly vulnerable to soft tissue invasion by fungi due to their underlying microangiopathy.

Myopathy in the elderly: evaluation of the histopathologic spectrum and the accuracy of clinical diagnosis.

We undertook a retrospective clinicopathologic study to ascertain the spectrum of histopathologic muscle biopsy changes in the elderly thought to have a myopathy, and to determine the accuracy of clinical diagnosis of myopathy in the elderly compared with a younger control population. We compared muscle histology and case histories, as well as EMG and creatine kinase (CK) data, obtained over 10 years from 77 consecutive patients aged 65 years or older (75 +/- 6, mean +/- SD; group 1) with those from 104 patients aged 30 to 50 years (group 2). Prominent myopathic features were present in 42% (group 1) versus 51% (group 2) of all biopsies. Neurogenic changes (17% versus 9%, p < 0.04) and type II fiber atrophy (22% versus 6%, p < 0.0005) were more common in the elderly, whereas normal findings tended to be less frequent (19% versus 35%). In at least 68% of patients in both groups with the histologic diagnosis of myopathy, either the CK was elevated or the EMG was consistent with that diagnosis. Our study indicates that (1) the spectrum of histopathologic changes in the two groups differs because of a higher frequency of neurogenic change and type II atrophy in the elderly, and (2) the accuracy of clinical diagnosis of myopathy in the elderly approximates that in a younger population.

Acute myopathy and neuropathy in status asthmaticus: case report and literature review.

A 38-year-old woman developed acute, severe weakness during the treatment of status asthmaticus that included high-dose intravenous corticosteroids. A muscle biopsy and EMG indicated a myopathy, and nerve conduction studies disclosed a neuropathic component. In association with corticosteroid tapering, the clinical, EMG, and nerve conduction abnormalities resolved. In some patients, intensive treatment of status asthmaticus may cause a reversible, toxic disorder of muscle and nerve.

Angiotropic lymphoma (intravascular large cell lymphoma) presenting with cauda equina syndrome.

A 50-year-old man developed cauda equina syndrome of unknown etiology that was stable for 20 months. Two months prior to sudden death, he experienced new back pain, confusion, seizures, and multiple cranial nerve palsies. Neuropathologic examination revealed angiotropic lymphoma without parenchymal involvement or infarcts in the brain, spinal cord, and muscle. In addition, nerve roots in the cauda equina contained angiotropic lymphoma and infarcts of various ages. Angiotropic lymphoma should be considered as a cause of cauda equina syndrome and of disorders that affect the central and peripheral nervous systems concurrently.

Childhood onset oculopharyngeal muscular dystrophy.

Oculopharyngeal muscular dystrophy is an inherited disorder, usually autosomal dominant, which typically becomes symptomatic during the fifth decade of life with slowly progressive ptosis and dysphagia; childhood onset has not been reported. A 13-year-old female of French-Canadian descent developed nasal speech and strabismus at 5 years of age; there was no family history of neuromuscular disease. Ptosis and mild facial and proximal muscle weakness were present by 9 years of age. Over the next 4 years, the patient developed dysphagia, palatal paralysis, weight loss, decreased ocular motility, scoliosis, shortness of breath, and obstructive apnea. Tracheostomy and gastrostomy were required. Creatine kinase and repetitive facial nerve stimulation were normal. Edrophonium testing was negative and electromyography revealed myopathic motor units in the iliopsoas muscle. A preponderance of type I fibers and scattered atrophic and angulated muscle fibers were present in 3 muscle biopsies. The clinical presentation and findings are consistent with childhood onset oculopharyngeal muscular dystrophy.

MR imaging of paraneoplastic limbic encephalitis.

Paraneoplastic limbic encephalitis is a rare disorder that has been previously diagnosed on clinical and pathologic grounds without good radiologic correlation. We present the case of a 42-year-old woman who developed gradually progressive limbic dysfunction 4 years after undergoing mastectomy for breast cancer. Although CT scans were normal, magnetic resonance (MR) imaging showed signal abnormalities in the medial portions of both temporal lobes, the amygdaloid nuclei, and the hypothalamus. An MR-guided temporal lobe biopsy confirmed the presence of encephalitis.