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.

The epidemiology of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults and is characterized by neurodegeneration of motor neurons in the brain and spinal cord. The incidence of ALS is approximately 1-2.6 cases per 100 000 persons annually, whereas the prevalence is approximately 6 cases per 100 000. The average age of onset of ALS is currently 58-60 years and the average survival from onset to death is 3-4 years. Between October 19, 2010 and December 31, 2011, there were an estimated 12 187 prevalent cases diagnosed with definite ALS in the USA alone. Sporadic ALS (90-95%) constitutes the large majority of cases, while the remaining 5-10% are hereditary and termed familial ALS. Sporadic ALS is suspected to involve genetic susceptibility to environmental risk factors. The purpose of this review is to present a clinical overview of ALS and provide an epidemiologic summary of personal and environmental risk factors shown to be related to the risk of disease. A discussion of the most recent research initiatives is also included.

Chronic inflammatory demyelinating polyneuropathy and ventilatory failure: report of seven new cases and review of the literature.

BACKGROUND: Ventilatory involvement is rarely reported in chronic inflammatory demyelinating polyneuropathy (CIDP), but small prospective studies showed frequent involvement of phrenic nerves, which is usually overshadowed by severe limb weakness. OBJECTIVES: To report the clinical features of CIDP associated with ventilatory failure. RESULTS: There were seven patients (43% women), with a mean age of 58.6 (range 38-82). The clinical courses were relapsing in five and progressive in two. Four patients had an initial event simulating Guillain-Barre syndrome (GBS). Ventilatory failure was recurrent in three patients. Five patients had full or nearly complete recoveries; one still requires nocturnal ventilation; and one died (14%) of myocardial infarction while still requiring mechanical ventilation. CONCLUSIONS: Clinical ventilatory dysfunction in CIDP is usually not an indicator of poor prognosis, and many patients recover without significant permanent disability. The mortality rate is similar to intubated patients with GBS. Patients with cardiopulmonary comorbidities and acute GBS-like onset of CIDP may be at higher risk of ventilatory failure which typically responds to 'standard' treatments of CIDP. Larger prospective studies are needed to define the prevalence, clinical spectrum and significance of ventilatory involvement in CIDP and to establish guidelines for evaluation and treatment.

Hemorrhage in posterior reversible encephalopathy syndrome: imaging and clinical features.

BACKGROUND AND PURPOSE: Hemorrhage is known to occur in posterior reversible encephalopathy syndrome (PRES), but the characteristics have not been analyzed in detail. The purpose of this study was to evaluate the imaging and clinical features of hemorrhage in PRES. MATERIALS AND METHODS: Retrospective assessment of 151 patients with PRES was performed, and 23 patients were identified who had intracranial hemorrhage at toxicity. Hemorrhage types were identified and tabulated, including minute focal hemorrhages (<5 mm), sulcal subarachnoid hemorrhage, and focal hematoma. Clinical features of hemorrhage and nonhemorrhage PRES groups were evaluated, including toxicity blood pressure, coagulation profile/platelet counts, coagulation-altering medication, and clinical conditions associated with PRES. Toxicity mean arterial pressure (MAP) groups were defined as normal (<106 mm Hg), mildly hypertensive (106-116 mm Hg), or severely hypertensive (>116 mm Hg). RESULTS: The overall incidence of hemorrhage was 15.2%, with borderline statistical significance noted between the observed clinical associations (P = .07). Hemorrhage was significantly more common (P = .02) after allogeneic bone marrow transplantation (allo-BMT) than after solid-organ transplantation. The 3 hemorrhage types were noted with equal frequency. A single hemorrhage type was found in 16 patients, with multiple types noted in 7. Patients undergoing therapeutic anticoagulation were statistically more likely to develop hemorrhage (P = .04). No difference in hemorrhage incidence was found among the 3 blood pressure subgroups (range, 14.9%-15.9%). CONCLUSIONS: Three distinct types of hemorrhage (minute hemorrhage, sulcal subarachnoid hemorrhage, hematoma) were identified in PRES with equal frequency. The greatest hemorrhage frequency was seen after allo-BMT and in patients undergoing therapeutic anticoagulation. Hemorrhage rate was independent of the toxicity blood pressure.

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.

Grief support for informal caregivers of patients with ALS: a national survey.

Providing emotional support to caregivers is integral to comprehensive ALS care. The authors surveyed ALS Association centers and clinics and Muscular Dystrophy Association/ALS centers. Respondents thought that grief and bereavement support was integral to ALS care but thought that the support provided by their centers was often inadequate.

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.

Myositis-specific and -associated autoantibodies: a review from the clinical perspective.

Twenty-five percent to 50% of patients with polymyositis (PM) and dermatomyositis (DM) have autoantibodies that are specific for or associated with the presence of myositis. Because of a relatively low sensitivity for the diagnosis of PM or DM, these autoantibodies are inadequate as a screening test for PM or DM in patients with suspected inflammatory myopathy. However, they may be used to support the diagnosis of myositis, and they help exclude the diagnosis of inclusion body myositis in which autoantibodies are infrequent. In addition, these antibodies are associated with homogeneous syndromes with the following reproducible clinical features and prognosis: (I) the antisynthetases generally occur with moderately severe myositis, often in association with interstitial lung disease. Raynaud's phenomenon, and arthropathy; (2) anti-SRP is a marker of severe PM with associated cardiac disease and high mortality; (3) anti-Mi-2 occurs in generally corticosteroid-responsive DM associated with a potentially severe rash; and (4) the myositis-associated autoantibodies anti-PM-ScI and anti-Ku portend a moderately favorable prognosis. Anti-PH-Scl occurs in systemic sclerosis, often in association with arthropathy and Raynaud's syndrome. Anti-Ku occurs in systemic sclerosis and other connective tissue diseases with or without myositis. Thus, both myositis-specific and -associated antibodies have clinical use in the diagnosis of PM and DM and are predictive of certain clinical syndromes and responses to treatment.

Comparison of different modalities for detection of small fiber neuropathy.

OBJECTIVES: In general, large fiber sensory function is easier to assess than small fiber function both clinically and electrophysiologically. Therefore, small fiber sensory neuropathies are more difficult to diagnose. The relative sensitivities of different electrodiagnostic tests for small fiber neuropathy are not known. We sought to determine and compare the sensitivities of quantitative thermal sensory testing (QST), quantitative sudomotor axon reflex testing (QSART), and cardiovascular autonomic testing for diagnosis in patients with clinically suspected small fiber neuropathy. METHODS: 15 adult patients with clinically suspected small fiber sensory neuropathy underwent neurologic examination, QST, and QSART. Twelve also underwent cardiovascular autonomic testing. RESULTS: 80% had an abnormal neurologic examination consistent with small fiber neuropathy, while 93% had at least one abnormal quantitative test. QSART was most sensitive with 12 of 15 (80%) having abnormal studies while 10 of 15 (67%) had abnormal thermal thresholds by QST. Abnormal heart rate with deep breathing was detected in 9 of 12 (75%) patients. CONCLUSION: Of the modalities tested, QSART was most sensitive in confirming the clinical suspicion of a small fiber neuropathy. Autonomic cardiovascular abnormalities were also common in our patients. Clinical examination and QSART may be optimal for screening patients for small fiber neuropathy.

Fluctuating clinical myotonia and weakness from Thomsen's disease occurring only during pregnancies.

Advances in molecular genetics are allowing better phenotype to genotype correlation of the non-dystrophic myotonic disorders. We report a 32-year-old woman, who first noted myotonia that was associated with weakness during her first pregnancy. The work-up disclosed that she had Thomsen's disease which is not known to be associated with weakness. In addition, her myotonia was of the fluctuating type and occurred (symptomatically) only during two pregnancies. We discuss the evaluation of myotonia in the pregnant woman which led to the diagnosis of Thomsen's disease and we conclude that in exceptional cases, fluctuating myotonia and weakness occurs in autosomal dominant chloride channel myotonia (Thomsen's disease).

Multifocal small fiber sensory neuropathy.

PURPOSE: : To report four patients with unusual multifocal patterns of small fiber sensory neuropathy METHODS: : Four patients who developed multifocal sensory symptoms after infectious illnesses underwent neurologic examinations, nerve conduction studies, and serologic testing. All had one to three types of electrodiagnostic assessments of small nerve fibers by evaluation of thermal and vibratory thresholds. quantitative sudomotor axon reflex testing, or autonomic cardiovascular testing. RESULTS: Nerve conduction and serologic studies were normal. Quantitative sudomotor axon reflex testing, autonomic cardiovascular testing, or both revealed abnormalities of small fiber function in all patients, and thermal thresholds were abnormal in one. Three had progression and fluctuations of symptoms for months. CONCLUSIONS: : Small fiber sensory neuropathies occasionally occur in a multifocal rather than the typical distal distribution and may comprise part of the spectrum of postinfectious sensory neuropathies. Objective testing of small fiber function is useful in distinguishing small fiber sensory neuropathy from other causes of paresthesias in this setting.

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.