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Introduction Causes of small-fiber peripheral neuropathies (SFN) are often undefined. In this study we investigated associations of serum autoantibodies, immunoglobulin G (IgG) vs fibroblast growth factor receptor-3 (FGFR-3), and immunoglobulin M (IgM) vs trisulfated heparan disaccharide (TS-HDS) in cryptogenic SFN. Methods One hundred fifty-five patients with biopsy-proven SFN and no identified cause for their neuropathy were blindly tested for serum IgM vs TS-HDS and IgG vs FGFR-3. Results Forty-eight percent of SFN patients had serum antibodies, 37% with IgM vs TS-HDS and 15% with IgG vs FGFR-3. TS-HDS antibodies were more frequent in SFN patients than in controls (P = .0012). Both antibodies were more common in females, and with non-length-dependent nerve pathology. Nintey-two percent of patients with acute-onset SFN had serum IgM vs TS-HDS. Discussion Autoantibodies directed against TS-HDS and FGFR-3 suggest an immune disorder in otherwise idiopathic SFN. Serum IgM vs TS-HDS may be a marker for SFN with an acute onset.

Objective: We studied mitochondrial impairment as a factor in the pathologic equivalent of sarcopenia, muscle fiber atrophy associated with increased age. Methods: Mitochondrial oxidative enzyme activities and coenzyme Q10 levels were measured in frozen human proximal limb muscles with combined age and atrophy, age alone, atrophy alone, denervation, immune myopathies, and mitochondrial disorders with ophthalmoplegia. Results: Sarcopenia (age and atrophy) had reduced mean activities of mitochondrial Complexes I, II, and II+III, with severe reduction of Complex I activity in 54% of patients. Atrophy, and specific denervation atrophy, had similar patterns of changes. Age alone had moderately reduced Complex I activity. Mitochondrial myopathies had mildly lower Complex IV activity. Immune myopathies had unchanged enzyme activities. Interpretation: Mitochondrial oxidative enzyme activities, especially Complex I, but also Complexes II and II+III, are reduced in muscles with the pathologic equivalent of sarcopenia. Individually, atrophy and age have different patterns of oxidative enzyme changes. This article is protected by copyright. All rights reserved.

Introduction: The radial nerve and posterior interosseous nerve (PIN) are prone to injury at multiple sites. Electrodiagnostic (EDx) studies may only identify the most proximal lesion. Nerve ultrasound could augment EDx by visualizing additional pathology. Methods: This investigation was a retrospective examination of ultrasound and EDx from 26 patients evaluated for posterior cord/radial/PIN lesions. Results: Eighteen of 26 patients had abnormalities on EDx (15 radial, 2 PIN, 1 posterior cord). Ultrasound identified 15 of 18 (83%) of the EDx abnormalities and provided additional diagnostic information. In 6 of 15 (40%) patients with EDx evidence of radial neuropathy, ultrasound identified both radial nerve enlargement and additional, unsuspected PIN enlargement (53% to 339% enlarged vs. unaffected side). Ultrasound also identified: nerve (dis)continuity at the trauma site (n = 8); and nerve tumor (n = 2; 1 with normal EDx). Conclusion: In radial neuropathy, ultrasound often augments EDx studies and identifies a second lesion in the PIN. Further studies are required to determine the etiology and significance of this additional distal pathology. Muscle Nerve 53: 379–383, 2016

Introduction Different disease patterns result from loss of myelinated and unmyelinated axons, but quantitation to define their loss has been difficult. Methods We measured large and small endoneurial axons in axonal neuropathies by staining them with peripherin and comparing their area to that of nonmyelinating Schwann cells stained with neural cell adhesion molecule (NCAM). Results Loss of myelinated and unmyelinated axons was typically proportional, with predominant myelinated or unmyelinated axon loss in a few patients. Myelinated axon loss was associated with loss of distal vibration sense and sensory potentials (P

Introduction: Nerves are often enlarged in chronic inflammatory demyelinating polyneuropathy (CIDP). In this investigation we studied changes with treatment over time. Methods: We retrospectively compared serial ultrasound measurements of median and ulnar nerve size with clinical and electrodiagnostic evaluations in 23 CIDP subjects. We defined remission as stable clinical improvement on low or decreasing amounts of medication. Results: Nerves were normal at last follow-up more often in subjects who achieved remission than in those who did not (10 of 13 vs. 0 of 10, P = 0.0001). Nerves were normal or smaller (>30% reduction) more often in subjects whose grip strength improved or remained strong compared those whose grip strength weakened (12 of 16 vs. 0 of 3, P = 0.04), and in subjects whose demyelinating electrodiagnostic features resolved compared with those whose demyelination persisted (7 of 7 vs. 6 of 12, P = 0.04). Over time, nerve size decreased more in subjects with baseline nerve enlargement who achieved remission than in those who did not (−41% vs. 7%, P = 0.04). Conclusion: In CIDP, enlarged nerves normalized or decreased with remission. Muscle Nerve 50: 733–738, 2014

Introduction: Neurological disorders with low tissue coenzyme Q10 (CoQ10) levels are important to identify, as they may be treatable. Methods: We evaluated retrospectively clinical, laboratory, and muscle histochemistry and oxidative enzyme characteristics in 49 children with suspected mitochondrial disorders. We compared 18 with CoQ10 deficiency in muscle to 31 with normal CoQ10 values. Results: Muscle from CoQ10-deficient patients averaged 5.5-fold more frequent type 2C muscle fibers than controls (P

Introduction: Ipilimumab, a monoclonal anti–CTLA-4 antibody, is used to treat melanoma. Neuromuscular side effects, possibly autoimmune, may occur. Methods: In this investigation we undertook a retrospective review of patient records. Results: After 3 doses of ipilimumab, a 31-year-old man developed asymmetric, severe weakness involving all limbs, respiration, and cranial nerves, which was progressive over 2 weeks. EMG/NCS showed an axonal polyradiculoneuropathy with multifocal motor conduction blocks. CSF protein was 749 mg/dl. Nerve pathology showed inflammation around the endoneurial microvessels and subperineurial edema and inflammation. Spine MRI showed leptomeningeal and anterior and posterior root enhancement. Strength improved slowly over months after ipilimumab discontinuation and immunomodulating treatment. Conclusions: Ipilimumab toxicity presented as a monophasic, multifocal, asymmetric polyradiculoneuropathy involving roots and peripheral and cranial nerves. Ipilimumab may produce a polyradiculoneuropathy with disruption of the blood–nerve barrier due to a microvasculopathy. Muscle Nerve 48: 440–444, 2013

Introduction: Muscle cramps are a common complaint and are thought to arise from spontaneous discharges of the motor nerve terminal. Polyneuropathy is often causative, but small-fiber neuropathy (SFN) has not been assessed. Methods: We performed skin biopsies on consecutive patients with cramps but without neuropathic complaints. Twelve patients were biopsied, 8 with normal small-fiber sensation. Results: Seven patients had decreased intraepidermal nerve fiber density (IENFD), 2 with non–length-dependent loss. A cause for neuropathy was found in 1 patient with cramp–fasciculation syndrome. Creatine kinase was elevated in 8 patients, 4 with decreased IENFD. Muscle biopsy, performed in 8 patients, but was diagnostic in only 1, with McArdle disease. Conclusions: Our data show that 60% of patients with muscle cramps who lack neuropathic complaints have SFN, as documented by decreased IENFD. Cramps may originate as local mediators of inflammation released by damaged small nerve that excite intramuscular nerves. Muscle Nerve, 48: 252–255, 2013

Introduction: We studied ultrasound features of muscle after nerve injury. Methods: We evaluated ultrasound measurements of muscle thickness and backscatter in injured and contralateral uninjured elbow flexors of 51 children with newborn brachial plexus palsy (NBPP) and compared the results to elbow flexor function (Active Movement Scale), defined as normal, moderate, or severe. Results: Compared with uninjured limbs, muscle in injured arms was 15% thinner with severe impairment, 17% thicker with moderate impairment, and no different with normal function. Relative to uninjured limbs, moderately impaired muscle was thicker than both severely impaired and normal strength muscle. Backscatter was higher in injured than in uninjured limbs regardless of function. In 17 patients with sequential measures, muscle thickness, but not backscatter, increased with function over time. Conclusions: Muscle thickness differentiates moderate from severe impairment after NBPP and increases with recovery over time. Muscle backscatter identifies prior injury regardless of function. Muscle Nerve, 2013

Introduction: In this investigation we studied clinical and laboratory features of polyneuropathies in patients with serum IgM binding to the trisulfated disaccharide IdoA2S-GlcNS-6S (TS-HDS). Methods: We retrospectively compared 58 patients with selective IgM binding to TS-HDS to 41 consecutive patients with polyneuropathies without TS-HDS binding. Results: Patients with IgM vs. TS-HDS commonly had distal, sensory, axonal neuropathies. Weakness was associated with IgM M-proteins. Hand pain and serum IgM M-proteins were more common than in control neuropathy patients. TS-HDS antibody binding was often selectively κ class. Biopsies showed capillary pathology with thickened basal lamina and C5b9 complement deposition. IgM in sera with TS-HDS antibodies often bound to capillaries. Conclusions: Serum IgM binding to TS-HDS is associated with painful, sensory > motor, polyneuropathies with an increased frequency of persistent hand discomfort, serum IgM M-proteins, and capillary pathology. Serum IgM binding to TS-HDS suggests a possible immune etiology underlying some otherwise idiopathic sensory polyneuropathies. Muscle Nerve 45: 866–872, 2012

Introduction: Acid maltase deficiency (AMD, or Pompe disease) is an inherited myopathic disorder of glycogen degradation. Diagnosis is often delayed. Muscle ultrasound could improve diagnosis. Methods: We compared skeletal muscle ultrasound images from adults with AMD (n = 10) to other myopathies (n = 81) and, in AMD, compared qualitative (Heckmatt) and quantitative (backscatter) ultrasound measurements with strength and function. Results: Qualitative ultrasound was abnormal in at least one muscle in all AMD subjects. Ultrasound patterns specific for AMD were: normal triceps brachii despite abnormalities in elbow flexors (89% vs. 17%, P < 0.0001); focal abnormalities affecting deep more than superficial biceps brachii (40% vs. 4%, P = 0.002); and more severe involvement of vastus intermedius than rectus femoris (40 vs. 11%, P = 0.03). In AMD, both qualitative (Heckmatt) and quantitative (backscatter) ultrasound measures increased with decreasing strength and function. Conclusions: Muscle ultrasound identifies the presence and specific patterns of AMD pathology, measures disease severity, and can help in the diagnosis of AMD. Muscle Nerve 44: 418–423, 2011

Introduction: Corticosteroid treatment slows dis- ease progression and is the standard of care for Duchenne muscular dystrophy (DMD). Coenzyme Q10 (CoQ10) is a potent antioxidant that may improve function in dystrophin-defi- cient muscle. Methods: We performed an open-label, '' pilot study of CoQ10 in thirteen 5-10-year-old DMD patients on steroids. The primary outcome measure was the total quantita- tive muscle testing (QMT) score. Results: Twelve of 16 children (mean age 8.03 6 1.64 years) completed the trial. Target se- rum levels of CoQ10 (� 2.5 lg/ml) were shown to be subject- and administration-dependent. Nine of 12 subjects showed an increase in total QMT score. Overall, CoQ10 treatment resulted in an 8.5% increase in muscle strength (P ¼ 0.03). Conclu- sions: Addition of CoQ10 to prednisone therapy in DMD patients resulted in an increase in muscle strength. These results warrant a larger, controlled trial of CoQ10 in DMD. Muscle Nerve 000: 000-000, 2011

Ultrasound has been used for visualizing peripheral nerve pathology. Our goal was to use ultrasound to quantitate the sizes of upper extremity nerves along their length in control subjects and patients with neuropathy. We measured median and ulnar nerve cross-sectional areas (NCSA) in the arms of 190 subjects, including 100 with neuropathies and 90 controls. We found that NCSAs in healthy child and adult controls were greater with increasing height, at proximal sites, and at sites of entrapment. Nerves were enlarged in all Charcot-Marie-Tooth 1A (CMT-1A) (11 of 11; 100%), most chronic inflammatory demyelinating polyneuropathy (CIDP) (31 of 36; 86%), half of Guillain-Barre syndrome (GBS) (8 of 17; 47%), but few axonal neuropathy (7 of 36, 19%) subjects. In GBS, nerve enlargement occurred early and with minimal electrodiagnostic abnormalities in some patients. We conclude that NCSA measured by ultrasound is a quantifiable marker of nerve features that should be corrected for patient characteristics and nerve site. NCSA is generally larger in demyelinating than it is in axonal polyneuropathies.

The objective of this 12-month study was to describe the clinical features of late-onset Pompe disease and identify appropriate outcome measures for use in clinical trials. Assessments included quantitative muscle testing (QMT), functional activities (FAA), 6-min walk test (6MWT), and pulmonary function testing (PFT). Percent predicted values indicated quantifiable upper and lower extremity weakness, impaired walking ability, and respiratory muscle weakness. Significant declines in arm and leg strength and pulmonary function were observed during the study period. The outcome measures were demonstrated to be safe and reliable. Symptom duration was identified as the best predictor of the extent of skeletal and respiratory muscle weakness.

We evaluated the ability of an ultrasound method, which can characterize cardiac muscle pathology and has reliability across different imaging systems, to obtain calibrated quantitative estimates of backscatter of skeletal muscle. Our procedure utilized a tissue-mimicking phantom to establish a linear relationship between ultrasound grayscale and backscatter levels. We studied skeletal muscles of 82 adults: 45 controls and 37 patients with hereditary myopathies. We found that skeletal muscle ultrasound backscatter levels varied with probe orientation, age, and muscle contraction and pathology. Reliability was greater with the probe in longitudinal compared with transverse planes. Backscatter levels were higher in those >40 years of age, in muscle extension than flexion, and in myopathic patients than controls. Calibrated measurements of muscle backscatter have sensitivity and specificity in identifying and reliably measuring levels of skeletal muscle pathology.

This study was performed to determine whether there are distinctive features to the pattern of muscle denervation in motor neuron disease. We first compared muscle biopsies from patients with amyotrophic lateral sclerosis (ALS) or Kennedy's disease with other causes of denervation. Groups of atrophic muscle fibers, with individual groups containing both fiber types I and II, occurred frequently in motor neuron disease but not other causes of denervation. We then identified 11 additional muscle biopsies with frequent atrophic groups containing mixed fiber types. Chart review revealed that 10 patients had a final diagnosis of motor neuron disease or ALS and one had multifocal motor neuropathy. We conclude that muscle biopsy may have diagnostic utility early in the course of motor neuron disease. The muscle biopsy pattern of frequent atrophic groups containing mixed fiber types should suggest a diagnosis of a motor neuron syndrome or motor neuropathy.

Peripheral neuropathy is common in patients with Sjögren's syndrome (SS), but its precise prevalence is unknown. Most prior studies were conducted at neurology or rheumatology specialty clinics and likely selected for a more severely affected population. We evaluated 22 SS patients and 10 controls for evidence of neuropathy in an outpatient setting at a regional meeting of the Sjögren's Syndrome Foundation. We performed neurological examinations and nerve conduction studies (NCSs) and measured serum antinuclear antibody (ANA) and SS-A and SS-B antibody levels. Participants filled out a questionnaire pertaining to symptoms, diagnosis, and treatment. We found that signs and symptoms related to small axons were more common in patients with SS than in controls. Complaints of painful distal paresthesias in the feet were noted in 59% of patients but in only 10% of controls, and of abnormal sweating in 41% and 0%, respectively. Examination revealed decreased pinprick sensation in 64% of patients with SS, but in only 30% of controls. Overall, 45% of the patients but none of the controls were thought to have an isolated small-fiber neuropathy. Large-fiber dysfunction (as measured by testing vibration, deep tendon reflexes, and NCSs) was similar between the two groups. We conclude that small-fiber neuropathy is common in patients with SS.

We studied clinical and serological features of five patients with polyneuropathy and serum immunoglobulin M (IgM) binding to the trisulfated disaccharide IdoA2S-GlcNS-6S (TS-HDS), the most abundant disaccharide component of heparin oligosaccharides. The patients all had painful, predominantly sensory polyneuropathies. Sensory loss was distal and panmodal. Electrophysiological and pathological studies were consistent with axonal loss, especially of unmyelinated axons. Immunohistochemistry showed IgM and kappa light chains deposited around the rim of intermediate-sized veins in the perimysium and epineurium. Serum IgM binding to TS-HDS was selective, present in high titer (>12,000), and limited to kappa light chains. We conclude that TS-HDS is a newly identified target carbohydrate antigen of some IgM M-proteins. Monoclonal IgM binding to TS-HDS is associated with a painful, predominantly sensory, polyneuropathy syndrome with axonal loss and deposition of IgM in veins. The role of IgM binding to TS-HDS in the pathogenesis of the neuropathy remains to be determined.

Several polyneuropathy syndromes have been described with polyclonal serum immunoglobulin G (IgG) or immunoglobulin M (IgM) binding to gangliosides GM2 and GalNAc-GD1a that contain the terminal trisaccharide moiety GalNAc(β1-4)Gal(α2-3)NeuAc. We describe the clinical and electrodiagnostic features in two patients with serum IgM monoclonal anti-GM2 and anti-GalNAc-GD1a antibodies. These patients had slowly progressive, panmodal sensory loss with severe sensory ataxia. Electrodiagnostic testing showed demyelinating features. Prominent improvement in gait ataxia occurred after treatment with human immune globulin but not after other immunomodulating therapies. Enzyme-linked immunoabsorbent assay and thin-layer chromatography demonstrate that the patient's serum monoclonal IgM bound to gangliosides GM2 and GalNac-GD1a but not to gangliosides without the GalNAc(β1-4)Gal(α2-3)NeuAc moiety. This neuropathy differs from previously reported neuropathy syndromes associated with polyclonal GM2 and GalNAc-GD1a antibodies and from other chronic demyelinating polyneuropathies. We conclude that a distinct syndrome of chronic demyelinating neuropathy with sensory ataxia, unresponsive to corticosteroids, is associated with monoclonal IgM binding to gangliosides with a terminal GalNAc(β1-4)Gal(α2-3)NeuAc trisaccharide moiety. Diagnosis of this syndrome is important to direct appropriate treatment. © 2002 Wiley Periodicals, Inc. Muscle Nerve 25: 000–000, 2002

Inflammatory myopathy with cytochrome oxidase negative muscle fibers (IM/COX-) is characterized by slowly progressive weakness, most prominent in the quadriceps, muscle fibers with reduced COX staining and mitochondrial DNA mutations, and a poor response to corticosteroid treatment. We reviewed records of quantitative measurements of muscle strength in 7 IM/COX- patients to evaluate the outcomes after treatment with oral, once weekly, methotrexate for an average of 15 months. We compared the results to 6 patients with IM/COX- who received no long-term immunosuppression, and to 4 with inclusion body myositis (IBM) who received methotrexate during the same period. Methotrexate treatment of IM/ COX- was followed by improved muscle strength in 5 of 7 patients, averaging 17+/-5%. In contrast, there was no improvement in the strength of 6 untreated IM/COX- patients (-6+/-4%; P=0.003), or 4 methotrexate-treated IBM patients (1+/-2%; P=0.03). We conclude that, despite clinical similarities to inclusion body myositis, which is usually refractory to immunosuppressive therapy, strength in IM/COX- appears to improve with methotrexate treatment. Biopsy studies of inflammatory myopathies with evaluation of muscle for mitochondrial changes and vacuoles can help to direct the choice of appropriate immunomodulating treatments.

An 8-year-old girl developed weakness over 2 years and an elevated creatine kinase. The biopsy was most consistent with an active dystrophy with many inflammatory cells present. A trial of immunosuppression was started. In the first 2 months of treatment with prednisone, she had functionally and quantitatively significant improvement in her proximal strength. Over 3 years of treatment she maintained stable strength. Subsequent genetic studies showed that she had primary alpha-sarcoglycan deficiency. The timing and the degree of benefit in strength were similar to that seen in boys with Duchenne muscular dystrophy who are treated with prednisone.

N lines can be seen by electron microscopy within the I band of skeletal muscle, but are poorly visualized in conventional preparations. We present a case of acute quadriplegic myopathy with myosin loss and prominent N lines. The only other reported cases of N lines were also seen in patients with myosin loss from diverse etiologies. Myosin loss and the subsequent detachment of titin from myosin may result in the formation of prominent N lines.

We studied clinical and electrodiagnostic features of 9 patients with very high titers (>1:10, 000) of serum IgM binding to a CNS myelin antigen (CMA) preparation that copurified with myelin-associated glycoprotein (MAG). We found that 8 of the 9 patients had a combined syndrome of gait ataxia and polyneuropathy (GAPN) with late-age onset (mean = 70 years of age). In the 8 GAPN patients progressive difficulty with ambulation led to significant functional disability and frequent falling. Examination showed a wide-based unsteady gait, especially when standing still or turning. There was mild-to-moderate distal sensory loss with involvement of joint position sense only in the toes. Motor changes, when present, were mild and mainly involved distal leg musculature. Treatment of 5 GAPN patients resulted in clear improvement of 2 after intravenous human immunoglobulin and of 3 others after other immunodulating agents. Immune-mediated GAPN syndromes with high titers of serum IgM binding to CMA appear to be treatable causes of gait disorders in older patients. © 1994 John Wiley & Sons, Inc.

There is increasing evidence that multifocal motor neuropathy (MMN) and some lower motor neuron (LMN) syndromes are immune-mediated and treatable. The frequent occurrence of high titers of anti-GM1 antibodies in these motor neuropathies raised hopes that serum testing would provide useful diagnostic information. Unfortunately, in routine practice, simple quantification of IgM binding to GM1 ganglioside has proved to be a test with poor sensitivity and specificity. We have found that much greater sensitivity and specificity for MMN and LMN syndromes can be obtained by determining serum antibody binding to panels of antigens, such as GM1, histone H3, and NP-9. These results suggest that combined measurement of serum antibody binding to GM1 and other antigens can provide tests that are useful in the diagnosis and management of motor neuropathy syndromes.