Sensorimotor Peripheral Nerve Function and the Longitudinal Relationship With Endurance Walking in the Health, Aging and Body Composition Study.

OBJECTIVES: To determine whether lower extremity sensorimotor peripheral nerve deficits are associated with reduced walking endurance in older adults. DESIGN: Prospective cohort study with 6 years of follow-up. SETTING: Two university research clinics. PARTICIPANTS: Community-dwelling older adults enrolled in the Health, Aging and Body Composition Study from the 2000-2001 annual clinical examination (N=2393; mean age ± SD, 76.5±2.9y; 48.2% men; 38.2% black) and a subset with longitudinal data (n=1178). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants underwent peripheral nerve function examination in 2000-2001, including peroneal motor nerve conduction amplitude and velocity, vibration perception threshold, and monofilament testing. Symptoms of lower extremity peripheral neuropathy included numbness or tingling and sudden stabbing, burning, pain, or aches in the feet or legs. The Long Distance Corridor Walk (LDCW) (400 m) was administered in 2000-2001 and every 2 years afterward for 6 years to assess endurance walking performance over time. RESULTS: In separate, fully adjusted linear mixed models, poor vibration threshold (>130 µm), 10-g and 1.4-g monofilament insensitivity were each associated with a slower 400-m walk completion time (16.0 s, 14.4s, and 6.9 s slower, respectively; P<.05 for each). Poor motor amplitude (<1 mV), poor vibration perception threshold, and 10-g monofilament insensitivity were related to greater slowing per year (4.7, 4.2, and 3.8 additional seconds per year, respectively; P<.05), although poor motor amplitude was not associated with initial completion time. CONCLUSIONS: Poorer sensorimotor peripheral nerve function is related to slower endurance walking and greater slowing longitudinally. Interventions to reduce the burden of sensorimotor peripheral nerve function impairments should be considered to help older adults maintain walking endurance-a critical component for remaining independent in the community.

Sensorimotor Peripheral Nerve Function and Physical Activity in Older Men.

We determined whether sensorimotor peripheral nerve (PN) function was associated with physical activity (PA) in older men. The Osteoporotic Fractures in Men Study Pittsburgh, PA, site (n = 328, age 78.8 ± 4.7 years) conducted PN testing, including: peroneal motor and sural sensory nerve conduction (latencies, amplitudes: CMAP and SNAP for motor and sensory amplitude, respectively), 1.4g/10g monofilament (dorsum of the great toe), and neuropathy symptoms. ANOVA and multivariate linear regression modeled PN associations with PA (Physical Activity Scale for the Elderly [PASE] and SenseWear Armband). After multivariable adjustment, better motor latency was associated with higher PASE scores (160.5 ± 4.8 vs. 135.6 ± 6.7, p < .01). Those without versus with neuropathy symptoms had higher PASE scores (157.6 ± 5.3 vs. 132.9 ± 7.1, p < .01). Better versus worse SNAP was associated with slightly more daily vigorous activity (9.5 ± 0.8 vs. 7.3 ± 0.7, p = .05). Other PN measures were not associated with PA. Certain PN measures were associated with lower PA, suggesting a potential pathway for disability.

The neurology of solid organ transplantation.

Transplantation is the rescue treatment for end-stage organ failure with more than 110,000 solid organs transplantations performed worldwide annually. Recent advances in transplantation procedures and posttransplantation management have improved long-term survival and quality of life of transplant recipients, shifting the focus from acute perioperative critical care needs toward long-term chronic medical problems. Neurologic complications affect up to 30-60 % of solid organ transplant recipients. Common etiologies include opportunistic infections and toxicities of antirejection medications, and wide spectrum of toxic and metabolic disturbances. Most complications are common to all allograft types, but some are relatively specific for individual allograft types (e.g., central pontine myelinolysis in liver transplant recipients). Close collaboration between neurologists and other transplant team members is essential for effective management. Early recognition of complications and accurate diagnosis leading to timely treatment is essential to reduce the morbidity and improve the overall transplant outcome.

Peripheral nerve function and lower extremity muscle power in older men.

OBJECTIVE: To assess whether sensorimotor peripheral nerve function is associated with muscle power in community-dwelling older men. DESIGN: Longitudinal cohort study with 2.3±0.3 years of follow-up. SETTING: One clinical site. PARTICIPANTS: Participants (n=372; mean age ± SD, 77.2±5.1y; 99.5% white; body mass index, 27.9±3.7kg/m(2); power, 1.88±0.6W/kg) at 1 site of the Osteoporotic Fractures in Men Study (N=5994). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: A nerve function ancillary study was performed 4.6±0.4 years after baseline. Muscle power was measured using a power rig. Peroneal motor nerve conduction amplitude, distal motor latency, and mean f-wave latency were measured. Sensory nerve function was assessed using 10-g and 1.4-g monofilaments and sural sensory nerve conduction amplitude and distal latency. Peripheral neuropathy symptoms at the leg and feet were assessed by self-report. RESULTS: After adjustments for age, height, and total body lean and fat mass, 1 SD lower motor (ß=-.07, P<.05) and sensory amplitude (ß=-.09, P<.05) and 1.4-g (ß=-.11, P<.05) and 10-g monofilament insensitivity (ß=-.17, P<.05) were associated with lower muscle power/kg. Compared with the effect of age on muscle power (ß per year, -.05; P<.001), this was equivalent to aging 1.4 years for motor amplitude, 1.8 years for sensory amplitude, 2.2 years for 1.4-g monofilament detection, and 3.4 years for 10-g detection. Baseline 1.4-g monofilament detection predicted a greater decline in muscle power/kg. Short-term change in nerve function was not associated with concurrent short-term change in muscle power/kg. CONCLUSIONS: Worse sensory and motor nerve function were associated with lower muscle power/kg and are likely important for impaired muscle function in older men. Monofilament sensitivity was associated with a greater decline in muscle power/kg, and screening may identify an early risk for muscle function decline in late life, which has implications for disability.

Diagnosing X-Linked Myopathy With Excessive Autophagy After 30 years: Genetic, Ultrasonographic, and Electrodiagnostic Findings.

ABSTRACT: X-linked myopathy with excessive autophagy is a rare disorder caused by a mutation in the vacuolar ATPase assembly factor gene which causes slowly progressive early onset proximal weakness and loss of ambulation by the age of 50-70 years. Electrodiagnostic (EDx) testing usually shows widespread complex repetitive and myotonic discharges, even in muscles unaffected clinically. We report a 65-year-old man who presented with progressive proximal weakness since his teenage years. Extensive workup over 30 years revealed inconclusive EDx and muscle histopathology findings. The diagnosis was finally made with genetic testing. Subsequent neuromuscular ultrasound was more informative of disease severity than repeat EDx and directed a muscle biopsy that showed an autophagic vacuolar myopathy and the novel identification of vacuoles in capillary endothelial cells. Although genetic testing is required for confirmation, in milder cases of X-linked myopathy with excessive autophagy, neuromuscular ultrasound may aid in diagnosis even when EDx findings are inconclusive.

A randomized study of alglucosidase alfa in late-onset Pompe's disease.

BACKGROUND: Pompe's disease is a metabolic myopathy caused by a deficiency of acid alpha glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Late-onset Pompe's disease is characterized by progressive muscle weakness and loss of respiratory function, leading to early death. We conducted a randomized, placebo-controlled trial of alglucosidase alfa, a recombinant human GAA, for the treatment of late-onset Pompe's disease. METHODS: Ninety patients who were 8 years of age or older, ambulatory, and free of invasive ventilation were randomly assigned to receive biweekly intravenous alglucosidase alfa (20 mg per kilogram of body weight) or placebo for 78 weeks at eight centers in the United States and Europe. The two primary end points were distance walked during a 6-minute walk test and percentage of predicted forced vital capacity (FVC). RESULTS: At 78 weeks, the estimated mean changes from baseline in the primary end points favored alglucosidase alfa (an increase of 28.1+/-13.1 m on the 6-minute walk test and an absolute increase of 3.4+/-1.2 percentage points in FVC; P=0.03 and P=0.006, respectively). Similar proportions of patients in the two groups had adverse events, serious adverse events, and infusion-associated reactions; events that occurred only in patients who received the active study drug included anaphylactic reactions and infusion-associated reactions of urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure (each of which occurred in 5 to 8% of the patients). CONCLUSIONS: In this study population, treatment with alglucosidase alfa was associated with improved walking distance and stabilization of pulmonary function over an 18-month period. (ClinicalTrials.gov number, NCT00158600.)

A Case of Probable Multifocal Motor Neuropathy With Clinical Stability for Ten Years After a Single Treatment of Rituximab.

ABSTRACT: Multifocal motor neuropathy is a rare, immune-mediated motor neuropathy with asymmetric, often debilitating progressive weakness. The efficacy of intravenous immunoglobulin in this disease is well established; however, the response typically wanes over time. No other agent has shown similar therapeutic efficacy. We describe a case of anti-ganglioside GM1 IgM-positive multifocal motor neuropathy with typical incomplete and diminishing response to intravenous immunoglobulin over time. Sixteen years after symptom onset, rituximab was administered at 2 g/m2 over 2 weeks. No significant progression of disease has occurred over the following 10 years despite no additional treatments, including intravenous immunoglobulin, being given. Only case reports and small, mostly uncontrolled studies have reported the use of rituximab in multifocal motor neuropathy with mixed results. However, given its potential benefits and lack of an established second-line agent, treatment with rituximab may be considered in select patients with refractory multifocal motor neuropathy.

The clinical spectrum of neurologic disorders after intestinal and multivisceral transplantation.

BACKGROUND: Intestinal transplantation has evolved into an effective therapy for patients with intestinal failure and the inability to be maintained on total parenteral nutrition. Long-term heavy immunosuppression and complex systemic disturbances increase the risk of the neurologic complications. METHODS: This retrospective analysis identified the post-transplant neurologic complications in adult patients who underwent intestinal transplantation at the University of Pittsburgh Medical Center between May 1990 and August 1998. The recipients received 28 isolated intestine, 17 composite liver-intestine, and nine multivisceral allografts. RESULTS: With a median follow-up of 25 months, 46 of 54 recipients (68%) developed headaches (n = 27; 50%), encephalopathy (n = 23; 43%), seizures (n = 9; 17%), neuromuscular disorders (n = 4; 7%), opportunistic CNS infections (n = 4; 7%), and ischemic stroke (n = 2; 4%). CONCLUSIONS: Under high maintenance immunosuppression, intestinal transplant recipients were at high risk for neurologic complications. Future studies are needed to describe post-transplant neurologic complications with modern immunosuppression protocols.

Amyotrophic Lateral Sclerosis Among Veterans Deployed in Support of Post-9/11 U.S. Conflicts.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a recognized military service-connected condition. Prior prevalence studies of ALS among U.S. war Veterans were not able to address concerns related to neurodegenerative sequelae of traumatic brain injury (TBI) and disregarded risk heterogeneity from occupational categories within service branches. MATERIALS AND METHODS: We identified the prevalence of definite and possible ALS and cumulative incidence of definite ALS among Post-9/11 U.S. Veterans deployed in support of Post-9/11 conflicts (mean age 36.3) who received care in the Veterans Health Administration during fiscal years 2002-2015. Using a case-control study design, we also evaluated the association of TBI and major military occupation groups with ALS adjusting for demographics and comorbidities. RESULTS: The prevalence of ALS was 19.7 per 100,000 over 14 years. Both prevalence and cumulative incidence of definite ALS were significantly higher among Air Force personnel compared to other service branches and among tactical operation officers and health care workers compared to general and administrative officers. Neither TBI nor younger age (<45 years) was associated with ALS. Depression, cardiac disease, cerebrovascular disease, high blood pressure, and obstructive sleep apnea were clinical comorbidities significantly associated with ALS in this population of Veterans. CONCLUSION: This study among a cohort of relatively young Veterans showed a high ALS prevalence, suggesting an early onset of ALS among deployed military service members. The higher prevalence among some military specific occupations highlights the need to determine which occupational exposures specific to these occupations (particularly, Air Force personnel, tactical operations officers, and health care workers) might be associated with early onset ALS.

Phenotypes of Late-Onset Transthyretin Amyloid Neuropathy: A Diagnostic Challenge.

Hereditary transthyretin amyloidosis (hATTR) is a rare cause of severe neuropathy, typically with progressive sensorimotor and autonomic manifestations. The clinical course is marked by progressive worsening with typical survival of 7-11 years following the onset of symptoms. The phenotype may resemble other types of neuropathy, and dysautonomia may be absent at onset delaying the diagnosis. Two medications were recently approved for treatment of hATTR neuropathy in the United States and more may follow. Three major phenotypes of hATTR include neuropathic, cardiac, and mixed. Diagnostic clues include "red-flag" symptoms reflecting typical multisystem involvement, often presenting with cardiomyopathy, gastrointestinal dysmotility, or kidney insufficiency. We present a case series of 4 patients with late-onset hATTR neuropathy who were initially diagnosed with vasculitic neuropathy and chronic inflammatory demyelinating polyneuropathy to illustrate diagnostic challenges encountered with hATTR. Early diagnosis is even more urgent now given the availability of disease modifying treatments.

Clinical spectrum of neuromuscular complications after immune checkpoint inhibition.

Cancer immunotherapy has transformed the field of oncology and enabled more effective management of previously refractory neoplasms by activation of the immune response. Upregulation of the immune response may also trigger autoimmune adverse events, including neuromuscular complications. We performed a systematic review of autoimmune neuromuscular complications following immune checkpoint blockade. We searched PubMed database and identified 81 cases described, including 30 cases of myasthenia gravis (MG), 29 cases of neuropathy and 22 cases of myopathy. Most patients (89%) developed neuromuscular complications within 3 months from starting immune checkpoint blockade and 40% of all patients had elevated serum CK>1000 IU/L (typical normal <200). Guillain-Barre syndrome variants and overlaps of MG with myositis and/or myocarditis also occurred. One quarter of myasthenia patients presented with exacerbations of previously diagnosed myasthenia gravis, while neuropathy and myopathy typically presented with a new onset. Most patients improved with immunomodulatory treatment, but neuromuscular complications were sometimes refractory and associated with high mortality of 26% from cancer recurrence, comorbidities, or treatment complications. Poor outcomes were more common with exacerbations of pre-existing myasthenia gravis and myocarditis overlap. Future prospective studies are needed to elucidate mechanisms and risk factors for autoimmune adverse events following immune checkpoint blockade.

Evaluating Prognostic Factors for Liver Transplantation Among United States Patients With Hereditary Transthyretin-Mediated (hATTR) Amyloidosis Using National Registry Data.

INTRODUCTION: Orthotopic liver transplantation has been used as a treatment for hereditary transthyretin-mediated (hATTR) amyloidosis, a rare, progressive, and multisystem disease. RESEARCH QUESTION: The objective is to evaluate survival outcomes post-liver transplantation in patients with hATTR amyloidosis in the United States and assess whether previously published prognostic factors of patient survival in hATTR amyloidosis are generalizable to the US population. DESIGN: This cohort study examined patients with hATTR amyloidosis undergoing liver transplant in the United States (N = 168) between March 2002 and March 2016 using data reported to the Organ Procurement and Transplantation Network (UNOS)/United Network for Organ Sharing (OPTN). RESULTS: A multivariable Cox hazards regression model showed among all factors tested, only modified body mass index (kg/m2 × g/L) at the time of transplant was significantly associated with survival. Higher modified BMI was associated with lower risk of death relative to a reference population (<600) with historically poor post-transplant outcomes. Patients with modified BMI 1000 to <1200 (hazard ratio [HR] = 0.27; 95% confidence interval [CI] = 0.10-0.73), 1200 to <1400 (HR = 0.20; 95% CI = 0.06-0.75), and ≥1400 (HR = 0.15; 95% CI = 0.04-0.61) exhibited improved adjusted 5-year post-transplant survival of 74%, 80%, and 85%, respectively, versus 33% in the reference population. DISCUSSION: The association between a higher modified BMI threshold at the time of transplant and improved post-transplant survival suggests that the previously published patient selection criterion for modified BMI may not be applicable to the US population.

R+ pramipexole as a mitochondrially focused neuroprotectant: initial early phase studies in ALS.

R+ pramipexole (PPX) is a lipophilic cation that concentrates into brain and mitochondria and efficiently scavenges reactive oxygen and nitrogen species (RONS). Under the auspices of a Physician-Sponsor IND, R+PPX was dosed to small numbers of ALS patients for tolerability and safety while efficacy measures were also collected. The purpose of this paper is to describe the outcomes of these initial clinical studies. In a futility design study, 30 patients with early SALS were evaluated monthly for ALSFRS-R scores and FVC measurements for three months during lead-in, followed by open-label dosing at 30 mg/day of R+PPX for the next six months. In the dose escalation study, 10 subjects with early ALS received daily doses of R+PPX from 10 mg t.i.d. to 100 mg t.i.d. over seven weeks. In the open-label extension analysis, subjects from the initial studies were treated with 30 mg/day for at least six months, then switched to 60 mg/day. R+PPX was tolerated well in all studies. In the futility study, slopes of decline in ALSFRS-R scores and neurophysiological index (NI) values yielded non-significant reductions during treatment. In the dose-escalation study, all subjects increased daily R+PPX intake safely to 100 mg t.i.d. Markers of ALS did not change (ALSFRS-R) or improved (FVC). Trough and peak plasma (PPX) increased linearly with dosing, and several subjects achieved plasma (PPX) >1 microM. In the open-label extension protocol, changing from 30 to 60 mg/day caused a non-significant 17% reduction in slope of decline of ALSFRS-R. It was concluded that R+PPX was tolerated well in long-term dosing at 30 and 60 mg/day. Encouraging but non-significant effects of R+PPX on ALS decline were observed. High doses of R+PPX were tolerated well and yielded neuroprotective plasma levels. These findings support longer-term testing of higher R+PPX doses as a potential disease-altering therapy for SALS.

Guillain-Barré syndrome after orthotopic liver transplantation: A clinical manifestation of immune reconstitution inflammatory syndrome?

Guillain-Barrè Syndrome, as part of the spectrum of dysimmune neuropathies, is unexpected to occur in immunocompromised hosts. We describe a clinical case of Guillain-Barrè syndrome, occurred a few weeks after a liver transplant, and we postulate that our case would satisfy all requirements to explain this peripheral nervous system complication as a clinical manifestation of an Immune reconstitution inflammatory syndrome. In this setting of liver transplantation, complicated by potentially multiple infective triggers, reduction of immunosuppression and reversal of pathogen-induced immunosuppression, through antimicrobial therapy, may have led to pro-inflammatory response. The pro-inflammatory pattern would have sustained the pathophysiologic mechanism of this immune neuropathy.

Neuroimaging and neurologic complications after organ transplantation.

Neurologic complications are common after transplantation and affect 30-60% of transplant recipients. The etiology of most of the posttransplant neurologic disorders is related to the opportunistic infections, both systemic and involving central nervous system (CNS), toxicity of immunosuppressive medications, and the metabolic insult created by the underlying primary disease and the transplant procedure. Neuroimaging studies are one of the key tools in the evaluation and enable early diagnosis of neurologic complications in transplant patients, especially posterior reversible leukoencephalopathy syndrome, central pontine myelinolysis, intracerebral hemorrhage, and fungal and bacterial abscesses. Magnetic resonance imaging (MRI) is the preferred technique, but each of the available neuroimaging techniques offers a unique insight into the pathophysiologic mechanisms underlying neurologic complications of transplantation. The role of neuroimaging in this population includes early detection of calcineurin inhibitor neurotoxicity, opportunistic infections, neoplasia, metabolic disorders, or cerebrovascular diseases. In addition, we can monitor longitudinal progression of disease and treatment response.

Myasthenia gravis and scleroderma: two cases and a review of the literature.

Myasthenia gravis is uncommon in patients with scleroderma, and when diagnosed is usually associated with previous use of d-penicillamine. Clinically, both myasthenia and scleroderma may present with fatigue, weakness and bulbar symptoms, so one of diagnoses may be delayed. We report two new cases and review clinical features of 12 other reported cases of co-existing scleroderma and myasthenia gravis, unrelated to previous d-penicillamine therapy. Co-occurrence of myasthenia and scleroderma was reported almost exclusively (13/14) in women with a mean latency of 7.03 years. Most patients (10/11) had seropositive generalized myasthenia, and there were no cases with exclusively ocular symptoms. Three patients with pre-existing myasthenia were safely treated with d-penicillamine. Myasthenia and scleroderma occur in the context of an underlying autoimmune diathesis, but their co-occurrence could be underreported as the recognition of either disorder may be delayed by overlapping clinical symptoms. Our findings also suggest that d-penicillamine may be cautiously used in selected patients with pre-existing scleroderma and myasthenia, when potential benefits outweigh the risk of possible myasthenia exacerbation.

Iatrogenic amyloid polyneuropathy after domino liver transplantation.

Liver transplantation has been used in treatment of transthyretin amyloidosis, and some patients undergo domino liver transplantation (DLT) with explanted liver being transplanted to another patient with liver failure as the liver is otherwise usually functionally normal. Until end of 2015, there were 1154 DLT performed worldwide. DLT for transthyretin amyloidosis is associated with the risk of developing de novo systemic amyloidosis and amyloid neuropathy, and the risk may be greater with some non-Val30Met mutations. De novo amyloid neuropathy has been described in up to 23% of transplant recipients. Neuropathy may be preceded by asymptomatic amyloid deposition in various tissues and symptoms of neuropathy started after a median of 7 years following DLT (5.7 ± 3.2 years; range 2 mo to 10 years). Typical initial symptoms include neuropathic pain and sensory loss, while dysautonomia usually starts later. Progression of neuropathy may necessitate liver re-transplantation, and subsequent improvement of neuropathy has been reported in some patients. Explant allograft recipients need close monitoring for signs of systemic amyloidosis, neuropathy and dysautonomia as progressive symptoms may require re-transplantation.

Myasthenia triggered by immune checkpoint inhibitors: New case and literature review.

Immune checkpoint molecules are potent regulators of immunologic homeostasis that prevent the development of autoimmunity while maintaining self-tolerance. Inhibitors of immune checkpoint molecules are used as immunotherapy in the treatment of melanoma and different types of refractory cancer, and can trigger various autoimmune complications including myositis and myasthenia gravis. We describe a case of generalized myasthenia gravis induced by pembrolizumab and review 11 other cases. Five patients also had elevated serum CK levels ranging from 1200 to 8729 IU/L, and biopsy showed myositis in one. Severity was highly variable as symptoms normalized spontaneously in one patient, but three others developed myasthenic crisis (including two with fatal outcomes). Steroids have been recommended as a preferred treatment of autoimmune complications of immune-checkpoint inhibitors. Myasthenia gravis should be considered when weakness, diplopia or bulbar symptoms are seen after treatment with immune checkpoint inhibitors, and additional studies are needed to characterize association with hyperCKemia.

Relationship between sensorimotor peripheral nerve function and indicators of cardiovascular autonomic function in older adults from the Health, Aging and Body Composition Study.

BACKGROUND: Age-related peripheral nervous system (PNS) impairments are highly prevalent in older adults. Although sensorimotor and cardiovascular autonomic function have been shown to be related in persons with diabetes, the nature of the relationship in general community-dwelling older adult populations is unknown. METHODS: Health, Aging and Body Composition participants (n=2399, age=76.5±2.9years, 52% women, 38% black) underwent peripheral nerve testing at the 2000/01 clinic visit. Nerve conduction amplitude and velocity were measured at the peroneal motor nerve. Sensory nerve function was assessed with vibration detection threshold and monofilament (1.4-g/10-g) testing at the big toe. Symptoms of lower-extremity peripheral neuropathy were collected by self-report. Cardiovascular autonomic function indicators included postural hypotension, resting heart rate (HR), as well as HR response to and recovery from submaximal exercise testing (400m walk). Multivariable modeling adjusted for demographic/lifestyle factors, medication use and comorbid conditions. RESULTS: In fully adjusted models, poor motor nerve conduction velocity (<40m/s) was associated with greater odds of postural hypotension, (OR=1.6, 95% CI: 1.0-2.5), while poor motor amplitude (<1mV) was associated with 2.3beats/min (p=0.003) higher resting HR. No associations were observed between sensory nerve function or symptoms of peripheral neuropathy and indicators of cardiovascular autonomic function. CONCLUSIONS: Motor nerve function and indicators of cardiovascular autonomic function remained significantly related even after considering many potentially shared risk factors. Future studies should investigate common underlying processes for developing multiple PNS impairments in older adults.