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.

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.

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.

Use of repetitive nerve stimulation in the evaluation of neuromuscular junction disorders.

Neuromuscular junction (NMJ) disorders are characterized by fuctuating muscle weakness. Acquired myasthenia gravis is the most common NMJ disorder with an overall prevalence in United States estimated at 60,000. Depending on the site of neuromuscular transmission failure, NMJ disorders have been classified as: (1) presynaptic (e.g., Lambert-Eaton myasthenic syndrome), (2) synaptic (e.g., cholinesterase inhibitor toxicity), and (3) post-synaptic (e.g., myasthenia gravis). Electrodiagnostic techniques used for investigation of NMJ disorders include repetitive nerve stimulation (RNS) and single fiber electromyography (SFEMG). Recent literature widely explores the use of SFEMG in the diagnosis and monitoring of myasthenia gravis, but this technique has a lesser role in the daily clinical practice outside of academic institutions. RNS is not as sensitive as SFEMG, but it is the most widely used electrodiagnostic method in the evaluation of suspected neuromuscular transmission disorders. RNS is technically easier and does not require special technical training and skill as SFEMG. Repetitive nerve stimulation was utilized first by Jolly in 1895 using an electrical drum and faradic tetanization to demonstrate a "myasthenic reaction" (weakening muscle contractions). In 1941, decremental response following the repetitive nerve stimulation was described by Harvey and Masland. While the technology has improved tremendously since then, the RNS testing is still based on supramaximal repetitive nerve stimulation and the measurement of decremental (or incremental) responses.

A case of area-specific stimulus-sensitive postanoxic myoclonus.

The authors report a case of area-specific stimulus-sensitive postanoxic myoclonus and discuss possible pathophysiology. A 71-year-old man sustained cardiorespiratory arrest that lasted 10 minutes and remained unresponsive. On the first EEG obtained 8 hours after the arrest there was no cerebral electrical activity before stimulation of the trigeminal-innervated areas. Periorbital stimulation was associated with bursts of spike-wave activity and generalized myoclonic jerks, whereas other types of stimulation did not elicit any response. A second EEG obtained 32 hours later showed a nonreactive alpha coma pattern. The patient died 7 days after the arrest. Area-specific stimulus-sensitive postanoxic myoclonus is very rare. The regularity of generalized bursts of spike-wave activity (cortical response) in response to stimulation of trigeminal-innervated areas suggests that the resting EEG electrocerebral silence may have been a result of cortical suppression with disinhibition of stimulus-sensitive brainstem-generated myoclonus.

Electrodiagnostic evaluation of motor neuron disorders.

Amyotrophic lateral sclerosis (ALS) is the most common adult motor neuron disorder and leads usually to death within two to five years after diagnosis. Clinically, ALS presents with fasciculations, progressive weakness, muscle atrophy, and spasticity. It is a clinical diagnosis, supported by electrodiagnostic and laboratory tests. Nerve conduction studies (NCS) and needle electromyography (EMG) are essential in the evaluation of suspected ALS. NCS are primarily used to exclude any potentially treatable motor neuropathy that may mimic ALS. Standard nerve conduction studies should include at least four sensory and four motor nerves in an arm and leg. At least three sites in three different nerves should be stimulated when searching for conduction blocks, which may distinguish motor neuropathy from ALS. Needle EMG is very valuable as it can demonstrate widespread involvement of muscles that are not clinically weak. Characteristic findings include widespread non-myotomal denervation (both acute and chronic), with fibrillations and fasciculations. Extensive needle examination should include at least two limbs (arm and leg; at least five muscles each), thoracic paraspinal and bulbar muscles.

Neurologic aspects of multiple organ transplantation.

Complex multiorgan failure may require simultaneous transplantation of several organs, including heart-lung, kidney-pancreas, or multivisceral transplantation. Solid organ transplantation can also be combined with hematopoietic stem cell transplantation to modulate immunologic response to a solid organ allograft. Combined multiorgan transplantation may offer a lower rate of allograft rejection and lower immunosuppression needs. In recent years, intestinal and multivisceral transplantations became viable as a rescue treatment for patients with irreversible intestinal failure who can no longer tolerate total parenteral nutrition with 70% survival after 5 years which is comparable to other types of solid organ allografts. Post-transplant neurologic complications were reported in up to 86% of allograft recipients and greatly overlap in intestinal and multivisceral allograft recipients, without a significant effect on the outcome of transplantation. Other common organ combinations in multiorgan transplantation include kidney-pancreas, which is mostly used for patients with renal failure and uncontrolled diabetes, and heart-lung for patients with congenital heart disease and idiopathic pulmonary arterial hypertension. Kidney-pancreas transplantation frequently results in an improvement of diabetic complications, including diabetic neuropathy. Heart-lung allograft recipients have very similar clinical course and spectrum of neurologic complications to lung transplant recipients. At this time there are no reports of an increased risk of graft-versus-host disease with combined transplantation of solid organ allograft and hematopoietic stem cells. Chronic immunosuppression and complex toxic-metabolic disturbances after multiorgan transplantation create a permissive environment for development of a wide spectrum of neurologic complications which largely resemble complications after transplantations of individual components of complex multiorgan allografts.

Localized scleroderma and regional inflammatory myopathy.

Inflammatory myopathy is rare in localized scleroderma. We report 2 new cases of regional inflammatory myopathy associated with localized scleroderma and review 10 reported cases of localized scleroderma associated with an inflammatory myopathy with regional muscle involvement, more often in the upper extremities. Serum creatine kinase was mildly elevated or normal. Histopathology often showed perimysial inflammation and plasma cell infiltration. These cases demonstrate that inflammatory myopathy should be considered in patients with localized scleroderma and regional muscle weakness, pain or atrophy. Muscle biopsy can confirm the diagnosis of myositis, which if identified, will require anti-inflammatory and/or immunosuppressive therapy.

Neurologic complications after liver transplantation.

Neurologic complications are relatively common after solid organ transplantation and affect 15%-30% of liver transplant recipients. Etiology is often related to immunosuppressant neurotoxicity and opportunistic infections. Most common complications include seizures and encephalopathy, and occurrence of central pontine myelinolysis is relatively specific for liver transplant recipients. Delayed allograft function may precipitate hepatic encephalopathy and neurotoxicity of calcineurin inhibitors typically manifests with tremor, headaches and encephalopathy. Reduction of neurotoxic immunosuppressants or conversion to an alternative medication usually result in clinical improvement. Standard preventive and diagnostic protocols have helped to reduce the prevalence of opportunistic central nervous system (CNS) infections, but viral and fungal CNS infections still affect 1% of liver transplant recipients, and the morbidity and mortality in the affected patients remain fairly high. Critical illness myopathy may also affect up to 7% of liver transplant recipients. Liver insufficiency is also associated with various neurologic disorders which may improve or resolve after successful liver transplantation. Accurate diagnosis and timely intervention are essential to improve outcomes, while advances in clinical management and extended post-transplant survival are increasingly shifting the focus to chronic post-transplant complications which are often encountered in a community hospital and an outpatient setting.

Reproducibility of peroneal motor nerve conduction measurement in older adults.

OBJECTIVE: While neuropathy is common in the elderly, nerve conduction (NC) reproducibility in older adults is not well-established. We sought to evaluate intraobserver reproducibility of peroneal motor NC measures in a diverse sample of older adults. METHODS: We measured peroneal motor NC amplitude and velocity in a subset of participants (mean age=82.9±2.7, n=62, 50% female, 51.6% black, 35.5% DM) in the Health, Aging, and Body Composition Study. Using coefficients of variation (CVs), intraclass correlation coefficients (ICCs), and Bland Altman Plots, we compared two sets of measurements taken by the same examiner hours apart on the same day. RESULTS: Low CVs (2.15-4.24%) and moderate to high ICCs (0.75-0.99) were observed. No systematic variation was found across measures. Despite small numbers in some subgroups, we found no differences in reproducibility by diabetes, race or study site. CONCLUSION: NC measures have moderate to high intraobsever reproducibility in older adults and are not affected by diabetes, race, or gender. SIGNIFICANCE: These data provide evidence to support use of these measures in aging research.

Neurologic emergencies in patients who have cancer: diagnosis and management.

The nervous system can be significantly affected by cancer. Neurologic symptoms are present in 30% to 50% of oncologic patients presenting to the emergency department or in neurologic consultation at teaching hospitals. Evaluation and treatment require collaborative effort between specialties. The causes of neurologic emergencies in patients with cancer are mostly related to effects of cancer, toxicities of treatments, infections, and paraneoplastic syndromes. These complications cause significant morbidity and mortality and require prompt and accurate diagnostic and treatment measures. This article reviews the common neurologic emergencies affecting patients with cancer and discusses epidemiology, clinical presentation, diagnosis, and treatment modalities.