Yuebing Li

Myasthenia gravis exacerbation associated with pembrolizumab.

A 59-year-old woman presented for neurological evaluation. She suffered from rheumatoid arthritis, and there was a remote history of myasthenia gravis (MG). In her 30s, she developed mild ptosis, hoarseness, and neck flexor weakness. The acetylcholine receptor (AChR) binding antibody assay was positive. Following pyridostigmine treatment for a few months, her symptoms resolved quickly without further treatment. Three months before presentation, she received pembrolizumab infusion once every 3 weeks for metastatic melanoma. After the third infusion, she developed rapidly progressive hoarseness and dysphagia and eventually required placement of a percutaneous endoscopic gastrostomy. Other symptoms included exertional dyspnea and generalized weakness without ptosis or diplopia. Brain MRI, CT scan of soft tissues of the neck, and esophagogastroduodenoscopy were unremarkable. Evaluation by an otolaryngologist showed severe pharyngeal and palatal weakness and vocal fold hypomobility. Neurological exam revealed proximal limb muscle weakness with normal sensation. AChR and muscle-specific tyrosine kinase antibodies were negative. The 3 HZ repetitive stimulation studies of the facial and fibular nerves revealed 13% and 19% postexercise amplitude decrement, respectively, without postexercise facilitation, consistent with a postsynaptic neuromuscular junction disorder such as MG. Treatment with plasmapheresis, intravenous immunoglobulin, and prednisone 40 mg daily led to steady improvement of all symptoms. Her speech became nearly normal, and a regular diet was resumed. Repeat endoscopy showed significant improvement in pharyngeal, palatal, and glottic movement. Pembrolizumab is an anti-programmed cell death protein-1 (anti-PD-1) monoclonal antibody recently approved for treatment of melanoma and nonsmall cell lung cancer. PD-1 is a cell surface receptor that prevents Tcell activation, reduces autoimmunity, and promotes selftolerance. Pembrolizumab treatment results in enhanced immune responses to tumor cells and normal host tissues. An association of pembrolizumab treatment with inflammatory arthritis has been described, but so far no case of MG has been reported. Two prior case reports described development of MG following the use of another anti-PD-1 monoclonal antibody, nivolumab. One patient received co-administration of nivolumab and ipilimumab, and ipilimumab was believed to be the more likely causative agent based on prior similar reports. In another patient, a retrospective examination of the patient’s serum before nivolumab administration detected anti-AChR antibodies, suggesting nivolumab may have exacerbated previously clinically silent MG. Our patient has 2 significant features. First, there was a remote history of mild MG symptoms, and pembrolizumab use caused an exacerbation of the latent MG. The AChR binding antibody was initially positive in our patient, but it became negative with the recent MG exacerbation. The precise explanation for this observation is unknown, but could be related to possible antigenic spreading or antigenic shifting from AChR to other components of the neuromuscular junction that occurs rarely during the course of MG. The results in our patient and the Shirai et al. patient supports a mechanism that anti-PD-1 therapy allows preexisting autoimmune T-cell clones to escape tolerance by suppressing regulatory T cells. Second, predominantly focal manifestation with prominent palatal and pharyngeal weakness was noted. Whether this is a unique clinical feature of MG in association with anti-PD-1 therapy awaits further study. T-lymphocyte-activating drugs are now used with increasing frequency in cancer treatment. Development of MG symptoms following the use of anti-PD-1 monoclonal antibodies should be recognized promptly. Drug discontinuation and initiation of MG therapy are appropriate treatment strategies that can lead to improved outcome.

Statin induced necrotizing autoimmune myopathy.

Statin induced necrotizing autoimmune myopathy (SINAM) is a recently characterized entity belonging to the spectrum of statin myotoxicity. It is a more severe form, and is usually associated with significant proximal muscle weakness, strikingly elevated creatine kinase levels and persistent symptoms despite statin discontinuation. The characteristic pathological finding is a marked muscle fiber necrosis with minimal or no inflammation on muscle biopsy. SINAM is an autoimmune disorder associated with an antibody against 3-hydroxy-3-methyglutaryl-coenzyme A reductase (HMGCR), and the antibody titer is a useful marker for assessing treatment response. However, anti-HMGCR positive myopathies are also caused by unknown etiologies other than statin exposure, especially in the younger population. SINAM should be promptly recognized as immunosuppressive therapy can improve its clinical outcome significantly. Further research is needed to elucidate its pathogenesis and provide evidence based guidelines for management.

Maintenance immunosuppression in myasthenia gravis

Therapies for myasthenia gravis (MG) include symptomatic and immunosuppressive treatment. Options for immunosuppression include corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, methotrexate, rituximab, cyclophosphamide, intravenous immunoglobulin, plasmapheresis, and thymectomy. The practical aspects of long-term immunosuppressive therapy in MG will be critically reviewed in this article. Treatment for ocular and generalized myasthenia gravis will be discussed. Application of these therapies needs to be considered in conjunction with their efficacy, disease subtypes and severity, and patient co-morbidities.

Clinical experience of seropositive ganglionic acetylcholine receptor antibody in a tertiary neurology referral center

Introduction: Antibody against the acetylcholine receptor of autonomic ganglia (gAChR‐Ab) is implicated in the pathogenesis of autoimmune autonomic ganglionopathy (AAG) and several other disorders. Methods: This study was a retrospective evaluation of 95 patients positive for gAChR‐Ab. Results: Twenty‐one (22%) patients had AAG, with a greater median gAChR‐Ab level (0.21 nmol/L) and higher percentage (57%) of antibody levels >0.20 nmol/L when compared with the remaining 74 patients without autonomic manifestations (non‐AAG group, 0.10 nmol/L and 15%, respectively). Only 2 new cases of malignancy were diagnosed after gAChR‐Ab detection. The non‐AAG group was associated with high frequencies of neurological and non‐neurological autoimmunity, but also included 23 (31%) patients with mostly degenerative disorders. Conclusion: Detection of gAChR‐Ab, especially at a higher level, is helpful for the diagnosis of AAG in patients with corresponding autonomic symptoms. However, its value is limited for predicting cancer risk and for diagnosis and management of patients without autonomic symptoms. Muscle Nerve 52:386–391, 2015

Clinical utility of seropositive voltage-gated potassium channel-complex antibody.

Background:Antibodies against voltage-gated potassium channel (VGKC)–complex are implicated in the pathogenesis of acquired neuromyotonia, limbic encephalitis, faciobrachial dystonic seizure, and Morvan syndrome. Outside these entities, the clinical value of VGKC-complex antibodies remains unclear. Methods:We conducted a single-center review of patients positive for VGKC-complex antibodies over an 8-year period. Results:Among 114 patients positive for VGKC-complex antibody, 11 (9.6%) carrying the diagnosis of limbic encephalitis (n = 9) or neuromyotonia (n = 2) constituted the classic group, and the remaining 103 cases of various neurologic and non-neurologic disorders comprised the nonclassic group. The median titer for the classic group was higher than the nonclassic group (p < 0.0001). A total of 90.9% of the patients in the classic and 21.4% in the nonclassic group possessed high (>0.25 nM) VGKC-complex antibody levels (p < 0.0001). A total of 75.0% of the patients in the high-level group had definite or probable autoimmune basis, while nonautoimmune disorders were seen in 75.6% of patients from the low-level group (p < 0.0001). A total of 26.3% of patients were found with active or remote solid organ or hematologic malignancy, but no antibody titer difference was observed among subgroups of absent, active, or remote malignancy. Compared to age-matched US national census, rates of active cancer in our cohort were higher in patients older than 45 years. Conclusions:High VGKC-complex antibody titers are more likely found in patients with classically associated syndromes and other autoimmune conditions. Low-level VGKC-complex antibodies can be detected in nonspecific and mostly nonautoimmune disorders. The presence of VGKC-complex antibody, rather than its level, may serve as a marker of malignancy.

Longitudinal ultra-extensive transverse myelitis as a manifestation of neurosarcoidosis.

OBJECTIVE To analyze the clinical characteristics and outcome of patients with neurosarcoidosis manifesting as longitudinal transverse myelitis spanning 6 or more spinal segments. METHOD Retrospective analysis of 7 cases from a single institution. RESULTS Four males and 5 African-American were included. The mean onset age for neurological symptoms was 49.1 years old. Only 1 patient had a prior diagnosis of sarcoidosis. In all patients, spinal MRI showed contiguous cervical and/or thoracic cord lesions predominantly in a central or centrodorsal location, associated with parenchymal or leptomeningeal gadolinium enhancement. Cerebral spinal fluid (CSF) pleocytosis was present in all and hypoglycorrhachia in 3 patients. Angiotensin-converting enzyme (ACE) level was elevated in the serum of 1 patient while being normal in the CSF of all 4 cases tested. Chest imaging facilitated the diagnosis of sarcoidosis in all cases. The use of corticosteroid and immunosuppressive agents including infliximab and methotrexate led to improved outcome. CONCLUSIONS Neurosarcoidosis should be considered in the differential diagnosis of longitudinal ultra-extensive myelitis, even in the absence of previously diagnosed sarcoidosis. Timely usage of corticosteroid and immunosuppressive agents improves the clinical outcome of patients with ultra-extensive spinal cord sarcoidosis.

Optimizing muscle selection for electromyography in amyotrophic lateral sclerosis

We compared the yield of limb and thoracic paraspinal muscle examination for revealing lower motor neuron (LMN) dysfunction on electromyography (EMG) in amyotrophic lateral sclerosis (ALS).

Presence of voltage-gated potassium channel complex antibody in a case of genetic prion disease.

Voltage-gated potassium channel (VGKC) complex antibody-mediated encephalitis is a recently recognised entity which has been reported to mimic the clinical presentation of Creutzfeldt-Jakob disease (CJD). Testing for the presence of this neuronal surface autoantibody in patients presenting with subacute encephalopathy is therefore crucial as it may both revoke the bleak diagnosis of prion disease and allow institution of potentially life-saving immunotherapy. Tempering this optimistic view is the rare instance when a positive VGKC complex antibody titre occurs in a definite case of prion disease. We present a pathologically and genetically confirmed case of CJD with elevated serum VGKC complex antibody titres. This case highlights the importance of interpreting the result of a positive VGKC complex antibody with caution and in the context of the overall clinical manifestation.

Intravascular T-cell lymphoma: A rare, poorly characterized entity with cytotoxic phenotype

Intravascular T‐cell lymphomas are rare, poorly characterized lesions. We discuss the clinical, radiologic and especially the laboratory characteristics of a lesion which presented in a 62‐year‐old woman with a history of progressive CNS abnormalities. Throughout the course of the disease, radiologic findings consisted mainly of multifocal mixed areas of ischemia and vasogenic edema involving cortical and subcortical regions. A brain biopsy identified an abnormal T‐cell population confined to lumens of vessels. These T‐cells were abnormal cytotoxic cells, positive for CD3, CD8, and negative for CD2, CD4, CD5, CD7 and CD30. While flow cytometry and immunohistochemistry failed to identify a similar population in the blood or bone marrow, molecular studies showed a clonal T‐cell population in both the brain and the bone marrow. No other organs were involved. In spite of aggressive treatment, the patients medical condition continued to progress and she passed away. In conclusion, this abnormal population of cytotoxic T‐cells with intravascular localization probably represents a specific type of T‐cell lymphoma with specific clinical, radiologic, molecular and immunophenotypic characteristics.

Rhabdomyolysis associated with levetiracetam administration: Levetiracetam and Rhabdomyolysis

Levetiracetam is a commonly used medication for the treatment of partial-onset and primary generalized epilepsy due to its favorable pharmacokinetics, lack of drug interactions, and availability of bioequivalent oral and intravenous forms. Commonly reported adverse effects of levetiracetam are somnolence, asthenia, headache, and irritability. We report a 27-year-old man with a history of Moyamoya disease who presented with 2 brief episodes of new-onset generalized tonic–clonic seizures. After treatment with 1 mg intravenous lorazepam he recovered rapidly, and intravenous levetiracetam was started. After the first levetiracetam dose of 1,000 mg, his serum creatine kinase (CK) level was elevated at 718 U/L (normal 30–220 U/L), which was initially attributed to muscle breakdown from his seizure. Intravenous levetiracetam was continued at 1000 mg twice daily. Eight hours after the second dose, serum CK increased to 7,600 U/L. On electrophoresis, the isoenzyme CK MM accounted for 100% of the total CK, with no CK BB or CK MB fractions. Urine myoglobin was elevated at 6 mg/L (normal 0–1 mg/L). His other medications included docusate and prophylactic subcutaneous heparin. CK levels continued to climb rapidly. Levetiracetam was stopped after a total of 6 doses, while heparin and docusate were continued. Serum CK reached a peak at 49,539 U/L 48 h after discontinuation of levetiracetam and then gradually declined (Fig. 1). Throughout his 10-day hospitalization, the patient had no further seizures. He denied myalgia, muscle cramps, or weakness. His neurological exam was normal. There was no history of trauma, metabolic derangement, or infection, and no personal or family history of rhabdomyolysis or a neuromuscular disorder. Serum CK dropped to 3,353 U/L on discharge and returned to normal (98 U/L) 40 days later. There have been 4 reports of levetiracetam-associated rhabdomyolysis. All occurred in the setting of epilepsy treatment and involved young patients aged 13 to 29 years, with resulting CK levels ranging from 986 to 29,136 U/L. Myalgia was reported in 2 patients and muscle weakness in 1. Three of 4 patients received other medications which could have contributed to the occurrence of rhabdomyolysis, including valproate and phenytoin, oxcarbamazepine, clobazam, and propofol. In the remaining patient, levetiracetam monotherapy was associated with a modest CK elevation of 986 U/L. In our patient, the rapid development of severe but asymptomatic rhabdomyolysis was encountered in a young man following initiation of levetiracetam monotherapy. Although causality cannot be proven without a levetiracetam re-challenge, rhabdomyolysis should be considered a possible adverse effect associated with the drug, especially in young individuals. Ethical Publication Statement: We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.