Nicholas Silvestri

Treatment-Refractory Myasthenia Gravis

Abstract Myasthenia gravis (MG) is the most common disorder of neuromuscular transmission and is a prototypical autoimmune disorder. Most patients with MG are successfully treated with acetylcholinesterase inhibitors, corticosteroids, and/or steroid sparing agents such as azathioprine and mycophenolate mofetil. There is a small subset of patients, however, with treatment-refractory disease. In these cases, medications such as rituximab, high-dose cyclophosphamide, and eculizumab may be used. Thymectomy (in some cases repeat thymectomy) is another option in selected patients. Studies evaluating these and other forms of therapy in treatment-refractory MG are reviewed.

Asymptomatic/pauci-symptomatic creatine kinase elevations (hyperckemia)

Neuromuscular clinicians are frequently asked to evaluate patients referred for asymptomatic elevations in creatine kinase (CK), a catalytic enzyme that combines creatine and ATP to form phosphocreatine and ADP. This reaction is crucial for cellular energy generation and metabolism. This laboratory finding, often referred to in simplified lexicon as asymptomatic hyperCKemia, continues to generate controversy at several levels, including definition, the extent of evaluation, and the yield of diagnostic testing. In this review, we summarize the literature based on series of patients with asymptomatic hyperCKemia and provide a rational clinical approach to reveal identifiable underlying causes. Muscle Nerve 47: 805–815, 2013

Amyloid-beta-related angiitis: a rare cause of recurrent transient neurological symptoms.

Background A 79-year-old woman presented with transient right-sided weakness. She subsequently developed further transient neurological signs and symptoms across a range of vascular territories. Diagnostic workup revealed no clear etiology. The patient developed a sudden, fatal intracerebral hemorrhage, and the diagnosis was only revealed at autopsy.Investigations Neurological examination, head CT, brain MRI, fluid-attenuated inversion recovery imaging, magnetic resonance angiography, lumbar puncture, CT angiography, electroencephalography, and brain autopsy.Diagnosis Amyloid-β-related angiitis.Management The patient expired before treatment could be initiated. Immunosuppressants are recommended for future cases.

International clinimetric evaluation of the MG-QOL15, resulting in slight revision and subsequent validation of the MG-QOL15r.

Introduction: The MG‐QOL15 is a validated, health‐related quality of life (HRQOL) measure for myasthenia gravis (MG). Widespread use of the scale gave us the opportunity to further analyze its clinimetric properties. Methods: We first performed Rasch analysis on >1,300 15‐item Myasthenia Gravis Quality of Life scale (MG‐QOL15) completed surveys. Results were discussed during a conference call with specialists and biostatisticians. We decided to revise 3 items and prospectively evaluate the revised scale (MG‐QOL15r) using either 3, 4, or 5 responses. Rasch analysis was then performed on >1,300 MG‐QOL15r scales. Results: The MGQOL15r performed slightly better than the MG‐QOL15. The 3‐response option MG‐QOL15r demonstrated better clinimetric properties than the 4‐ or 5‐option scales. Relative distributions of item and person location estimates showed good coverage of disease severity. Conclusions: The MG‐QOL15r is now the preferred HRQOL instrument for MG because of improved clinimetrics and ease of use. This revision does not negate previous studies or interpretations of results using the MG‐QOL15. Muscle Nerve 54: 1015–1022, 2016

Rituximab as treatment for anti-MuSK myasthenia gravis: Multicenter blinded prospective review

Objective: To evaluate the efficacy of rituximab in treatment of anti-muscle-specific kinase (MuSK) myasthenia gravis (MG). Methods: This was a multicenter, blinded, prospective review, comparing anti-MuSK-positive patients with MG treated with rituximab to those not treated with rituximab. The primary clinical endpoint was the Myasthenia Gravis Status and Treatment Intensity (MGSTI), a novel outcome that combines the Myasthenia Gravis Foundation of America (MGFA) postintervention status (PIS) and the number and dosages of other immunosuppressant therapies used. A priori, an MGSTI of level ≤2 was used to define a favorable outcome. Secondary outcomes included modified MGFA PIS of minimal manifestations or better, mean/median prednisone dose, and mean/median doses of other immunosuppressant drugs. Results: Seventy-seven of 119 patients with anti-MuSK MG evaluated between January 1, 2005, and January 1, 2015, at 10 neuromuscular centers were selected for analysis after review of limited clinical data by a blinded expert panel. An additional 22 patients were excluded due to insufficient follow-up. Baseline characteristics were similar between the rituximab-treated patients (n = 24) and the controls (n = 31). Median follow-up duration was >3.5 years. At last visit, 58% (14/24) of rituximab-treated patients reached the primary outcome compared to 16% (5/31) of controls (p = 0.002). Number needed to treat for the primary outcome is 2.4. At last visit, 29% of rituximab-treated patients were taking prednisone (mean dose 4.5 mg/day) compared to 74% of controls (mean dose 13 mg/day) (p = 0.001 and p = 0.005). Classification of evidence: This study provides Class IV evidence that for patients with anti-MuSK MG, rituximab increased the probability of a favorable outcome.

Posterior reversible encephalopathy syndrome secondary to blood transfusion

The appearance of posterior reversible encephalopathy syndrome (PRES) after blood transfusion is rare and has only been reported in three patients to our knowledge. We report a fourth patient with PRES secondary to blood transfusion. A 36-year-old woman with a history of menorrhagia presented to the emergency department with severe fatigue. She had a hemoglobin of 1.7 g/dl and received four units of red blood cells over 15 hours. On day 6 post-transfusion she returned with confusion, headache and a generalized tonic-clonic seizure. The MRI of her brain was consistent with PRES. The following day her confusion worsened, repeat MRI of the brain showed new T2-weighted lesions. Over next 10 days her mental status gradually improved close to her baseline. A repeat MRI of the brain showed resolution of the T2-weighted lesions. The clinical presentation, radiological findings and disease progression in our patient was consistent with PRES. Other than the blood transfusions, there were no apparent risk factors for PRES. The prior three patients with post-transfusion PRES have been reported in middle-aged women with uterine fibroids. It is suspected that these patients have a subacute to chronic anemic state due to ongoing menorrhagia. It is interesting to note that no cases of PRES post-transfusion have been reported in the setting of acute blood loss, such as from trauma. It is postulated that an abrupt increase in hemoglobin causes a rapid rise in blood viscosity and loss of hypoxic vasodilation. Subsequent endothelial damage and brain capillary leakage results in PRES. This constellation of changes may not occur after transfusion in patients with more acute blood loss.

Ablation of Perk in Schwann Cells Improves Myelination in the S63del Charcot-Marie-Tooth 1B Mouse.

In factory cells, the accumulation of misfolded protein provokes the unfolded protein response (UPR). For example, deletion of serine 63 (S63del) in myelin protein zero (P0) induces P0 accumulation in the endoplasmic reticulum (ER) of Schwann cells and a persistent UPR associated with Charcot-Marie-Tooth 1B (CMT1B) demyelinating peripheral neuropathy in human and mouse. PERK (protein kinase RNA-like ER kinase) is the ER stress sensor that attenuates global translation by phosphorylating eIF2α. Inhibition of the eIF2α holophosphatase GADD34:PP1, increases the phosphorylation of eIF2α in Schwann cells and largely rescues S63del neuropathy. Nonetheless, reducing phosphorylation of eIF2α, by Perk haploinsufficiency, also ameliorates the myelin defects of S63del nerves. This contradictory finding prompted us to investigate whether the beneficial effect of Perk deficiency on myelination could derive from neurons. To test this hypothesis, we generated and compared Schwann cell- and neuron-specific ablation of Perk in S63del nerves. Our data suggest that the detrimental effect of Perk in CMT1B derives primarily from Schwann cells. Furthermore, we show that Perk loss of function in Schwann cells restores myelination without diminishing accumulation of P0 or markers of ER stress, suggesting that Perk may modulate myelination through a pathway independent of the UPR. SIGNIFICANCE STATEMENT In many endoplasmic reticulum (ER) stress-related disorders, activation of the unfolded protein sensor protein kinase RNA-like ER kinase (PERK) kinase is beneficial. Nonetheless, in Charcot-Marie-Tooth 1B neuropathy mice, we show that activation of PERK in Schwann cells, but not in neurons, is detrimental for myelination. PERK may interfere with myelination, independent of its role in ER stress.

Cardiac involvement in the muscular dystrophies: CM in Muscular Dystrophy

Cardiac disease is a common clinical manifestation present in a variety of neuromuscular disorders, most notably the muscular dystrophies. Heart disease may produce the presenting or predominant symptoms in these disorders but more often not does not result in clinical features at the time of initial presentation. Cardiac involvement in the muscular dystrophies results from pathologic changes in the myocardium and the cardiac conduction system, leading to cardiomyopathy and/or rhythm disturbances including supraventricular arrhythmias, life‐threatening ventricular arrhythmias, and sudden cardiac death. This Review covers the spectrum of cardiac dysfunction in these inherited muscle disorders and proposes practical recommendations for monitoring and management. Muscle Nerve 57: 707–715, 2018

Generalized Myasthenia Gravis: Classification, Clinical Presentation, Natural History, and Epidemiology

Myasthenia gravis (MG) is a rare disease, but the most common disorder of the neuromuscular junction. It is the prototypic autoimmune disease most commonly caused by antibodies to the acetylcholine receptor (AChR) leading to characteristic fatigable weakness of the ocular, bulbar, respiratory, axial, and limb muscles. The majority of patients with MG first present with ocular symptoms. Most patients with MG will experience at least 1 exacerbation of symptoms throughout the course of their illness. This article will cover the epidemiology, clinical presentation, classification, and natural history of MG.

Low-Dose Medication and Long-Term Outcome in Myasthenia Gravis.

Objectives: Many advances have been made in the diagnosis, treatment, and management of myasthenia gravis (MG) and most patients will eventually progress to experience minimal manifestations (MM) of the disease or remission. However, there is a paucity of literature on medication dosing needed to achieve such a favorable clinical status in the long term. The objective of this article was to (1) study the course of MG and identify clinical predictors of maintenance of eventual disease remission or minimal manifestations and (2) determine if patients on low-dose medications have comparable MG Foundation of America (MGFA) scores and postintervention statuses (PIS) with those on conventional therapeutic dosing. Methods: This is a retrospective longitudinal chart review of 74 patients with MG. A subset of 28 of 74 patients diagnosed with MG after 2000 who were followed for at least 3 consecutive years from the year of diagnosis were also analyzed. An annual MGFA score, PIS, medication doses, and thymectomy status were obtained. Remission or MM of disease was defined as MGFA clinical classification <2 that persisted over the past 2 follow-up visits. Results: Thirty-four of 74 patients were on low-dose medications at last follow-up. There was no statistical difference between medication dosages and MGFA scores. In a subset of 28 patients, 23 (88.5%) with eventual disease remission or MM at last follow-up had an MGFA class <2 at their third year of diagnosis. In contrast, only 3 of 9 subjects with more symptomatic disease had similar results (P = 0.005). In terms of PIS at last follow-up, most patients were either in complete stable remission, pharmacologic remission, or MM status. Most patients (78.3%) had an MGFA class of 0 or 1 at last follow-up; 45% were on low-dose medications. Conclusions: Most patients with MG will realize disease stability characterized by either remission or MM status. A significant number of such patients were able to be maintained on low doses of medications to treat MG. The MGFA class at year 3 of diagnosis is a clinical predictor of long-term disease prognosis. There was no statistical difference between medication doses and MGFA scores at last follow-up.