Rituximab therapy for morvan syndrome associated with myasthenia gravis

Morvan syndrome is a rare disorder characterized by a combination of stiffness, muscle twitching and cramping, hyperhidrosis, insomnia, and encephalopathy, often associated with antibodies to voltage gated potassium channels. The outcome of the disease is unpredictable, as some patients require chronic immunosuppression or succumb to the condition, while others remit spontaneously or with short courses of immunosuppression. A case of refractory Morvan syndrome coexisting with seropositive myasthenia gravis is presented that was ultimately responsive to rituximab. The patient is a 22-year-old man with a history of mild developmental delay and Kawasaki disease who was transferred from another hospital for leg and oculobulbar weakness and muscle twitching. He was initially thought to have atypical Gullain-Barre syndrome. Upon presentation, he appeared as an alert young man with moderate weakness of the legs more than the arms and mild oculobulbar weakness, including bilateral mild fatigable ptosis. He also exhibited frequent twitching of the muscles of his thighs. At times, he had transient plantar flexion posturing of the left foot. His recent history included hyperhidrosis and progressive insomnia, symptoms which are commonly seen in Morvan syndrome. Sensory and motor nerve conduction studies were normal, without evidence of motor conduction block or other signs of demyelination. However, repetitive discharges were noted following F-waves in the upper and lower extremities (Fig. 1A and B). Repetitive nerve stimulation study of the left ulnar and spinal accessory nerves failed to demonstrate a significant incremental or decremental response. Single fiber needle EMG was not performed due to the progressive, precarious nature of the patient’s condition. Needle EMG showed spontaneous grouped repetitive discharges in the form of doublets, triplets, and multiplets in several muscles in the upper and lower extremities (Fig. 1C). These findings were thought to indicate peripheral nerve hyperexcitability. A lumbar puncture demonstrated a mild CSF pleocytosis (22 WBC, largely all lymphocytes), mildly elevated protein of 53 mg/dl, (normal < 45 mg/dl), and oligoclonal bands not seen in the serum, but the glucose, cytology and flow cytometry were normal. Serologic testing revealed elevated antibodies to several antigens, including thyroid peroxidase (9.5 SD, normal <1.9 SD) with a mildly elevated thyroid stimulating hormone level (5.947 uIU/ml, normal < 5.000 uIU/ml), acetylcholine receptor binding antibody (4.2 nmol/L, normal <0.04 nmol/ L), glutamic acid decarboxylase (GAD65) (0.86 nmol/L, normal <0.02 nmol/L), and voltage gated potassium channels (0.04 nmol/L, normal <0.02 nmol/L). Brain MRI with and without contrast was normal. CT of the chest, abdomen, and pelvis was remarkable only for enlarged axillary lymph nodes. No thymic abnormality was noted. PET scan showed increased activity in the axillary lymph nodes which, when biopsied, were found to demonstrate only reactive follicular hyperplasia. The patient failed to respond to a course of intravenous immunoglobulin (2 grams/kg of body weight over 5 days), followed by one gram of methylprednisolone daily for 5 additional days, initiation of prednisone 80 mg daily, and 10 courses of plasma exchange. He continued to worsen in regard to his strength and muscle twitching and then became increasingly somnolent. An EEG demonstrated generalized slowing and was notable also for the absence of normal sleep architecture including REM sleep, which is typical of Morvan syndrome. He eventually developed respiratory failure requiring intubation. Given the evidence for multiple humorally mediated neurologic conditions, he was treated with 4 weekly infusions of rituximab 375 mg/m. Within approximately 4 weeks of completion of the therapy, he exhibited improved cognition, oculobulbar and limb strength and had resolution of his abnormal leg movements and clinical myokymia. Repeat testing of the aforementioned antibodies at this time, and on other occasions since, has been within normal limits (0.00 nmol/liter for acetylcholine receptor binding, GAD65, and voltage gated potassium channel antibodies and <1.9 SD for thyroid peroxidase antibodies). Repeat EMG demonstrated grouped repetitive discharges in the form of multiplets in the left deltoid muscle only. At present, approximately 16 months after the completion of rituximab therapy, the patient has only modest ptosis and ophthalmoparesis with minimal diplopia, mild residual limb weakness, complete resolution of cognitive VC 2012 Wiley Periodicals, Inc.