Paraneoplastic anti-NMDAR encephalitis: long term follow-up reveals persistent serum antibodies

Abstract

Encephalitis associated with antibodies to N-methyl-Daspartate receptor (NMDAR) is a severe but treatable condition [3]. It is often paraneoplastic, affecting mostly women harboring ovarian teratomas. Its characteristic clinical picture includes confusion, agitation, psychiatric manifestations, memory loss, seizures and abnormal movements, and often leads to decreased level of consciousness, autonomic instability, and central hypoventilation [1, 5]. We present the long term follow-up of a patient with paraneoplastic anti-NMDAR encephalitis diagnosed several months after symptom onset who was in a comatose state for 1 year. A prolonged recovery followed after tumor resection and immunotherapy. Two notable observations are the absence of a detectable tumor at an early stage of the disease, and the persistent detection of serum NMDAR antibodies 4 years after disease onset. A 42-year-old woman suffering from headaches 2 months before disease onset, was admitted to an Athens hospital with neck pain, nausea, dizziness and high fever. She was alert and oriented. Her initial work up (brain and spinal MRI, chest and abdominal CT, routine laboratory tests) was normal. Lumbar puncture revealed pleiocytosis (421 lymphocytes/ mm) but no oligoclonal bands. CSF and serum cultures for bacterial, fungal and viral infections were negative. Two days after admission she became delusional with visual hallucinations, confusion, central hypoventilation and a progressive consciousness decline that led to a coma requiring ventilation 10 days after admission. Her EEG was slowing, disorganized, with no basic rhythm but without epileptic foci. The initial diagnosis was viral encephalitis with non convulsive status epilepticus and she was treated with antibiotics, antivirals and antiepileptics. Her condition worsened with episodes of hyperpyrexia, agitation, orofacial dyskinesias, stiffness, and seemingly violent movements of her upper arms. These episodes diminished significantly with dantrolene. A transvaginal echo was normal. She was treated with steroids and one course of IVIg but she remained unresponsive. In ICU the patient had multiple episodes of septicemia but she responded well to therapy. Seven months after disease onset she was transferred to our institution in a comatose state with tracheostomy and gastrostomy. Repeated CSF analysis for bacterial and viral infections was negative. Other systemic autoimmune causes were excluded and all autoantibody tests were negative (ANA, Ro, La, cANCA, pANCA, rheumatoid factor). Brain MRI was normal. An upper and lower abdominal MRI (looking for ovarian tumors) was negative. A suspected immune mediated encephalitis was treated with IVIg infusions, 2 g/ kg/36 h per month. A month later (month 9 from disease onset), a CT re-examination of the lower abdomen revealed a cystic formation at the left ovary. Following resection, pathology revealed a mature ovarian teratoma. NMDAR autoantibodies were detected in the serum and CSF using a qualitative assay (Fig. 1a). The patient started to communicate 40 days after tumor resection. IVIg infusions continued monthly for 7 months and she continued to improve slowly. No steroids, cyclophosphamide or plasmapheresis were added due to H. Alexopoulos M. L. Kosmidis M. C. Dalakas (&) Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias St, 11527 Athens, Greece e-mail: mdalakas@med.uoa.gr