Skip to main content
Article thumbnail
Location of Repository

N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes

By Sarosh R. Irani, Katarzyna Bera, Patrick Waters, Luigi Zuliani, Susan Maxwell, Michael S Zandi, Manuel A Friese, Ian Galea, Dimitri M. Kullmann, David Beeson, Bethan Lang, Christian G. Bien and Angela Vincent


Antibodies to the N-methyl-d-aspartate subtype of glutamate receptor have been associated with a newly-described encephalopathy that has been mainly identified in young females with ovarian tumours. However, the full clinical spectrum and treatment responses are not yet clear. We established a sensitive cell-based assay for detection of N-methyl-d-aspartate receptor antibodies in serum or cerebrospinal fluid, and a quantitative fluorescent immunoprecipitation assay for serial studies. Although there was marked intrathecal synthesis of N-methyl-d-aspartate receptor antibodies, the absolute levels of N-methyl-d-aspartate receptor antibodies were higher in serum than in cerebrospinal fluid. N-methyl-d-aspartate receptor antibodies were of the immunoglobulin G1 subclass and were able to activate complement on N-methyl d-aspartate receptor-expressing human embryonic kidney cells. From questionnaires returned on 44 N-methyl-d-aspartate receptor antibody-positive patients, we identified a high proportion without a detected tumour (35/44, 80%: follow-up 3.6-121 months, median 16 months). Among the latter were 15 adult females (43%), 10 adult males (29%) and 10 children (29%), with four in the first decade of life. Overall, there was a high proportion (29%) of non-Caucasians. Good clinical outcomes, as defined by reductions in modified Rankin scores, correlated with decreased N-methyl-d-aspartate receptor antibody levels and were associated with early (<40 days) administration of immunotherapies in non-paraneoplastic patients (P < 0.0001) and earlier tumour removal in paraneoplastic patients (P = 0.02). Ten patients (23%) who were first diagnosed during relapses had no evidence of tumours but had received minimal or no immunotherapy during earlier episodes. Temporal analysis of the onset of the neurological features suggested progression through two main stages. The time of onset of the early features, characterized by neuropsychiatric symptoms and seizures preceded by a median of 10-20 days, the onset of movement disorders, reduction in consciousness and dysautonomia. This temporal dichotomy was also seen in the timing of cerebrospinal fluid, electroencephalographic and in the rather infrequent cerebral imaging changes. Overall, our data support a model in which the early features are associated with cerebrospinal fluid lymphocytosis, and the later features with appearance of oligoclonal bands. The immunological events and neuronal mechanisms underlying these observations need to be explored further, but one possibility is that the early stage represents diffusion of serum antibodies into the cortical grey matter, whereas the later stage results from secondary expansion of the immunological repertoire within the intrathecal compartment acting on subcortical neurons. Four patients, who only had temporal lobe epilepsy without oligoclonal bands, may represent restriction to the first stag

Topics: R1
Year: 2010
OAI identifier:
Provided by: e-Prints Soton

Suggested articles


  1. (2010). 133; 1655–1667 | 1667 a t U n i v e r s i t y o f S o u t h a m p t o n o n A p r i l , b r a i n . o x f o r d j o u r n a l s . o r g D o w n l o a d e d f r o m doi
  2. (2001). Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. doi
  3. (2008). Anti-NMDA receptor encephalitis in Japan: long-term outcome without tumor removal. Neurology doi
  4. (2009). Anti-Nmethyl-D-aspartate receptor-related grave but reversible encephalitis with ovarian teratoma in 2 Japanese women presenting with excellent recovery without tumor resection. Eur Neurol doi
  5. (2008). Antibody to aquaporin-4 in the long-term course of neuromyelitis optica. doi
  6. AntiN-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol 2009; 66: 11–18. 1666 | Brain 2010: 133; doi
  7. (2008). AntiNMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol doi
  8. (2008). Aquaporin-4 antibodies in neuromyelitis optica and longitudinally extensive transverse myelitis. Arch Neurol doi
  9. (2006). Autoimmune channelopathies and related neurological disorders. Neuron doi
  10. (2009). Cognitive performance is related to cortical grey matter volumes in early stages of schizophrenia: a populationbased study of first-episode psychosis. Schizophr Res doi
  11. (2009). CSF study in paraneoplastic syndromes. J Neurol Neurosurg Psychiatry.
  12. (2009). Diagnostic value of N-methyl-D-aspartate receptor antibodies in women with new-onset epilepsy. Arch Neurol doi
  13. (2009). Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma. doi
  14. (2009). Gyral and sulcal cortical thinning in adolescents with first episode early-onset psychosis. Biol Psychiatry doi
  15. (2008). IgG1 antibodies to acetylcholine receptors in ’seronegative’ myasthenia gravis. doi
  16. (2008). Immunotherapy-responsive seizure-like episodes with potassium channel antibodies. Neurology doi
  17. (2007). Limbic encephalitis as a precipitating event in adult-onset temporal lobe epilepsy. Neurology doi
  18. (2009). Limbic encephalitis associated with antibodies to the NMDA receptor in Hodgkin Lymphoma. Neurology doi
  19. (2008). Neuronal surface antigen antibodies in limbic encephalitis: clinical-immunologic associations. Neurology doi
  20. (2003). Neurosurg Psychiatry doi
  21. (2010). NMDA Receptor Antibodies are a Common Cause of Encephalitis Requiring Intensive Care. Crit Care Med doi
  22. (2007). Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol doi
  23. (2002). Peripheral neuropathies and anti-glycolipid antibodies. doi
  24. (2001). Potassium channel antibodies in two patients with reversible limbic encephalitis. Ann Neurol doi
  25. (2004). Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. doi
  26. (2004). Potentially reversible autoimmune limbic encephalitis with neuronal potassium channel antibody. Neurology doi
  27. (2008). Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody. Neurology doi
  28. (2005). Serum antibodies in epilepsy and seizure-associated disorders. Neurology doi
  29. (2006). Steroid-responsive encephalopathy associated with autoimmune thyroiditis. Arch Neurol doi
  30. (2009). Successful treatment of anti-N-methyl D-aspartate receptor encephalitis presenting with catatonia. Arch Dis Child doi
  31. (2008). The distinctive movement disorder of ovarian teratoma-associated encephalitis. Mov Disord doi
  32. (1999). The neuropathology of schizophrenia. A critical review of the data and their interpretation. doi
  33. (2007). The spectrum of neuromyelitis optica. Lancet Neurol doi
  34. (2005). Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. doi

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.