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

N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes
N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes
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 stage
0006-8950
1655-1667
Irani, Sarosh R.
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Bera, Katarzyna
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Waters, Patrick
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Zuliani, Luigi
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Maxwell, Susan
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Zandi, Michael S
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Friese, Manuel A
f856065b-c3cf-41e0-ab03-8c57436b1ccf
Galea, Ian
66209a2f-f7e6-4d63-afe4-e9299f156f0b
Kullmann, Dimitri M.
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Beeson, David
597379f4-ab66-4857-97ec-9687638c0523
Lang, Bethan
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Bien, Christian G.
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Vincent, Angela
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Irani, Sarosh R.
e886af63-d685-44b4-bcc8-b25a825d4720
Bera, Katarzyna
75600510-5534-430b-a8e7-9c355958a17c
Waters, Patrick
9b96f131-85bd-4ac3-b711-a28b8a294097
Zuliani, Luigi
79072ea4-c8ca-487a-926d-e06cb813eea0
Maxwell, Susan
b8aa7b2f-5799-468a-9dc2-9b6a4bd6f093
Zandi, Michael S
7b16aa95-e1fc-4951-9f38-33f8f4332d5e
Friese, Manuel A
f856065b-c3cf-41e0-ab03-8c57436b1ccf
Galea, Ian
66209a2f-f7e6-4d63-afe4-e9299f156f0b
Kullmann, Dimitri M.
7425b0ef-50ce-4696-8275-058056c5f7dc
Beeson, David
597379f4-ab66-4857-97ec-9687638c0523
Lang, Bethan
5097472b-a4c5-4439-bb48-b98f1929953f
Bien, Christian G.
5710b58f-8869-4414-90fd-075e5645eaca
Vincent, Angela
f93585a3-7aeb-4bbc-aa9c-ec6d66b3c3e6

Irani, Sarosh R., Bera, Katarzyna, Waters, Patrick, Zuliani, Luigi, Maxwell, Susan, Zandi, Michael S, Friese, Manuel A, Galea, Ian, Kullmann, Dimitri M., Beeson, David, Lang, Bethan, Bien, Christian G. and Vincent, Angela (2010) N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain, 133 (6), 1655-1667. (doi:10.1093/brain/awq113). (PMID:20511282)

Record type: Article

Abstract

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 stage

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Published date: June 2010
Organisations: Biological Sciences, Clinical Neurosciences

Identifiers

Local EPrints ID: 179637
URI: http://eprints.soton.ac.uk/id/eprint/179637
ISSN: 0006-8950
PURE UUID: b4496ce2-b0fa-4231-9c9b-403cc81cf45f
ORCID for Ian Galea: ORCID iD orcid.org/0000-0002-1268-5102

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Date deposited: 08 Apr 2011 10:37
Last modified: 17 Dec 2019 01:49

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