EDITORIAL
Seizures as first symptom of anti-NMDA receptor encephalitis are more common in men Maarten J. Titulaer, MD, There has been a rapid increase in the characterization PhD of encephalitis associated with antibodies to cell surJosep Dalmau, MD, PhD face or synaptic proteins,1 starting with the report of 4 patients with prominent psychiatric symptoms who rapidly progressed into hypoventilation and Correspondence to coma.2 The disorder was subsequently identified as Dr. Dalmau: anti-NMDA receptor (NMDAR) encephalitis, now [email protected] the best characterized and most frequently recognized autoimmune encephalitis,3 demonstrating that “newly Neurology® 2014;82:550–551 identified” does not always mean “infrequent” or “rare.” In addition to frequency, 2 reasons for the sharp increase in the identification of patients with this syndrome are the characteristic clinical features that facilitate its recognition on clinical grounds and the specificity of the diagnostic test that when properly used leaves no margin for error.4 The latter is straightforward: examine the patient’s CSF with HEK cells expressing GluN1 or GluN1/2 subunits of the NMDAR (the cell-based assay [CBA] used commercially or in research laboratories). If only serum is used, there is a risk (;15%) of false-negative or falsepositive results5; this risk decreases if the serum is examined with an additional confirmatory test, such as immunohistochemistry with rat brain tissue. If these criteria are not used, the specificity of the test decreases and the presumed “spectrum” of symptoms enlarges. In the current issue of Neurology®, Viaccoz et al.6 applied both techniques (immunohistochemistry with brain tissue and CBA) to determine the presence of CSF NMDAR antibodies because a “3% falsepositive rate” was found using serum. Considering the high specificity of these combined tests using CSF, it is not surprising that these findings are similar to those of our series4,7 regarding demographics; clinical, immunologic, and oncologic associations; and response to treatment and outcome. The study, which included 71 adult patients, is the third-largest series on anti-NMDAR encephalitis; the initial series was 100 patients4 and the most recent included 577 cases.7 The novel observation is that adult men (13/71, 18%) more often presented with seizures (8 of those 13, 61.5%) than adult women (8 of the remaining 58,
14%, p , 0.001), who usually presented with abnormal behavior and psychiatric symptoms. The initial seizures in men were frequently partial (5/8), while in women they were usually generalized (1/58 had partial seizures). All patients, regardless of sex, subsequently progressed to develop a classic picture of antiNMDAR encephalitis. At the peak of the disease, each of the following symptoms was present in $50% of the patients: behavioral and psychiatric features, seizures, cognitive dysfunction (anterograde amnesia, speech disorder, alteration of mental status), movement disorders, and fluctuating level of consciousness. An underlying tumor was identified in 41% of women (all ovarian teratomas) and in only one man (perineal schwannoma, of unlikely relationship to the syndrome). Most of the 71 patients were treated with steroids and IV immunoglobulin, and if these treatments failed, the most common second-line therapy used was rituximab. Twelve months after onset of the disease, ;80% had substantially improved (modified Rankin Scale score 0–1). One man (8%) died from sepsis; in women the mortality rate was 5% (3 patients). Viaccoz et al.6 attribute this novel observation to the fact that anti-NMDAR encephalitis is more prevalent in women and until now all previous series had pooled men and women without noting the difference in symptom presentation. The authors suggest hormonal factors as a possible explanation for the different sex-related symptom presentation. In support of this theory, the authors use the experience with pediatric series (less marked hormonal effects); in children the first symptom is frequently seizures (64 of 211, 30%) compared to adult series of mostly women (49 of 363, 13%, p , 0.0001).7 This has led us to interrogate our series of 577 patients for the first symptom of the disease according to age and sex. The findings confirm that seizures as initial symptom are more frequent in adult male patients (14/52, 27%) than in adult women (35/313, 11%, p 5 0.007), but in both sexes psychiatric symptoms remain the most frequent initial symptom (54% in men, 67% in women) (table). Moreover, a similar sex difference
See page 556 From the Department of Neurology (M.J.T.), Erasmus Medical Center, Rotterdam, the Netherlands; Service of Neurology at Hospital Clinic (J.D.), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 550
© 2014 American Academy of Neurology
Table
First symptom of anti-NMDA receptor encephalitis according to age and sex ,12 y Female, N 5 68
12–17 y Male, N 5 44
Adults
Female, N 5 87
Male, N 513
Female, N 5 313
All Male, N 5 52
p Value (adults)
Female, N 5 468
Male, N 5 109
p Value
Behavior
27 (40)
10 (23)
50 (58)
6 (46)
209 (67)
28 (54)
0.083
286 (62)
44 (40)
,0.0005
Seizures
22 (32)
19 (43)
19 (22)
4 (31)
35 (11)
14 (27)
0.007
76 (16)
37 (34)
,0.0005
Cognitive deficits
9 (13)
5 (11)
13 (15)
2 (15)
49 (16)
10 (19)
0.54
71 (15)
17 (16)
1.00
b
10 (15)
10 (23)
4 (5)
1 (8)
18 (6)
0 (0)
0.088
32 (7)
11 (10)
0.31
0 (0)
0 (0)
1 (1)
0 (0)
2 (1)
0 (0)
a
Other symptoms Unknown
3 (1)
0 (0)
Data are n (%). Fisher exact test was used to determine uncorrected p values. a Cognitive deficits include memory deficits and speech disorder. b Other symptoms include movement disorders and altered level of consciousness.
in the frequency of seizures as first symptom is retained at younger ages (children #12 years, or ages 12 to 17 years), decreasing the importance of hormonal factors as the main explanation for this observation. A possible contribution to the different seizure frequency between sexes at presentation of anti-NMDAR encephalitis is a selection bias whereby women with acute onset of psychiatric symptoms are more frequently suspected to have the disorder than men with a similar presentation. In men antibody testing and other ancillary investigations may not be considered until they develop seizures. Interestingly, Viaccoz et al.6 show a higher frequency of MRI abnormalities in men than in women, which suggests an initial clinical underrecognition of the disorder in men. This finding would be similar to series of elderly patients8 or patients with isolated psychosis9 in whom the diagnosis is not suspected until ancillary tests (e.g., brain MRI) suggest an organic etiology and thereby prompt antibody testing. Regardless of the first symptom, the subsequent classic progression of symptoms suggests that, rather than missing the diagnosis, there is a delay in diagnosis. The astute observation of Viaccoz et al.6 should help improve diagnosis in adult men, prompting early therapy and possibly better outcomes. AUTHOR CONTRIBUTIONS Maarten J. Titulaer: drafting/revising the manuscript, acquisition of data, statistical analysis. Josep Dalmau: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data, statistical analysis, study supervision, obtaining funding.
STUDY FUNDING No targeted funding reported.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
REFERENCES 1. Lancaster E, Dalmau J. Neuronal autoantigens-pathogenesis, associated disorders and antibody testing. Nat Rev Neurol 2012;8:380–390. 2. Vitaliani R, Mason W, Ances B, Zwerdling T, Jiang Z, Dalmau J. Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol 2005;58:594–604. 3. Dalmau J, Tuzun E, Wu HY, Masjuan J, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007;61: 25–36. 4. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDAreceptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008;7:1091–1098. 5. Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2013 Dec 18. pii: S1474-4422(13)70282-5. doi: 10.1016/ S1474-4422(13)70282-5. 6. Viaccoz A, Desestret V, Ducray F, et al. Clinical specificities of adult male patients with NMDA receptor antibodies encephalitis. Neurology 2014;82:556–563. 7. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12:157–165. 8. Titulaer MJ, McCracken L, Gabilondo I, et al. Late-onset anti-NMDA receptor encephalitis. Neurology 2013;81: 1058–1063. 9. Kayser MS, Titulaer MJ, Gresa-Arribas N, Dalmau J. Frequency and characteristics of isolated psychiatric episodes in anti-N-methyl-d-aspartate receptor encephalitis. JAMA Neurol 2012. doi: 10.1001/jamanuerol.2013.3216.
Neurology 82
February 18, 2014
551
Seizures as first symptom of anti-NMDA receptor encephalitis are more common in men Maarten J. Titulaer and Josep Dalmau Neurology 2014;82;550-551 Published Online before print January 17, 2014 DOI 10.1212/WNL.0000000000000131 This information is current as of January 17, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/7/550.full.html
References
This article cites 7 articles, 2 of which you can access for free at: http://www.neurology.org/content/82/7/550.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Cognitive Disorders/Dementia http://www.neurology.org//cgi/collection/all_cognitive_disorders_deme ntia All Epilepsy/Seizures http://www.neurology.org//cgi/collection/all_epilepsy_seizures All Psychiatric disorders http://www.neurology.org//cgi/collection/all_psychiatric_disorders Diagnostic test assessment http://www.neurology.org//cgi/collection/diagnostic_test_assessment_
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Seizures as first symptom of anti-NMDA receptor encephalitis are more common in men Maarten J. Titulaer, MD, There has been a rapid increase in the characterization PhD of encephalitis associated with antibodies to cell surJosep Dalmau, MD, PhD face or synaptic proteins,1 starting with the report of 4 patients with prominent psychiatric symptoms who rapidly progressed into hypoventilation and Correspondence to coma.2 The disorder was subsequently identified as Dr. Dalmau: anti-NMDA receptor (NMDAR) encephalitis, now [email protected] the best characterized and most frequently recognized autoimmune encephalitis,3 demonstrating that “newly Neurology® 2014;82:550–551 identified” does not always mean “infrequent” or “rare.” In addition to frequency, 2 reasons for the sharp increase in the identification of patients with this syndrome are the characteristic clinical features that facilitate its recognition on clinical grounds and the specificity of the diagnostic test that when properly used leaves no margin for error.4 The latter is straightforward: examine the patient’s CSF with HEK cells expressing GluN1 or GluN1/2 subunits of the NMDAR (the cell-based assay [CBA] used commercially or in research laboratories). If only serum is used, there is a risk (;15%) of false-negative or falsepositive results5; this risk decreases if the serum is examined with an additional confirmatory test, such as immunohistochemistry with rat brain tissue. If these criteria are not used, the specificity of the test decreases and the presumed “spectrum” of symptoms enlarges. In the current issue of Neurology®, Viaccoz et al.6 applied both techniques (immunohistochemistry with brain tissue and CBA) to determine the presence of CSF NMDAR antibodies because a “3% falsepositive rate” was found using serum. Considering the high specificity of these combined tests using CSF, it is not surprising that these findings are similar to those of our series4,7 regarding demographics; clinical, immunologic, and oncologic associations; and response to treatment and outcome. The study, which included 71 adult patients, is the third-largest series on anti-NMDAR encephalitis; the initial series was 100 patients4 and the most recent included 577 cases.7 The novel observation is that adult men (13/71, 18%) more often presented with seizures (8 of those 13, 61.5%) than adult women (8 of the remaining 58,
14%, p , 0.001), who usually presented with abnormal behavior and psychiatric symptoms. The initial seizures in men were frequently partial (5/8), while in women they were usually generalized (1/58 had partial seizures). All patients, regardless of sex, subsequently progressed to develop a classic picture of antiNMDAR encephalitis. At the peak of the disease, each of the following symptoms was present in $50% of the patients: behavioral and psychiatric features, seizures, cognitive dysfunction (anterograde amnesia, speech disorder, alteration of mental status), movement disorders, and fluctuating level of consciousness. An underlying tumor was identified in 41% of women (all ovarian teratomas) and in only one man (perineal schwannoma, of unlikely relationship to the syndrome). Most of the 71 patients were treated with steroids and IV immunoglobulin, and if these treatments failed, the most common second-line therapy used was rituximab. Twelve months after onset of the disease, ;80% had substantially improved (modified Rankin Scale score 0–1). One man (8%) died from sepsis; in women the mortality rate was 5% (3 patients). Viaccoz et al.6 attribute this novel observation to the fact that anti-NMDAR encephalitis is more prevalent in women and until now all previous series had pooled men and women without noting the difference in symptom presentation. The authors suggest hormonal factors as a possible explanation for the different sex-related symptom presentation. In support of this theory, the authors use the experience with pediatric series (less marked hormonal effects); in children the first symptom is frequently seizures (64 of 211, 30%) compared to adult series of mostly women (49 of 363, 13%, p , 0.0001).7 This has led us to interrogate our series of 577 patients for the first symptom of the disease according to age and sex. The findings confirm that seizures as initial symptom are more frequent in adult male patients (14/52, 27%) than in adult women (35/313, 11%, p 5 0.007), but in both sexes psychiatric symptoms remain the most frequent initial symptom (54% in men, 67% in women) (table). Moreover, a similar sex difference
See page 556 From the Department of Neurology (M.J.T.), Erasmus Medical Center, Rotterdam, the Netherlands; Service of Neurology at Hospital Clinic (J.D.), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and Institució Catalana de Recerca i Estudis Avançats (ICREA) (J.D.), Barcelona, Spain. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 550
© 2014 American Academy of Neurology
Table
First symptom of anti-NMDA receptor encephalitis according to age and sex ,12 y Female, N 5 68
12–17 y Male, N 5 44
Adults
Female, N 5 87
Male, N 513
Female, N 5 313
All Male, N 5 52
p Value (adults)
Female, N 5 468
Male, N 5 109
p Value
Behavior
27 (40)
10 (23)
50 (58)
6 (46)
209 (67)
28 (54)
0.083
286 (62)
44 (40)
,0.0005
Seizures
22 (32)
19 (43)
19 (22)
4 (31)
35 (11)
14 (27)
0.007
76 (16)
37 (34)
,0.0005
Cognitive deficits
9 (13)
5 (11)
13 (15)
2 (15)
49 (16)
10 (19)
0.54
71 (15)
17 (16)
1.00
b
10 (15)
10 (23)
4 (5)
1 (8)
18 (6)
0 (0)
0.088
32 (7)
11 (10)
0.31
0 (0)
0 (0)
1 (1)
0 (0)
2 (1)
0 (0)
a
Other symptoms Unknown
3 (1)
0 (0)
Data are n (%). Fisher exact test was used to determine uncorrected p values. a Cognitive deficits include memory deficits and speech disorder. b Other symptoms include movement disorders and altered level of consciousness.
in the frequency of seizures as first symptom is retained at younger ages (children #12 years, or ages 12 to 17 years), decreasing the importance of hormonal factors as the main explanation for this observation. A possible contribution to the different seizure frequency between sexes at presentation of anti-NMDAR encephalitis is a selection bias whereby women with acute onset of psychiatric symptoms are more frequently suspected to have the disorder than men with a similar presentation. In men antibody testing and other ancillary investigations may not be considered until they develop seizures. Interestingly, Viaccoz et al.6 show a higher frequency of MRI abnormalities in men than in women, which suggests an initial clinical underrecognition of the disorder in men. This finding would be similar to series of elderly patients8 or patients with isolated psychosis9 in whom the diagnosis is not suspected until ancillary tests (e.g., brain MRI) suggest an organic etiology and thereby prompt antibody testing. Regardless of the first symptom, the subsequent classic progression of symptoms suggests that, rather than missing the diagnosis, there is a delay in diagnosis. The astute observation of Viaccoz et al.6 should help improve diagnosis in adult men, prompting early therapy and possibly better outcomes. AUTHOR CONTRIBUTIONS Maarten J. Titulaer: drafting/revising the manuscript, acquisition of data, statistical analysis. Josep Dalmau: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data, statistical analysis, study supervision, obtaining funding.
STUDY FUNDING No targeted funding reported.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
REFERENCES 1. Lancaster E, Dalmau J. Neuronal autoantigens-pathogenesis, associated disorders and antibody testing. Nat Rev Neurol 2012;8:380–390. 2. Vitaliani R, Mason W, Ances B, Zwerdling T, Jiang Z, Dalmau J. Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol 2005;58:594–604. 3. Dalmau J, Tuzun E, Wu HY, Masjuan J, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007;61: 25–36. 4. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDAreceptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008;7:1091–1098. 5. Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2013 Dec 18. pii: S1474-4422(13)70282-5. doi: 10.1016/ S1474-4422(13)70282-5. 6. Viaccoz A, Desestret V, Ducray F, et al. Clinical specificities of adult male patients with NMDA receptor antibodies encephalitis. Neurology 2014;82:556–563. 7. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12:157–165. 8. Titulaer MJ, McCracken L, Gabilondo I, et al. Late-onset anti-NMDA receptor encephalitis. Neurology 2013;81: 1058–1063. 9. Kayser MS, Titulaer MJ, Gresa-Arribas N, Dalmau J. Frequency and characteristics of isolated psychiatric episodes in anti-N-methyl-d-aspartate receptor encephalitis. JAMA Neurol 2012. doi: 10.1001/jamanuerol.2013.3216.
Neurology 82
February 18, 2014
551
Seizures as first symptom of anti-NMDA receptor encephalitis are more common in men Maarten J. Titulaer and Josep Dalmau Neurology 2014;82;550-551 Published Online before print January 17, 2014 DOI 10.1212/WNL.0000000000000131 This information is current as of January 17, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/7/550.full.html
References
This article cites 7 articles, 2 of which you can access for free at: http://www.neurology.org/content/82/7/550.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Cognitive Disorders/Dementia http://www.neurology.org//cgi/collection/all_cognitive_disorders_deme ntia All Epilepsy/Seizures http://www.neurology.org//cgi/collection/all_epilepsy_seizures All Psychiatric disorders http://www.neurology.org//cgi/collection/all_psychiatric_disorders Diagnostic test assessment http://www.neurology.org//cgi/collection/diagnostic_test_assessment_
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
