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Anti-NMDA receptor encephalitis: an important differential diagnosis in psychosis

  • Helen Barry (a1), Orla Hardiman (a2), Daniel G. Healy (a2), Mary Keogan (a3), Joan Moroney (a4), Peter P. Molnar (a5), David R. Cotter (a6) and Kieran C. Murphy (a6)...

Summary

We present four cases of confirmed anti-NMDA receptor encephalitis; three presented initially with serious psychiatric symptoms and the other developed significant psychiatric symptoms during the initial phase of illness. Brain biopsy findings of one patient are also described. Psychiatrists should consider anti-NMDA receptor encephalitis in patients presenting with psychosis and additional features of dyskinesias, seizures and catatonia, particularly where there is no previous history of psychiatric disorder.

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Copyright

Corresponding author

David R. Cotter, Department of Psychiatry, Royal College of Surgeons in Ireland, RCSI Education and Research Centre, Smurfit Building, Beaumont Hospital, Dublin 9, Ireland. Email: drcotter@rcsi.ie

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These authors contributed equally to this work.

Declaration of interest

None.

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References

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1 Folstein, MF, Folstein, SE, McHugh, PR. ‘Mini-mental state’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–98.
2 Iizuka, T, Sakai, F, Ide, T, Monzen, T, Yoshii, S, Iigaya, M, et al. Anti-NMDA receptor encephalitis in Japan: long-term outcome without tumor removal. Neurology 2008; 70: 504–11.
3 Dalmau, J, Gleichman, AJ, Hughes, EG, Rossi, JE, Peng, X, Lai, M, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008; 7: 1091–8.
4 Baldridge, EB, Bessen, HA. Phencyclidine. Emerg Med Clin North Am 1990; 8: 541–50.
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Anti-NMDA receptor encephalitis: an important differential diagnosis in psychosis

  • Helen Barry (a1), Orla Hardiman (a2), Daniel G. Healy (a2), Mary Keogan (a3), Joan Moroney (a4), Peter P. Molnar (a5), David R. Cotter (a6) and Kieran C. Murphy (a6)...
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eLetters

Anti NMDA receptor Encephalitis, need for interdisciplinary collaboration

Bo Wynn, Speciality Registrar in Adult Psychiatry
16 February 2012

We were interested in the report by Helen et al published in the December 2011 issue of the Journal of four confirmed cases of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis.

NMDAR encephalitis was first described in 2007, and a growing body ofliterature has developed on aetiology, clinical course and therapeutic interventions. Worldwide Incidence is not clear but a UK multicenter prospective study in 2010 indicated that it accounts for 4% of cases.1

Since a psychiatric diagnosis was provisionally made in many cases described especially at the early stages of presentation, the implication is that most cases will be seen by frontline acute psychiatric mental health services.

We recently treated an unusual case with NMDAR encephalitis. A 33-year-old female with no past psychiatric history was admitted to an acute psychiatric assessment ward with first onset psychotic episode. Prior to this, there was a one-week history of general debility, difficulties in concentration and episodes of unresponsiveness.

On the psychiatric ward, she was behaving bizarrely and perplexed. She then developed persecutory delusions, delusions of religious themes, delusion of guilt, auditory and visual hallucinations. Her speech was incoherent, fast in rate and loud in volume. Her mood was irritable and elevated; affect was labile. Over the next few days, she deteriorated mentally and physically. We observed episodic muscular rigidity in limbs and orofacial dyskinetic movements. At that point, she was transferred toa specialist neurology unit for further investigation and treatment.

MRI was unremarkable and did not show characteristic hyperintensity changes, and routine and sleep EEGs were normal. Unlike cases described byHelen et al, in our case, an initial blood sample for NMDA receptor antibodies sent during the first two weeks of illness was positive but later samples after 5 weeks and 6 weeks were negative. After conformationof the diagnosis, the patient was treated with IV methyl prednisolone and intravenous immunoglobulin (IVIg) although she had already shown improvement prior to initiation of therapies.

Her psychotic symptoms and confusion including auditory and visual hallucinations resolved completely over 3 months. Apart from PRN benzodiazepine and promethazine, she did not require antipsychotic treatment. Trans-vaginal ultrasound revealed a right mature cystic teratoma which was removed. After 9 months since her presentation, she made a full recovery with no neuropsychological deficits. Mini-Mental State Examination score = 30/30.

Our case mirrored previous reports and demonstrated a clear temporal relationship between the onset of autoimmune encephalitis and neuropsychiatric symptoms and the phasic course described by Iizuka and colleagues. 2,3. However, as Helen et al mention, sequential phases are not always clear cut. In terms of broad categorization, our case would be more to be keeping with the dyskinesia type as no epileptiform activity was observed. In fact, she developed severe dyskinetic movements in the mouth and lips including chewing movements which resulted in significant tissue damage needing plastic corrective surgery.

There is a clear lesson to be learned from this case. Namely, it is crucial to send blood for confirmation of NMDA receptor antibody encephalitis as soon as it is suspected since, since, contrary to previousreports, antibody levels may not persist despite the presence of clinically active disorder. Other investigations such as MRI and EEG may also be normal. Early recognition, prompt investigations, efficient communication and interface between mental health services and medical teams are essential for successful management of such cases.

References1.Granerod J, Ambrose HE, Davies NW, et al. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis 2010; published online Oct 15. DOI:10.1016/S1473-3099(10)70222-X.2. Iizuka T, Sakai F, Ide T, Monzen T, Yoshii S, Ligaya M, et al. Anti-NMDA receptor encephalitis in Japan: Long -term outcome without tumour removal. Neurology 2008: 70:504-113. Iizuka T, Sakai F. Anti-nMDA receptor encephalitis--clinical manifestations and pathophysiology. Brain Nerve. 2008 Sep : 60(9):1047-60.

Prof. Anthony David, Consultant Psychiatrist,Institute of Psychiatry

Dr. Oliver Howes,Group Head and Honorary Consultant,MRC Clinical Sciences Centre (Imperial Hammersmith Campus) & Department of Psychosis Studies, Institute of Psychiatry

Dr Nick Moran, Consultant Neurologist,King’s College Hospital, London SE5.

Dr Naomi Sibtain, Consultant Neuroradiologist, King’s College Hospital, London SE5.

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Conflict of interest: None declared

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Re:Antibody-mediated encephalitis and psychosis

David R. Cotter, Department of Psychiatry
01 February 2012

We thank Pollak and colleagues for reiterating that anti NMDA (NMDAr)receptor encephalitis should be included as a differential diagnosis for patients presenting with acute psychosis. The association of anti NMDAr encephalitis with psychosis is new, having been identified only as recently 2008 [1] although the disorder has likely gone unrecognized and indeed untreated previously. While to date there are no estimates regarding population prevalence rates of anti NMDAr encephalitis, the California Encephalitis project retrospectively screened 3000 idiopathic encephalitis patients with dyskinesia or movement disorders and identified10 (0.3%) anti NMDA receptor positive cases.[2] Examining the incidence ofcatatonia in psychosis, Fink and Taylor estimate a prevalence of between 9-17% of patients in academic psychiatry inpatient units [3]while Peralta et al found that 31% of drug na?ve first onset psychosis patients demonstrated at least one catatonic symptom and an interesting subgroup which showed a clear association with disorganization and dyskinesia.[4]

The neuropsychiatric presentation underlying NMDAr encephalitis has only recently been published in the psychiatric literature [5]. Consequently, this clinical presentation involving psychiatric symptoms in approximately 77% of affected individuals has not been widely disseminated among psychiatrists. This was the driving force behind the publication of our case series.

Pollak and colleagues restate our view that "there may be a pure psychiatric presentation associated with lower antibody titres", and point to their own very recent work showing that 3 of 46 patients with first-episode psychosis had NMDA receptor antibodies.[6] This extremely important finding has profound implications for future differential diagnoses of first onset psychosis, potentially involving relevant auto-antibody and specifically anti NMDA receptor screening. Further, plasmaphoresis may be required and in some cases may even be clinically indicated before a diagnosis of NMDAr encephalitis is confirmed. This willhave implications for hospital resources and will require close liaison between psychiatry and neurology services.

NMDA receptor hypofunction, whether due to exposure to PCP ingestion, NMDA receptor autoantibody, or altered NMDA receptor trafficking [7,8] is now implicated even more strongly in schizophrenia. Future studies focusing on this area may provide clues not only to the screening and management of NMDA receptor encephalitis among first episodepsychosis populations, but may also lead to a broader understanding of schizophrenia pathophysiology with the potential for development of novel treatment strategies.

D.R. Cotter(a) H. Barry(a) D.G.Healy (b) Joan Moroney (b) Kieran C Murphy(a)

(a) Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.

(b)Department of Neurology, Beaumont Hospital, Dublin 9, Ireland .





[1] Dalmau J et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet neurology. 2008; 12: 1091-8.

[2]Gable MS et al. Anti-NMDA receptor encephalitis: report of ten cases and comparison with viral encephalitis. Eur J Clin Microbiol Infect Dis. 2009; 28: 1421-9.

[3]Fink M, Taylor MA. The many varieties of catatonia. Eur Arch Psychiatry Clin Neurosci. 2001; 251 Suppl 1: I8-13.

[4]Peralta V, et al. DSM-IV catatonia signs and criteria in first-episode, drug-naive, psychotic patients: psychometric validity and response to antipsychotic medication. Schizophrenia research. 2010; 118: 168-75.

[5]Chapman MR et al. Anti-NMDA receptor encephalitis: diagnosis, psychiatric presentation, and treatment. The American journal of psychiatry.2011 ; 168: 245-51.

[6]Zandi MS et al. Disease-relevant autoantibodies in first episode schizophrenia. Journal of neurology. 2010; 258: 686-8.

[7]Focking M et al . Common proteomic changes in the hippocampus in schizophrenia and bipolar disorder and particular evidence for involvement of cornu ammonis regions 2 and 3. Arch Gen Psychiatry. 2011; 68: 477-88.

[8]Schubert KO et al Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolardisorder? Mol psychiatry. 2011: Oct. E-pub ahead of print

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Conflict of interest: None declared

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Anti-NMDA receptor encephalitis: an important differential diagnosis in psychosis. Response to Article. Olivia Fiertag*, Sharon Taylor*, Nelly Ninis, Sushil Beri. *The first two authors contributed equally to this work.

Olivia Fiertag, ST6 Child and Adolescent Psychiatrist and Honorary Lecturer Imperial College
13 January 2012

We read with interest this article and would like to add the importance of considering this diagnosis in children presenting with any neuropsychiatric symptoms and not just psychosis. Functional psychosis in childhood is rare (age specific prevalence for all psychoses is 0.9 -17.6/ 10 000 in 13-18 age group (1), point prevalence for schizophrenia is0.19/ 10 000 in 2-12 age group) (2) and so consideration of organic causesis all the more imperative. In addition, we would like to highlight the high prevalence of this disorder in young females (91% females, median ageof 23) (3) as in the authors' experience.

We are currently involved in the care of two female paediatric patients, with Anti-NMDA receptor encephalitis. Both children presented with predominant mental health symptoms and as child psychiatrists, we have a role in identifying this disorder.

The first child (11 years old), presented with a 3-day-history of headaches, speech changes (increased pressure, echolalia, whispering), reduced sleep, emotional lability, auditory and visual hallucinations. Shewas observed to be talking to people not in the room and complained of hearing music when she closed her eyes. She was intermittently febrile, associated with confusion, disorientation, sexualised behaviour and agnosia of her parents, yet completely lucid at other times. After a week she developed writhing, twitching facial movements, and became mute. There was no personal or family psychiatric history and all initial relevant investigations were normal. Lumbar Puncture (LP) was reactive. MRI brain showed T2 focal changes and EEG was diffusely encephalopathic. Anti-NMDA receptor antibodies were positive in the serum. Repeated convulsive seizures required ventilation. She was treated with steroids, IVIg and plasmapheresis. There was no evidence of ovarian teratoma.

The second child, (13-years-old), had a one-week history of irrational behaviour, angry outbursts, claustrophobia, emotional lability,new onset obsessive-compulsive behaviour (washing rituals, checking behaviour), fatigue, midline motor movements (hand wringing), orofacial dyskinesia and hyperacusis. On the day of admission she collapsed, with transient left sided weakness, seizures, dysarthria, expressive dysphasia,dyspraxia, agitation, hyperacusis, impaired sleep and echopraxia. She alsohad rhythmic contractions of her pectoral muscle- neuromyotonia, fluctuating insight and disorientation. MRI was normal. EEG was consistentwith an encephalopathy and the Anti-NMDA receptor antibodies were positivein blood but not CSF. She responded to high dose steroids and IVIg. In total she received 6 doses of IVIg, given monthly and a long course of oral steroids. Following an 8 months remission, (but only 8 weeks after stopping steroids) she relapsed with dysarthria and nominal dysphasia. Again she responded to immunosuppression. To prevent further relapse azothiaprine is being considered.

The number of reported cases has exponentially increased worldwide, even in young children. The majority present with neuropsychiatric symptoms and the diagnosis is often not considered early. The disease is potentially treatable with the prognosis dependent on early recognition and prompt immunomodulatory treatment.

These cases highlight that Anti-NMDA receptor encephalitis needs to be considered in children with new onset, acute or subacute neuropsychiatric symptoms.

Consent:

Consent has been obtained.

References:

1 Gillberg C, Wahlstrom J, Forsman A, Hellgren L and Gillberg C. Teenage Psychosis- Epidemiology, Classification and Reduced Optimality in the Pre-, Peri- and Neonatal Periods. J Child Psychol Psychiat 1986; 27: 87-98.

2 Burd L and Kerbeshian J. A North Dakota Prevalence Study of Schizophrenia Presenting in Childhood. J Amer Acad Child Adol Psychiat 1987; 26: 3: 347-350.

3 Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008; 7(12): 1091-1098.

Authors:

*Dr Olivia Fiertag MBChB, MrcPsych, is a ST6 in Child and Adolescent Psychiatrist andHonorary Lecturer at Imperial College, Academic Unit of Child and Adolescent Psychiatry, St Mary's Hospital, London.

*Dr Sharon Taylor MRCP, MRCPsych, PGDip is a Consultant Child and Adolescent Psychiatrist; Honorary Lecturer at Imperial College Academic Unit of Child and Adolescent Psychiatry, St Mary's Hospital, London and Vertical Module tutor at University College London Medical School.

Dr Nelly Ninis MD, MRCP is a Consultant Paediatrician, St Mary's Hospital, Imperial College Healthcare NHS Trust, London.

Dr Sushil Beri MD, MRCPCH is aConsultant Paediatric Neurologist, St Mary's Hospital, Imperial College Healthcare NHS Trust, London

* The first two authors contributed equally to this work

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Conflict of interest: Olivia Fiertag, Sharon Taylor and Nelly Ninis all have no competing interests. Sushil Beri received an educational grant from the UCB pharmaceuticals in the last 3 years.

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Antibody-mediated encephalitis and psychosis

Tom A. Pollak, Academic Clinical Fellow
21 December 2011

TO THE EDITOR:

The four cases of NMDA receptor antibody encephalitis with associatedpsychosis reported in the December issue of the journal1 raise an important and emerging issue and highlight that psychiatrists should include the condition in the differential diagnosis for patients presenting with acute psychosis. But there are some aspects that need clarification. The authors state that "this case series demonstrates a newand treatable cause of psychosis", inferring that the association of psychosis with these antibodies was previously unknown. However, since thefirst 100 patients with NMDAR receptor antibody encephalitis were reportedin 2008,2 this association has been well documented; psychosis is typically the first presentation and many cases were seen by psychiatrists before the neurologists become involved2,3.

The association of these antibodies with psychosis is highly relevantbecause they bind to key neuronal surface proteins, and are therefore likely to be pathogenic. Indeed, NMDA receptor antibody encephalitis is a condition that responds to immunotherapies and importantly there is thought to be an initial "treatment window" for optimal immunomodulation4,5. The authors1 speculate that "there may be a pure psychiatric presentation associated with lower antibody titres". Indeed, arecent study found that three of 46 patients with first-episode psychosis (with no neurological or other clinically distinguishing features) had NMDA receptor antibodies6. One of these resolved with plasmapheresis and steroid treatment. An additional patient had voltage gated potassium channel antibodies, which can also be found in patients with other psychiatric presentations5,7. It now appears increasingly likely that other neuropsychiatric (e.g. catatonia) and psychiatric (e.g. obsessive-compulsive) symptoms may be associated with cell-surface neuronal antibodies8.

As Barry et al.1 point out, the condition does indeed provide some support for the NMDA receptor hypofunction hypothesis for psychosis. Some proponents of this theory have linked NMDA receptor hypofunction to first-rank psychotic symptoms in particular9. It is important that future studies of autoantibody associated psychosis characterise symptomatology in full as this could allow for a level of clinical-pathological correlation rarely attained in psychiatry.

Yours sincerely,

T.A. Pollak(a)B. R. Lennox(b)A. Vincent(c)T.R. Nicholson(a)

aDivision of Psychological MedicineThe Institute of Psychiatry, King's College LondonDe Crespigny ParkLondon SE5 8AF, UK

bDepartment of Psychiatry, University of Cambridge,Herchel Smith Building for Brain and Mind Sciences,Cambridge Biomedical CampusCambridge CB2 0SZ, UK

cNeurosciences Group, Department of Clinical Neurology,University of Oxford, John Radcliffe Hospital,Oxford OX3 9DU, UK

1.Barry, H., et al. Anti-NMDA receptor encephalitis: an important differential diagnosis in psychosis. Br J Psychiatry 199, 508-509 (2011).2.Dalmau, J., et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 7, 1091-1098 (2008).3.Lennox, B. Antibody-mediated encephalitis - a treatable cause of schizophrenia? Br J Psychiatry (in press)4.Irani, S.R., et al. N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 133, 1655-1667 (2010).5.Vincent, A., Bien, C.G., Irani, S.R. & Waters, P. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol 10, 759-772 (2011).6.Zandi, M.S., et al. Disease-relevant autoantibodies in first episode schizophrenia. J Neurol 258, 686-688 (2011).7.Spinazzi, M., et al. Immunotherapy-reversed compulsive, monoaminergic, circadian rhythm disorder in Morvan syndrome. Neurology 71, 2008-2010 (2008).8.Kayser, M.S., Kohler, C.G. & Dalmau, J. Psychiatric manifestations of paraneoplastic disorders. Am J Psychiatry 167, 1039-1050 (2010).9.Stephan, K.E., Friston, K.J. & Frith, C.D. Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring. Schizophr Bull 35, 509-527 (2009).

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Conflict of interest: TRN is supported by the Medical Research Council. TP and BL receive support from the NIHR. AV receives royalties from Athena Diagnostics. AV and the Nuffield Department of Clinical Neurosciences in Oxford receives royalties and payments for antibody assays. BL has an editorial on this topic in press in the British Journal of Psychiatry.

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