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Antibody-mediated encephalitis: a treatable cause of schizophrenia

  • Belinda R. Lennox (a1), Alasdair J. Coles (a2) and Angela Vincent (a3)

Psychiatrists need to be vigilant for the newly recognised and treatable disorder of antibody-mediated encephalitis. Psychiatric symptoms are common, and individuals with the disorder often present initially to psychiatric services. We describe the clinical features of the disorder and make recommendations for further investigations.

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Corresponding author
Belinda R. Lennox, DM, MRCPsych, Department of Psychiatry, University of Cambridge, Herchel Smith Building, Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. Email:
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Declaration of interest

A.J.C. reports receiving consulting fees, lecture fees and grant support from Genzyme. A.V. and the Nuffield Department of Clinical Neuroscicences/University of Oxford, hold patents, receive royalties from Athena Diagnostics and receive payments for antibody assays.

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1 Bullmore, E, Fletcher, P, Jones, PB. Why psychiatry can't afford to be neurophobic. Br J Psychiatry 2009; 194: 293–5.
2 Dalmau, J, Tüzün, E, Wu, HY, Masjuan, J, Rossi, JE, Voloschin, A, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007; 61: 2536.
3 Irani, SR, Bera, K, Waters, P, Zuliani, L, Maxwell, S, Zandi, MS, 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 2010; 133: 1655–67.
4 Dalmau, J, Lancaster, E, Martinez-Hernandez, E, Rosenfeld, M, Balice-Gordon, R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011; 10: 6374.
5 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.
6 Vincent, A, Bien, CG, Irani, SR, Waters, P. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol 2011; 10: 759–72.
7 Vincent, A, Buckley, C, Schott, JM, Baker, I, Dewar, BK, Detert, N, et al. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain. 2004; 127: 701–12.
8 Parthasarathi, UD, Harrower, T, Tempest, M, Hodges, JR, Walsh, C, McKenna, PJ, et al. Psychiatric presentation of voltage-gated potassium channel antibody-associated encephalopathy. Case report. Br J Psychiatry 189: 182–3.
9 Zandi, MS, Irani, SR, Lang, B, Waters, P, Jones, PB, McKenna, P, et al. Disease-relevant autoantibodies in first episode schizophrenia. J Neurol 2011; 258: 686–8.
10 Kraepelin, E. Dementia Praecox and Paraphrenia (ed. Robertson, G). Livingstone, 1919.
11 Pomarol-Clotet, E, Honey, GD, Murray, GK, Corlett, PR, Absalom, AR, Lee, M, et al. Psychological effects of ketamine in healthy volunteers. Phenomenological study. Br J Psychiatry 2006; 189: 173–9.
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The British Journal of Psychiatry
  • ISSN: 0007-1250
  • EISSN: 1472-1465
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Antibody-mediated encephalitis: a treatable cause of schizophrenia

  • Belinda R. Lennox (a1), Alasdair J. Coles (a2) and Angela Vincent (a3)
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K.A.L.A. Kuruppuarachchi, Professor of Psychiatry
20 April 2012

The recent editorial on "Antibody - mediated encephalitis : a treatable cause of schizophrenia( Lennox et al 2012) is facilitating to unravel an important aspect of biological psychiatry particularly with regard to the aetiology and management.

Uncertainty in the diagnosis and management of acutely onset psychiatric disorders is a common problem globally. This is more often seen in resource poor regions as facilities including advanced technologies are scarce to carry out a comprehensive assessment.

In countries like Sri Lanka psychiatric manifestations secondary to infections and inflammatory processes are commonly encountered. However inmost instances only the basic investigations are performed due to lack of facilities and financial constraints. In depth investigations including antibody screening etc are not requested routinely even though viral infections are abound.

In our countries there is a considerable overlap between the disciplines of neurology and psychiatry and many patients in the neuropsychiatric borderland may present to neurologists or to psychiatrists depending on the nature of the predominant symptoms. Patients with acutely onset psychotic symptoms , behavioural disturbances, neurological symptoms and seizures may be labeled as havingclinical conditions such as epilepsy related psychiatric disorders, delirium etc. depending on the nature of the presentation and symptoms.

On the other hand patients with "lethal catatonia" may present with neurological symptoms , abnormal movements( movement disorder) , fluctuation of level of consciousness with a rapid progression and generally seem to have a poor outcome unless treated promptly and vigorously. Lethal catatonia as a syndrome and diverse nature of the aetiological factors, importance of thorough assessment and proper management have been discussed even a few decades ago( Mann et al 1986). Also the possible benefits of steroids in the therapy has been mentioned.Still in our countries clinicians encounter patients presenting with acutely onset catatonic symptoms, fluctuation of level of consciousness and associated psychotic symptoms and they are treated as for catatonia . If neuroleptics or antidepressants such as SSRIs are administered then one may consider Neuroleptic Malignant Syndrome or Serotonin Syndrome respectively in the differential diagnosis.

Visceral malignancies associated with psychiatric manifestations are commonly missed due to a variety of reasons including poor awareness. As"somatization" is also commonly seen in illnesses such as depression thereis a possibility of missing the underlying organic pathology unless the clinician pays attention to the other possibilities of causation of such symptoms. Neurological symptoms and associated delirium may be misperceived/ misinterpreted as other related factors such as dehydrationand electrolyte imbalance etc. Obviously it is important to be aware of the associated visceral malignancies particularly when the symptoms are complex and unremitting.

Another area needs to be highlighted is the thyroid dysfunction and associated psychiatric morbidity. A preliminary study carried out in NorthColombo Teaching Hospital , Sri Lanka demonstrated that thyroid hormonal abnormalities are often found amongst patients present with "psychiatric symptoms" (more details are available from the author on request). We needto do further studies with regard to this area including assessment of thyroid auto antibodies to ascertain the association.

It is interesting to note that patients with voltage- gated potassiumchannel antibody encephalopathy present with neuropsychiatric symptoms andhyponatraemia or seizures and features simulating/mimicking myoclonic jerks. Similar presentations are seen in our countries as well and many misinterpret the causation of hyponatraemia and tend to relate it either to medication induced hyponatraemic state or to psychogenic polydipsia associated with schizophrenia.Complex neuropsychiatric presentation , differential diagnosis, possible aetiological factors and the management of anti-NMDA receptor encephalitisand difference of anti-NMDA receptor encephalitis from other paraneoplastic encephalitedes have been highlighted in a clinical case conference (Chapman & Vause 2011). When the syndrome presents with symptoms such as autonomic dysregulation, muscle rigidity there is a possibility of making a misdiagnosis of NMS or Serotonin Syndrome depending on whether anti psychotics or antidepressants are administered. Also there is a possibility of mild to moderate elevation of CPK levels which may lead to further confusion in the diagnosis and management.

In children and adolescents , some of the behavioural disturbances/manifestations may be related to antibody mediated pathophysiological conditions. It has been recommended to assess antistreptococci antibody teters and pay attention to associated neurological symptoms in assessing OCD in children particularly when suspecting PANDAS- Associated OCD (American Academy of Child and Adolescent Psychiatry 2012).

The benefits of incorporation of intravenous immunoglobulin (IVIg) inthe management of Autoimmune Neurological Disorders has been discussed andthe need for identification and isolation of particular antibodies or prepare supplementary monoclonal antibodies in order to design more specific therapeutic interventions in the future research work has been addressed (Bhagavati & Singhal 2004).

Clinicians particularly Psychiatrists and Neurologists need to be aware of this important area in order to minimize the mismanagement of such patients. Obviously research work in this area will facilitate the researchers to shed light on the mysteries of possible aetiologies in acute psychoses and catatonia.


Lennox BR, Coles AJ, Vincent A. Antibody-mediated encephalitis: a treatable cause of schizophrenia. British Journal of Psychiatry 2012; 200:92-94.

Mann SC, Caroff SN, Bleier HR et al. Lethal Catatonia. Am J Psychiatry 1986; 143: 1374-1381.

Chapman MR, Vause HE. Anti-NMDA Receptor Encephalitis: Diagnosis, Psychiatric Presentation, and Treatment. Am J Psychiatry 2011; 168: 245-251.

American Academy of Child and Adolescent Psychiatry. Practice Parameter for the Assessment and Treatment of Children and Adolescents With Obsessive-Compulsive Disorder. J. Am.Acad. Child Adolesc. Psychiatry,2012; 51(1): 98-113.

Bhagavati SB, Singhal BS. Application of IVIG in Autoimmune Neurological Diseases. Neurosciences Today 2004; 8 : 101-107.

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Conflict of interest: None declared

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Antibody -mediated encephalitis: A treatable cause of schizophrenia

Kieran O'Loughlin, Senior Registrar
17 March 2012

We read with interest the two recent articles1,2 concerning the psychiatric manifestations of antibody-mediated encephalitis. Both articles are important reminders that a well informed differential diagnosis has far reaching implications for providing optimal patient care.It is indeed instructive to note that a marked recovery is possible with immunosuppressant therapy. Additionally, the need for close liaison with plasma exchange facilities, gynaecologists, neurologists and immunologistsrepresents a novel departure for many practitioners we presume.We did have some concerns with the title of the Lennox et al editorial1. Describing the encephalitis as a treatable cause of schizophrenia jarred alittle. Firstly, we were concerned that the editorial title could give theimpression that other causes of schizophrenia are not treatable. This brings to mind another excellent editorial by Williams et al.3 They proposed that we should use the term 'neuroleptic resistance' as opposed to treatment resistance when discussing clozapine therapy to avoid therapeutic nihilism. Secondly, is what is being described schizophrenia or a schizophrenia-like illness? The ICD-104 states that "schizophrenia should not be diagnosed in the presence of overt brain disease..." As neuroimaging progresses this stipulation might no longer be tenable. Now is it preferable to refer to this type of presentation as a psychosis? However, these are minor quibbles and we will certainly view initial psychotic presentations differently as a consequence of these two important contributions to the psychiatric literature.

1Lennox BR, Coles AJ, Vincent A. Antibody -mediated encephalitis: A treatable cause of schizophrenia. Br J Psych 2012; 200:92-4.2Barry H, Hardiman O, Healy DG, Keogan M, Moroney J, Molnar PP, Cotter DR, Murphy KC. Anti-NMDA receptor encephalitis: an important differential in psychosis. Br J Psych 2011; 199:92-4.3Williams L, Newton G, Roberts K, Finlayson S, Brabbins C. Clozapine-resistant schizophrenia a positive approach. Br J Psych 2002; 181:184-87.4World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders: Clinical descriptions and diagnostic guidelines, WHO 1992.

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Conflict of interest: None declared

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Infections and antibody-mediated encephalitis

Feargus F. O'Croinin, Psychiatrist
23 February 2012

I read with interest the recent important papers on antibody-mediatedencephalitis (1) and anti-NMDA receptor encephalitis (2). One area worthy of further study is the possibility of an infective contribution to the clinical presentations. For example, in Clostridium difficile infections the common antigen is glutamate dehydogenase (GDH), produced by both toxigenic and nontoxigenic strains. GDH has an affinity for NMDA receptors, which are found in colonic tissue and are involved in visceral pain transmission. The chance resemblance of a pathogen and host antigen is called molecular mimicry, an example of which is Streptococcus pyogenesand rheumatic fever. Infectious agents are known to trigger autoimmune diseases e.g. Campylobacter jejuni can trigger Guillain-Barre syndrome. Could the GDH antigen of C. difficile and the NMDA receptor be another example of molecular mimicry?

Further research into an infective component to antibody-mediated encephalitis would be of interest.

Lennox BL, Coles AJ and Vincent A. Antibody-mediated encephalitis: a treatable cause of schizophrenia. Br J Psychiatry 2012, 200:92-94

Barry H, Hardiman O, Healy DG, Keogan M, Moroney J, Molnar PP et al. Anti-NMDA receptor encephalitis: an important differential diagnosis in psychosis. Br J Psychiatry 2011, 199:508-509

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Conflict of interest: None declared

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Antibody mediated encephalitis: a treatable cause of schizophrenia

Jasvinder Singhi, ST - 6
16 February 2012


I read with interest the article on antibody mediated encephalitis. Iagree with the author that we as psychiatrists are losing grip on the organic side of things or to say that with the dawn of new psychiatry model we are losing grip over psychiatry. With the rapid changes in the psychiatry services we might no more be called a psychiatrist and rather adepression specialist, bipolar specialist, dementia specialist and so on. Anyhow, before my words start irking the bosses up there responsible for all these changes I would like to thank the authors for bringing up another article on this important topic. This entity has been very well described by Angela Vincent in her previous articles and papers. With the new ways of functioning and the emphasis being more on psychosocial model there is a fear that organic part might get lost. This can be dangerous and this article is one good example.

I think we cannot shy away from organic side of psychiatry and it is good to know that we are getting more articles on this subject. This is the second article on this topic, the first was a case series report on anti -NMDA receptor published in Dec 2011 edition of BMJ1.

From my own experience, working as a higher trainee, it is not uncommon to come across patients presenting with first episode psychosis or dementia and showing positive autoantibodies. I can't stop myself from thinking that how many patients we would have missed of this treatable condition either because of pressure from general wards and A&E because they couldn't have handled the behaviour of some of the patients or because of limited knowledge of ours about this group of condition. It is well recognised that this group of encephalopathies is often missed2. It is highly crucial not to miss this group of encephalopathies because of good prognosis if treated well in time with immunosuppression; otherwise, it can lead to irreversible cognitive deficits, on-going seizures and death2.

The concept of autoimmunity causing psychiatric disturbances such as schizophrenia and depression has been there for decades 3-5. The larger group called paraneoplastic disorder in which antibodies are triggered by neural antigens expressed by tumours outside the CNS is a well-recognised entity in the group of autoimmune encephalopathies. The commonest tumour is small cell lung tumour. Hashimoto encephalopathy is the nonparaneopastic group of autoimmune encephalopathy which is characterizedby high levels of antithyroid antibodies in the serum. Both of the above conditions like NMDA receptor antibody and VGKC complex antibody encephalopathies can present with psychosis, cognitive impairment and behavioural disturbances6.

Apart from the well-recognised autoimmune encephalopathies - paraneoplastic, non - paraneoplastic, N-methyl -D-aspartate receptor antibodies and Voltage gated potassium channel antibodies, newer autoantibodies keep emerging up like AMPA receptors antibody mentioned by authors and anti GABAB receptor antibodies6. This can be really challenging for treating clinicians especially when the known tests for autoantibodies come back as negative and there is high suspicion of autoimmune basis.

The other interesting fact is that there is more rate of schizophrenia in patients with auto immune disease. The risk increases in patients who have autoimmune disease and severe infection. The possible hypothesis is due to the changes in brain blood barrier that makes people vulnerable to a CNS insult by autoimmune antibodies7. This raises a very crucial debate whether the patients who present with first episode of psychosis or acute confusion secondary to infections should be screened for autoantibodies. I personally feel it makes a case not only for screening these autoantibodies but also to look for tumour markers.

I see patients with a neurologist colleague of mine a atypical dementia clinics. It is not uncommon to see patients being referred to these clinics for cognitive assessment from medical wards, after being admitted there for acute confusion. On assessment, the history points to the acute or subacute onset of acute confusion. They lack the typical clinical features of common dementia conditions and thus are difficult to diagnose. I strongly feel that these patients were the ones we missed to diagnose as autoimmune encephalopathies. This is why it is very important to have a very vigilant approach in diagnosing this group of patients because of the wide range of psychiatric conditions they can present with - schizophrenia, depression, anxiety and dementia.

The take home message is that organic psychiatry is our speciality, we just need to be more aware of it. The autoimmune encephalopathies represent a heterogeneous group of disorders with common pathogenic mechanism. They are the treatable causes of many psychiatric conditions. We as psychiatrists need to have this entity in mind especially when we are asked to see someone with so called acute confusion state (favourite term among nonpsychiatrists).

References : 1.Barry H, Hardiman O, Healy DG, Keogan M, Moroney J, Molnar PP, Cotter DR,Murphy KC. Anti-NMDA receptor encephalitis: an important differential diagnosis in psychosis. Br J Psychiatry. 2011 Dec;199(6):508-9. Epub 2011 Oct 7.

2.Irani SR, Vincent A, Schott JM. Autoimmune encephalitis. BMJ. 2011Apr21;342.

3.Goldsmith CA, Rogers DP. The case for autoimmunity in the etiologyof schizophrenia. Pharmacotherapy.2008;28:730-741

4.Nemeroff CB, Simon JS, Haggerty JJ Jr, Evans DL. Antithyroid antibodies in depressed patients. Am J Psychiatry.1985;142:840-843.

5.Eaton WW, Byrne M, Ewald H, Mors O, Chen CY, Agerbo E, Mortensen PB.

Association of schizophrenia and autoimmune diseases: linkage of

Danish national registers. Am J Psychiatry. 2006 Mar; 163(3):521-8.

6.Psychiatric presentation of autoimmune eencephalopathies.Kayser MS, Dalmau J. Psychiatric Times. 2010 Mar 8. 27(3).

7.Benros ME, Nielsen PR, Nordentoft M, Eaton WW, Dalton SO, Mortensen PB. Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. Am J Psychiatry. 2011 Dec 1;168(12):1303-10.

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