Anti-NMDA Encephalitis: A Novel Presentation of Schizophrenia

Stephen A Belz B Pharm MPS
The Prince Charles Hospital Pharmacy Department
Rode Road, Chermside QLD 4032
ABSTRACT
Background: It has been suggested that the modulation of dopamine is not the complete story when it comes to the pathophysiology of schizophrenia. Multiple other neurotransmitters have been linked to the condition such as NMDA & Serotonin. N-methyl D-asparate (NMDA) modulation has been used with success for a number of other conditions such as pain control and Alzheimer’s disease. Due to the high incidence of relapse and treatment failure of current therapies, it is vitally important that medical science looks further into the modulation of the other neurotransmitters involved.
Aim: To report one case that illustrates a novel presentation of treatment resistant schizophrenia, that through extensive investigation produced a diagnosis of anti-NMDA antibody encephalitis.
Clinical details and outcome: The patient had experienced extensive treatment for schizophrenia over at least 5 documented years at a number of institutions & hospitals with varying degrees of success. The patient’s presentation to TPCH resulted in the detection of Anti-NMDA antibodies leading to the diagnosis. Treatments used included immunomodulators and antipsychotics.
Conclusions: After a prolonged admission, the patient was discharged back to her family substantially improved and is receiving maintenance immunoglobulin doses every 3 months. The antipsychotic medications have been weaned over a prolonged period to ensure no relapse of symptoms.
Abstract Word count: 206
Case report word count: 1601

INTRODUCTION
Schizophrenia is a chronic neuropsychiatric disorder that has a worldwide prevalence of 1% and doesn’t vary significantly between geographical regions1. The disorder is characterised by positive and negative symptoms that lead to a varying degree of cognitive dysfunction and social issues. Predominantly the pharmacological treatments used target dopamine & serotonin to help manage particularly the positive symptoms. Pharmacological therapy delivers very little improvement in the negative symptoms. Current data shows an approximate relapse rate of 40% within 2 years of treatment2. This clearly indicates more effective treatments are required.
Modulation of NMDA has been shown to be effective in treating Alzheimer’s disease and as an adjunct to pain relief. Under or over activity of this neurotransmitter has quite varied effects on the CNS and the systemic function of the human body. The physiological effect of reduced NMDA activity has been noted during the use of NMDA receptor antagonists (ketamine or phencyclidine - PCP), causing the emergence of symptoms clinically similar to schizophrenia3. The ability to modulate NMDA activity safely would provide another useful treatment option for the management of schizophrenia.
Anti-NMDA encephalitis is a rare condition with a prevalence that has not been well established; however, the California Encephalitis Project retrospectively found 0.3% of encephalitis patients had anti-NMDA antibodies present in their serum4. Other literature sources claim that it is not as rare as first thought; just under recognised and occurring more frequently than other paraneoplastic encephalitides5. It is substantially more prevalent in females compared to males (8.5:1.5) with a median age onset of ~19 years. The condition follows two predominant aetiologies; either paraneoplastic (commonly ovarian teratoma) or auto-immune mediated6. The effect is thought to be mediated via the production of auto-antibodies to NR1 & NR2 subtypes, in particular in both aetiologies7. Antibody titres have been reported to be higher in those patients who have a teraroma present8. The severity of the condition can vary greatly from the need for intensive care unit admission (commonly due to significant hypoventilation) to milder symptoms9. The condition typically presents with a prodromal flu-like illness and quite varied combinations of symptoms, including intractable seizures, psychosis and dyskinesia and in very severe cases hypoventilation10. The flu-like illness that precedes this encephalitis is thought to increase the permeability of the blood brain barrier so the immune cells producing the antibodies can more readily enter the CNS 5.
Case 1.
A 34 year old female with a documented 5 year history of schizophrenia presented to the emergency department with florid psychosis. She presented with symptoms including visual hallucinations, fixated delusional concepts, periods of catatonia, severe paranoia, seizures, erratic behaviours, memory problems, language disintegration & sexual disinhibition. The patient’s medical history of note included an acute brain injury suffered at 18 years of age due to a fall from a horse, leading to temporal lobe epilepsy. Prior to admission, her epilepsy had been previously well controlled on lamotrigine 100mg nocte. The patient had spent a number of months in multiple hospitals over the previous 5 years with varying response to treatment for similar psychiatric symptoms however; seizures were not documented during previous admissions. Antipsychotic medications had been weaned in the community after prolonged admission for a psychotic episode a few months prior to this admission. Olanzapine was recommenced as this was previously well tolerated and used to treat the recent episode, and the patient was admitted to the psychiatric intensive care unit (PICU) for close observation due to risk of harm to herself and other patients. Pharmacological therapy was modified over the next two months with no noticeable response in the psychiatric symptoms. Routine organic screening returned no abnormalities. This prompted review with neurology leading to broad spectrum antibody screening to rule out any unusual aetiology. The patient’s serum tests returned positive for Anti-NMDA antibodies. Full body CT imaging was performed to observe any teratoma; however, this came back negative leading to the diagnosis of auto-immune anti-NMDA encephalitis. Immunoglobulin (Ig G) was initiated and two 24gram doses were given on consecutive days resulting in marginal improvement. Rituximab was given as two 500mg doses one month apart and the patient responded well. 1000mg of methylprednisolone was administered on the same days as Rituximab. Neurology recommended Ig G to be given every two weeks and gauge response. Improvement was so significant the patient was discharged after one more IgG dose and received the remaining Ig G infusions as an outpatient in the hospitals day unit. No further seizure activity was documented. She is currently still being followed up by allied health in particular occupational therapy to help regain lost deficits in language. Her current management in the community is a small dose of olanzapine with a view to wean. Neurology outpatient follow up will be continued every six months to monitor for presence of the NMDA receptor antibodies.

DISCUSSION
The presentation of psychosis associated anti-NMDA encephalitis gives another physiological pathway to investigate in the management of schizophrenia. Removal of the offending teratoma & immunotherapy generally results in a full recovery from symptoms (~75%)11 . In contrast to those patients without a neoplasm have a 16% chance of full recovery8. If solely mediated via the autoimmune pathway, then relapses after treatment are common (~30%) and can require long term immunomodulation9. However, this is an area that is lacking in solid evidence possibly due to the uncommon presentation of this condition. Our patient had a number of the key symptoms associated with this condition (Young, female, psychosis, seizures, loss of language utility, memory problems) which made the diagnosis more likely once the full investigations were completed. The seizure activity was difficult to differentiate from possible non-compliance of her antiepileptic medication due to the breakthrough of her schizophrenaform illness. Anti-NMDA encephalitis has become a diagnosis that requires a high level of suspicion in patients who are resistant to treatment, as the only current reliable diagnostic tool is the presence of NR1 or NR2 antibodies in the serum and CSF12. CSF antibody screening is not always done if the serum tests positive, as the presence of antibodies in the serum is generally diagnostic. Lumbar puncture may also be a difficult procedure to undertake in an acutely psychotic patient, and may only be necessary if the condition is suspected and serum tests negative.
The use of immunomodulation therapy has been used in a number of case series presented in the literature9,10,11. The combination of glucocoritcoids, immunoglobulin and rituximab are common regimens. Dosing regimens are not clearly elucidated and appear to be quite varied. This is more than likely due to this condition only being recognised in 2005 and entering the mainstream of neurology and psychiatry in 2007. Dalmau et al also proposed that the combination of glucocortoids and therapeutic plasma exchange (TPE) should be considered first line for both tumour and auto-immune mediated conditions 13. The dosing strategy used in our patient closely mirrored that used by Ishura et al. Treatment included Methylprednisolone 1g being given on the days of Rituximab with Rituximab being dosed as 375mg/m2 given in our patient on a monthly basis where as some literature showed weekly administration, however, the use of immunoglobulin has not been widely documented8,10. Literature searches have shown that the use of general immunomodulation including glucocorticoids, TPE, immunoglobulins, Cyclophosphamide8 & rituximab has been effective in the treatment of this condition regardless of tumour or auto-immune mediate aetiology. Immunoglobulins in particular IgG have been used in the treatment of auto-immune conditions for more than 25 years. Even with this extensive usage the true interaction this has with the immune system is not fully understood. Clinical & laboratory investigations have shown a complex range of immunological reactions resulting in changes in cytokine activity, T & B Cell activity & macrophage effects mediated by Fc-gamma receptors14. Rituximab’s role in this treatment is not fully elucidated in the literature, however; its ability to deplete B cells may lead to the reduction in antibody production. If the patient is to relapse, there are some case reports in the paediatric setting for long term immunosuppression with azathioprine8. Relapses were noted to be higher in those with the non-neoplastic presentation and who had not received early immunotherapy interventions6. Pharmacist involvement in these patients is helpful in ensuring antipsychotic medications are managed appropriately pre & post-immunomodulatory therapy. Psychiatric practitioners would not necessarily be familiar with the agents used in the immunomodulation therapy and having a pharmacist available for advice and recommendations would be of benefit. Agents such as rituximab are dosed via body surface area which is a rare concept outside of oncology units and adds complexity to treatment protocols. Pharmacists are ideally equipped to ensure the wards are prepared for the use and management of these agents and any adverse reactions that may appear. As well as educating patients in the correct use of any long term therapy that may be required.
CONCLUSIONS
NMDA encephalitis should be considered in patients (particularly young women) who present with prominent psychiatric symptoms accompanied by seizures, autonomic dysfunction, dyskinetic movements and hypoventilation. Screening of serum and CSF for the presence of antibodies early has been shown to produce the better outcomes and reduce the risk of relapse. Intervention with immunomodulation in this case gave quite rapid relief from symptoms and this combination of pharmacological agents has been used in a number of other published case reports however, there is a significant lack of evidence available to determine a standard regimen of therapy nor for long-term therapy if the patient suffers relapse. Pharmacist involvement is crucial in the management of these patients as they commonly treated in psychiatric facilities away from medical staff familiar with the use of immunotherapies.

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