Encephalitis is associated with high mortality, especially when caused by the herpes virus, and it is important to begin treatment as quickly as possible. A treatment delay of more than two days is an independent risk factor for severe neurological sequelae or death (2). Long-term sequelae including cognitive impairment, personality changes and epilepsy occur in up to 70 % of patients who survive. Around 40–55 % manage to resume normal daily activities (2, 9). Rapid treatment with acyclovir reduces mortality from 70 % (if left untreated) to around 20 % (2).
Our patient could potentially have been treated earlier, but encephalitis is challenging to diagnose, especially in the early stages. Behavioural changes accompanied by fever and headache should raise suspicion of encephalitis, but the severity of symptoms can vary, and changes in mental status may be subtle. Headache and fever can also be absent, although they are seen in most patients with herpes simplex encephalitis. Seizures occur in about half of patients (2). The annual incidence of herpes simplex encephalitis is 2–4 cases per million (8), so general practitioners will rarely encounter the condition. Prominent neuropsychiatric symptoms may contribute to patients being incorrectly admitted to psychiatric wards, which can delay diagnosis and life-saving treatment. It is therefore extremely important that clinicians suspect encephalitis and keep it in mind as a differential diagnosis.
The discovery of increasing numbers of biomarkers associated with neurological disease has helped transform our understanding of several disorders, including conditions previously thought to be psychological in nature (10, 12). The patient in this case report developed non-infectious encephalitis late in the course of herpes simplex encephalitis. As described above, anti-NMDA receptor encephalitis is a known complication of herpes simplex encephalitis. The condition was first described in 2007 as a paraneoplastic phenomenon and is a form of subacute autoimmune cerebral inflammation that typically manifests with neuropsychiatric symptoms. The prevalence of anti-NMDA receptor encephalitis has increased over time, and it is now the most common autoimmune encephalitis (3, 13–15).
Anti-NMDA receptor encephalitis typically has a prodromal phase resembling a viral infection, before symptoms such as behavioural change, delusions and psychosis become more prominent (16). If the condition is suspected, the patient's CSF should be screened for anti-NMDA receptor antibodies. Up to 14 % of those with anti-NMDA receptor encephalitis will be negative for antibodies in serum. Screening for antibodies in blood alone may therefore potentially delay diagnosis and treatment (17).
Neuronal death can probably be averted in cases of anti-NMDA receptor encephalitis if treatment is initiated promptly. Anti-NMDA receptor antibodies bind to a subunit of the NMDA receptor, leading to internalisation of the receptor and a reduced density of NMDA receptors on the cell surface. This leads to altered neuronal function, but not necessarily to cell death (18). By contrast, in herpes simplex encephalitis, reactivation of the virus leads to activation of toll-like receptor (TLR) proteins on macrophages in the brain, resulting in inflammation and cell death (19).
A confirmed diagnosis of anti-NMDA receptor encephalitis requires detection of anti-NMDA receptor antibodies in serum or CSF, plus the presence of clinical symptoms. However, in the absence of antibodies, a probable diagnosis can be made if at least four of the most common symptoms are present: behavioural changes/cognitive dysfunction, speech dysfunction, seizures, abnormal movements, impaired consciousness and autonomic dysfunction. There must additionally be findings consistent with encephalitis on EEG and/or pleocytosis in the CSF (17), and other diagnoses must be excluded.
First-line treatment for anti-NMDA receptor encephalitis consists of corticosteroids, intravenous immunoglobulins or plasmapheresis (3). About half of patients respond to this treatment (15). If there is an insufficient response in four weeks, then rituximab, cyclophosphamide and azathioprine can be used as second-line treatment (3, 15). About 80 % of patients respond to immunomodulatory therapy (3). Early treatment has been shown to be crucial for achieving good outcomes (9). In one large study, 29 % of cases resulted in severe sequelae or death (15).
In our patient, it was probably the viral encephalitis that was responsible for most of the lasting damage (Figures 3a and b).