Neurology clinic - encephalitis

A 21-year-old student presented to his GP with a two-day history of generalised global headache. It was associated with nausea and he reported vomiting eight times. There were no visual changes or focal weakness. He reported no head injury or loss of consciousness, but describes a ‘flu-like’ illness starting approximately four days ago when he felt hot and ‘shivery’. He did not have a past medical history of headaches. Basic neurological examination did not identify any weakness of his arms or legs, but he appeared distracted and irritable and was consequently difficult to examine.

He was advised to take simple analgesia, was prescribed metoclopramide, and was advised to return if his symptoms did not settle. Later that night his mother, concerned about his unusual behaviour, took him to a walk-in centre, and he was admitted to the Clinical Decision Unit for observation. He subsequently had a generalised tonic-clonic seizure and was transferred to the medical admissions unit after a normal computed tomography brain scan with a working diagnosis of alcohol withdrawal.

He was then moved to the gastroenterology ward for an inpatient detox. During this period he was noted to have a low-grade fever and a ‘septic screen’ was ordered including urine and blood cultures, however, cardiovascular, respiratory and abdominal examinations were normal. The ward test urine identified 1+ nitrates and 1+ protein and he was started on trimethoprim.

The following night he developed status epilepticus, which was unresponsive to intravenous diazepam twice and subsequent intravenous phenytoin. He was sedated and intubated, and transferred to ITU. He had a further CT brain scan, with contrast, which demonstrated bilateral, but asymmetrical contrast enhancement of the temporal, and to a lesser extent, frontal lobes, with marked mass-effect, effacement of the sulci and evidence of herniation of the uncus and cerebellar tonsils. Intravenous aciclovir was started for presumed herpes simplex virus (HSV) encephalitis. Over the course of the following 24 hours, he became completely ventilator dependent and lost his brainstem reflexes. He was confirmed as brainstem dead and treatment was withdrawn.

Post-mortem neurohistopathological examination confirmed evidence of HSV encephalitis.

The problem

Encephalitis is inflammation of the brain parenchyma usually caused by infection or, less commonly, a primary antibody mediated process, which may be principally autoimmune or paraneoplastic, but in many cases no cause is identified. Although there is a wide spectrum of potential pathogens globally, the most commonly identified cause in the UK is HSV. Encephalitis due to HSV has a bimodal distribution with peaks in young adults and the elderly, however, due to the wide range of aetiologies, the encephalitis patient may be any age.

There are an estimated 4,000 new cases every year within the UK.

Features

Traditionally, encephalitis was described by the classical triad of fever, altered consciousness and headache. However, it is now recognised that the fever may be mild, or even absent in around 10% of cases – instead many patients may present with a preceding fever or coryzal illness rather than concomitant pyrexia.

The alteration in consciousness is often not as severe as a reduction in the Glasgow coma score (GCS), but instead there are usually alterations in personality, behaviour or cognition.¹ Consequently, many patients may be misdiagnosed with a psychiatric disorder or substance misuse – the delays caused by these misdiagnoses can result in death from the condition. Clinicians should therefore be attentive to the possibility of encephalitis when faced with a patient with these acute or sub-acute changes, rather than relying on the GCS alone. Particularly, clinicians should include encephalitis high on the differential when a relative or friend says that the patient is ‘just not themselves’ or ‘just not right’, therefore a collateral history can be invaluable.

The headache may be associated with features suggestive of raised intracranial pressure, such as exacerbations when lying flat and or performing valsalva manoeuvres. In addition, it is important to ask about transient periods of drowsiness, confusion, or odd behaviour, which may represent ictal or post-ictal events – again a collateral history is pivotal. Although there may sometimes be gross neurological signs, such as a hemiparesis, the clinician needs to assess for evidence of more subtle focal signs such as movement disorders, including myoclonic jerks, dystonic movements, Parkinsonism, and papilloedema.

The following are things to ask a presenting patient:

A travel history is important given the presence of geographically-restricted infections, such as the arboviruses, (such as Japanese encephalitis virus); and also for cerebral malaria.
Vaccination history is important for considering potential pathogen for which the patient is at risk and also because acute disseminated encephalomyelitis (ADEM) may follow recent vaccination.
Establish if the patient has evidence of immune compromise, such as established infection or high-risk behaviour for HIV, or immunosuppressive therapy.
Has there been contact with others who have been unwell?

Often the ‘infectious diseases mantra’ is helpful: ‘Why did this person, from this place, at this time, get this disease?’

The following features may be present on examination:

Rash, including shingles due to Varicella zoster virus and other non-specific rashes due to enteroviruses. However, as 90% of adults are infected with HSV and periodic, typically asymptomatic re-activation and shedding are the norm, the presence or absence of a cold sore does not predict the likelihood of HSV as the cause of encephalitis.
Meningism may be present.
Focal neurological signs, including disorders of language and higher executive function such as planning, which reflect temporo-parietal and frontal lobes respectively
Other focal signs include evidence of brainstem inflammation, such as cranial nerve palsies.
Papilloedema.

After treatment of the acute encephalitis, many patients will have lifelong brain injury and may consult their GP at any time following the acute illness. They may describe one or a number of the difficulties presented in figure 1 below. The consequences and severity of these will vary and in most cases they are unlikely to recover fully. The impairment following viral encephalitis is usually static or slowly improving. If there is progressive cognitive decline consider viral re-activation – possibly due to under-treatment, which typically occurs early, but may occur even several years after the acute event – or an alternative diagnosis. If there is progressive cognitive decline in patients who have had antibody-associated encephalitis at any time following the acute event, especially if no tumour was identified and resected, consider a resurgence in antibody levels, requiring more aggressive immunosuppression under specialist supervision.

Reprinted with kind permission from the Encephalitis Society©

Diagnosis

The diagnosis of encephalitis is confirmed or refuted by the detection of leucocytes and changes in pressure, protein and glucose in the CSF obtained at lumbar puncture. The infectious aetiology is determined by molecular analysis or antibody detection in the CSF. Neuroimaging may be supportive. There are currently no investigations that can be performed in primary care to confirm or refute the diagnosis, and all patients in whom encephalitis is included in the differential should be transferred to secondary care urgently to be assessed for a lumbar puncture and neuroimaging.

Management

Current UK guidelines recommend that treatment be started within six hours of admission to hospital, as intravenous aciclovir can reduce mortality of HSV encephalitis from around 70% to 20-30%, and can reduce mortality even further in cases that are treated before there is a significant decline in consciousness.^2,3

If the features of meningism are present, intramuscular benzyl penicillin should be considered in accordance with the British Infection Society (now Association), and NICE guidelines.^4-6

Dr Benedict Michael is a neurology NIHR doctoral research fellow at the Institute of Infection and Global Health, University of Liverpool.

Dr Ava Easton is the chief executive of The Encephalitis Society, and a health scientist at the University of York.

References