Focused

Nervous System & Special Senses


Diagnosis and reasoning

Evaluation of a 'first seizure' is a common and very important clinical problem; while the differential diagnosis is extremely wide, careful observation of the salient characteristics of the seizure often helps narrow down the possibilities.


First and foremost, note that this is a seizure associated with fever; in an adult, this should raise the suspicion of a central nervous system (CNS) infection such as meningitis, encephalitis, or even a brain abscess. A less common possibility is CNS inflammation due to non-infective conditions such as SLE.


Secondarily, note the focal nature of the seizure; this suggests at a focal brain lesion.


While the classical triad of fever, headache and neck stiffness initially appears to hint at meningitis, note the absence of Kernig’s and Brudzinski's signs and negative jolt accentuation test (JAT).


The JAT has a sensitivity of 97% and specificity of 60% for the diagnosis of meningitis, thus making this diagnosis highly unlikely.


However, meningoen

cephalitis may demonstrate all these clinical features; and given the history of a flu-like illness, the possibility of a cerebral abscess must still be considered.


Neuroimaging is probably the best first step; an MRI should be considered due to the superior resolution.


Not only does the MRI exclude a cerebral abscess; it also shows focal edema of the temporal and frontal lobes, which is almost characteristic of herpes simplex encephalitis (HSE).


A lumbar puncture should probably be the next step in his evaluation (note that this can be performed safely as the cerebral edema is focal and mild); the resulting findings are suggestive of a viral infection, lending further credence towards HSE; subsequently, PCR demonstrates the presence of HSV, and confirms the diagnosis.


Note that an EEG should also be performed in all cases of encephalitis as this may aid in differentiating focal encephalitis from generalised encephalopathy. However, the generalized slow wave patterns seen here are common in the postictal period and do not enhance the diagnosis.


Acyclovir is the mainstay of treatment in HSE and should be commenced as soon as possible.


Cephalosporins are of little use in viral infections; sedatives should be avoided as this patient is already drowsy. It is unclear if corticosteroid therapy in HSE is of benefit; currently, most clinicians avoid their use.

Discussion

Acute encephalitis is an acute, usually diffuse, inflammatory process affecting the brain. This is often associated with concomitant inflammation of the meninges, i.e. meningoencephalitis.


Acute encephalitis is most often caused by viral pathogens; Herpes Simplex Virus (HSV-1, HSV-2), Varicella Zoster Virus (VZV) and Japanese Encephalitis Virus (JEV) are the most common organisms implicated; however, Cytomegalovirus (CMV), Epstein-Barr virus (EBV), HIV, and Adenovirus can also give rise to the condition.


When considering the likely pathogen, epidemiological and geographical trends should be considered (for example, St Louis Virus Encephalitis, which is caused by an arbovirus, occurs in the USA, but not in the UK).


The mode of onset and progression of the disease may also provide valuable clues to the etiology: a biphasic onset with a systemic illness is characteristic of enterovirus encephalitis, while an abrupt onset with rapid progression over a few days is seen in HSE.


Other factors such as recent animal bites (i.e. tick-borne encephalitis), recent travel to foreign countries, recent contact with infected persons, recent vaccinations, recreational activities, and occupational exposure should be evaluated in the history.


Note that HSV encephalitis is the most common form in the western world; the remainder of this discussion focuses on this entity.


The classical presentation of HSE usually consists of fever, headache, and altered consciousness; this may be associated with seizures and focal or diffuse neurological signs in some patients. However, no pathognomonic clinical findings reliably distinguish HSE from other neurologic disorders with similar presentations.


There is a considerable overlap of clinical features with meningitis; it may often be challenging to differentiate between the two. In particular, bacterial CNS infections due to listeriosis, mycoplasma, borreliosis, chlamydia pneumoniae and syphilis may mimic the clinical features of HSE.


In addition, metabolic encephalopathy can mimic HSE; factors favoring this diagnosis include the absence of fever (although this is not definite as encephalopathy can be precipitated by infection or sepsis), absence of a headache, lack of meningism or focal neurological signs, and presence of normal CSF and MRI findings.


Frontotemporal signs with aphasia, personality changes, and focal seizures are significant features of HSE, however no pathognomonic clinical feature has yet been identified.


A prompt and proper workup must be initiated in all patients with HSE, so as to avoid delays in the management.


Magnetic resonance imaging (MRI) is the most sensitive neuroimaging test and changes usually appear early; focal edema of the temporal lobes, orbital surface of the frontal lobes as well as the insular cortex and angular gyrus are typical.


Non-contrast CT imaging may be performed if MRI facilities are unavailable or contraindicated; however, it may take days to weeks for changes apparent on CT to develop.


SPECT (single photon emission computed tomography) with Technetium-99m labelled hexamethylpropyleneamine may yield additional information supporting the diagnosis of HSE.


EEGs are recommended in these patients, as these may help distinguish HSE from other types of encephalopathy; the most common findings include periodic, lateralizing, epileptiform discharges from the temporal lobes and slowing of the waves.


CSF analysis should be carried out provided that intracranial pressure is not raised. When significant cerebral oedema is present, lumbar puncture should be performed following treatment with mannitol or steroids.


In HSE, the CSF analysis is typical of viral meningitis, with lymphocytic pleocytosis, increased proteins, and normal glucose levels. Xanthochromia may be present, but is of no specific diagnostic value.


PCR of the CSF has a specificity of 95% for HSE, and thus is a very useful diagnostic tool. However, note that a negative result does not necessarily exclude HSE.


Detection of HSV specific IgM antibodies in the CSF is definitive, but is time consuming and not widely available, limiting its use in the acute setting.


A brain biopsy should not be routinely performed, unless the diagnosis is in serious doubt or if the patient deteriorates despite treatment with acyclovir.


Treatment should be initiated upon clinical suspicion, because of markedly higher mortality rates in untreated patients; therefore intravenous acyclovir (which is both safe and effective) is usually started on all patients with suspected HSE.


Seizures should be managed with anticonvulsants; supportive care should be provided as appropriate.


The mortality rate is around 70% when untreated, and only 20% when treated.


Almost half of patients recover satisfactorily following treatment, with the prognosis being better in younger patients and in those where the disease lasted for four days or less.

Take home messages

1. Encephalitis is usually viral in origin, although the exact etiology goes unknown in many cases.

2. HSE should be suspected in patients with fever, sudden headache, confusion, or clouding of consciousness.

3. In many settings, the diagnosis of HSE has to be initially made on clinical grounds alone; this is sufficient justification for starting treatment.

4. As HSE is the commonest identified cause of encephalitis, and one of the few forms of encephalitis for which specific treatment exists, it is now a common practice to immediately start treatment with aciclovir in all cases of encephalitis.

References

  1. J Neurol Neurosurg Psychiatry. 2004 March; 75(Suppl 1): i10–i15. doi:10.1136/jnnp.2003.034280. PMCID: PMC1765650; VIRAL ENCEPHALITIS: CAUSES, DIFFERENTIAL DIAGNOSIS, AND MANAGEMENT: P Kennedy.
  2. National Institute of Neurological Disorders and Stroke: Meningitis and Encephalitis Fact Sheet
  3. N Engl J Med 1990; 323:242-250July 26, 1990DOI: 10.1056/NEJM199007263230406; Viral Encephalitis; Richard J. Whitley.
  4. IDSA Guidelines for Management of Encephalitis, CID 2008:47 (1 Aug); The Management of Encephalitis: Clinical Practice,Guidelines by the Infectious Diseases Society of America: Allan R. Tunkel, Carol.Glaser,Karen. Bloch, James J. Sejvar, Christina M. Marra, Karen L. Barry J. Hartman, Sheldon L. Kaplan, W. Michael Scheld, Richard J. Whitley.
  5. J Neurol Neurosurg Psychiatry 2002;73:237-238 doi:10.1136/jnnp.73.3.237: Encephalitis-Herpes simplex encephalitis; P G E Kennedy, A Chaudhuri.
  6. BMJ. 2012 Jun 6;344:e3166. doi: 10.1136/bmj.e3166; Herpes simplex encephalitis; Sabah M, Mulcahy J, Zeman A.
  7. Curr Opin Neurol. 2011 Jun;24(3):268-74. doi: 10.1097/WCO.0b013e328346be6f; Herpes simplex virus encephalitis: new infection or reactivation?; Steiner I.
  8. J Clin Neurosci. 2010 Sep;17(9):1221-3; Extra-temporal involvement in herpes simplex encephalitis; A.F. Fernandes, M.C. Lange, F.T.M. Novak, J.A. Zavala, L.N. Zamproni, F.M.B. Germiniani, E.J. Piovesan, H.A.G. Teive.