Viral Encephalitis

2. Viral Encephalitis Evidence Based Management

3. M. Amir Hossain Professor (Medicine) Chittagong Medical Colle, Bangladesh

4. Introduction Encephalitis means inflammation of the brain parenchyma, and strictly speaking this is a pathological diagnosis Encephalitis is a relatively rare, its importance lies in that fact that for many forms treatment is effective if started promptly; in contrast, delays in treatment can be devastating..

5. Etiology Hundreds of viruses are capable of causing encephalitis, although only a limited subset is responsible for most cases in which a specific cause is identified The most commonly identified viruses causing sporadic cases of acute encephalitis in immunocompetent adults are herpesviruses (HSV, VZV, EBV).

7. Etiology New viral CNS infections are appearing, as in recent outbreak in • Southeast Asia by Nipah virus, • Europe caused by Toscana virus, • epidemics of Chikungunya virus,in Africa, India, and Southeast Asia

8. Etiology New viral CNS infections are appearing, as in recent outbreak in • Southeast Asia by Nipah virus, • Europe caused by Toscana virus, • epidemics of Chikungunya virus,in Africa, India, and Southeast Asia

9. Etiology The global incidence of Encephalitis varies according to the location, population studied, and differences in case definitions and research methods

10. Etiology In the United States, there are 20,000 reported cases of encephalitis per year The actual number of cases is likely to be significantly larger. The majority of cases of acute encephalitis of suspected viral etiology remain of unknown cause

11. Etiology Incidence in western settings ranges from 0.7-13.8/100,000 for all ages, 0.7-12.6/100,000 for adults 10.5-13.8/100,000 children.1-3

12. Etiology Most HSV Encephalitis is due to HSV-1, but about 10% is caused by HSV-2 in immunocompromised individuals and neonates, and causes disseminated infection

13. Etiology VZV is also a relatively common cause of viral Encephalitis, especially in immunocompromised CMV occurs exclusively in immunocompromised Enteroviruses is an important cause of Encephalitis.

14. Etiology

15. Chronology of Nipah virus outbreaks in South-East Asia, 2001-2012

16. Classification of Encephalitis The causes of Encephalitis can be defined as those due to 1. Direct infection of the Central Nervous System 2. Para, or post-infectious causes 3. Non-infectious causes

17. Classification of Encephalitis Most viral Encephalitis is • Acute • Sub-acute and • Chronic presentations are characteristic of particular pathogens, especially in the immunocompromised.

18. Classification of Encephalitis • Infectious: viruses, bacteria, parasites and fungi • Post infectious: ADEM • Non-infectious: antibody-associated Encephalitis, which may or may not be paraneoplastic.

19. Clinical evaluation

20. Clinical manifestations The diagnosis of viral encephalitis is suspected in the context of a febrile episodes accompanied by headache,and symptoms and signs of cerebral dysfunction.

21. Clinical manifestations Cerebral dysfunctions are of 4 groups • Cognitive dysfunction: acute memory disturbances • Behavioural changes: disorientation, hallucinations, psychosis, personality changes, agitation • Focal neurological abnormalities: anomia, dysphasia, hemiparesis, hemianopia etc. • Seizures: Focal ,generalize.

22. Approach to the patient The approach to the patients consist of obtaining a meticulous history and a careful general and neurological examination.

23. Questions to consider in the history (Solomon, Hart et al. 2007) • Current or recent febrile or influenza-like illness? • Altered behaviour or cognition, personality change or altered consciousness? • New onset seizures? • Focal neurological symptoms? • Rash? (varicella zoster, roseola, enterovirus)

24. Questions to consider in the history (Solomon, Hart et al. 2007) • Others in the family, neighbourhood ill? (measles, mumps, influenza) • Travel history? (prophylaxis and exposure for malaria, arboviral encephalitis, rabies, trypanosomiasis) • Recent vaccination? (ADEM)

25. Questions to consider in the history (Solomon, Hart et al. 2007) • Contact with animals? (rabies) • Contact with fresh water (leptospirosis) • Exposure to mosquito or tick bites (arboviruses, Lyme disease, tick-borne encephalitis) • Known immunocompromise? • HIV risk factors?

26. Examination findings (Solomon, Hart et al., 2007) • Airways, Breathing, Circulation (ABC) • Mini-mental state, cognitive function, behaviour • Evidence of prior seizures? (tongue biting, injury) • Subtle motor seizures? (mouth, digit, eyelid twitching) • Meningism • Focal neurological signs

27. Examination findings (Solomon, Hart et al., 2007) • Papilloedema • Flaccid paralysis (anterior horn cell involvement) • Rash? (purpuric-meningococcus; vesicular - varicella zoster; rickettsial disease) • Injection sites of drug abuse? • Bites from animals (rabies) or insects (arboviruses) • Movement disorders, including Parkinsonism

28. Diagnosing encephalitis • Which clinical features should lead to suspicion of encephalitis? • How do they differ from other encephalopathies ? • And can they be used to diagnose the underlying cause?

29. GRADE rating system for the strength of the guidelines recommendations and the quality of the evidence (Atkins, Best et al., 2004). 19

30. Which clinical features should lead to suspicion of Encephalitis? Recommendations • The constellation of a current or recent febrile illness with altered behaviour or consciousness, or new seizures, or new focal neurological signs, should raise the possibility of Encephalitis (A, II)

31. Which clinical features should lead to suspicion of Encephalitis? Recommendations • Metabolic, toxic, autoimmune and non-CNS sources of sepsis as other causes for encephalopathy should be considered early in patients presenting with encephalopathy (B, III) • If there are features suggestive of a non-encephalitic process, such as a past history of similar episodes, symmetrical neurological findings, myoclonus, asterixis, lack of fever, acidosis, or unexplained negative base excess (B, III)

32. Which clinical features should lead to suspicion of Encephalitis? Recommendations • Features, such as a sub-acute presentation (weeks-months), orofacial dyskinesia, choreoathetosis, faciobrachial dystonia, intractable seizures or hyponatraemia, may suggest an antibody-mediated Encephalitis, although these features are not all exclusive to antibody- mediated disease (B, II)

33. Investigations

34. Laboratory Diagnosis • All routine investigations • CSF examination: PCR, Culture • Serologic: antigen and antibodies • Radiology: MRI, CT, EEG, others • Brain biopsy

35. Diagnosing Encephalitis Recommendations • The investigation priority is determined by the patient’s clinical history and clinical presentation (C, III)

36. GRADE rating system for the strength of the guidelines recommendations and the quality of the evidence (Atkins, Best et al., 2004). 19

37. Recommendations for diagnostic tests

38. Recommendations for diagnostic tests

40. Microbiologic Evaluation for Viruses Causing Encephalitis

41. Diagnosing Encephalitis • Which patients with suspected Encephalitis should have a lumbar puncture? • And in whom should this be preceded by a computed tomography scan?

42. Which patients with suspected Encephalitis should have a lumbar puncture? Recommendations • All patients with suspected Encephalitis should have LP as soon as possible after hospital admission, unless there is a clinical contraindication (A, II)

43. In whom should LP be preceded by a computed tomography scan? Recommendations • If CF indicates raised ICP, CT scan should be performed as soon as possible (A, II). • An immediate LP following CT be considered, unless the imaging reveals significant brain shift or tight basal cisterns or an alternative diagnosis, or the patient’s clinical condition changes (B, III)

44. Which patients with suspected Encephalitis should have a lumbar puncture? Recommendations • If a CT is not needed before a LP, a CT or MRI should be performed as soon as possible afterwards (A, II) • In situations where a LP is not possible at first, the situation should be reviewed every 24 hours, and a LP performed when it is safe to do so (B, II)

45. Diagnosing Encephalitis Recommendations • LP should be performed with needles that meet the standards set out by the National Patient Safety Agency (A, III)

46. What information should be gathered from the LP? Recommendations • CSF opening pressure (A, II) • Total and differential WBC, RBC, microscopy, culture and sensitivities for bacteria (2x2.5ml) (A, II)

47. What information should be gathered from the LP? • Protein and glucose (1-2ml), should be compared with a plasma glucose taken just before the LP (A, II) • Virological or other investigation are considered in the next section (2ml) (A, II) • AFBis to be done (6ml) when clinically indicated (A, II) • If initial LP is non-diagnostic, a second LP should be performed 24-48 hours later (B, II)

48. What virological investigations should be performed? Recommendations • All patients should have a CSF PCR test for HSV (1 and 2), VZV & EV, as this will identify 90% of cases due to viral pathogens (B, II) • Further testing should be guided by the clinical features, occupation, travel history and animal or insect contact (B, III)

49. What antibody testing should be done on serum and CSF? Recommendations • Guidance from microbiological, virological or infectious diseases specialist should be sought (B, III) • If PCR of the CSF not performed acutely, a later CSF and serum sample (10-14 days later) should be sent for HSV specific IgG antibody (B, III)

50. What PCR/culture should be done on other samples (e.g. throat swab, stool, vesicle etc)? Recommendations • Investigation should be undertaken through close collaboration between a laboratory specialist in microbiology or virology and the clinical team (B, III) • In all patients with suspected viral Encephalitis throat and rectal swabs for enterovirus investigations should be considered (B, II); and swabs should also be sent from vesicles, if present (B, II)