Clinical Presentation and Diagnosis of Viral CNS infections

[This post was written by Ahmed Abdul Azim, a senior infectious disease fellow at Beth Israel Deaconess Medical Center]

During the fall and winter season, you are likely to see a few cases of viral meningitis. Even though viral encephalitis is less common, it is important to try to differentiate these clinical entities as a clinician, since they carry different prognoses. (The bulk of this review is adapted from Mandell, Douglas and Bennett’s principles and practice of infectious diseases)1

Cerebral spinal fluid analysis

Before we go any further, let’s briefly review cerebral spinal fluid findings on lumbar puncture for different syndromes:

 WBC(cells/mm3)Primary cellsGlucose(mg/dL)Protein(mg/dL)
Viral50-1000Lymphocytic>45<200
Bacterial1000-5000Neutrophilic<40100-500
Mycobacterial50-500Lymphocytic<4550-300
Cryptococcal/fungal20-500Lymphocytic<40>45

Important points to consider:
·       Bacterial meningitis: 10% of cases have a lymphocyte predominant CSF cell analysis
·       WNV encephalitis: over a 1/3 of patients with WNV encephalitis had neutrophil predominant CSF pleocytosis
·       Enteroviruses: CSF analysis done early in illness course may yield neutrophil predominant pleocytosis in 2/3 of cases – generally will convert to lymphocytic predominant if repeated in 12-24 hours.

Take home point: always interpret CSF within the clinical context in front of you!

  • CSF to serum glucose ratio of < 0.4 is suggestive of bacterial meningitis
  • Traumatic LP may cause elevated CSF protein:
    for every 1000 RBC/mm3, subtract 1 mg/dL protein
  • Traumatic LP may cause elevated CSF WBC:
    for every 500-1000 RBC/mm3, subtract 1 WBC/mm3
  • RBC Adjustment for WBC in CSF = Actual WBC in CSF – (WBC in blood x RBC in CSF/RBC in blood)

Viral meningitis versus encephalitis

Both syndromes often present with a triad of2:
(1) FEVER
(2) HEADACHE and
(3) ALTERED MENTAL STATUS
However, the trick is to explore the history and signs further. Epidemiological clues include:

  • travel history
  • prevalence of disease in the local area
  • occupational exposure
  • animal and insect exposure
  • immunization history
  • underlying immune status

Patients with viral encephalitis: tend to have diffuse cerebral cortex involvement with abnormal cerebral function
Symptoms: altered mental status, motor/sensory deficits, altered behavior and/or personality changes, speech and/or movement disorders

Patients with viral meningitis: DO NOT have diffuse cerebral cortex involvement → cerebral function IS INTACT
Symptoms: headache, lethargy, neck stiffness/pain

Patients with meningoencephalitis: tend to have a combination of meningitis and encephalitis symptoms

Regardless, if a patient has symptoms and/or signs of meningitis or encephalitis, a lumbar puncture can be helpful.

Viral Meningitis – Common Pathogens

Overall, most cases of aspectic meningitis syndromes are caused by viruses

1. Enteroviruses (e.g. Coxsackie, echovirus, other non-polio enteroviruses) – by far the most common cause of viral meningitis/aseptic meningitis3

  • Summer/fall seasons (less commonly in the winter)
  • Clinical manifestations:
    • abrupt onset fever
    • headache
    • vomiting/diarrhea
    • photophobia
    • malaise
    • +/- meningismus
  • Think of enterovirus viral meningitis in patients when rash and/or diarrhea is present
  • CSF analysis done early in illness course may yield neutrophil predominant pleocytosis in 2/3 of cases – generally will convert to lymphocytic predominant if repeated in 12-24 hours4.
  • Take home point: always interpret CSF within the clinical context in front of you!
  • Diagnostics: CSF PCR 86-100% sensitive, 92-100% specific5,6,7

2. Herpes virus simplex viral meningitis – usually caused by HSV-2 >> HSV-18

  • Only accounts for 0.5-3% of viral meningitis/aseptic meningitis cases9
  • Typically mild symptoms
  • 80% with HSV-2 genital lesions/ulcers up to 1 week prior to presenting with viral meningitis
  • Patients with a clinical picture consistent with aseptic meningitis and have HSV isolated in CSF will end up having HSV-2 in 95% of cases. This is a self-limited illness3

3. West Nile Virus – more likely to cause an encephalitis syndrome. Yet, may present with aseptic meningitis or asymmetrical flaccid paralysis10

Viral Encephalitis – Common Pathogens 

A cause is identified in approximately 36-63% of cases10,11

Causes of encephalitis (Most common to least common in US study of patients that met criteria for encephalitis)12:

  • Viruses (70%)
    • Enteroviruses: 25%
    • HSV-1: 24%
    • Varicella zoster virus (VZV): 14%
    • West Nile virus (WNV): 11%
    • EBV: 10%
    • Others: 16%
  • Bacteria (20%)

*In a study of HIV uninfected patients, viruses caused up to 38% of cases, followed by bacterial pathogens at 33%, Lyme disease at 7%, and fungi at 7%. Syphilis was identified as the culprit in 5% of cases, and mycobacterial infections at 5%, while prion disease was responsible for 3% of cases of encephalitis11

1. HSV encephalitis: most common cause of encephalitis in the US (1/250,000 population annually). HSV-1 accounts for greater than 90% of HSV encephalitis in adults13. Fewer than 6% of CSF PCR cases had a “normal” neurological exam14.

  • > 96% have CSF pleocytosis14,15,16
  • Protein is elevated; glucose is normal 95% of the time14,15,16
  • MRI > CT, revealing changes of temporal lobes in ~89% of cases confirmed by CSF PCR15
  • CSF PCR is highly sensitive and specific, with an excellent positive and negative predictive value17
  • If HSV encephalitis is suspected and PCR is negative, repeat HSV PCR testing in 3-5 days
  • HSV PCR remains positive up to 7 days in 98% of cases after onset of symptoms
  • Treatment: IV acyclovir is the treatment of choice; call your nearest ID colleague for help
  • Mortality in acyclovir-treated patients stratified by age group18:
    • 11% in < 2 year olds
    • 22% in 22-59 year olds
    • 62% in > 60 year olds
      (initial level of consciousness strongly predicted mortality16)

2. West Nile Virus encephalitis: transmitted via a mosquito (vector) bite, currently the most common cause of epidemic viral encephalitis nationally19

  • Most are asymptomatic (80%); macular rash in up to 50% of cases20
  •  <1% develop neuroinvasive disease, of which 60% develop encephalitis21
  • High risk patients for neuroinvasive disease: solid organ transplant patients22
  • Clinical presentation21
    • Fever: 70-100%
    • Headache: 50-100%
    • Encephalopathy: 45-100%
    • Cranial neuropathies, mostly facial palsy: 20%
    • Lower motor neuron type lesion: areflexia, hypotonia, preserved sensation
    • Tremors are not uncommon either
  • CSF analysis: pleocytosis (>60% of cases lymphocytic predominant), elevated protein and normal glucose13
  • WNV encephalitis will likely have neuroimaging findings; that is not the case with WNV meningitis
  • MRI much more sensitive than CT. Most common abnormalities seen involving basal ganglia, brain stem and thalamus1
  • CSF diagnosis: WNV-specific IgM in CSF23
  • No established therapy for neuroinvasive disease. Case reports of improvement with IVIG for neuroinvasive disease1
  • Mortality: 12% in severe neuroinvasive disease. Residual neurological changes such as parkinsonism not uncommon
  • Approximately 30% of patients reported fatigue symptoms 6 months to 5 years after infection onset24

Viral Meningoencephalitis – Clinical Approach  

So you are the house officer encountering a patient with 1-2 weeks of progressively worsening fevers, headaches and severe behavioral changes or depressed mental status: what do you do next?

As a standard work up for likely encephalitis in the United States, CSF studies should include1:

  • CSF opening pressure
  • Cell count and differential
  • Protein and glucose (paired with serum glucose)
  • Gram stain and bacterial cultures
  • Initial viral studies to include:
    • HSV-1/2 PCR;
    • VZV PCR;
    • Enterovirus PCR;
    • WNV IgM serology (if seasonally appropriate);
    • CSF viral cultures

Imaging in encephalitis: Magnetic resonance imaging (MRI) of the brain is more sensitive than computed tomography (CT)15. Unless contraindicated, all patients with encephalitis should undergo MR imaging.

  • Temporal lobe and limbic changes → HSV, HHV-619
  • Hemorrhagic strokes and demyelinating lesions → VZV vasculopathy25
  • Subependymal enhancement → CMV ventriculitis25
  • Predominant demyelination → PML (JC virus)

References:

1. Mandell, Douglas and Bennett’s principles and practice of infectious diseases (8th ed. 2015 / Philadelphia, PA : Elsevier)
2. Whitley RJ, and Gnann JW: Viral encephalitis: familiar infections and emerging pathogens. Lancet 2002; 359: pp. 507-513
3. Connolly KJ, and Hammer SM: The acute aseptic meningitis syndrome. Infect Dis Clin North Am 1990; 4: pp. 599-622
4. Gomez B, Mintegi S, Rubio MC, et al: Clinical and analytical characteristics and short-term evolution of enteroviral meningitis in young infants presenting with fever without source. Pediatr Emerg Care 2012; 28: pp. 518-523
5. Rotbart HA: Diagnosis of enteroviral meningitis with the polymerase chain reaction. J Pediatr 1990; 117: pp. 85-89
6. Sawyer MH, Holland D, and Aintablian N: Diagnosis of enteroviral central nervous system infection by polymerase chain reaction during a large community outbreak. Pediatr Infect Dis J 1994; 13: pp. 177-182
7. Ahmed A, Brito F, Goto C, et al: Clinical utility of polymerase chain reaction for diagnosis of enteroviral meningitis in infancy. J Pediatr 1997; 131: pp. 393-397
8. Shalabi M, and Whitley RJ: Recurrent benign lymphocytic meningitis. Clin Infect Dis 2006; 43: pp. 1194-1197
9. Corey L, and Spear PG: Infections with herpes simplex viruses (2). N Engl J Med 1986; 314: pp. 749-757
10. Kupila L, Vuorinen T, Vainionpaa R, et al: Etiology of aseptic meningitis and encephalitis in an adult population. Neurology 2006; 66: pp. 75-80
11. Tan K, Patel S, Gandhi N, et al: Burden of neuroinfectious diseases on the neurology service in a tertiary care center. Neurology 2008; 71: pp. 1160-1166
12. Glaser CA, Gilliam S, Schnurr D, et al: In search of encephalitis etiologies: diagnostic challenges in the California Encephalitis Project, 1998-2000. Clin Infect Dis 2003; 36: pp. 731-742
13. Tyler KL: Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret’s. Herpes 2004; 11: pp. 57A-64A
14. Raschilas F, Wolff M, Delatour F, et al: Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study. Clin Infect Dis 2002; 35: pp. 254-26
15. Domingues RB, Tsanaclis AM, Pannuti CS, et al: Evaluation of the range of clinical presentations of herpes simplex encephalitis by using polymerase chain reaction assay of cerebrospinal fluid samples. Clin Infect Dis 1997; 25: pp. 86-91
16. Whitley RJ, Alford CA, Hirsch MS, et al: Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N Engl J Med 1986; 314: pp. 144-149
17. Lakeman FD, and Whitley RJ: Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis 1995; 171: pp. 857-86
18. Whitley RJ, Alford CA, Hirsch MS, et al: Factors indicative of outcome in a comparative trial of acyclovir and vidarabine for biopsy-proven herpes simplex encephalitis. Infection 1987; 15: pp. S3-S8
19. Kramer LD, Li J, and Shi PY: West Nile virus. Lancet Neurol 2007; 6: pp. 171-181
20. Watson JT, Pertel PE, Jones RC, et al: Clinical characteristics and functional outcomes of West Nile Fever. Ann Intern Med 2004; 141: pp. 360-365
21. Sejvar JJ, Haddad MB, Tierney BC, et al: Neurologic manifestations and outcome of West Nile virus infection. JAMA 2003; 290: pp. 511-515
22. Jean CM, Honarmand S, Louie JK, et al: Risk factors for West Nile virus neuroinvasive disease, California, 2005. Emerg Infect Dis 2007; 13: pp. 1918-1920
23. Shi PY, and Wong SJ: Serologic diagnosis of West Nile virus infection. Expert Rev Mol Diagn 2003; 3: pp. 733-741
24. Garcia MN, Hause AM, Walker CM, et al: Evaluation of prolonged fatigue post-West Nile virus infection and association of fatigue with elevated antiviral and proinflammatory cytokines. Viral Immunol 2014; 27: pp. 327-333
25. Gilden DH, Mahalingam R, Cohrs RJ, et al: Herpesvirus infections of the nervous system. Nat Clin Pract Neurol 2007; 3: pp. 82-94

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