Infectious Disease Emergencies: Part 3, CNS Infections

ABSTRACT: Bacterial meningitis and herpes simplex virus type 1 (HSV-1) encephalitis are both associated with significant morbidity and mortality. Thus, hospitalization and prompt initiation of therapy are essential. Patients with bacterial meningitis are usually extremely ill and commonly present with severe and generalized headache and at least 1 symptom from the following classic triad: nuchal rigidity, fever, and mental status changes. Analysis of cerebrospinal fluid (CSF) helps distinguish bacterial from viral meningitis by Gram staining, culture, and composition. Imaging studies such as CT are typically used only when the diagnosis is uncertain or if there is concern about increased intracranial pressure. Patients with HSV-1 encephalitis may complain of headache and fever of rapid onset; they may also exhibit 1 or more focal neurological findings. CSF analysis typically shows a lymphocytic pleocytosis with an increased number of erythrocytes and an elevated protein level.

Key words: community-acquired bacterial meningitis, herpes simplex type 1 encephalitis

Potentially life-threatening infectious diseases need to be recognized early so that intervention can be started promptly. The goal of this 3-part series is to help you quickly narrow the diagnostic possibilities and assess the likelihood of serious illness.

In the first 2 articles in this series, we addressed Rocky Mountain spotted fever, meningococcemia, and necrotizing fasciitis (CONSULTANT, November 2010, page 473) and staphylococcal toxic shock syndrome (TSS) and streptococcal TSS (CONSULTANT, December 2010, page 507). Here we focus on CNS infections (Table).

COMMUNITY-ACQUIRED BACTERIAL MENINGITIS
Overview. Bacterial meningitis is primarily caused by Streptococcus pneumoniae, Neisseria meningitidis, and Listeria monocytogenes (especially in patients older than 60 years). Each year an estimated 1.2 million cases occur worldwide.¹ It is among the most common infectious causes of death, responsible for about 135,000 deaths annually throughout the world. Despite proper treatment, survivors often have neurological sequelae (eg, hearing loss).

Clinical features.Patients are usually extremely ill and commonly present with at least 1 symptom from the following classic triad^2-5:

• Nuchal rigidity.
• Fever.
• Mental status change.

Patients also typically complain of a severe and generalized headache. Other findings or manifestations of illness may include^2-5:

• Photophobia.
• Seizures.
• Focal neurological deficits.
• Petechiae or palpable purpura (especially in cases of meningitis caused by N meningitidis).

Patients usually have an abnormal temperature (either hypothermic or febrile)⁶ and may even be hypotensive, depending on the severity of illness. Nuchal rigidity can be easily demonstrated by either the Brudzinski sign (ie, spontaneous flexion of hips during attempted passive flexion of the neck) or the Kernig sign (ie, inability or reluctance to allow full extension of the knee when the hip is flexed 90 degrees); both are effective in illustrating nuchal rigidity, even if patients do not specifically complain of neck stiffness. The presence of hypotension, altered mental status, and/or seizures was found to correlate with adverse outcome (ie, death or neurological deficit) in several cohort studies.⁷

Diagnostic studies. Results of a complete blood cell count with differential may include leukocytosis with left shift or leukopenia. More useful laboratory studies are blood cultures and analysis of cerebrospinal fluid (CSF) obtained by lumbar puncture (LP). Analysis of CSF helps distinguish bacterial from viral meningitis by Gram staining, culture, and composition. CSF chemistry and cytological findings highly suggestive of bacterial meningitis include^2,3:

• Protein concentration greater than 500 mg/dL.
• Glucose concentration less than
45 mg/dL.
• White blood cell count greater than 1000/¨L.

Imaging studies such as CT have a limited role in the diagnosis of bacterial meningitis. Instead, they are typically used when the diagnosis is uncertain or if there is concern about increased intracranial pressure. The Infectious Diseases Society of America (IDSA) has published recommended criteria for adult patients with suspected bacterial meningitis who should undergo CT scanning before LP; these include⁸:

• Immunocompromised state.
• History of CNS disease (eg, mass lesion, stroke, or focal infection).
• New-onset seizure within 1 week of presentation.
• Papilledema.
• Abnormal level of consciousness.
• Focal neurological deficit.

For patients in whom CT scanning is warranted before LP, blood cultures should be obtained and empiric antibiotic therapy (with the assumption that antimicrobial resistance is likely) started without delay.

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Treatment. Because bacterial meningitis is a life-threatening illness, hospitalization and prompt initiation of antibiotics are required. Targeted antimicrobial therapy is based on presumptive pathogen identification by CSF Gram staining-for example:
• Gram-positive diplococci suggest pneumococcal infection (treat with vancomycin and ceftriaxone or cefotaxime).
• Gram-negative diplococci suggest meningococcal infection (treat with ceftriaxone or cefotaxime).
• Small pleomorphic gram-negative coccobacilli suggest Haemophilus influenzae (treat with ceftriaxone or cefotaxime).
• Gram-positive rods and coccobacilli suggest listerial infection (treat with ampicillin).

If empiric antibiotic treatment is required, the IDSA recommends an antimicrobial regimen consisting of vancomycin, and ceftriaxone or cefotaxime; ampicillin is also added, depending on the age of the patient and on whether listerial infection is suspected.⁸ As CSF and blood cultures return, the antimicrobial coverage can be narrowed and made more specific against isolated organisms.

The role of dexamethasone as an adjunctive treatment was evaluated in a Cochrane systematic review.⁹ The pathophysiological rationale for adjunctive corticosteroid use is based on experimental animal models of infection, which have shown that the inflammatory response during bacterial meningitis is a major factor contributing to morbidity and mortality. One large clinical trial, which used the following regimen, forms the basis for current guidelines on the appropriate dosing of dexamethasone in adults: dexamethasone should be given 15 to 20 minutes before or at the time of antibiotic administration-at a dose demonstrating efficacy-0.15 mg/kg every 6 hours for 4 days.¹⁰ The IDSA recommends that initiation of dexamethasone with antibiotics be reserved for adult patients with suspected or proven pneumococcal meningitis who have not already received antimicrobial therapy. This is based on trials that demonstrated limited benefit in meningitis caused by other meningeal pathogens; however, some argue that dexamethasone treatment should be initiated in all adult patients, since the cause of meningitis is not always ascertained or readily apparent at initial evaluation. These same trials did, however, suggest benefit with adjunctive dexamethasone treatment in patients with moderate to severe disease on the Glasgow Coma Scale.⁸

HERPES SIMPLEX VIRUS TYPE 1 ENCEPHALITIS
Overview. Herpes simplex virus type 1 (HSV-1) is the most common cause of sporadic fatal encephalitis throughout the world. In the United States, HSV-1 encephalitis accounts for about 10% to 20% of the annual viral encephalitis cases^11,12 and is associated with significant morbidity and mortality.

Infection of the CNS by HSV-1 is believed to occur through 1 of 3 routes¹¹:
• Primary HSV-1 of the oropharynx with subsequent infection of the CNS via the olfactory tract or trigeminal nerve.
• Viral reactivation or recurrent HSV-1 infection with spread into the CNS.
• Reactivation of latent HSV within the CNS (ie, in patients without primary or recurrent HSV-1 infection).

Clinical features. Patients may complain of headache and fever of rapid onset. In addition, patients may present with 1 or more focal neurological findings, such as¹³:
• Altered mentation or impaired
consciousness.
• Cranial nerve deficits.
• Hemiparesis.
• Dysphasia.
• Aphasia.
• Ataxia.
• Seizures.

 HSV-1 is known to have affinity for the temporal lobe and limbic structures, and patients may demonstrate behavioral syndromes (eg, hypomania, Klver-Bucy syndrome, varying levels of amnesia) that correspond with this phenomenon.^13,14

Diagnostic studies. CSF analysis in patients with HSV-1 encephalitis typically shows a lymphocytic pleocytosis with an increased number of erythrocytes and an elevated protein level; however, results may be normal early in the disease course.¹⁵ Imaging studies (particularly MRI) of the brain may also prove useful in strengthening the clinical suspicion of HSV-1 encephalitis, particularly if temporal lobe abnormalities can be demonstrated. The characteristic temporal lobe lesions are usually unilateral and may have associated mass effect.

Despite the classic findings on CSF analysis and imaging studies, the gold standard for diagnosis of HSV-1 encephalitis is the detection of HSV DNA in the CSF by means of polymerase chain reaction (PCR).^16,17 Treatment should not be delayed pending the results of PCR testing, however.

Treatment. Because of the high morbidity and mortality associated with HSV-1 encephalitis, hospitalization and prompt initiation of acyclovir are required. The duration of treatment is 14 to 21 days.^13,18,19 Mortality in untreated patients may be as high as 70% and decreases only to 20% to 30% in those who receive appropriate treatment. Survivors may have significant behavioral and cognitive impairments despite treatment.^13,18 Early and aggressive antiviral therapy with acyclovir may help prevent fatality and limit the severity of potential neurobehavioral and neuropsychiatric problems.

References:

REFERENCES:

1.

Scheld WM, Koedel U, Nathan B, Pfister HW. Pathophysiology of bacterial meningitis: mechanism(s) of neuronal injury.

J Infect Dis.

2002;186(suppl 2):S225-S233.

2.

Durand ML, Calderwood SB, Weber DJ, et al. Acute bacterial meningitis in adults. A review of 493 episodes.

N Engl J Med.

1993;328:21-28.

3.

Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing.

Ann Intern Med.

1998;129:862-869.

4.

van de Beek D, de Gans J, Spanjaard L, et al. Clinical features and prognostic factors in adults with bacterial meningitis [published correction appears in

N Engl J Med.

2005;352:950].

N Engl J Med.

2004;351:1849-1859.

5.

Attia J, Hatala R, Cook DJ, Wong JG. The rational clinical examination. Does this adult patient have acute meningitis?

JAMA.

1999;282:175-181.

6.

Domingo P, Mancebo J, Blanch L, et al. Fever in adult patients with acute bacterial meningitis.

J Infect Dis.

1988;158:496.

7.

Thomas KE, Hasbun R, Jekel J, Quagliarello VJ. The diagnostic accuracy of Kernig’s sign, Brudzinski’s sign, and nuchal rigidity in adults with suspected meningitis.

Clin Infect Dis.

2002;35:46-52.

8.

Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis.

Clin Infect Dis.

2004;39:1267-1284.

9.

van de Beek D, de Gans J, McIntyre P, Prasad K. Corticosteroids for acute bacterial meningitis.

Cochrane Database Syst Rev.

2007;24(1):CD004405.

10.

de Gans J, van de Beek D; Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with bacterial meningitis.

N Engl J Med.

2002;347:1549-1556.

11.

Levitz RE. Herpes simplex encephalitis: a review.

Heart Lung.

1998;27:209-212.

12.

Whitley RJ. Viral encephalitis.

N Engl J Med.

1990;323:242-250.

13.

Hart RP, Kwentus JA, Frazier RB, Hormel TL. Natural history of Klüver-Bucy syndrome after treated herpes encephalitis.

South Med J.

1986;79:1376-1378.

14.

Fisher CM. Hypomanic symptoms caused by herpes simplex encephalitis.

Neurology.

1996;47:1374-1378.

15.

Nahmias AJ, Whitley RT, Visintine AN, et al. Herpes simplex virus encephalitis: laboratory evaluations and their diagnostic significance.

J Infect Dis.

1982;145:829-836.

16.

Tyler KL. Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret’s.

Herpes.

2004;11(suppl 2):57A-64A.

17.

Boivin G. Diagnosis of herpesvirus infections of the central nervous system.

Herpes.

2004;11(suppl 2):48A-56A.

18.

Arciniegas DB, Anderson CA. Viral encephalitis: neuropsychiatric and neurobehavioral aspects.

Curr Psychiatry Rep.

2004;6:372-379.

19.

Jeffries DJ. Clinical use of acyclovir.

Br Med J (Clin Res Ed).

1985;290:177-178.