Differential Diagnosis of Meningitis and Encephalitis

Figure 1

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Figure 2

Table 7

This article discusses:

• Clinical presentation of meningitis and encephalitis (and subtypes)
• Diagnostic workup: CSF analysis, imaging, electroencephalogram
• Treatment options

Case Vignette

A 26-year-old man with a history of intravenous drug use and hepatitis C presented with headache and neck pain. Magnetic resonance imaging (MRI) of the brain and cervical spine are shown in FIGURE 1. T1 post-contrast imaging (right) shows diffuse leptomeningeal enhancement at the cervico-medullary junction and throughout the cord. At the time of presentation the patient was started on empiric broad spectrum bacterial meningitis coverage with ampicillin, vancomycin, and ceftriaxone without significant improvement. Leptomeningeal biopsy revealed fungal meningitis with visualized candida albicans species. Patient improved with fluconazole treatment.

The differential diagnosis of meningitis and encephalitis includes bacterial, viral, fungal, and autoimmune etiologies. Initial diagnostic testing should be directed at excluding life-threatening, common, and treatable etiologies; further work up should be focused on the temporal pattern of the illness, clinical clues, and epidemiological risk factors. Often, the first step is to distinguish between the clinical entities of meningitis, encephalitis, and encephalopathy.

Clinical presentation

Meningitis

Meningitis refers to the inflammation of the leptomeninges. The classic clinical presentation of meningitis includes the triad of headache, fever, and neck stiffness, though this occurs in less than half the cases, however almost all patient have at least 2 of the 4 symptoms of headache, fever, neck stiffness, and altered mental status.

Viral meningitis has the highest prevalence; the average annual rate in the US isgreater than 36,000 cases per year. The most common cause of viral meningitis are the non-polio enteroviruses, accounting for over half of reported cases.¹ Other causes of viral meningitis include the herpesviruses with Herpes simplex virus (HSV)-2 as the most common cause of aseptic meningitis in the immunocompetent.

Chronic or recurrent meningitis remains a challenge and often takes several weeks to months to correctly diagnose. HSV-2 remains the most common organism for chronic meningitis. In those with eosinophils present in the cerebrospinal fluid (CSF), one must rule out parasitic infections, syphilis, and tuberculosis as potential causes. Fungal infections such as Cryptococcus neoformans and histoplasmosis can also lead to chronic meningitis and should be evaluated in the correct geographical context.

Encephalitis

Encephalitis is defined by major and minor criteria (Table 1). Although a patient can have concurrent involvement of the spinal cord (encephalomyelitis) or meninges (meningoencephalitis), evidence of brain inflammation is the key distinguishing feature. Encephalopathy, by contrast, is a symptom that may result from underlying encephalitis or a host of toxic, metabolic, or vascular causes (Table 2).

The main differential for encephalitis includes infectious (viruses being the most common), and autoimmune etiologies. There are more than 100 pathogens known to cause infectious encephalitis. Autoimmune etiologies associated with neural autoantibodies are becoming increasingly recognized making the diagnosis challenging.

Infectious encephalitis. HSV infection is the most common and treatable cause of viral encephalitis. HSV encephalitis (HSVE) generally has temporal lobe involvement visualized on MRI defined by abnormal T2 signal abnormalities and contrast enhancement, typically with asymmetric involvement. This is in contrast to autoimmune limbic encephalitis, which tends to be symmetric involvement and without contrast enhancement.

Evaluation includes an initial HSV polymerase chain reaction on the CSF as well as immediate treatment with empiric intravenous acyclovir. If clinical suspicion remains high in the setting of a negative initial polymerase chain reaction, therapy should be continued until a repeat polymerase chain reaction is obtained. In younger patients, especially under the age of 30 years, anti N-methyl-d-aspartate (NMDA) receptor encephalitis can have a similar clinical presentation and should be evaluated for if the HSV polymerase chain reaction is negative. MRI findings in these patients are normal in about 50% of cases and can provide a useful tool with differentiating these syndromes.

If patients with recent HSVE present with relapsing symptoms a few weeks after a course of acyclovir for 14 to 21 days, repeat diagnostic work up should include evaluation for NMDA receptor antibodies. Studies suggest that HSVE can trigger anti-NMDA receptor encephalitis.^2-5

Arbovirus encephalitis (Table 3) also have to be considered in the appropriate seasonal and geographical context. In the US, West Nile virus is the most common and ubiquitous arbovirus. Most infections present with a prodromal flu-like illness and, although rare, can progress to CNS involvement later in the course.

Autoimmune encephalitis. Autoimmune etiologies are increasingly recognized as a common cause of encephalitis and have been associated with neuronal autoantibodies (Table 4). Often presenting with an infectious prodrome, they can generally be distinguished from infectious etiologies through MRI, CSF analysis, and neuronal autoantibody testing.

Diagnostic workup

It is essential that the workup for a patient with meningitis or encephalitis begins with a thorough history and physical exam. An important initial consideration is the immune status of the patient including human immunodeficiency virus (HIV) status and functionally compromised immune systems (post-transplant, rheumatologic disorders, use of immunosuppressive therapy, unvaccinated, or immune deficiencies). Possible animal exposures and travel history should also be elicited. All patients should have blood cultures, basic chemistries, cell blood counts, HIV and syphilis serological testing. In autoimmune encephalitis, systemic markers of autoimmunity including antinuclear antibody can be helpful.

CSF analysis

Computed tomography (CT) of the head should be performed in patients with decreased consciousness, seizures, immunocompromised status, or focal neurologic deficits prior to lumbar puncture. Initial studies include opening pressure, glucose, protein, cell count with differential, gram stain and culture, and oligoclonal bands. HSV polymerase chain reaction is often tested with initial studies because this is a common and treatable cause of encephalitis.

Glucose is diminished in both bacterial and fungal meningitis but typically remains normal with viral infections. In both bacterial and fungal cases, CSF has a strong neutrophilic pleocytosis, viral infections demonstrate mononuclear lymphocytic cells. With West Nile virus, however, there can be a shift from initial neutrophilic to lymphocytic predominance. In those tested before the administration of antibiotics, 60% to 90% of bacterial meningitis is positive on CSF gram stain and culture.⁶ Some bacterial infections such as Listeria are difficult to diagnose on both CSF culture and gram stain.

Additional CSF studies should focus on temporal pattern of illness, clinical clues, and seasonality. For most arboviruses, serologic testing is preferred to molecular testing, or polymerase chain reaction because the peak of viremia typically occurs before symptom onset. Special consideration should be given to immunosuppressed patients (Table 5).

Pathogen-specific polymerase chain reaction testing is the current diagnostic method for infections, however next-generation sequencing holds promise for rapid unbiased detection of unknown pathogens. There have been several case reports in immunocompromised patients in which next-generation sequencing allowed for a rapid diagnosis with therapeutic implications.^7-9 For example, there is a case of a 14 year-old boy with severe combined immunodeficiency in a coma in which unbiased next generation sequencing allowed for the diagnosis of leptospira santarosai despite a negative brain biopsy.⁷ Given the information provided by next generation sequencing, this patient was subsequently treated with appropriate antimicrobial agents with a positive clinical outcome. This technology, however, is still in development and requires clinical validation before use in broad practice. For suspected autoimmune encephalitis (Table 4), both serum and CSF should be tested for neuronal autoantibodies, however not all are commercially available.

Imaging

MRI is an important diagnostic tool and should be done with gadolinium if renal function allows. Certain infectious etiologies of encephalitis have anatomical tropisms with specific MRI findings (Table 6).

Electroencephalogram

An electroencephalogram can be helpful if the patient is confused, obtunded, or comatose to rule out non-convulsive status epilepticus. Periodic lateralizing epileptiform discharges are often seen in conjunction with temporal lobe abnormalities in HSV-1 infection. Other abnormalities, such as the presence of triphasic waves, can indicate an underlying metabolic encephalopathy.

Treatment

The treatment for viral meningitis is supportive with fluids, antipyretics, and analgesic use. Antimicrobial treatment recommendations for bacterial meningitis are listed in Table 7.

For suspected encephalitis, empiric acyclovir (10 mg/kg IV every 8 hours) coverage for HSV should be continued until a negative CSF polymerase chain reaction is confirmed or a second negative polymerase chain reaction in the setting of strong clinical suspicion. If the polymerase chain reaction is positive, treatment is continued for 14 to 21 days. For arbovirus encephalitis, treatment is supportive

In the cases of suspected autoimmune encephalitis, guidelines for immunosuppressive therapy are largely based on expert opinion and on data from a retrospective analysis of anti-NMDA recptor encephalitis (Figure 2).^10-13

Disclosures:

Dr Khan is a Neuro-Infectious Diseases Neuroimmunology Fellow and Dr Piquet is Assistant Professor, Department of Neurology, University of Colorado School of Medicine, Aurora, CO.

References:

1. Kupila L, Vuorinen T, Vainionpää R, et al. Etiology of aseptic meningitis and encephalitis in an adult population. Neurology. 2006;66:75-80.

2. Linnoila JJ, Binnicker MJ, Majed M, et al. CSF herpes virus and autoantibody profiles in the evaluation of encephalitis. Neurol Neuroimmunol Neuroinflamm. 2016;3:e245.

3. Morris NA, Kaplan TB, Linnoila J, Cho T. HSV encephalitis-induced anti-NMDAR encephalitis in a 67-year-old woman: report of a case and review of the literature. J Neurovirol. 2016;22:33-37.

4. Armangue T, Titulaer MJ, Málaga I, et al. Pediatric anti-N-methyl-d-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients. J Pediatr. 2013;162:850-856.

5. Leypoldt F, Titulaer MJ, Aguilar E, et al. Herpes simplex virus-1 encephalitis can trigger anti-NMDA receptor encephalitis: case report. Neurology. 2013;81:1637-1639.

6. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39:1267-1284.

7. Wilson MR, Naccache SN, Samayoa E, et al. Actionable diagnosis of neuroleptospirosis by next-generation sequencing. N Engl J Med. 2014;370:2408-2417.

8. Wilson MR, Suan D, Duggins A, et al. A novel cause of chronic viral meningoencephalitis: Cache Valley virus. Ann Neurol. 2017;82:105-114.

9. Naccache SN, Peggs KS, Mattes FM, et al. Diagnosis of neuroinvasive astrovirus infection in an immunocompromised adult with encephalitis by unbiased next-generation sequencing. Clin Infect Dis. 2015;60:919-923.

10. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12:157-165.

11. Rosenfeld MR, Dalmau JO. Paraneoplastic disorders of the CNS and autoimmune synaptic encephalitis. Continuum (Minneap Minn). 2012;18:366-383.

12. Rosenfeld MR, Dalmau J. Diagnosis and management of paraneoplastic neurologic disorders. Curr Treat Options Oncol. 2013;14:528-538.

13. Linnoila J, Pittock SJ. Autoantibody-associated central nervous system neurologic disorders. Semin Neurol. 2016;36:382-396.

14. Venkatesan A, Tunkel AR, Bloch KC, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis. 2013;57:1114-1128.

15. Tunkel AR, Glaser CA, Bloch KC, et al. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2008;47:303-327.

16. Cho TA, Mckendall RR. Clinical approach to the syndromes of viral encephalitis, myelitis, and meningitis. Handbk Clin Neurol. 2014;123:89-121.

17. Lai M, Hughes EG, Peng X, et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol. 2009;65:424-434.

18. van Sonderen A, Ariño H, Petit-Pedrol M, et al. The clinical spectrum of Caspr2 antibody-associated disease. Neurology. 2016;87:521-528.

19. Tobin WO, Lennon VA, Komorowski L, et al. DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients. Neurology. 2014;83:1797-1803.

20. Petit-Pedrol M, Armangue T, Peng X, et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol. 2014;13:276-286.

21. Höftberger R, Titulaer MJ, Sabater L, et al. Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology. 2013;81:1500-1506.

22. Lancaster E, Lai M, Peng X, et al. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol. 2010;9:67-76.

23. Flanagan EP, Kotsenas AL, Britton JW, et al. Basal ganglia T1 hyperintensity in LGI1-autoantibody faciobrachial dystonic seizures. Neurol Neuroimmunol Neuroinflamm. 2015;2:e161.

24. Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol. 2011;69:892-900.

25. Lai M, Huijbers MG, Lancaster E, et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol. 2010;9:776-785.

26. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10:63-74.

27. Leypoldt F, Buchert R, Kleiter I, et al. Fluorodeoxyglucose positron emission tomography in anti-N-methyl-D-aspartate receptor encephalitis: distinct pattern of disease. J Neurol Neurosurg Psychiatry. 2012;83:681-686.

28. Schmitt SE, Pargeon K, Frechette ES, et al. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology. 2012;79:1094-1100.

29. McGill F, Heyderman RS, Panagiotou S, Tunkel AR, Solomon T. Acute bacterial meningitis in adults. Lancet. 2016;388:3036-3047.

30. Roos KL. Bacterial infections of the central nervous system. Continuum (Minneap Minn). 2015;21:1679-1691.