A diagnostic hypothesis for a suspected central nervous system (CNS) infection has two components: an anatomic and a microbiologic or etiologic diagnosis. The anatomic diagnosis localizes the inflammation to a specific part of the CNS. The microbiologic or etiologic diagnosis identifies the pathogen or etiology that is causing the CNS inflammation. An accurate anatomic and microbiologic hypothesis requires a detailed history (including symptoms, duration, exposure, and epidemiologic risk factors); a complete physical examination, including a thorough neurologic examination; and an appropriate diagnostic workup, including imaging and cerebrospinal fluid (CSF) laboratory tests. Prognosis and management depend on an accurate diagnosis. For instance, if the diagnosis is pneumococcal meningitis, the anatomic site of inflammation is the pia–arachnoid layer of the meninges, and the etiology is Streptococcus pneumoniae. The antimicrobial treatment is ceftriaxone, which penetrates the anatomic site (subarachnoid space) and has activity against S. pneumoniae .
A practical approach to the patient with suspected CNS infection would be to answer the following questions to make a diagnosis and asses the prognosis:
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Where is the “-itis” or inflammation (anatomic site)?
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How long has it been going on (duration of illness)?
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Is it community acquired or health care acquired?
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What is the exposure or epidemiologic history?
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Is the patient a “normal host” or an “ immunocompromised host”?
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Is it an acute severe infection or a chronic stable infection?
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What is the type of CSF inflammatory response on routine analysis?
Question 1: Where Is the Inflammation?
Microorganisms have a tropism to certain anatomic sites both in the CNS and outside. So anatomic localization helps identify the etiology or organism . S. pneumoniae and Neisseria meningitidis have tropism to the leptomeninges or pia-arachnoid layer. Herpes simplex virus-1 (HSV-1) has tropism to the medial temporal lobe, and West Nile virus has tropism to the basal ganglia. At a cellular level, poliovirus infects the anterior horn cells, and JC virus infects the oligodendrocytes, which produce myelin in the CNS. Anatomic localization can be done based on history, neurologic examination, imaging—especially with magnetic resonance imaging (MRI) of the CNS, and CSF analysis. A patient with meningitis can have headache, meningeal signs, leptomeningeal enhancement on a T1 post-contrast MRI of the brain, and increased white blood cells, with a low glucose on routine CSF analysis. The patient with HSV-1 encephalitis can present with amnesia and temporal lobe changes on brain MRI. Often clues to the diagnosis can be present at anatomic sites outside the CNS. Nocardia causes brain abscesses and lung nodules. Sarcoidosis causes basilar leptomeningeal meningitis, but a clue to the diagnosis could be bilateral hilar lymphadenopathy. Classifying the patient into the following anatomic syndromes is diagnostically useful, as that gives clues about the etiology or organism:
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Meningitis: Leptomeningeal meningitis is inflammation of the pia–arachnoid layer, and pachymeningitis is inflammation of the dura.
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Encephalitis or meningo-encephalitis: This is inflammation within the brain parenchyma with or without meningeal involvement.
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Myelitis or myelo-radiculitis: This is inflammation of the spinal cord with or without involvement of the spinal nerve roots.
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Space-occupying, ring-enhancing lesions in the brain on post-contrast CNS imaging.
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Stroke or strokelike syndromes involving vascular territories of the brain ( Fig. 14.1 ).
Fig. 14.1
Where is the inflammation (anatomic location in the CNS)? MRI brain imaging.
Question 2: How Long Has It Been Going On?
Some microorganisms cause acute infections that progress over days, and some cause chronic infections that progress over weeks to months. Subacute infections, which are generally around 2 to 3 weeks in duration, could be either an acute infection that has lingered longer or a chronic infection that was diagnosed earlier. Virulent fast-growing bacteria like S. pneumoniae or N. meningitidis cause severe acute meningitis, but indolent slow-growing organisms like fungi and Mycobacterium tuberculosis cause chronic meningitis. A patient can also have recurrent acute CNS infections. This could be because of an immunodeficiency making one prone to a CNS infection multiple times. An example would be recurrent meningococcal infection with terminal complement deficiencies. Recurrent acute meningitis could also be from recurrent reactivation of a latent virus like HSV-2, which causes Molleret meningitis or benign recurrent lymphocytic meningitis.
Question 3: Is It Community Acquired or Health Care Acquired?
In the CNS, unlike other anatomic sites, hospital- or health care–acquired infections usually occur in the context of either neurotrauma or neurosurgery. The skull and the meninges are an effective barrier and defense against nosocomial pathogens entering the CNS. Only when the skull and dura are breached by trauma or surgery do hospital-acquired pathogens like Escherichia coli and Staphylococcus aureus find a portal of entry into the CNS. These organisms, unlike organisms that cause community-acquired bacterial meningitis like S. pneumoniae or N. meningitidis, lack the capacity to directly invade the CNS. It would be unusual to have a nosocomial pathogen causing CNS infection in a patient on the non-neurosurgical or non–critical care wards.
Question 4: What Is the Exposure or Epidemiologic History?
The following three factors are essential for the pathogenesis of a CNS infection:
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The organism should be capable of not only infecting a human host but also have tropism to the CNS.
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The host should be susceptible to an infection by a particular organism . S. pneumoniae is a highly virulent organism capable of causing an infection even in a normal host and is also neurotropic. On the contrary, Listeria monocytogenes usually causes meningitis in the elderly and hosts with deficient T-cell immunity.
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A conducive environment and host behavior for transmission (exposure or epidemiology) is necessary in addition to the host and pathogen factors. For instance, a patient should have traveled to a tropical country and been bitten by a female Anopheles mosquito to get cerebral malaria. On the contrary, anyone can sporadically get HSV encephalitis.
Obtaining a tailored exposure history is important in establishing the etiology and ordering appropriate diagnostic tests. A few examples are provided here:
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Travel: Travel to Arizona puts the patient at risk for chronic meningitis from coccidioidomycosis.
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Insect bites: Tick bites are a risk factor for neuroborreliosis and mosquito bites for West Nile virus.
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Animal bites: Raccoon bites or bat contact puts one at risk for rabies.
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“Sick contacts”: Close contact with someone with meningococcal meningitis (in a college dorm or military barrack) increases risk for acquiring it. Health care workers and prison inmates are at a higher risk for chronic meningitis from tuberculosis.
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Sexual history: An acute lymphocytic meningitis in a patient with recent unprotected sexual intercourse could be acute retroviral syndrome from HIV or neurosyphilis.
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Question 5: Is the Patient Immunocompetent or an Immunocompromised Host?
The susceptibility of a patient to different infections depends on which arm of the immune system is compromised and the net state of immunosuppression. Opportunistic pathogens are organisms that are usually nonpathogenic in a normal host but are pathogenic in an immunocompromised host. Hematopoietic stem cell transplant patients are at a higher risk for opportunistic infections pre-engraftment and subsequently if they need to be treated with immunosuppressive medications for graft-versus-host disease. Solid-organ transplant patients are at highest risk immediately after transplantation and subsequently if they need to be treated for transplanted organ rejection. Patients with HIV and patients with hematologic and rheumatologic conditions requiring treatment with biologics and other immunosuppressive medications are also more prone to opportunistic infections. Treatment with eculizumab, a terminal complement inhibitor, is associated with an increased risk of meningococcal meningitis.
The differential diagnosis for the same anatomic syndrome changes significantly based on the host. For example, ring-enhancing lesions or abscesses on brain imaging (post-contrast MRI or computed tomography [CT]) in an immunocompetent host are usually bacterial abscesses. However, in an HIV patient with a CD4 count of less than 100/μL, cerebral toxoplasmosis should be considered. In a solid-organ transplant recipient, invasive molds are higher on the differential.
Question 6: Is It an Acute Severe Infection or a Chronic Stable Infection?
Differentiating a life-threatening CNS infection from a chronic stable infection is vital. Clinicians should act fast if a patient has acute worsening of mental status or rapidly progressive neurologic deficits within hours. A 3-hour delay in treatment of critically ill patients with pneumococcal meningitis can increase mortality by about 14 times. A patient with a spinal epidural abscess who develops sudden lower extremity weakness and incontinence needs emergent surgery. On the contrary, there is no rush to treat a patient who presents with headaches for weeks and no focal neurologic features from chronic stable lymphocytic meningitis.
Question 7: What Is the Type of CSF Inflammatory Response?
Routine cell counts and chemistry analysis of the CSF can be done quickly and can provide valuable diagnostic information. CSF can be obtained either by lumbar puncture from the subarachnoid space or from the cerebral ventricles via an external ventricular drain or ventricular shunt.
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CSF total nucleated white blood cell (WBC) count and differential: If the CSF WBC count/μL is in the thousands and is predominantly neutrophilic, it is suggestive of a bacterial meningitis from a virulent organism like S. pneumoniae. If the CSF WBC count/μL is close to 100,000 and is neutrophilic, it is suggestive of intraventricular rupture of a brain abscess. The differential diagnosis for a mild to moderate lymphocytic CSF pleocytosis is very broad, including viral, fungal, mycobacterial, neoplastic, and immune-mediated meningitis or encephalitis. The differential diagnosis for a predominantly eosinophilic CSF pleocytosis (greater than 10%) is very narrow and includes parasitic worm infections, coccidioidomycosis, or an adverse reaction to intrathecally administered drugs. Certain CNS infections like Creutzfeldt–Jakob disease (CJD) and progressive multifocal leukoencephalopathy (PML) do not usually cause CSF pleocytosis.
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CSF:blood glucose ratio is another discriminatory test. A very low ratio (0.4 or less) is suggestive of a bacterial, fungal, mycobacterial, or neoplastic meningitis. It is important not to rely just on the CSF glucose level and to obtain a blood glucose level at 30 to 45 minutes around the time of CSF sampling. CSF glucose levels usually equilibrate with blood levels in less than an hour. CSF glucose of 60 mg/dL is “normal,” but the CSF:blood glucose ratio would be very low if the patient’s blood sugar were 600 mg/dL.
Diagnostic Testing in a Patient with a CNS Inflammatory or Infectious Syndrome
It is beyond the scope of this chapter to go into the details of diagnostic testing, but we will briefly discuss general principles of testing. Diagnostic imaging, especially MRI brain with and without contrast, is not just useful for anatomic localization—the radiographic pattern on different sequences can give clues about etiology. For example, a ring-enhancing lesion on T-1 post-contrast MRI with restricted diffusion in the center on diffusion-weighted images is more suggestive of an abscess than a tumor.
Tests for organism detection can be performed in the blood, serum, CSF, or tissue from a biopsy of the brain or meninges. Traditional stains and cultures for bacteria, fungi, and Mycobacteria still play an important role, though the yield might be low, especially when the CSF or tissue sample is of an inadequate volume. There are newer CSF molecular diagnostic tests like multiplex polymerase chain reactions (PCRs), universal 16S or 18S ribosomal RNA PCRs, and unbiased meta-genomic sequencing available for organism detection. The same principles of diagnostic testing that apply to traditional stains and cultures are also relevant when interpreting molecular diagnostic tests. There could be false-positive tests from contamination during specimen collection, both with traditional and molecular tests. An example would be of a single colony of Staphylococcus epidermidis that grows from the CSF bacterial culture or is detected by a molecular test. Both these “positive CSF tests” are suggestive of a contamination. Latent viruses like Epstein–Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus 6 (HHV-6) can reactivate in the context of another CNS inflammatory disease, and a positive test from the CSF does not necessarily mean they are the cause of the disease.
Serum and CSF antibodies, both for infectious and immune-mediated etiologies, are also problematic to interpret. Antibodies to infectious organisms often remain positive for months and years after the resolution of the infection, and a positive test does not always mean that the patient has an active infection. Borderline positive antibody tests are often false positive. The clinician should be extremely cautious in interpreting these “positive” tests, especially in the workup of chronic meningitis and chronic encephalitis, as the false-positive rate increases with the number of tests ordered.
A Clinical Syndrome-Based Approach to CNS Infections
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Acute meningitis: This is inflammation of the meningitis, which occurs rapidly within hours to days. Acute neutrophilic meningitis in adults is usually from community-acquired bacterial pathogens like S. pneumoniae, N. meningitidis, and Listeria. Acute lymphocytic meningitis is usually from enteroviruses or arboviruses like West Nile virus. In the postcraniotomy patient, virulent pathogens like E. coli and Staphylococcus aureus can cause an acute meningitis or cerebral ventriculitis. It is also important to note that postcraniotomy meningitis from indolent pathogens like Staphylococcus epidermidis can present as chronic meningitis.
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Recurrent acute meningitis: The differential diagnosis depends on the type of CSF pleocytosis. The causes of recurrent lymphocytic meningitis are:
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Mollaret meningitis from recurrent HSV-2 reactivation in the pia–arachnoid layer.
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Intermittent leaking into the subarachnoid space from epidermoid cysts or craniopharyngiomas.
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Recurrent episodes of autoimmune disease (Bechet, sarcoid, or granulomatous polyangiitis).
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Drug-induced meningitis from recurrent use of the same medication (nonsteroidal antiinflammatory drugs [NSAIDs], trimethoprim, or intravenous immunoglobulin [IVIG]).
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The causes of recurrent neutrophilic meningitis are:
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Recurrent bacterial meningitis secondary to anatomic communication of the subarachnoid space with a nonsterile surface (mucosa or skin). This could be secondary to congenital defects or from trauma to the face, head, or spine. If the patient has clear rhinorrhea or otorrhea, test the fluid for beta-2 transferrin. Its presence in the fluid is highly suggestive that it is CSF.
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IG deficiency or asplenia can lead to recurrent infections from encapsulated organisms like S. pneumoniae, N. meningitidis, and Haemophilus influenza. These organisms are neurotropic and cause meningitis.
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Chronic meningitis: This is meningitis that has an indolent presentation and lasts weeks to months. Often an etiologic diagnosis is difficult, requiring multiple lumbar punctures and extensive testing. A few of the causes to consider in the differential diagnosis are:
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Cryptococcus
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Coccidioidomycosis, histoplasmosis, blastomycosis
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Spirochetes (syphilis, Lyme, leptospirosis)
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Mycobacterium tuberculosis
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Leptomeningeal carcinomatosis (adenocarcinomas of the lung, breast, and melanoma)
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Lymphomatous leptomeningitis (non-Hodgkin lymphoma [NHL], acute lymphoblastic leukemia [ALL])
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Leptomeningeal gliomatosis
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The differential diagnosis for chronic meningitis that predominantly involves the basilar leptomeninges includes fungal meningitis, tuberculous meningitis, neoplastic meningitis, and neurosarcoidosis. If there is concomitant uveitis (inflammation of the iris, ciliary body, or choroid of the eye), consider the following etiologies:
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Sarcoidosis
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Bechet syndrome, which can also involve the brainstem
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Vogt–Koyanagi–Harada syndrome, which presents with meningitis; deafness; granulomatous uveitis; alopecia; vitiligo; and poliosis of eyelashes, eyebrows, and hair
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Wegner granulomatosis
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Sjogren syndrome
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Tropheryma whippeli
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Encephalitis: This is inflammation of the brain parenchyma. Like chronic meningitis, making an etiologic diagnosis for chronic encephalitis is often difficult. It can linger like smoldering embers, evading a diagnosis and testing a clinician’s acumen and perseverance. Most commonly known etiologies are either infections (usually viral) or immune-mediated encephalitis. The most common infectious etiology for acute sporadic encephalitis is herpes simplex, which has a predilection to involve the medial temporal lobes. Episodes of encephalitis involving deep gray matter (basal ganglia) during the summer and fall in the United States is suggestive of West Nile viral infection. Japanese B encephalitis, which is more common in Asia, can have a presentation similar to West Nile encephalitis.
Autoimmune encephalitis can often mimic infectious encephalitis, so it is important for infectious disease clinicians to be aware of them. It was initially described as a paraneoplastic syndrome, but is now reported without any association with tumors as well. It is either associated with antibodies against neuronal cell-surface synaptic proteins or with antibodies against intracellular proteins. Please see Table 14.1 for details about autoantibodies associated with autoimmune encephalitis. Even today, a significant number of encephalitis cases remain undiagnosed. In most published series around 40% or more of cases do not have an etiologic diagnosis (see Table 14.1 ).
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Myelitis or myelo-radiculitis: Myelitis is inflammation of the spinal cord, and myelo-radiculitis is inflammation of both the spinal cord and spinal nerve roots. The causes are infectious, postinfectious or postvaccination, and noninfectious immune mediated. Depending on the part of the spinal cord and level of the spinal cord involved, the symptoms could be weakness; sensory disturbances; and bowel, bladder, or sexual dysfunction. Infectious organisms that usually cause extensive transverse and vertical myelitis are herpes simplex and varicella zoster virus (VZV). CMV usually causes myeloradiculitis in immunocompromised patients, especially in HIV patients with CD4 counts of 100/μL or less. Certain viruses have a predilection to infect anterior horn cells and cause acute flaccid paralysis. These viruses are West Nile virus, nonpolio enterovirus like enterovirus D68, and Japanese B encephalitis virus. Among the noninfectious etiologies of extensive myelitis, the most important is neuromyelitis optica, which can cause significant CSF pleocytosis and can mimic an infectious myelitis.
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Space-occupying, rim-enhancing lesions in the brain on post-contrast T-1 MRI can be caused by brain abscesses, demyelinating lesions, tumors, or hematomas. Multiple brain abscesses in different vascular territories of the brain are usually from hematogenous spread and are caused by a single organism like S. aureus or Streptococcus species. Solitary brain abscesses are usually infections that spread from a contiguous focus like mastoiditis or paranasal sinusitis and are polymicrobial with Gram-positive cocci, anaerobes, and sometimes Gram-negative rods. “Complete” ring enhancement of the lesions is usually seen in brain abscesses and tumors, whereas “incomplete” ring enhancement or the C-shaped enhancement is usually seen in demyelinating lesions like acute demyelinating encephalomyelitis (ADEM) or in tumefactive demyelinating lesions.
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Stroke or strokelike syndromes from infectious and inflammatory etiologies : Infections of the CNS can cause ischemic strokes either by direct invasion of the vessel wall to cause vasculitis or when meningeal inflammation in meningitis spreads to the Virchow–Robin spaces surrounding the blood vessels and eventually to the cerebrovascular arterial wall to cause strokes. Infectious and inflammatory causes of stroke are:
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Varicella zoster vasculitis
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Meningovascular syphilis
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Basilar meningitis from yeasts like Cryptococcus , Candida and dimorphic fungi, or Mycobacterium tuberculosis
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Secondary to systemic vasculitis like granulomatous polyangiitis, giant cell arteritis, or Takayasu arteritis
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Primary CNS angiitis, which is a diagnosis of exclusion of other secondary causes
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Intravascular lymphoma
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