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Infections of the Central Nervous System


There are a broad number of organisms that can cause damage to the central or peripheral nervous system, either directly or indirectly. These conditions are often life-threatening. Diagnosis can be challenging because patients often present with nonspecific clinical syndromes that can be caused by infectious and noninfectious causes. Prompt diagnosis and treatment are essential to prevent death or permanent neurologic disability. The combination of fever, headache, and neurologic signs or symptoms must be treated as a central nervous system (CNS) infection until proven otherwise. A management algorithm ( Fig. 22.1 ) should be followed for suspected cases of bacterial meningitis. Empirical treatment for bacterial causes is outlined in Table 22.1 . Based on presentation and risk factors, antiviral (e.g., acyclovir) and antifungal agents should be included in the empirical treatment. Definitive treatment will later be based on the results of cultures or other diagnostic tests.

Fig. 22.1
Magnetic resonance imaging (MRI) findings of tuberculous meningitis. (A) T2-weighted and (B) precontrast T1-weighted images show hydrocephalus. (C) Postcontrast T1 image demonstrates thick enhancement of the basal meninges and exudates.

(Reproduced with permission from Kapra P, et al. Infectious meningitis: Prospective evaluation with magnetization transfer MRI. Br J Radiol. 2004;77:387–394.)

Table 22.1
Cerebrospinal Fluid Findings in Selected Infections of the Central Nervous System
Number of White Blood Cells (per mm 3 ) Cell Type Concentration of Protein (mg/dL) Concentration of Glucose (mg/dL) CSF Pressure (cm H 2 O)
Normal ≤ 5 Lymphocytes and monocytes only 15–45 45–80 80–180
Bacterial meningitis 5–10,000 Polymorphonuclear leukocytes Increased Decreased Increased
Viral meningitis 5–1000 Lymphocytes Increased Normal Normal, occasionally increased
Tubercular meningitis 5–500 Lymphocytes Increased Decreased Increased
Cryptococcal meningitis 5–100 Lymphocytes Increased Normal, occasionally decreased Increased
Active neurosyphilis 5–500 Lymphocytes Increased Normal, occasionally decreased Normal

Approach to the Patient With Suspected Central Nervous System Infection

Historical Features

  • 1.

    Age is a major feature that can aide a clinician regarding risk of specific pathogens (table).

  • 2.

    Ascertain the acuity and tempo of symptoms.

  • 3.

    Identify any predisposing risk factors:

    • Immunosuppression: diabetes, alcoholism, malignancy, steroids or other immunomodulatory medications, transplanted organs, chemotherapy, HIV infection

    • Head trauma , otologic or neurosurgical procedures

    • Unusual exposures: foreign travel, wooded areas, sick contacts, animals, or insects, ingestion including raw meats, recreational activities

    • Vaccine history

Check for the following symptoms: fever, headache or neck pain, change in mental status, focal weakness, numbness, visual problems, back pain, urinary or bowel symptoms.

Examination Features

  • 1.

    Check for evidence of infection elsewhere in the body: conjunctivitis, retinitis, uveitis, sinusitis, endocarditis, lymphadenopathy pneumonia, osteomyelitis, urinary tract infection, skin rash.

  • 2.

    Always be sure to check for the following signs: vital signs, papilledema, meningismus, exanthem, sinus tenderness, otitis media, or spine tenderness.

Lumbar Puncture

Lumbar puncture (LP) is the most important test to confirm a CNS infection and identify the causative organism. The technique for performing LP is covered in Chapter 3 . If CNS infection is suspected, when deciding whether to perform an LP, the following clinical rule may be helpful ( any two of these three require LP):

  • 1.

    Fever

  • 2.

    Headache

  • 3.

    Change in mental status

Because herniation is a serious but rare complication of LP, a computed tomography ( CT) scan may be required prior to LP .

LP should not be performed before CT in patients with suspected bacterial meningitis when one or more of the following risk factors is present:

  • Altered mentation

  • Focal neurologic signs

  • Papilledema

  • Seizure within the previous week

  • A patient is immunocompromised

Relative contraindications to LP: Although there are no absolute contraindications to performing the procedure, caution should be used in patients with:

  • Possible raised intracranial pressure (ICP)

  • Thrombocytopenia or other bleeding diathesis (including ongoing anticoagulant therapy)

  • Suspected spinal epidural abscess

Acute Meningitis

Acute Bacterial Meningitis

The classic triad of acute bacterial meningitis consists of fever, nuchal rigidity, and a change in mental status, although a number of patients do not have all three features. Most patients have high fevers, but a small percentage have hypothermia. Almost no patients have a normal temperature. Neurologic complications such as seizures, focal neurologic deficits (including cranial nerve palsies), and papilledema may be present early or occur later in the course. The presentation is usually dramatic but may be less obvious at the extremes of age (in infants and in the elderly), in whom change in mental status is often the only symptom.

Etiologies

Seeding of the leptomeninges usually occurs from hematogenous spread of the infecting organism (e.g., pneumococcal pneumonia complicated by meningitis); it also can result from a parameningeal infection (e.g., otitis media) or after trauma, cochlear implants, or neurosurgery (e.g., cerebrospinal fluid [CSF] leak). Streptococcus pneumoniae (50% of cases) and Neisseria meningitidis (25% of cases) are the most common causes of bacterial meningitis. Mortality is approximately 20%.

Laboratory Diagnosis

The diagnosis is established by abnormal CSF indices including polymorphonuclear pleocytosis, elevated protein level, and reduced glucose level (see Table 22.1 ). The organism is identified by CSF cultures. However, when CSF is sterile—for example, in cases in which antibiotics are given prior to LP—blood cultures often identify the causative organism. At least 50% of patients with bacterial meningitis have positive blood cultures. Interpreting CSF profiles in neurosurgical patients with recently placed ventricular drains can be difficult. A rising white blood cell (WBC) count and falling glucose level suggests an infection. Because of impaired CSF circulation in shunted patients, CSF should be sampled from the drain or shunt when possible. Radiographic findings of bacterial meningitis are often nonspecific and include evidence of enhancement of leptomeninges.

Treatment

The prognosis in bacterial meningitis depends on the interval between onset of disease and initiation of therapy. Selection of empirical antibiotics depends on age and risk factors, as shown in Table 22.1 . Most adults with suspected community-acquired bacterial meningitis should be treated with dexamethasone 6 mg intravenously (IV) every 6 hours for 4 days (first dose given 15 minutes prior to antibiotics), and ceftriaxone and vancomycin until cultures provide for a definite diagnosis and antibiotic sensitivity. Treatment with dexamethasone blunts the acute inflammatory response and results in a 50% reduction in mortality; efficacy is greatest with pneumococcal meningitis. In neonates and older or immunosuppressed patients, ampicillin should be added as well to cover Listeria monocytogenes infection. Recently placed shunts or intracranial hardware should be removed.

Viral (Aseptic) Meningitis

Viral meningitis is typically a self-limited illness seen most frequently in children and young adults. The manifestations of viral meningitis are generally similar to bacterial meningitis but often less severe. Older children and adults may present with headache, fever, nausea, vomiting, stiff neck, and sensitivity to noise or light. In infants, the clinical presentation can be nonspecific, and may lead to irritability, vomiting, and diarrhea. They should be evaluated for nuchal rigidity and a bulging fontanelle.

Etiologies

A number of viruses produce aseptic meningitis including enteroviruses, herpes simplex virus (HSV), HIV, West Nile virus (WNV), varicella-zoster virus (VZV), mumps, and lymphocytic choriomeningitis (LCM) virus. Mollaret meningitis is a form of recurrent benign lymphocytic meningitis (RBLM), which is an uncommon illness characterized by greater than three episodes of fever and meningismus lasting 2 to 5 days, followed by spontaneous resolution.

Laboratory Diagnosis

The diagnosis is suggested by lymphocytic pleocytosis with a normal glucose level in the CSF (see Table 22.1 ) and negative CSF and blood bacterial cultures. In some cases of viral meningitis, the virus can be cultured or amplified (polymerase chain reaction [PCR]) from CSF, blood, nasal pharyngeal secretions, or fecal material. The presence of intrathecal production of virus-specific IgG antibodies acquired weeks after the onset of symptoms can establish a retrospective diagnosis (for WNV, immunoglobulin [Ig]M can be found as early as 1 week after onset of symptoms). The most common causes of viral meningitis include enteroviruses, arthropod-borne viruses (especially WNV), HSV-2, LCM virus, and infection with HIV during the acute conversion period. Medications can cause aseptic meningitis simulating viral meningitis. The usual culprits include nonsteroidal antiinflammatory drugs (NSAIDs), metronidazole, carbamazepine, trimethoprim/sulfamethoxazole, and IV immunoglobulin (IVIG). Also in the differential are other infections including fungal and parasitic infections, as well as cancer of the leptomeninges. Treatment is supportive. Prognosis is excellent.

Chronic Meningitis

Chronic meningitis is defined as meningitis lasting for 4 weeks or more and is a complex entity with both infectious and noninfectious causes. A wide array of infectious agents can present as chronic meningitis, but a nearly identical syndrome can result from a number of inflammatory, malignant, or other noninfectious diseases. All patients with chronic meningitis should be questioned about travel or residence in geographic areas known to be endemic for possible causes of chronic meningitis including coccidioidomycosis, histoplasmosis, paracoccidioidomycosis, blastomycosis, schistosomiasis, trypanosomiasis, Angiostrongylus cantonensis infection, or cysticercosis. Analysis of CSF reveals abnormalities in patients with chronic meningitis, but these abnormalities are rarely diagnostic with some notable exceptions. The presence of eosinophilia can provide an important clue to the presence of a parasitic etiology or coccidioidomycosis. Antigen testing of the CSF for the presence of Cryptococcus neoformans and a Venereal Disease Research Laboratory (VDRL) test for syphilis should be performed on all patients with chronic meningitis. Here we discuss a few examples of causes of chronic meningitis.

Tuberculosis Meningitis

Tuberculosis (TB) meningitis, caused by the bacterium Mycobacterium tuberculosis, typically evolves over weeks to months, but the diagnosis is often overlooked until a fulminant syndrome develops. Cranial nerve palsies, vasculitic small-vessel infarctions, and obstructive hydrocephalus occur frequently and result from severe granulomatous inflammation of the basal meninges (see Fig. 22.1 ). TB can cause focal abscess formation, which can evolve into space-occupying mass lesions (tuberculoma), even without meningitis. Patients who are chronically exposed, immunosuppressed (AIDS or alcoholic patients), or at the extremes of age are particularly at risk. Morbidity and mortality are high unless treated early. Hydrocephalus, seizures, and cognitive impairment are frequent late complications.

Diagnosis

The CSF shows lymphocytic pleocytosis, elevated protein level, and moderately reduced glucose level (see Table 22.1 ). The diagnosis is established by observing acid-fast mycobacteria in the CSF; the yield exceeds 50% when multiple large-volume taps (10–25 mL) are examined. M. tuberculosis also can be cultured from the CSF, but the yield is low, and up to 6 weeks are needed for the organism to grow. PCR testing can establish the diagnosis by amplifying small amounts of tubercle bacillus DNA, but sensitivity is variable depending on the quantity of nucleic acid circulating in the CSF. Evidence of active pulmonary disease is found in only 30% of the cases; purified protein derivative (PPD) testing is too unreliable to be a useful diagnostic tool in working up TB meningitis. Common radiographic findings are basilar meningeal enhancement, cerebral infarcts in the basal ganglia, and evidence of hydrocephalus.

Treatment

Initial treatment consists of the four-drug regimen of isoniazid (also give pyridoxine 50 mg per day ), rifampin, pyrazinamide, and ethambutol . There is evidence that higher doses of rifampicin in IV formulations and replacing ethambutol with a fluoroquinolone improve outcomes. Cotreatment with dexamethasone 6 mg IV every 6 hours also may be used in severe cases (with depressed level of consciousness, focal deficits, or multiple cranial nerve palsies) to inhibit the inflammatory response and limit damage. An infectious disease specialist should be consulted, given possible drug resistance and the high rate of unacceptable drug toxicity arising from these agents. After the intensive phase for 2 months, treatment with isoniazid and rifampicin should continue for 9 to 12 months. In patients with hydrocephalus, an external ventricular device may be needed.

Neurosyphilis

Syphilis is a chronic systemic infection caused by the spirochete Treponema pallidum. Primary infection is characterized by a chancre (firm, painless genital ulcer). A secondary bacteremic stage may occur 2 to 12 weeks later, resulting in generalized mucocutaneous lesions (palmar and plantar rash) and lymphadenopathy. In up to 60% of cases, the CNS is seeded during the bacteremic stage; 10% of these patients will develop symptomatic early neurosyphilis (meningitis, meningovasculitis, cranial neuritis). Mild inflammatory CSF changes (elevation of cells and protein) can be detected at this stage.

After a latent period of 15 to 20 years, tertiary syphilis manifests as a slowly progressive, systemic inflammatory disease of the skin (gummas), heart (aortitis), eyes (chorioretinitis), or CNS. Tertiary neurosyphilis develops in 5% of patients with untreated primary syphilis. The classic manifestations include the following:

  • 1.

    General paresis

    This condition results from chronic, diffuse encephalitis and manifests as dementia with prominent psychiatric features and bilateral upper motor neuron signs.

  • 2.

    Tabes dorsalis

    Tabes dorsalis results from chronic spinal polyradiculitis with secondary dorsal root and column degeneration. Symptoms may include neuropathic shooting pains in the lower extremities, loss of posterior column sensation, and areflexia.

  • 3.

    Argyll Robertson pupils

    These are small irregular pupils that react to accommodation but not to light and reflect chronic optic neuritis. Optic atrophy and blindness also may occur.

    In HIV patients the course of syphilis is often accelerated, and the early symptomatic forms of secondary syphilis (meningitis and meningovasculitis) predominate. Symptoms may occur during any stage of HIV infection.

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