Christina M. Marra, Richard J. Whitley, and W. Michael Scheld
Infections of the central nervous system (CNS) are notable for their diversity. They range from common to rare, acute to chronic, and benign to fatal. Although some are self-limited or are easily cured with modern treatment, others are relentlessly progressive despite treatment or have no known treatment. For the many CNS infections that are treatable, prompt diagnosis and aggressive management afford the best chance of recovery without sequelae.
The clinical hallmarks of CNS infection are fever, headache, and alteration of mental status. Focal neurologic signs may also be evident. Nonetheless, these four symptoms and signs are nonspecific and can also be seen in noninfectious CNS syndromes. To narrow the differential diagnosis, other characteristics must be evaluated. Among these, risk factors for CNS infections are particularly helpful. Physical examination may also yield information that provides clues to the etiology of a given infection. An approach to the diagnosis of CNS infections is shown in Figure 1.1.
RISK FACTORS FOR CENTRAL NERVOUS SYSTEM INFECTIONS
Many infections of the CNS are geographically distributed or occur seasonally. Therefore, a thorough travel history and consideration of the date of onset of illness can provide clues to the etiology. For example, Lyme disease is endemic in the northeastern United States but uncommon in the southwestern states. Similarly, transmission of arborviral encephalitides requires the presence of an insect vector, and thus these illnesses most commonly occur in summer and fall. Certain environments facilitate acquisition and transmission of CNS infections, as exemplified by outbreaks of meningococcal infection in military recruits and college students. Concomitant illnesses such as HIV infection or diabetes, alcoholism, receipt of immunosuppressant medications, or cancer chemotherapy all predispose to specific CNS infections. Similarly, receipt of prophylactic therapies protects against individual CNS infections. For example, primary prophylaxis against Pneumocystis jiroveci pneumonia with trimethoprim-sulfamethoxazole in HIV-infected individuals decreases the risk of CNS toxoplasmosis.
CLUES ON PHYSICAL EXAMINATION
Physical examination in the setting of suspected CNS infection has three purposes: (a) to identify contraindications to lumbar puncture, (b) to identify concomitant sites of infection or pathology that provide clues to the infectious etiology, and (c) to define the site of CNS infection. Depressed level of consciousness, focal neurologic abnormalities, or seizures may indicate a structural CNS abnormality that poses a risk of brain or spinal cord herniation after lumbar puncture. Such findings mandate neuroimaging before lumbar puncture. Identification of concomitant pneumonia, diarrhea, and skin or bone lesions may offer clues to the etiology of infection. Most importantly, findings on neurologic examination allow for identification of the most likely site or sites of infection among cerebrospinal fluid (CSF) space, brain, or spinal cord and allow for a “syndrome recognition” approach to diagnosis, as described below.
Acute Meningitis Syndrome
The dominant features of the acute meningitis syndrome are acute onset over a few hours to a few days of fever, headache, photophobia, stiff neck, and altered mental status. The latter may range from simple irritability to confusion, obtundation, or coma. Vomiting may occur, especially in young children. In many cases, there is no warning, but an acute upper respiratory tract infection may precede the onset of meningitis by a few days. The two leading causes of acute meningitis are bacteria and viruses. The differential diagnosis includes noninfectious conditions, such as systemic lupus erythematosus and Behçet syndrome, or rare chemical meningitis caused by nonsteroidal antiinflammatory drugs.
Subacute or Chronic Meningitis Syndrome
In contrast to acute meningitis, subacute and chronic meningitis syndromes run their course over weeks, months, or years. Because symptoms and signs may fluctuate, subacute or chronic meningitides may be confused with the syndrome of recurrent acute meningitis. Although in subacute and chronic meningitis the clinical findings of fever, headache, stiff neck, and altered mental status may resemble those of acute meningitis, the time course is quite different. Onset is usually gradual, often without any evident predisposing condition. Fever, though often present, tends to be lower and less hectic than in acute meningitis. The patient with chronic meningitis is likely to be lethargic and generally debilitated, in addition to having symptoms referable to the CNS. Focal neurologic findings are more common than in acute meningitis, although less common than in the space-occupying syndromes.
The differential diagnosis for subacute and chronic meningitis is extensive. The most likely infectious causes are tuberculosis; fungal infections including cryptococcosis, coccidioidomycosis, and histoplasmosis; and spirochetal infections including syphilis and Lyme disease. Important noninfectious conditions include sarcoidosis, systemic lupus erythematosus, systemic or primary CNS vasculitides, and neoplastic meningitis. Establishing a specific diagnosis is challenging. Of the important treatable conditions, cryptococcosis and syphilis usually can be diagnosed or excluded quickly on the basis of serology or antigen detection. However, tuberculous meningitis is more difficult to diagnose or exclude, and patients with suspected tuberculous meningitis should be treated empirically while evaluation continues. The decision whether and when to obtain a meningeal biopsy is complex and depends on many factors, including the unfortunate fact that in practice even this invasive “gold standard” test often does not yield a definitive diagnosis.
Acute Encephalitis Syndrome
The acute encephalitis syndrome is characterized by inflammation of the cerebral cortex and is most commonly caused by viruses. It shares many features with the acute meningitis syndrome. Indeed, the two conditions often coexist as meningoencephalitis. Acute encephalitis may be either diffuse or focal. Focal encephalitis reflects tropism of some viruses for specific locations in the CNS, such as temporal lobe infection by herpes simplex virus type 1 (HSV-1), or the anterior horn cells in flavivirus infections, such as West Nile. Nonviral organisms that may produce the acute encephalitis syndrome include Rickettsia, Mycoplasma, and Bartonella species that may cause encephalitis as one component of systemic infection. Diverse conditions, including infective endocarditis, Whipple disease, and recrudescent toxoplasmosis in the immunocompromised host may cause diffuse or focal acute encephalitis.
Chronic Encephalitis Syndrome
The chronic encephalitis syndrome shares many features with the acute encephalitis syndrome. However, the onset is more gradual and the course is less hectic. The clinical findings may be less dramatic or less severe. The patient with chronic encephalitis is likely to be generally debilitated rather than acutely ill. Chronic encephalitis evolves over weeks to months or years and relapses or recrudescences may occur. Complications such as pressure sores, contractures, or dementia may ensue in the course of disease.
Space-Occupying Lesion Syndrome
Patients with space-occupying brain lesions have focal neurologic abnormalities referable to the location of the lesion or lesions. These include cognitive abnormalities, weakness, sensory changes, and visual loss. Clinical manifestations, such as headache, nausea, or vomiting, often begin intermittently, but they progress steadily to a crisis at about the time the patient is admitted to the hospital. This crisis may consist of (a) a focal or generalized seizure or (b) onset of obtundation progressing to coma.
When a space-occupying lesion occurs in the extramedullary space in the spinal canal, a distinctive set of manifestations may develop in a typical sequence: first, localized back pain, often severe; second, nerve root pain with associated alteration in reflexes and sometimes paresthesias, often described as “shooting sensations” or “electric shocks”; third, motor weakness followed by sensory changes with bowel or bladder dysfunction; and fourth, paralysis, often accompanied by lessening in pain. The rate of progression from one stage to the next is unpredictable. Because the incidence and severity of neurologic sequelae depend on the stage of the disease and the degree of neural damage sustained before intervention, this syndrome presents an emergency that requires immediate diagnosis and treatment.
Toxin-Mediated Syndromes
Microbial toxins mediate several distinctive neurologic syndromes. The leading examples are tetanus and botulism. Toxin-mediated conditions are the least likely to show the usual manifestations of CNS infection, including fever, headache, disturbance of consciousness, and focal neurologic signs. For example, botulism is characterized by absence of fever and normal consciousness in most patients.
Encephalopathy with Systemic Infection
Many systemic infections involve the CNS, for example, rickettsial diseases, infective endocarditis, typhoid fever, malaria, and Whipple disease. Usually, the systemic manifestations of the disease dominate the clinical picture, but sometimes the CNS findings are prominent. In a few cases, CNS symptoms are the only features. Because this is such a large and varied group of diseases, the syndromic approach to diagnosis is less effective. In the setting of an undiagnosed CNS infectious syndrome, an important principle is to consider systemic infection as a possible underlying cause.
Postinfectious Syndromes
Several important CNS syndromes can develop following microbial infections. The usual sequence begins with a common, often rather trivial, viral infection that may go unnoticed. A postinfectious neurologic syndrome develops. Rarely, these syndromes follow routine vaccinations. Examples include postinfectious encephalitis, postinfectious encephalomyelitis, and transverse myelitis. These reactions are presumably mediated by an immunologic response to the etiologic microbe or to antigens revealed as a result of the initial infection. Although rare, these syndromes can be severe or fatal.
CONCLUSION
A systematic approach to the patient with a suspected CNS infection can be undertaken. This includes assessment of risks and a careful physical examination to assess safety of lumbar puncture, identify non-CNS sites of infection, and define the site of CNS infection. A consideration of the different CNS infection “syndromes” as outlined above can then be used to promptly establish a diagnosis and implement therapy.