Chapter 72: Central Nervous System Infections

Central nervous system (CNS) infections are often life-threatening and can have severe sequelae. These infections cause inflammation and edema within the unyielding cranium, resulting in damage to brain tissue and loss of function. The most common causes of CNS infections are bacteria and viruses, but fungi, protozoa, and helminths also cause these infections.

In addition to the history and physical examination, clinical diagnosis of CNS infections requires a spinal fluid analysis combined with neuroimaging using either magnetic resonance imaging (MRI) or computed tomography (CT) scan. Microbiologic diagnosis of bacterial infections frequently is made using Gram stain and culture of spinal fluid and blood. Polymerase chain reaction (PCR) assays and serologic tests are also useful. Antimicrobial therapy requires that the antibiotics be bactericidal and that they penetrate the blood–brain barrier. Some CNS infections, such as a brain abscess, often require surgical drainage.

Examination of cerebrospinal fluid (CSF) is critical in making the diagnosis of CNS infections. CSF is obtained by performing a lumber puncture at the L3–L4 interspace. During the process, the CSF pressure is measured and fluid obtained for analysis of cells (both number and cell type, i.e., neutrophils or lymphocytes), protein, and glucose. The results of CSF analysis in acute bacterial meningitis, acute viral meningitis, and subacute meningitis are described in Table 72–1.

Although CSF analysis is a very important step in the diagnosis of many CNS infections, a lumbar puncture should not be performed if there are signs of increased intracranial pressure, such as papilledema or focal neurologic signs, because herniation of the brainstem and death may occur. A CT scan should be performed prior to the lumbar puncture to determine whether a mass lesion, such as a brain abscess or cancer, is present. If a mass lesion is seen, a lumbar puncture should not be performed.

Definition

Meningitis is an infection of the meninges, the membranes that line the brain and spinal cord (Figure 72–1). Meningitis can be categorized as acute, subacute, or chronic depending on the speed of onset of the initial presentation and the rate of progression of the illness. Acute meningitis is caused by either pyogenic bacteria, such as Streptococcus pneumoniae and Neisseria meningitidis, or viruses, such as Coxsackie virus and herpes simplex virus type 2 (HSV-2). Viral meningitis is often called aseptic meningitis because routine cultures for bacterial pathogens are negative. Subacute meningitis is caused by Mycobacterium tuberculosis and fungi, such as Cryptococcus. The causative organisms are often found in the spinal fluid located in the subarachnoid space.

Pathophysiology

Hematogenous spread (i.e., bacteremia or viremia) is the most common route by which organisms reach the meninges. Direct spread via adjacent infections, such as otitis media and sinusitis; via neurosurgery, such as a shunt to relieve hydrocephalus; or via trauma, such as a fracture of the cribriform plate, occurs less frequently. The importance of hematogenous spread is emphasized by the success of the conjugate vaccines against S. pneumoniae, N. meningitidis, and Haemophilus influenzae type B that induce circulating IgG antibodies that neutralize the bacteria in the blood.

Acute bacterial meningitis begins with nasopharygeal colonization followed by local invasion, entry into the bloodstream, and invasion of the meninges (Figure 72–2). This is followed by an inflammatory response that causes many of the clinical manifestations, especially the edema resulting in increased intracranial pressure leading to headache. Cerebral vasculitis and infarction can also occur.

Clinical Manifestations

Early symptoms include the classic triad of fever, headache, and stiff neck (nuchal rigidity). Altered mental status also commonly occurs. If untreated, meningitis may progress to vomiting, seizures, photophobia, and focal neurologic deficits. Different pathogens can present with different rates of clinical progression, from acute onset and rapid progression (hours to days) to subacute or chronic onset and slow progression (days to weeks). N. meningitidis infection can be associated with disseminated disease (meningococcemia) and result in petechial rash and ultimately purpura fulminans (Figure 72–3).

Pathogens

Bacterial Pathogens Causing Acute Meningitis

The most common bacterial cause of acute meningitis overall is S. pneumoniae. However, Streptococcus agalactiae (group B Streptococcus) predominates in neonates, and N. meningitidis is common in teenagers and young adults (Table 72–2).

H. influenzae type B used to be an important cause in young children, but the widespread use of the conjugate polysaccharide vaccine has greatly decreased its incidence. Listeria monocytogenes is reasonably common in the very young, the very old, and immunocompromised patients. Less common pathogens include Borrelia burgdorferi (Lyme disease) and Treponema pallidum (syphilis).

Viral Pathogens Causing Acute Meningitis

The most common viral causes of acute meningitis are enteroviruses such as Coxsackie virus, echovirus, and enterovirus 71. Enteroviral meningitis occurs primarily in young children, and the peak incidence is in the summer and fall seasons.

HSV-2 is also a common cause of meningitis. Note that HSV-2 typically causes meningitis, whereas herpes simplex virus type 1 (HSV-1) causes encephalitis. Primary genital infections with HSV-2 are more likely to result in meningitis than recurrent HSV-2 infections. Primary and reactivation varicella-zoster virus (VZV) infection can also be associated with meningitis.

Although arboviruses typically cause encephalitis, arboviruses such as West Nile virus (WNV) and St. Louis encephalitis virus can also cause meningitis. Mumps virus used to be a common cause of meningitis, but widespread use of the mumps vaccine has greatly reduced its incidence.

Pathogens Causing Subacute and Chronic Meningitis

The most common causes of subacute and chronic meningitis are M. tuberculosis and fungi such as Cryptococcus, Coccidioides, and Histoplasma. Cryptococcal meningitis occurs most commonly in immunocompromised patients, such as those with acquired immunodeficiency syndrome (AIDS), but can cause subacute and chronic meningitis in immunocompetent patients as well. Other causes of chronic meningitis include T. pallidum and B. burgdorferi. Human immunodeficiency virus (HIV) is the most common viral cause of chronic meningitis.

Diagnosis

A microbiologic diagnosis of acute bacterial meningitis is typically made by Gram stain and culture of CSF. However, PCR-based tests are being increasingly used because they yield results rapidly and with great accuracy. For example, a PCR-based panel is now available that tests for the presence in spinal fluid of six common bacteria, seven common viruses, and the yeast Cryptococcus with a turnaround time of 1 hour.

Analysis of spinal fluid can distinguish between acute bacterial meningitis and viral meningitis (see Table 72–1). While they both tend to have elevated white blood cells (WBCs) and protein in CSF, bacterial infections tend to be neutrophil predominant, whereas viral infections are lymphocyte predominant. Bacterial infections are associated with low glucose concentrations in CSF, whereas viral infections have normal glucose levels.

Subacute and chronic meningitis tend to be lymphocyte predominant with very high protein levels and low glucose. Viral infections are often diagnosed by using PCR assay for viral DNA or RNA in CSF or by serologic tests for specific antibody. Gram stain and bacteriologic cultures of CSF are negative in viral meningitis. Fungal infections can be diagnosed by culture or by serologic tests. In the case of Cryptococcus, the India ink test and the cryptococcal antigen test are also useful.

Treatment

Empiric therapy for acute bacterial meningitis must include drugs with excellent penetration into the CSF (able to pass the blood–brain barrier), that are bactericidal, and that are active against the most common pathogens. In older children and adults, ceftriaxone or cefotaxime plus vancomycin is a common empiric regimen. Vancomycin is added to cover for penicillin- or cephalosporin-resistant pneumococci. Ampicillin should be added if Listeria is a likely cause.

Empiric therapy for neonatal bacterial meningitis includes ampicillin plus either ceftriaxone or cefotaxime, with or without gentamicin. Acyclovir is used for the treatment of HSV and VZV infection.

Prevention

Prevention strategies include both immunization and chemoprophylaxis. Vaccines are effective in preventing bacterial meningitis, caused by S. pneumoniae, N. meningitidis, and H. influenzae type B. The immunogen in the conjugate vaccines is the capsular polysaccharide of the organism.

The current conjugate pneumococcal vaccine (Prevnar 13) protects against the 13 most common serotypes. The current conjugate H. influenzae vaccine protects only against the type B serotype.

The current conjugate meningococcal vaccine protects against four common serotypes (A, C, Y, and W-135). Note, however, it does not contain the type B polysaccharide. The vaccine against type B meningococcus contains factor H binding protein (fHbp) as the immunogen. A second vaccine against type B meningococci containing four surface proteins (fHbp, NadA, NHBA, and PorA) is also available.

Chemoprophylaxis against S. agalactiae (group B Streptococcus) is aimed at reducing vaginal carriage in the mother. If vaginal or rectal cultures are positive at 35 to 37 weeks of gestation, then ampicillin should be given. Chemoprophylaxis is also used to reduce nasopharyngeal carriage of N. meningitidis and H. influenzae type B. Close contacts of patients with meningitis caused by these organisms should receive either ciprofloxacin for Neisseria or rifampin for Haemophilus.

Definition

Encephalitis is an infection of the brain parenchyma predominantly caused by viruses. Sometimes both the brain and the meninges are involved, a condition called meningoencephalitis.

Pathophysiology

The mode of acquisition of the viruses that cause encephalitis varies (Table 72–3). Neonates acquire HSV-2 during passage through the birth canal. HSV-2 then reaches the brain by hematogenous spread. Mothers with visible vesicular lesions are much more likely to have newborns with serious HSV-2 infections than mothers who are asymptomatic shedders of HSV-2 because the amount of virus present is significantly greater in the former.

In contrast, HSV-1 probably reaches the temporal lobe by travel within neurons following activation of latent infection in the trigeminal ganglion (Figure 72–4). Rabies virus also reaches the brain by axonal travel from the site of the animal bite.

Arboviruses, such as WNV, are acquired primarily by mosquito bite and then travel to the brain via the bloodstream. The incidence of arboviral encephalitis peaks in the summer and early fall because that is when mosquitoes are most active.

VZV can cause encephalitis during the primary infection (varicella is also known as chickenpox) or during the reactivation infection (zoster is also known as shingles). VZV also causes a postinfectious encephalomyelitis involving the brain and spinal cord after resolution of the primary infection. Cytomegalovirus (CMV) causes encephalitis primarily in immunocompromised individuals such as AIDS patients and those receiving drugs to prevent transplant rejection. Encephalitis caused by Epstein–Barr virus (EBV) is a rare complication of infectious mononucleosis.

Postinfection encephalitis typically follows an infection or an immunization by several weeks. It is a demyelinating disease caused by an immune attack on neurons, primarily those of the white matter.

Note that the lesions in encephalitis are inflammatory (contain WBCs, especially lymphocytes), whereas the lesions of an encephalopathy show degenerating neurons but no inflammation and do not contain WBCs. Encephalopathy is discussed later in a separate section.

Clinical Manifestations

The most characteristic clinical manifestations of encephalitis include fever, headache, and altered mental status, as well as seizures and focal neurologic deficits.

Rabies encephalitis has two clinical manifestations. Most cases of rabies (80%) present with hyperactivity, agitation, delirium, hydrophobia, and seizures (called furious rabies). The other 20% of cases have paralytic symptoms in which an ascending paralysis without hyperactivity is the predominant feature (called dumb rabies). Coma and death are the final common pathway in both forms.

Pathogens

Viruses are the main cause of encephalitis; however, the cause of at least half of the cases of encephalitis is unknown. Approximately 15% are caused by HSV-1. Encephalitis caused by HSV-1 and HSV-2 is very important because HSV-1 and HSV-2 are the most common causes for which antiviral drugs are available, namely acyclovir. About 5% are caused by arboviruses such as WNV. Rabies virus is a rare cause in the United States but occurs more frequently in countries where immunization of dogs is not a common practice. VZV, CMV, and EBV also cause encephalitis.

WNV is the most common arboviral cause of encephalitis in the United States. Most WNV infections (80%) are asymptomatic. Most of the remaining 20% develop an acute febrile “flulike” illness. Less than 1% develop CNS disease, of which half have encephalitis. Other arboviruses that cause encephalitis with some frequency are St. Louis encephalitis virus, the La Crosse strain of California encephalitis virus, and Eastern and Western equine encephalitis viruses (EEE and WEE, respectively). They are all transmitted by either Culex or Aedes mosquitoes.

Poliovirus causes meningoencephalitis in a few countries as of 2018, such as Nigeria, Pakistan and Afghanistan. It has been eradicated from the Western Hemisphere and most other countries as a result of widespread use of the vaccine. However, disease may occur in these countries when imported by travelers from countries where the virus is endemic.

Postinfection encephalitis follows immunization or infection caused most often by VZV, measles, and influenza.

Diagnosis

In contrast to meningitis, CSF findings in encephalitis are more variable. A mild elevation in CSF lymphocytes (pleocytosis) can be seen along with an elevation of protein and a normal glucose. A normal CSF pattern can also be seen in encephalitis.

PCR-based testing of CSF is commonly used to determine a specific etiology, such as with HSV and VZV. WNV encephalitis is often diagnosed by finding WNV-specific IgM in the spinal fluid.

Rabies can be diagnosed by direct fluorescent antibody staining of a biopsy of skin from the nape of the neck. A PCR assay using CSF, saliva, or tissue is also available. The PCR assay has the advantage of identifying the animal reservoir and the geographic location of the virus because the base sequence of the RNA genome varies in accord with those two features.

Radiographic findings can be useful as well. In particular, in HSV encephalitis, temporal lobe abnormalities are frequently seen.

Treatment

Intravenous acyclovir is the treatment of choice for HSV-1, HSV-2, and VZV encephalitis. Ganciclovir is used for CMV encephalitis. There is no antiviral therapy for arboviral or rabies encephalitis.

Prevention

Prevention of rabies includes both preexposure (before the bite) and postexposure (after the bite) prophylaxis. Preexposure prophylaxis with the killed vaccine should be given to veterinarians and others at risk of exposure. Postexposure prophylaxis consists of both the killed vaccine and the hyperimmune globulins that contain a high titer of anti-rabies virus antibodies. They are inoculated at different sites so the antibodies do not neutralize the virus in the vaccine. This is an important example of passive–active immunization. There is no vaccine for HSV-1, HSV-2, and WNV.

To reduce the transmission of HSV-2 to the neonate, pregnant women with active lesions late in pregnancy should receive acyclovir and should be considered for cesarean section.

Definition

Acute flaccid myelitis (AFM) is an infection of the spinal cord, particularly of the motor neurons, which results in paralysis. AFM is also known as acute flaccid paralysis. The term “myelitis” refers to infection/inflammation of the spinal cord.

Pathophysiology

Following viral infection of the upper respiratory tract and/or the gastrointestinal tract, the virus enters the blood stream and infects the motor neurons in the spinal cord. Death of the motor neurons results in weakness or paralysis.

Outbreaks of AFM began in the United States in 2014 and have continued at 2-year intervals ever since. AFM affects young, healthy children, especially in the summer and fall seasons.

Clinical Manifestations

Patients with AFM frequently report antecedent symptoms consisting of mild fever and/or respiratory tract infection (rhinorrhea and cough) or gastrointestinal tract infection (vomiting and diarrhea). Three to ten days later, the sudden onset of weakness or paralysis of an arm or leg occurs. In addition, facial nerve palsy can occur along with slurred speech or swallowing difficulty. Respiratory failure is rare but life-threatening. MRI will show characteristic changes in the gray matter of the spinal cord. CSF analysis often shows a pleocytosis (an increase in the number of cells).

Pathogens

Enterovirus D68 and enterovirus A71 are suspected of causing most cases of AFM. Poliovirus has not been detected in patients with AFM in the United States. Many cases of AFM have identified no viral pathogen in the spinal fluid.

Diagnosis

Microbiologic diagnosis is made by isolating viruses from the spinal fluid or stool. Nucleic acid amplification tests (NAAT) for viral RNA is also useful.

Treatment

No antiviral drugs are available for treatment. Supportive care is important.

Prevention

No antiviral drugs or vaccines are available. Handwashing and other infection control techniques are useful.

Definition

A brain abscess is a localized, walled-off collection of pus surrounded by a fibrous capsule within the brain parenchyma. Bacteria are the most common cause of brain abscesses, but fungi and protozoa are also involved. Viruses do not cause brain abscess.

Pathophysiology

Brain abscess is a recognized complication of head and neck pyogenic infections, such as sinusitis, otitis media, and dental infections. Sinusitis predisposes to lesions in the frontal lobe, whereas otitis media predisposes to lesions in the temporal lobe. Hematogenous spread from an infected site, such as with infective endocarditis, also occurs. Table 72–4 correlates various predisposing conditions with the organisms likely to cause brain abscess.

With increasing use of immunosuppressive drugs, indwelling intravenous catheters, and hyperalimentation, fungal brain abscesses have become more common. Immunocompromised patients, especially those with AIDS, also have brain abscesses caused by Toxoplasma gondii.

Clinical Manifestations

Headache alone is the most common symptom of brain abscess, and thus, when headache alone occurs early in the disease, the diagnosis of brain abscess can often be missed. As the lesion progresses, patients may develop fever, behavioral changes, focal neurologic deficits, and seizures.

Pathogens

Bacteria

Streptococci, both aerobic and anaerobic, are most commonly isolated from bacterial brain abscesses. They are typically of oropharyngeal origin, such as Streptococcus anginosus and viridans group streptococci. They are typically seen in mixed infections with oral anaerobes such as Prevotella, Fusobacterium, and Bacteroides. Nocardia asteroides also causes brain abscesses. Monomicrobial infections with Staphylococcus aureus are often associated with infective endocarditis.

Fungi

Fungal abscesses occur primarily in immunocompromised patients. Aspergillus fumigatus can occur in neutropenic patients, rhinocerebral mucormycosis (caused by Mucor and Rhizopus species) in diabetic patients with ketoacidosis, and cryptococcal infection in patients with HIV/AIDS. Candida species are also involved.

Protozoa

T. gondii is the main protozoal cause of brain abscess. It is an important cause in immunocompromised patients, especially those with AIDS, patients receiving cancer chemotherapy, or patients on immunosuppressive drugs used to enhance transplant survival. T. gondii can be transmitted by solid organ transplant, especially heart transplants, as well as by the more common modes of transmission, namely ingestion of raw meat containing cysts or by exposure to cat feces containing oocytes. Transplacental transmission of T. gondii can cause intracranial calcifications in the fetus.

Diagnosis

MRI is an important diagnostic modality, often revealing a “ring-enhancing” lesion (Figure 72–5). A microbiologic diagnosis requires obtaining pus from the abscess and performing a culture for aerobic and anaerobic bacteria and fungi. In bacterial brain abscesses, the Gram stain frequently reveals several types of bacteria indicting a mixed infection. Aspiration of pus from the lesion is both diagnostic and therapeutic, having the effect of draining the abscess.

A microbiologic diagnosis of Toxoplasma infection is usually made by identifying specific radiographic findings in an at-risk host (e.g., HIV/AIDS) with a positive Toxoplasma IgG and a response to specific antiprotozoal therapy. A PCR-based assay for Toxoplasma nucleic acid is also available.

Treatment

Empiric antimicrobial therapy for bacterial brain abscesses consists of a third-generation cephalosporin, such as ceftriaxone or cefotaxime, plus metronidazole. The latter is coverage for the anaerobic bacteria. Vancomycin should be added if the patient has undergone a neurosurgical procedure. Treatment of bacterial and fungal brain abscesses may require aspiration of pus from the abscess in addition to antibacterial or antifungal drugs.

Brain abscess caused by Nocardia can be treated with trimethoprim-sulfamethoxazole. Brain abscess caused by Aspergillus can be treated with voriconazole. Treatment of Toxoplasma brain abscess includes a combination of pyrimethamine and sulfadiazine.

Prevention

There are no vaccines to prevent brain abscesses. Early treatment of odontogenic and sinus infections may prevent these complications. Tight control of blood glucose may prevent rhinocerebral mucormycosis in diabetics. Treatment of AIDS patients with antiretroviral therapy may prevent Toxoplasma brain abscess, and when the CD4 count is <100 cells/µL, primary prophylaxis with trimethoprim-sulfamethoxazole is recommended in patients who are positive for Toxoplasma IgG.

Subdural empyema is a collection of pus on the inner surface of the dura mater, whereas epidural empyema is a collection of pus on the outer surface. They can occur adjacent to the dura of either the brain or spinal cord.

Sinusitis and otitis media are common predisposing factors, and the bacteria causing these empyemas are those that cause sinusitis and otitis media, namely, aerobic and anaerobic streptococci, staphylococci, enteric gram-negative rods such as Escherichia coli, and anaerobic gram-negative rods such as Prevotella. Mixed infections are common.

The clinical features include fever plus symptoms of increased intracranial pressure, such as headache, vomiting, focal neurologic deficits, and altered mental status. MRI with gadolinium enhancement reveals a mass adjacent to the dura. Microbiologic diagnosis involves aspirating pus from the lesion and performing a Gram stain and culture. Treatment involves surgical drainage of the pus combined with antibiotics appropriate for the bacteria isolated from the aspirated pus.

Encephalopathy refers to altered brain function in the absence of inflammation. In general, patients with encephalopathy do not have fever, headache, seizures, focal neurologic signs, and an increased WBC count in the blood and spinal fluid, whereas patients with encephalitis often do. Common manifestations of encephalopathy include confusion, personality changes, disorientation, aphasia, delirium, and dementia.

There are several infection-related causes of encephalopathy (see later), but most causes are noninfectious (e.g., alcohol, drugs, lead, uremia, or liver failure).

Important infection-related causes of encephalopathy include the following:

• Progressive multifocal leukoencephalopathy (PML). PML is caused by JC virus and occurs in immunocompromised patients, notably AIDS patients. Infection with JC virus occurs early in life and remains latent until the immune system is compromised. PML has occurred in multiple sclerosis patients being treated with natalizumab and in transplant recipients being treated with mycophenolate. Microbiologic diagnosis is made by detecting JC virus DNA using PCR assay on brain specimens or spinal fluid. There is no antiviral drug therapy and no vaccine. Additional information can be found in Chapter 44.

• HIV encephalopathy including AIDS dementia. Another CNS disease that is seen in HIV-infected individuals is encephalopathy caused by HIV itself. It can vary from mild symptoms such as memory problems and apathy to more serious disease such as profound memory loss and psychosis (AIDS dementia). AIDS dementia is more likely to occur when CD4 counts are below 200/µL and when the viral load in the CSF is high.

• Creutzfeldt-Jakob disease (CJD) and kuru. CJD is one of the human transmissible spongiform encephalopathies. The term “spongiform” refers to the spongy, Swiss cheese-like appearance of the brain of patients with CJD. CJD is caused by prions, a misfolded protein in which the normal alpha-helical configuration has changed to a beta-pleated sheet, thereby altering the function of the protein and leading to death of neurons. Additional information on prions can be found in Chapter 44.

  • CJD occurs sporadically worldwide at a rate of about one case per million population. CJD has been transmitted iatrogenically by corneal transplant, intracerebral electrodes, and dura mater grafts. CJD does not have any relationship to the ingestion of any food, unlike variant CJD, which is discussed later.

  • The main clinical findings in CJD are dementia and myoclonus. The progression is gradual but inexorable, resulting in coma and death. Definitive diagnosis is made by observing spongiform changes in brain biopsy followed by histochemical staining with anti-prion antibodies. There is no drug treatment for CJD and no vaccine.

  • Variant CJD is acquired by the ingestion of prion-containing beef. It is declining as a result of the ban on the addition of animal products to cattle feed.

  • Kuru is a spongiform encephalopathy found in the Fore tribe in New Guinea. It is now very rare because the eating rituals that transmitted the agent are no longer practiced.

• Reye’s syndrome. Reye’s syndrome is a postinfectious disease consisting of encephalopathy plus liver failure. It occurs primarily following influenza B and varicella infections in children and is associated with aspirin use. The role of aspirin in pathogenesis is uncertain but a toxic effect on mitochondria has been proposed.

  • After the child has recovered from the viral infection, Reye’s syndrome begins with prominent vomiting followed by encephalopathic changes such as lethargy and combative behavior progressing to coma and death. Cerebral edema is marked. Fatty degeneration of the liver occurs, and liver enzymes such as transaminases are elevated. Blood ammonia levels are elevated.

  • Treatment should be instituted promptly. If coma occurs, treatment is less effective. Antiviral drugs are not effective. Supportive measures such as cooling blanket, ventilator to provide respiratory support, control of intracranial pressure, hemodialysis, and fluid and electrolyte balance are used. Vaccines against varicella and influenza and public health campaigns to reduce aspirin use in febrile children have greatly reduced the incidence of this disease. Acetaminophen should be used to reduce fever in children.