Other Bacterial Central Nervous System Infections and Toxins
Barnett R. Nathan
Acute bacterial meningitis (see Chapter 61) occurs when bacteria invade and infect the leptomeninges, causing an acute clinical syndrome of fever, headache, meningismus, and neurologic dysfunction with polymorphonuclear pleocytosis in the cerebrospinal fluid (CSF). This chapter discusses a wide variety of less common bacterial infections that can either infect the central nervous system (CNS) directly, cause parainfectious central or peripheral neurologic syndromes, or create toxins that lead to neurologic dysfunction.
Rickettsiae are obligate, intracellular pleomorphic coccobacilli. Each Rickettsia pathogenic for humans is capable of multiplying in arthropods and in animals and humans. They have a gramnegative cell wall and an internal structure similar to that of bacteria (i.e., with a prokaryotic DNA arrangement and ribosomes). Diseases due to rickettsiae are divided into five groups on the basis of their biologic properties and epidemiologic features: typhus, spotted fever, scrub typhus, Q fever, and trench fever. Invasion of the nervous system is common only in infections with organisms of the first three groups. Infection with Rocky Mountain spotted fever is the most important rickettsial infection currently in the United States. A sixth group of rickettsiae in the genus Ehrlichia have come to be recognized as significant pathogens in humans in the past 15 years. Ehrlichial infections have also been associated with CNS symptoms, but the frequency of nervous system infection is still not certain.
ROCKY MOUNTAIN SPOTTED FEVER
Rocky Mountain spotted fever (RMSF) is an acute endemic febrile disease due to infection with Rickettsia rickettsii. R. rickettsii is a gram-negative, obligate intracellular bacterium. It is transmitted to humans by various ticks, the most common of which are the Dermacentor andersoni (wood tick), which is found in western region of the United States, and the Dermacentor variabilis (dog tick), which is found in the East and South. Rhipicephalus sanguineus (brown dog tick) is also a vector for RMSF in the southwestern United States. Rabbits, squirrels, and other small rodents serve as hosts for the ticks and are responsible for maintaining the infection in nature. Diseases of the RMSF group are present throughout the world. Because this is a tick-borne disease, it has a seasonal variation, with the summer months having the greatest number of reports.
The disease has been reported from almost all states and from Canada, Mexico, and South America. Approximately 1,000 to 2,000 cases are reported annually in the United States, mostly from rural areas of southwestern and south-central states. Most cases are seen during the period of maximal tick activity—the late spring and early summer months. Men are more commonly affected than women, and cases are most frequently reported in those older than 40 years.
Preventative measures include personal care and vaccination. Tick-infested areas should be avoided. If exposure is necessary, high boots, leggings, or socks should be worn outside the trouser legs. Body and clothing should be inspected after exposure, and attached ticks should be removed with tweezers. Hands should be carefully washed after handling the ticks. Workers whose occupations require constant exposure to tick-infested regions should be vaccinated yearly just before the advent of the tick season.
The agent has a tropism for vascular endothelial cells. Thus, any organ can be infected. The pathologic changes are most severe in the skin, but the heart, lungs, and CNS are also involved. The brain is edematous, and minute petechial hemorrhages are present. The characteristic microscopic lesions are small, round nodules composed of elongated microglia, lymphocytes, and endothelial cells. These are scattered diffusely through the nervous system in close relationship to small vessels. Vessels in the center of the lesions show severe degeneration. The endothelial cells are swollen, and the lumen may be occluded. Minute areas of focal necrosis are common as the result of thrombosis of small arterioles. Some degree of perivascular infiltration without the presence of nodules may be seen in both the meninges and the brain parenchyma.
A history of tick bite is elicited in about 70% of patients. The incubation period varies from 3 to 12 days. The onset is usually abrupt, with severe headache, fever, chills, myalgias, arthralgias, restlessness, prostration, anorexia, nausea, vomiting, and at times, delirium and coma. A rose-red maculopapular rash appears between the second and sixth day (usually on the fourth febrile day) on the wrists, ankles, palms, soles, and forearms. The rash rapidly spreads to the legs, arms, and chest. The rash becomes petechial and fails to fade on pressure by about the fourth day. Although cardiac, pulmonary, hepatic, and renal involvement can occur, they are less frequent than neurologic disease.
Neurologic symptoms occur early and are frequently a prominent feature. CNS signs and symptoms affect 20% to 25% of patients. Headache, restlessness, insomnia, and neck and back stiffness are common. Delirium, lethargy, or coma alternating with restlessness is present during the height of the fever. Tremors, athetoid movements, convulsions, opisthotonos, and muscular rigidity may occur. Retinal venous engorgement, retinal edema, papilledema, retinal exudates, and choroiditis may occur. Deafness, visual disturbances, slurred speech, and confusion may be present and may persist for a few weeks following recovery. Encephalitis is the most common major complication. Other major complications include adult respiratory distress, syndrome, cardiac arrhythmias, pulmonary edema, skin necrosis, gastrointestinal bleeding, and coagulopathies.
The white cell count (WBC) is either normal or mildly elevated. Thrombocytopenia may develop and is common. Proteinuria, hematuria, and oliguria commonly occur. Hyponatremia is also common. CSF pressure and glucose concentration are usually normal. The CSF is clear, but a slight lymphocytic pleocytosis and a slight increase in the protein concentration may occur. Eosinophilic meningitis has been reported.
The diagnosis is made on the basis of the development of the characteristic rash and other symptoms of the disease after exposure to ticks. Clinical distinction from typhus fever may be impossible. The onset of the rash in distal parts of the limbs favors a diagnosis of RMSF. In rare instances, however, neurologic signs may occur before the rash appears.
Diagnosis of RMSF is best performed by indirect immunofluorescence assay (IFA) with R. rickettsii antigen performed on twopaired serum samples to demonstrate a significant (fourfold) rise in antibody titers. The first titer, taken in the first week of the disease, will typically be very low or absent. After 2 to 4 weeks, those with disease should have a fourfold rise in antibody titer. Immunoglobulin (Ig) G titers are more specific than IgM. Unfortunately, because the organism is an obligate intercellular bacterium which resides in the endothelial cells, blood for polymerase chain reaction (PCR) is typically low yield. Nonspecific testing including blood work may demonstrate a leukocytosis (with left shift), thrombocytopenia, hyponatremia, and elevated liver function tests. In patients with neurologic involvement, CSF may be normal but may also develop a lymphocytic or neutrophilic pleocytosis (1 to 200 WBC) and a mild to moderate protein elevated in 30% to 50%. Neuroimaging is nonspecific with cerebral or spinal cord edema, white matter lesions, and at times microhemorrhages.
Doxycycline 100 mg twice a day for 7 to 14 days is the first-line treatment for adults and children of all ages and should be initiated immediately whenever RMSF is suspected.
Tetracycline 500 mg four times a day can also be used. There may be value to ciprofloxacin or chloramphenicol in patients unable to tolerate tetracycline or doxycycline. In children, chloramphenicol is the alternative to doxycycline to avoid tooth discoloration caused by tetracyclines. Any patient seriously considered to have RMSF should be treated promptly while diagnostic tests proceed.
Other spotted fever group rickettsiae in the United States that rarely cause an RMSF picture are Rickettsia akari (causes rickettsialpox), Rickettsia parkeri (eschars and a maculopapular or vesiculopapular rash), and Rickettsia felis (cat fleas). Except for some variation in their incubation times, the pathology and clinical picture are similar to those of RMSF. All such infections respond to tetracyclines (doxycycline) or chloramphenicol.
There has been a dramatic fall in the mortality rate, decreasing from 28% in 1944 to less than 1% in 2001. In patients who recover, the fever is over by the end of the third week, although mild cases may become afebrile before the end of the second week. Convalescence may be slow, and neurologic sequelae may persist for several months. Long-term prognosis depends on the severity of the infection, host factors (e.g., age, the presence of other illness), and the promptness with which antimicrobial treatment is started.
Three types of infection with rickettsiae of the typhus group are recognized: primary louse-borne epidemic typhus; its recrudescent form, Brill-Zinsser disease; and flea-borne endemic murine typhus.
Since its recognition in the 16th century, typhus has been known as one of the great epidemic diseases of the world. It is especially prevalent in times of war or whenever there is a massing of people in camps, prisons, or ships.
Epidemic typhus (caused by Rickettsia prowazekii) is spread among humans by the human body louse (Pediculus humanus corporis). Outbreaks of epidemic typhus last occurred in the United States in the 19th century. Freedom from lice explains the absence of epidemics in the United States. Sporadic cases in the United States have been associated with flying squirrel contact. The location of epidemic disease is now limited to the Balkans, the Middle East, North Africa, Asia, Russia, and the Andes. All age groups are affected.
Rickettsiae may remain viable for as long as 20 years in the tissues of recovered patients without manifesting symptoms. Brill-Zinsser disease is a recrudescence of epidemic typhus that occurs years after the initial attack and may cause a new epidemic.
Murine typhus (Rickettsia typhi) is worldwide in distribution and is spread to humans by fleas. In the United States, the disease is most prevalent in southeastern and Gulf Coast states and southern California, among individuals whose occupations bring them into rat-infested areas. The disease is most common in the late summer and fall months.
A presumptive diagnosis of typhus fever may be made on the basis of the characteristic skin rash and signs of involvement of the nervous system. The diagnosis is established by serology. Antibodies to specific rickettsiae may be detected.
The course of typhus fever usually extends over 2 to 3 weeks. Death from epidemic typhus usually occurs between the 9th and 18th day of illness. In patients who recover, the temperature begins to fall after 14 to 18 days and reaches normal levels in 2 to 4 days. Complications include bronchitis and bronchopneumonia; myocardial disease; gangrene of the skin or limbs; and thrombosis of large abdominal, pulmonary, or cerebral vessels. Common neurologic manifestations include confusion, drowsiness, seizures, focal deficits, and coma.
Treatment is with doxycycline, clarithromycin, or chloramphenicol, as with RMSF.
The prognosis of epidemic typhus depends on the patient’s age and immunization status. The disease is usually mild in children younger than 10 years. After the third decade, mortality increases steadily with each decade. Death is usually due to the development of pneumonia, circulatory collapse, and renal failure. The mortality rate for murine typhus in the United States is low (<1%). There are no neurologic residua in patients who recover.
Scrub typhus is an infectious disease caused by Orientia tsutsugamushi (previously called Rickettsia tsutsugamushi), which is transmitted to humans by the bite of larval trombiculid mites (chiggers). It resembles the other rickettsial diseases and is characterized by sudden onset of fever, cutaneous eruption, and the presence of an ulcerative lesion (eschar) at the site of attachment of the chigger.
The disease is limited to eastern and southeastern Asia, India, and northern Australia and adjacent islands.
The disease begins abruptly after an incubation period of 10 to 12 days, with fever, chills, and headache. The headache increases in intensity and may become severe. Conjunctival congestion, moderate generalized lymphadenopathy, deafness, apathy, and anorexia are common symptoms. In one series, meningitis and encephalitis occurred in 15%. Delirium, coma, restlessness, and muscular twitchings are also present in severe cases. A primary lesion (the eschar) is seen in nearly all cases and represents the former site of attachment of the infected mite. There may be multiple eschars. The cutaneous rash appears between the fifth and eighth day of the disease. The eruption is macular or maculopapular and nonhemorrhagic. The trunk is involved first with later extension to the limbs.
The diagnosis is made on the basis of the development of typical symptoms, the presence of the characteristic eschar, and serology. Sensitive PCR techniques are becoming available. Elevation of hepatic enzymes and creatinine as well as thrombocytopenia is common with severe illness.
Treatment and Outcome
In patients who recover, body temperature begins to fall at the end of the second or third week. Permanent residua are not common, but the period of convalescence may extend over several months. In fatal cases, death usually occurs in the second or third week as a result of pneumonia, cardiac failure, or cerebral involvement. In the preantibiotic era, mortality could reach 60% depending on geographic locale and virulence of the strain. Deaths are rare with appropriate antibiotic treatment, which is similar to the treatment for RMSF (doxycycline).
EHRLICHIOSIS AND ANAPLASMOSIS
Ehrlichiosis or anaplasmosis are tick-borne diseases with the preponderance of disease occurring in the summer months. They are small, gram-negative, obligate intracellular bacteria that infect leukocytes. Three forms of human infection have been identified in the United States. One species, Ehrlichia chaffeensis, is associated with human monocytotropic ehrlichiosis (HME), and the organism may be preferentially found in these cells. Human granulocytotropic ehrlichiosis (HGE) is also referred to as human granulocytotropic anaplasmosis (HGA). HGE is caused by Anaplasma phagocytophilum. Both human infections are detectable in the appropriate cells as coccobacillary forms. It has become possible to cultivate the organisms, and PCR reactions are increasingly available. Most diagnostic studies still rely on antibody detection. HME is transmitted by Amblyomma americanum (lone star tick) and possibly other ticks, whereas HGE is transmitted by ixodid ticks and probably D. andersoni. A third agent, Ehrlichia ewingii, causes canine granulocytic ehrlichiosis. It is transmitted by A. americanum.
The epidemiologic range for both agents appears to be extending. In 2010, Unites States cases attributed to E. chaffeensis declined almost 22% (944 to 740 cases), whereas those cases attributed to A. phagocytophilum increased by 52% (1,161 to 1,761 cases). HME is more common in the states in the South and Southeast region, whereas HGE was first found in the Midwest. Now, cases are regularly reported from New England, all Atlantic Coast states, south-central states, and California. Coinfection of HGE with Borrelia burgdorferi and HME with RMSF has been reported. E. ewingii is found in south-central, southeastern, mid-Atlantic, and coastal states.
Infection usually presents as a febrile, systemic process often associated with myalgia and headache. CNS complications occur in 20% to 35% of infected patients. Changes in mental status, meningitis, meningoencephalitis, seizures, cranial nerve palsies, and ataxia have also been noted and are correlated with more serious illness. Cardiac and respiratory failure can occur. Rashes have been reported in about 20% of cases. This makes it difficult to distinguish the illness from RMSF, whose distribution overlaps with E. chaffeensis. E. ewingii is more likely to occur in immunocompromised hosts. Children tend to have more severe disease.
Because of the nonspecific nature of the symptoms and signs, a high index of suspicion is required. A history of exposure to ticks may be helpful, but epidemiologic studies have shown that serologic evidence of infection usually is not correlated with known tick bites. Lymphopenia is often a feature of E. chaffeensis infection, whereas granulocytopenia is usually noted with the HGE infection. Thrombocytopenia and leukopenia are seen with E. ewingii infection. Elevated hepatic enzymes are usually present. Microscopic blood examination with a Wright-Giemsa stain may reveal the classic intraleukocytic morula. CSF pleocytosis and an increased protein concentration have been reported and appear to correlate with altered mental status. The most widely available diagnostic test remains a fourfold rise in antibody titer. Confirmation of the diagnosis can be attained by immunofluorescent detection of the intracellular organisms. PCR is available for both HME and HGA, although this test has yet to be standardized and not always readily available. Culturing of the causative organisms is now also possible but is not as sensitive as PCR.
Treatment and Outcome
Complete understanding of the course of ehrlichiosis has yet to be achieved. Initially, a high proportion of reported cases was fatal in both HME and HGE. However, serologic studies indicate that asymptomatic or minor infections are common. Currently reported case fatality rates are 3% to 10%. Clinically, it has also been found that some cases may be self-limited even without treatment. Treatment with doxycycline 100 mg twice a day for 7 days often results in rapid improvement. Therefore, prognosis seems to be good if accurate diagnosis is made and treatment started promptly.
Brucellosis (undulant fever) is a disease with protean manifestations, resulting from infection with short, slender, rod-shaped, gram-negative microorganisms of the genus Brucella. The infection is transmitted to humans from animals (cattle, pigs, sheep, goats, and others). The illness is prone to occur in slaughterhouse workers, livestock producers, veterinarians, and persons who ingest unpasteurized milk or milk products.
The two major species that can infect humans are Brucella suis from swine and Brucella abortus from cattle. Inoculation is via the skin, inhalation, or ingestion. It is a slow-growing organism having an incubation time of up to 2 to 3 weeks.
There is a broad clinical spectrum from asymptomatic to fatal disease.
An acute, febrile illness is characteristic of the early stages of the disease. The common symptoms include chills, night sweats, fever, weakness, and generalized malaise; 70% of patients experience body aches and nearly 50% complain of headache. Other symptoms on presentation can include anorexia, nausea and vomiting, arthritis, endocarditis, malodorous sweat, or orchitis. Early constitutional symptoms are followed by the subacute and chronic stages in about 15% to 20% of patients with localized infection of the bones, joints, lungs, kidneys, liver, lymph nodes, and other organs. Neurologic complications have been reported in up to 25% but are more likely much less common occurring in about 5% of cases. These complications can include meningitis, encephalitis, myelitis, radiculitis, neuritis, and meningovasculitis. Nonspecific neurologic signs and symptoms may include seizures, cranial neuropathies, gait disturbances, hemiparesis and hemisensory disturbance, and mental status changes.
Diagnosis is made with culture. This is a slow-growing organism and may take up to 30 days to grow. Blood, CSF, or bone marrow can be cultured. Additionally, PCR may be helpful. Screening blood work may demonstrate a pancytopenia. Lumbar puncture may reveal a mildly increased opening pressure and a lymphocytic pleocytosis (<500 WBC), slightly elevated protein, and a small decrease in the glucose concentration. The CSF has increased gamma globulin levels and often contains Brucella-agglutinating antibodies. Neuroimaging may demonstrate white matter changes in the brain, particularly in a periventricular distribution. These white matter lesions are seen best with fluid-attenuated inversion recovery (FLAIR) sequences and can enhance with gadolinium.
TREATMENT AND OUTCOME
Treatment likely requires multiple antibiotics for multiple months, although there has been success with monotherapy with doxycycline 100 mg orally (PO) twice a day (b.i.d.) for 45 days, with fewer recurrences than a 30-day course [Level 1].1 Treatment of systemic disease is with doxycycline plus an aminoglycoside (intramuscular streptomycin or intravenous [IV] gentamicin), rifampin, or ofloxacin [Level 1].2,3 Trimethoprim/sulfisoxazole is an alternative to the tetracyclines. Neurologic disease is treated with triple therapy with the addition of trimethoprim-sulfamethoxazole or ceftriaxone to one of the aforementioned regimens.
Bacillus anthracis is a large endospore-forming, aerobic, grampositive nonmotile bacterium that produces a black, eschar-like cutaneous lesion after cutaneous inoculation.
Anthrax is primarily a disease of herbivores; however, it causes cutaneous lesions as well as respiratory and gastrointestinal infections in humans. Anthrax is one of the oldest documented infectious diseases. It may have caused two Egyptian plagues in 1491 BC. Inhalational anthrax occurred in England in the 19th century as woolsorter’s disease, and in Germany, it became known as ragpicker’s disease as a result of the infection of mill workers with anthrax spores from contaminated fibers from goats. Prior to the 2001 bioterrorism-related outbreak of 11 inhalational cases and 12 suspected or confirmed cases of cutaneous anthrax, there had been only 18 sporadic cases total in the United States during the 20th century, with the last case in 1976. Therefore, other than bioterrorist attacks or laboratory accidents, the populations most at risk for anthrax are individuals who work closely with domesticated animals. Countries such as Turkey have much higher incidences of anthrax than the United States.