Viral hemorrhagic fevers: neurologic complications
Aug. 17, 2021
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Leptospirosis is a common and significantly underdiagnosed multisystem zoonotic infection, most often presenting with conjunctival suffusion and myalgias. Although usually self-limited, it can pose a serious threat to patients and a management challenge to clinicians. The author reviews the range of clinical manifestations of this frequently occurring infection, with particular emphasis on the uncommon but potentially serious forms of nervous system leptospirosis. Diagnostic and therapeutic strategies are reviewed in detail.
• Leptospirosis is a common zoonosis, resulting in 1,000,000 severe infections and 60,000 deaths worldwide annually.
• Leptospirosis is typically spread in warm weather months through contact with bodies of water contaminated with urine or feces of infected rodents or other animals.
• Common clinical manifestations include conjunctival suffusion, headache, and myalgias.
• The illness tends to be biphasic, with the immune response playing an important pathogenic role in the second phase.
• The causative organism is responsive to multiple antibiotics, including penicillins and tetracyclines.
• Multiorgan damage, and even death, occurs in severe cases.
In 1886, Weil described a clinical syndrome that now bears his name. Twenty-one years later, the leptospirosis spirochete was first visualized in the kidney of a patient who had died during a yellow fever epidemic (57). In 1916, 2 different groups isolated leptospires from Japanese mine workers and from subjects in France suffering from German trench disease (27; 59).
Leptospirosis, which is frequently underdiagnosed, is the most common zoonosis in the world, estimated to affect more than 1,000,000 people worldwide annually (13; 46). It is caused by pathogenic leptospires and is characterized by a wide range of clinical manifestations, varying from a subclinical infection to a fulminant, lethal disease. The majority of symptomatic individuals have the mild and usually anicteric form of leptospirosis, with or without meningitis. Severe leptospirosis, also known as Weil syndrome, is characterized by icterus, renal impairment, and bleeding diathesis; it develops in 5% to 10% of infected individuals (15) and may be less common in reinfection (33).
The incubation period is usually from 1 to 2 weeks but can range from 2 to 26 days. An acute leptospiremic phase is typically followed by an immune leptospiruric phase.
Anicteric leptospirosis may manifest as an acute febrile illness with fever, chills, headache, nausea, vomiting, and myalgias, with symptoms that can suggest dengue, giving rise to diagnostic delay (51). Muscle pain is a significant feature of leptospiral infection and involves the calves, abdomen, and back. Patients usually have intense headache and occasionally develop photophobia. Other less common features are sore throat, rash, and mental confusion.
The most common physical examination findings in leptospirosis are conjunctivitis (42%), splenomegaly (15% to 25%), lymphadenopathy (21%), pharyngitis (17%), hepatomegaly (15% to 25%), nuchal rigidity (12%), rash (7%), and jaundice (1.5%). There is frank myositis in up to 37%. There may be tachycardia, bradycardia, and hypotension. Ocular findings are reported in 3% to 92% of patients and include early conjunctival injection, optic neuritis, bilateral or unilateral uveitis, cotton wool spots, and necrotic retinitis (11). Uveitis may be a late feature, reported to occur months to years after the initial infection.
The symptoms resolve in most patients within 1 week. However, after an interval of 1 to 3 days, the illness may resume. This second (immune) phase coincides with the development of antibodies. Symptoms tend to be more variable than during the first (leptospiremic) phase and may last for a few days to a few weeks. Fever is less pronounced, and the myalgias are less severe than in the leptospiremic phase. A significant feature of the immune phase is the involvement of the central nervous system. Signs and symptoms include severe headache, photophobia, blurred vision, nuchal rigidity, and altered mental status. These findings may occur in the absence of any hepatic, renal, or pulmonary involvement. Delirium, hallucinations, encephalitis, seizures, cerebral edema, ataxia (55), and coma have been reported (38; 51). Meningitis is estimated to complicate 5% to 24% of cases (48). In 1 report, white blood cells in the cerebrospinal fluid consisted of 4% to 89% lymphocytes and 2% to 93% neutrophils, showing the variable host response to leptospira (37). In a large Laotian series of cases of meningitis, leptospirosis accounted for 12% of all patients admitted with various forms of meningitis; about 1 out of 3 patients had hypoglycorrhachia (20).
Clinical manifestations of meningitis can be seen early after infection but are commonly observed after development of an antibody response (31). Therefore, the neurologic manifestations of leptospirosis are not necessarily due to direct tissue damage by the organism but instead may be secondary to the host immune response. The meningeal symptoms usually resolve within a few days but may last for a few weeks. The cerebrospinal fluid pleocytosis may disappear in a few days or occasionally persist for months. In addition to meningitis, a variety of central nervous system and peripheral nervous system findings occur in about 7% of patients (see Table 1). Acute disseminated encephalomyelitis has been reported as an uncommon complication of leptospira infection (32). A few cases of Guillain-Barre syndrome have been reported following leptospirosis (05; 29), including acute motor and sensory axonal neuropathy (23). Rare cases of meningoencephalitis (28), hydrocephalus (47), and unilateral (30) or bilateral (36; 54) facial palsy have been reported. Iritis, iridocyclitis, and chorioretinitis are late complications but may appear as early as the third week. These ocular manifestations often persist for several months after the initial infection.
Headache, pain, neck stiffness, encephalopathy
Meningitis (acute, chronic)
Meningoencephalitis, encephalitis, encephalomyelitis, hemorrhage (subarachnoid, subdural, spinal), cranial neuropathy
• Peripheral nervous system abnormalities
Radiculoneuritis, mononeuritis, plexitis, axonal or demyelinating neuropathy
Severe leptospirosis (or Weil syndrome) manifests with jaundice, renal dysfunction, bleeding diathesis, and has a high mortality. Weil syndrome is frequently associated with infection due to serovar icterohemorrhagic or copenhageni. The onset of Weil syndrome is similar to the less severe form of leptospirosis, but within 4 to 9 days, jaundice, renal impairment, and vasculitis develop. This form of leptospirosis lacks the biphasic pattern seen with the less severe form. The jaundice usually is not associated with severe hepatic injury, and hepatic failure is a rare cause of death. Hepatic and splenic enlargement are detected in 20% of patients with Weil syndrome.
Renal insufficiency often develops in the second week of illness. Hypovolemia as well as lowered renal perfusion contribute to the development of acute tubular necrosis with oliguria or anuria. Other less-common manifestations of Weil disease include dyspnea, chest pain, bloody sputum, epistaxis, petechiae, purpura, ecchymoses, gastrointestinal bleeding, adrenal hemorrhage, pericarditis, myocarditis, congestive heart failure, and rhabdomyolysis (14). Several patients with renal involvement have become sufficiently hypokalemic to develop hypokalemic paralysis (16; 56).
The mild anicteric form of leptospirosis is not life-threatening; however, the severe icteric form (Weil syndrome) has a mortality of 5% to 10%. Mortality is increased in older patients. In a series, multivariate analysis indicated that central nervous system and pulmonary involvement were the 2 strongest predictors of mortality (44). An analysis suggested that increased creatinine, leukocytosis, and thrombocytopenia predicted a fatal outcome (51). In most fatal cases, death is not due to hepatic failure but rather to acute renal failure, massive hemorrhage, acute respiratory failure, or cardiovascular collapse. There are limited sequelae from leptospirosis, and in general, most survivors recover completely.
Leptospira are aerobic spirochetes with a Gram negative-like cytoplasmic membrane and cell wall, surrounded by an outer membrane containing porins that allow solute exchange between the microorganism and the environment. They belong to the order Spirochaetales and the family Leptospiraceae. Leptospires are coiled, highly motile microorganisms with flagella attached to a basal body through a hook; these flagella allow the spirochetes to propel themselves through connective tissue, rapidly redirecting themselves in response to their chemoreceptors (46). These microorganisms are 3 µm to 20 µm long and about 0.1 µm in diameter; they require special media and conditions to grow and require weeks in culture before a positive result is obtained.
In the past, the genus Leptospira was divided into 2 species: the free-living L biflexia and the pathogenic L interrogans. However, 9 species of pathogenic leptospires have been identified based on genetic studies (66). Serologically, the pathogenic leptospires are divided into more than 250 serovariants (based on their antigenic structure), which comprise 23 serogroups (34).
The pathogenesis of leptospirosis is only partially understood. Leptospires may gain access to the host through abraded skin or through intact mucous membranes, especially the conjunctiva and the lining of the oropharynx and nasopharynx. Following invasion of the host, leptospiremia develops, and organisms invade other organs. Proliferation of leptospires occurs in blood and tissues, and the invading microorganism can be isolated from blood and cerebrospinal fluid within the first 10 days of the illness. All forms of pathogenic leptospires can damage the walls of blood vessels and cause vasculitis with leakage and extravasation of cells and hemorrhages. The spirochetes contain immunoglobulin-like (Lig) proteins that bind to laminin, collagen, and fibrinogen. They also bind host plasminogen, converting it to plasmin and using it to degrade the extracellular matrix and fibrin clots (46). These Lig molecules also bind Factor H, the major negative regulatory molecule of the alternative pathway, and C4b binding protein, the major negative regulatory protein of the classical and lectin pathways (08), protecting the leptospires from these important host protective mechanisms. Finally, leptospira may capture host plasminogen, generating plasmin and upregulating matrix metalloproteinase 9 transcription, enhancing penetration of endothelial cells (62). The majority of clinical manifestations of leptospirosis are due to diffuse vasculitis with capillary injury. The widespread capillary endothelial damage is associated with hemorrhage, which is worsened by thrombocytopenia, renal disease, and coagulation disturbances. There may be hemolysis (perhaps due to a hemolysin released by certain serotypes) as well as focal hemorrhagic myocarditis. The brunt of hepatocellular damage appears to be subcellular. Although focal hepatocellular necrosis occurs, it is unusual, and leptospires are generally not found in the affected liver tissue. However, in a guinea pig model, the presence of leptospiral antigen paralleled morphologic liver changes, prompting the investigators to postulate a direct cytotoxic effect of the spirochetes on endothelial and liver cell membranes (04). In contrast to the situation in the liver, renal damage occurs at a tubular level, with organisms commonly seen in the tubular lumen. Leptospires appear to have a direct toxic effect on kidney; an early decrease in aquaporin 2 expression in the collecting duct may play a role in the development of nonoliguric renal failure despite the frequent hypovolemia (49), or lead to hypoxic damage. Later stages of renal disease can be associated with inflammatory infiltrates and immune complex deposition. Studies suggests possible antigenic cross reactivity between several prominent leptospiral lipoproteins (LruA and LruB) and antigens in the lens and ciliary body, raising the possibility of molecular mimicry as a mechanism underlying several of the ophthalmologic processes associated with this infection (61).
Pathologic changes within the brain and spinal cord include edema and congestion, meningeal thickening with mononuclear infiltration, perivascular cuffing (67), inflammation, loss of cerebellar granule cells, and chromatolysis of neurons. Microglial nodules may be prominent (38). Like other spirochetes, leptospira adhere to brain microglia; pathogenicity appears to be inversely related to the ability of the microglia to kill internalized leptospires (12).
Cerebrovascular changes may include panarteritis, multiple occlusions, and hemorrhage (intraparenchymal, subarachnoid, subdural) (42). Muscles of individuals experiencing myalgias demonstrate mild cytoplasmic vacuolization of myofibrils, mild neurotrophic neutrophilic or mononuclear infiltration, and focal necrotic changes.
Leptospirosis affects at least 160 species of mammals around the globe. Leptospira species are endemic to feral and domestic mammals as well as reptiles and amphibians, all of which serve as reservoirs for more than 250 identified serovars of the genus Leptospira. Rodents, particularly rats, are the most significant reservoir hosts for human infection. Leptospires establish a symbiotic relationship with their host and can survive in the renal tubules for a long time. An infected animal can remain asymptomatic and continue to shed infectious microorganisms in the urine for its entire life. In addition, in warm weather, leptospires can survive for weeks in moist soil or alkaline water. Animals, such as dogs, that are vaccinated against leptospira can also excrete microorganisms in the urine. Human infection occurs through either direct or indirect contact with urine, blood, or tissue from infected animals or exposure to a contaminated environment. Human-to-human transmission is rare. Farmers, sewer workers, miners, fishermen, and meat workers are at highest risk for infection. However, exposures have occurred in numerous environments associated with flooding (45) and poor general hygiene (26).
The incidence of leptospirosis is higher in warm climates than in temperate regions, but endemic areas are expanding (63; 03). The disease is seasonal with peak incidence during the summer and fall. The reported incidence of reported leptospirosis reflects the clinical index of suspicion, the actual incidence of the disease, and the availability of laboratory diagnosis. Of 183 cases reported in the United States in 2018 (the year with the most recent data), the 3 areas with the most cases were Puerto Rico with 84, Hawaii with 22, and New York City with 9 (09).
Individuals who may have been exposed to leptospires through their occupation or their involvement in recreational water activities should be warned and informed about the risks of infection. Preventive measures to control the spread of leptospirosis consist of avoidance of exposure to urine and tissues from infected animals, vaccination of animals, and rodent control. Effective human vaccination against a specific serovar prevalent in an area has been carried out in some European and Asian countries and has been effective, including a multivalent inactivated whole cell vaccine in use in China (65). However, creating vaccines effective against a broad range of serovars remains challenging (24). Preventive measures to avoid exposure include careful sterilization of potentially contaminated work areas and prohibition of swimming at sites that are likely to be contaminated. Prophylaxis also involves the judicious use of antimicrobials. Prophylactic antibiotics (doxycycline 200 mg per week) have been prescribed to prevent infection and decrease major morbidity in people exposed to high-risk situations (22), although an outbreak among an exposed group of marines suggests this approach may be less effective than long assumed (17).
There are seasonal (summer and early fall) and regional (rural areas) risk factors for leptospirosis. Young males are most likely to be exposed. Certain jobs increase workers’ risk of infection: agricultural workers (farmers, gardeners), animal handlers (veterinarians, hunters, livestock or kennel workers, exterminators), meat handlers (abattoir and meat packing workers), construction workers, forestry workers, and sewer workers. Other risk factors include the use of rainwater for drinking, and the presence of skin cuts (48). Recreational activities that provide exposure to polluted water (swimming, boating, camping, picnicking, fishing, nature study) are also risk factors. In one study of U.S. servicemen stationed in Japan, 3.5% had serologic evidence of infection during their tours (10).
Leptospirosis has diverse manifestations including fever, meningoencephalitis, hepatitis, and acute liver or renal insufficiency. The differential diagnosis includes noninfectious disorders as well as a number of bacterial, rickettsial, viral, and parasitic infections such as influenza, pneumonitis and enteric infections, brucellosis, dengue (07; 51), tularemia, rickettsioses, various causes of aseptic meningitis and encephalitis, acute abdominal disorders, and Hantavirus infections.
The laboratory diagnosis of leptospirosis remains challenging (53; 02). Leptospires can be isolated from blood or cerebrospinal fluid during the first 10 days of disease and from urine for several weeks beginning about 1 week after disease onset. Cultures may take 2 to 4 weeks to become positive, with a range of 1 week to 4 months. Polymerase chain reaction detection of the organisms can be useful in the first week or 2 of infection. Recent efforts to reduce the cost of this technique using TaqMan real time PCR show promise, but sensitivity remains low, as it is with less expensive rapid diagnostic tests (18; 52). Flow cytometry, using fluorescent labelling, may provide a less resource-intensive option for rapid early organism detection (21). By the second week, IgM antibody is usually detectable by either microagglutination or ELISA assays, although sensitivity of both is incomplete (53; 60), no doubt because antibody levels are too low to be detected until the second week of illness (19). The macroscopic slide agglutination test uses formalin-fixed antigen and is useful for screening but lacks specificity (39). Recent tests of several veterinary IgM detecting rapid point of care diagnostic tests appeared promising (35). Early treatment may delay elevation of the antibody titer. There is no rapid, sensitive, inexpensive, and widely available diagnostic procedure for leptospirosis. The diagnosis is usually suspected based on history of direct or indirect animal contact or water exposure, biphasic illness, aseptic meningitis, conjunctivitis, severe myalgias, and renal and hepatic involvement. The definitive diagnosis of leptospirosis is based on either isolation of the microorganism from the patient or on seroconversion demonstrated by a rise of antibody titer in the microscopic agglutination test (06). Detection of an antibody titer of greater than 1:100 in the microscopic agglutination test or a positive macroscopic slide agglutination test in the presence of a compatible clinical syndrome supports a presumptive diagnosis of leptospirosis.
Other laboratory blood abnormalities are nonspecific and include: a normal or slightly elevated white blood cell count with neutrophil predominance in the range of 75% to 90%, increased erythrocyte sedimentation rate, elevated creatine kinase, and mildly elevated transaminases (in contrast to viral hepatitis). Up to half of patients have thrombocytopenia, which correlates with renal insufficiency. Blood urea nitrogen is generally less than 100 mg/dL and creatinine less than 8 mg/dL. Urinalysis may show proteinuria, hematuria, and casts. ECG abnormalities (eg, first-degree atrioventricular block, ST-T wave changes, pericarditis changes) are noted in 39% of more severe leptospirosis infections.
The cerebrospinal fluid is frequently abnormal. The opening pressure may be increased. Pleocytosis, generally less than 500 cells/mL, occurs in up to 90% of anicteric infections during the second week of illness. Although neutrophils may be prominent initially, later cell counts are predominantly mononuclear. Cerebrospinal fluid protein can be normal or increased up to 300 mg% or more (47). Cerebrospinal fluid glucose is usually normal but may be somewhat decreased in up to a third of patients (20). Although not a widely available procedure, in at least 1 instance diagnosis was made by unbiased next generation sequencing of a CSF sample (64).
Leptospires are sensitive in vitro to most antibiotics, and treatment should be started as early as possible. For severe cases of leptospirosis, intravenous penicillin (6 mU/day), amoxicillin, or erythromycin is suggested. Milder cases can be treated with oral tetracycline, doxycycline, ampicillin, or amoxicillin. When given in the first 3 days of illness, doxycycline (at least 200 mg/day) has been effective in reducing clinical abnormalities, in reducing the duration of illness, and in preventing leptospiruria. Treatment is generally given for 5 to 7 days. Ampicillin and amoxicillin are also reasonable alternatives in specific cases. In experimental infections, effective antibiotics include penicillins, tetracyclines, cephalosporins, and erythromycin, but not chloramphenicol.
A Jarisch-Herxheimer reaction may occur with antibiotic therapy (25). This reaction follows soon after initiation of treatment and involves fever with temporary disease exacerbation. There is initial vasoconstriction with increased blood pressure, followed by a fall in blood pressure and in peripheral resistance. Treatment is supportive, with full hydration and appropriate nursing care. The reaction is probably mediated by tumor necrosis factor. Possible future therapies include antibodies to tumor necrosis factor, pentoxifylline (which inhibits production of tumor necrosis factor), or polymyxin B (an antiendotoxin). Meningitis also has been reported as a possible feature of the Jarisch-Herxheimer reaction in leptospirosis.
The role of corticosteroids in treatment of neuroleptospirosis remains controversial. Anecdotal reports suggest potential benefit as they may decrease the severity and duration of illness (01; 43; 41). Plasma exchange has reportedly been effective as well (58).
Ocular involvement in leptospirosis requires a somewhat different approach. Uveitis is treated with topical corticosteroids and mydriatics, with systemic corticosteroids reserved for late severe cases.
Supportive treatment, including antipyretics, analgesics, and adequate hydration, is important. Renal failure, bleeding, and hepatic disease should be aggressively managed. Hemodialysis is required for some patients with Weil syndrome.
Leptospirosis is a significant cause of spontaneous abortion in animals, particularly during the last third of gestation. Human data are limited (40). A review of the literature revealed 16 cases of maternal infection, with 8 spontaneous abortions, 3 healthy babies, and 4 congenitally infected infants, including 1 who died (50). In 1 case, the fetal outcome was not reported. Two of the mothers had a subclinical infection but had infected fetuses. However, no signs of congenital stigmata were noted in any of the cases. The authors concluded that congenital leptospirosis is rare and that the associated spontaneous abortions may be due to maternal disease rather than to direct effects on the fetus. They felt that maternal infection was not an indication for termination of pregnancy. In cases of maternal infection, parenteral penicillin was recommended as the safest therapeutic option.
There are no published data to indicate that leptospirosis, in and of itself, poses any specific risk for anesthesia.
John J Halperin MD
Dr. Halperin of Overlook Medical Center and Sidney Kimmel Medical College of Thomas Jefferson University has stock ownership in Merck, Abbott, Abbvie, and Johnson & Johnson.See Profile
John E Greenlee MD
Dr. Greenlee of the University of Utah School of Medicine received consulting fees from Sommer Schwartz for service as an expert witness.See Profile
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