Histoplasmosis of the nervous system
Histoplasmosis is an infection caused by the fungus Histoplasma capsulatum. Infection is endemic to certain areas of the United States, including the
Jun. 09, 2021
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This article includes discussion of brucellosis of the nervous system, Crimean fever, Malta fever, Mediterranean fever, micrococcus melitensis, remittent fever, and undulant fever. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Brucellosis is a multisystem bacterial illness and is 1 of the most common zoonotic diseases worldwide, endemic in many Mediterranean and Middle Eastern countries. Globally, more than 500,000 new cases occur each year. The disease is transmitted to humans through consumption of infected, unpasteurized animal milk or through direct contact with infected animals. Nonspecific complaints include irregular fevers, malaise, arthralgia, myalgia, weight loss, and night sweats. Infection of the nervous system, known as neurobrucellosis, occurs in 4% of patients. The neuropathology involves direct bacterial invasion, complicated by an inflammatory response. Isolation of Brucella remains the gold standard for diagnosis, but serological tests, including point-of-care assays and polymerase chain reaction, aid in establishing the diagnosis. Forty-five percent of patients will have abnormal neuroimaging findings. Parenteral ceftriaxone in combination with doxycycline and rifampin is now recommended as first-line therapy to achieve eradication and reduce the risk of relapse.
• Brucellosis is an acute, subacute, or chronic zoonotic illness caused by nonmotile, unencapsulated, intracellular, gram-negative coccobacilli that involves the central and peripheral nervous systems in approximately 4% of patients.
• Neurologic disease is caused by infection of the bacterium, as well as the inflammatory response elicited by the infection.
• The diagnosis of neurobrucellosis is made definitively by isolation of the bacteria in the CNS or presumptively in the context of a systemic infection with a neurologic syndrome.
• Forty-five percent of neurobrucellosis patients have abnormal neuroimaging findings, including inflammatory findings in the dura, leptomeninges, cranial nerve and/or spinal nerve roots, white matter involvement, vascular involvement, or hydrocephalus/cerebral edema.
• Treatment of neurobrucellosis using combined antibiotics regimens with a minimum of 1 month of parenteral ceftriaxone is recommended to achieve eradication and reduce the risk of relapse.
Brucellosis has been present for millennia (12). In 1859, JA Marston gave the first clinical account of the disease that he named “Mediterranean fever” (18). At that time, the condition was also known as “undulant,” “remittent,” “Malta,” or “Crimean fever.” Surgeon David Bruce was the first to isolate a “micrococcus” bacterium and identify it as the causative agent of Malta fever (11). This gram-negative coccobacilli was later renamed “Brucella” in his honor (67).
Some medical historians have proposed that the chronic headaches and severe weakness suffered by Florence Nightingale may be attributable to neurobrucellosis contracted while serving during the Crimean War (73).
Brucellosis was 1 of 5 infectious agents (including anthrax, tularemia, Q fever, and Venezuelan equine encephalitis) developed by the United States during the Cold War as a potential biologic weapon (34). The U.S. National Institutes of Health have classified Brucella melitensis as a category B priority pathogen and possible bioterrorist agent due to its potential for infection via aerosol (69).
Brucellosis is an acute (25% to 77%), subacute (12.5% to 59%), or chronic (5% to 27.5%) illness that presents with a spectrum of nonspecific signs and symptoms (43). The disease is severely disabling with fever, sweating, fatigue, weight loss, headache, and joint pain that can persist for weeks to months (19). Fever is commonly reported by patients (78%), but it is detected as a sign in only 19.7% of cases, likely due to the irregular and intermittent pattern of “undulant” fever in brucellosis (42). Debilitating arthralgia (65%), myalgia (47%), and back pain (45%) affect about half of all patients (19). Localized infections develop in 40% of cases. The musculoskeletal system is most commonly involved (30.6%), but the genitourinary, respiratory, cardiovascular, and reproductive systems can also be affected (42). Asymptomatic subclinical infection is also encountered. Due to the protean manifestations of brucellosis, obtaining a detailed history, with focus on epidemiology, is the cornerstone of clinical diagnosis (26).
Nervous system involvement in brucellosis, also known as neurobrucellosis, occurs in 4% of patients (19). Although patients with neurobrucellosis can present with purely neurologic features (62), concurrent systemic symptoms or signs are present in the majority of patients (10). There is often overlapping involvement of both the central and peripheral nervous systems. Neurobrucellosis is a master mimic of other more common neurologic conditions and can manifest with a kaleidoscope of neurologic symptoms including:
Meningitis. Meningitis is the most common manifestation of neurobrucellosis, with an incidence ranging from 40% to 90% (42). Fever, vomiting, and headache are the main symptoms; nuchal rigidity is the chief sign. When these symptoms are accompanied by confusion or an altered level of consciousness, the correct terminology is meningoencephalitis. Onset of symptoms varies from abrupt to indolent. The infection has a predilection for the base of the skull, thereby involving the cranial nerves. Cranial nerves II, III, VI, VII, and VIII are affected alone or in combination in approximately 19% of neurobrucellosis patients (33). Cranial nerve VIII is the most frequently involved, followed by VI and VII (29). Consequently, hearing loss, diplopia, and facial weakness may be part of the clinical presentation.
Encephalitis. Invasion of the brain commonly accompanies meningitis. The signs and symptoms of encephalitis include a depressed level of consciousness, psychiatric symptoms, seizures, hemiparesis, and ataxia (71). Isolated cerebellar ataxia without pleocytosis (03) and lesions clinically and radiologically indistinguishable from a cerebral tumor have been described (47). Mantur and colleagues reported a case of chorea secondary to neurobrucellosis (46).
Demyelination. Multiple sclerosis-like white matter lesions have been detected in the cranial MRI scans of neurobrucellosis patients (02; 15). The development of multiple sclerosis following symptomatic brucellosis has also been reported (49). Because of the similarities in presentation to demyelinating disease, Brucella is included on the long list of infectious agents implicated as possible environmental triggers for multiple sclerosis (51).
Meningovascular complications. Stroke-like symptoms and focal neurologic deficits, such as hemiplegia, dysarthria, tremor, or parkinsonism, have been described in neurobrucellosis patients. Cerebrovascular disease is explained mainly by 2 mechanisms (29). The first mechanism is rupture of a mycotic aneurysm. The other mechanism is inflammatory cerebrovascular disease, particularly arteritis, with resultant lacunar infarcts, small hemorrhages, or venous thrombosis. Transient ischemic attacks and cerebral infarction may also be related to cerebral vasospasm, or cardioembolism (35). Sagittal sinus thrombosis was detected in a patient presenting with aphasia and sensory loss in the upper and lower extremities (15).
Myelopathy. Myelopathy is described in approximately 12% of patients with neurobrucellosis and may be due to intramedullary lesions or extrinsic spinal cord compression from epidural abscess or Brucella spondylitis (37; 52). Although acute and recurring transverse myelitis have been reported (40), myelopathy more often develops chronically, often after systemic symptoms have subsided. Intramedullary lesions may be caused by a granulomatous response to the bacteria, localized vasculitis, or an immune-mediated demyelination (37; 52). There are reports of isolated spinal cord brucellar involvement without other CNS site involvement (30).
Peripheral neuropathy. Polyradiculopathy and peripheral neuropathy frequently coincide with spinal cord disease. There are reports of patients with active neurobrucellosis presenting with the Guillain-Barré syndrome and Miller Fisher syndrome (42). Several studies suggest that brucellosis may be a cause of both clinical and subclinical peripheral neuropathy, which may be reversible with appropriate treatment (09).
Myositis. Acute-onset myositis is an extremely unusual presenting feature of neurobrucellosis. It is hypothesized that deposition of humoral antibodies in the muscle fiber causes the inflammatory reaction leading to the muscle weakness (14). Although fulminant myositis is rare, some degree of muscle weakness is found in 23% of patients (33).
Abscess. Brucella abscesses are reported in virtually every organ system, and the brain is no exception. Abscesses develop in the pituitary gland (32), brain (37), or within (intramedullary) or around (epidural) all levels of the spinal cord (28).
Intracranial hypertension. Brucella meningoencephalitis causes raised intracranial pressure with or without neurologic signs in 23% to 30% of patients (49; 02). Papilledema (55) and divergent paralysis (54) as a result of intracranial hypertension have been reported. Basilar meningitis impedes the flow of spinal fluid producing reversible obstructive hydrocephalus (31). Neurobrucellosis can present as pseudotumor cerebri (15).
Neuropsychiatric. Neurobrucellosis can cause psychiatric symptoms and cognitive and emotional changes in patients (25). Depression has been reported in 5% of patients in a large series of neurobrucellosis patients (Gul et al. 2009). However, depression can also be present in patients with brucellosis without neurologic manifestations. Mild depression may only be detected by meticulous examination and neuropsychological evaluation (63). Agitation (25%), behavioral disorders (25%), and disorientation (21%) are not uncommon in neurobrucellosis (33). In a case report, a vocal tic completely resolved after diagnosis and treatment of neurobrucellosis (07).
Ocular involvement. Binocular vision loss and ophthalmoplegia have been observed rarely in patients with neurobrucellosis. MRI imaging demonstrated optic nerve, meningeal, and brain white matter involvement (45).
Neuroendocrine. The syndromes of inappropriate antidiuretic hormone secretion, diabetes insipidus, and hypothyroidism are recognized as complications of neurobrucellosis (65).
Neuro-oncolgic. Brucella sp DNA was identified in 25% of medulloblastomas, 60% of glioblastomas, and 25% of metastatic carcinomas of 52 tumors examined from the tissue repository of the Armed Forces Institute of Pathology (AFIP) (74). Further investigation is required to determine if there is any true association between Brucella sp DNA and CNS tumor formation.
With the advent of antimicrobial therapy, mortality from neurobrucellosis is rare (0.5%) (29). Endocarditis (a complication in 1% of all brucellosis cases) is the most common cause of death (20). The prognosis for neurobrucellosis once recognized and treated is good. Most patients recover even from protracted courses of disease with few or no residual neurologic deficits. Patients with acute and uncomplicated meningitis consistently make the best recoveries. Significant hearing impairment occurs in approximately 12% of neurobrucellosis cases and is often irreversible. Patients with myelopathy tend to have a severe and long-lasting disability (02), but complete remission is possible with proper diagnosis and treatment (30). Duration of illness in adults is typically longer when compared to children less than 15 years of age, averaging 8 weeks versus 4 weeks (04).
Brucella is a nonmotile, unencapsulated gram-negative coccobacilli belonging to the α2 subdivision of the Proteobacteria. The organisms are facultative intracellular bacteria that reside in host macrophages (56). Brucellosis primarily infects a variety of both wild and domesticated animals, including sheep, goats, cattle, camels, cows, horses, elks, pigs, dogs, rabbits, rats, and other small rodents, but it has also been isolated from a variety of marine mammals (66). Usually, infection in animals is a chronic, asymptomatic process (41).
Taxonomically, Brucella is divided into 6 species with multiple biovars. Four species, melitensis, suis, abortus, and canis, are clinically relevant. B. melitensis is the most pathogenic and accounts for most human infections. B. melitensis is the pathogen usually affecting goats or sheep, whereas B. abortus is responsible for infection of bovine products. B. abortus was so named after discovering that the organism was responsible for abortion in cattle (68). Infection spreads to the mammary glands of infected animals, and the organism is secreted in the milk.
Consequently, disease often spreads to humans who ingest unpasteurized dairy products (64% to 81% of cases). Transmission may also occur secondary to direct contact with infected animals (42% of cases) or during occupational exposure among animal herders, veterinarians, butchers, and abattoir workers (6% of cases) (19; 42). Inhalation of aerosolized infectious particles or inadvertent inoculation into the conjunctiva or open wounds are rarer forms of transmission (48). Brucella melitensis infection has occurred in an obstetrician who was infected during the delivery of an infant suffering from congenital brucellosis (59), and transmission by blood transfusion is possible (01). There are reports of human-to-human infection via sexual contact and vertically from mother to child (16), but the disease does not typically spread from person to person.
Once inside the body, polymorphonuclear leukocytes and macrophages phagocytize the organism. Multiplication within these cells is permitted by interference of the bactericidal myeloperoxidase-dependent mechanism. Inside the phagocytic cell, the organisms are protected from antibiotics and antibodies. They are transported by the lymphatics to regional lymph nodes, and if not contained, enter the bloodstream. Brucella shows tropism for the reticuloendothelial system (liver, spleen, and bone marrow) and also seeds the kidneys, genital system, and mammary glands. The precise mechanisms by which Brucella enters the central nervous system are unknown.
Spontaneous cure and immunity is provided by activated macrophages that kill Brucella. Tissues react to infection by formation of granuloma with epithelioid cells, giant cells, plasma cells, and lymphocytes that histologically resembles sarcoidosis. Caseation is rare but occurs. Calcification and fibrosis result as the granuloma heals.
CNS invasion by bacteria results in inflammation, a key contributor to the pathogenesis of neurobrucellosis (27). There is increasing in vivo and in vitro evidence that Brucella and its lipoproteins infect endothelial and glial cells and activate the innate immunity of the CNS. Secretion of matrix metalloproteases (MMP) and cytokines and upregulation of Toll-like receptor 2 (TLR2) signaling elicits an inflammatory response that has been demonstrated in macaques to increase the number and change the morphology of astrocytes. This tissue remodeling has been linked to neurologic complications, including depressive behavior and memory loss (44). Moreover, infection of astrocytes and microglia induce the secretion of other inflammatory cytokines such as interleukin (IL)-6, IL-1beta, tumor necrosis factor (TNF)-alpha, macrophage chemoattractant protein (MCP)-1, and chemokine keratinocyte chemoattractant (KC) (CXCL1).
Human brucellosis is 1 of the most common zoonotic diseases worldwide with an annual occurrence of over 500,000 new cases (58). It is uncommon in developed nations owing to state-sponsored disease surveillance and eradication programs, of which mandatory pasteurization of milk is the most important. Incidence varies widely between, and within, countries. Although traditionally prevalent in countries of the Middle East, Mediterranean basin, South America, and possibly sub-Saharan Africa, particularly in regions where goats, sheep, or camels are herded, the epidemiology is evolving. The changes are due to various sanitary, socioeconomic, and political reasons together with the evolution of international travel. Several areas traditionally considered to be endemic have achieved control of the disease (eg, France, Israel, and most of Latin America). New foci of the disease have emerged, particularly in central Asia and in countries of the former Soviet Union (60). Syria currently has the highest annual incidence of 1603.4 cases per 100,000 (58). Iraq (52.29 to 268.81 cases per 100,000), Saudi Arabia (6.00 to 149.54 cases per 100,000), Iran (0.73 to 141.60 cases per 100,000), and Jordan (25.70 to 130.00 cases per 100,000) also continue to have a high incidence of disease (20). The disease is still present in both European countries and the United States. In the United States, a limited number of cases are reported per year. Counties within 100 km of the USA-Mexico border have a 8-fold increased average annual disease incidence (0.18 vs. 0.02 cases per 100,000 population) than those in nonborder counties (21).
Increased age and prolonged duration of systemic brucellosis have been shown to be risk factors in the development of neurobrucellosis. Sex, nationality, and regional distribution are not (75).
Twenty to 25% of systemic brucellosis cases occur in children in endemic B. melitensis areas (46). Neurobrucellosis, however, is less common in pediatric populations. It occurs as a complication in about 2% of children with brucellosis (20).
Effective preventive measures include state-sponsored disease surveillance, pasteurization of milk, livestock vaccination, and elimination of infected animals (60). Experimental forms of human vaccines are under development (70).
The clinical presentations of infectious mononucleosis, toxoplasmosis, tuberculosis, hepatitis, typhoid fever, malaria, and systemic lupus erythematosus potentially resemble systemic brucellosis. Complicating the diagnosis further, brucellosis is endemic in many of the same world regions where tuberculosis and malaria remain a major health risk.
When the presentation is acute, Brucella meningitis resembles pyogenic bacterial meningitis. When the presentation is more chronic, neurobrucellosis can mimic tuberculosis and fungal meningitis. Aseptic meningitis, neurosyphilis, Mollaret meningitis, new-onset migraine, transient ischemic attack, vasculitis, and Lyme disease should also be considered in the differential (50). The diagnosis of neurobrucellosis is a strong consideration for anyone who has traveled to or resides in an endemic region and presents with central nervous system infection, neuromuscular disease, fever of unknown origin, or psychiatric symptoms (14). A history of consuming unpasteurized dairy products or occupational contact with sheep, goats, camels, cattle, their carcasses, products of conception, or excreta should be explored.
The development of a definitive diagnostic test for brucellosis remains an elusive target (56). In the literature, the diagnostic criteria of neurobrucellosis are inconsistent and problematic. Some authors favor diagnosis based on clinical neurologic symptoms not explained by any other neurologic disease in an individual at risk for this infection. Others require microbiological and/or biochemical evidence isolated from the cerebrospinal fluid (CSF) (33).
Typically, neurobrucellosis is diagnosed when clinical suspicion is high and any of the following criteria are met: (1) symptoms and signs consistent with neurobrucellosis (meningitis or meningoencephalitis) in the setting of systemic brucellosis; (2) isolation of Brucella species from CSF and/or presence of anti-Brucella antibodies in CSF; (3) presence of typical CSF findings consistent with meningitis (lymphocytosis, increased protein concentration, and decreased glucose concentration); (4) presence of positive culture or serological tests for brucellosis in the blood; or (5) diagnostic findings in cranial MRI or CT (24; 33).
Laboratory tests. In the acute stage, the white blood cell count is usually normal or low with lymphocytic predominance. There may be thrombocytopenia. Anemia and mildly elevated liver enzymes are observed in most brucellosis cases (72). High erythrocyte sedimentation rate (ESR) is a relatively accurate indicator of focal involvement (42). Examination of the spinal fluid shows pleocytosis with lymphocytic predominance, normal or low glucose concentration, and elevated protein concentration (36). Opening pressures on lumbar puncture are elevated in about 50% of cases. Occasionally, IgG oligoclonal bands are detected.
Culture. Isolation of Brucella is the gold standard for diagnosis. Unfortunately, blood cultures are positive in only 16% to 30% of patients with neurobrucellosis; and CSF cultures are positive in only 14% to 24% of cases (29; 33). Isolation of Brucella on blood culture requires 1.8 to 30 days, depending on the culture techniques used (08). Successful spinal fluid or bone marrow culture, however, sometimes occurs with negative blood cultures (05).
There are 2 broad categories of serologic methods for diagnosing brucellosis: those based on antibody production against lipopolysaccharide (agglutination tests) and those based on antibody production against other bacterial antigen (ELISA). However, serological testing in the diagnosis of neurobrucellosis has met with varying success (26).
Agglutination tests. A variety of agglutination tests, such as the Rose Bengal test, the serum agglutination test, and the antiglobulin (Coombs) test, measure antibodies against Brucella lipopolysaccharide antigens. The sensitivity and specificity of these tests depend on the cut-off value used and on the background level of reactive antibodies in the population. Serum titers above 1:160 are considered diagnostic in conjunction with a compatible clinical presentation. However, in areas of endemic disease, a titer of 1:320 may be more specific. CSF Coombs test agglutination with a cut-off titer ≥1:8 was found to have a high sensitivity and specificity (0.94 and 0.96 respectively) (33). The immunocapture agglutination anti-Brucella test (BrucellaCapt) has been reported to detect agglutinating and nonagglutinating antibodies with very high sensitivity (13).
Enzyme-linked immunosorbent assay (ELISA). Anti-Brucella antibodies are detected in spinal fluid by ELISA. In patients with neurobrucellosis, ELISA offers significant diagnostic advantages over conventional agglutination methods as it yields higher sensitivity and specificity (06).
Rapid point-of-care assays. Rapid tests, such as the fluorescent polarization immunoassay (FPA) for brucellosis and the immunochromatographic Brucella IgM/IgG lateral flow assay (LFA), have great potential as point-of-care tests as they obviate the need for a well-equipped laboratory. However, studies are needed to confirm the usefulness of these tests in different clinical settings in endemic areas (26).
Polymerase chain reaction (PCR). PCR is a useful tool for the diagnosis of human brucellosis as it has superior sensitivity and specificity over other diagnostic tests (56; 26). Real-time PCR offers the possibility of results in 30 minutes and was shown to be more sensitive and specific than conventional microbiological techniques and seroagglutination tests when the assay was performed using CSF samples (17).
Imaging. Magnetic resonance imaging (MRI) with contrast is the imaging modality best equipped to demonstrate cranial nerve involvement and parenchymal lesions in neurobrucellosis. Imaging abnormalities in the disease are variable and commonly mimic other infectious and inflammatory conditions (39). The Istanbul-3 study reviewed CT and MRI brain imaging of 263 adult patients with CNS brucellosis. The majority of patients (54.3%) had normal neuroimaging. Forty-five percent had abnormal neuroimaging findings. Abnormal imaging findings were grouped into 4 categories: (1) inflammatory findings (dural, leptomeningeal, cranial nerve, spinal nerve root, brain abscess, granulomas, arachnoiditis); (2) white matter involvement (with or without demyelinating lesions); (3) vascular involvement (chronic ischemic changes, lacunes, small hemorrhages); and (4) hydrocephalus/cerebral edema. Duration of symptoms, presence of polyneuropathy and radiculopathy, high CSF protein concentration, and low CSF/serum glucose ratio were associated with higher incidence of inflammatory findings on imaging analysis (23).
Antibiotic treatment is given to shorten the duration of symptoms and prevent relapse and complications. Streptomycin, trimethoprim-sulfamethoxazole, tetracyclines, rifampin, and fluoroquinolones are effective against systemic Brucella. Monotherapies are characterized by high relapse rates; hence, multiple drug regimens are presently used. Although specific regimens are inconsistent among reference sources, a systematic review recommended doxycycline for 6 weeks, rifampicin for 6 weeks, and gentamicin for 2 weeks; doxycycline for 6 weeks and gentamicin for 2 weeks; or doxycycline for 6 weeks and streptomycin for 2 weeks as a first-line therapy (64). The relapse rate for systemic brucellosis ranges from 2% to 10% following 2-drug therapy (42). Relapse typically occurs within the first 6 months following completion of treatment, but can occur as late as 12 months (30).
A multicenter study examined whether neurobrucellosis can be treated solely with oral antibiotics or whether extended-spectrum cephalosporins, namely, ceftriaxone, should be added to the protocol (24). This study was the first to describe treatment of neurobrucellosis specifically, and it aimed to compare the efficacy and tolerability of ceftriaxone-based antibiotic regimens versus oral treatment. It demonstrated significant difference in effectiveness of ceftriaxone-based regimens when composite negative outcomes of relapse plus therapeutic failure were considered. The study also concluded that ceftriaxone-based regimens required significantly shorter treatment time than oral therapies. Present recommendations are 1 month of parenteral ceftriaxone in combination with doxycycline (4 mg/kg/d) and rifampin (10 mg/kg/d) for the treatment of neurobrucellosis.
In clinical practice, corticosteroids are sometimes used to treat increased intracranial pressure, cranial nerve palsy, and papilledema associated with neurobrucellosis. However, their use has not been evaluated in controlled clinical trials, and their effectiveness in neurobrucellosis treatment is unclear (57).
Brain abscesses due to Brucella are usually surgically drained. The antibiotic regimens used to treat Brucella brain abscesses are similar to those used in Brucella meningitis and range in duration from 3 weeks to 7 months (61). Full recovery was reported in 9 patients with spinal cord epidural abscesses that were treated with antibiotics for 6 to 12 weeks (28). Surgical drainage of spinal cord epidural abscess was required in only 1 patient.
In a patient with recurrent myelitis due to a post-infectious rather than an infectious etiology, immune modulation with intravenous cyclophosphamide and plasma exchange was beneficial (40).
Abortion rates in pregnant female patients with brucellosis are reported to be as high as 46% (38). Perinatal maternal-to-child transmission and congenital brucellosis are reported (22; 59). Pregnant women with brucellosis can be successfully treated with no effect on the fetus (53).
There are no specific contradictions. If increased intracranial pressure is present, agents that elevate intracranial pressure, such as halothane, methoxyflurane, or ketamine are generally avoided.
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