Epstein-Barr virus infections of the nervous system
Nov. 11, 2023
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Brucellosis is a multisystem bacterial illness. It is one of the most common zoonotic diseases worldwide and is endemic in many Mediterranean and Middle Eastern countries. Globally, more than 500,000 new cases occur each year, with an estimated 2.4 billion people at risk (56). The disease is transmitted to humans through consumption of infected, unpasteurized animal milk; through direct contact with infected animals; or via inhalation of infected aerosol particles. Laboratory workers who handle patient specimens or prepare Brucellosis vaccines for animal use are also at risk of infection (109). 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 (71). The neuropathology involves direct bacterial invasion, complicated by an inflammatory response. Isolation of Brucella in blood or CSF or positive bone marrow culture remain the gold standards for diagnosis (96), 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 (91).
• 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 with the bacterium, as well as the inflammatory response elicited by the infection.
• The diagnosis of neurobrucellosis is made definitively by isolation of the bacteria from brain or cerebrospinal fluid or presumptively in the context of a systemic infection with a neurologic syndrome.
• Forty-five percent of neurobrucellosis patients have abnormal neuroimaging findings, including inflammation of the dura, leptomeninges, cranial nerve and/or spinal nerve roots; white matter abnormalities; and vascular involvement through vasculitis, hydrocephalus, and cerebral edema (33; 89).
• 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 recognized for millennia (18). In 1859, JA Marston gave the first clinical account of the disease that he named “Mediterranean fever” (27). 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 (17). This gram-negative coccobacillus was later renamed “Brucella” in his honor (108).
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 (119).
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 (50). 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 aerosols (114).
Brucellosis may be 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 (67). The disease is severely disabling with fever, sweating, fatigue, weight loss, headache, and joint pain that can persist for weeks to months (30). Fever is commonly reported by patients (78%), but it is detected as a sign in only 19.7% of cases, likely due to its irregular and intermittent or “undulant” pattern (66). Debilitating arthralgia (65%), myalgia (47%), and back pain (45%) affect about half of all patients (30). 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 (66). Asymptomatic subclinical infection is also encountered. Due to the protean manifestations of brucellosis, obtaining a detailed history, with a focus on epidemiology, is the cornerstone of clinical diagnosis (40).
Nervous system involvement in brucellosis, also known as neurobrucellosis, occurs in 4% of patients (30). Although patients with neurobrucellosis can present with purely neurologic features (101), concurrent systemic symptoms or signs are present in most patients (16). 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 present with several different syndromes, which are summarized below.
Meningitis. Meningitis is the most common manifestation of neurobrucellosis, with an incidence ranging from 40% to 90% (66). 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 (48; 76; 52).
Cranial nerve VIII is the most frequently involved, followed by VI and VII (44). 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 (117). Isolated cerebellar ataxia without pleocytosis (05) and lesions clinically and radiologically indistinguishable from a cerebral tumor have been described (77). Mantur and colleagues reported a case of chorea secondary to neurobrucellosis (72), and Qasim and colleagues reported a case of ataxia in a child (94).
Demyelination. Multiple sclerosis-like white matter lesions have been detected on MRI scans of neurobrucellosis patients (04; 23). These lesions are steroid responsive (09).
The development of multiple sclerosis following symptomatic brucellosis has also been reported (79; 82). 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 (82).
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 (44). The first is rupture of a mycotic aneurysm (105). 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 (57). Sagittal sinus thrombosis has been described (23; 25).
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 (60; 83; 73; 78; 111). Although acute and recurring transverse myelitis has been reported (64; 116), 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 immune-mediated demyelination (60; 83). There are reports of isolated spinal cord brucellar involvement without other CNS site involvement (45; 78; 113; 116; 99).
Peripheral neuropathy. Polyradiculopathy and peripheral neuropathy frequently coincide with spinal cord disease (73; 01). Several studies suggest that brucellosis may be a cause of both clinical and subclinical peripheral neuropathy, which may be reversible with appropriate treatment (15; 54; 70).
There are reports of patients with active neurobrucellosis presenting with Guillain-Barré syndrome and Miller Fisher syndrome (66; 07).
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 muscle weakness (21). Although fulminant myositis is rare, some degree of muscle weakness is found in 23% of patients (48).
Abscess. Brucella abscesses are reported in virtually every organ system, and the brain is no exception. Abscesses may develop in the pituitary gland (47; 84), brain (60), or within (intramedullary) or around (epidural) all levels of the spinal cord (42; 110; 111; 75; 26).
Intracranial hypertension. Brucella meningoencephalitis causes raised intracranial pressure with or without neurologic signs in 23% to 30% of patients (79; 04). Papilledema (88) and divergent paralysis (87) as a result of intracranial hypertension have been reported. Basilar meningitis impedes the flow of spinal fluid producing reversible obstructive hydrocephalus (46). Neurobrucellosis can present as pseudotumor cerebri (23). The CSF may or may not have pleocytosis (88; 55).
Neuropsychiatric. Neurobrucellosis can cause psychiatric symptoms and cognitive and emotional changes (37). Depression has been reported in 5% of patients in a large series of neurobrucellosis patients (44). 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 (103). Agitation (25%), behavioral disorders (25%), and disorientation (21%) are not uncommon in neurobrucellosis (48). In a case report, a vocal tic completely resolved after diagnosis and treatment of neurobrucellosis (13). Neurobrucellosis should be considered in the differential diagnosis of any patient presenting with acute psychosis, particularly in endemic regions (11; 102).
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 (69).
Neuroendocrine. The syndromes of inappropriate antidiuretic hormone secretion, diabetes insipidus, and hypothyroidism are recognized as complications of neurobrucellosis (106; 61).
With the advent of antimicrobial therapy, mortality from neurobrucellosis is rare (0.5%) (44). Endocarditis (a complication in 1% of all brucellosis cases) is the most common cause of death (31). 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 (04), but complete remission is possible with proper diagnosis and treatment (45). Duration of illness in adults is typically longer when compared to children less than 15 years of age, averaging 8 weeks versus 4 weeks (06; 51).
Brucellae are small (0.5 to 0.7 by 0.6 to 1.5 μm), nonmotile, non-spore-forming, slow-growing Gram-negative coccobacilli belonging to the Brucellaceae family in the alpha-2 subclass of the Proteobacteria, together with the Mycoplana, Pseudochrobactrum, Paenochrobactrum, Daeguia, Crabtreella, and Ochrobactrum genera (115). The organisms are facultative intracellular bacteria that reside in host macrophages (89). 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 (107; 104; 29; 98).
Usually, infection in animals is a chronic, asymptomatic process (65).
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 bovine infection. B abortus was so named after discovering that the organism was responsible for abortion in cattle (112). Infection spreads to the mammary glands of infected animals, and the organism is secreted in milk.
Consequently, disease often spreads to humans who ingest unpasteurized dairy products (64% to 81% of cases) (38). 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) (30; 66). Inhalation of aerosolized infectious particles or inadvertent inoculation into the conjunctiva or open wounds are rarer forms of transmission (92). Brucella melitensis infection has occurred in an obstetrician who was infected during the delivery of an infant suffering from congenital brucellosis (93), and transmission by blood transfusion is possible (02). There are reports of human-to-human infection via sexual contact and vertically from mother to child (24), but the disease does not typically spread from person to person.
Once inside the body, polymorphonuclear leukocytes and macrophages phagocytize it. Multiplication within these cells is permitted by interference with 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 are 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 (41). There is increasing in vivo and in vitro evidence that Brucella and its lipoproteins infect endothelial and glial cells and activate the innate CNS immune response (95).
Owing to involvement of host genetic factors in susceptibility to brucellosis infection and its outcome, Zafari and colleagues aimed to carry out a comprehensive systematic review and meta-analysis to derive a precise evaluation of the association between the risk of brucellosis and its focal complication and all cytokines examined in case-control studies, including interferon gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), tumor necrosis factor-beta (TNF-β), transforming growth factor-beta (TGF-β), IL-2, IL-4, IL-6, IL-10, IL-12B, IL-15, and IL-18 polymorphisms (120). Of the 158 initial results, 25 eligible studies were included in the meta-analysis. Overall, the pooled results showed that the statistical gene-dominant models (53; 122) of IFN-γ UTR5644, TGF-β rs1800470 and rs1800471, TNF-α rs1800629, and IL-10 rs1800872 were significantly less frequent in patients with brucellosis than in the controls. Also, the pooled analysis of the mutant allele versus the wild type allele of TGF-β rs1800471 and IL-10 rs1800872 showed a negative association with brucellosis risk, ie, a decreased risk of brucellosis. On the other hand, the pooled analysis demonstrated that individuals with a mutant allele of IL-4 rs2243250 and IL-18 rs1946519 had increased susceptibility to brucellosis, and those with a mutant allele in IFN-γ UTR5644 or TGF-β rs1800470 were less likely to have focal forms of the disease. IL-4 rs2243250 and IL-18 rs1946519 have a positive correlation with brucellosis, whereas IFN-γ UTR5644, TGF-β rs1800470 and rs1800471, TNF-α rs1800629, and IL-10 rs1800872 show a negative association with this disease. The association between the other single-nucleotide polymorphisms and brucellosis risk was not confirmed in the current meta-analysis.
Human brucellosis is one of the most common zoonotic diseases worldwide, with an annual occurrence of over 500,000 new cases (90). It is uncommon in nations with 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 (97). Syria had the highest annual incidence of 1603.4 cases per 100,000 (90). 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 (31). The disease is still present in both European countries. 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 (32).
Epidemiological studies from Saudi Arabia, China, and Tunisia refer to the Brucella epidemiology in these localized areas (85; 03; 07). In the systemic review from Saudi Arabia, 17 studies were included. Three studies reported on the prevalence of brucellosis among pregnant women and pregnancy outcomes, 3 on the prevalence among children, 2 on the prevalence among personnel exposed to Brucella, and 9 addressed risk factors associated with brucellosis. The impact of brucellosis on the health of populations in developing countries and adverse reproductive outcomes was studied in this review. In the comprehensive study from Tunisia spanning 17 years, 13 hospitalized patients were treated and followed up. It was noted that brucellosis was severe when the nervous system was affected and that brucellosis should be considered as a differential of any neurologic illness in the endemic areas or in people who have traveled to or originate from those areas.
Increased age and prolonged duration of systemic brucellosis are risk factors for the development of neurobrucellosis. Sex, nationality, and regional distribution are not (122).
Twenty to 25% of systemic brucellosis cases occur in children in endemic B melitensis areas (72). Neurobrucellosis, however, is less common in pediatric populations. It occurs as a complication in about 2% of children with brucellosis (31; 10).
Effective preventive measures include disease surveillance, pasteurization of milk, livestock vaccination, and elimination of infected animals (97; 19).
The most effective measure is to control brucellosis in animal populations, thereby reducing zoonotic transmission and number of carrier hosts. Human anti-Brucella vaccines should have the property of cross-protecting across different Brucella species. A vaccine that evokes a strong cell-mediated immunity confers a better level of protection by targeting the host cell-mediated immunity via induction of IL-12 and IFN-γ. The ideal human vaccine against Brucella has yet to be developed (68).
The clinical presentations of infectious mononucleosis, toxoplasmosis, tuberculosis, visceral leishmaniasis, endocarditis, HIV, enteric fever/salmonellosis, occult malignancies, arthritis (reactive, septic, and spondyloarthritic), hepatitis, malaria, systemic lupus erythematosus, sarcoidosis, and systemic fungal infections 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 (49). Aseptic meningitis, neurosyphilis, Mollaret meningitis, new-onset migraine, transient ischemic attack, vasculitis, and Lyme disease should also be considered in the differential (80; 08).
The diagnosis of neurobrucellosis is a strong consideration for anyone who has traveled to or resides in an endemic region. Brucellosis is worldwide in animals. Brucellosis in humans is most common in developing countries, South America, central Asia, the Mediterranean, and the Middle East and presents with central nervous system infection, neuromuscular disease, fever of unknown origin, or psychiatric symptoms (21). A history of consuming unpasteurized dairy products or occupational contact with sheep, goats, camels, cattle, their carcasses, or products of conception should be explored.
The clinical presentation of brucellosis in humans is variable and nonspecific; thus, laboratory corroboration of the diagnosis is essential for the proper treatment of the patient. The diagnosis of brucellar infections can be made by culture, serological tests, and nucleic acid amplification assays. Modern automated blood culture systems enable detection of acute cases of brucellosis within the routine 5- to 7-day incubation protocol employed in clinical microbiology laboratories, although a longer incubation and performance of blind subcultures may be needed for protracted cases. Although serological tests lack specificity and provide results that may be difficult to interpret in individuals repeatedly exposed to Brucella organisms, they remain a diagnostic cornerstone in resource-poor countries. Nucleic acid amplification assays combine exquisite sensitivity, specificity, and safety and enable rapid diagnosis of the disease. However, long-term persistence of positive molecular test results in patients that have apparently fully recovered is common and has unclear clinical significance and therapeutic implications. Therefore, as long as there are no sufficiently validated commercial tests or studies that demonstrate an adequate interlaboratory reproducibility of the different homemade polymerase chain reaction assays, cultures and serological methods will remain the primary tools for the diagnosis and post-therapeutic follow-up of human brucellosis.
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 or presence of anti-Brucella antibodies in CSF (48; 96); (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 (36; 35; 48; 115; 22; 28).
Laboratory tests. In the acute stage, the peripheral 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 (118). High erythrocyte sedimentation rate (ESR) is a relatively accurate indicator of focal involvement (when specific organ involvement was predominant in any patient, the situation is defined as “focal” or “localized”) (66; 59). Examination of the spinal fluid shows pleocytosis with lymphocytic predominance, low glucose concentration, and elevated protein concentration (58). Opening pressures on lumbar puncture are elevated in about 50% of cases. Occasionally, CSF IgG oligoclonal bands are detected (115).
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 (44; 48). Isolation of Brucella from blood culture requires 1.8 to 30 days, depending on the culture techniques used (14). Bone marrow culture is more sensitive than blood culture and is considered the gold standard for the diagnosis of brucellosis. In a study of 50 patients diagnosed with brucellosis, bone marrow culture was positive in 92% of cases (43). Bone marrow culture has a shorter time to detection than blood culture, and its sensitivity is not diminished by prior antibiotic use.
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 antigens (ELISA). However, serological testing in the diagnosis of neurobrucellosis has met with varying success (40).
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) (48). The immunocapture agglutination anti-Brucella test (BrucellaCapt) is reported to detect agglutinating and nonagglutinating antibodies with very high sensitivity (20).
Enzyme-linked immunosorbent assay (ELISA). Anti-Brucella antibodies can be 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 (12).
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) are in use.
In a study on sera from blood donors and in patients suffering from acute infections or relapses caused by the Brucella species, the FPA technology showed a specificity of 97.9% and an overall sensitivity of 96.1%, respectively. The ease of the procedure allows the FPA technology to be adopted for use in clinical laboratories, blood banks, and, given portable equipment, also in the field (115).
In the published experience of Smits and colleagues, the sensitivity of the lateral flow assay was similar to that of the standard agglutination test at a cutoff value of 1:160 (> 95%) and was superior to that of the comparator when a standard agglutination test titer of 1:320 was employed, with a specificity of 98% for samples obtained from asymptomatic controls (115).
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 neurobrucellosis are variable and commonly mimic other infectious and inflammatory conditions (63). The Istanbul-3 study reviewed CT and MRI brain imaging of 263 adult patients with CNS brucellosis. Most 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 or 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 (35).
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 (36). 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 a significantly better 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 2 g intravenously every 12 hours for 6 weeks or varied duration dependent on clinical decisions in combination with doxycycline (4 mg/kg/d) and rifampin (10 mg/kg/d) for the treatment of neurobrucellosis (39).
A relapse of symptoms should prompt an assessment for focal disease in the form of specific organ involvement and usually manifests as focal bony disease and spondylolisthesis. Relapse due to antibiotic resistance is rare; nonetheless, antimicrobial susceptibility should be performed on all culture isolates. Most relapses can be successfully treated with a repeat course of a standard regimen. Patients with a second or third relapse should be treated with an alternative regimen.
Alternative agents include fluoroquinolones and trimethoprim-sulfamethoxazole (TMP-SMX), used in combination regimens.
• Fluoroquinolones may be used as alternative second or third agents in combination regimens containing doxycycline or rifampin. They are not appropriate first-line agents (given decreased activity in acidic environments as well as cost) but may be beneficial in the setting of drug resistance, antimicrobial toxicity, and some cases of relapse. Options include ciprofloxacin (500 mg orally twice daily for 6 weeks) or ofloxacin (200 to 400 mg orally twice daily for 6 weeks).
• TMP-SMX may be used as an alternative second or third agent in combination regimens containing doxycycline or rifampin for the treatment of patients with relapse or refractory disease. Dosing consists of 1 double-strength tablet (160 mg TMP and 800 mg SMX) orally twice daily for 6 weeks. TMP-SMX should be used with caution for prolonged treatment of brucellosis given its potential for the development of antimicrobial resistance.
The routine use of corticosteroids has no role in the treatment of neurobrucellosis. The use of steroids may be appropriate in the setting of neurobrucellosis complicated by iritis, papilledema, myelopathy, polyneuropathy, or cranial nerve palsies (74).
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 (100). A multicenter retrospective study in 2011 showed that the most adequate daily treatment protocol for Brucella brain abscess is ceftriaxone (2 doses of 2 g), rifampin (600–900 mg), and doxycycline (2 doses of 100 mg) (63). The treatment period was significantly shorter (median = 5 months) than an oral treatment protocol (median = 6 months). Kizilkilic and Calli used antibiotic treatment alone to cure a case of brucellosis in the cerebellum, suggesting that a single intracerebral abscess caused by Brucella can be cured by antibiotics alone (63). In the presence of raised intracerebral pressure from multiple cerebellar abscesses, urgent measures to address the same becomes a priority, in addition to the antibiotic therapy.
The optimal treatment for Brucella subdural empyema is controversial. Failure of medical therapy alone has been documented (121). Munusamy and Dinesh suggested that if the subdural pus is relatively thin and a capsule has not formed, then drilling to drain the subdural empyema is feasible (81).
Full recovery was reported in 9 patients with spinal cord epidural abscesses that were treated with antibiotics for 6 to 12 weeks (42). Surgical drainage of spinal cord epidural abscess was required in only 1 patient.
Abortion rates in pregnant women with brucellosis can be as high as 46% (62). Perinatal maternal-to-child transmission and congenital brucellosis are reported (34; 93). Pregnant women with brucellosis can be successfully treated with no effect on the fetus (86).
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.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Partha Ray MD
Dr. Ray of IMA India and NHS England and Liverpool University has no relevant financial relationships to disclose.See Profile
Christina M Marra MD
Dr. Marra of the University of Washington School of Medicine has no relevant financial relationships to disclose.See Profile
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