Brucellosis of the nervous system …

Infectious Disorders

Updated 07.12.2025
Released 04.10.1998
Expires For CME 07.12.2028

Brucellosis of the nervous system

Authors: Asad Haydar MD, Ali Slim, Rita Abdo MD, Vanessa Nasrallah BSc, Rosette Jabbour MD FAAN

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Editor: Christina M Marra MD

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Brucellosis of the nervous system

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Introduction

Overview

Brucellosis is a globally distributed zoonotic disease caused by the Brucella species, a gram-negative, aerobic, nonmotile, and facultative intracellular coccobacillus (08). Of the six recognized species, five are pathogenic to humans: B melitensis, B abortus, B suis, B canis, and B marina (55). Human infection typically occurs through ingestion of unpasteurized dairy products or direct contact with infected cattle. The clinical course is often nonspecific, with an acute phase marked by intermittent fever, night sweats, arthralgia, fatigue, and malaise, commonly termed “undulant fever” (34).

Notably, neurobrucellosis, central and/or peripheral nervous system involvement by Brucella spp, represents one of the most severe and diagnostically challenging forms. Though occurring in only approximately 5% to 10% of infected individuals, neurobrucellosis causes significant morbidity and potentially irreversible neurologic sequelae if untreated (47). Its clinical spectrum varies, including meningoencephalitis, cranial neuropathies, intracranial hypertension, myelitis, and psychiatric manifestations (56).

Given the high variability in its presentation, the diagnosis of neurobrucellosis requires a high index of suspicion, especially in endemic regions. Confirmatory workup includes laboratory and radiological testing. Management requires prolonged antimicrobial therapy with close monitoring of CSF parameters.

This article provides an updated understanding of neurobrucellosis, emphasizing clinical recognition, diagnostic strategies, and therapeutic approaches.

Key points

	• Metagenomic next-generation sequencing (mNGS) enhances early diagnosis. The swift diagnosis through CSF mNGS underscores its value in early detection, especially when traditional cultures are negative (40).
	• In February 2025, the Tuberculous Meningitis Subcommittee of the Tuberculosis Branch of the Chinese Medical Association released updated guidelines for neurobrucellosis diagnosis and treatment.
	• The role of corticosteroids is still debatable; a new systematic review reignites the discussion.
	• A systematic review on the treatment of neurobrucellosis showed a worse prognosis with the use of corticosteroids; however, the study had limitations, and conclusive evidence could not be drawn (26).

Historical note and terminology

“Bruce”-llosis is an ancient zoonotic disease once commonly referred to as “Malta fever” or “Mediterranean fever,” reflecting its discovery in Malta/the Mediterranean, or “undulant fever,” due to its characteristic relapsing fever pattern (08). The etiologic agent was first isolated in 1887 by Sir David Bruce from the spleen of a British soldier in Malta (Bruce 1889; 47). Sir Bruce identified a coccobacillary organism (later named Brucella melitensis in his honor) as the cause (47).

By modifying previous culturing techniques, Dr. Themistocles Zammit discovered that infected goats were the source of Brucella melitensis transmission to humans. His work led to the development of what is now known as the Zammit Test (61). Subsequent investigators, including Bernhard Bang and Alice Evans, recognized related bacteria causing abortions in cattle (B abortus) and pigs (B suis), unifying them under the genus Brucella in the early 20th century. The term “brucellosis” was introduced to denote infection by the Brucella species, honoring Bruce’s contributions (55).

In 1896, Surgeon Captain M Louis Hughes recognized the involvement of the central and/or peripheral nervous system by Brucella infection (35). Dr. Hughes, who had assisted Bruce in Malta, noted that patients with “undulant fever” had neuropsychiatric symptoms, coining the term “neurobrucellosis” for this complication (34).

Despite the wealth of studies reported since 1993, neurobrucellosis remains a diagnostic challenge, and it is often misidentified as other neurologic diseases (32; 56; 62).

Clinical manifestations

Presentation and course

Most studies that describe the signs and symptoms of neurobrucellosis are case reports or case series. There is only one systematic review of the manifestations of neurobrucellosis (57). This lack of prospective data contributes to the absence of clinical diagnostic criteria for the disease.

With these limitations in mind, commonly reported manifestations of neurobrucellosis in adults include fever (57%–74%) (32; 59), headaches (57%–77.4%) (32), nausea or vomiting (25.3%–83%) (20; 57), and muscle weakness (25.8%–52.8%) (33; 64). The prevalence of these symptoms may differ in the pediatric population, with an increased likelihood of reported fever, vomiting, and convulsions compared to adult patients (57).

Mandell and colleagues classified neurobrucellosis into three major categories: (1) acute meningitis or meningoencephalitis, (2) chronic peripheral disease (radiculopathy), and (3) chronic CNS disease (43). Others have categorized presentations in terms of clinical syndromes (04; 64), disease course (37), or neuroanatomical involvement (32; 55; 16). An overlap within and between categories may be present.

Clinical syndromes

Meningitis. Meningitis is the most frequently reported clinical presentation of neurobrucellosis, particularly in endemic regions. It is often the initial or sole manifestation of CNS involvement (16).

The classic triad of fever, headache, and lymphocytic pleocytosis is commonly associated with neurobrucellar meningitis. However, not all patients exhibit all three components, and atypical presentations may lead to diagnostic delays (48).

In some cases, meningeal inflammation extends to involve the brain parenchyma, resulting in meningoencephalitis, which may manifest as confusion, seizures, or behavioral disturbances (01).

Cranial neuritis. Cranial nerve VIII involvement (sensorineural hearing loss) is most common (64). Cranial nerves VI and VII are also often affected.

Neuropsychiatric syndromes. The most common neuropsychiatric syndromes are depression, personality changes, euphoria, and psychosis (24; 57). Behavioral changes are reported in 15% to 60% of individuals with neurobrucellosis (33; 24).

Cerebrovascular syndromes. These include lacunar infarcts, venous thrombosis, and hemorrhagic strokes secondary to Brucella-induced vasculitis and may overlap with atherosclerotic findings, thus, posing a diagnostic challenge (59).

Spinal and vertebral involvement. Brucellar spondylodiscitis and vertebral osteomyelitis are well-recognized complications of systemic brucellosis, occurring in up to 53% of cases in some endemic series. The lumbar spine is most frequently affected, followed by the thoracic and cervical regions. The disease typically begins as spondylodiscitis with infection of the intervertebral disc and adjacent vertebral bodies, eventually progressing to vertebral osteomyelitis. Hematogenous dissemination of Brucella to the spine reflects the organism’s tropism for the reticuloendothelial and osteoarticular systems (55).

Direct or inflammatory extension from infected vertebrae may lead to arachnoiditis, transverse myelitis, or radiculopathy, particularly in the lumbosacral region. These manifestations may occur due to compression, vascular compromise, or inflammatory infiltration of spinal nerves or cord tissue (63). Enhancement of spinal nerve roots and patchy T2 hyperintensities on MRI are key radiological indicators.

In advanced cases, brucellar osteomyelitis may be complicated by epidural or paravertebral abscesses, which can exert mass effect on the spinal cord or cauda equina, leading to neurologic deficits or compressive myelopathy. Early diagnosis through imaging and targeted antimicrobial therapy is essential to prevent irreversible damage (59).

Disease course

An acute disease course, typically acute meningitis, is rare (37).

Subacute or chronic polyradiculopathy or chronic meningitis is the most common disease course, typically with symptoms for at least 3 months since the onset of infection.

A relapsing course typically occurs due to inadequate antibiotic penetration into the CNS or premature cessation of therapy (42). It can mimic the initial presentation or present with new neurologic symptoms.

Neuroanatomical involvement

Central involvement most commonly includes meningitis, meningoencephalitis, and myelitis and can be acute or chronic. The main mechanism is granulomatous inflammation (54).

Peripheral involvement includes radiculopathy, cranial neuritis, or sensory polyneuropathy. It results from less intense inflammation compared to CNS inflammation but is usually more resistant to treatment (54).

Diffuse involvement includes both central and peripheral nervous system manifestations.

Biological basis

Etiology and pathogenesis

Neurobrucellosis is a severe neurologic complication of brucellosis, a zoonotic disease caused by the genus Brucella, a small, Gram-negative, nonmotile, facultative intracellular coccobacillus (44).

Of the more than 12 known species, five classically affect humans:

(1) Brucella melitensis is the most virulent and neurotropic species, found in sheep and goats.

(2) Brucella abortus is found in cattle and typically causes milder systemic disease.

(3) Brucella suis is found in pigs and wild boars and is known for suppurative complications.

(4) Brucella canis is found in canines; human infection is rare and usually mild (El-Sayed and Awad 2018; 36).

(5) Brucella marina is found in marine species, particularly cetaceans and seals (55; 31). B ceti and B pinnipedialis also infect marine mammals and rarely infect humans.

Brucella spp transmission to humans occurs via multiple routes, including cutaneous abrasions, conjunctival or respiratory mucosa, and, most commonly, the gastrointestinal tract following ingestion of unpasteurized dairy products or undercooked meat (19; 30). Following exposure, Brucella gains entry into nonphagocytic epithelial cells through a zipper-like mechanism, wherein bacterial outer membrane proteins interact with host cell surface molecules to induce localized cytoskeletal rearrangement and endocytosis. Host factors implicated in this process include heparan sulfate proteoglycans (HSPGs) and lipid rafts, both of which facilitate bacterial adhesion and membrane engagement (19; 30). Although direct evidence remains limited in Brucella, additional putative adhesion sites, such as gangliosides GM1 and GD1a, have been proposed based on analogous mechanisms in related intracellular pathogens. Internalization is mediated by actin-dependent endocytosis, triggered via activation of Rho-family GTPases (Rho, Rac, and Cdc42), which orchestrate membrane invagination and bacterial engulfment (10).

Once intracellular, Brucella can survive for up to 72 hours within epithelial cells, after which it may be released or transferred to professional phagocytes, particularly macrophages and dendritic cells, which serve as critical reservoirs for persistence and systemic dissemination (58; 10). Uptake by these phagocytes occurs via opsonin-dependent mechanisms involving Fcγ receptors or complement receptor 3 (CR3) in the presence of antibody or complement opsonization, or via opsonin-independent pathways, which include lectin-like receptors and fibronectin-mediated interactions with alpha5beta1 integrins wherein fibronectin bridges host receptors to bacterial surface proteins, such as Omp25 and Omp31 (17; 15).

Within phagocytes, Brucella evades host degradation by residing in a specialized Brucella-containing vacuole that avoids lysosomal fusion and matures into a replicative niche derived from the endoplasmic reticulum (10). The establishment and maintenance of this niche are dependent on the VirB type IV secretion system, which translocates effector proteins into the host cytosol, in turn, modulating intracellular trafficking, suppressing apoptosis, and facilitating chronic intracellular persistence (17).

Dissemination to distant organs occurs as infected phagocytes circulate through the reticuloendothelial system, enabling Brucella to reach immune-privileged sites. Neurobrucellosis develops when these infected phagocytes breach the blood-brain barrier via a Trojan horse mechanism, wherein host immune cells ferry intracellular bacteria across endothelial tight junctions. This phenomenon, well characterized in other neuroinvasive pathogens, is supported by both in vitro and in vivo evidence (27; 51; 62).

On CNS entry, Brucella localizes to the meninges, perivascular spaces, and occasionally the brain parenchyma, where it initiates a neuroinflammatory cascade characterized by activation of microglia and astrocytes, perivascular lymphocytic infiltration, and cytokine-mediated blood-brain barrier disruption (27; 51).

Elevated levels of proinflammatory cytokines, including TNF-alpha, IL-1beta, IL-6, and monocyte chemoattractant protein-1 (MCP-1), have been detected in the CSF of patients with neurobrucellosis, contributing to blood-brain barrier dysfunction, neuronal injury, and immune cell recruitment. Although direct evidence of Brucella is limited, IL-6 trans-signaling, a process by which IL-6 bound to soluble IL-6 receptor (sIL-6R) activates gp130-expressing cells, has been implicated in neuronal damage and glial activation in related CNS infections and is hypothesized to play a role in neurobrucellosis pathogenesis (51; 62).

Histopathological findings demonstrate both infectious and immune-mediated injury, including granulomatous inflammation, particularly in the meninges and perivascular parenchyma, composed of epithelioid macrophages, lymphocytes, and multinucleated giant cells, reflecting a chronic host containment response. Demyelination, reactive gliosis, and white matter lesions resembling multiple sclerosis suggest a superimposed autoimmune component potentially driven by molecular mimicry or cross-reactive anti-ganglioside antibodies (27; 52).

Epidemiology

Brucellosis is a globally distributed zoonosis, with the highest prevalence in regions where livestock farming is common and veterinary control is limited. Endemic areas include the Middle East, Mediterranean Basin, South and Central Asia, sub-Saharan Africa, and Latin America (50; 26). Turkey, Iran, Saudi Arabia, and China each report thousands of human cases annually (62; 64). A 2022 global modeling study estimated 1.6 to 2.1 million human cases annually, 4-fold higher than earlier estimates, based on veterinary, serologic, and limited human health data (39).

In contrast, incidence is low in high-income countries. The United States and Canada report only a few dozen cases per year, mostly linked to travel or consumption of unpasteurized imported cheeses. Most of Western and Northern Europe have eliminated domestic animal brucellosis (03). Occupational exposure places farmers, shepherds, abattoir workers, veterinarians, and laboratory personnel at higher risk (13; 14).

Among the general population, ingestion of unpasteurized milk, cheese, or other dairy products remains the primary transmission route. Brucellosis is, thus, a prototypical “One Health” disease, linking human infection to animal health and agricultural practices (13).

Neurologic involvement occurs in 1.45% to 13% of brucellosis cases, depending on geography, bacterial species, and diagnostic access (21; 62), suggesting a global neurobrucellosis burden approaching 100,000 cases per year. It accounts for approximately 0.5% of all community-acquired CNS infections (21). Regional disparities persist. In Asia, nearly 40% of neurobrucellosis cases originate from northern Chinese provinces, such as Inner Mongolia and Heilongjiang (64).

Prevention

Animal vaccination and control. Livestock vaccination, namely the Rev.1 vaccine against Brucella melitensis for sheep and goats and the RB51 vaccine against B abortus for cattle, combined with test-and-slaughter policies (animals testing serologically positive are culled) and quarantine policies (immediate movement restriction of the entire herd or flock when one or more animals test positive; remains in place for at least two consecutive tests in the remaining herd at 30- and 60-day intervals), have significantly reduced human brucellosis infections in high-income countries (44; 50).

Food safety. Pasteurization of milk and dairy products is essential to prevent brucellosis. Public health campaigns have successfully reduced foodborne transmission by educating rural communities to boil milk and to avoid undercooked meat (18; 29; 50).

Occupational protection. Workers in high-risk settings, including farmers, veterinarians, slaughterhouse employees, and laboratory personnel, require personal protective equipment and hygiene training. In laboratories, Brucella spp must be handled under biosafety level 3 (BSL-3) conditions (49; 18; 12).

Surveillance and public health infrastructure. Integrated human and veterinary surveillance systems facilitate early outbreak detection and targeted control efforts (29; 39).

Post-exposure prophylaxis. Following high-risk exposures, such as aerosol inhalation in a laboratory or mucosal contact during necropsy, post-exposure prophylaxis with a 3-week course of doxycycline 100 mg twice daily plus rifampin 600 mg once daily can prevent systemic infection and neurobrucellosis (49; 12).

Future directions. Currently, no licensed human vaccine against Brucella exists. Ongoing trials are exploring subunit and mRNA platforms across several countries, including Iran, China, and India (18; 50).

Differential diagnosis

Confusing conditions

The differential diagnosis includes infectious, inflammatory, and neoplastic etiologies, especially those causing chronic meningitis, cranial neuropathies, or demyelination.

Tuberculous meningitis. Diagnostic differentiation is essential, particularly in regions where Brucella and Mycobacterium tuberculosis infections coexist, such as in the Middle East, South Central Asia, and sub-Saharan Africa (62; 64). Both tuberculous meningitis and neurobrucellosis cause subacute to chronic meningitis, cranial nerve palsies, basal meningeal enhancement, and CSF profiles with elevated protein and low glucose concentrations and lymphocytic pleocytosis (62; 63). A history of pulmonary disease, a positive tuberculin skin test, interferon-gamma release assay reactivity, and suggestive chest imaging support tuberculosis, including tuberculous meningitis, whereas fever, diaphoresis, arthralgia, and hepatosplenomegaly suggest neurobrucellosis (57; 64).

Other chronic infections. Fungal meningitis, especially cryptococcal meningitis in immunocompromised patients or Coccidioides meningitis in endemic regions, can present with headache, visual changes, and raised intracranial pressure, along with CSF lymphocytosis and low glucose (62).

Neurosyphilis may present with stroke as well as cranial, psychiatric, and cognitive abnormalities and is diagnosed by reactive syphilis serologies, CSF lymphocytic pleocytosis, and reactive CSF-VDRL (57).

Neuroborreliosis, endemic to the northeastern United States and Europe, may cause facial palsy, headache, and radiculopathy, sharing CSF lymphocytosis and cranial neuropathy with neurobrucellosis but lacking systemic signs (63).

Other chronic viral infections, including HTLV-1-associated myelopathy, HIV-related chronic meningitis, and chronic enteroviral infections in immunodeficient hosts may mimic neurobrucellosis to varying degrees (62; 64).

Inflammatory and demyelinating CNS disorders. Multiple sclerosis is a key noninfectious mimic. Neurobrucellosis may cause white matter lesions on MRI similar to those seen in multiple sclerosis and may even respond partially to steroids, potentially misleading clinicians (64).

Neurosarcoidosis can resemble neurobrucellosis with basilar meningitis, cranial nerve involvement, and lymphocytic CSF pleocytosis. Noncaseating granulomas identified on tissue biopsy, such as mediastinal lymph nodes, lungs, skin, meningeal, or brain, and lack of infectious organisms help establish this diagnosis (57).

CNS vasculitis may cause encephalopathy, infarcts, or focal deficits. Compared to neurobrucellosis, CSF findings in CNS vasculitis typically demonstrate milder pleocytosis and lack histopathologic evidence of granulomatous inflammation (64). Although CSF in granulomatous infections such as neurobrucellosis may exhibit chronic lymphocytic pleocytosis, elevated protein concentrations (> 1 g/L), hypoglycorrhachia, and raised opening pressure, these findings are nonspecific. The diagnosis of granulomatous inflammation requires histological confirmation via tissue biopsy as CSF cytology alone is insufficient (05; 64).

Malignancy and paraneoplastic syndromes. Carcinomatous meningitis (leptomeningeal metastases) can closely mimic neurobrucellosis with lymphocytic CSF pleocytosis and cranial neuropathies. Identification of malignant cells in CSF is diagnostic (23; 62).

Paraneoplastic neurologic syndromes and acute disseminated encephalomyelitis (ADEM) may be considered in the differential when demyelination or encephalopathy is prominent.

Other focal CNS infections. Rarely, neurobrucellosis may present with granulomas or micro-abscesses, and radiologic features may overlap with those of other focal infections (63).

Diagnostic workup

Laboratory diagnostics

CSF analysis (47). CSF analysis is a cornerstone of neurobrucellosis diagnosis, though findings are often variable and nonspecific. Neurobrucellosis typically presents with a mild lymphocytic pleocytosis, often less than 50 cells/μL, though values may range from under 10 to over 100 cells/μL. A lymphocytic predominance (approximately 72%) is characteristic, although early or acute cases may show a neutrophilic response, potentially mimicking tuberculous or viral meningitis.

Elevated CSF protein is a common feature, frequently exceeding 300 mg/dL, and reflects blood-brain barrier disruption and CNS inflammation. Protein levels often correlate with the degree of CSF cellularity and chronicity of the infection. CSF glucose is typically normal or mildly reduced. A CSF-to-serum glucose ratio under 0.6 may suggest an infectious or inflammatory process, though it is not specific for brucellosis.

Culture yield. Brucella isolation from CSF is notoriously difficult, with positive culture rates ranging from 5% to 30%, even in confirmed cases. Yields are higher in acute stages and decline significantly in chronic or previously treated patients. When CSF culture is negative, blood and bone marrow cultures can improve diagnostic sensitivity. Blood culture positivity ranges from 15% to 37%, whereas bone marrow culture can yield positivity in up to 90% of cases due to higher bacterial load in the reticuloendothelial system.

Serologic testing: blood (38). Serologic assays remain a central tool in the diagnosis of systemic and neurobrucellosis. The standard tube agglutination test (STA/SAT) detects agglutinating antibodies (IgM and IgG) against Brucella lipopolysaccharides. Titers of 1:160 or more in endemic areas or 1:320 or more in nonendemic areas are generally considered diagnostic. Sensitivity is approximately 94.2%, though specificity is moderate. False negatives may occur in chronic disease due to blocking antibodies, and cross-reactivity can occur with Yersinia or Francisella.

The Rose Bengal test is a rapid slide agglutination test using stained Brucella antigens. With a sensitivity of approximately 95.9%, it is widely used for screening, although a negative result does not exclude neurobrucellosis. The enzyme-linked immunosorbent assay (ELISA) detects Brucella-specific IgM and IgG antibodies. It offers high sensitivity and specificity (> 95%) and is particularly useful in chronic or relapsing cases, where it may detect infection even when agglutination tests are falsely negative due to prozone or blocking effects. ELISA can also help differentiate acute (IgM) from chronic (IgG) infections.

In chronic brucellosis, standard agglutination tests such as SAT may yield false-negative results due to the presence of non-agglutinating or “blocking” IgG antibodies. The Coombs anti-Brucella test, also known as the indirect antiglobulin test, can detect these incomplete antibodies by adding antihuman globulin to facilitate agglutination. This enhances test sensitivity, particularly in chronic, subacute, or relapsing cases. It is considered more sensitive than SAT in such settings, including in neurobrucellosis when CNS symptoms are present but standard serologic tests are nonreactive. In rare cases in which serum SAT and RBT are negative despite compatible CNS findings, a positive Coombs anti-Brucella test may provide critical diagnostic support, especially in endemic regions with high background exposure.

Serologic testing: cerebrospinal fluid (23). Although less commonly employed, CSF serologic testing is supportive in cases of isolated or subacute neurobrucellosis. CSF-STA detects antibodies in CSF; titers of 1:8 to 1:16 are considered significant. Sensitivity is approximately 78%, with limitations due to blood contamination and passive antibody diffusion from serum. CSF-RBT is rapid and easy to perform but has lower sensitivity (approximately 71%) and is best used as an adjunct to serum testing. Although not widely available, CSF-ELISA shows promise in detecting intrathecal antibody synthesis and may improve diagnostic confidence in CSF-isolated presentations.

Interpretation strategy (55). A positive serum test confirms systemic brucellosis but does not alone confirm CNS involvement. The combination of positive serum and CSF serology, neurologic symptoms, and CSF pleocytosis significantly improves diagnostic accuracy. False positives may result from cross-reactivity (Yersinia, Salmonella, Francisella), prior exposure or treated infection, or inappropriate titer thresholds, especially in endemic settings

Molecular diagnostics (38; 47; 60). Polymerase chain reaction (PCR) offers a rapid detection of Brucella DNA in CSF with increased sensitivity in both acute and chronic stages. Limitations include lack of standardization, variable availability, and cost constraints. Metagenomic next-generation sequencing (mNGS), on the other hand, is a highly sensitive method capable of detecting Brucella spp in CSF without prior organism-specific knowledge. Sensitivity rates approach 90%, with turnaround times of 1 to 4 days. mNGS is particularly valuable in culture-negative or atypical presentations.

Pathophysiologic and metabolomic biomarkers (41). Studies have explored novel metabolic signatures in neurobrucellosis. Key biomarkers, such as creatinine, hypoxanthine, and niacinamide, have been associated with disease activity and potential treatment response. However, these biomarkers remain experimental and are not yet validated for routine clinical use.

Table 1. Summary of Diagnostic Tests in Neurobrucellosis: Ranges, Abnormalities, and Diagnostic Accuracy

Test	Findings in neurobrucellosis	Sensitivity	Specificity
CSF WBC count	Elevated (10–1000/µL), lymphocytic predominance; early neutrophilia in some cases	Approximately 80% to 90%	Low (nonspecific; normal in rare cases)
CSF protein	Elevated (often 50–500 mg/dL)	Approximately 90%	Low (elevated in many CNS infections)
CSF glucose	Normal or mildly low; under 40 mg/dL in approximately 47%	Approximately 50%	Low (decreased in tuberculosis, fungal CNS infections)
CSF ADA	Often elevated; over 12.5 IU/L supports diagnosis	92% (at cutoff)	88% (at cutoff)
Serum SAT	Usually ≥1:160 or 1:320 in neurobrucellosis	Approximately 95% (in systemic brucellosis)	High in endemic areas; false positives possible
Rose Bengal	Positive early in disease	Approximately 99%	Moderate (cross-reactivity possible)
ELISA IgM/IgG	High IgG ± IgM (subacute/chronic cases)	Over 95%	Over 90%
CSF Brucella antibodies	Positive (≥1:40) supports neurobrucellosis	Approximately 94%	Approximately 96%
Blood culture	Positive in approximately 30% to 50% (chronic neurobrucellosis)	Variable (30% to 70%)	Approximately 100%
CSF culture	Rarely positive; confirms diagnosis	Approximately 10% to 30%	Approximately 100%
CSF PCR	Positive in early/seronegative cases	Approximately 70% to 90%	Approximately 98% to 100%
CSF mNGS	Detects Brucella DNA, even in cryptic cases	Approximately 90%	High (sequence-specific)
(22; 25; 47; 55; 64; 41; 60; 12)

Radiological findings

Magnetic resonance imaging. MRI with gadolinium contrast is the preferred modality for evaluating neurobrucellosis (63). Radiologic findings include the following.

Normal imaging. In early or mild cases, MRI may be normal. This does not exclude neurobrucellosis, and clinical-laboratory correlation is essential (63).

Leptomeningeal enhancement. This is frequently seen, particularly in the basal cisterns, reflecting chronic meningitis (64).

Cranial and spinal nerve involvement. Enhancement of cranial nerves (eg, CN VII, VIII) and spinal nerve roots (especially lumbosacral) indicate cranial neuritis or radiculitis (63). Patchy T2 hyperintensity in the spinal cord suggests transverse myelitis or arachnoiditis, particularly in coexisting vertebral osteomyelitis (55).

Granulomas and abscesses. Although rare, focal ring-enhancing lesions, “brucellomas,” can mimic tuberculomas, bacterial brain abscesses, or neoplasms (64; 63).

White matter changes. T2/FLAIR multifocal and subcortical hyperintensities resemble demyelinating diseases, particularly multiple sclerosis (55; 62).

Vascular involvement. Lacunar infarcts and venous thrombosis are occasionally seen, likely due to Brucella-induced vasculitis. Infarcts may occur in the basal ganglia, thalamus, or pons (62; 63).

Hydrocephalus. Due to the granulomatous arachnoiditis and the leptomeningeal inflammation obstructing CSF reabsorption, a communicating hydrocephalus is noted on MR as ventricular dilation without significant periventricular edema, unless intracranial pressure is elevated (63).

Computed tomography. CT imaging is less sensitive but may be useful in emergencies or when MRI is unavailable. Notable findings include the following.

Hydrocephalus. Ventricular enlargement due to chronic meningeal inflammation and CSF obstruction is noted on CT (63).

Cerebral infarcts. Ischemic lesions may be visible on CT, especially with vasculitis, but CT is inferior to MRI in detecting small infarcts.

Calcifications. Chronic granulomatous inflammation may result in calcified parenchymal lesions that are seen as hyperdensities on non-contrast CT (63).

Diagnostic challenges. Diagnosing neurobrucellosis is inherently difficult due to its various manifestations and diagnostic overlaps with other disorders.

Atypical presentations. Neurobrucellosis can present with peripheral neuropathy, psychiatric symptoms, or nonspecific headache, mimicking a wide range of neurologic and systemic conditions.

Culture limitations. CSF culture confirms diagnosis but has low sensitivity (10% to 30%) due to low organism load and Brucella’s intracellular nature (63).

Prior antibiotic exposure. Empiric antibiotic use can decrease bacterial load and antibody titers, leading to false-negative cultures and serology. In such cases, PCR or mNGS may increase diagnostic yield (40).

Attribution errors. Not all neurologic symptoms in patients with brucellosis are due to neurobrucellosis. Distinguishing Brucella-related vasculitic strokes from unrelated events like atherosclerotic infarcts requires careful clinical and imaging correlation (62).

Limited diagnostic resources. In endemic regions, access to MRI, PCR, and CSF culture may be lacking. Many diagnoses rely on clinical judgment alone, leading to underdiagnosis or misdiagnosis, especially in mild or resolving cases (64).

Diagnostic criteria for brucellosis of the nervous system

There is no single universal diagnostic standard for neurobrucellosis; the traditional diagnostic model relies on a combination of clinical suspicion and supporting investigations. Although widely used, this approach lacks formal thresholds and varies by clinician experience. However, in 2025, the Chinese Medical Association published an expert consensus that supports a syndromic approach that integrates neurologic findings, CSF analysis, microbiological/serological evidence, and imaging features.

Traditional diagnostic criteria (not an official framework). A diagnosis of neurobrucellosis is considered established when a patient presents with neurologic signs and symptoms suggestive of CNS involvement, with exclusion of other differential diagnoses, in addition to at least one of the following four criteria (07; 53; 02; 22; 33; 09).

1. Positive identification of Brucella spp in CSF (one of the following)
	• Detection of Brucella organisms via culture or polymerase chain reaction (PCR) from CSF
	• Presence of anti-Brucella antibodies in CSF by serological methods (eg, CSF-STA, CSF-ELISA)
2. CSF biochemical abnormalities (all of the following)
	• Lymphocytic pleocytosis
	• Elevated protein concentration
	• Low glucose levels, often resulting in a CSF-to-serum glucose ratio <0.6
3. Neuroimaging findings consistent with neurobrucellosis on cranial MRI or CT (any combination of the following)
	• Meningeal or cranial nerve enhancement
	• T2 hyperintensities (suggestive of demyelination, myelitis, or encephalitis)
	• Arachnoiditis or spinal root involvement
4. Systemic evidence of brucellosis (one of the following)
	• Positive serological testing (eg, STA ≥1:160, RBT, or ELISA IgM/IgG)
	• Positive blood/bone marrow culture for Brucella spp

Chinese expert panel criteria. A diagnosis of neurobrucellosis requires meeting all three of the following essential criteria, with additional findings strengthening diagnostic certainty (16).

Essential criteria

1. Confirmed or probable systemic brucellosis (one of the following)
	• Positive serum serology (SAT ≥1:160 in endemic regions or ≥1:320 in non-endemic regions)
	• Positive RBT or ELISA (IgG or IgM)
	• Culture-confirmed Brucella from blood, bone marrow, or another sterile site
	• Relevant epidemiological exposure, such as unpasteurized dairy, animal handling
2. Neurologic manifestations (any combination of the following)
	• Meningitis, meningoencephalitis
	• Cranial nerve palsies (especially CN VII or VIII)
	• Myelitis, radiculopathy, or psychiatric/behavioral symptoms
3. Cerebrospinal fluid abnormalities (all of the following)
	• Lymphocytic pleocytosis (10–100 cells/μL)
	• Elevated protein (> 100 mg/dL)
	• Normal or mildly decreased glucose
	• CSF serology (eg, STA ≥1:8 or positive ELISA)
	• Exclusion of other infectious, autoimmune, or neoplastic causes

Supportive criteria (any of the following)

	• Positive Brucella PCR or culture from CSF
	• Neuroimaging consistent with CNS brucellosis (eg, meningeal or cranial nerve enhancement, T2 hyperintensities, arachnoiditis)
	• Clinical improvement following appropriate anti-brucellar therapy

Classification based on criteria

Definite neurobrucellosis	All three essential criteria plus microbiologic confirmation from CSF (culture or PCR)
Probable neurobrucellosis	All three essential criteria plus supportive imaging or therapeutic response
Possible neurobrucellosis	Confirmed systemic brucellosis plus neurologic symptoms, but lacking CSF or imaging confirmation

Management

Antimicrobial therapy

The following guidelines, derived from the consensus of the Chinese Medical Association, outline the standard of care (16).

Recommended regimens for adult patients. There are established first-line and second-line regimens, with the choice depending on disease severity, drug tolerance, and potential allergies.

First-line recommended regimen (intravenous-based). This combination is typically administered for a total of 4 to 6 months, with the intravenous ceftriaxone course being completed in the first 4 to 6 weeks.

Ceftriaxone	2 grams intravenously twice daily, OR 4 grams intravenously once daily. Once or twice daily, depending on the chosen dosage, for the first month of treatment.
Doxycycline	100 mg orally twice daily, continued for a total course of at least 12 weeks up to 6 months. Doxycycline is favored for its long half-life and high CNS penetrance.
Rifampin	600 mg orally once daily OR 10 mg/kg once daily, up to a maximum of 900 mg/day. Continued for a total course of at least 12 weeks up to 6 months.

Second-line recommended regimen (all oral). This regimen is recommended for patients who are allergic to ceftriaxone or who do not respond adequately to the first-line treatment.

Doxycycline	100 mg orally, twice daily, for 4 to 6 months
Rifampin	10 mg/kg orally, once daily (up to 900 mg/day), for 4 to 6 months
Trimethoprim-sulfamethoxazole (TMP-SMX)	960 mg orally, twice daily, for 4 to 6 months

Other alternative agents. For specific scenarios, other antibiotics can be substituted or added to a combination therapy.

Fluoroquinolones. Levofloxacin (400 mg/day IV) for 4 to 6 weeks can be used as an alternative for patients with a cephalosporin allergy. Ciprofloxacin (500 mg twice daily, oral) is an alternative for those who cannot tolerate TMP-SMX.

Other antibiotics. The Chinese Medical Association reported efficacy of the following based solely on the findings provided within the collected case reports: amikacin (7.5–10 mg/kg, maximum 800 mg, intravenously once daily) and minocycline (an initial dose of 200 mg, followed by 100 mg orally every 12 or 24 hours). The consensus doesn’t provide a treatment duration for both of these medications.

Streptomycin. Although historically a primary antibiotic for neurobrucellosis, its use has declined significantly due to poor blood-brain barrier penetration and the risk of ototoxicity (hearing damage). It is no longer recommended by the 2025 consensus report.

Adjunctive and supportive therapies. Corticosteroids are selectively used for severe meningeal inflammation, vasculitic complications, or spinal cord compression. Typical regimens include dexamethasone 4 mg intravenously every 6 hours or oral prednisone 1 mg/kg/day, tapered over 2 to 4 weeks. However, their use remains controversial; a 2024 meta-analysis showed that those treated with steroids had increased risk of sequelae or relapse, possibly due to indication bias or impaired immune clearance (26).

The 2025 Chinese guidelines suggest cautious steroid use in life-threatening inflammation but do not recommend routine administration (16).

Other acute interventions. These may include (1) CSF diversion procedures, such as ventriculoperitoneal shunting in hydrocephalus with or without a trial of acetazolamide (dosage and frequency not specified by consensus); (2) surgical drainage of granulomas or abscesses; or (3) antiepileptics for seizures (63).

For peripheral nervous system involvement, vitamin B1, 10 mg orally 3 times per day for 6 weeks, and mecobalamin (vitamin B12), 500 mcg intramuscularly once per day for 6 weeks, may be used (09).

Outcomes

Prognosis. There are multiple factors that affect the prognosis of patients with neurobrucellosis. Older individuals, those with preexisting medical conditions, and those who present with seizures may have a worse prognosis (06). Brucellosis in pregnancy can complicate both maternal and fetal outcomes (06).

Neurobrucellosis has a higher relapse rate compared to other forms of brucellosis. Relapse often indicates a poorer prognosis and may require longer or more aggressive treatment (26). Mortality in treated cases remains low, ranging from 0% to 5.5%. Fatal outcomes are typically associated with fulminant meningoencephalitis, intracerebral hemorrhage, or concurrent systemic involvement, such as endocarditis. In a systematic review of 221 patients, only four deaths (approximately 1.8%) were reported (26).

Treatment of Brucella meningitis generally favors good prognosis, whereas those with parenchymal brain involvement, spinal cord syndromes, or neurovascular complications tend to experience poorer outcomes. Delayed diagnosis or prolonged disease course significantly increases the risk of permanent neurologic injury (62). Motor deficits and hearing loss at presentation are the strongest independent predictors of incomplete recovery, with odds ratios of 3 to 4 for persistent sequelae (26).

Complications. Cerebrovascular events include stroke, venous sinus thrombosis, and, rarely, intracerebral or subarachnoid hemorrhage, typically due to Brucella-induced vasculitis or mycotic aneurysms in individuals with Brucella endocarditis (62). Hydrocephalus may develop in chronic basilar meningitis from inflammation-related CSF obstruction. Ventriculoperitoneal shunting may be required (56).

Despite adequate treatment, cognitive (personality changes, memory impairment) and psychiatric (depression) sequelae may persist, with a subset developing chronic fatigue-like syndrome (62).

Spinal osteomyelitis (spondylitis) is the most common focal complication and may coexist with neurobrucellosis, particularly in patients presenting with back pain or spinal cord compression. Endocarditis is a rare but leading cause of brucellosis-related death (62; 63).

Special considerations

Pregnancy

Brucellosis during pregnancy poses substantial risks for both mother and fetus. Vertical transmission can result in spontaneous abortion (reported rates between 2.5% and 54.5%), intrauterine fetal demise (approximately 20%), and preterm delivery (1% to 28%), with outcomes largely dependent on disease severity and timing of therapy initiation (08; 50).

The treatment regimen must be adjusted to avoid fetal harm (55).

Ceftriaxone	2 g intravenously twice daily for 4 to 6 weeks
Rifampin	600 mg orally once daily for at least 12 weeks
Trimethoprim-sulfamethoxazole (TMP-SMX)	160/800 mg (one double-strength tablet) orally twice daily for at least 12 weeks
Important note: Doxycycline is replaced with TMP-SMX. However, TMP-SMX should be avoided in the last month of pregnancy (at or after 36 weeks’ gestation) due to the risk of neonatal kernicterus. In this situation, the patient should be treated with ceftriaxone and rifampin until delivery.

Congenital brucellosis is a severe but rare zoonotic bacterial infection in newborns caused by the Brucella genus and is particularly concerning in the endemic regions previously listed. Transmission is typically vertical and occurs when an infected mother passes the bacteria to her infant either across the placenta, during childbirth, or through breast milk, often after the mother herself has been exposed to infected animals or unpasteurized dairy products (28). Although some infected neonates may be asymptomatic, many present with serious clinical signs, such as low birth weight, severe respiratory distress, neonatal sepsis, and jaundice (28).

Diagnosing congenital brucellosis is challenging and requires a high index of suspicion, relying on a combination of the mother’s exposure history, the infant’s symptoms, and laboratory tests like blood cultures. However, these tests are not always conclusive, so a negative result does not exclude a diagnosis in a neonate, and central nervous system involvement must be always investigated (28). Breastfeeding is generally deferred until maternal infection is resolved and antimicrobial therapy is completed due to the potential for Brucella excretion in milk (08).

Treatment is complex due to the challenges of drug choice and high risk of relapse, necessitating a prolonged course of combination antibiotics like oral trimethoprim/sulfamethoxazole and rifampin for 6 to 8 weeks. Early diagnosis and intervention are critical for a positive outcome as the disease carries a high risk of morbidity and mortality and has no available vaccine (28).

Anesthesia

Neurobrucellosis introduces specific considerations for anesthetic planning.

Neuraxial anesthesia is relatively contraindicated during active infection due to the risk of introducing organisms into the CNS. It may be reconsidered with appropriate caution once infection is controlled (63).

General anesthesia must account for elevated intracranial pressure and airway compromise from cranial nerve deficits.

Intraoperative infection control requires standard precautions, particularly during neurosurgical procedures involving CSF or abscess drainage.

Children

In children, neurobrucellosis may present acutely with fever, vomiting, convulsions, or more subtle signs, such as lethargy or gait disturbances (57).

Tetracyclines and fluoroquinolones are avoided in younger children (57).

Studies in the pediatric population are even more scarce. Common antibiotic regimens in this population, however, are generally similar to those used in adults, with weight-based dosing adjustments (64).

Rifampicin	20 mg/kg/day divided into two doses, with a maximum of 600 mg daily
Doxycycline	5 mg/kg/day in two divided doses, not exceeding 200 mg per day (exclusively reserved for children older than 8 years); to avoid side effects, doxycycline is typically replaced with TMP-SMX or ceftriaxone
Trimethoprim-sulfamethoxazole	6–8 mg/kg/day of the trimethoprim component (up to 480 mg daily) and 30–40 mg/kg/day of the sulfamethoxazole component
Ciprofloxacin	30 mg/kg/day divided into two doses, with a maximum daily dose of 1500 mg; to be used with special care

The total duration of therapy should be individualized, ranging from 3 to 12 months, and guided by the patient's clinical improvement and normalization of CSF findings (64).

Immunocompromised individuals

In immunocompromised individuals, brucellosis may present atypically or progress rapidly, causing neurobrucellosis. Diagnostic sensitivity of serology is reduced in these populations; PCR and culture are critical (46).

People with HIV may have higher serum bacterial loads and increased complications. Rifampin must be carefully managed due to interactions with antiretroviral therapy; rifabutin is a safer alternative (12; 64).

Patients on anti-TNF therapy may exhibit poor granuloma formation, leading to disseminated infection and less pronounced CSF abnormalities (45).

Treatment duration is typically extended to 6 months or longer. Regular monitoring and adjustments of immunosuppressing agents (eg, steroid doses), if possible, are advised. Relapse risk is higher, necessitating long-term follow-up (64).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Asad Haydar MD

Dr. Haydar of the University of Balamand has no relevant financial relationships to disclose.
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Ali Slim

Dr. Slim of the American University of Beirut has no relevant financial relationships to disclose.
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Rita Abdo MD

Dr. Abdo of Saint George University of Beirut has no relevant financial relationships to disclose.
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Vanessa Nasrallah BSc

Ms. Nasrallah of Saint George University of Beirut has no relevant financial relationships to disclose.
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Rosette Jabbour MD FAAN

Dr. Jabbour of Beirut/Saint George University Hospital and Saint George Hospital University Medical Center has no relevant financial relationships to disclose.
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Editor

Christina M Marra MD

Dr. Marra of the University of Washington School of Medicine has no relevant financial relationships to disclose.
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Former Authors

Robert M Elfont MD PhD
Ajitesh Rai MD
Mostafa Farache MD
John B Selhorst MD
Kevin Tan MD
Katelyn Bird
Karen L Roos MD FAAN
Partha Ray MD
Joseph Hawly MD
Muhieddine Doughan MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male>female, >1:1
Heredity: none
Population groups selectively affected: Asian

Mediterranean

Middle Easterners

Latin Americans

some sub-Saharan Africans
Occupation groups selectively affected: Abattoir workers

Animal Breeders

Butchers

Camel herders

Goat herders

Laboratory Workers

Sheep herders

Tannery workers

Veterinarians

ICD & OMIM codes

ICD-10: Brucellosis, unspecified: A23.9

Brucellosis due to Brucella abortus: A23.1

Brucellosis due to Brucella melitensis: A23.0
ICD-11: Brucellosis: 1B95

Brucella abortus: XN7A8

Brucella canis: XN84J

Brucella melitensis: XN7ZW

Brucella suis: XN3UP

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Brucellosis of the nervous system

Differential Diagnosis

tuberculous meningitis
fungal meningitis
neurosyphilis
neuroborreliosis
HTLV-1-associated myelopathy
- HIV-related chronic meningitis
- chronic enteroviral infections in immunodeficient hosts
- multiple sclerosis
- neurosarcoidosis
- CNS vasculitis
- carcinomatous meningitis
- paraneoplastic neurologic syndromes
- acute disseminated encephalomyelitis
- focal CNS Infections

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Recurrent meningitis
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Brucellosis of the nervous system

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Clinical syndromes

Disease course

Neuroanatomical involvement

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Laboratory diagnostics

Table 1. Summary of Diagnostic Tests in Neurobrucellosis: Ranges, Abnormalities, and Diagnostic Accuracy

Radiological findings

Diagnostic criteria for brucellosis of the nervous system

Essential criteria

Supportive criteria (any of the following)

Classification based on criteria

Management

Antimicrobial therapy

Outcomes

Special considerations

Pregnancy

Anesthesia

Children

Immunocompromised individuals

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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