Brucellosis of the nervous system …

Infectious Disorders

Updated 05.14.2024
Released 04.10.1998
Expires For CME 05.14.2027

Brucellosis of the nervous system

Authors: Rosette Jabbour MD FAAN, Asad Haydar MD, Joseph Hawly MD, Muhieddine Doughan MD

See Contributor Disclosures

Editor: Christina M Marra MD

Brucellosis of the nervous system

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Introduction

Overview

Brucellosis is a zoonotic infection caused by the bacteria of genus Brucella, a gram-negative, small, nonmotile, intracellular, and aerobic gram-negative bacterium. (Bennett 2023). It is composed of six different species, five of which cause brucellosis in humans (Brucella abortus, B melitensis, B suis, B canis, and B marina) (50). In the acute stage, with an incubation period of 1 to 4 weeks, undulant fever is common and is characterized by nonspecific symptoms, such as night sweats, chills, fatigue, headache, and arthralgia. After replication, the bacteria can spread via the bloodstream and may also replicate in different organs of the body, causing both localized and systemic infection. It can also invade the central nervous system (CNS) causing neurobrucellosis, which is a rare but serious complication of brucellosis (39). The clinical symptoms include headaches, fever, neurologic deficits, and potentially life-threatening complications if left untreated. Diagnosis often involves a combination of clinical evaluation, imaging studies, and laboratory tests, with treatment consisting of long-term antibiotic therapy tailored to the specific strain of Brucella. Early recognition and treatment are crucial to prevent severe neurologic sequelae and improve outcomes (51).

In this updated literature review of neurobrucellosis, the epidemiology, risk factors, pathophysiological mechanisms, clinical manifestations, and diagnostic criteria based on laboratory tests and imaging studies, along with the different modalities of treatment, differential diagnosis, and clinical outcomes, will be discussed.

Key points

	• Brucellosis is an acute, subacute, or chronic zoonotic illness caused by nonmotile, unencapsulated, intracellular, gram-negative coccobacilli that is attributable to five microorganisms.
	• Neurologic disease, known as neurobrucellosis, is a rare manifestation of brucellosis and is caused by infection with the bacterium, as well as the inflammatory response elicited by the infection.
	• The diagnosis of neurobrucellosis includes multiple diagnostic methods (laboratory and radiologic findings) with different criteria.

Historical note and terminology

Although brucellosis has been known since antiquities, its description in humans as a clinical entity, “Mediterranean gastric remittent fever,” was only made in the nineteenth century by JA Marston in 1859. Also known as “undulant fever,” “Mediterranean fever,” or “Malta fever,” it is a zoonotic infection caused by the bacteria of genus Brucella (50). Dr. Bruce was able to isolate the bacteria in 1889 and identify it as the attributive agent for the “undulant fever” (09).

Dr. Themistocles Zammit discovered that infected goats transmitted brucellosis through modifying the previous culturing techniques, now known as Zammit test. At the time, he recommended that banning the use of goat milk would be effective. During World War II, during a siege on the Maltese Island, many goats were eaten causing a spike in brucellosis and leading to a ban on drinking goat milk until the development and application of pasteurization in the early 1940s (54).

Interestingly, after this discovery, brucellosis became one of the infectious agents used as part of biological warfare during the Cold War (23). Since then, brucellosis has been considered a category B pathogen within the biological warfare classification (45).

Clinical manifestations

Presentation and course

Neurobrucellosis may present with a variety of symptoms. A summary of these symptoms and their prevalence can be found in Table 1 (21; 18; 39). Mandell and colleagues classify neurobrucellosis into three major categories: (1) acute meningitis or meningoencephalitis, (2) chronic peripheral disease (radiculopathy), and (3) chronic CNS disease (35). The most common symptoms that were reported in the literature involved meningeal involvement followed by fever, headache, nausea and vomiting, and cranial nerve palsies (21; 39). Cranial nerve eight involvement, the vestibulocochlear nerve, is the most commonly reported and leads to sensorineural hearing loss. The abducens nerve and the facial nerve were the second and third most affected, respectively, with minimal case reports describing the extent of their involvement. Other neurologic manifestations of brucellosis include intracranial hypertension, sinus thrombosis, and psychiatric symptoms (39). Cases have reported the presence of behavioral changes at a range of 15% to 60% and seizures at around 11% (22; 18; 39). It is important to note that the behavioral changes were reversible with the appropriate treatment given. Psychiatric symptoms are reversible as well; the most commonly observed are depression, personality changes, euphoria, and psychosis (48; 18). Peripheral nervous system involvement occurs in 7% of neurobrucellosis cases that are typically acute (such as monophasic immune-mediated polyradiculoneuropathy, also known as Guillian-Barre syndrome), subacute, or chronic polyradiculoneuropathy and can present with or without sensory involvement (02).

Table 1. Statistically Significant Presenting Signs and Symptoms of Neurobrucellosis and Their Prevalence

Sign and Symptoms	Prevalence
Anxiety	72.2%
Ataxia/Walking difficulties	5.5% to 17%
Behavioral changes	Up to 60%
Convulsions	8%
Depression	5% to 55%
Dysarthria	5.5%
Facial palsy	5.5%
Fever	57%
Headache	57%
Hearing loss	10%
Hemiplegia/Hemiparesis /Paraplegia	4% to 5.5%
Loss of deep reflexes	11.1%
Loss of orientation	18% to 27.8%
Neck rigidity	16% to 37%
Papilledema/blurred vision	3% to 6%
Pyramidal signs	11.1%

Prognosis and complications

Neurobrucellosis prognosis can vary depending on factors, such as the severity of neurologic involvement, timely diagnosis, and appropriate treatment. With prompt and adequate antibiotic therapy, many patients can achieve full recovery or significant improvement. However, delayed diagnosis or inadequate treatment may lead to complications, such as chronic neurologic deficits or relapses. Regular follow-up and monitoring are essential to assess treatment response and prevent potential complications. The clinical outcomes of neurobrucellosis vary according to its clinical syndromes, and although Brucella meningitis carries a good prognosis, sensorineural hearing loss is one the most common permanent deficits reported (20% to 30%) (01). A pooled case report of 187 cases of neurobrucellosis listed cranial nerve involvement as a common complication reaching 19%. Other noted complications of neurobrucellosis are polyneuropathy/radiculopathy (7%), CNS abscess (3%), and paraplegia (4%) (21). However, the mortality rate of neurobrucellosis with a proper regimen is low, ranging between 0% to 5.5% in the literature (01). An efficient and adequate treatment strengthens the immune system against Brucella impact on the CNS, which significantly limits the surge of ominous complications and sequelae.

Biological basis

Etiology and pathogenesis

Brucella is a zoonosis, meaning that it is transmitted from animals to humans. Brucella spp initially exist in animal hosts: Brucella abortus infects cattle, Brucella suis infects pigs, Brucella melitensis infects goats, and Brucella ovis infects sheep. These gram-negative rods can be transmitted to human hosts by multiple routes, including cutaneous and mucous routes (through abrasions), as well as gastrointestinal (as in consuming unpasteurized dairy products) and respiratory (20). Humans who consume or handle unpasteurized milk and its derivatives, as well as those working in close contact with livestock, are the most prone to infection with brucellosis (12; 20). Once the Brucella bacilli have entered the human body, the coccobacilli migrate through the mucosal and epithelial cell layers, and they enter nonphagocytic mucosal epithelial cells via a “zipper-like mechanism,” where the pathogen binds multiple cell-surface receptors that contain sialic acid and sulfated residues (12; 20). Brucella rods survive for up to 72 hours inside these epithelial cells, allowing them to break through the epithelial barrier. Then the surviving brucella rods are phagocytosed by macrophages and dendritic cells. This happens either via opsonization (involving complement and Fc receptors) or via fibronectin and lectin receptors. To note, the Brucella microbes that were phagocytosed via the fibronectin/lectin receptors are more likely to survive within the phagocytic cell than the opsonized bacteria (12; 20).

Another mechanism by which bacteria can enter the phagocytes is via the interaction of a structure that exists on the surface of macrophages called the “lipid raft” and the O-polysaccharide of the lipopolysaccharide in the brucella outer membrane, characteristic of Gram-negative microorganisms (20).

By virtue of its virulence factors, brucella evades the immune response inside the phagocytes and spreads through the lymph nodes to multiple organs of the body. One mechanism of immune evasion includes the inhibition of Toll-like receptor 4 (TLR4) by the lipid A of the brucella’s lipopolysaccharide. TLR4 is a transmembrane protein that induces the innate immune response. Another mechanism is the inhibition of host cell apoptosis thanks to the interaction between the brucella’s O-polysaccharide and tumor necrosis factor (TNF)-alpha. Inside the host cells, brucella pathogens also express a type IV secretion system on their cell membrane, enabling them to secrete molecules that are necessary for intracellular survival. Brucella also produces a protein called outer membrane protein 25 (Omp25) that regulates the secretion of TNF-alpha, thus, suppressing the maturation of dendritic cells, antigen presentation, and naive T-cell activation (12; 20).

It is generally accepted in the literature that the neurologic symptoms of neurobrucellosis are attributed to an inflammatory process within the CNS, leading to neuronal damage (37; 19; 46). Research is still ongoing on how brucella penetrates the CNS. One proposed mechanism is that brucella replicates in macrophages residing in the CNS, namely the microglia (19). Another possible mechanism is endothelial cell invasion, which facilitates the passage of inflammatory cells through the blood-brain barrier (19). It has been shown that the presence of brucella abortus within the CNS leads to reactive microgliosis and astrogliosis, which are hallmarks of the inflammatory response in neurobrucellosis. Astrocytes and microglia, activated by the presence of B abortus, secrete a variety of cytokines that lead to inflammation and damage of the neuronal tissue: TNF-alpha, interleukin (IL)-1beta and IL-6, and chemokines and monocyte chemoattractant protein-1 (MCP-1). Brucella virulence factors Omp19 and Pam3Cys were implicated in the secretion of these cytokines (19).

Epidemiology

As neurobrucellosis constitutes a small proportion of brucellosis, a globally underreported disease in humans and often misdiagnosed, there is a severe lack of data for accurately reporting its prevalence and incidence (32; 50). However, the present data show that it is highly prevalent in remote areas with limited access to academic centers (47; 41). Systematic reviews of available reported cases have found that occurrences of human brucellosis were most frequently reported in Syria, Tadjikistan, Mongolia, Iraq, Saudi Arabia, Iran, Turkey, and Kyrgyzstan (24). Laine and colleagues conducted an in-depth analysis of worldwide reports of brucellosis and found that only 48.4% of data on human brucellosis were complete; this is in direct comparison with the 83.1% of data on brucellosis in livestock (32). Their study also concluded that 43.2% of the world population has been considered at risk. Laine and colleagues applied statistical models with extrapolation and estimated that the global incidence of human brucellosis reached 1.6 to 2.1 million new cases per year (32). The highest average yearly incidence of human brucellosis was estimated in Africa (750 cases per million of population at risk) and Asia (500 per million), versus 10 new cases per million in Europe. Research done on published data has shown that neurobrucellosis accounts for 1.45% to 13% of all human brucella infections and 0.5% of community-acquired CNS infections (14).

A thorough literature review on brucellosis produced 16 articles, including case series and systematic reviews (34; 43; 37; 05; 31; 21; 47; 27; 41; 53; 39; 46). Combining the data from the selected publications amounts to 543 reported cases of neurobrucellosis. Being a rare symptomatology of Brucella spp, neurobrucellosis is most commonly found in endemic areas. Most published cases of neurobrucellosis were diagnosed in Turkey (n=332, 61%), followed by Iran (n=74, 14%). Other countries with reported cases include China, Kuwait, Lebanon, Saudi Arabia, Tunisia, India, Spain, and Italy. Cases of neurobrucellosis were also reported in Syria and Albania (14). Two studies have found that half of the patients lived in rural areas (47; 41). Studies that provided demographic data report that most neurobrucellosis patients are male (n=195/310, 63%). However, in a minority of studies, most of the patients included were female. The gender distribution could be attributed to the different rates of involvement of either gender in the dairy industry and in animal breeding (26; 27; 46). No age predilection was noted within the review, and neurobrucellosis is widely distributed across all ages. The mortality of neurobrucellosis according to the data we retrieved is 1% (n=6/543). This is in line with the consensus in the literature that cites a mortality rate of 0% to 5.5% (38; 07; 27).

Differential diagnosis

Confusing conditions

When facing such broad signs and symptoms, the diagnosis of neurobrucellosis can be elusive. Currently, within the literature, there are various differential diagnoses that can mimic neurobrucellosis.

“Base of skull” syndromes. With the signs of infectious processes predominantly in the base of the skull and leptomeningeal enhancement, the suspicion of neurotuberculosis and other granulomatous diseases, such as neurosarcoidosis, should be raised (50).

Ischemic cerebrovascular accident. There are case reports of the first presenting symptom of neurobrucellosis being an acute stroke (3.2%). In addition, part of the presenting symptoms can include sensory involvement (13%) or weakness (15%) in extremities, or hemiparesis (4.5%), thus, making the differential diagnosis of a cerebrovascular accident warranted to be thought of by clinicians, missing the diagnosis of neurobrucellosis (21; 33).

Peripheral neuropathy. When the initial presentation consists of difficulty walking, distal weakness in extremities, and loss of deep tendon reflexes associated with nerve roots enhancement on spine MRI, the diagnosis of peripheral neuropathy should be considered (21).

Demyelinating disorders. In the context of the involvement of white matter and inflammatory changes on brain MRI, clinicians could consider the possibility of demyelinating disorders (25).

Psychiatric disorders. Psychiatric symptoms could be the initial presentation, leading to a misdiagnosis with other psychiatric illnesses (40).

Other bacterial infections. Conditions such as meningitis or encephalitis caused by other bacteria, such as tuberculosis, Lyme disease, or syphilis, may present with similar neurologic symptoms (21; 50).

Viral infections. Viral infections, such as herpes simplex virus, varicella-zoster virus, or West Nile virus, can also cause neurologic symptoms resembling those of neurobrucellosis (50).

Autoimmune disorders. Oligoclonal bands can be found in the CSF of patients with neurobrucellosis (43). Conditions like multiple sclerosis or lupus can present with neurologic symptoms and may be considered in the differential diagnosis, especially if there is no clear infectious cause (50).

Central nervous system tumors. Brain tumors can cause neurologic symptoms, and imaging studies may be necessary to rule out this possibility (16).

Accurate diagnosis of neurobrucellosis often requires a combination of clinical evaluation, laboratory tests (such as blood cultures or cerebrospinal fluid analysis), and imaging studies to rule out other possible causes and confirm the presence of the Brucella infection in the central nervous system.

Diagnostic workup

Laboratory. Samples of blood and cerebrospinal fluid (CSF) are required for laboratory testing. On CSF analysis, around 50% of patients with neurobrucellosis were found to have mild CSF pleocytosis of fewer than 50 leukocytes/µL of CSF, with 17% with five or fewer leukocytes/µL. It is important to note that although 90% of patients were found to have lymphocytic pleocytosis, about one tenth of cases had CSF polymorphonuclear cell pleocytosis (39). The yield of Brucella from CSF automated cultures of patients with neurobrucellosis is low, ranging between 5% to 30% (52). In a case series of 54 cases of neurobrucellosis, only 9% of cases were confirmed by culture-based blood or CSF microbiological tests (39).

There are several serologic tests that could be used for confirming neurobrucellosis of various sensitivities, depending on serum or CSF (Table 2), and specificities, including the Rose Bengal test (RBT), standard tube agglutination (STA), enzyme-linked immunosorbent assay (ELISA), complement fixation, indirect Coombs, and immunocapture agglutination (BrucellaCapt) (50).

Table 2 shows the sensitivities of different laboratory investigations in comparison with each other and to the bodily fluid being tested.

Table 2. Sensitivities of Different Laboratory Investigations

	CSF sensitivity	Serum sensitivity
ELISA IgM	80%	70%
ELISA IgG	80%	91%
Standard tube Agglutination	76%	94%
Rose Bengal test	71%	96%
Automated culture	25%	37%

Conventionally, the Standard Tube Agglutination (STA) was used as the main method of diagnosis; however, ELISA tests offer higher sensitivity and specificity for the diagnosis of neurobrucellosis, in both complicated and chronic cases as well (50). The current recommendation reports the usage of two different modalities to increase accuracy (29). Although it was noted in multiple studies, and in reference to Table 2, that the CSF-STA test was not shown to be statistically superior to the CSF-Rose Bengal Test (RBT), it is important to note that the CSF-STA titers were significantly higher in CSF-RBT positive patients, and the CSF-RBT remains negative with lower CSF-STA titers. Subsequently, CSF-RBT was positive when the CSF-STA titer was equal to or higher than 1/40, making CSF-STA titers more effective in detecting a positive result (15).

Imaging. The current literature provides four patterns of CNS involvement that can be found on imaging in patients with neurobrucellosis: (1) normal, (2) inflammatory changes (including granulomas, lumbar nerve root enhancements, cranial nerve involvement, meningeal and perivascular space enhancements), (3) white matter changes (including subcortical T2 hyperintensities, and myelopathies), and (4) vascular changes (including lacunar infarcts, venous thrombosis, microhemorrhages) (30; 17; 11; 39). However, 45% of neurobrucellosis cases showed changes on MRI, as per the Istanbul-3 study (17).

Diagnostic criteria. A literature review demonstrated the different diagnostic criteria for neurobrucellosis reported and used within the literature. They are summarized in Table 3.

Table 3. Diagnostic Criteria for Neurobrucellosis

Suspected symptoms and signs of neurobrucellosis (22)
	• Isolation of brucella from CSF or positive anti-brucella antibodies in CSF
	• Presence of lymphocytic pleocytosis, decreased glucose, and elevated protein in CSF
	• Cranial MRI or CT scan findings
Signs and symptoms associated with neurobrucellosis that cannot be explained by other etiologies (36)
	• Positive CSF culture for Brucella organisms or a positive IgG agglutination titer for Brucella organisms in the blood
	• Presence of lymphocytic pleocytosis and elevated proteins in CSF
	• Response to specific antibiotics with significant improvement in CSF parameters mentioned in criteria above
Signs and symptoms suggestive of a neurologic infection with CSF analysis indicative of meningitis (44)
	• Detection of Brucella organisms from CSF and/or blood, and/or antibody titer ≥ 1:160 (mainly IgM) in serum-STA, and/or presence of anti-brucella antibodies (ELISA for both IgM and IgG) in CSF, and/or brucella organism-specific DNA from CSF using PCR

Management

Currently, the choice of antimicrobials and duration of treatment is limited by the following factors: its ability to penetrate the blood-brain barrier and the normalization of CSF findings with resolution of symptoms (13). High relapse rates are observed with monotherapy, and a combined therapy is favored for treatment control of neurobrucellosis. In recent reports, the antimicrobial regimen used is ceftriaxone 4 g/day (a third-generation cephalosporin with excellent CNS penetration) for the first 4 to 6 weeks or trimethoprim/sulfamethoxazole (TMP-SMX) at a dose of 160/800 mg taken orally twice a day (04). If patients have any allergic reactions to TMP-SMX, they are usually switched to a fluoroquinolone, usually ciproﬂoxacin at a dose of 500 mg twice daily for at least 6 weeks.

As for children, the recommended regimen is similar to that of the adult; however, the dosages are as follows: rifampicin at a dose of 20 mg/kg/day divided into two doses per day (maximum dose of 600 mg), doxycycline at 5 mg/kg/day divided into two doses per day (maximum dose of 200 mg, and only for children above the age of 8 years), TMP-SMX at 6 to 8 mg of TMP/kg/day (maximum dose of 480 mg) and at 30 to 40 mg of SMX/kg/day, ciprofloxacin at 30 mg/kg/day divided into two doses per day (maximum of 1500 mg) (10).

In addition, rifampin is administered orally at a dose of 600 mg per day, and doxycycline is also administered orally at a dose of 100 mg twice daily for at least 12 weeks. The duration of treatment varies from 3 to 12 months depending on the CSF response (04).

If a patient is allergic to ceftriaxone or has gastric intolerance to this medication, levoﬂoxacin hydrochloride (0.4 g intravenously) is administered once on a daily basis for 4 to 6 weeks (55).

If clinical symptoms have not resolved or the CSF findings have not normalized by the end of the treatment course at 12 weeks (3 months), the treatment is usually continued for 6 months. Subsequently, patients ought to be followed up every 3 months due to the risk of relapse following treatment (relapse rate 5% to 15% after the end of the first 6 months of treatment) through a thorough clinical examination and a lumbar puncture, with subsequent CSF studies aimed to identify the presence of the pathogen/antibodies (41).

Corticosteroids appear to protect against long-term complications. Within the literature, case reports suggest the usage of steroids in cases with major CNS involvement (cranial nerve involvement, myelopathy, optic neuritis, papilledema, arachnoiditis), but no controlled study has confirmed the use, efficacy, and long-term outcomes of steroids in neurobrucellosis (50). There are no data that recommend a specific corticosteroid; however, from clinical experience, a pulse steroid therapy with methylprednisolone 500 to 1000 mg can be given daily over a course of 3 to 5 days followed by prednisone 1 mg/kg orally daily with a 10 mg/week taper (04). Data on corticosteroids use in pediatrics are even further limited.

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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

Rosette Jabbour MD FAAN

Dr. Jabbour of the University of Texas Houston Health Science Center has no relevant financial relationships to disclose.
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Asad Haydar MD

Dr. Haydar of Saint George Hospital University Medical Center has no relevant financial relationships to disclose.
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Joseph Hawly MD

Dr. Hawly of the American University of Beirut has no relevant financial relationships to disclose.
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Muhieddine Doughan MD

Dr. Doughan of 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

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

“Base of skull” syndromes
Ischemic cerebrovascular accident
Peripheral neuropathy
Demyelinating disorders
Psychiatric disorders
- Other bacterial infections
- Viral infections
- Autoimmune disorders
- Central nervous system tumors

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Clinical Categories

Infectious Disorders

Patient Handouts

Brucellosis

Web References

Clinical Trials

NIH: Meningitis

Brucellosis of the nervous system

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Statistically Significant Presenting Signs and Symptoms of Neurobrucellosis and Their Prevalence

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Table 2. Sensitivities of Different Laboratory Investigations

Table 3. Diagnostic Criteria for Neurobrucellosis

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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