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Neurological involvement is central and peripheral
Abstract
Brucellosis is a common Zoonosis affecting half a million people annually. The most common mode of infection is by consuming unpasteurized milk or milk products. The general manifestations are those of fever with generalized symptoms. The nervous system is affected in 4–7% of cases. The manifestations are protean and include meningo-encephalitis as well as peripheral nervous system involvement. The diagnosis relies on culture, which is cumbersome and can be falsely negative. Agglutination tests for the various species of the organism are the mainstay for diagnosis. Treatment is for 3–6 months with combination therapy including Doxycycline, Rifampicin and ceftriaxone. The main issue is prevention and better animal husbandry.
This is an ancient zoonosis described before Hippocrates in human skeletons. It is the most common bacterial zoonosis and remains prevalent across the world. WHO defines zoonotic diseases as infectious diseases that are naturally transmissible from vertebrate animals to humans. Brucellosis (Undulant fever, Malta fever) causes major animal and human morbidity in many parts of the world. The infection is intracellular and in man it causes a myriad of symptoms. The illness is commonly acquired through ingestion of unpasteurized contaminated milk or its products or from direct contact with infected animals. Aerosol transmission is an occupational hazard in those who come in contact with infected material such as placentae resulting in inhalation of aerosol particles.
]; its description in humans as a clinical entity “Mediterranean Gastric Remittent Fever” was only made in the nineteenth century by JA Marston in 1860. David Bruce (1865–1931) described the organism as a “micrococcus” in 1887 with the help of a Maltese microbiologist Carruana Scicluna. In 1905, Zammit a Maltese doctor showed that goats transmitted the disease (Fig. 1). Bruce moved to Africa and identified ‘Trypanosoma Brucei” as a cause of Sleeping sickness [
Bang was Danish veterinarian who identified an intracellular bacillus as the cause of miscarriage in cattle (Bang's bacillus). For many years no relation was thought to exist between Bruce's micrococcus and Bang's bacillus. Many others contributed to the development of knowledge on brucellosis; however, two have to be specifically mentioned. The first is Mary Elizabeth Steel, the daughter of a Scottish doctor and wife of David Bruce. She was a trained microbiologist and was instrumental in the early work on brucellosis. The second is Alice Evans (1881–1975); an American microbiologist, who was not only the first person to prove that micrococcus melitensis and Bang's bacillus were different species of the same genus but she worked for many years to establish that milk was the source of the infection and her work led to the pasteurization of cow's milk [
The assistant of David Bruce, Surgeon Captain M Louis Hughes, made the first report on the isolation of M. melitensis from the brain in Malta. His classic monograph in 1897 dedicated to his mentor Lord Lister is the clearest description of brucellosis, which he suffered from himself. Hughes was killed in the second Boer war at the age of 32 years. Brucella melitensis was isolated from the CSF by Lemaire in 1924 [
Brucellosis is an old disease with minimal mortality. Yet human brucellosis remains the commonest zoonotic Disease worldwide with more than 500,000 new cases annually [
in: World Health Organization in collaboration with the Food and Agriculture Organization of the United Nations and World Organization for Animal Health. 2006
]. The global epidemiology of the disease has drastically evolved over the past decades. Neurobrucellosis is the most serious form of the disease and affects between 5 and 7% of those involved. Countries affected are many and are widely distributed across the globe. Not only around the Mediterranean basin but extend from China to the Americas. The incidence has remerged in the last decade in spite of enhanced surveillance and the wide reporting of animal cases [
Exposure, Testing, and Prevention Bacterial Special Pathogens Branch (BSPB) Division of High-Consequence Pathogens and PathologyNational Center for Emerging and Zoonotic Infectious Diseases Centers for Disease Control and Prevention.
The genus Brucella is composed of an increasing number of species that infect a wide variety of mammals as primary hosts, such as bovine (B. abortus), caprine (B. melitensis), swine (B. suis), ovine (B. ovis), camels, elk, bison (B. abortus), canine (B. canis), rodents (B. neotomae, B. microti), monkeys (B. papionis), as well as marine mammals such as seals, porpoises, dolphins and whales (B. pinnipidialis and B. ceti), and also amphibians (B. inopinata) [
] The only ones that affect humans are abortus, melitensis, suis, and canis.
4. Transmission
The commonest infection route is by ingestion of unpasteurized/raw dairy products. The milk of infected sheep, goats, cows, or camels can be contaminated with the bacteria.
Unpasteurized milk from infected animals will transmit the disease to people who consume the milk and/or cheese products. Moreover brucellosis is an occupational hazard in veterinarians, slaughterhouse workers, meat packers and laboratory workers. Breathing in the bacteria can cause the infection in those exposed in laboratories and slaughterhouses. Hunters of wild animals can get infected when butchering as the bacteria can gain access through skin cuts and abrasions. Trans-Placental, breast feeding and sexual transmission is extremely rare [
Exposure, Testing, and Prevention Bacterial Special Pathogens Branch (BSPB) Division of High-Consequence Pathogens and PathologyNational Center for Emerging and Zoonotic Infectious Diseases Centers for Disease Control and Prevention.
Systemic brucellosis may present in a non-specific illness with fever, malaise, anorexia, headaches, muscle aches, arthralgia, fatigue and sweats. Some symptoms may persist for a long time with recurrent fevers, fatigue, depression, arthritis, orchitis, endocarditis, with hepato-splenomegaly. Neurological involvement can be the only presenting feature [
Neurological involvement is perhaps the most serious complication and it only occurs in a minority of those affected by brucellosis. The rate of involvement varies from 4 to 7% the Centers for Diseases Control and Prevention (CDC) figure of 5%, seems appropriate [
Exposure, Testing, and Prevention Bacterial Special Pathogens Branch (BSPB) Division of High-Consequence Pathogens and PathologyNational Center for Emerging and Zoonotic Infectious Diseases Centers for Disease Control and Prevention.
]. Both the central and peripheral nervous systems can be affected. Attempts to classify neurological involvement are difficult and imprecise. A broad central nervous system category including vascular pathology, a peripheral category or a combination seems the most practical [
Meningoencephalitis can present with headache, lethargy and altered consciousness in addition to features of meningism. The presentation can be relatively acute of few days or indeed chronic and brucellosis has to be considered in the differential diagnosis of chronic meningitis. It is of interest to note that as with other conditions affecting the meninges, cranial nerves involvement are well recognized with vestibulocochlear, facial, oculomotor, and sixth nerve palsies. Cerebellar involvement usually with cranial nerve palsies especially nerve deafness has been reported [
]. This can be a process, which can linger for months with eventual bladder and bowel involvement.
Peripheral nervous system involvement with proximal polyradiculoneuropathy can be the main feature; back pain especially related to sacroiliitis is an important pointer to the diagnosis. Flaccid paraparesis with hypotonia and areflexia can be the main features and can remain for weeks without any further evolution. On the other hand there are reports of patients presenting with an acute meningitic picture with lymphocytic CSF pleocytosis and low CSF sugar is well recognized. Moreover a chronic neurologic involvement may start months or even years later [
]. However, at times other body organs can be involved such as arthritis or orchitis happening at some stage during the evolution of the neurological syndrome.
It is important therefore to remember that Brucellosis can present in a protean manner involving the cranial nerves, brain, brainstem, cerebellum, spinal cord and peripheral nerves [
A high index of suspicion is required. The bacteria is widely spread and even in the absence of history of ingestion of raw/unpasteurized milk or milk products one has to preform the necessary blood and in case of neurological involvement CSF examination.
Bacterial isolation is the gold standard, however, the sensitivity may not be high depending of the presence of the organism in blood. In acute cases culture results can be quite high with a 10–20% false negative results. But in neurobrucellosis blood culture sensitivity is low at around 20–30%. Bone marrow cultures are more sensitive than blood cultures especially in those with previous antibiotic use [
In the absence of a positive culture the diagnosis relies on serological tests. The agglutination tests such as Rose Bengal test, which is used as a screening test, the serum agglutination tests, and the CDC utilizes a test called the Brucella micro-agglutination test (BMAT), a modified version of the serum (tube) agglutination test (SAT), that can detect antibodies to Brucella species – abortus, melitensis or suis. There is no serological test available to detect antibodies to B. canis [
Exposure, Testing, and Prevention Bacterial Special Pathogens Branch (BSPB) Division of High-Consequence Pathogens and PathologyNational Center for Emerging and Zoonotic Infectious Diseases Centers for Disease Control and Prevention.
]. These agglutination tests are based on the reactivity of antibodies against smooth polysaccharide. The antibodies persist in the patient's serum long after recovery. This off course raises the issue of positivity in endemic areas and the possible misinterpretation when investigating other chronic infective processes. There could be cross reactivity with other gram-negative bacilli such as Yersinia, vibrio cholerae and E coli. The sensitivity and specificity of the confirmatory agglutination tests depends on the cut off value used on the background of the population. A high cut off value will reduce the sensitivity [
]. The use of 2-mercaptoethanol test for measuring specific IgG antibodies can supplement agglutination tests. ELISA is now popular and commercial brands are used in various locations. The use of Brucellacapt showed a high sensitivity and specificity. Serological agglutination and ELISA has been applied to CSF with varying degrees of sensitivity [
], two serum samples are required. The first serum sample should be taken when a person is acutely ill (≤7 days following symptom onset); the second serum sample should be drawn 2–4 weeks later to check for a rise in antibodies (a fourfold or greater rise in antibodies would mean an individual is positive for brucellosis) [
Exposure, Testing, and Prevention Bacterial Special Pathogens Branch (BSPB) Division of High-Consequence Pathogens and PathologyNational Center for Emerging and Zoonotic Infectious Diseases Centers for Disease Control and Prevention.
Although imaging with MRI and CT can be normal, but could be fairly suggestive, with high signal white matter lesions seen in cases of meningoencephalitis, enhancing lesions, which can be periventricular, are a reported [
). Meningeal enhancement is seen in cases of meningitis and ventriculitis (Fig. 2). Spinal imaging can perhaps be more informative and even be quite typical. Brucella affects the vertebral endplates and then may totally destroy the vertebra (Fig. 3). When the sacro-iliac joints are involved Brucellosis become highly likely [
Fig. 2MRI brain of a 52 year old male farmer with meningoencephlitis, leptomeningitis and active CSF with Positive brucella serology. (Courtesy Prof Faouzi Belahsen, Fes University, Morocco).
Fig. 3(A) Spinal spondylodiscit's MRI at L4 leading to destruction of the vertebrae. (B) CT scan bone windows showing the vertebral involvement as well as the SI joints. (courtesy Dr. Ashish Atre, Star Imaging Centre Pune, Dr. Sudhir Kothari Poona Hospital, Pune India.
The essence of treating complicated brucellosis such as neurobrucellosis is combination therapy to reduce the chances of relapse. The CDC recommendation is to use oral doxycycline in a dose of 2–4 mg/kg a day with a maximum of 200 mg/day in two divided doses OR tetracycline 30–40 mg/kg a day maximum of 2 g daily, in four divided doses AND Rifampicin 15–20 mg/kg per day, maximum 600–900 mg/day in a single dose for six weeks. Combination therapy with trimethoprim-sulfamethoxazole (TMP-SMZ) can be used if tetracyclines are contraindicated [
Exposure, Testing, and Prevention Bacterial Special Pathogens Branch (BSPB) Division of High-Consequence Pathogens and PathologyNational Center for Emerging and Zoonotic Infectious Diseases Centers for Disease Control and Prevention.
Streptomycin or gentamycin for the first 2 weeks of therapy in addition to tetracycline and rifampicin can be used. It is recommended that in case of meningoencephalitis, the duration of therapy should be for 4–6 months with a case fatality rate of less than 1% [
], the conclusion was that triple therapy with doxycycline, aminoglycoside and rifampicin is the optimal combination. However, one has to accept that patients prefer using oral combinations rather than additional injectable aminoglycoside either in the form of streptomycin or gentamycin [
]. Moreover, the use of aminoglycosides in neurobrucellosis with the well-recognized complication of hearing loss is not advisable. Ceftriaxone has been found to be effective as the third drug in addition to doxycycline and rifampicin [
Brucella being an intra-cellular infection creates a vacuole like acidic compartment within the cell and therefore antibiotics have to enter the cell and attack the organism [
The duration of antibiotic treatment with triple regime is probably the most likely to lead to satisfactory outcome. The end points of treatment are again unclear, some use repeated lumbar punctures and stop treatment when the CSF is clear. Others rightly feel that this is not practical and opt either for a fixed period ranging from 3 to 6 months depending on the clinical presentation. With no randomized trails on the length of treatment, an arbitrary time limit is what is applicable [
]. There is no evidence that the additional use of steroids which is an accepted practice leads to better outcome especially for hearing loss, myelopathy, arachnoiditis and optic nerve involvement [
]. One has to remember that the two most likely persisting disabilities following the eradication of Brucella from the nervous system is hearing loss and paraparesis.
9. Prevention
There are two issues here; the first is concerned with immediate contacts in those working in laboratory facilities, farms, slaughterhouses and the milk industry who are considered at risk. Using Doxycycline 100 mg twice daily and Rifampicin 600 mg daily for three weeks is recommended [
Exposure, Testing, and Prevention Bacterial Special Pathogens Branch (BSPB) Division of High-Consequence Pathogens and PathologyNational Center for Emerging and Zoonotic Infectious Diseases Centers for Disease Control and Prevention.
The disease is wide spread in animals and it is notifiable in various countries. There are animal vaccines for some strains, however human vaccines are not available [
]. This is by and large a result of the peculiar way that Brucella behaves as an intracellular organism. Various measures to control zoonotic brucellosis [
in: World Health Organization in collaboration with the Food and Agriculture Organization of the United Nations and World Organization for Animal Health. 2006
Exposure, Testing, and Prevention Bacterial Special Pathogens Branch (BSPB) Division of High-Consequence Pathogens and PathologyNational Center for Emerging and Zoonotic Infectious Diseases Centers for Disease Control and Prevention.
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