eMedicine Specialties > Neurology > Neurological Infections

Brucellosis

Robert Stanley Rust Jr, MD, MA, Thomas E Worrell Jr Professor of Epileptology and Neurology, Co-Director of FE Dreifuss Child Neurology and Epilepsy Clinics, Director, Child Neurology, University of Virginia; Chair-Elect, Child Neurology Section, American Academy of Neurology

Updated: Jan 11, 2010

Introduction

Background

Brucellosis is a zoonotic infectious illness to which humans became vulnerable at some point after the domestication of animals and the establishment of animal husbandry as an important element of the rise of civilization. It is the most common zoonosis in the world, accounting for the annual occurrence of more than 500,000 cases.^{[1 ]}Careful modern studies have demonstrated that the prevalence of the disease in domesticated nonhuman mammals subject to brucellosis increases with herd density. Close contact with animals raised for milk, meat, the products of such animals, or with certain beasts of burden accounts for most of the risk sustained by humans for infection with Brucella species.

Of particular importance have been cows, goats, camels, sheep, pigs, and dogs. Brucellosis also may be found in wild animals of North America that are naturally gregarious and exist in herds, such as bison or elk. In Germany, a similar reservoir is found in wild boars.^{[2 ]}Humans experience only limited risk from wild animals due to lack of proximity, intimate contact, or use of milk and meat products from these animals. Concern about the interaction of wild with domesticated animals, leading to infection of agricultural herds, has been voiced, although supportive evidence is quite limited.

In nonhuman domesticated mammals, brucellosis chiefly affects sexual organs, the most common and serious results of which are abortion of fetuses, infertility of males, metritis, orchitis, and epididymitis. Brucella abortus and Brucella ovis play a particularly important role in such effects. Within herds, infection may also cause disabling conditions such as discospondylitis, bursitis, or arthritis. Thus, brucellosis poses a threat to the economy and to the provision of meat, milk, and milk products, and in some cultures brucellosis threatens the supply of camels, whether they are used for transportation or other uses.

In animals, the disease is spread by contact with infected excreta, milk feeding, licking of aborted fetuses, or as a venereal disease with female-to-male and male-to-male transmission. Introduction of an infected animal into an uninfected herd results in rapid spread of disease. In the Middle East, the seroprevalence for Brucella antigens is greater in larger herds and mixed farming operations, while the seroprevalence is less in farming operations where disinfectants are used or where adequate veterinary services existed.^{[3 ]}

Human disease prevalence in any given area of the world closely parallels the extent to which the indigenous cultures engage in animal husbandry. Risk is also proportional to degree of contact with Brucella- infected animals, their excreta, or their edible byproducts, particularly milk or cheese. Pasteurization of milk is of great importance in preventing human brucellosis, as is care in the slaughtering of animals for meat and assurance of adequate cooking of that meat.

An unmistakable description of Brucella melitensis infection of goats is found in Genesis 31:38. A description of a chronic illness with undulating fever and relapses, found in the Hippocratic corpus, likely referred to ancient brucellosis. Prior to and especially during the 19th century, various febrile illnesses were described that were likely brucellosis. Local names were often attached to the term fever—the predominant manifestation of brucellosis—by exogenous military garrisons that may have been more vulnerable than the indigenous population to infection from endemic brucellosis. Hence, Constantinople fever as well as the fevers of Malta, Naples, Gibraltar, Crete, Crimea, Levant, Syria, and so forth. The undulating quality of fever caused the term malarial to be placed in some designations. Since febrile gastrointestinal manifestations may also be prominent, other names for the affliction included various terms designating typhoid.

In 1860, Marston provided the first modern clinical description of brucellosis, which he termed Mediterranean gastric remittent fever. The etiologic role of Brucella melitensis first was demonstrated in Malta in 1887 by Bruce and Carrauna-Secluna, who cultured and isolated this bacterium from the spleens of individuals who died from brucellosis. The original genus designation (Micrococcus) was subsequently changed in honor of David Bruce, a physician with the British army who carried out extensive studies of the organism. It must be mentioned in passing that Dr G. Carruana-Secluna played an important technical role in the success that was achieved in culturing the organism, although it is said that Dr Bruce did not permit him to be listed as a coauthor.

Dr M. Louis Hughes, another colleague of Dr Bruce, was the first to isolate B melitensis from brain, and it was he who provided the species name melitensis. Hughes published a classic description of this illness in 1897, just prior to his death at age 32 in the Boer War. Hughes' term undulant fever became the most widely accepted clinical designation until brucellosis obtained currency, although Malta fever has also shown some staying power as a designation.

Hughes incorrectly concluded that the organism was to be found in the soil. Here again, Dr Carruana-Secluna played an important role together with Dr Themistocles Zammit. Their investigations (with the leading role accorded variously to one or the other) of goats at Chadwick Lakes established one of the most important principles of the epidemiology of infectious diseases, the zoonotic principle of the role of animals in transmission of disease to human. They demonstrated that more than half of Maltese goats were asymptomatically infected and that the organism could be transmitted to humans by the consumption of unpasteurized milk and milk products or by contact with infected goat urine. Naval grog, sometimes a milk-containing drink, was identified as the likely cause of the infection of British seamen at Malta.^{[4 ]}

Lemaire first isolated B melitensis from spinal fluid in 1924. Brucellosis subsequently has been recognized as an endemic illness in almost all Mediterranean countries, as well as in India, China, South Africa, and much of Central America and South America. Three additional Brucella species subsequently have been identified that together with Brucella melitensis comprise the most important agents of human brucellosis. Sporadic outbreaks occur in many other parts of the world, including North America. Brucella canis has also been identified, although it plays only a minor zoonotic role.

Pasteurization of milk and the monitoring and culling of herds of sheep, goats, cows, and pigs for brucellosis have considerably reduced the incidence of such outbreaks. Great importance has been assigned to such methods of control and great and justifiable pride is taken by countries such as New Zealand who have earned the designation brucellosis free. Upon such achievements, progress in international human health depends, as do agricultural efforts and investments worth many millions of dollars. A more recent matter of international concern is the possibility that this agent might be used as a biological instrument of terror since in aerosolized form merely 10-100 organisms might be capable of producing infection of humans and animals.

The breeds of animals that may harbor Brucella organisms and the threat that the organisms pose to the health of these various animals and to their veterinarians, herders, handlers, and slaughterers are considered in Pathophysiology and Frequency. The chief veterinary problems include abortion of calves and sterility of rams or billy goats.

Pathophysiology

Brucella are gram-negative intracellular coccobacillary organisms. The organisms seek out cells that are capable of providing the nutrient erythritol, hence their predilection to live within cells of the genital tracts of animals. Reticuloendothelial cells are also a favored location in animals and are the chief site of infection in humans, particularly human macrophages. Recent evidence further suggests that the host environment must also provide choline, a necessary precursor for the synthesis, by Brucella organisms, of the cell envelope without which the organisms are not virulent. However, the lipopolysaccharides contained in this membrane are less pyrogenic than those of many other virulent gram-negative organisms.

Of the 6 nominal species of Brucella, only 4 are known to engender human brucellosis. Worldwide, B melitensis (harbored in sheep, goats, and camels) is the most common cause of human brucellosis, the consequences of which ranges from mild-to-severe illness. It has considerable veterinary importance as a cause of sterility in rams. Brucella abortus (harbored in cattle) is more widely distributed throughout the world. It is of extraordinary economic importance as a cause of bovine abortion; however, it has a lower degree of pathogenicity for animals and humans than B melitensis. Nonetheless, it is the most common cause of the rare human brucellosis cases of North America.

Brucella suis (harbored in pigs, hares, rabbits, and reindeer) and Brucella canis (harbored in dogs) are the other Brucella species capable of inducing brucellosis. B suis is the second most common cause of brucellosis in North America and may produce serious human disease.

Typically, the organism is ingested and enters the bloodstream via the gastrointestinal tract. However, transmission may occur through mucous membranes (eyes, nose, gastrointestinal system, genitourinary system), as well as via cuts, abrasions, inhalation, or, in the case of veterinarians and microbiologists, parenteral injection. As few as 10-100 inhaled organisms are thought adequate in some individuals to establish infection. Once within the bloodstream, the organism quickly becomes an intracellular pathogen contained within circulating polymorphonuclear cells and macrophages. The organisms are capable of evading the bactericidal systems of the macrophages that ingest them. Among the mechanisms of this avoidance may be the adaptive reduction of bacterial metabolic processes entailed in energy, protein, and nucleic acid metabolism.^{[5 ]}

The cells then colonize the lymphatic system (ie, lymph nodes, spleen, bone marrow) as well as other organs, particularly the liver and spleen, but also the kidney, breast and genital tissues, joints, and periosteum. Although the likelihood that organisms resident in these various locations might be passed to humans, breastmilk is as noted an important source of infection from domesticated animals, and evidence exists that sexual transmission may occur. Genitourinary infection is responsible for the abortions found in B abortus infected cows.

This phase of colonization of various organs is usually accompanied by the development of a prolonged interval of undulating fever and malaise in humans, a phase much less likely to arise in domesticated animals. Liver, spleen, and other reticuloendothelial tissues may develop characteristic pathological changes that include infiltration with epithelioid cells, foreign body and Langhans type giant cells, lymphocytes, and plasma cells.

The initial host response to infection is chiefly cellular. Macrophages mediate control of infection during the acute phase, although as noted above in many instances the organisms evade further processing once ingested by the macrophages wherein they may find a safe harbor for replication, evading other arms of the immune response. Initially, the macrophages perform this function without specific activation, but after the first 2 weeks of infection, sensitized T lymphocytes specifically activate the macrophage response. This considerably reduces the survival rate of Brucella organisms in the liver and spleen of most infected individuals.

Humoral immune mechanisms may participate in the control of acute infection, although the nature of that participation is not yet well understood. The capacity of humoral immune mechanisms to influence the course of the infectious reaction is likely limited because of the intracellular repose achieved by Brucella organisms. Nonetheless, the level of immunoglobulin M (IgM) antibodies begins to rise at the end of the first week of infection and usually peaks at approximately 1 month, when immunoglobulin G (IgG) antibodies begin to appear. The level of IgG antibodies often declines in the ensuing months, while IgM antibody titers may remain elevated for years. In some instances there is persistent elevation of IgG antibodies in association with chronic active infection. In other instances IgG a spike of IgG titers occurs after a phase of decline in concentration, suggesting a relapse of illness. Immunoglobulin A (IgA) antibodies are elaborated late and also may persist for very long intervals.

Mediation of the most common neurological manifestations of acute brucellosis is not well understood. These are quite common, and consist of irritability, lethargy or lassitude, fatigue, headache, disturbances of mood, inattentiveness, anorexia, and sleep disturbance. These manifestations are not dissimilar from constitutional symptoms encountered in many other forms of systemic infectious disease. Some of them, specifically headache, anorexia, and mood and sleep disturbances, suggest that brainstem reticular and serotonergic pathways may be involved.

Direct infection of the central nervous system (CNS) may play a role in these abnormalities. Some support for this conception is provided by the facts that, in some cases of acute brucellosis, Brucella organisms can be recovered from the cerebrospinal fluid (CSF) and that the spinal fluid, during the acute phase of illness, may exhibit pleocytosis, hypoglycorrhachia, and elevation of protein concentration. Because the organisms within the nervous system are chiefly in intracellular locations, they are recovered from cultures of spinal fluid in no more than 25% of cases. The likelihood of recovery of organisms from the blood is also only about 25%. The constitutional symptoms that occur in brucellosis suggest that an inflammatory reaction has been mounted against the invading organism, both within or outside the nervous system.

By convention, these constitutional manifestations referable to the nervous system (lethargy, headache, depression, and so on) are not termed neurobrucellosis. Most instances of neurobrucellosis arise during the chronic phase of brucellosis. There are, however, cases in which neurobrucellosis does complicate acute brucellosis. When it does, it usually assumes the form of more profound degrees of encephalopathy or of a meningoencephalitic syndrome.

Other forms of neurological dysfunction that may accompany the acute phase of brucellosis are hearing loss and peripheral neuritis. In regions where B melitensis is endemic, brucellosis may be the most common cause of acquired hearing loss, the onset of which may be during the acute, subacute, or chronic phase of disease. It is especially important, therefore, that we develop a better understanding of the cause of this complication.

The occurrence of neurobrucellosis during the acute phase of illness may be due to direct deleterious effects of organisms invading nervous tissues, to the release of circulating endotoxins, or to the immunological and inflammatory reactions of the host to the presence of these organisms within the nervous system or within other tissues of the body. The importance of inflammatory mediation of some forms of tissue injury during the acute stage of brucellosis is suggested by the occurrence, in some patients, of brain edema.

Some of the more severe cases thought to be acute brucellosis complicated by focal neurological dysfunction or focal dysfunction referable to other organ systems actually may not be primary acute brucellosis infections. Some authorities have argued that these more severe examples of acute brucellosis are actually second infections in a host sensitized to brucellar antigens by a prior unrecognized infection. This theory argues that the greater severity of illness in these cases is due to the preexisting hyperimmune potential of the reinfected host. Some support for this theory is provided by the marked signs and symptoms that may occur acutely in veterinarians who have mistakenly inoculated themselves with Brucella vaccines.

Most neurological, and indeed most significant multisystemic, manifestations of brucellosis develop after a latent interval, and are thought to be the consequences of a chronic state of infection with a Brucella organism. The development of clinical manifestations usually is heralded by return of fever and associated constitutional signs and symptoms.

Chronic Brucella infection occurs because of the difficulties inherent in killing an intracellular parasite. It is more likely to occur in cases in which the initial antibiotic treatment of brucellosis was inadequate. Chronic infectious etiology for chronic brucellosis is supported in some cases by the fact that organisms can be cultured or identified in tissues of patients with chronic brucellosis.

Additional support for the conception of chronic infection as the source of chronic brucellosis is the fact that adequate treatment of acute brucellosis reduces the likelihood of chronic brucellosis. Conversely, it could be reasoned that inadequate treatment renders a potentially deleterious autoimmune response to infection more likely; this response would mature during the latent interval between the acute and chronic phases of illness.

Since chronic brucellosis does not develop in all untreated individuals, other host factors likely play a role in susceptibility to chronic infection. Certain individuals may be more vulnerable than others to development of a chronic state of infection because they have greater than average immunoincompetence specific for Brucella species. Macrophages have greater-than-average difficulty killing circulating Brucella organisms. These individuals also may have greater-than-average failure of T-cell sensitization or T-cell mediation of macrophage activation. Other factors also may play a role.

Although it is possible that certain individuals are destined to develop chronic brucellosis because they are genetically deficient in their immune response to infection or are subject to immunodysregulation in response to infection, there is no clear evidence to support this contention. Thus, there is no clear familial or racial predilection for acute or chronic brucellosis. Although the greater tendency of males to develop either form of brucellosis is clear and could suggest a genetic basis, this predilection is at least as well explained by occupational or hygienic considerations.

In many cases, chronic infection is clearly an element of chronic brucellosis. Animals are susceptible to this chronic infection and tend to harbor Brucella organisms in their genital tracts. Humans that remain chronically infected usually harbor Brucella organisms in their lymphatic/reticuloendothelial system. Bones and joints are the organ systems next most likely to remain chronically infected. Inflammatory changes of chronic brucellosis variously detectable in the nervous system, eyes, heart, lungs, kidneys, liver, and human genital tissues suggest that these also may be sites of chronic infection.

Each of these various tissues has the capacity to manifest abnormalities in patients with chronic brucellosis. The specific manifestations of chronic brucellosis may be limited to one or a few organ systems, in which case the chronic disease is termed focal, or may involve a number of organ systems, in which case the disease is termed diffuse. In some instances, a single organ system is the primary site of chronic disease, most commonly the heart (subacute bacterial endocarditis) or the bones and joints (most commonly chronic infection of the vertebrae and associated joints and soft tissues). We do not know why certain organ systems should be favored sites for infection.

Evidence of focal dysfunction of the nervous system, either central or peripheral, is found in 5-10% of cases of chronic brucellosis, and this condition is properly termed neurobrucellosis. Nervous system involvement may be the only manifestation of focal chronic brucellosis, or the nervous system may be one of several systems involved in chronic diffuse brucellosis. Nervous system dysfunction may be a primary element (produced either by the invading organism or by the host response to the invading organism) or secondary (occurring as a complication of endocardial, cerebral endovascular, or spinal infectious/inflammatory processes).

Why the nervous system presents itself as the primary site of focal brucellosis in some patients is not known. It may be a favored site of chronic infection because of inadequate immune surveillance, or it may be particularly vulnerable to autoimmunity engendered by Brucella organisms that have chronically infected other parts of the body or by reintroduction of infection to an already sensitized individual.

Where tissues manifest changes consistent with primary involvement, a classic hallmark is development of a granulomatous cellular response to brucellosis. This is not the only type of pathological change seen in brucellosis, either within or outside of the nervous system. But when this response is present and fully developed, changes include the appearance of epithelioid cells, giant cells of Langhans/foreign body types, lymphocytes, and plasma cells. In most cases of chronic brucellosis, granulomata are noncaseating. These may develop in almost any organ system, but are most likely to be found in the reticuloendothelial system. The next most common sites are bones (usually spinal), testes, and endocardium.

Caseating granulomata may be encountered in various tissues and organs, particularly in chronic brucellosis due to B suis. The pathology of granulomata related to B suis may very closely resemble that of granulomata found in tuberculosis or sarcoidosis. Either inadequate or dysregulated immune responses of the host likely account not only for the chronic infectious illness that may occur in some cases, but also for the inflammatory changes that may themselves be responsible for many of the various systemic and neurological complications of chronic brucellosis. Noncaseating granulomata may be found in the CNS.

Evidence of intrathecal inflammation, either in response to infections of CNS tissues or as an aspect of the host's immune response, is suggested by the findings in CSF. CSF may show, as in some cases of acute brucellosis, elevation of spinal fluid protein level and hypoglycorrhachia. More commonly than in cases of acute neurobrucellosis, brain edema may develop as a feature of chronic neurobrucellosis.

The occurrence of inflammatory central and peripheral demyelination as the pathological manifestation of some types of neurobrucellosis, associated with inflammatory perivenular infiltration but not with histologically demonstrable organisms, strongly suggests that autoimmune mechanisms play a role in some types of neurobrucellosis. The pathological appearance of this change in the brain is virtually identical to that found in acute disseminated encephalomyelitis (ADEM), while the change that may be found in peripheral nerves or spinal roots may be identical to that found in acute inflammatory polyneuritis of the Guillain-Barré (GBS) variety.

In these types of chronic neurobrucellosis, axons tend to be spared, although in severe cases, as in severe ADEM or GBS, there may be considerable axonal loss and associated encephaloclasia or peripheral neuraxonal dissolution. The pathological changes observed also share certain aspects of their appearance with multiple sclerosis (MS) or neuroborreliosis.

As with ADEM or GBS, it remains uncertain whether the autoimmunity is due to an overexuberant or dysregulated response to Brucella that has been present in the tissue that displays the inflammatory demyelination (bystander effect), whether the demyelination develops because infection or inflammation uncovers hidden host epitopes to which the host immune system has not developed tolerance, or whether immunogenic epitopes of Brucella organism that have been present within these tissues or in some other location closely resemble human epitopes found in the tissues that become demyelinated (molecular mimicry).

The mechanisms that produce changes that resemble ADEM or GBS in patients with chronic brucellosis are also very likely to participate in the pathogenesis of isolated papillitis, brucellotic meningitis, meningoencephalitis, and some cases of myelitis. These mechanisms may account for the development of syndromes that closely resemble MS both clinically and radiologically.

It is also possible that the occurrence of a hyperergic immune response after latency from a bout of acute brucellosis is not due to the slow working out of autoimmunity during a phase of chronic infection, but to reinfection. Thus, host sensitization to brucellar epitopes occurred during the primary acute bout, and the appearance of chronic brucellosis takes place only after reinfection. The recovery of organisms or their identification in the tissues could be viewed, in the light of this hypothesis, as the result of reinfection rather than persistence of infection.

As with cerebral malaria, Lyme disease, neurosyphilis, and other infectious diseases that provoke significant intrathecal inflammation, the manifestations of chronic neurobrucellosis are protean. Prominent meningoencephalitic inflammatory changes may be found with arachnoid thickening. Infectious, parainfectious, or postinfectious demyelination with perivenular inflammatory infiltration is a prominent feature in many cases. The perivenular infiltrate is predominantly lymphocytic. Retrobulbar neuritis and papillitis may occur. These various pathological changes often closely resemble those of ADEM.

Chronic inflammatory changes may be found in the perineurium in patients with neurobrucellosis, and adhesive arachnoiditis may develop in the subarachnoid space. Perineural inflammation may lead to dysfunction of cranial or peripheral nerves, with resulting focal cranial neuropathies or radiculitis syndromes, especially if these inflammatory changes progress to the point of granuloma formation.

True arteritic vasculitis also may occur, resulting in focal or multifocal arterial occlusion or infarction or mycotic aneurysm formation. The vascular infiltrate includes lymphocytes, plasma cells, and macrophages. These vascular changes may occur in large or smaller caliber arteries. Vasculitis may be due either to bacterial proliferation in the vascular endothelium or in some instances to the actions of bacterial toxins. Once these initial changes have occurred, host-engendered inflammatory responses also may participate in pathogenesis.

Whether the establishment of bacterial infection in cerebral arteries is the result of invasion by individual organisms circulating in the septicemic phase of infection or of septic embolization from brucellar endocarditis is not always clear. Either mode of tissue invasion may be pertinent. Pathological evidence for endovascular infection, dissolution of the endovascular and mesovascular layers, and formation and rupture of aneurysms with intraparenchymal or subarachnoid hemorrhage all may be found in pathological analysis of brains obtained from individuals with a fatal case of neurobrucellosis.

Transient ischemic events or stroke with ensuing encephaloclasia may cause neurological dysfunction in patients with neurobrucellosis, on the basis of either vasculitic luminal compromise or embolization from heart or areas of vasculitic ulceration. Septic embolization may in rare instances result in Brucella brain abscess.

Lumbar vertebral body and disk granulomata as well as other sites of spinal column inflammation may result in spondylitic extraaxial spinal cord compression. Brucellar spondylitis is most likely to occur in the lumbar region. Sacroiliac joints also may be involved. Inflammatory investment of the cauda equina may occur. Degeneration of anterior horn cells and of both ascending and descending fiber tracts may occur.

There is not as yet any generally accepted explanation for the increased likelihood of brucellosis or neurobrucellosis in the second through fourth decades of life and the considerably reduced likelihood of infection in children, except for the age-related variation in exposure to infected animals. It is conceivable that some aspect of maturation of the immune system plays a role.

Additional forms of neurological dysfunction may occur as the secondary result not only of Brucella endocarditis or arthritis, but of Brucella disease in other organ systems, including kidney, liver, and lung.

Frequency

United States

As in the rest of the world, incidence of brucellosis in the United States is likely to peak during summer. Since pasteurization of milk and milk products has become routine and abattoirs have become closely regulated, the United States has remained essentially free of brucellosis for quite a few years. Incidental cases arise as a result of relaxation of surveillance standards or because of the increasing international exchange of foodstuffs and animals that may harbor Brucella organisms.

In North America, cattle-related B abortus has been the most common cause of brucellosis, except in isolated regions of the Midwest where pig farming is prevalent. Dramatic reductions in B abortus prevalence in the cattle of the United States owing to the Cooperative State and National Brucellosis Surveillance project between 1945 and 1960 caused B suis to emerge as the major public and agricultural health threat. The peak occurrence of human cases of B abortus brucellosis (6321) occurred in 1947. Comparatively few cases are now observed in the United States.

Subsequent concentration of surveillance on hog farms and abattoir workers was devoted to the elimination of B suis, which became the predominant cause of human brucellosis in the United States in the 1970s. These programs have significantly reduced the prevalence of this Brucella species as well. In the decade of 1973-1982, 2215 cases were reported, as compared to 1056 cases from the decade 1993-2002. Most of these cases are now confined to California and Texas, although cases occasionally arise in isolated regions of the Midwest.^{[1 ]}

Currently most human cases in the United States are due to B melitensis, with 80% of cases wherein an ethnic label was applied are Hispanic, likely due to the large number of Hispanic workers in abattoirs. Moreover, the largest regional cluster is in the Southwestern, Mountain, and Pacific states nearest to Mexico; these regions experience comparatively large numbers of cases chiefly within the Hispanic population related perhaps in part to abattoir work, as well, and perhaps more importantly to travel to Mexico and to the consumption of unpasteurized soft Mexican cheese.^{[1 ]}

In the decade of 1993-2002, at least one case was reported in 46 states, with 26 states recording a case in 2002. Although the number of cases is small, the highest annual incidence is in Wyoming. North Carolina (27 cases in 1993) and Arkansas (9 cases in 2001) experienced clusters of cases. States with the highest recent annual incidence (cases per million) are Wyoming (1.46), Texas (1.38), Hawaii (1.09), Arkansas (0.95), Arizona (0.92), California (0.83), Iowa (0.77), New Mexico (0.69), and Illinois (0.57).^{[1 ]}

B abortus continues to be harbored in gregarious North American wild animals that tend to exist in herds, such as the bison of Yellowstone National Park and adjacent regions of the nearby Rocky Mountain States. The potential for social interaction between bison and cattle poses a threat for spread of infection, a prospect that is monitored carefully. Brucella organisms also are harbored by the reindeer of Alaska, accounting for occasional human cases.

Large-scale pig farming in eastern Tennessee prior to the Civil War may have accounted for undulant febrile illnesses in that region. Whether the growth of large-scale hog farming in the southeastern United States will provoke cases of brucellosis in that region is not known.

Immunization of animal herds, combined with surveillance and culling of infected animals, has proven, in the United States, the best method for prevention of human risk for disease, as for the tremendous economic toll that brucellosis may exert on agriculture owing to abortion of fetuses or sterility of rams or billy goats.

The B abortus and B suis species that have accounted for most brucellosis in North America are less likely to engender clinical disease in humans than B melitensis. When disease develops in North Americans, it often does so with greater latency to onset and milder manifestations.

International

Considerable changes have taken place in the epidemiology of brucellosis during the past few decades with declining prevalence in some regions as the result of extension to increasing numbers of countries of sanitary or herd surveillance/culling practices, although contrary forces have negatively impacted distribution elsewhere. The negative forces have included political and socioeconomic forces that have fueled regional wars or reduced vigilance in control programs, as well as international travel of people and agricultural products that may carry the organisms far and wide.

Of importance, such formerly endemic areas as Israel, France, and much of Latin America have achieved control of the disease.^{[1 ]}South Korea, where the disease was formerly controlled may have experienced a resurgence. Considerable worsening may be taking place in Syria as well as in various nations of central Asia.

In countries where brucellosis continues to be a common problem, epidemiologically and retrospectively distinguishing brucellosis from the many other zoonotic or arboviral causes of fever prevalent in such locations may be difficult. Indeed, individuals may be co-infected such as a recently reported case of febrile illness due to both malaria and brucellosis acquired by a traveler in Chad.^{[6 ]}Thus, the prevalence of brucellosis remains difficult to estimate.

Among the nations for which reliable data are available those with the highest current incidence in annual cases per million people (indicated in parentheses) are Syria (1603.4), Mongolia (605.9), Kyrgystan (362.2), Iraq (278.4), Turkey (262.2), Iran (238.6), Saudi Arabia (214.4), Tajikistan (211.9), Macedonia (148), Kazakhstan (115.8), Algeria (84.3), Albania (63.6), Azerbaijan (52.6), Turkmenistan (51.5), Lebanon (49.5), United Arab Emirates (41), Oman (35.6), Peru (34.9), Tunisia (34.5), Kuwait (33.9), Armenia (31.3), Mexico (28.7), Georgia (27.6), Jordan (23.4), Greece (20.9), and Bosnia/Herzegovina (20.8). No data are available among other regions of importance for India, Pakistan, or Afghanistan, where the disease undoubtedly endemic.^{[1 ]}

Inspection of the list suggests that disease prevalence is adversely affected by poverty, famine, political unrest, and war and is understandably more common in regions where sheep, goats, and camels are abundant. Absence of careful supervision of abattoirs likely considerably increases risk of human brucellosis. Movement of herds of sheep and other animals in pursuit of grass may variably spread Middle Eastern cases of brucellosis from one nation to another.

Of interest in this regard was the fall in annual incidence of brucellosis in Kuwait during the 1991 interval of Iraqi invasion during which many sheep were slaughtered or otherwise removed. Reconstitution of these herds has resulted in an ensuing increase of incidence toward preinvasion levels.

The data for Syria, manifesting the highest international rate of human brucellosis cases (1603 cases per million population per year), are particularly alarming, and there is evidence that the number of cases have been nearly doubling each recent year. Turkey, with very high rates in the eastern portions of the country, also has worsening statistics, although the Turkish government has instituted a control project. Iran may have cut the annual incidence by more than 75% between 1989 and 2003.

Employing surveillance and animal vaccination/culling techniques, many nations have rid themselves of zoonotic reservoirs, thereby freeing these nations from locally acquired human brucellosis. Additionally, the export of meat or dairy products from countries certified to be free from these Brucella species can be undertaken without risk of transmission of brucellosis to individuals who consume such foods. However, individuals resident in certified countries and the United States remain vulnerable to brucellosis cases that arise due to travel to endemic regions or dietary acquisition via the consumption of dairy or other products imported from endemic regions. Other nations continue to have reservoirs for various Brucella species that pose a threat for transmission of brucellosis to humans.

More than occasional cases are detected in countries surrounding the Mediterranean; India; China; other parts of Southwest, Central, and Southeast Asia; Africa; Central America; and South America (eg, Peru). Northwest Iran and Northeast Turkey are areas of particularly high density of cases of brucellosis. Epidemiological factors of importance include consumption of unpasteurized dairy products obtained from cow, goat, and camel. Close occupational contact with animals (eg, cows, goats, sheep, camels, pigs, hares, rabbits, reindeer) increases risk, as does the consumption of raw, poorly cleaned, or partly cooked meat from such animals. Aerosol and hand-to-mouth transmission may occur in abattoirs or laboratories.

Brucellosis is much more common during summer than winter months, even in regions of the world where winters are comparatively mild. Worldwide, B abortus accounts for the largest number of human and veterinary cases of brucellosis. Estimates of the veterinary toll alone in Latin America due to this organism range as high as $700,000,000. B suis ranks second as a threat to public and veterinary health in the western hemisphere.

In the Mediterranean region and Middle East, the species of greatest importance is B melitensis. In Malta, during the prime of Malta fever due to B melitensis, peak incidence was in August, while the lowest incidence was in January and February. B melitensis is harbored in sheep, goats, and camels. The brucellosis produced by this species is typically more severe than the brucellosis produced by other Brucella species.

The World Health Organization "Mediterranean Zoonoses Control Project" has implemented surveillance, herd vaccination, and culling of infected animals using methods similar to those employed in the United States since 1945. This project has steadily eroded the prevalence of brucellosis in this region. Similar methods have been projected for other portions of the world, but implementation has been inadequate in many areas because of expense, warfare, lack of concern, and other reasons.

Among the highest prevalences for human B melitensis brucellosis is that of the Bedouins of Kuwait, who have more than 540 cases per 100,000. Seroprevalence for Brucella antibodies is 1-7% in Turkey and Iraq, and 10% in Egypt. More than 40% of all cases of fever of unknown origin in Egypt are believed to be due to brucellosis.

Saudi Arabia and several adjacent countries experienced a very considerable rise in prevalence of human and animal brucellosis disease as the result of the investment of oil revenues into massive expansion of husbandry. The importation of considerable numbers of untested and unvaccinated goats, sheep, and other animals outstripped efforts to monitor veterinary brucellosis. This husbandry was designed to provide food for Hajj pilgrims. As a result, 20% of Saudi Arabians have demonstrated seropositivity, and 2% of the population are believed to have active disease. The incidence of new cases is highest during the Hajj; the increase is due to cases among pilgrims to Mecca.

Estimates of prevalence of human or animal brucellosis are not available for many countries of the world. Prevalence is likely high in many countries of Africa and Asia. In Nigeria, 55% of the population was found to be seropositive for Brucella species.

The economic importance of large-scale cattle and sheep husbandry in New Zealand and Australia has made brucellosis a particularly important consideration.

Fortunately, neither B melitensis nor B suis have ever been endemic in either country, and well-designed regulations have long been in place to prevent any threat of introduction. The few human cases of brucellosis due to these agents diagnosed in these countries (few in Australia and very few in New Zealand) in the last few decades have been carefully investigated and have been shown to have been acquired in other endemic areas of the world to which these individuals had traveled. Australian cases tend to be confined to the area of Queensland, one of the poorest regions in Australia.^{[1 ]}The most recent estimate of incidence of human brucellosis in Australia is 0.9 cases per million people per year, while the rate in New Zealand is virtually nil.

B abortus was endemic in both Australia and New Zealand from at least the 1920s until the 1980s. However, a rigorous and remarkably effective program of herd surveillance, vaccination, and a "test and slaughter" culling of infected animals has eliminated this Brucella species from both countries. The last documented bovine case in New Zealand occurred in 1989, and both New Zealand and Australia were certified free from bovine brucellosis in 1992.

As a result of internationally sanctioned programs for zoonosis control that have included national projects for eradication of reservoirs, certification of herds, regulation of the shipping of animals, and periods of preshipping and arrival quarantine, the meat and dairy products of countries such as New Zealand and Australia can be offered to the world without risk for transmission of brucellosis. Such work has been undertaken on a species by species basis, depending upon which Brucella species is endemic within a given country, followed by certification (after adequate intervals of effective surveillance) of freedom from a particular Brucella species. For example, the eradication and ensuing freedom from B abortus has been certified not only for Australia and New Zealand, but also for Austria, Canada, Denmark, Finland, Japan, Switzerland, and various other countries.

Mortality/Morbidity

Brucellosis is only rarely fatal with many mild cases, and in more severe cases, excellent response to appropriate antibiotics. However, brucellosis remains a major cause of morbidity throughout the world, particularly in medically underserved regions. Brucella species are capable of causing protean manifestations, ranging from mild to severe. Illnesses caused by Brucella species may be ascribed incorrectly to other pathogens or to unspecified viral illnesses. In many countries, the etiology may not be identified correctly. In many parts of the world, brucellosis is not a reportable illness.

• Overall mortality rate in recognizably symptomatic acute or chronic cases of brucellosis is very low, probably less than 2%. It is usually the result of the rare instance of Brucella endocarditis or is the result of severe central nervous system involvement, often as a complication of endocarditis.
• The outcome from acute Brucella meningoencephalitis is usually excellent, although some individuals develop chronic neurobrucellosis.
• Chronic neurobrucellosis may result in permanent neurological deficits.
• The chronic phase of illness may persist for as long as 25 years, but such cases are quite rare.
• Neurological complications occur in approximately 5% of all cases of brucellosis, usually in the chronic phase of illness.
• Relapses occur in approximately 10% of cases of brucellosis.
• Granulomatous disease of bone or joints may result in pain, deformity, and disability of spine or limbs. Some form of osteoarticular disease is present in nearly 30% of cases.

Race

No racial predilection for brucellosis or neurobrucellosis is known.

Sex

Young adult males predominate in most series of patients with brucellosis compiled in areas of endemic disease. A recent report from Northern Saudi Arabia found a male-to-female ratio of 1.7:1, chiefly individuals aged 13-40 years.^{[7 ]}

• The cases represented in such series are caused chiefly by B melitensis.
• Occupational exposure to animals likely plays an important role in the enhanced vulnerability of men to the development of brucellosis.
• Whether the increased risk manifested by males is additionally influenced by aspects of personal hygiene, immunological factors, or other circumstances is not known.

Age

Brucellosis in the Mediterranean, chiefly due to B melitensis, has the highest age/sex-related incidence in males in their mid 20s. A recent report from Northern Saudi Arabia found that 60% of cases of brucellosis occurred in individuals aged 13-40 years, while 21% were younger than 13 years, 16% were aged 40-60 years, and 2.5% were older than 60 years.^{[7 ]}

• For unknown reasons, men aged 13-40 years are particularly vulnerable to the manifestation of illness due to B melitensis. Possible explanations include engaging in activities such as animal husbandry that increase exposure to Brucella organisms and less diligent personal hygiene. The predilection is not universal since 60% of cases in Jordan occur in individuals younger than 24 years.
• Elderly individuals with acute localized brucellosis are particularly likely to manifest destructive localized brucellosis of the spine.^{[8 ]}
• Prepubertal children account for fewer than 2% of all cases of neurobrucellosis; fewer than 50 such cases have been described in peer-reviewed medical literature over the past 50 years.
• Brucellosis is quite uncommon in infants. Transmission to infants may occur through breast milk or ingestion of raw milk.

Clinical

History

In various series, neurological abnormalities have been found in 3-25% of patients with brucellosis. If the headache, irritability, and other constitutional symptoms found in acute brucellosis were included, the prevalence would be much higher. Having excluded these symptoms, the best-documented studies suggest that the prevalence of discrete neurological abnormalities in brucellosis is approximately 5%. In most cases, these abnormalities arise as features of chronic brucellosis, hence their development in the wake of a latent period after an initial bout of acute brucellosis is what is generally meant by the term neurobrucellosis. In some instances, similar abnormalities may arise during acute or subacute phases of brucellosis.

Because an acute phase of brucellosis usually precedes the subsequent development of neurobrucellosis, this acute phase constitutes an important clue to the etiology of the neurological syndrome. Therefore, the historical and clinical aspects of acute brucellosis are considered first in this section.

Historical details of importance in establishing that acute brucellosis has occurred include risk for exposure to Brucella organisms and evidence of clinical illness consistent with acute brucellosis.

Risk factors for acute brucellosis

The risk factors for brucellosis differ somewhat depending upon whether a given individual resides in or has recently visited a region of endemic disease.

• Endemic exposure: Brucellosis should be considered in all patients whose place of residence or dietary, travel, or occupational history suggests a risk for the infection, if they are experiencing any of the various known neurological or non-neurological complications of brucellosis. It must be borne in mind that latency from infection to onset of symptoms of primary brucellosis may be as long as months.
  • Threshold for consideration of brucellosis is low in regions of endemic disease, where diagnostic testing is undertaken for any of the many atypical presentations or unusual complications.
  • Dietary history is especially helpful in diagnosing brucellosis in individuals who live in or visit regions of endemic disease.
  • Unpasteurized dairy products, especially goat's cheese, frequently are implicated as sources of human infection.
  • Raw or poorly cooked meats are also important sources of infection in regions of endemic disease.
  • Occasional person-to-person transmission has been reported, including transmission to infants via breastfeeding. There is a little evidence for sexual transmission of brucellosis.
  • Laboratory transmission of brucellosis may occur, especially in regions of endemic disease. It is estimated that 12% of laboratory workers in Spain acquire brucellosis.^{[9 ]}
• Nonendemic exposure: Brucellosis poses a particular diagnostic challenge in persons not from regions of endemic disease.
  • In areas of the world where brucellosis is rare, the diagnosis may be missed even in patients who manifest typical signs, such as otherwise uncomplicated persistent undulating fever. The possibility of brucellosis is even less likely to be recognized promptly in cases that present atypically.
  • Dietary history is important in evaluating individuals who live in regions where the disease is not endemic for the possibility of brucellosis, since the disease may be acquired by ingestion of infected foods shipped from regions of endemic disease. The foods most likely to transmit brucellosis are noted in the previous paragraph.
  • Although a wide variety of potential intermediate hosts have harbored brucellosis in the extra-Mediterranean world, dairy cattle infected with B abortus have been a particularly important host in North America.
  • Ingestion of unpasteurized milk from cows or goats enhances risk of infection in both regions of endemic disease and regions in which the disease is not endemic.
  • The infection is often symptomatic in cattle. Outbreaks of epizootic bovine abortion due to B abortus should alert health care providers to the possibility of human brucellosis.
  • Some cases in humans in North America have been traced to eating pork from hogs infected with B suis.
  • Brucellosis has developed in infants who have breastfed from mothers who either visited regions of endemic disease or ingested foodstuffs shipped from such regions.
  • In nonendemic regions, physicians, veterinarians, pathologists, and laboratory personal exposed to tissues from infected animals (including humans) are at particular risk for brucellosis, as is the case, of course, in endemic regions.^{[9 ]}Surprisingly, infection with Brucella species accounts for as many as 10% of laboratory-acquired infections, 24% of laboratory-acquired bacterial infections, and 11% of occupational-exposure deaths in the United States.^{[10 ]}
  • Aside from laboratory workers, the risk for brucellosis is highest for individuals with exposure to goats, sheep, cows, camels, pigs, reindeer, rabbits, or hares in both areas of endemic disease and areas in which the disease is not endemic. Therefore, herders, hunters, farmers, dairy workers, veterinarians, abattoir workers, and meatpackers are at elevated risk for brucellosis.
  • In Scandinavia and Alaska, reindeer are an especially important source of brucellosis.

Clinical manifestations of acute brucellosis

In most instances, the manifestations of acute brucellosis consist of a characteristic fever and various constitutional signs and symptoms, but few localizing features.

• The latency from infection to onset of symptoms of acute brucellosis is usually between 5 and 21 days. Occasionally, the interval between infection and first worrisome symptoms, including fever, may be as long as 7 months^{[10 ]}, or perhaps longer. The classic ensuing septicemic course is most likely to occur in regions of endemic disease and is usually due to B melitensis infection.
• The severity of the illness ranges from mild to seriously ill. Mild cases may last for just a few days, while the acute phase of severe cases may persist for weeks to many months. In some cases this lingering illness consists of fever and malaise, which occur in most cases. In some cases, severe debilitation may occur.
• Common manifestations of acute brucellosis include fever (80-90% of cases, as high as 40 º C or higher), chills, anorexia, insomnia, joint pain (60-80% of cases), bone pain (40-60% of cases), myalgia (20-70% of cases), profuse night sweats (20-25% of cases), and irritability (common). Cough may develop in individuals with cervical brucellotic epidural abscess.^{[10 ]}
• The fever of acute brucellosis caused by B melitensis usually lasts for 10-30 days, undulates irregularly, and is not associated with rash.
  • Some very severe cases are termed malariform brucellosis because the undulating fever spikes reach very high temperatures and are associated with chills, drenching sweats, and prostration from the very onset of illness.
  • The irregular undulation of fever spikes distinguishes malariform acute brucellosis from malaria, which produces quite regular fever spikes; the periodicity of malaria fever spikes (eg, tertiary, quaternary) is determined by the type of malarial parasite that has infected the host.
  • Fever and other constitutional manifestations of acute brucellosis tend to be more severe and persistent in patients who attempt to remain active. Severity and duration typically are reduced by enforced bedrest.
  • Classic acute septicemic presentations of brucellosis are very uncommon in North America and other regions in which the disease is not endemic.
• Some patients manifest focal abnormalities during acute brucellosis.
  • The spine is one of the most frequent sites for acute localized brucellosis, particularly in elderly individuals.^{[8 ]}Thus, the most common focal manifestation of acute brucellosis is pain, usually localized to the lower spine, paraspinous muscles, or upper buttocks. In some cases, neuralgic pain is distributed along lumbosacral peripheral nerves, especially the sciatic. The region of the lumbosacral vertebrae may be tender to percussion, as may the course of the sciatic nerve. Thus, these clinical features may closely resemble sciatica. The costovertebral joints may be similarly afflicted.
  • Discomfort in the region of the spine may precede onset of fever by intervals of 3 months or longer. The diagnosis of brucellosis should not be discarded in endemic or nonendemic regions merely because of this long nonspecific prodrome, particularly where exposure to brucellosis has been documented. Prolonged absence of radiculopathy or of definite motor or sensory findings does not exclude the diagnosis of brucellosis.^{[10 ]}
  • Brucellosis of the cervical vertebrae may present with neck swelling and pain worsened by neck rotation or extension/flexion. Neck muscles may be tense or rigid and range of motion may be reduced. Mild headaches may occur in association with the neck pain. These findings may wax and wane and may be incorrectly credited to neck strain. Pain on swallowing may be a complaint. Associated subjective complaints such as intermittent finger tingling or numbness should be taken seriously in patients with neck complaints as noted above, even where objective findings are not confirmed. A sense of focal warmth in neck or low back may accompany onset of the febrile phase of spinal brucellotic osteomyelitis with epidural abscess, as may tachycardia.^{[10 ]}
  • In individuals with a history of neck pain as noted above, the development of limb weakness and objective sensory changes, especially in regions where brucellosis is endemic or in individuals in nonendemic areas with exposure to brucellosis, should elevate the urgency of consideration of brucellotic epidural abscess. This is particularly true if fever, involuntary muscular tension, or sensory abnormalities are discerned in an appropriate radicular distribution.^{[10 ]}
  • Occasionally, patients develop pain, tenderness, swelling of limb joints (often monoarticular, knees more than elbows), or bone ends.
  • Skin ulcerations, purpura, erythema, or petechiae may be found, from which organisms may at times be cultured. Some of these changes, especially the purpura, arise as consequences of immune-mediated thrombocytopenia.
  • Abdominal discomfort or pain may be associated with anorexia and weight loss. The pain may in some instances suggest an acute abdomen. In instances where there is right upper quadrant pain, hepatic abscess must be excluded, especially if associated jaundice is present.
  • In some cases, tender enlargement of the spleen is discerned.
  • Some patients develop constipation.
  • In male patient instances, tender enlargement of the testicles due to epididymo-orchitis, resembling mumps orchitis, develops after the first few days of high fever and chills or chilliness. Although it can be painfully persistent for a number of days, unlike mumps orchitis or brucellosis in sheep or goats, it seldom leads to sterility in humans.
  • Urethritis or urinary tract infection may be found. Occasionally, the kidneys are involved, although the disease seldom results in renal failure.
• Unlike brucellosis of cattle, human acute brucellosis does not appear to carry any higher risk for abortion than any other form of bacteremic illness.
• Rarely, some severe varieties of focal involvement of nonneurologic organ systems may occur as complications of acute brucellosis, complications that may secondarily injure the nervous system during the acute or ensuing chronic phase of brucellosis. These complications tend to arise in patients who are quite ill.
  • Patients may develop such pulmonary complications as pleuritis or pneumonia, causing shortness of breath, pleuritic chest pain, and considerable fatigue. These complications are more common during the chronic phase of brucellosis.
  • Rarely, bacterial endocarditis develops in patients who are very ill with acute brucellosis, causing chest pain, weight loss, severe fatigue, and various cardiopulmonary findings. Much more commonly, subacute brucellotic endocarditis arises during the chronic phase of brucellosis.
• The neurological manifestations of acute brucellosis include constitutional complaints (very common) and focal neurological disorders (rare).
  • Nonfocal neurological manifestations of acute brucellosis include headache, irritability, lethargy, depression, disturbed consciousness and concentration, anorexia, and disturbed sleep.
  • As noted above, headache, waxing and waning over a considerable period, may be the only sign of acute brucellosis, with symptoms suggesting migraine.
• The neurological syndrome most likely to arise in individuals in the acute phase of intracranial brucellosis is encephalopathy, with or without evidence of meningeal irritation.
  • Encephalopathic acute brucellosis is most likely to arise with B melitensis infection.
  • Mental status changes in acute brucellosis range along a continuum that includes irritability, confusion, obtundation, and coma.
  • When an encephalopathic syndrome arises during acute brucellosis, it may evolve gradually over weeks to months. During this period, findings may wax and wane. This evolution tends to blur the distinction between acute and chronic brucellosis.
  • In some patients with an encephalopathic form of acute brucellosis, the evolution may suggest development of MS or other chronic inflammatory diseases of the CNS.
  • Some patients with encephalopathic acute brucellosis manifest meningismus, seizures, or CSF pleocytosis, suggesting acute meningitis or meningoencephalitis.
  • Some patients with acute brucellosis have mild or more marked problems with language or memory.
• Sensorineural hearing loss is the second most common focal neurological abnormality to develop in the wake of acute brucellosis; it is localized to the vestibuloacoustic nerve.
• Rarely, neurological complications such as stroke or abscess may complicate brucellar endocarditis when the complication develops during the acute phase of brucellosis.
• Rare instances of hemiparesis complicating acute brucellosis have been described, some of which are due to brucellar endocarditis.
• Inflammatory pituitary abscess has been described in patients with acute brucellosis.
• Elevation of intracranial pressure rarely complicates acute brucellosis.
• Some patients have very mild courses of acute brucellosis, without strong suggestion of a septicemic course.
  • Findings consist chiefly of fever and malaise suggestive of influenza, without any additional focal complaints.
  • The long duration of fever and malaise, which may persist for 3 months or more, usually distinguishes brucellosis from influenza and many other febrile viral illnesses.
  • Low-grade, long-term exposure to Brucella organisms is especially likely to engender mild brucellosis, hence this form of disease is seen in regions of endemic disease as well as in veterinarians and some individuals with occupational animal exposure in regions in which the disease is not endemic.
• Evidence for spinal brucellosis includes sensory changes (due to posterior cervical epidural abscess) or weakness or loss of reflexes (due to cord compression). These findings may be asymmetrical.^{[11,12,10 ]}

Subacute brucellosis is distinguished from mild acute brucellosis by its more insidious onset, but this distinction is not always clear; hence, these 2 types of brucellosis exist on a continuum.

• Subacute brucellosis does not have discrete onset of undulating fevers and does not produce marked constitutional symptoms.
• Low-grade fevers, aches and pains, and malaise are noted, but are relatively mild, resembling mild cases of influenza; their course persists for 10-13 days (in some cases many weeks, longer than is typical for influenza.
  • As with mild acute brucellosis, the subacute form is most likely to be engendered by long-term, low-grade exposure to Brucella organisms, hence this form arises in some veterinarians or individuals with occupational exposure to herd animals.
  • As with mild acute brucellosis, B abortus or B suis infection is more likely than B melitensis infections to cause of subacute brucellosis.
• Chronic brucellosis develops in the wake of some, but not all, subacute cases.
• In some instances, the development of neurological abnormalities is the first definite evidence that an individual is experiencing subacute brucellosis. These neurological abnormalities may evolve over time into a chronic form of brucellosis.
• Brucella-related deafness is among the most common of the neurological consequences of subacute brucellosis in regions of endemic disease.
• Note that some patients with findings suggestive of subacute brucellosis are actually experiencing manifestations of a nonbrucellotic "chronic fatigue syndrome" or are manifesting psychologically induced complaints.
  • Brucella titers must be interpreted cautiously in attempting to distinguish brucellotic from psychogenic complaints in patients who are resident in areas of endemic disease, because of the high seroprevalence of anti-Brucella antibodies even in patients who have not manifested actual brucellosis.

Historical and clinical manifestations of chronic brucellosis

Chronic brucellosis develops in fewer than 15% of all patients who have had acute brucellosis. The risk for chronic brucellosis is reduced considerably if adequate treatment, including enforced rest, is provided for the acute phase of illness. Patients with chronic brucellosis are particularly likely to manifest anorexia and weight loss.

• Recurrence of fever after a fever-free interval is often the first sign of progression into the chronic phase of brucellosis.
• The interval between the acute and chronic phases of brucellosis varies from days to many months.
• Neurobrucellosis and other manifestations of chronic brucellosis are complications that often--although not always--are prevented by adequate treatment of acute brucellosis.

Neurobrucellosis and other forms of chronic brucellosis may in some instances develop without a known preceding bout of acute brucellosis.

• In such instances, the bout of acute brucellosis may have been very mild and mistaken for influenza or some other mild infectious illness, or the neurobrucellosis may develop as a complication of subacute brucellosis.
• Failure to diagnose acute brucellosis prevents administration of adequate antibiotic treatment, hence missing the opportunity to prevent possible chronic brucellosis.
• The apparent development of a relapse suggesting the onset of chronic brucellosis in individuals who have had a prior bout of acute brucellosis may in some instances actually be the result of reinfection with Brucella organisms, prompting a hypersensitivity reaction with or without additional contributions of infecting organisms to pathogenesis.

The onset of chronic brucellosis generally is announced by the reappearance of fever and constitutional symptoms (eg, lethargy, irritability, fatigue).

• In many cases, the relapses consist solely of typical features of acute brucellosis, such as undulant fever, aches, sweats, and generalized weakness. The recurrence of such bouts is thus highly suggestive of malarial recurrences.
• Relapses resembling acute brucellosis have been known to continue, in the preantibiotic era, over intervals longer than 20 years. This was the case with the pioneering epidemiologist of brucellosis, Alice Evans, who contracted her illness in the laboratory.
• In such cases, the intervals between febrile relapses may entail sustained periods of easy fatigability, weakness, mental depression, headache, and other chronic aches and pains. The punctuating epochs of febrile relapse are markedly more debilitating than the intercurrent nonfebrile epochs.
• In these cases, calcified caseating or noncaseating granulomata may be found in various organs, including the liver, spleen, and kidneys. In association with granulomata is inflammatory infiltration consisting of epithelioid cells, giant cells, lymphocytes, and plasma cells.

In other cases, the relapsing illness includes additional abnormalities referable to specific organ systems.

• If these abnormalities are preponderantly or solely referable to a single organ system, the chronic brucellosis is referred to by some authorities as "focal." If many organ systems are involved, it is referred to as "diffuse."
• Organ systems that may be involved include cardiovascular, pulmonary, musculoskeletal, and nervous systems (neurobrucellosis).
  • Review of various case series suggests that musculoskeletal involvement is a focal complication in 10-85% of cases of human brucellosis.^{[8 ]}In many instances, this is manifested as swelling overlying appendicular skeletal bones and joints.
  • Vertebral brucellosis is one of the most common focal forms of brucellosis, tending especially to effect elderly individuals. Although it is a serious and destructive process leading to pain, deformation, disability, and associated neurological abnormalities, much remains to be learned about choice and duration of antibiosis. Despite aggressive therapy, relapses are common.^{[8 ]}Spinal brucellosis is considered among forms of neurobrucellosis.

Neurobrucellosis develops in about 5% of all brucellosis cases.

• It may appear, along with constitutional signs and symptoms, as the sole specific manifestation of the chronic illness (ie, as focal chronic brucellosis) or in combination with manifestations in one or more other systems (ie, as an element of diffuse chronic brucellosis).
• Where neurobrucellosis is an element of diffuse chronic brucellosis, the resulting neurological dysfunction may be a primary result of brucellotic infection of nervous system tissues or the immune reaction to that infection, or it may be secondary to abnormalities in other organ systems, particularly the cardiovascular (eg, subacute bacterial endocarditis) or musculoskeletal (eg, disease of the bones and joints of the spine) systems.

Clinical manifestations of neurobrucellosis

Clinical manifestation of neurobrucellosis are protean, and may suggest a wide variety of alternative diagnoses, including other chronic infectious, inflammatory, vasculitic, rheumatologic, or granulomatous diseases. Manifestations also may suggest neoplastic, cardiovascular, or metabolic diseases. As noted, these manifestations are either primary (due to primary abnormalities of nervous tissues) or secondary (due to diseases that have arisen primarily in other bodily systems, such as musculoskeletal or cardiovascular systems). The primary forms of neurobrucellosis are considered first here.

• General categories of primary neurobrucellotic manifestations of chronic brucellosis, arranged in their approximate order of frequency from highest to lowest, include 1) diffuse encephalopathy/meningoencephalitis, 2) inflammatory peripheral neuritis/radiculitis, 3) inflammatory demyelinative syndromes, 4) papilledema or papillitis without other focal features, 5) meningomyelitis, 6) posterior fossa (ataxic or brainstem) syndromes, and 7) neuropsychiatric syndromes.
  • The boundaries of these various categories tend to overlap.
  • Although they arise chiefly as manifestations of chronic rather than acute brucellosis, the onset of these various syndromes is usually abrupt, occurring at the time of recurrence of fever after remission of acute brucellosis and an ensuing latent interval. Thus, they are manifestations of chronic brucellosis, but they are acutely manifested neurological disorders that may subsequently become chronic problems. Associated rigors, sweats, and headache are not uncommon.
• Diffuse encephalopathy/meningoencephalitis: Findings suggesting diffuse encephalopathy or meningoencephalitis account for approximately half of the cases of neurobrucellosis.
  • Manifestations include varied degrees of abnormality of mental status and other cerebral cortical functions. The substrate is presumed to be widespread abnormalities of cerebral cortex or its connections.
  • The most common neurobrucellosis syndrome is that which arises in the wake of a preceding bout of acute brucellosis due to B melitensis. In these cases, the relapse of illness is characterized a few days of irregular intermittent fever, headache, lethargy, achiness, and drowsiness, followed by the development of waxing and waning headache that resembles migraine owing to the throbbing, anorexic manifestations, and periods of intense pain and photophobia. Headache may lateralize. Meningismus is common and, in some instances, seizures occur.
  • In other instances, higher cortical function abnormalities develop that range from varied degrees of difficulty with concentration, language, or memory to obtundation or coma. The patient's condition may in some instances be so severe as to require intubation and considerable support.
  • Headache, lethargy, irritability, and disturbances of mood and sleep are common. Severe headache suggests the possibility of increased intracranial pressure from various causes and may require the exclusion of remediable space-occupying lesions. However, severe headache may occur without such underlying causes.
  • Hemiparesis or aphasias may develop.
  • In most instances, meningeal signs may be present (as may be the case in other subcategories of neurobrucellosis) and may be quite marked.
  • In some cases, meningeal signs are the only findings, other than the expected constitutional features of fever, lethargy, and generalized nonspecific weakness.
  • Seizures may occur.
  • In rare instances, abnormalities referable to the basal ganglia and associated systems develop, including parkinsonism, chorea, athetosis, narcolepsy, or cataplexy.
  • Cranial nerve abnormalities may manifest themselves in addition to the cortical signs in some patients, in which case there may be evidence of brainstem lesions or of basilar arachnoiditis or granuloma formation.
  • Basilar arachnoiditis in the posterior fossa may be associated with development of hydrocephalus.
• Inflammatory peripheral neuritis/radiculitis involving the peripheral portions of cranial or spinal nerves and nerve roots occurs in almost 20% of cases of neurobrucellosis.
  • It is probable that some of the peripheral neuritides of brucellosis are pathologically similar to or identical to those of acute inflammatory demyelinating polyneuropathy (AIDP), producing as they do clinical syndromes resembling those encountered in the Landry-type GBS, Miller-Fisher syndrome, or encephalomyeloradiculoneuropathy.
  • More commonly, however, inflammation of the perineurium or axon likely accounts for nerve injury rather than demyelination. This appears to be true of the most common peripheral neuritic syndrome of brucellosis, hearing loss due to vestibuloacoustic neuritis. The pathogenesis of some peripheral brucellotic neuritides, such as the mononeuritis multiplex of the sciatic nerve, likely resembles that of chronic inflammatory demyelinating polyneuropathy.
• Primary cranial neuritis is more common in patients with neurobrucellosis than primary neuritis of somatic or autonomic peripheral nerves.
  • Neuritis of the vestibuloacoustic nerve is the most commonly encountered form of primary peripheral nerve neurobrucellosis. The hearing loss is usually bilateral and the degree of impairment of the function of this nerve ranges from mild to quite severe loss of hearing.
  • Hearing loss may be the only finding in the wake of a relapse of brucellosis. In some series, as many as half of all patients with neurobrucellosis have some degree of hearing loss. Hence, this is an important diagnostic clue for brucellosis.
  • Any of the other cranial nerves may manifest brucellotic neuritis, but those most commonly affected are the oculomotor, trochlear, trigeminal, abducens, and facial nerves as well as the motor divisions of the glossopharyngeal, vagus, cranial accessory, and hypoglossal nerves. The physical findings are appropriate to the specific nerve or group of nerves involved.
  • More than half of all cases of neurobrucellosis include some form of cranial nerve involvement. It is often difficult to know whether these findings are due to inflammatory polyneuropathy or to other possible etiologies, including brainstem encephalitis, basilar arachnoiditis, granulomatous disease of spinal nerve roots, vasculitis, stroke, or increased intracranial pressure.
  • Nerves subserving limbs and trunk are also subject to inflammatory mononeuritis multiplex. The sciatic nerve and its branches are most commonly affected. Radiculitis due to compression by inflammatory disk or bone disease must be excluded.
  • Features that strongly support the diagnosis of mononeuritis multiplex include rapid onset of appropriate neurological signs and symptoms, occurrence in individuals who are not elderly, and loss of the F-wave response. Radiculitis secondary to bone or disk disease is unlikely to arise suddenly in patients who have not had a history of recognized vertebral bone or disk disease.
  • In cases involving some doubt, bone or disk disease can be excluded by spine CT, MRI, and/or myelography. There are instances, however, in which mononeuritis occurs together with disease of bones, disks, and/or associated soft tissues.
  • Mononeuritis multiplex tends to produce demyelination of nerve roots, brachial and sacral plexi, and proximal trunks more than distal portions of the peripheral nerve network. It tends to affect both motor and sensory fibers, leading to areflexic paralysis and sensory ataxia. It resembles chronic inflammatory demyelinating polyneuropathy both clinically and pathologically.
  • A similar process may affect the circumflex, intercostal, and radial nerves and their roots; it also may affect autonomic nerves, causing Horner syndrome and vasomotor and/or trophic disturbances.
  • Brucellar mononeuritis multiplex responds fairly well to treatment of brucellosis, with recovery of F waves and resolution of neuropathic changes.
• Acute inflammatory cerebral white matter demyelinative syndromes, sharing clinical features with ADEM or MS, arise in nearly 10% of all cases of neurobrucellosis.
  • Brucellar inflammatory demyelinating syndromes may wax and wane in a manner that is so similar to that of MS as to have suggested to some authorities that Brucella organisms might be the infectious etiology of MS.
  • Manifestations include abnormalities of higher cortical function, upper motor neuron motor disease, sensory disturbances, retrobulbar neuritis, papillitis, ataxia, and a wide variety of brainstem signs. Optic neuritis with ataxia, paraparesis, or quadriparesis is a comparatively common syndrome; hence, there is an overlap with the ataxic category of neurobrucellosis.
  • Neuromyelitis optica, combining optic neuritis and transverse myelitis, has been described. Optic neuritis with or without transverse myelitis may be unilateral or bilateral; if bilateral, the onset in one eye may precede onset in the other.
  • These various signs and symptoms may relapse and remit or wax and wane, closely resembling the clinical course of MS. Autopsy studies of severe cases have demonstrated demyelinative changes in white matter tracts of brain and spinal cord that closely resemble the changes of MS or ADEM.
  • Meningeal signs and associated abnormalities of cranial nerve function, including papillitis, are not uncommon associated features, and seizures may occur. Hence, there is an overlap between this syndrome and diffuse meningoencephalitis.
  • T2-weighted MRI images may disclose multiple plaques as are seen in MS or ADEM. These lesions tend to be found in the frontal white matter and the centrum semiovale, and often have the "smudge"-like margins characteristic of ADEM.
  • In some cases, there are fairly symmetrical and extensive areas of confluent periventricular and subcortical white matter abnormality involving both hemispheres that is suggestive of Schilder diffuse sclerosis, 1912 type.
  • Patients with demyelinative neurobrucellosis may have oligoclonal bands in CSF, but unlike in MS, simultaneous serum discloses the same oligoclonal bands.
• Papilledema or papillitis without other focal neurological features is a finding in approximately 5% of all cases of neurobrucellosis. Some but not all patients with this finding have signs of meningeal irritation or encephalitis.
  • The findings may suggest Behçet syndrome, venous sinus thrombosis, pseudotumor cerebri, tumor, MS, or other differential considerations.
  • These changes in the optic nerve head may be associated with sixth cranial nerve palsies, in which case elevation of intracranial pressure due to brucellotic pseudotumor, brain edema, obstructive hydrocephalus, venous sinus thrombosis, or intracranial hemorrhage from a ruptured mycotic aneurysm must be excluded. Intracranial pressure is elevated in approximately 25% of cases. Rapid diagnosis and treatment often leads to prompt and complete recovery.
  • Even in patients who manifest isolated optic disk findings but do not have elevation of intracranial pressure, delay in making the diagnosis of neurobrucellosis and instituting adequate therapy places the patient at risk for the development of more severe meningoencephalitic manifestations.
• Inflammatory meningomyelitis, that is, the association of meningeal signs, mental status changes, and inflammatory disease of the spinal cord, occurs in approximately 5% of all cases of neurobrucellosis. There is overlap between this syndrome and the diffuse meningoencephalitic and acute inflammatory demyelinative syndromes already noted.
  • In some instances, myelitis develops in association with the usual constitutional signs of chronic brucellosis (fever, pain, sweats) but with little or no evidence of cerebral dysfunction. These cases may, however, be associated with meningismus.^{[10 ]}
  • The pathogenesis of myelitis may be a direct effect of invasive organisms, although it is more likely to represent an inflammatory demyelinative process.
  • The myelitic component of this syndrome must be distinguished from myelitic syndromes that are secondary to brucellosis of the spine, adhesive arachnoiditis of the spinal canal, or stroke syndromes secondary to vasculitis, vasculopathy with hemorrhage, or subacute bacterial endocarditis with embolization.
  • Myelitic syndromes of very rapid onset are more suggestive of an inflammatory or vascular etiology, while a more insidious course of onset suggests compressive myelopathies due to arachnoiditis, granulomatous changes, or arthritic brucellosis of the spine.
  • Neurobrucellotic myelitis may be more or less extensive, producing various combinations of spinal signs, including sensory levels, although sensory tract involvement is less common than motor involvement, with weakness and pyramidal signs. Sphincter dysfunction may develop.
• Syndromes that are predominantly referable to the posterior fossa arise in approximately 5% of all cases of neurobrucellosis. Subtypes include ataxic syndromes (referable to the cerebellum or its brainstem connections) and cranial nucleus syndromes (single or multiple)
  • Posterior fossa signs, including ataxia and cranial nerve palsies, are fairly common features of various neurobrucellotic syndromes; hence, there is considerable overlap between this and other neurobrucellotic syndromes. This subgrouping is set apart from others chiefly by the predominance of brainstem/cerebellar findings.
  • Cranial nerve nucleus signs may include abnormalities of pupils, eye movements, or facial movements or sensation, diplopia, dysphagia, dysarthria, and other abnormalities. The localization must be distinguished, where possible, from peripheral cranial neuritis by detection of neighborhood signs.
  • Associated long-tract findings are not uncommon. Crossed findings (eg, findings consistent with various known brainstem syndromes or long-tract findings that involve an arm and the contralateral leg) help to distinguish the fact that localization is predominantly posterior fossa.
  • Ataxic syndromes may be the sole focal manifestations of neurobrucellosis or may occur in association with signs referable to brainstem or cerebellum. It is not always clear whether ataxia is the result of cerebellar, brainstem, or sensory dysfunction.
  • Ataxia may occur as a primary neurological component in other neurobrucellotic syndromes, including "central ataxia" in diffuse meningoencephalitis or inflammatory demyelinating syndromes of the brain, or "peripheral ataxia" in myelitis with posterior column dysfunction or inflammatory peripheral neuritis. It also may develop as a secondary feature of basilar adhesive arachnoiditis or inflammatory disease of the spine and spinal canal that disturbs the function of the posterior columns.
  • The pathogenesis is presumed to be inflammatory or possibly vasculitic disease that involves brainstem or cerebellum primarily and should be distinguished from cranial nerve dysfunction secondary to basilar arachnoiditis, peripheral neuritis, or hydrocephalus. It also should be distinguished from brainstem or cerebellar disease that arises secondary to emboli from subacute brucellotic endocarditis or hemorrhages from mycotic brucellotic aneurysms.
• Some predominantly neuropsychiatric syndromes may arise as manifestations of acute brucellosis. The findings should be more than the nonspecific depression and disturbances of sleep and concentration that are common in patients with chronic brucellosis.
  • Isolated neuropsychiatric syndromes probably account for fewer than 5% of all cases of chronic neurobrucellosis, if any at all.
  • This syndrome must be set apart from the nonorganic neuropsychiatric syndromes that are not infrequently encountered in areas of endemic disease as well as in areas in which the disease is not endemic. Most such syndromes have little if any fever or constitutional symptoms and no supportive laboratory evidence (excepting in some instances the seropositivity that is found in many individuals from regions of endemic disease). These neuropsychiatric syndromes share the clinical features of many cases labeled as neurasthenia or nonorganic chronic fatigue syndrome.

Secondary forms of neurobrucellosis arise as the result of primary chronic brucellotic inflammatory disease of other organ systems. General categories of secondary neurobrucellotic manifestations of chronic brucellosis include the following, in approximate order of frequency:

• Compressive myelopathy/radiculitis (due to disease of bones, adjacent soft tissues, joints, and extraaxial spaces of the CNS)
• Cerebrovascular syndromes (due to disease of the heart or cerebral vasculature)

Chronic brucellosis of bones and joints may produce a wide variety of neurological abnormalities. The most common form of brucellotic bone disease, vertebral osteomyelitic progressing to spondylosis, is the form most likely to give rise to neurological abnormalities. The secondary radiculopathic neurological consequences of brucellar osteoarticular disease of the spine arise more commonly than any of the primary forms of neurobrucellosis.

• Vertebral osteomyelitis with spondylosis is a complication that tends to be experienced by elderly males and is confined largely to the lumbosacral vertebrae. These facts suggest the possibility that preexisting lumbosacral disease predisposes to this complication.
• Although most patients who develop brucellar osteomyelitis have a remote history of acute brucellosis, the advent of clinical signs of this form of chronic brucellosis tends not to be associated with signs and symptoms that are otherwise common concomitants of relapses of chronic brucellosis. Hence, there is little or no fever and few constitutional complaints.
• Localized pain and tenderness are the common presenting symptoms of brucellar vertebral osteoarticular disease, usually without radicular features at the beginning.
• Approximately 84% of cases of brucellar vertebral osteomyelitis occur in lumbosacral vertebrae, 7% predominantly in cervical vertebrae, and 9% predominantly in thoracic vertebrae.
  • Brucellar osteomyelitis may be focal or diffuse. If focal, neurological tissues often are spared. If diffuse, compression of neurological tissues may result, with neurological decompensation lagging appreciably behind the development of symptoms of osteoarticular disease.^{[11 ]}
  • Focal osteomyelitis tends to involve the anterior aspect of vertebral endplates, just at the diskovertebral junction.
  • The L3 and L4 vertebral bodies are especially prone to development of brucellar osteomyelitis. Infection and inflammation may spread to the disk and paraspinous soft tissues, but the spinal canal and foramina usually are spared.
  • Diffuse osteomyelitis involves the entire vertebral endplate or the whole of a given vertebral body (usually lower lumbar), and tends to spread via ligaments or blood vessels to adjacent disks and vertebral bodies.
  • The involved vertebrae demonstrate progressive osteomalacia and necrosis, with disk herniation. This, in turn, may compress nerve roots. Mechanical instability of the chondral endplates and disks of the spinal column may further compromise the cord because of progressive spondylosis with possible compression of nerve roots, nerve bundles, and the spinal cord.
  • Extradural granulomata and infection may spread to involve the dura and nerve roots. Bone or extradural granulomata may participate in the compressive process involving nerve roots or spinal cord.
  • Disk herniation, bone and disk fragments, and granulation tissues in the spinal canal may compress the thecal sac and spinal cord at various cervical or thoracic levels.
• The myeloradiculitic neurobrucellosis that develops secondary to vertebral osteomyelitis, spondylosis, and associated inflammatory processes tends to have gradual onset, in most instances involves the lumbar plexus asymmetrically, and may trouble patients for months to years.^{[11,12 ]}
  • Hence, it is important to remember that peripheral nerve dysfunction secondary to osteoarticular brucellosis tends to arise much more insidiously and gradually than mononeuritis multiplex of peripheral nerves, plexi, and nerve roots.
  • Compression of nerve roots and nerves by osteoarticular inflammatory disease occurs after a preceding history of progressive pain at the appropriate spinal level to explain the radicular syndrome, pain that is often severe at the onset of the radiculopathy. Invariably, this pain is associated with tenderness to percussion of the same level of the spinal column and diminished mobility at that level.
  • Cases have been reported in which the etiology of lower motor neuron dysfunction was a combination of osteomyelitic compression of nerve roots and nerves and mononeuritic inflammatory changes in the sciatic nerve roots or sacral plexus.
  • The most common manifestations of peripheral nerve dysfunction secondary to brucellar spinal osteoarticular disease (eg, low back pain, radicular pain, areflexia, progressive leg weakness) closely resemble sciatica. Pain is usually the earliest and most troublesome aspect of radiculopathic disease secondary to brucellar osteoarticular disease. Motor patterns include monoparesis, monoplegia, or paraparesis.
  • Sensory disturbance is variable.
  • The presence of upper motor neuron signs suggests the possibility of spinal cord compression due either to spondylosis or to the compressive effects of extradural or intrathecal granulomatous inflammatory lesions. In some instances, however, these signs are referable to brucellotic vascular or inflammatory parenchymal disease of brain, brainstem, or spinal cord.
  • Disturbances of autonomic sphincter function may occur with any of these various etiologies for lower spinal cord, spinal root, or peripheral nerve disease.
  • In patients with known brucellar lumbar osteoarticular disease, sudden onset of monoparesis or especially paraparesis in association with the development of a sensory level and sphincter dysfunction is a surgical emergency implying cord compression from decompensation of unstable spondylosis or critical compression from various inflammatory processes. In such cases it is also possible, but less likely, that the etiology is myelitis of vascular or inflammatory etiology.
• Osteomyelitic disease of the skull may compress the cerebral contents, producing focal signs. The usual location is in the basilar portions of the skull. Similar symptomatic compression may occur with brucella osteomyelitis/epidural abscess/spondylitis of the spinal cord.^{[11,12 ]}
• Adhesive arachnoiditis or granuloma formation within the CNS, with or without associated brucellar osteomyelitis, is most likely to develop in the basilar posterior fossa of the head or in the spinal canal. It may develop in the anterior and middle fossae of the head.
  • Depending on location, this process may produce various neurological signs due to compression of nervous tissues.
  • These inflammatory changes may secondarily compress or distort neurological tissues because of obstruction of CSF pathways, possibly provoking development of such secondary abnormalities as hydrocephalus or spinal block.

Neurovascular neurobrucellosis is the result of endocarditis or of disease of the arteries subserving the brain or spine.

• Brucella may lead to inflammatory vasculitis or to endovascular infection that may in turn lead to changes ranging from ulceration to the formation of mycotic aneurysms.
  • Patients may manifest panarteritis or inflammatory focal vasculitis. In the first instance, coma and a wide variety of associated neurological abnormalities may manifest themselves, including seizures, weakness, long-tract signs, and movement disorders. Focal inflammatory vasculitis is more common, leading to mental status disturbances, monoparesis, hemiparesis, aphasia, seizures, or other manifestations depending on location.
  • In some instances, vasculitis may produce the presenting signs and symptoms of neurobrucellosis in patients who have recovered from acute brucellosis, producing a postinfectious syndrome resembling that of postvaricella vasculitis.
  • Vasculopathic changes due to endovascular invasion of Brucella organisms are usually a complication of brucellar endocarditis with septic embolism. However, endovascular invasion of cerebral or spinal arteries may occur without endocardial disease. The presence of any of several forms of vasculopathy may predispose to transient ischemic events or stroke due to embolic or thrombotic mechanisms.
  • Endomysial infection from either mechanism produces an ulcerated surface from which septic emboli may be released into the downstream cerebral circulation. This can produce stroke syndromes, typically in the middle cerebral artery distribution, with acute onset of various manifestations, including hemiparesis, aphasia, and other higher cortical deficits. These events may be transient ischemic events or actual strokes.
  • The presentation of this process closely resembles the presentation of inflammatory arterial vasculitis, from which it should be distinguished by imaging studies if possible, because the ulcerative vasculopathy may progress. Similar vascular abnormalities may be seen in CNS syphilis or tuberculosis, from which the brucellar etiology must be distinguished.
  • The progression of ulcerative vasculopathy leads to deeper bacterial invasion of the vascular wall and formation of a mycotic aneurysm, which may rupture. Various stroke syndromes may ensue, as can intracerebral and subarachnoid hemorrhages.
  • Hemorrhagic stroke may exert effects on intracranial pressure as space-occupying lesions and the subarachnoid hemorrhage may produce secondary generalized vascular spasm.
  • These strokes produce lesions that are visible with various appropriate imaging techniques and are likely to be reflected in spinal punctures that disclose elevation of intracranial pressure and, in the case of subarachnoid hemorrhage, bloody CSF.
  • In cases of Brucella -related transient ischemic attacks or stroke, emboli may originate in the heart or in vascular regions of arteritis or aneurysmal dilatation. Recognizing and providing appropriate treatment for Brucella endocarditis is especially important.
  • The prudence of lumbar puncture in these instances depends on the presence of localizing signs and an estimate of the likelihood of cerebral herniation due to the presence of an acute space-occupying lesion.
• Subacute bacterial endocarditis, which may manifest itself during the acute phase of brucellosis, more commonly becomes apparent as an element of chronic brucellosis.
  • Neurological complications of brucellar subacute bacterial endocarditis include septic embolization with stroke or abscess formation, and as already noted, embolization to the endomysium of cerebral arteries with formation of endovascular ulceration that may lead to formation of a mycotic aneurysm.
  • The possible consequences of these lesions are discussed in the preceding subsection.
• Spinal motor nerves may become dysfunctional on the basis of a similar polyradiculopathic process, especially those subserving the lower extremities. This produces flaccid areflexic paraparesis with ensuing amyotrophy. The clinical appearance may closely resemble GBS or, in patients whose sensory abnormalities are subtle or overlooked, poliomyelitis.^{[12 ]}
• Guillain Barre syndrome (GBS) often has a more accelerated onset and development of symptoms and signs than neurobrucellosis.
• Where sensory loss occurs, it is most characteristically the loss of proprioception, since the process tends to affect large, heavily myelinated sensory fibers.
• CSF protein level may be elevated.
• In severe cases, inflammation of the spinal nerve root may be found at autopsy.
• Spinal epidural abscess, often in association with brucellar spondylitis, may produce neurological findings due to compression of the anterior or posterior spinal nerve roots or of the spinal cord itself.^{[12 ]}

Physical

Acute brucellosis

• Usually, acute brucellosis occurs without focal abnormalities.
• Nonfocal weakness may be noted.
• The tissues overlying the spine or peripheral nerves may be tender to percussion.
• Tenderness, swelling, or effusion of joints may be found.
• In some instances, orchitis appears after a few days of illness. Testicular swelling and tenderness in the wake of chills and high fever thus resembles mumps orchitis.
• Some patients manifest constipation.
• Occasionally, abdominal tenderness suggests an acute abdomen.
• In some more severe cases, tender enlargement of the spleen may be detected.
• Murmurs, friction rubs, acute-onset blindness or visual field disturbance, tachycardia, oropharyngeal or conjunctival petechiae (some with pale centers), Roth spots, splinter hemorrhages of the nailbeds, Osler nodes, Janeway lesions, or hepatosplenomegaly may develop as manifestations of bacterial endocarditis, a complication that is much rarer as an aspect of acute brucellosis than as an element of focal or diffuse chronic brucellosis.
• Rarely, disease of the lungs or pleura is a feature of acute brucellosis, manifestations of which could include rales, wheezes, abnormalities of percussion or egophony, or pleural friction rubs.
• Rarely, findings suggesting subacute brucellar bacterial endocarditis may be noted.
• Meningismus, papilledema, mental status changes, and long-tract signs are found in a small fraction of cases of acute brucellosis as manifestations of acute neurobrucellosis.
• Radicular sensory or motor changes may arise in individuals with brucellotic osteomyelitis with associated epidural abscess. Focal tenderness or pain in the perispinous region may precede fever and objective sensory or motor findings in osteomyelitic brucellosis. Brucellotic cervical epidural abscess may produce tenderness and movement restriction without the classic triad (fever, neck pain, radiculopathy) of streptococcal or other types of epidural abscess. However, such findings may eventually develop, prompting delayed consideration of such a diagnostic entity.^{[10 ]}

Chronic brucellosis

• Chronic brucellosis may be associated with deforming arthritis.
• Chronic neurobrucellosis may manifest a wide variety of neurological findings, including abnormalities of mental status, vision, hearing, and other functions subserved by cranial nerves; long-tract signs; cerebellar ataxia; spinal syndromes; and deficits referable to anterior horn cells, peripheral nerves, or muscles.

Causes

• B melitensis (harbored in sheep, goats, and camels) is the most common cause of brucellosis. It may be acquired by exposure to animals or animal products and, in the case of laboratory technicians, to specimens from animals (including humans) whose tissues are operated upon or submitted for culture or pathological analysis.^{[9 ]}
• B abortus (harbored in cattle) is more widely distributed throughout the world than B melitensis, but it has a lower degree of pathogenicity for both animals and humans. It is, however, the most common cause of brucellosis in North America.
• B suis (harbored in pigs, hares, rabbits, and reindeer) is the second most common cause of brucellosis in North America.
• B canis (harbored in dogs) also can induce brucellosis.

Differential Diagnoses

Other Problems to Be Considered

Abducens (CN VI) nerve palsy
Granulomatous (eg, tuberculous) or pyogenic osteomyelitis/spinal epidural abscess
Ischemic optic neuropathy
Metastatic vertebral, paraspinous, or intraspinal tumor
Intracerebral or spinal lymphoma 
Partially treated meningitis
Behçet syndrome
Tularemia
Influenza encephalitis
Malaria with or without cerebral manifestations
Typhoid fever with cerebral manifestations
Psychoneurosis
Chronic nervous exhaustion
Carotid disease and stroke

Cases of neurobrucellosis with spinal abnormalities and Freund syndrome closely resemble CNS tuberculosis, another disease that can be acquired by drinking raw milk.^{[13,14 ]}Important distinguishing features include the facts that those with neurobrucellosis seldom develop communicating hydrocephalus despite the very elevated CSF protein and, unlike those with tuberculous meningitis, are at high risk for manifestation of hearing loss.

Workup

Laboratory Studies

• Establishment of the diagnosis of brucellosis is rendered more difficult in areas of endemic disease by the high prevalence of positive titers and by the failure, in many cases, to culture the organism from various tissue samples. In areas where the disease is not endemic, failure to diagnose may be related to failure to consider or recognize brucellosis and obtain appropriate laboratory studies. Consideration in nonendemic regions must be extended in particular to travelers to endemic areas; veterinary physicians, pathologists, and laboratory technicians^{[9 ]}; and individuals exposed to cheeses or other foodstuffs imported from endemic areas. In general, the diagnosis of neurobrucellosis usually requires satisfaction of the following criteria:
  • Clinical features of the illness compatible with a known neurobrucellosis syndrome
  • Typical CSF changes (pleocytosis, elevated protein concentration)
  • Positive results of either CSF culture or appropriate serological tests (eg, IgG agglutination testing titers of >1:160 in CSF or >1:320 in blood)
  • Clinical improvement as well as improvement in CSF pleocytosis and fall in CSF and blood Brucella titers after appropriate treatment
  • Inability to prove a more suitable alternative diagnosis
• Of these criteria, the single most specific, and the only one that in and of itself is diagnostic of neurobrucellosis, is isolation of Brucella organisms from CSF. This is achieved in fewer than 30% of all cases of neurobrucellosis.
• Routine laboratory tests, such as blood counts, erythrocyte sedimentation rate, liver enzymes, and CSF cell counts, glucose, and protein, are not specific for brucellosis.
  • Anemia may develop in the months preceding the subacute onset of brucellosis.^{[10 ]}
  • Total blood leukocyte count may be normal or slightly reduced, usually with relative lymphocytosis. WBC counts seldom exceed 10X10⁹/L.
  • In cases associated with brucellotic renal suppuration, urine samples may reveal abacteriuric pyuria.
  • The erythrocyte sedimentation rate may be low, normal, or elevated. If elevated, the degree of elevation is often moderate.
  • Aminotransferase and alkaline phosphatase levels may be elevated (especially with bone involvement).
  • CSF discloses abnormalities in almost every case of every type of neurobrucellosis. The abnormalities include lymphocytic pleocytosis (lymphocyte count often 0.01-0.05X10⁹/L, but in some cases >1.0X10⁹/L) and hypoglycorrhachia. CSF protein often is elevated, and in severe cases may be as high as 400-600 mg/dL (Freund syndrome).
  • Microscopic analysis of gram-stained serum or CSF may disclose characteristic appearing Brucella bacteria, suggesting the diagnosis, but such a finding is quite uncommon.
• Bone marrow specimens, particularly from the sternum, or biopsy specimens of lymph nodes or other infected tissues may disclose Brucella organisms.
• Positive cultures of blood, CSF, bone marrow, lymph nodes, or other infected tissues definitively implicate Brucella organisms as the cause of clinical abnormalities thought consistent with one of the several forms of brucellosis. As has been noted, isolation of Brucella organisms from CSF is the only criterion that, in and of itself, is sufficient to prove that a patient has neurobrucellosis. However, CSF cultures prove negative in more than 70% of cases of neurobrucellosis. Samples of urine, bile, or feces are not suitable material for Brucella cultures.
  • Brucella species are slow-growing, fastidious organisms, and many strains are carboxyphilic, requiring 10% ambient carbon dioxide for growth. Appropriate media include trypticase soy broth or tryptose phosphate broth, maintained at 37 degrees at pH 6.6-6.7. Positive results may require weeks of culture maintenance.
  • The organisms are gram negative. It is important to note that the penetration of counterstain may be slow and limited; 3 minutes of immersion may be necessary to identify the gram negativity. The organisms are small, nonmotile coccobacilli or short rods (0.5-1.5 µm in length, 0.5-0.8 µm in width). They are devoid of flagella or endospores, and if any capsule is found, it may be quite small. They occur singly or in small groups. They are usually slow-growing, strict anaerobes, although in some instances minimal facultative aerobic growth may occur.
  • Blood cultures are positive for Brucella infections in only 23-37% of all cases of clinically and serologically typical brucellosis, irrespective of CNS involvement. Blood cultures are usually positive where there is acute spinal infection with Brucella. Pretreatment with antibiotics such as azithromycin may interfere with positivity of blood cultures.^{[10 ]}
  • Results of CSF cultures are positive in only 13-28% of cases of neurobrucellosis.
  • Some authorities consider bone marrow culture the diagnostic method of choice, especially if the specimen is obtained from the sternum. In most instances this approach is unnecessary, and it is possible for bone marrow cultures to be negative in cases of brucellosis. It is also possible for sternal bone marrow cultures to be positive in patients who are not experiencing an active phase of brucellosis.
• Serologic testing has been of great importance in sorting out possible cases of acute or chronic brucellosis. The persistence of the antibodies may render a less certain verdict in patients from regions of endemic disease and those suspected of having a chronic form of brucellosis.
  • In the United States, the CDC currently recommends that individuals exposed to brucellosis in working directly with animals (including humans) who have brucellosis and laboratory workers or pathologists exposed to specimens that may contain Brucella be clinically observed for at least 6 months for the development of fever and that these individuals should also be tested by serial sampling for seroconversion with a microagglutination assay performed at the CDC or at an accredited state public health laboratory.^{[15 ]}
  • Serum and CSF agglutination (STA) tests using 2-mercaptoethanolamine have been the most widely used methods for ascertainment of diagnosis by microagglutination methods. Although this method may be somewhat less sensitive than ELISA, the rate of false positive results is lower. Using both methods to better assess the likelihood of brucellosis in individual cases may be prudent and useful.
  • The 19S IgG agglutinins more reliably indicate active disease than the 7S IgG agglutinins. IgG antibody titers rise after approximately 4 weeks, peaking and diminishing more rapidly than IgM antibodies. A titer of greater than 1:320 in serum or 1:160 in CSF is considered a positive result. There are problems with the sensitivity and specificity of available tests, rendering false-positive and false-negative serological results possible in any given case. This reinforces the importance of obtaining follow-up studies to confirm a rise or fall in titer of at least 4-fold.
  • Rarely, a prozone phenomenon may occur in Brucella testing where very high titers of blocking antibodies interfere with agglutination, possibly producing a false negative result.^{[10 ]}This phenomenon may be seen in chronic brucellosis.
  • On the other hand, serological cross-reactivity in patients with Cholera vibrio or Pasteurella tularensis infections is possible and may yield a falsely positive Brucella titer.
  • IgM antibody titers rise during the first to third week of acute brucellosis in the vast majority of cases, usually peaking at approximately 4 weeks, but the elevations persist thereafter for many months to years. A positive titer is considered to be any titer greater than 1:100 by some authorities, any greater than 1:160 by others. In areas of endemic disease and in individuals with potential occupational exposure, elevated Brucella IgG titers must be interpreted against the relatively high background prevalence of positivity for these long-persisting antibodies. In such instances, diagnosis requires satisfaction of the usual epidemiological standard of a 4-fold rise or 4-fold fall of a given antibody response. This is particularly important in cases in which the IgG titer rise and fall have been missed.
  • IgA antibody titers are the last to rise but the elevations persist for long intervals. IgA titers have not proven useful in the establishment of the diagnosis of acute or chronic forms of brucellosis.
• The rose bengal plate test for IgG and IgM antibodies proves most useful in areas of less endemic disease. The standard microagglutination tests for IgM, IgG, and IgA, with a repeat examination at 4-6 weeks after the initial test, is another test that is most useful in areas where the disease is not endemic. Both these tests have fairly high rates of false negativity, remaining negative in the blood of 20-25% of patients with brucellosis or neurobrucellosis. These tests are positive in CSF of only 20-25% of patients with neurobrucellosis. The 2-mercaptoethanol-extraction test for IgA and IgG antibodies may be more indicative of active disease in areas of endemic disease.
• Enzyme-linked immunosorbent assays
  • IgM and IgG enzyme-linked immunosorbent assay (ELISA) for Brucella species capsular lipopolysaccharide is positive in CSF and blood of most or all patients with neurobrucellosis and is becoming the test of choice both for acute brucellosis and neurobrucellosis.^{[16 ]}It manifests very low rates of false positivity in cases of brucellosis without CNS involvement and in various nonbrucellar CNS diseases, although the rate of false-positivity may be higher than for microagglutination testing. Some have advocated using both tests to best achieve high sensitivity and specificity. Inconsistency between the results of the 2 methods (ELISA and microagglutination) should lead to ongoing surveillance.
  • IgA ELISA for Brucella species capsular lipopolysaccharide in blood is positive in virtually all patients with brucellosis, irrespective of CNS involvement. IgA ELISA is positive in CSF in about 85% of patients with neurobrucellosis.
  • IgM ELISA is much less reliable than other available tests.
  • IgG ELISA for Brucella species cytoplasmic protein is a newer test that is positive in both the CSF and blood of patients with neurobrucellosis; it is positive only in the blood of patients with brucellosis without CNS involvement.
  • These various ELISA tests appear to have quite low rates of false positivity, at least when performed in patients with pyogenic meningitis.
• Laboratory changes consistent with diabetes insipidus are encountered in some patients with disease of the sellar region.

Imaging Studies

• Cranial CT scans and MRI scans of patients with acute neurobrucellosis may demonstrate cerebral edema with small ventricles. If there is associated meningocephalitis, meningeal inflammation and contrast enhancement may be demonstrable, especially in the regions of the basilar subarachnoid cisterns.
• Cranial CT or MRI/magnetic resonance angiography (MRA) scans, with appropriately selected techniques, may disclose any of a wide variety of abnormalities in patients with chronic brucellosis or neurobrucellosis, the nature of which depend on the type of chronic brucellosis manifested by the patient. These include the following:
  • Chronic epidural or subdural effusion, abscess, empyema, adhesive arachnoiditis, or granulomata
  • Meningeal inflammation and contrast enhancement, especially in the region of the basilar subarachnoid cisterns
  • Enhancement, swelling, or granulomatous investment of cranial or spinal nerves or optic neuritis
  • Pseudotumor cerebri (slit ventricules, periventricular edema)
  • Focal or diffuse brain edema
  • Obstructive hydrocephalus
  • Sellar and suprasellar mass lesions or inflammation, in some instances cavitation
  • Periventricular and deep white matter abnormalities on T1- and T2-weighted MRI images resembling those seen in MS, ADEM, or other demyelinative illnesses: These lesions may be found in periventricular or other deep white matter areas, with sharp margins, contours, and contrast enhancement that are often virtually indistinguishable from the changes observed in a typical case of MS. Other lesions show indistinct margins, subcortical location with cortical involvement, and limited contrast response, similar to lesions observed in ADEM.
  • Bland or hemorrhagic vascular territory infarction
  • Vasculitic or vasculopathic changes or arterial mycotic aneurysms
  • Intraparenchymal or subarachnoid hemorrhage from mycotic aneurysms
  • Calvarial osteoarthritis
• Classic angiography or MRA may disclose nervous system changes consistent with vasculitis, vasculopathy, mycotic aneurysm, infarction, or mass effects.
• CT and MRI/MRA studies of the spine, with various special techniques, may disclose a wide variety of abnormalities, including spinal stroke, transverse myelitis or myelopathy, arachnoiditis, granulomatous investment or extradural compression, epidural abscess or granuloma, diskitis, osteomyelitis, nerve root inflammation or demyelination, cervical or lumbosacral spondylitis, or sacroiliitis.
  • CT and CT myelography are especially sensitive methods for the evaluation not only of characteristic changes in the vertebrae and associated tissues, but also of epidural extension of brucellosis of the spine. Vertebral body abnormalities initially are observed at the superior endplate, spreading to the entire vertebral body over time, with bony softening and spondylitic displacement. Disk changes, such as herniation into the softened bony vertebral body endplate, are secondary. Granulation tissue may be apparent in the epidural space.
  • MRI changes in brucellotic osteomyelitis often produce high intensity changes in the vertebral bodies, likely due to edema. Associated brucellotic epidural abscess typically shows a T2-bright epidural lesion, while T1-weighted images with gandolinium may show linear enhancement of the margins of the epidural lesion, enhancement of the overlying dura, and evidence of cord compression.^{[10 ]}Such changes must be interpreted with regard to the clinical setting as they are also seen in granulomatous osteomyelitis or as an atypical presentation of pyogenic vertebral osteomyelitis, as well as of metastatic tumors or spinal lymphoma.^{[17,18,14 ]}
  • Osteomyelitis of the anterior aspect of the L4 vertebral endplate, which may involve adjacent disks and other soft tissues, may be well demonstrated and is particularly characteristic of brucellosis.
• These techniques may disclose granulomatous inflammation or fragments of bone or disk within the spinal canal, including disk herniation, spondylitic or epidural granulomatous impingement on the cord, or complete spinal block. These techniques also may be helpful in defining the pathological anatomy of inflammatory disease of the vertebrae and associated soft tissues, such as brucellar radiculopathy due to nerve root or thecal sac compression. However, normal myelography does not exclude significant disease of the spine or spinal column. 
  • Except in parts of the world where brucellosis is common (eg, Iran, the Middle East) spinal epidural abscess in association with boney changes should bring to mind other causes. In North America and Europe, Staphylococcus aureus should be considered.^{[17 ]}With S aureus there is typically a preceding history of febrile illness and evidence of a possible site of Staphylococcal infection from which hematogenous dissemination to the spine has occurred.
  • Regional endemicity of tuberculosis or evidence of preceding tubercular infection of the lung should cause suspicion to focus on that disease as a cause of spinal infection. Tuberculous vertebral body disease tends to involve the thoracic or lumbar spine and paravetebral abscess formation is more likely to occur with tuberculosis than with spinal epidural abscess.^{[10 ]}
• CT or MRI imaging of nonneurological tissues may disclose diagnostically and therapeutically pertinent findings.
  • Imaging of muscles may disclose changes consistent with inflammatory myositis.
  • Nonspinal osteoarticular arthritic and inflammatory changes of wide variety may be discerned on imaging of various symptomatic bones or joints. A particularly characteristic abnormality is diminished MRI signal in the endplates of the L3-L4 vertebrae. Other common findings include diminished definition of the diskovertebral junctions on T1-weighted images and bright signal within vertebrae on T2-weighted images. Narrowing of the spinal canal due to epidural inflammation may be associated with these other changes.
  • Appropriate techniques may demonstrate aneurysmal dilation of segments of peripheral arterial trunks, cardiomyopathy, cardiac valve vegetation, pulmonary effusions, and pulmonary nodular granulomatous inflammation.
  • Inflammatory changes, including caseating or noncaseating granulomata with or without calcification, may be discerned in liver, spleen, or kidney.
• Radioisotope bone scans may prove particularly informative with regard to active osseous inflammation, especially in the lower lumbar region. Bone scans demonstrate arthritic changes in approximately 25% of all patients with chronic brucellosis. In addition to lumbar and sacroiliac bone and intercostal changes, these scans may demonstrate abnormalities of large and small limb joints and of the sternoclavicular joints.
• Plain radiographs may prove helpful for the following indications:
  • Demonstration of bone and joint abnormalities associated with chronic brucellosis, particularly those involving the lumbosacral spine (eg, sacroiliitis), and for the demonstration of deforming arthritides in any suspected location: The changes of brucellotic spondylosis are often indistinguishable from those of degenerative spondylosis or vertebral osteoarthritis. Abnormalities of the upper to mid thoracic ribs may be found in brucellosis. Plain radiographs of the spine may fail to disclose abnormalities in osteomyelitic brucellosis with epidural abscess.^{[10 ]}
  • Identification of calcified caseating or noncaseating granulomata of the spleen, liver, or kidneys
  • In the chest, effusions, granulomatous inflammatory changes, or cardiomegaly

Other Tests

• Electroencephalography (EEG) should be performed in all patients with brucellosis who have disturbed consciousness and in patients in whom seizures are suspected or known to be present. The typical EEG changes are diffuse slowing, sometimes with focal emphasis or sharp activity. The EEG may show focal or diffuse paroxysmal activity.
• Electromyography (EMG) and nerve conduction testing may disclose abnormalities in patients with myeloradiculitic or peripheral neuropathic manifestations of brucellosis. These studies may reveal denervation (needle examination), delay in F-wave latencies, and mild slowing of nerve conduction (motor nerves affected more than sensory nerves).
• Visual-evoked potential (VEP) abnormalities may be found in patients with papillitis and retrobulbar neuritis (see Clinical Utility of Evoked Potentials). Perform VEPs in patients with visual disturbance.
• Brainstem auditory-evoked responses (BAER) may detect slowing due to brainstem dysfunction (see Clinical Utility of Evoked Potentials). These changes are observed in patients with sensorineural hearing loss, and they may be found in patients who do not have clinically apparent auditory disturbances.

Procedures

• Lumbar puncture: CSF cell count is abnormal in most, if not all, cases complicated by acute or chronic neurobrucellosis. As a rule, lymphocytic pleocytosis with moderate elevation of CSF protein is observed.
  • Lymphocytosis is highest in patients with acute meningoencephalitis. WBC counts as high as 1.2X10⁹/L of CSF have been reported, though in most instances, WBC counts are less than 0.4X10⁹/L of CSF. A rising CSF cell count with change from lymphocytic to polymorphonuclear predominance after treatment is consistent with a posttreatment Jarisch-Herxheimer reaction.
  • CSF protein level typically is elevated. Albuminocytological dissociation may be found in cases in which the chronic manifestation is predominantly that of peripheral neuropathy. Hypoglycorrhachia is found in 20-60% of patients with neurobrucellosis. Determine CSF opening pressure as a matter of routine, since it may be elevated.
  • CSF immune profile testing, including qualitative testing for oligoclonal bands, quantitative testing for CSF/serum IgG index, or estimation of CNS IgG synthetic rate (eg, the Tourtellotte expression) may render positive results.
  • Positivity of these tests is not specific for brucellosis. It is important to be aware that positivity does not distinguish between brucellosis and diseases that it may resemble that also frequently yield positive results, such as MS, neuroborreliosis, subacute sclerosing panencephalitis, CNS tumor, or sarcoidosis.
  • Myelin basic protein may be elevated in CSF, irrespective of the positivity of other tests of CSF for signs of inflammation. Brucellosis shares this characteristic with ADEM, which it may resemble clinically.
  • CSF lactate may be elevated in patients with neurobrucellosis.
• Classic angiography may disclose vascular changes consistent with stroke, the presence of mycotic aneurysms, or vasculitis. The various pertinent findings are considered in Imaging Studies.
• Tissue biopsies (lymph nodes, sternal bone marrow, diseased organs) may disclose characteristic changes, such as those noted in Histologic Findings.

Histologic Findings

Biopsies obtained from lymph nodes, bone marrow, other reticuloendothelial tissues, or other infected organs may disclose the organisms, the appearance and staining characteristics of which are noted in Lab Studies. These tissues also may disclose the characteristic inflammatory appearance of brucellosis lesions: epithelioid cells, foreign body and Langhans' type giant cells, lymphocytes and plasma cells, as well as the noncaseating granulomata of B melitensis or B abortus, or the caseating granulomata of B suis.

Treatment

Medical Care

• Initial treatment of patients presenting with acute meningoencephalitis usually entails treatment for herpes encephalitis, until that entity has been excluded. In some instances, treatment under the presumption that partially treated meningitis is the cause of illness may entail the use of appropriate antibiotics, until that possibility also is excluded. In some instances where various other zoonoses are considered, broader initial coverage to include ciprofloxacin may be considered. This is especially true of the case of suspected infection from the use of a biological warfare weapon.
• Once acute brucellar infection has been presumed or established as the cause of acute illness, treatment for 2 weeks with the combination of tetracycline and rifampicin (Rifampin) is the standard therapy. Whether this treatment influences recovery from meningoencephalitis, which usually occurs over several days with or without such treatment, is not clear. However, this treatment is aimed at preventing the development of chronic manifestations. Streptomycin has been combined with tetracycline in the treatment of some serious cases of brucellosis.
• A standard treatment for adults with acute spinal brucellosis is the combination of doxycycline (100 mg bid) for at least 12 weeks, combined during the first 2-3 weeks with streptomycin (1 g qd). Alternative therapies include combinations of drugs including rifampin, co-trimoxazole, and fluoroquinolones.^{[8 ]}
• The standard treatment for chronic neurobrucellosis entails triple therapy. The 3 agents may be selected from a group of agents that includes rifampicin, doxycycline, gentamicin, streptomycin, and ciprofloxacin.
  • One common combination used in adolescents or adults includes oral rifampicin (600-900 mg/d) and doxycycline (100-200 mg/d) for 3 months, combined for the first 6 weeks of therapy with 0.5-1 g of streptomycin administered intramuscularly.
  • Emphasis has been placed on the importance of including an aminoglycoside in the combined therapy for chronic neurobrucellosis; gentamicin may be substituted for streptomycin. However, these agents probably should not be employed in patients with acute brucellosis-induced deafness or in patients who have impaired renal function. Doses of all selected medications must be adjusted in children weighing less than 40 kg, in elderly patients, or in patients with renal or hepatic abnormalities.
• Duration and effectiveness of therapy should be judged on clinical and radiological grounds rather than on the basis of changes in antibody titer.
• Patients have been treated with antibiotic courses lasting for only 8 weeks.
• The addition of methylprednisolone may be beneficial in patients with severe or diffuse CNS involvement, cranial neuropathies, optic neuritis or other MS-like presentations, or arachnoiditis.

Surgical Care

Although antibiotic treatment is usually sufficient for the management of brucellosis, spinal disease with severe neurological impairment may require surgery. Whether or not extensive surgery is planned, surgery also affords the opportunity to obtain tissue for diagnosis. Epidural abscesses approached surgically also afford the opportunity to improve the likelihood of response to antibiotic therapy. Surgery with discectomy or transpedicle drainage may be of importance in the alleviation of pain due to radiculopathy as well via transpedicle drainage.

Among the presentations of spinal brucellosis to which surgical techniques have been applied are spondylitis, spondylodiscitis, discitis, epidural abscess, paraspinal abscess, and vertebral collapse.^{[19 ]}In selected instances, the response rate to the combination of surgery and antibiotics may be excellent.

Consultations

Infectious diseases consultation may be warranted, especially with regard to diagnosis and antibiotic treatment.

• Orthopedic or neurosurgical consultation may be required for management of inflammatory disturbances of vertebrae and spinal disks.
• Other consultations may be required when other nonneurological organ systems are involved.

Diet

Discuss with patients the importance of consuming pasteurized milk and milk products and on the avoidance of other possible sources of infection. Obviously, the impact of such education will have the greatest effect on family and friends who may be at risk for infection.

Activity

Restriction of activity with bed rest appears to confer benefit in the acute phase of brucellosis, increasing the rate of recovery.

Medication

Some patients presenting with acute brucellar meningoencephalitis cannot be distinguished reliably from patients with herpes encephalitis, and the presentations of other patients may not be distinguishable from that of bacterial meningitis. In such cases, the initial therapeutic interventions should include agents appropriate for the management of those conditions.

Once acute brucellosis is established as or considered to be the most likely diagnosis, standard initial therapy entails 2-4 weeks of therapy with tetracycline or doxycycline and rifampin, more according to some authorities to prevent the development of chronic meningitis than to influence the course of the acute illness. In some instances of serious acute disease, streptomycin has been administered in addition to tetracycline or doxycycline and rifampin.

A lack of unanimity exists concerning the best treatment for nervous system infections due to Brucella species. The trend toward advocacy of doxycycline in place of tetracycline or aminoglycosides is based upon the possibility that the latter choices are less likely to cross the blood-brain barrier in adequate quantities. Particular concerns have been raised about generic tetracycline. Furthermore, many authorities have preferred a 3-drug (doxycycline/streptomycin/rifampin or doxycycline/trimethoprim-sulfamethoxazole/rifampin) regimen treatment to the use of 2-drug therapy.

Third-generation cephalosporins have been used in Brucella meningitis, but susceptibility is variable and must be ensured by in vitro sensitivity studies. Duration of therapy has ranged in various cases from 1-19 months, with persistence in treating until the CSF is found to be without evidence of organisms or inflammation. In the year following cessation of treatment, agglutinins for Brucella should be followed in serum to ensure that relapse does not occur.

Chronic brucellosis is treated with antibiotic triple therapy. The combination of rifampin, doxycycline, and streptomycin often is used. Dosage and duration of treatment are noted in Medical Care.

Ciprofloxacin and trimethoprim-sulfamethoxazole are among the possible alternatives to doxycycline; gentamicin may be used in place of streptomycin, but some authorities suggest that neither aminoglycoside be administered to patients exhibiting brucellosis-induced deafness or renal failure. Other cautions in using these agents are noted above.

Antibiotics

Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.

Rifampin (Rifadin, Rimactane)

Inhibits DNA-dependent RNA polymerase activity in susceptible cells. No known cross-resistance of microbes to this agent except by other rifamycins. Readily absorbed after oral dosing. Renal and hepatobiliary routes of elimination are active.

Dosing

Adult

600-900 mg PO as single dose, either 1 h before or 2 h after meal

Pediatric

10-20 mg/kg PO qd, either 1 h before or 2 h after meal; not to exceed 600 mg

Interactions

Liver enzyme–inducing agent and therefore may reduce activity of wide variety of agents metabolized by liver enzymes; may become more difficult to control diabetes with oral hypoglycemic agents; may render oral contraceptives ineffective; doses of anticoagulants, some cardiac medications, anticonvulsants, antibiotics, and other drugs may require adjustment
Halothane may enhance hepatotoxic properties of both medications; ketoconazole may reduce serum levels of both drugs
If para-aminosalicylic acid (PAS) treatment required, should be administered 12 h apart from rifampicin, since PAS may lower serum rifampicin levels

Contraindications

Liver diseases or potentially hepatotoxic drugs; evidence of hepatocellular injury after initiation of rifampicin therapy should prompt withdrawal of this agent; use with caution or not at all in patients with porphyria; should not be initiated prior to exclusion of possibility that patient has meningococcal meningitis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause urine, feces, saliva, sputum, sweat, and tears to turn orange-yellow; may permanently discolor soft contact lenses; women using oral contraceptives while receiving rifampicin therapy may become pregnant

Doxycycline (Doryx, Vibramycin, Doxy)

Synthetic broad-spectrum antibiotic derived from oxytetracycline. As with other tetracyclines, activity essentially bacteriostatic, exerted through mechanism of inhibition of microbial protein synthesis. Readily absorbed, and eliminated by biliofecal and urinary excretion. Dosage must be adjusted in patients with impaired renal function.

Dosing

Adult

100 mg PO bid on day 1, followed by 100 mg qd or 50 mg bid
100 mg PO bid administered for periods of days to weeks in severe cases, but higher doses may increase risk for adverse effects

Pediatric

<100 pounds: 2 mg/lb of body weight PO on day 1, divided bid; thereafter, 1 mg/lb of body weight PO qd or divided bid
>8 years and >100 pounds: Administer as in adults

Interactions

Bismuth subsalicylate, antacids containing aluminum, calcium, or magnesium, and iron-containing preparations may reduce absorption
Barbiturates, phenytoin, and carbamazepine enhance clearance, reducing elimination half-life; depresses plasma prothrombin activity, may necessitate reduction of anticoagulant dosage; may result in spurious elevation of urinary catecholamine levels by interfering with fluorescence assay; coadministration with methoxyflurane (Penthrane) has been reported to result in fatal renal toxicity

Contraindications

Documented hypersensitivity; phototoxic effects with development of skin eruption; concomitant methoxyflurane (Penthrane), which has been reported to result in fatal renal toxicity
Relative contraindications: Ingestion during period of tooth development (last half of gestation to age 8 y); breastfeeding

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Crosses placenta and excreted in breast milk; avoid in pregnancy and while breastfeeding, since may cause permanent yellow-grey-brown discoloration of teeth if taken during period of tooth development (last half of gestation to age 8 y); moreover, reversible retardation of fibular growth rate may occur in premature infants; animal studies of tetracyclines (but not of doxycycline specifically) have suggested risk for embryotoxicity, if used early in pregnancy
Patients should avoid excessive exposure to sunlight and should consider sunblockers or sunscreen to avoid potential complication of photosensitivity dermatitis; liberal use of fluids with doses and between doses should be recommended to reduce risk for esophageal irritation or ulceration

Streptomycin

Aminoglycoside indicated in triple therapy of chronic neurobrucellosis. Bactericidal inhibitor of microbial protein synthesis, typically achieves peak serum concentration within 1 h of IM injection. Good penetration of all organ systems, except CNS. Readily passes through placental membrane barriers. Excreted by renal glomerular filtration; dosage adjustment necessary in patients with diminished renal function. Indicated as cotherapeutic agent when tetracycline therapy used for neurobrucellosis (see Tetracycline for dosage).

Dosing

Adult

0.5-1.0 g/d IM, administered during first 6 wk of triple therapy for neurobrucellosis; usually in upper outer quadrant of buttock or in mid lateral thigh of adults; alternate injection sites
>60 years: Reduction of dosage recommended because of increased risk of toxicity

Pediatric

Infants and small children: Avoid injecting in buttock since injury of sciatic nerve possible; employ mid lateral muscles of thigh for injections; alternate injection sites
Older children and adolescents: 20-40 mg/kg IM, divided into 2-4 injections; not to exceed 1g IM

Interactions

Ethacrynic acid, mannitol, furosemide, and possibly other diuretics may potentiate ototoxic effects

Contraindications

Documented hypersensitivity; since cross-sensitivity to other aminoglycosides has been documented, history of hypersensitivity to other drugs in this class may contraindicate use of this agent; documented sulfite sensitivity; patients with brucellosis-related deafness and those with significant renal function impairment probably should not receive streptomycin or other aminoglycosides

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May result in vestibular and auditory dysfunction (vestibulotoxic potential greater than cochlear toxic potential); degree of ototoxicity proportional to dosage and duration of therapy and to degree of preexistent auditory dysfunction; risk for ototoxicity higher in young children, in adults older than 60 years, and in patients with impaired renal function; vestibular toxicity heralded by nausea, headache, vomiting, and disequilibrium; cochlear injury indicated by tinnitus or loss of high-frequency hearing; monitor these indicators of ototoxicity during therapy, and discontinue if such toxicity manifested; early discontinuation may permit recovery, while additional therapy may result in irreversible sensorineural cell damage; ototoxicity especially likely to develop within 4 wk of therapy in patients receiving total daily doses of 1.8-2 g, particularly in those older than 60 years and those with impaired renal function
Use during pregnancy exposes fetus to risk for ototoxicity; patients who are pregnant, may possibly become pregnant, or become pregnant during treatment should be apprised of this risk; mothers who are breastfeeding may secrete sufficient amounts of streptomycin in breast milk to result in infant toxicity
Sensitive individuals handling streptomycin injections may develop cutaneous hypersensitivity reactions; facial paresthesias, rash, fever, urticaria, angioneurotic edema, eosinophilia, exfoliative dermatitis, anaphylaxis, azotemia, leukopenia, thrombocytopenia, pancytopenia, hemolytic anemia, muscular weakness, or amblyopia may occur; infants receiving excessive streptomycin dosage may manifest encephalopathy with stupor or coma and flaccidity, and, occasionally, deep respiratory depression
Although least nephrotoxic of all aminoglycosides, nephrotoxicity occasionally occurs; patients with preexisting renal function impairment are at considerable risk for toxicity; single dose may prove ototoxic in individuals with severe uremia; ototoxicity (vestibular potential greater than cochlear potential), optic nerve dysfunction, arachnoiditis, peripheral neuritis, and encephalopathy all have been reported in individuals with impaired renal function; peak serum concentrations in such individuals should not exceed 20-25 mcg/mL
Respiratory paralysis has been reported due to neuromuscular blockade in individuals receiving streptomycin, especially if administered soon after anesthesia for administration of muscle relaxants

Tetracycline (Sumycin)

Readily absorbed antibiotic with bacteriostatic effects produced by inhibition of microbial protein synthesis. Concentrated by liver in bile and excreted in feces and urine. Dosage must be adjusted for patients with renal impairment because excessive systemic accumulation may occur, which can result in possible hepatic toxicity or worsening of azotemia, hyperphosphatemia, and acidemia. In patients with significant renal function abnormality, monitoring serum concentrations may be warranted.

Dosing

Adult

500 mg PO qid for 3 wk; usually, when tetracycline used in treatment of brucellosis, streptomycin 1 g IM bid should be coadministered for first wk of therapy and 1 g IM qd for second wk of therapy

Pediatric

>8 years: 25-50 mg/kg/d PO, divided bid/qid; not to exceed 2 g/d

Interactions

Food and dairy products may interfere with absorption; therefore, administer 1 h before or 2 h after meals; antacids containing calcium, magnesium, or aluminum may interfere with absorption and therefore should not be coadministered; may depress prothrombin activity and thus anticoagulant medication may have to be titrated to lower dose; oral contraceptive medications may be rendered less effective, breakthrough bleeding may occur

Contraindications

Documented hypersensitivity; pregnancy; children younger than 8 y

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Crosses placental membranes readily; use in pregnancy associated not only with risk for permanent tooth discoloration and tooth enamel hypoplasia in fetus, but also with interference with fetal skeletal growth and maturation; animal experimentation suggests possibility of embryotoxicity due to use in early pregnancy; administration to breastfeeding mothers carries risk of transfer to infant through breast milk
May result in photosensitivity with enhanced risk of serious sunburn; rarely, hypersensitivity exfoliative dermatitis has been reported; drug eruptions can include urticaria, angioneurotic edema, anaphylaxis, anaphylactic purpura, pericarditis, and exacerbation of systemic lupus erythematosus
Balanitis and other fixed drug eruptions have been reported, but rarely; pseudotumor cerebri has been reported in adults and infants; rarely, hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported; esophagitis or esophageal ulceration may develop during course of treatment—drinking adequate amounts of fluids with medication doses and avoiding dosage immediately before retiring to sleep may reduce risk for these complications; dizziness, tinnitus, visual disturbances, myasthenic syndrome, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, pancreatitis, and anogenital monilial inflammatory lesions have been reported with tetracycline administration

Ciprofloxacin (Cipro)

Synthetic broad-spectrum antimicrobial agent of quinolone class. Bactericidal activity due to interference with microbial DNA gyrase activity. Well absorbed orally and largely cleared unchanged in urine.

Dosing

Adult

500 mg PO bid; preferred time of dosing is 2 h after meals

Pediatric

<18 years: Not established

Interactions

Serious and fatal reactions reported in patients taking concurrent theophylline; reactions have included cardiac arrest, seizures, status epilepticus, and respiratory failure
Antacids containing calcium, magnesium, or aluminum, products containing iron, and multivitamins containing zinc may interfere substantially with absorption; may interfere with metabolism of caffeine, prolonging serum half-life of that drug; may alter serum levels of phenytoin; on rare occasions, sulfonylurea glyburide has resulted in severe hypoglycemia; cyclosporine has been associated with transient increases in serum creatinine level; may enhance anticoagulant effects of warfarin or its derivatives—where coadministration necessary, monitor coagulation function; probenecid interferes with renal tubular secretion of ciprofloxacin and therefore increases its serum level

Contraindications

Documented hypersensitivity; concurrent theophylline

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Safety and effectiveness have not been established in children, adolescents younger than 18 y, and pregnant or breastfeeding women (is excreted in breast milk)
Convulsions, increased intracranial pressure, and toxic psychosis have been reported; tremors, restlessness, lightheadedness, confusion, and hallucinations also have been reported; these reactions may necessitate discontinuation of ciprofloxacin
Use with great care in patients with epilepsy or conditions that predispose to occurrence of seizures
Serious and occasionally fatal anaphylactic reactions have been reported, sometimes after single dose; manifestations of these reactions have included cardiovascular collapse, loss of consciousness, pharyngeal or facial edema, dyspnea, and urticaria; only a few of these patients had history of hypersensitivity reactions
Reactions with fever, rash, eosinophilia, jaundice, or hepatic necrosis have been reported in patients receiving ciprofloxacin in combination with other drugs; discontinue ciprofloxacin after first appearance of skin rash or other signs compatible with hypersensitivity; moderate or severe phototoxicity may occur
Pseudomembranous colitis has been reported, as it has in patients receiving virtually any other antimicrobial agent
Achilles and other tendon ruptures that may require surgical repair have been reported; discontinue in patients reporting pain, inflammation, or rupture of tendon
Administration of oral ciprofloxacin to immature dogs provoked acute lameness due to permanent lesions of articular cartilage and other arthropathic changes in weight-bearing joints; not known whether similar changes occur in immature humans
Alteration of dosage necessary in patients with impaired renal function

Anti-inflammatory Agent

The addition of anti-inflammatory therapy with methylprednisolone or some other corticosteroid may be beneficial in patients with severe or diffuse CNS involvement, cranial neuropathies, optic neuritis or other MS-like presentations, or arachnoiditis.

Methylprednisolone (Adlone, Medrol, Solu-Medrol)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Dosing

Adult

Initial dose: 1 g IV qd for 3-5 d
May be followed with 3-wk oral taper: Initially 2 mg/kg/d; initial dose not to exceed 80 mg/d
Administer initial dose under close supervision since rare instances of anaphylaxis after initial dose have been reported

Pediatric

Initial dose: 20 mg/kg/d IV for 3-5 d; not to exceed 1 mg/d
Followed in some instances by a 3-wk oral taper: Initially 2 mg/kg/d prednisone PO

Interactions

Phenytoin, phenobarbital, ephedrine, or rifampicin may enhance clearance of corticosteroids, lowering anticipated serum levels
May result in unpredictable alteration in response to warfarin; usual effect is to lower response to anticoagulation, necessitating in some instances upward adjustment of dose based upon careful determination of prothrombin time
May enhance risk for hypokalemia with potassium-depleting diuretics; may increase requirements for oral hypoglycemic agents or insulin in patients with diabetes mellitus

Contraindications

Documented hypersensitivity; systemic fungal infection; concurrent amphotericin B; concomitant cerebral malaria; latent or active amoebiasis; active chickenpox or measles; most cases of active tuberculosis; many cases of recent myocardial infarction; most cases of ulcerative colitis, active or latent peptic ulcer disease, impending gastrointestinal perforation, or enteric abscess

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May interfere with ascertainment of presence or location of infections; may interfere with ability of treated patients to contain and eliminate infectious pathogens; may cause electrolyte disturbances and worsen congestive heart failure or hypertension in susceptible patients; may result in muscle weakness, loss of muscle mass, osteoporosis, vertebral compression fractures, aseptic necrosis of femoral heads, pathologic fractures of long bones, tendon rupture, pancreatitis, ulcerative esophagitis, impaired wound healing, increased sweating, convulsions, pseudotumor cerebri, glaucoma, subcapsular cataracts, vertigo, headache, confusion or psychosis, menstrual irregularities, suppression of adrenocortical axis, expression of latent diabetes mellitus, or hirsutism; breastfeeding should be avoided in patients treated with pharmacological doses because these compounds are secreted in breast milk and may suppress growth of feeding child as well as any other potential complications noted above

Follow-up

Further Inpatient Care

Follow-up sampling of CSF in order to ensure clearance of evidence for inflammation or the presence of organisms is important in determining the efficacy and duration of antibiotic treatment.

Further Outpatient Care

• Follow-up care is needed to ensure compliance for a full 6-week course of antibiotics and to determine whether a relapse has occurred. In some instances, a relapsing and remitting course similar to MS develops. In such instances, treatment with triple therapy (as noted in Medical Care) may be undertaken for periods as long as 6 months or more.
• The prognosis for meningoencephalitis is generally good. Chronic forms tend to have a less favorable prognosis. The granulomatous and arachnoiditic changes tend to respond to antibiotic therapy, but the chronic meningoencephalitic and polyradiculopathic processes are less responsive. Residual deficits, including deafness and weakness, may be found in a fair number of patients.
• Relapsing brucellosis must be distinguished from instances in which patients experience reinfection. The degree of immunity induced by an initial attack of brucellosis may be inadequate to prevent reinfection. Second, third, or even more instances of reinfection may occur, especially in veterinarians and others individuals with continual exposure to animals. Some individuals acquire infection-induced hypersensitivity to Brucella antigens. This may result in a severe local reaction due to accidental self-inoculation with Brucella vaccines. Reactions of this sort are especially likely to be experienced by veterinarians and others who are responsible for inoculating animal herds.

Deterrence/Prevention

• Avoid consumption of unpasteurized milk and milk products, as well as raw or undercooked meats. Education may be provided to the patient and family concerning risks and should emphasize avoiding anything identified as a specific cause in the case at hand. Should the identified source be a live animal, the herd or flock from which it came should be investigated.
• Scrupulous hygiene may prevent infection, especially when practiced by individuals likely to have close contact with goats, sheep, cows, camels, pigs, reindeer, rabbits, or hares. Obviously, this contact is of greatest importance in areas of endemic disease.
• Considerable concern has been harbored by authorities concerning the utilization of Brucella species in biological weapons. Airborne transmission of these bacteria is readily achieved via the mucous membranes of the conjunctivae, nasal passages, oropharynx, and respiratory tract. Infection may occur as the result of lodging of organisms in cuts or abrasions. As few as 10-100 organisms may produce infection via aerosol exposure. The resulting disease may have any of the many various manifestations of which Brucella species are capable.
• Bichat guidelines have been established for the management of individuals at risk for or manifesting evidence of brucellosis after bioterroristic exposure. Treatment regimens combining doxycycline with either streptomycin or rifampin are thought adequate in such situations and the combination of ofloxacin with rifampin is also cited. However, currently no evidence exists concerning efficacy of postexposure prophylaxis as a method of preventing brucellosis.^{[20 ]}

Complications

Initiation of antibiotic treatment may provoke the Jarisch-Herxheimer reaction with clinical worsening and CSF changes from lymphocytic to polymorphonuclear predominance.

Prognosis

• In uncomplicated cases of acute brucellosis, fever, malaise, and many other manifestations improve rapidly with bed rest, while sustained physical activity may prolong or worsen the degree of illness.
  • Considerable improvement from the symptoms of the acute "toxic" phase of illness occurs in most cases within a few weeks, with or without treatment. In many cases this is followed by complete remission within 2-6 months.
  • Recovery tends to be more rapid in individuals infected with B abortus than in those infected with B melitensis or B suis.
• Death seldom occurs as the consequence of acute brucellosis, although it has been reported. Postmortem analysis of such cases confirms that the burden of acute brucellotic infection is borne by tissues of the lymphoreticular system.
• Recurrence of symptoms of acute brucellosis is not uncommon. The recurrent disease may be systemic or localized. In some of these patients, the condition evolves into chronic brucellosis, which if untreated may be progressive.
• Chronic brucellosis is variously classified, but includes systemic and specific localized forms (including various types of neurobrucellosis), the characteristics of which are discussed in the Clinical section.
  • The various forms of chronic brucellosis, including neurobrucellosis, are due to continued infectious disease, for which additional treatment is indicated and effective.
  • Objective clinical and laboratory evidence for ongoing disease is demonstrable. Patients who do not have such evidence and who complain of occasional mild symptoms similar to those found in acute brucellosis are likely to have psychoneurosis. This complication of acute brucellosis does not usually resolve with anti-brucellosis treatments, although such treatments may exert placebo effects for individual bouts. Psychiatric treatment may be indicated.
  • The likelihood of recurrence is greater in individuals who are not treated or who are inadequately treated for acute brucellosis.
  • Recurrence is possible even in properly treated patients who have had acute brucellosis. Addition of oral rifampicin to oral tetracycline may reduce the recurrence risk for patients who are treated with that combined therapy for acute brucellosis.
  • Chronic brucellosis may continue to trouble patients for as long as 25 years, but such cases are quite rare.
• Neurobrucellosis, a specific subtype of localized chronic brucellosis, has a variable outcome.
  • Recovery of patients with acute brucellotic meningitis, meningoencephalitis, or disseminated encephalomyelitis is typically excellent.
  • The likelihood of an excellent outcome from neurobrucellosis is thought to be increased when effective antimicrobial therapy is started early in the course of illness.
  • There is as yet, however, no agreement on the criterion standard for treatment of neurobrucellosis. The issues involved are considered in the Treatment section.
  • The Herxheimer reaction is either extremely uncommon or unknown in the treatment of neurobrucellosis.
  • The scrupulousness with which seizures and cardiovascular complications are treated and supportive care is undertaken to manage incontinence and to prevent of bedsores is likely also to influence outcome.
  • Some patients with neurobrucellosis manifest permanent deficits. The risk for permanent deficits is higher in certain subgroups of primary or secondary neurobrucellosis.
  • Outcome is worse in cases in which neurobrucellosis is complicated by critical elevations of intracranial pressure. Prompt recognition and effective treatment of raised intracranial pressure usually results in rapid and complete recovery, however. In cases of malignant intracranial hypertension, surgical decompression has been advocated by some authorities as improving outcome and as a method of preventing death due to herniation.
  • Permanent deficits may occur in individuals who have cerebrovascular occlusive strokes secondary to brucellar endocarditis, producing emboli that cause occlusions or prompt the development of intracerebral mycotic aneurysms. Outcome may be poor in cases of intracranial mycotic aneurysm rupture with intracerebral or subarachnoid hemorrhage.
  • The risk for permanent deficits is higher in individuals who develop osteoarthritic forms of brucellosis that compromise spinal cord or spinal roots due to spondylitic compressive myelopathy and radiculopathy. The outcome for peripheral neuritis of the lower spinal nerves, which may be difficult to distinguish from spondylitic myelopathy, may be better than the outcome for disease secondary to musculoskeletal abnormalities.

Patient Education

• Education with regard to vectors, consumption of pasteurized or appropriately cooked foods, and hygiene may reduce the risk of contracting brucellosis for family members living in areas of endemic disease.
• Reassurance concerning recurrent symptoms that are not associated with clinical or laboratory evidence of acute brucellotic disease is important in some instances.
• For excellent patient education resources, visit eMedicine's Brain and Nervous System Center and Public Health Center. Also, see eMedicine's patient education articles Brain Infection and Foreign Travel.

Miscellaneous

Medicolegal Pitfalls

• Standard medicolegal risks for an infectious disease are applicable to brucellosis. Misdiagnosis, delayed diagnosis, and medication reactions/allergies are also medicolegal risks.
• In the United States, federal regulations applicable to clinicians, pathologists, and laboratory staff govern the possession, use, and transport of specimens or cultures containing B abortus, B suis, and B melitensis. These are the select agent rules of the Department of Health and Human Services (DHHS) and of the Department of Agriculture (DOA). Isolations of these species and instances of potential laboratory exposure must be reported either to the CDC or to the USDA Animal and Plant Health Inspection Service.^{[10 ]}
• At least as strenuous reporting requirements exist in other parts of the world, especially those areas that are certified as Brucella -free. That designation carries economic importance of the first degree in such Brucella -free countries as New Zealand. The consequences of importation to New Zealand of Brucella may be extremely severe.

Special Concerns

The zoonotic issues have been discussed. Vectors for human infection include goats, sheep, cows, pigs, camels, reindeer, rabbits, and hares. Brucella species pose a medical threat to herd animals. This threat is of particular importance with regard to the induction of abortion by B suis infection. Herds can be protected by vaccination.

References

1. Pappas G, Papadimitriou P, Akritidis N. The new global map of human brucellosis. Lancet Infect Dis. Feb 2006;6(2):91-9. [Medline].

2. Al Dahouk S, Nockler K, Tomaso H. Seroprevalence of brucellosis, tularemia, and yersiniosis in wild boars (Sus scrofa) from north-eastern Germany. J Vet Med B Infect Dis Vet Public Health. Dec 2005;52(10):444-55. [Medline].

3. Al-Majali AM, Hussain NO, Amarin NM, Majok AA. Seroprevalence of, and risk factors for, peste des petits ruminants in sheep and goats in Northern Jordan. Prev Vet Med. Jun 15 2008;85(1-2):1-8. [Medline].

4. Edwards C, Jawad AS. History of brucellosis. J R Soc Med. Feb 2006;99(2):54. [Medline].

5. Al Dahouk S, Jubier-Maurin V, Scholz HC, Tomaso H, Karges W, Neubauer H, et al. Quantitative analysis of the intramacrophagic Brucella suis proteome reveals metabolic adaptation to late stage of cellular infection. Proteomics. Sep 2008;8(18):3862-70. [Medline].

6. Badiaga S, Imbert G, La Scola B. Imported Brucellosis associated with Plasmodium falciparum malaria in a traveler returning from the tropics. J Travel Med. Sep-Oct 2005;12(5):282-4. [Medline].

7. Fallatah SM, Oduloju AJ, Al-Dusari SN. Human brucellosis in Northern Saudi Arabia. Saudi Med J. Oct 2005;26(10):1562-6. [Medline].

8. Alp E, Doganay M. Current therapeutic strategy in spinal brucellosis. Int J Infect Dis. Nov 2008;12(6):573-7. [Medline].

9. Bouza E, Sánchez-Carrillo C, Hernangómez S, González MJ,. Laboratory-acquired brucellosis: a Spanish national survey. J Hosp Infect. Sep 2005;61(1):80-83. [Medline].

10. Gerberding JL, Romero JM, Ferraro MJ. Case records of the Massachusetts General Hospital. Case 34-2008. A 58-year-old woman with neck pain and fever. N Engl J Med. Oct 30 2008;359(18):1942-9. [Medline].

11. Solera J, Lozano E, Martínez-Alfaro E, Espinosa A, Castillejos ML, Abad L. Brucellar spondylitis: review of 35 cases and literature survey. Clin Infect Dis. Dec 1999;29(6):1440-9. [Medline].

12. Ugarriza LF, Porras LF, Lorenzana LM, Rodríguez-Sánchez JA, García-Yagüe LM, Cabezudo JM. Brucellar spinal epidural abscesses. Analysis of eleven cases. Br J Neurosurg. Jun 2005;19(3):235-40. [Medline].

13. James DG. A mimic of sarcoidosis: brucellosis [editorial]. Sarcoidosis. Sep 1990;7(2):87-8. [Medline].

14. Sharif HS, Clark DC, Aabed MY, Haddad MC, al Deeb SM, Yaqub B. Granulomatous spinal infections: MR imaging. Radiology. Oct 1990;177(1):101-7. [Medline].

15. Laboratory-acquired brucellosis--Indiana and Minnesota, 2006. MMWR Morb Mortal Wkly Rep. Jan 18 2008;57(2):39-42. [Medline].

16. Araj GF, Kattar MM, Fattouh LG, Bajakian KO, Kobeissi SA. Evaluation of the PANBIO Brucella immunoglobulin G (IgG) and IgM enzyme-linked immunosorbent assays for diagnosis of human brucellosis. Clin Diagn Lab Immunol. Nov 2005;12(11):1334-5. [Medline].

17. Darouiche RO. Spinal epidural abscess. N Engl J Med. Nov 9 2006;355(19):2012-20. [Medline].

18. Kayani I, Kamani I, Syed I, Saifuddin A, Green R, MacSweeney F. Vertebral osteomyelitis without disc involvement. Clin Radiol. Oct 2004;59(10):881-91. [Medline].

19. Katonis P, Tzermiadianos M, Gikas A, Papagelopoulos P, Hadjipavlou A. Surgical treatment of spinal brucellosis. Clin Orthop Relat Res. Mar 2006;444:66-72. [Medline].

20. Bossi P, Tegnell A, Baka A. Bichat guidelines for the clinical management of brucellosis and bioterrorism-related brucellosis. Euro Surveill. Dec 2004;9(12):E15-6. [Medline].

21. Abramsky O. Neurological features as presenting manifestations of brucellosis. Eur Neurol. 1977;15(5):281-4. [Medline].

22. Abu Shaqra QM. Epidemiological aspects of brucellosis in Jordan [In Process Citation]. Eur J Epidemiol. Jun 2000;16(6):581-4. [Medline].

23. Akdeniz H, Irmak H, Anlar O. Central nervous system brucellosis: presentation, diagnosis and treatment. J Infect. May 1998;36(3):297-301. [Medline].

24. al Deeb SM, Yaqub BA, Sharif HS. Neurobrucellosis: clinical characteristics, diagnosis, and outcome. Neurology. Apr 1989;39(4):498-501. [Medline].

25. al-Eissa YA. Clinical and therapeutic features of childhood neurobrucellosis. Scand J Infect Dis. 1995;27(4):339-43. [Medline].

26. Araj GF, Brown GM, Haj MM. Assessment of Brucellosis Card test in screening patients for brucellosis. Epidemiol Infect. Jun 1988;100(3):389-98. [Medline].

27. Araj GF, Lulu AR, Khateeb MI. ELISA versus routine tests in the diagnosis of patients with systemic and neurobrucellosis. APMIS. Feb 1988;96(2):171-6. [Medline].

28. Bahemuka M, Shemena AR, Panayiotopoulos CP. Neurological syndromes of brucellosis. J Neurol Neurosurg Psychiatry. Aug 1988;51(8):1017-21. [Medline].

29. Basaranoglu M, Mert A, Tabak F. A case of cervical Brucella spondylitis with paravertebral abscess and neurological deficits. Scand J Infect Dis. 1999;31(2):214-5. [Medline].

30. Bashir R, Al-Kawi MZ, Harder EJ. Nervous system brucellosis: diagnosis and treatment. Neurology. Nov 1985;35(11):1576-81. [Medline].

31. Bouza E, Garcia de la Torre M, Parras F. Brucellar meningitis. Rev Infect Dis. Jul-Aug 1987;9(4):810-22. [Medline].

32. Brouillard JE, Terriff CM, Tofan A. Antibiotic selection and resistance issues with fluoroquinolones and doxycycline against bioterrorism agents. Pharmacotherapy. Jan 2006;26(1):3-14. [Medline].

33. Bucher A, Gaustad P, Pape E. Chronic neurobrucellosis due to Brucella melitensis. Scand J Infect Dis. 1990;22(2):223-6. [Medline].

34. Cerri D, Ebani VV, Pedrini A. Evaluation of tests employed in serological diagnosis of brucellosis caused by Brucella ovis [In Process Citation]. New Microbiol. Jul 2000;23(3):281-8. [Medline].

35. Comerci DJ, Altabe S, de Mendoza D. Brucella abortus synthesizes phosphatidylcholine from choline provided by the host. J Bacteriol. Mar 2006;188(5):1929-34. [Medline].

36. DeJong RN. Central nervous system involvement in undulant fever, with the report of a case and survey of the literature. Lancet. 1936;430-442.

37. Dockal M, Carter DC, Ruker F. The three recombinant domains of human serum albumin. Structural characterization and ligand binding properties. J Biol Chem. Oct 8 1999;274(41):29303-10. [Medline].

38. Estevao MH, Barosa LM, Matos LM. Neurobrucellosis in children. Eur J Pediatr. Feb 1995;154(2):120-2. [Medline].

39. Fiori PL, Mastrandrea S, Rappelli P. Brucella abortus infection acquired in microbiology laboratories. J Clin Microbiol. May 2000;38(5):2005-6. [Medline].

40. Fleming DO, Byers KB. Biological safety: Principles and Practices. 2000.

41. Gokhle YA, Bichile LS, Gogate A. Brucella spondylitis: an important treatable cause of low backache. J Assoc Physicians India. Apr 1999;47(4):384-8. [Medline].

42. Gomez MC, Rosa C, Geijo P. [Comparative study of the Brucellacapt test versus the Coombs test for Brucella]. Enferm Infecc Microbiol Clin. Jun-Jul 1999;17(6):283-5. [Medline].

43. Hernandez MA, Anciones B, Frank A. [Neurobrucellosis and cerebral vasculitis]. Neurologia. Nov-Dec 1988;3(6):241-3. [Medline].

44. Hong PC, Tsolis RM, Ficht TA. Identification of genes required for chronic persistence of Brucella abortus in mice. Infect Immun. Jul 2000;68(7):4102-7. [Medline].

45. Jacobs F, Abramowicz D, Vereerstraeten P. Brucella endocarditis: the role of combined medical and surgical treatment. Rev Infect Dis. Sep-Oct 1990;12(5):740-4. [Medline].

46. Khuraibet AJ, Shakir RA, Trontelj JV. Brainstem auditory evoked potential (BAEP) abnormalities in brucellosis. J Neurol Sci. Nov 1988;87(2-3):307-13. [Medline].

47. Kochar DK, Kumawat BL, Agarwal N. Meningoencephalitis in brucellosis. Neurol India. Jun 2000;48(2):170-3. [Medline].

48. Leggiadro RJ. The threat of biological terrorism: a public health and infection control reality. Infect Control Hosp Epidemiol. Jan 2000;21(1):53-6. [Medline].

49. Lopes C, Oliveira J, Malcata L. [Spinal brucellosis. 4 years of experience]. Acta Med Port. Sep 1992;5(8):419-23. [Medline].

50. Lopez-Urrutia L, Alonso A, Nieto ML. Lipopolysaccharides of Brucella abortus and Brucella melitensis induce nitric oxide synthesis in rat peritoneal macrophages. Infect Immun. Mar 2000;68(3):1740-5. [Medline].

51. Lubani MM, Dudin KI, Araj GF. Neurobrucellosis in children. Pediatr Infect Dis J. Feb 1989;8(2):79-82. [Medline].

52. Lulu AR, Araj GF, Khateeb MI. Human brucellosis in Kuwait: a prospective study of 400 cases. Q J Med. Jan 1988;66(249):39-54. [Medline].

53. Madkour MM, Sharif HS, Abed MY. Osteoarticular brucellosis: results of bone scintigraphy in 140 patients. AJR Am J Roentgenol. May 1988;150(5):1101-5. [Medline].

54. Mainar-Jaime RC, Vazquez-Boland JA. Associations of veterinary services and farmer characteristics with the prevalences of brucellosis and border disease in small ruminants in Spain. Prev Vet Med. Jun 11 1999;40(3-4):193-205. [Medline].

55. Mantur BG, Akki AS, Mangalgi SS. Childhood brucellosis--a microbiological, epidemiological and clinical study. J Trop Pediatr. Jun 2004;50(3):153-7. [Medline].

56. McLean DR, Russell N, Khan MY. Neurobrucellosis: clinical and therapeutic features. Clin Infect Dis. Oct 1992;15(4):582-90. [Medline].

57. Milionis H, Christou L, Elisaf M. Cutaneous manifestations in brucellosis: case report and review of the literature. Infection. Mar-Apr 2000;28(2):124-6. [Medline].

58. Mousa AM, Bahar RH, Araj GF. Neurological complications of brucella spondylitis. Acta Neurol Scand. Jan 1990;81(1):16-23. [Medline].

59. Mousa AR, Koshy TS, Araj GF. Brucella meningitis: presentation, diagnosis and treatment--a prospective study of ten cases. Q J Med. Sep 1986;60(233):873-85. [Medline].

60. Murrell TG, Matthews BJ. Multiple sclerosis--one manifestation of neurobrucellosis?. Med Hypotheses. Sep 1990;33(1):43-8. [Medline].

61. Nimri LF. Diagnosis of recent and relapsed cases of human brucellosis by PCR assay. BMC Infect Dis. Apr 28 2003;3(1):5. [Medline].

62. Oliveri Rl, Matera G, Foca A. Polyradiculoneuropathy with cerebrospinal fluid albuminocytological dissociation due to neurobrucellosis [see comments]. Clin Infect Dis. Oct 1996;23(4):833-4. [Medline].

63. Omar FZ, Zuberi S, Minns RA. Neurobrucellosis in childhood: six new cases and a review of the literature. Dev Med Child Neurol. Nov 1997;39(11):762-5. [Medline].

64. Pedro-Pons A, Foz M, Codina A. [Neurobrucellosis: a study of 41 cases]. Munch Med Wochenschr. Mar 30 1973;115(13):531-6. [Medline].

65. Piampiano P, McLeary M, Young LW. Brucellosis: unusual presentations in two adolescent boys. Pediatr Radiol. May 2000;30(5):355-7. [Medline].

66. Public health consequences of a false-positive laboratory test result for Brucella--Florida, Georgia, and Michigan, 2005. MMWR Morb Mortal Wkly Rep. Jun 6 2008;57(22):603-5. [Medline].

67. Reviriego FJ, Moreno MA, Dominguez L. Risk factors for brucellosis seroprevalence of sheep and goat flocks in Spain. Prev Vet Med. Apr 28 2000;44(3-4):167-73. [Medline].

68. Roldan-Montaud A, Jimenez-Jimenez FJ, Zancada F. Neurobrucellosis mimicking migraine. Eur Neurol. 1991;31(1):30-2. [Medline].

69. Ruben B, Band JD, Wong P. Person-to-person transmission of Brucella melitensis. Lancet. Jan 5 1991;337(8732):14-5. [Medline].

70. Samartino L, Gregoret R, Gall D. Fluorescence polarization assay: application to the diagnosis of bovine brucellosis in Argentina. J Immunoassay. Aug 1999;20(3):115-26. [Medline].

71. Sanchez Chaparro MA, Merida de la Torre FJ, Gonzalez Alegre P. [Transverse myelitis caused by Brucella (letter)]. Rev Clin Esp. Nov 1999;199(11):778. [Medline].

72. Sanchez-Sousa A, Torres C, Campello MG. Serological diagnosis of neurobrucellosis. J Clin Pathol. Jan 1990;43(1):79-81. [Medline].

73. Sathiyaseelan J, Jiang X, Baldwin CL. Growth of Brucella abortus in macrophages from resistant and susceptible mouse strains. Clin Exp Immunol. Aug 2000;121(2):289-94. [Medline].

74. Savell VH, Parham DM, Jacobs RF. Pathological case of the month. Disseminated brucellosis. Arch Pediatr Adolesc Med. Mar 2000;154(3):311-2. [Medline].

75. Shaalan MA, Memish ZA, Mahmoud SA. Brucellosis in children: clinical observations in 115 cases. Int J Infect Dis. Sep 2002;6(3):182. [Medline].

76. Shakir RA. Neurobrucellosis. Postgrad Med J. Dec 1986;62(734):1077-9. [Medline].

77. Shakir RA, Al-Din AS, Araj GF. Clinical categories of neurobrucellosis. A report on 19 cases. Brain. Feb 1987;110 ( Pt 1):213-23. [Medline].

78. Shamelian SO. Diagnosis and treatment of brucellosis [letter; comment]. Neth J Med. May 2000;56(5):198-200. [Medline].

79. Silva CA, Rio ME, Maia-Goncalves A. Oligoclonal gamma-globulin of cerebrospinal fluid in neurobrucellosis. Acta Neurol Scand. Jan 1980;61(1):42-8. [Medline].

80. Spink WW. The Nature of Brucellosis. Minneapolis, Minn: University of Minnesota Press;1956.

81. Spink WW. What is chronic brucellosis?. Ann Int Med. 1951;35:358-374.

82. Thomas R, Kameswaran M, Murugan V. Sensorineural hearing loss in neurobrucellosis. J Laryngol Otol. Nov 1993;107(11):1034-6. [Medline].

83. Tur BS, Suldur N, Ataman S. Brucellar spondylitis: a rare cause of spinal cord compression. Spinal Cord. May 2004;42(5):321-4. [Medline].

84. Verghese S, Padmaja P, Elizabeth SJ. Bacterial endocarditis caused by Brucella melitensis biotype I. Indian Heart J. Mar-Apr 2000;52(2):203-4. [Medline].

85. Young EJ. Human brucellosis. Rev Infect Dis. Sep-Oct 1983;5(5):821-42. [Medline].

86. Young EJ. Serologic diagnosis of human brucellosis: analysis of 214 cases by agglutination tests and review of the literature. Rev Infect Dis. May-Jun 1991;13(3):359-72. [Medline].

87. Young EJ, Tarry A, Genta RM. Thrombocytopenic purpura associated with brucellosis: report of 2 cases and literature review. Clin Infect Dis. Oct 2000;31(4):904-9. [Medline].

Keywords

neurobrucellosis, Brucella melitensis, Brucella suis, Brucella abortus, Brucella canis, Malta fever, Naples fever, Neapolitan fever, Constantinople fever, Gibraltar fever, Crete fever, Mediterranean fever, undulant fever, rock fever, Levant fever, Syriac fever, Mediterranean gastric remittent fever, febricula tifoidea, intermittent typhoid fever, adeno-tifo fever, typhomalarial fever, subcontinuous malarial fever, gastrobilious fever, cesspit fever, mephitic fever

Contributor Information and Disclosures

Author

Robert Stanley Rust Jr, MD, MA, Thomas E Worrell Jr Professor of Epileptology and Neurology, Co-Director of FE Dreifuss Child Neurology and Epilepsy Clinics, Director, Child Neurology, University of Virginia; Chair-Elect, Child Neurology Section, American Academy of Neurology
Robert Stanley Rust Jr, MD, MA is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, American Headache Society, American Neurological Association, Child Neurology Society, International Child Neurology Association, and Society for Pediatric Research
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Aashit K Shah, MD, Associate Professor of Neurology, Wayne State University; Program Director, Clinical Neurophysiology Fellowship, Department of Neurology, Detroit Medical Center
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CME Editor

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