Neurologic Manifestations of Brucellosis Clinical Presentation

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

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]

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.

• 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.