eMedicine Specialties > Neurology > Neurological Infections

Brucellosis: Differential Diagnoses & Workup

Author: Robert Rust Jr, MD, Thomas E Worrell Jr Professor of Epileptology and Neurology, Co-Director of FE Dreifuss Child Neurology and Epilepsy Clinics, University of Virginia School; Clinical and Residency Training, Child Neurology, University of Virginia Hospital and Clinics
Contributor Information and Disclosures

Updated: Jun 8, 2006

Differential Diagnoses

Other Problems to Be Considered

Abducens (CN VI) nerve palsy
Ischemic optic neuropathy
Partially treated meningitis
Tuberculosis
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. 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 recognize brucellosis and obtain appropriate laboratory studies. 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.
  • 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.
  • 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.
  • 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.
  • Serum and CSF agglutination (STA) tests employing 2-mercaptoethanolamine have been the most widely employed methods for ascertainment of diagnosis. 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, patients with chronic brucellosis exhibit depressed Brucella agglutinin titers owing to the presence of blocking antibodies. There is the possibility of serological cross-reactivity in that patients with Cholera vibrio or Pasteurella tularensis infections may yield a 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
  • 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 has become the test of choice both for acute brucellosis and for neurobrucellosis. It manifests very low rates of false positivity in cases of brucellosis without CNS involvement and in various nonbrucellar CNS diseases.
  • 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.
  • 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.
• 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.
  • 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.

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