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Department of Internal Medicine
Shiraz E-Medical Journal

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Neurobrucellosis

S. Izadi, M.D.
Department of Internal Medicine, SUMS

Abstract 

Although uncommon, neurobrucellosis can affect any part of the central or peripheral nervous system clinical syndromes are ultimately diverse, and clinical picture may be confused by the coexistence of two or more clinical syndromes in the same patient. The most common neurologic manifestation is a subacute or chronic meningoencephalitis. Acute toxic manifestations (e.g., headache, neckache , backache , insomnia, depression and muscle weakness) are seen during the acute phase of infection. Incidence of eurobrucellosis cannot be exactly estimated. Most impportant clinical syndromes include:brucella meningitisand encephalitis, vascular syndromes, myelopathy and spinal disease and psychiatric disturbances. All of these syndromes usually occur without any underlying disease. Diagnosis is made by reviewing patient history, physical examination, CSF and serum serological and other laboratory studies. Detection of brucella antibodies in the CSF always indicates local infection, however, febrile agglutination tests are not reliable. Gram stains are usually negative and cultures are positive in only 25% of cases. Since the organism is located intracellularly, treatment is difficult. Doxycycline in addition to rifampin and streptomycin is the best-studied regimen which should be continued untill CSF is clear. In the yaer following treatment, serum agglutinins fall to normal. The efficacy of corticosteroids is not proved. Neurobrucella has a better prognosis than other forms of chronic meningitis and less mortality; however, incidence of minor sequella (not limiting the normal life) is high.

Introduction

Brucellosis, malta , Mediterranean or undulant fever is caused by infection in humans by some species of bacteria of genus Brucella. These bacteria infect domestic animals-including cows, sheep, goats , camels, horses, pigs, cats and dogs. Hippocrates and Aristotle have described malta fever in humans. The first identification of Brucellosis as a disease entity is attributed to Marston (1861). Human infection is acquired via the gastrointestinal tract by ingestion of infected milk or milk products , or by contact with infected animals or meat through the skin , conjunctiva or lungs. Males of working age are affected at least twice as frequently as females. Brucellae are slow-growing , small , non - spore forming , non-motile, non-encapsulated , aerobic , facultativelly intracellular , gram - negative coccobacilli. B. abortus, B. suis, B. melitensis , and B. canis are known to infect humans. B. neotomae and B. ovis do not infect humans. Once the organisms have entered the body they travel to the regional lymph nodes, thence by the blood stream to localize in the reticulo-endothelial system in spleen, lymph nodes, liver , and bone marrow. Other tissues including the nervous system, may be involved by hematogenous spread. Over 500000 cases of brucellosis are reported yearly from 100 countries. B. melitensis infection , distributed primarily in the Mediterranean region , latin America, the Persian gulf and Indian subcontinent , accounts for the majority of cases.

Neurobrucellosis:

Neurobrucellosis is uncommon and neurologic manifestations of neurobrucellosis are
diverse, and can affect any part of the central or peripheral nervous system, and clinical
picture may be confused by the coexistence of two or more clinical syndromes in the
same patient. It is difficult to know how frequently the nervous system is affected ,
because of difficulties in diagnosis and variability in reporting such complications. The clinical neurological syndromes which may be caused by Brucella include, acute toxic manifestations, meningitis , diffuse or localized encephalitis, myelitis , radiculitis, neuritis, multiple cerebral or cerebellar abscesses , ruptured mycotic aneuysm and subarachnoid hemorrhage, guillain - Barre syndrome , cranial nerve palsies , hemiplegia , sciatica, myositis, and rhabdomyolysis. Papillitis , papilledema, retrobulbar neuritis, optic atrophy and ophtalmoplegia due to lesion in cranial nerve III, IV, VI may occur in brucella meningoencephalitis. The most common neurologic manifestation is a subacute or chronic meningoencephalitis. Many other CNS manifestations of neurobrucellosis have been reported : arachnoidits, cerebellar syndromes, ruptured basilar aneurism, hemiparkinsonism, chorea , anterior poliomyelitis. Sometimes it may mimick brain tumor requiring neurosurgery. Acute toxic manifestations are seen during the acute phase of infection , and include headache, neckache , backache , insomnia, depression and muscle weakness.Motor manifestations occur frequently and generally present in the form of paresis of variable intensity ,with frequent gait disturbances. Sensory symptoms usually consist of paresthesias and occationaly gait apraxia.Involvment of the cranial nerves, generally the sixth , seventh , and eight , is relatively frequent findings.The involvment of the eight cranial nerve is reported a very chracteristic of the brucellar meningitis. All this diverse manifestations can lead to confusion and delay in diagnosis. It may also lead to difficulty in diffrentiating neurobrucellosis from other chronic infections, especially tuberculosis and syphilis.

Brucella meningitis :

Although headache and neckache are prominent features of acute illness , the more usual course of brucella meningitis is that of a chronic or relapsing form of meningitis, often associated with some features of encephalitis, or cranial nerve palsies and arachnoiditis , clinically indistinguishable form tuberculosis or fungal meningits , and CSF findings may be identical . The proportion of males to females is approximately 2:1.Brucellar meningitis , like other forms of brucellosis , generally occurs in patients without underlying disease , and may present as the first manifestation or at any time in the evolution of the disease. Another type of meningitis involves the spinal medulla and is secondary to spondylitis; this type of meningitis is generally caused by epidural abscesses. It is interesting to note that <50% of the patients with brucellar meningitis exhibited meningeal signs. Neurobrucellosis and brucellar meningitis may have an exclusively neurologic manifestations disease , mimicking vascular accidents or neurological disease that are frequently paroxysmal or recurrent.

Brucella encephalitis:

This is commonly associated with meningitis but may be encountered without neck stiffness, and the sign of meningitis may be subtle. There is depression and confusion and paranoid delusions , depression of consciousness (drowsy, stuprous , coma ) and sometimes long-tract signs and convulsions and focal neurologic deficit may appear. Also extra pyramidal and cerebellar sings have been recorded. Although most cases will resolve spontaneously after a protracted course , or after appropriate antibiotic therapy , encephalitis can be fatal.

Vascular syndromes :

In the course of brucella encephalitis or meningitis the cerebral vessels can be affected by vasculitic changes which may cause occlusion and infarction with resultant deficit according to the vessel involved. Intermittent neurological deficits attributable to vascular insufficiency have been reported. Emboli may derive from brucella endocarditis, and subarachnoid hemorrhage from rupture of mycotic aneurysms.

Myelopathy and spinal disease :

Myelopathy may result from several different mechanisms . Acute transverse myelitis, spinal cord infarction , adhesive arachnoiditis , compression from epidural abscess or from brucella spondylitis may occur. Brucella spondylitis affect the lumbosacral and lower thoracic region most frequently , causing erosion and vertebral collapse leading to cord or cauda equina compression. Diagnostic confusion with lumbar disc protrusion is not uncommon ,and tuberculous spondylitis produces an identical clinical picture. Direct involvement of the spinal cord and primary sciatic involvement are rare. In addition inflammatory radiculopathies may affect lumbar and sacral nerve roots and cervico-brachial plexus. Mononeuritis multiplex and peripheral neuropathy have been described. Cranial nerve involvment may result from basal meningitis , or can occur independently.

Psychiatric disturbances :

Psychiatric disturbances , most commonly depression , is frequent in brucellosis . This aspect of brucellosis , much more than other manifestations is confusing. A patient who is chronically ill as a result of chronic disease, and in whom no overt physical abnormality is found, it is very likely to be labeled as functional or malingering , unless brucellosis is suspected. In acute brucellosis , confusion and psychiatric reactions may occur. In some of the chronic cases organic brain damage may provide the substrate for the psychiatric picture.

Diagnosis :

The neurological syndromes require differentiation from other chronic meningitis, encephalitis , and granulomatous disease , most importantly tuberculosis and fungal infectious The spondylitic changes are similar to T.B.  and other chronic pyogenic infections. Myelopathies can mimic cord compression from tumor, and the periphral manifestations have to be distinguished from other neuropathies. The serologic study of both serum and CSF will usually reveal abnormality in brucella meningitis or encephalitis but the degree of abnormality varies and is not specific. CSF pressure is usually elevated ,and CSF may appear clear , turbid or hemorrhagic. Often there is a CSF pleocytosis with lymphocyte predominating CSF pleocytosis is seen in 91% of cases of brucella meningitis the protein content is usually raised and the sugar content may be reduced or normal . Antibody against Brucella may be demonstrated in CSF by enzyme - linked immuno-sorbant assay (ELISA). Most patients mount significant serologic response to Brucella infection , the most frequently used test is standard tube agglutination test (SAT). The detection of brucellar antibodies in the CSF is always indicative of local infection. CSF titers are , however much lower than those in serum in cases of systemic brucellosis. Coombs' test may provide the only positive data for CSF when result of agglutinin tests are negative. The screening of antibodies by coomb's test in CSF is the most reliable serologic test for diagnosis of brucellar meningitis. No single titer of brucella antibodies is diagnostic , however , most cases of active infection have titers higher than 1:160 in CSF. The febrile agglutination tests are insensitive and should not be relied on for diagnosis. In any suspected case of brucellosis attempts should be made to culture the organisms , although cultures are positive in less than one quarter of cases. Gram stains are usually negative.  
Diaz et. al. and others have shown an elevation of CSF oligocolonal IgG in patients with brucella meningitis. ESR is increased in <25% of patients and white blood cell count is often normal or low. The radiological abnormalities of neurobrucellosis are non specific. CT appearances of brucella meningitis and encephlitis are similar to other bacterial meningitides. The CT and x ray appearances of spinal brucellosis are similar to those of pyogenic osteomyelitis and require differentiation from tuberculous spondylitis.

Treatment :

The major problem in antibiotic treatment of brucellosis is intracellular location of the organism .There is no unanimity of opinion regarding the optimal regimen. Tetracycline and aminoglycosides may not achieve adequate CSF level. Nevertheless , most authorities recommend the use of doxycyclin 100 mg PO BID in combination with two or more other drugs (Rifampin 600-900 mg PO QD/ streptomycin 1gr IM QD) treatment should be continued for many weeks depending on the response. Doxycycline crosses the blood brain barrier better than generic tetracycline, and it has been used successfully with trimethoprim - sulfamethoxazole and rifampin for brucella meningitis. Third generation cephalosporins also achieve high concentrations in CSF but susceptibility of Brucella SPP. is variable , and in vitro sensitivity should be ensured. Antibiotic therapy should be continued for 1-19 months, till CSF will be cleared. Corticosteroids are often recommended for neurobrucellosis, however , in the absence of controlled studies, their efficacy is unproved. All patients should be kept under review for at least a year following completion of antibiotic course, when the serum agglutinins should be fallen to normal level.

Prognosis :

Burcellar meningitis differs from other forms of chronic meningitis in having a better prognosis. Mortality, for reasons which are not clear , is low, and the cause of death  is not always clearly related to brucellosis. The incidence of minor sequelae is high; however, only a few patients suffered important limitations in their normal activity due to motor , sensory or mental disturbances.

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