Statistics from Altmetric.com
In August 1994, a 19-year-old Pakistani girl developed nausea and vomiting while on holiday in Pakistan from her home in the UK. For the preceding 12 months, she had undergone unrewarding investigations of non-specific abdominal pain, loss of appetite, unexplained weight loss and secondary amenorrhoea. After 2 days, she was admitted to a hospital in Pakistan with rapid deterioration of conscious level resulting in coma. On examination, she had neck stiffness and a positive Kernig's sign but no other focal neurological deficit. A computed tomography scan showed dense meningeal enhancement but no focal intraparenchymal lesion. An electroencephalogram (EEG) showed gross generalised slowing with diffuse delta waves. A lumbar puncture was performed which showed the cerebrospinal fluid (CSF) to contain 198 × 106 leucocytes/l with 95% lymphocytes. The CSF glucose was 2.4 mmol/l with increased protein of 2.09 g/l. Culture and sensitivity, staining for acid/alcohol-fast bacilli and India ink test were negative. Tests for malaria were negative. She had a negative Mantoux test and a normal abdominal ultrasound scan.
It was assumed that she was suffering from herpes simplex encephalitis so she was treated with a course of intravenous acyclovir. In view of the possibility of tuberculous meningitis, she was also given quadruple antituberculous chemotherapy (rifampicin, isoniazid, ethambutol and pyrazinamide) along with a short course of oral steroids. She made a rapid recovery within 48 hours and repeat CSF study after approximately one week of treatment showed 120 × 106 cells/l with 80% lymphocytes and a protein of 2.09 g/l. Soon after, she developed mild bilateral sensorineural deafness which was felt to be in keeping with previous tuberculosis meningitis.
When she returned to Hull, she was referred to our unit where further investigations were performed in the hope of confirming a diagnosis of tuberculous meningitis. CSF study at this stage showed 70 white cells × 106/l (40% macrophages, 26% polymorphs and 22% lymphocytes). Polymerase chain reaction (PCR) forMycobacterium tuberculosis was negative as was a Ziehl-Neelsen stain and Lowenstein-Jensen culture. Brainstem evoked response potentials showed severe hearing loss in the 2–4 kHz region with residual cochlear function at low frequency so she was able to use a hearing aid.
She received a 9-month course of antituberculous chemotherapy which ended in March 1996. By this time she was asymptomatic and had returned to her A-level studies. She re-presented in July 1996 with a 24-hour history of headache, vomiting and diarrhoea. She was pyrexial but there was no neck stiffness and Kernig's sign was negative. There were no focal neurological signs but both plantar responses were extensor. The CSF showed an elevated protein of 6.15 g/l with a glucose of 0.7 mmol/l (plasma glucose 5.1 mmol/l). The CSF white cell count was 142 × 106 cells/l (32% polymorphs, 36% lymphocytes and 34% macrophages). The EEG showed diffuse cortical dysfunction with a focal cortical pathology in the right frontotemporal region. It was concluded that she had suffered a recurrence of the tuberculous meningitis and antituberculous chemotherapy was re-started. However, the CSF PCR forMycobacterium tuberculosis was still negative.
She again showed a rapid clinical improvement. Repeat CSF study after 12 days of treatment demonstrated a protein of 5.0 g/l, glucose 1.5 mmol/l and white cell count 36 × 106/l (100% lymphocytes). A synacthen test at this time was normal. Unfortunately, 2 months after the onset of this recurrence she went on to develop profound bilateral high tone sensorineural hearing loss. Further CSF analysis after 9 weeks showed 58 × 106 cells/l with 16% polymorphs, 68% lymphocytes and 16% macrophages.
- What is your diagnosis?
- What further investigations would you request?
- What are the major complications of the disease?
- What drugs are currently used to treat the condition?
Brucellosis is diagnosed by the quantified serum agglutination test, which assesses total antibodies to brucella antigen, and the quantified 2-mercaptoethanol agglutination test, which assesses only the IgG antibodies and is indicative of the activity of the disease. Enzyme-linked immunosorbent assay (ELISA) on the CSF is both sensitive and specific for the rapid diagnosis of neurobrucellosis. ELISA detectsBrucella-specific IgG, IgA, IgM which are significantly elevated in the serum of all treated patients. In the chronic variety, IgG and IgA are raised, while in the acute and subacute types IgG, IgA and IgM are raised. A marked cross-reactivity exists between Br abortus and Br melitensis and it is not often possible to decide on the infecting species on serological testing alone.
In this case, serology for Br melitensis was positive with the IgG over 1 in 10 240. The CSF at the same time showed the same organism with IgG titre of 1 in 32 000. COMPELISA for Br melitensis was positive in a titre of greater than 1 in 10 240 in the serum. These results were very strongly suggestive of infection with Br melitensis at some time. Serum IgG titres for Br abortuswere raised at greater than 10 240 and the CSF titre was also raised at greater than 8000, but the COMPELISA showed a titre of less than 1 in 80 in the serum, suggesting that these results were due to cross-reaction between the organisms, the primary infection being withBr melitensis.
The onset of brucellosis may be acute or insidious. Often there is an initial febrile illness with spontaneous resolution followed by a chronic relapsing disorder. The acute illness is characterised by fever, lymphadenopathy and splenomegaly. The chronic illness may be systemic or localised to the nervous system, cardiovascular system, bone, lungs or eyes, often running a relapsing, remitting course. Neurobrucellosis occurs in around 5% of patients with systemic brucellosis.1-5 Br melitensiscauses the most severe neurological disease. There is usually a chronic meningitis with microvascular changes and the development of non-caseating granulomata. Br suis may cause caseating granulomas indistinguishable pathologically from tuberculosis. Neurobrucellosis has protean manifestations from stroke, central demyelination and myelitis to peripheral neuropathy and spondylitis with compressive myeloradiculopathy. The clinical features of chronic meningitis due to brucellosis are similar to that caused by tuberculosis, syphilis or fungi. The eighth cranial nerve is commonly affected, as in the present case, with sensorineural hearing loss being a common presentation of occult neurobrucellosis in endemic areas.
In the absence of large-scale randomised controlled trials, debate surrounds the best antibiotic regime for the treatment of neurobrucellosis.3 4 Combinations of agents seem to be superior to individual antibiotics, particularly in chronic disease. The preferred agents are rifampicin, streptomycin, tetracycline, doxycycline and co-trimoxazole. It is recommended that treatment is continued for 3–4 months in chronic cases or until CSF normalises with regard to the pleocytosis; the CSF protein level falls later in the course of recovery.5 Jarisch-Herxheimer type reactions have been described but are usually not troublesome. Steroids may be used in active encephalitis, demyelination, meningitis, severe cerebral oedema or the Jarisch-Herxheimer reaction.5 Surgical treatment for hydrocephalus or spinal cord compression may be needed.
The prognosis is good in acute brucellosis, however, the relapse rate is high in chronic cases, particularly those with neurological involvement. In one series of chronic brucellosis, 20% of those treated with doxycycline and streptomycin relapsed. Triple chemotherapy has therefore been advocated in neurobrucellosis, especially after relapse.3 5
In this case, we elected to use a combination of rifampicin 600 mg od, doxycycline 200 mg od, and co-trimoxazole 960 mg bid. After 6 weeks, the CSF showed a normal white cell count of 3 × 106cells/l. The serum IgG titre to Br melitensis was 1 in 10 240 and in the CSF 5120; the COMPELISA to Br melitensis also remained high at 10 240 in the serum and 5120 in the CSF.
In a patient presenting with features of chronic or acute lymphocytic meningitis, a high index of suspicion for brucellosis is required, as exemplified by the present case. This is particularly true if the patient has a high risk occupational background, if they consume unpasteurised milk or raw meat, or if food products originate from an endemic area. Similarly, otolaryngologists need to be alert to the possibility of neurobrucellosis as a rare cause of sensorineural hearing loss.