Case Report: Brucellosis Mimicking Tuberculous Meningitis in a Child

ABSTRACT.

Neurobrucellosis is rare in children, presenting with a variety of clinical manifestations, including meningitis, meningoencephalitis, cranial neuropathies, and intracranial mass-like lesions. We present a case of a 17-year-old girl admitted to the hospital in Istanbul for headache. Lumbar puncture showed elevated intracranial pressure, monocytic pleocytosis, elevated total protein, and hypoglycorrhachia. Brucella melitensis grew from the cerebrospinal fluid. The patient was treated with doxycycline, rifampin, amikacin, and ceftriaxone and showed persistent sensorineural hearing loss. It is essential to consider brucellosis in the differential diagnosis of infectious neurological disease in areas where the disease is endemic. Serologic tests and cultures are needed for diagnosis, and efforts need to be made to identify the infecting organism to the species level to guide zoonotic source control efforts.

CASE REPORT

A previously healthy 17-year-old girl was admitted to Marmara University Pendik Training and Research Hospital with complaints of headache and vomiting for 4 months. She also experienced blurred vision, dizziness, loss of appetite, and weight loss. There was no history of traveling to rural areas or tuberculosis contact.

On physical examination, bilateral horizontal nystagmus, loss of strength in the lower extremities (4/5), and bilateral grade 2–3 papilledema were present. Cranial magnetic resonance imaging (MRI) revealed partially empty sella (Figure 1A), increased perioptic cerebrospinal fluid (CSF) distance (Figure 1B), and a tortuous course of optic nerves (Figure 1C). Hematological and biochemical parameters, as well as acute-phase reactants, were normal. Rheumatoid factor, anti-nuclear antibody, and extractable-nuclear-antigen antibody panels were negative. Serological tests for hepatitis viruses, HIV, and syphilis were also negative.

Figure 1.

Cranial magnetic resonance images (MRIs) of the patient. (A) Appearance of partially empty sella. (B) Increased perioptic cerebrospinal fluid (CSF) distance. (C) Tortuous course of optic nerves. Contrast-enhanced cranial MRI revealed the appearance of partially empty sella and increased bilateral perioptic CSF distance. Bilateral optic nerves showed a tortuous course.

A lumbar puncture was performed, revealing xanthochromic CSF with high opening pressure (270 mm H₂O), low glucose (9 mg/dL), and high protein (368 mg/dL) levels. No microorganisms were observed on Gram stain, and the CSF white blood cell count was 100 lymphocytes plus monocytes/mm³. Intravenous ceftriaxone therapy was initiated. On history, the patient had consumed mixed goat and sheep cheese made in her village, located in the Eastern Anatolia region of Turkey. Investigations for tuberculosis and brucellosis meningitis were carried out. The CSF adenosine deaminase level was normal. Sputum and CSF Mycobacterium tuberculosis PCR tests were negative, and the tuberculin skin test showed no reaction. In addition to the complaints of headache and vomiting on admission, the patient developed a fever of 38.9°C on the second day of hospitalization. On physical examination, the patient was lethargic and had nuchal rigidity. The treatment was modified to vancomycin and cefepime, but the symptoms persisted. On the fourth day, Brucella melitensis grew from the CSF. A combination antibiotic therapy of doxycycline, rifampin, amikacin, and ceftriaxone was initiated. The serum Brucella tube agglutination test result was positive at a dilution of 1/1,280. Acetazolamide was initiated to treat brain edema. The patient’s nuchal rigidity resolved after 14 days of treatment. Amikacin was completed in 14 days and then discontinued. Blood cultures were negative at 21 days. Ceftriaxone was stopped on the 21st day.

During the third week of admission, the patient reported hearing loss, which had been present since admission but not previously noted. An auditory brainstem response test revealed bilateral sensorineural hearing loss (left ear, 56 dB; right ear, 51 dB). Methylprednisolone (1 mg/kg/day) was initiated, gradually tapered over 21 days, and then discontinued.

At 4 weeks of treatment, the patient was discharged in good condition. Treatment continued with oral doxycycline, rifampin, and acetazolamide. Lumbar puncture was performed monthly to monitor CSF Brucella tube agglutination titers. Repeat CSF cultures showed no growth (Table 1). Acetazolamide was discontinued after resolution of papilledema. After treatment, the patient’s headache and nausea improved, and her weight percentile reached the appropriate range for her peers. Treatment was completed at 12 months. She has had no additional complaints during current follow-up and has only moderate sensorineural hearing loss.

Table 1.

CSF biochemical and microbiological findings and serum/CSF Brucella agglutination titers during treatment

Time of Treatment	CSF Findings					Brucella Agglutination Titers
	WBC/mm3 (% lymphocytes)	Protein (mg/dL) (15–45)*	Glucose (mg/dL) (40–70)*	Culture	Brucella PCR	CSF	Serum
Initial puncture	100 (70)	368	9	Brucella melitensis			1/1,280
Day 14	170 (60)	380	35	Sterile
First month	20 (80)	228	41	Sterile	Negative		1/1,280
Second month	0	213	25	Sterile		1/2,560	1/2,560
Third month	10	97	42	Sterile		Negative	1/1,280
Sixth month	0	60	45	Sterile	Negative	1/160	1/1,280
Twelfth month	0	40	60	Sterile		1/320	1/1,280

CSF = cerebrospinal fluid; PCR = polymerase chain reaction; WBC = white blood cell count.

^*The normal range is shown in parentheses.

DISCUSSION

Brucellosis is a common zoonotic infection that affects humans worldwide. It is prevalent in many countries in the Mediterranean, including Turkey, as well as in the Balkans, the Middle East, and Central and South America.¹ The infection is caused by Brucella species, which are small, nonmotile, Gram-negative coccobacilli. Transmission of the infection to humans typically occurs through consumption of contaminated milk or milk products and, to a lesser extent, direct contact with tissues or fluids of infected animals. We suspect that our patient may have been infected by consuming cheese made with contaminated, unpasteurized milk, as well as through unhygienic storage and processing practices.

In this case report, our main preliminary diagnoses were tuberculosis and brucellosis. The definitive diagnosis of brucellosis requires isolation of the bacteria. Additionally, identifying the Brucella isolate to the species level is crucial for understanding the zoonotic source and initiating control measures. Molecular typing techniques, such as variable number tandem repeats (VNTR) analysis, has been shown to be useful for identification of Brucella species.² Recent advancements in BACTEC systems have enabled the detection of Brucella spp. without the need for prolonged incubation.³ Upon detection of growth in the BACTEC system, Brucella isolates are subjected to further identification by use of a combination of biochemical assays, serological tests, and molecular typing, such as polymerase chain reaction (PCR) or VNTR analysis. In our case, the matrix-assisted laser desorption ionization–time of flight mass spectrometry method was used to identify the species. Notably, the yield from isolating Brucella species from CSF culture is very low. In one study, for example, only 14% of neurobrucellosis cases had a positive CSF culture.⁴ Therefore, most cases of suspected neurobrucellosis are diagnosed using serological methods.^5–9 Evidence of a 4-fold or greater increase in antibodies through serum tube agglutination tests obtained 2 weeks apart can indicate a probable diagnosis. Although a single titer is not sufficient for diagnosis, a serum tube agglutination titer greater than or equal to 1:160 can indicate brucellosis in suspected cases.¹⁰ Despite the uncertain diagnostic value of measuring antibodies in CSF for neurobrucellosis, some studies suggest that any agglutination titer in the CSF may indicate a Brucella infection.¹¹

In cases of neurobrucellosis, neuroimaging findings are not specific, as with our patient. Although computed tomography or MRI should be performed, these techniques often reveal nonspecific inflammatory changes similar to those of bacterial meningitis.¹²

We treated our patient with ceftriaxone (50 mg/kg twice daily, intravenously [IV], 21 days), amikacin (7.5 mg/kg twice daily, IV, 14 days), doxycycline (100 mg twice daily, per os [PO]), and rifampin (600 mg once daily, PO). The treatment of neurobrucellosis requires a combination of three different drugs for at least 4 to 6 months. For children older than 8 years, it is recommended to use oral doxycycline, whereas children under 8 years of age should be treated with trimethoprim-sulfamethoxazole. Additionally, rifampin and gentamicin should be used together, with gentamicin administered for 7 to 14 days.^3,13 Although different studies recommend using streptomycin, gentamicin, or amikacin, there is a concern that aminoglycosides do not penetrate well into the CSF.^5,14–16 A Turkish study showed that ceftriaxone-based regimens have shorter and more practical courses.¹⁷ In some adult cases, neurobrucellosis was treated successfully with a combination of doxycycline, rifampin, and ceftriaxone.^18,19

Neurobrucellosis can present with various clinical involvements, such as cranial nerve palsy,²⁰ hearing loss,²¹ papilledema,²² paraplegia, ataxia, and cerebrovascular disease. The diagnosis of neurobrucellosis is based on the presence of neurological signs and symptoms otherwise not explained.⁴ In neurobrucellosis, effective infection treatment can reverse hearing loss, but some patients may require a cochlear implant because of permanent sequelae. Our patient experienced neurological deterioration upon admission, and hearing loss was not noted. We suspect that the hearing loss might have been a complication of neurobrucellosis worsened by aminoglycoside ototoxicity. Unfortunately, there was no audiometric test before treatment to assess the patient’s baseline hearing status.

CONCLUSION

It is crucial to consider brucellosis in patients with unexplained neurological symptoms in regions where the disease is endemic and to perform serological tests concurrently with cultures. It is essential to obtain a relevant epidemiological exposure history early in the clinical presentation and to identify the infecting Brucella isolate to the species level to enable zoonotic source control and for public health purposes.