Neurobrucellosis Associated with Syndrome of Inappropriate

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Neurobrucellosis Associated with Syndrome of Inappropriate

     JOURNAL OF CLINICAL MICROBIOLOGY, Oct. 2010, p. 38063809 Vol. 48, No. 10 0095-1137/10/$12.00 doi:10.1128/JCM.00721-10 Copyright ? 2010, American Society for Microbiology. All Rights Reserved.

Neurobrucellosis Associated with Syndrome of Inappropriate

    Antidiuretic Hormone with Resultant Diabetes

    Insipidus and Hypothyroidism

    11221Giuseppe Sturniolo,Placido Mondello,Salvatore Bruno,Orsola Elena Bonfatto,Sabrina Frattima, 13344Antonio Albanese,Roberta Restivo,Giuseppe Liberti,Paolo Pasquali,and Cinzia Marianelli*

    1Department of Infectious Diseases, G. Martino Hospital, University of Messina, Messina, Italy; Department of Infectious Diseases, 2Cutroni Zodda Hospital, Barcellona Pozzo di Gotto, Italy; Department of Infectious Diseases, Cannizzaro Hospital, Catania, 34Italy; and Department of Food Safety and Veterinary Public Health, Istituto Superiore di Sanita`, Rome, Italy

    Received 7 April 2010/Returned for modication 21 June 2010/Accepted 2 August 2010

Neurological involvement of the central nervous system in brucellosis is uncommon. We describe a rare

    case of meningoencephalitis due to Brucella melitensis infection, associated with the syndrome of inap-

    propriate antidiuretic hormone secretion and leading to diabetes insipidus and hypothyroidism. Neuro-

    brucellosis, although rare, should be considered in cases of neurological disease of unknown etiology.

     Brucella melitensis biovar 3. A diagnosis of meningoenceph- CASE REPORT alitis due to Brucella infection was made, and the therapy A 17-year-old male patient presented with headache, back- was promptly modied as follows: ampicillin-sulbactam ache, fever, and marked asthenia. After 10 days, his headache was discontinued, and chloramphenicol (4 g/day), rifampin worsened and vomiting occurred. He was admitted to the De- (900 mg/day), and trimethoprim (Trimetoprim)-sulfame- partment of Infectious Diseases of the Cutroni Zodda Hospi- thoxazole (1,600/320 mg/day) were started. The serum ag- tal, Barcellona P.G., Sicily, Italy. Neurological examination glutination test for Brucella bacteria was repeated a week upon admission revealed diffuse hyperreexia, nuchal rigidity, after admission: the patient had seroconverted (anti-Bru- and hyposthenia of both legs. Laboratory examinations re- cella antibody titer, 1:320). vealed leukopenia with lymphocytosis and severe hyponatre- To characterize the isolate at the molecular level, rpoB se- mia (118 mEq/liter) with reduced serum osmolality (241 quencing and typing by the multiple-locus variable-number mOsm/kg) and elevated urine osmolality (455 mOsm/kg). Re- repeat analysis of 16 loci (MLVA-16) were performed as pre- nal, thyroid, and adrenal functions were normal. These data viously described (22). The former showed the presence of a were consistent with the diagnosis of syndrome of inappropri- nucleotide substitution (ATC to ATA) at codon position 1249 ate antidiuretic hormone secretion (SIADH). The patient was (M1249I), identifying the isolate as Brucella sp. rpoB genotype treated with intravenous NaCl (3%) and water restriction. His 3. The resulting MLVA prole was as follows: 3-6-3-14-1-1-3- plasma sodium concentration increased to 125 mmol/liter. -6-4-11-4-7-21-8-3 (loci Bruce06-08-11-12-42-43-45-55-04-07- 3Analysis of the cerebrospinal uid (CSF) showed pleocytosis 09-16-18-19-21-30). This prole was then compared both to the 3(175 white blood cells/mm, predominantly polymorphonu- Brucella2009 MLVA database ( clear leukocytes), low glucose levels (11 mg/dl), and high pro- /MLVAnet/querypub1.php) and to our database containing tein levels (1,020 mg/dl), indicating a disruption of the blood- previously characterized MLVA proles originating from the brain barrier. Both serum and CSF samples tested negative for area of Catania, Sicily (22). The analysis showed that the iso- Neisseria meningitidis, Haemophilus in;uenzae, and Streptococ- late in question belongs to a new genotype in the endemic area cus pneumoniae antigens. At admission, the standard Brucella covered by our database. tube agglutination test (Wright test) result was also negative Despite 20 days of treatment, symptoms persisted (fever, (titer 1:100). This result was further conrmed by the slide headache, hyponatremia, natriuresis, phosphaturia, and agglutination rose bengal test (4). While waiting for microbi- chloruresis). Thus, antibiotic therapy was further modied as ological results, the patient was treated with ceftriaxone (4 follows: trimethoprim-sulfamethoxazole and chloramphenicol g/day), ampicillin/sulbactam (12 g/day), and dexamethasone were discontinued, and tigecycline (100 mg/day) and dexa- (16 mg/day). methasone (16 mg/day) were added. A contrast cranial com- Suspected Brucella colonies were isolated from both puted tomography (CT) scan showed an enlarged posterior blood and CSF 7-day cultures and identied following stan- pituitary gland, pituitary stalk, and subarachnoid space, with dard procedures (4). Biochemical and agglutination tests hyperdensity in the basal cisterns. identied the pathogen isolated from both body uids as Due to his clinical condition, the patient was transferred to Cannizzaro Hospital in Catania and, shortly thereafter, to the * Corresponding author. Mailing address: Department of Food Messina University Department of Infectious Diseases. The Safety and Veterinary Public Health, Istituto Superiore di Sanita`, patient had evidence of dehydration, with dry skin on both legs, Viale Regina Elena 299, 00161 Rome, Italy. Phone: 39-06-49902522. and complained of excessive thirst. Fever, hyposthenia, natri- Fax: 39-06-49387077. E-mail: uresis, and chloruresis still persisted. Paresthesia in both legs Published ahead of print on 11 August 2010.


     VOL. 48, 2010 CASE REPORTS 3807

    and a consequent difculty in walking were also present, in the festations and complications; fever, night sweats, arthralgia, absence of Lase`gues sign. Tests revealed leukocytosis (12,300/ myalgia, and nonspecic neurological symptoms are common. 3mm), diuresis (5.5 liters per 24 h), normal serum, and low Neurological involvement of the CNS has been detected in 3 to urine osmolality (275 and 195 mOsm/kg, respectively; urine 5% of patients with brucellosis (32), but it nevertheless results

    in severe morbidity and is potentially life threatening (11, 37). specic gravity 1.004 gm/cc). Hyponatremia persisted (110

    The clinical spectrum of neurobrucellosis is very heteroge- mEq/liter), while urine and blood glucose levels were normal.

    neous and includes meningitis, encephalitis, polyradiculoneu- These results strongly suggested endocrine and metabolic dys-

    ritis, sensory and motor disorders, cranial nerve involvement, function. Specically, diabetes insipidus (DI) was suspected.

    epilepsy, depression, brain abscess, and subarachnoid hemor- The results of a water deprivation test with vasopressin injec- rhage (28). Rarer neurological manifestations are isolated in- tion were consistent with central DI. Thyroid function was also tracranial hypertension (26), Guillain-Barre? syndrome (25), DI tested with the following results: the serum concentration of (34), and pituitary abscess (16). The SIADH, rst described in thyroid-stimulating hormone (TSH) was 0.49 mU/liter (refer- 1988 (5), is a rare complication of brucellosis. The present ence interval, 0.27 to 4.2 mU/liter) with free thyroxine (fT4) at report describes a case of brucellosis in Sicily, with neurolog- 9.67 pmol/liter (reference interval, 12 to 22 pmol/liter). These ical complications characterized by extensive involvement of data were compatible with a diagnosis of secondary hypothyroid- the brain parenchyma, an infection which caused SIADH, ism. The patient was given rifampin at 600 mg/day, tigecycline at leading in turn to focal neuroendocrine disturbances such as 100 mg/day, vasopressin at 20 mg/day, and levothyroxine at 50 DI and hypothyroidism. mg/day. Hyponatremia resolved after 3 days of therapy. Due to its heterogeneous clinical manifestations, neurobru- One week after admission at the Messina hospital, the pa- cellosis is easily confused with many other neurological, neu- tients chest X ray was normal. Magnetic resonance imaging rosurgical, or even psychiatric disorders (2, 9). To complicate (MRI) showed pathological lesions within the suprasellar, pre- matters, its diagnosis, requiring direct or indirect evidence of pontine, and interpeduncular cisterns. Focal lesions of the Brucella bacteria in the CSF (9, 32), is difcult to establish and spinal cord were also noted, involving the D1 and D2 verte- frequently delayed. This is due to the fact that specic anti- brae. Antibiotic therapy was, therefore, modied as follows: Brucella antibody titers in CSF are usually low and that cul- tigecycline was substituted with levooxacin at 500 mg/day, tures take time and often give false-negative results (2). More- doxycycline at 200 mg/day, and streptomycin at 1 g/day. Treat- over, the neuroimaging of neurobrucellosis may appear normal ment with rifampin (600 mg/day) was continued. or mimic many other infectious or inammatory conditions (3). Despite the modication of therapy, spinal uid still re- These factors may contribute to false-negative diagnoses (6, vealed pleocytosis, low glucose levels (18 mg/dl), and elevated 29). In the case described here, blood and CSF samples initially protein levels (197 mg/dl). Anti-Brucella IgG results, as de- tested negative for anti-Brucella antibodies by using the Wright tected by a commercial enzyme-linked immunosorbent assay test which also excluded the presence of incomplete antibod- (ELISA) kit (NovaTec Immundiagnostica GmbH, Wald- ies, causing false-negative reactions. The absence of serocon- strasse, Germany), were positive; corresponding IgM results version was conrmed by the slide agglutination rose bengal were negative. During this period, the patient suffered an ep- test. It is likely that, at the time of admission, Brucella anti- isode of high fever with temporal and spatial disorientation bodies were not yet detectable in the patients samples. It is and hyperreexia. Antibiotic therapy was changed again; strep- intriguing that at admission the patient, with evident neuro- tomycin and levooxacin were replaced with ceftriaxone (4 logical symptoms, had no detectable anti-Brucella antibodies in g/day) and trimethoprim-sulfamethoxazole (4,800/960 mg/ the serum sample. It could be correlated with a slow immuno- day). Rapid clinical improvement followed. An MRI per- logical response induced by exogenous or endogenous factors formed 25 days after baseline showed a reduction in patholog- which, however, were not investigated because they are beyond ical lesion size in the suprasellar region. the scope of this report. The diagnosis of neurobrucellosis was, Two months after his last hospitalization, the patient was thus, made only a week later, when Brucella bacteria were discharged with the following therapy: doxycycline at 200 mg/ isolated from a 7-day CSF culture. As previously reported, a day, rifampin at 600 mg/day, ceftriaxone at 4 g/day, and tri- delay in diagnosis, and thus also in the administration of ap- methoprim-sulfamethoxazole at 4,800/960 mg/day. propriate antibiotic treatment, may cause neurological se- A follow-up performed 1 month after discharge showed a nor- quelae (23). This may be averted in the future thanks to novel mal CSF analysis result, with anti-Brucella IgG and IgM results diagnostic technology, such as molecular methods (10). both negative. Trimethoprim-sulfamethoxazole and ceftriaxone The molecular characterization of this human isolate has doses were reduced to 3,200/640 mg/day and 2 g/day, respectively. conrmed, as previously reported (22), that in Italy the disease A follow-up MRI performed 5 months after discharge is associated with B. melitensis biovar 3. Small ruminants and showed no residual lesions. All neurological symptoms had foods derived from them are the major source of brucellosis resolved, and no recurrence of symptoms was registered. An- and play a key role in the spread of infection both in cattle and tibiotic therapy was then stopped. Unfortunately, DI and hy- in humans. The MLVA-16 technique has allowed us to identify pothyroidism persist, and the patient is still in therapy. a new genotype in the endemic area covered by our database the area of Catania in Sicily. Further studies will be needed to evaluate possible correlations between specic genotypes and Brucellosis is a multisystem infection that can involve almost their respective pathogenic patterns.

    any organ or system, including the central nervous system The management of neurobrucellosis requires special atten-

    tion since the illness is potentially life threatening. Although no (CNS), and it has a broad spectrum of possible clinical mani-


    specic guidelines are available on the duration and type of In conclusion, our case provides evidence of metabolic and

    endocrine disorders following Brucella infection of the CNS. antibiotic therapy to be given in cases of neurobrucellosis, most

    Neurobrucellosis, although rare, should be considered in cases authorities recommend a combination of two or three drugs

    of neurological disease of unknown etiology, especially in pa- able to cross the blood-brain-CSF barriers, such as doxycycline,

    ciprooxacin, and rifampin (1, 23). Treatment should generally tients from endemic areas. The exact clinical manifestations

    and complications of neurobrucellosis have not been fully de- be continued until results of CSF analyses return to normal.

    termined as yet, and further studies are required to elucidate Individual signs and symptoms should also be taken into ac-

    count when prescribing treatment. In our case, the regimen this clinical heterogeneity. Through earlier diagnoses and was modied several times following developments regarding more appropriate antibiotic treatment, such information would symptoms, ndings, and the clinical course of the disease, and allow the prevention of neurological as well as endocrine se- the combination of ceftriaxone, doxycycline, rifampin, and tri- quelae. Hypothalamic and/or pituitary function should be methoprim-sulfamethoxazole has been administered for a long monitored in patients infected with Brucella species to ensure

    period of time. Antibiotics were given for a total of 32 weeks, the immediate treatment of any complications. until the complete resolution of all neurological symptoms that REFERENCES were observed at the second follow-up, performed 5 months 1. Akdeniz, H., H. Irmak, O. Anlar, and A. P. Demiro?z. 1998. Central nervous after discharge. By the end of the course of treatment, CFS system brucellosis: presentation, diagnosis and treatment. J. Infect. 36:297 analysis had returned to normal and neuroimaging showed no 301. 2. al Deeb, S. M., B. A. Yaqub, H. S. Sharif, and J. G. Phadke. 1989. Neuro- residual lesions. Clinical follow-up indicated that Brucella in- brucellosis: clinical characteristics, diagnosis, and outcome. Neurology 39: fection had indeed been eliminated, although DI and hypothy- 498501. roidism still persist. 3. Al-Sous, M. W., S. Bohlega, M. Z. Al-Kawi, J. Alwatban, and D. R. McLean. 2004. Neurobrucellosis: clinical and neuroimaging correlation. AJNR Am. J. 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