1
Accepted Article
Received date: 04/28/2014 Revised date: 07/07/2014 Accepted date: 08/11/2014 Patient reports
Neurobrucellosis in children: a case series from Turkey1 Neurobrucellosis in children
Turkan Aydın Teke MD1, Hilal Koyuncu MD2, Fatma Nur Oz MD1, Ozge Metin MD1, Gülsüm Iclal Bayhan MD1, Zeynep Gökce Gayretli Aydın MD1, Ayse Kaman1 MD, Gonul Tanir1 Assoc Prof
1
Dr Sami Ulus Maternity and Children’s Research and Education Hospital, Infectious Disease
2
Dr Sami Ulus Maternity and Children’s Research and Education Hospital, Pediatrics
Corresponding author: Türkan Aydın Teke Address: Dr. Sami Ulus Kadın Doğum ve Çocuk Sağlığı ve Hastalıkları Eğitim ve Araştırma Hastanesi Babür Caddesi No:44 (06080) Altındağ, Ankara/Turkey
Business telephone number: +903123056545 E-mail: [email protected] Fax number: +903123170353 Number of text pages: 7 Number of words: 1815 Number of reference pages: 2 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/ped.12510 This article is protected by copyright. All rights reserved.
2
Accepted Article
Number of tables: 3
Abstract
Brucellosis is a multisystem disease that may present with a broad spectrum of clinical
manifestations and complications. Neurobrucellosis is an uncommon and a serious complication of pediatric brucellosis. We present seven cases with neurobrucellosis. Ataxia (one patient), diplopia (one patient) and hearing loss (one patient) were among the neurological sign and symptoms. The most common diagnoses were acute meningitis and meningoencephalitis. Five of the patients fully recovered, one was lost to follow-up and the other had hearing loss as a sequela. It is concluded that neurobrucellosis should be kept in mind in patients with any neurological or neuropsychiatric diseases who live in endemic areas for brucellosis. Introduction Brucellosis is considered as the most widespread zoonosis in the world. It is estimated
that 500.000 human cases occur annually. Since the disease is endemic in countries bordering the Mediterranean Sea including Turkey, diagnosis is relatively easy in this region. It is a notifiable disease and the number of cases increased from 69 (morbidity rate, 0.17/100.000) in 1975 to 14.644 (morbidity rate, 20.32/100000) in 2005 in Turkey (1). It is considered that the increased rates of human brucellosis may be due to improvement in registration as it may be due to insufficiency of eradication programs. Brucellosis is a multisystem disease that may present with a broad spectrum of clinical manifestations and complications, including central nervous system (CNS) or peripheral nervous system known as neurobrucellosis. Neurobrucellosis is a rare but serious complication of brucellosis in children. Clinical presentation of neurobrucellosis is quite heterogenous including meningitis, encephalitis, This article is protected by copyright. All rights reserved.
3
Accepted Article
myelitis, neuritis, radiculopathy, mycotic aneurysms, and brain abscess. Rarer neurological manifestations are Guillain-Barre´ syndrome, isolated intracranial hypertension, papilledema, optic neuropathy, diabetes insipidus, pituitary abscess, cerebral venous thrombosis, and subdural hemorrhage (2, 3). The aim of this study is to describe clinical, laboratory, neuroradiological findings and treatment of a cohort of pediatric patients with neurobrucellosis. Material and method Dr. Sami Ulus Maternity and Children’s Health and Diseases Training and Research
Hospital is a referral and tertiary care community hospital in Turkey. Patients between 1 months and 18 years of age with brucellosis who attended to department of pediatric infectious diseases between January 2005 and January 2011 were retrospectively reviewed. The diagnosis of brucellosis was established by serum agglutination test (SAT) titer ≥1/160, Coombs (agglutinin) test titer ≥1/160, serum enzyme-linked immunosorbent assay (ELISA)
positivity for Brucella and/or isolation of Brucella species from the blood in a patient with clinical symptoms and signs compatible with brucellosis. In all patients, neuroimaging techniques, including computed tomography (CT) and/or magnetic ressonance imaging (MRI) were performed at the onset of illness. Neurobrucellosis was defined in a brucellosis patient (except one patient with isolated neuropsychiatric symptoms) who had any neurological symptom/sign and the presence of at least one of the following criteria: (1) lymphocytic pleocytosis, increased protein, and decreased glucose level in the cerebrospinal fluid (CSF); (2) isolation of Brucella species from CSF and/or presence of anti-Brucella antibodies in CSF at any titer; or (3) findings of CNS disease in cranial MRI or CT. Demographic data, medical and epidemiological history, physical examination findings, CSF laboratory test results, anti-
brucellosis treatment regimen, the period of follow-up and outcome of the patients were recorded. Control CSF examinations were performed to only one patient.
This article is protected by copyright. All rights reserved.
4
Accepted Article
The cells in CSF were counted by Thoma cytometer slide. In biochemical examination
of CSF, protein and glucose levels were measured with standard methods. Cerebrospinal fluid was tested by serial tube dilution from 1:4 to 1:512 by tube agglutination. Brucella abortus 99 antigen (Pendik Veterinarian Research Institute, Istanbul, Turkey) was used for serological tests. Blood and CSF cultures were analyzed by using an automated BacTAlert system (Organon Technica, Durham, NC, USA). If no growth was detected with the usual 7 day protocol of the microbiology laboratory, incubation was maintained for 14 days. Results
Of 74 brucellosis patients, seven (9.4%) were diagnosed with neurobrucellosis and
five of them were male. The mean patient age was 12 years (range: 5-15 years). CSF findings of the patients with neurobrucellosis are demonstrated in Table 1. Neurological or neuropsychiatric symptoms/signs, duration of symptom(s) before the diagnosis, diagnostic tests for brucellosis, diagnostic criteria for neurobrucellosis and treatment duration are summarized in Table 2. All patients except the fourth patient had diagnostic criteria listed above. These patients presented with meningitis and meningoencephalitis. The third and fifth patients with CSF antibody positivity had cranial nerve palsies. The second patient had vasogenic eudema on imaging modality on admission. One of the two patients who had positive blood culture for Brucella presented with ataxia. The fourth patient who had not CSF findings was diagnosed as vocal tic. Control CSF examination findings of the patient 3 were demonstrated in Table 3. All patients except the second patient (because she was under eight years old,
trimethoprim sulfamethoxazole was replaced by doxycycline) were treated with doxycycline
(4 mg/kg/d, per orally), ceftriaxone (100 mg/kg/d, intravenously) for 21 days, gentamicin (5 mg/kg/d, intravenously) for 14 days, doxycycline (4 mg/kg/d, per orally) and rifampin (20 mg/kg/d, per orally) for at least 8 weeks. No adverse reaction was observed and no relapses
This article is protected by copyright. All rights reserved.
5
Accepted Article
and mortality occurred during the treatment except the second patient was lost to follow up. Patients with ataxia and diplopia recovered without sequelae. Patient with eighth cranial nerve palsy had bilateral hearing loss as a sequelae and cochlear implantation was performed. Discussion
Although headache, inattention and mental depression are common complaints in
people with brucellosis, invasion of the nervous system is rare. There are few pediatric neurobrucellosis series in English literature. Data found in the literature are generally restricted to case reports and case series. Neurobrucellosis was reported as 2.2% in a large report of pediatric brucellosis (4). The higher rate (9.4%) of neurobrucellosis in the present report might be related to the referral of most complicated brucellosis patients to our center. The clinical presentation of neurobrucellosis cases in our series was mostly meningitis or meningoencephalitis similarly to other reported pediatric series (5, 6). Headache was the most common symptom of neurobrucellosis in the present study. It is thought that, CSF
examination should be performed in the presence of headache in pediatric brucellosis cases. Neurobrucellosis may present with psychiatric symptoms such as agitation, personality disorder, depression, psychosis and epilepsy (7). These were relatively better defined in adult patients. Patient presented with chronic cough was diagnosed as tic disorder as an unusual presentation of neurobrucellosis in this study, this patient was previously reported as a case
report. He recovered dramatically with anti-brucellosis treatment (8). Cranial nerve involvements are among the major complications of neurobrucellosis.
Although the acoustic nerve was described as the most frequently involved cranial nerve, it is reported that sixth and seventh cranial nerves might also be affected more than other cranial nerves in neurobrucellosis (2). In a recent adult report consisting of 48 neurobrucellosis cases, cranial nerve involvement was reported as 19%. One patient was left with a sequela of peripheral facial paralysis and two patients with sensorineural hearing loss in this report (9).
This article is protected by copyright. All rights reserved.
6
Accepted Article
Sixth and eight nerve involvements were observed in our series. The patient presented with diplopia due to sixth nerve involvement in acute stage recovered completely. The other patient with eight nerve involvement presented in the late of the disease had sensorineural hearing loss as a sequel. This patient was also reported previously as a case report (10). The under-diagnosed or overlooked neurobrucellosis had an unfavorable outcome in this patient. Ataxia is rarely (1-4%) reported in neurobrucellosis (2, 9). Ataxia was observed in one patient in this report. He recovered completely with anti-brucellosis treatment. Because the signs and symptoms of neurobrucellosis are not pathognomonic, the
clinical diagnosis should be confirmed on bacteriological or serological tests. It is reported that automated continuously monitored blood culture systems such as Bactec (BD Diagnostics, Sparks, MD, USA) and BacTAlert (bioMerieux, Durham, NC, USA) give higher yields than the conventional culture method and expedite the detection of bacterial growth (majority recovered within 1 week). There is no need to incubate bottles longer than 10–14
days in these culture systems (11). Although culture method is the gold standard, the growth rate is low and this method is time consuming. Antibodies to Brucella are present in CSF in the majority (12). Diagnostic agglutination titer in CSF varies in different studies. Any titer detected in CSF was accepted as diagnostic in some studies. Brucella tube agglutination with
Coombs test in CSF has been reported sensitive and spesific by using a cut off of ≥ 1:8 in a recent study (9). Unfortunately, CSF Brucella antibody tests were not avaliable in all of our patients because of the retrospective nature of the study. Radiological findings of neurobrucellosis are variable and may mimic other infectious
or inflammatory conditions. Imaging studies might be normal despite positive clinical findings (13). MRI examination of our patients, except the second patient, presented with normal findings. The second patient had vasogenic eudema on cranial CT and MRI on
This article is protected by copyright. All rights reserved.
7
Accepted Article
admission. Follow-up cranial imaging couldn’t be performed because this patient lost to follow-up.
Because Brucella spp. are intracellular pathogens, treatment of brucellosis should be
based on prolonged chemotherapy with a combination of agents that are capable of penetrating the cells, otherwise treatment failure or relapse may occur. The treatment of neurobrucellosis consists of the combination of two or three drugs which cross the blood-brain barrier. The primary drugs of choice are doxycycline, rifampin, trimethoprim-sulfamethoxazole, ciprofloxacin, and ceftriaxone. It has been questioned that neurobrucellosis as a CNS infection, can be treated with oral antibiotics alone. On the other hand suitability of ceftriaxone that does not accumulate in phagocytes for the treatment of brucellosis. Ceftriaxone diffuses into the CSF well and have good in vitro activity against Brucella spp. In a multicenter study, the efficacy of ceftriaxone, rifampin, and doxycycline was compared the regime of trimethoprim-sulfamethoxazole, rifampin, and doxycycline in 215 adult patients with brucellar meningitis or meningoencephalitis. It has been found that ceftriaxone-based regimens are more successful and require shorter therapy than the oral treatment protocol (14). The duration of the treatment of neurobrucellosis has been recommended a minimum of 6 to 8 weeks, and possibly longer, depending on the clinical response by World Health Organization. In the present study the duration of therapy was individualized, the patients were treated
with
a combination
of doxycycline or trimethoprim
sulfamethoxazole, rifampicin, gentamicin and ceftriaxone for 8-24 weeks based on their clinical follow-up findings. It is generally recommended that the duration of
neurobrucellosis treatment should be determined on basis of the CSF response. The antibiotics of one of the our patients had been stopped based on the clinical evaluation combined with the normalization of CSF profiles.
This article is protected by copyright. All rights reserved.
8
Accepted Article
In conclusion, neurobrucellosis should be kept in mind in patients with any
neurological diseases who live in endemic areas for brucellosis. It should be also kept in mind that cranial imaging can be normal in neurobrucellosis. Early diagnosis and combination treatment are critical to prevent neurological sequela. References
1. T.C. Saðlýk Bakanlýðý Ýstatistikler/Temel Saðlýk Hizmetleri Genel Müdürlüðü Çalýþma
Yýllýðý. Ankara: Saðlýk Bakanlýðý; 2004. Available at:http://www.saglik.gov.tr/TR/belge/12952/istatistik-yillýklarý.html. 2. Gül HC, Erdem H, Bek S. Overview of neurobrucellosis: a pooled analysis of 187 cases. Int J Infect Dis 2009; 13:339-343. 3. Sturniolo G, Mondello P, Bruno S, et al. Neurobrucellosis associated with syndrome of inappropriate antidiuretic hormone with resultant diabetes insipidus and hypothyroidism. J Clin Microbiol 2010;48:3806–3809.
4. Tanir G, Tufekci SB, Tuygun N. Presentation, complications, and treatment outcome of brucellosis in Turkish children. Pediatr Int. 2009; 51:114-119. 5. Al-Eissa. YA. Clinical and therapeutic features of childhood neurobrucellosis. Scand J Infect Dis 1995; 27: 339-343.
6. Lubani MM, Dudin KI, Araj GF, Manandhar DS, Rashid FY. Neurobrucellosis in children. Pediatr Infect Dis J 1989;8:79-82. 7. Sheybani F, Sarvghad MR, Bojdi A, Naderi HD. Brucellar psychosis. Arch Iran Med 2012; 15:723-725.
8. Bayhan GI, Tanir G, Ertan U, Bodur S. A case of vocal tic: an unusual presentation of neurobrucellosis. East Mediterr Health J 2013;19:393-395. 9. Güven T, Ugurlu K, Ergonul O, et al. Neurobrucellosis: clinical and diagnostic features.
Clin Infect Dis 2013;56:1407-1412. This article is protected by copyright. All rights reserved.
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Accepted Article
10. Oz FN, Tanir G, Simsek G, Gürcan Kaya N, Akin I. A case of underdiagnosed Brucella
meningitis presented with hearing loss. Inf Dis Clin Practice 2013;21:136-138. 11. Araj GF. Update on laboratory diagnosis of human brucellosis. Int J Antimicrob Agents 2010; 36:12-17.
12. Mantur BG, Akki AS, Mangalgi SS, Patil SV, Gobbur RH, Peerapur BV. Childhood brucellosis: a microbiological, epidemiological and clinical study. J Trop Pediatr 2004;50:153-157. 13. Al-Sous MW, Bohlega S, Al-Kawi MZ, Alwatban J, McLean DR. Neurobrucellosis: clinical and neuroimaging correlation. Am J Neuroradiol 2004;25:395-401. 14. Erdem H, Ulu-Kilic A, Kilic S. Efficacy and tolerability of antibiotic combinations in
neurobrucellosis: results of the Istanbul study. Antimicrob Agents Chemother 2012;56:1523-1528.
This article is protected by copyright. All rights reserved.
Accepted Article
Table 1. CSF findings of the patients with neurobrucellosis Case
Presence CSF of cells protein (/mm3) (mg/dL)
CSF/Blood glucose ratio
CSF culture
1
17
22
0.57
Negative
2
19
27
0.89
Negative
3
82
233
0.14
Negative
4
0
23
0.68
Negative
5
61
58
0.56
Negative
6
49
33
0.50
Negative
7
33
139
0.32
Negative
Accepted Article
Table 2. Neurological or neuropsychiatric symptoms/signs, duration of symptom(s) before the diagnosis, diagnostic tests, diagnostic criteria and treatment duration for neurobrucellosis Case
Age (years) /sex
Diagnosis
Neurological or neuropsychiatric symptom/sign
Duration of symptom(s) before the diagnosis of neurobrucellosis 2 Months
1
12/M
Brucella meningitis
Headache
2
5/F
Brucella meningitis
2 Months
3
13/M
Brucella meningitis
Afebril convulsion, right upper and lower limb hypertonicity, optic disc pallor at right Headache, hearing loss
4
11/M
Neuropsychiatric disorder
Vocal tic
2 Months
5
14/F
Brucella meningoencephalitis
Headache, diplopia, left abducens nerve palsy
3 Weeks
6
14/M
Brucella meningitis
Fever, headache, neck rigidity
1 Week
7
15/M
Brucella meningitis
Fever, headache, ataxia
1 Week
15 Months
Diagnostic test for brucellosis
Diagnostic criteria for neurobrucellosis
Treatment duration
Brucella IgM, IgG positivity, Brucella Coombs agglutination positivity at a titer of 1/640 Brucella IgG positivity, Brucella Coombs agglutination positivity at a titer of 1/160 Brucella IgG positivity, Brucella Coombs agglutination positivity at a titer of 1/160, SAT positivity at a titer of 1/1280
Lymphocytic pleocytosis
8 weeks
Lymphocytic pleocytosis and cranial MRI finding (vasogenic edema)
Lost to follow up
Lymphocytic pleocytosis, increased protein, and decreased glucose level in CSF, CSF Brucella agglutination positivity at a titer of 1/80 None
24 weeks
Lymphocytic pleocytosis, increased protein level in CSF, CSF Brucella agglutination positivity at a titer of 1/20 Lymphocytic pleocytosis, increased protein level in CSF
16 weeks
Lymphocytic pleocytosis, increased
8 weeks
Brucella IgM positivity Brucella SAT positivity at a titer of 1/1280
Brucella SAT positivity at a titer of 1/1600, blood culture yielded Brucella spp. Brucella SAT positivity at a titer of
24 weeks
Lost to follow up
Accepted Article
1/640, blood culture yielded Brucella spp.
protein level in CSF
Accepted Article
Table 3. The CSF Findings and Serum Tube Agglutination Test Results in CSF and Blood During the Anti-brucella Treatment of the Patient 3.
Months of treatment
CSF Findings WBC/mm3 (% lymphocyte)
Brucella reciprocal titers
Protein (mg/dl)
Glucose (mg/dl)
CSF
Serum
Initial
82 (% 90)
233
15
1/80
1/1280
Second month
74 (%70)
152
24
1/40
1/1600
Third month
19 (%100)
131
48
1/80
1/640
Fourth month
10 (%100)
93
42
1/40
1/640
Sixth month
10 (%100)
78
53
1/20
1/160
Accepted Article
Received date: 04/28/2014 Revised date: 07/07/2014 Accepted date: 08/11/2014 Patient reports
Neurobrucellosis in children: a case series from Turkey1 Neurobrucellosis in children
Turkan Aydın Teke MD1, Hilal Koyuncu MD2, Fatma Nur Oz MD1, Ozge Metin MD1, Gülsüm Iclal Bayhan MD1, Zeynep Gökce Gayretli Aydın MD1, Ayse Kaman1 MD, Gonul Tanir1 Assoc Prof
1
Dr Sami Ulus Maternity and Children’s Research and Education Hospital, Infectious Disease
2
Dr Sami Ulus Maternity and Children’s Research and Education Hospital, Pediatrics
Corresponding author: Türkan Aydın Teke Address: Dr. Sami Ulus Kadın Doğum ve Çocuk Sağlığı ve Hastalıkları Eğitim ve Araştırma Hastanesi Babür Caddesi No:44 (06080) Altındağ, Ankara/Turkey
Business telephone number: +903123056545 E-mail: [email protected] Fax number: +903123170353 Number of text pages: 7 Number of words: 1815 Number of reference pages: 2 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/ped.12510 This article is protected by copyright. All rights reserved.
2
Accepted Article
Number of tables: 3
Abstract
Brucellosis is a multisystem disease that may present with a broad spectrum of clinical
manifestations and complications. Neurobrucellosis is an uncommon and a serious complication of pediatric brucellosis. We present seven cases with neurobrucellosis. Ataxia (one patient), diplopia (one patient) and hearing loss (one patient) were among the neurological sign and symptoms. The most common diagnoses were acute meningitis and meningoencephalitis. Five of the patients fully recovered, one was lost to follow-up and the other had hearing loss as a sequela. It is concluded that neurobrucellosis should be kept in mind in patients with any neurological or neuropsychiatric diseases who live in endemic areas for brucellosis. Introduction Brucellosis is considered as the most widespread zoonosis in the world. It is estimated
that 500.000 human cases occur annually. Since the disease is endemic in countries bordering the Mediterranean Sea including Turkey, diagnosis is relatively easy in this region. It is a notifiable disease and the number of cases increased from 69 (morbidity rate, 0.17/100.000) in 1975 to 14.644 (morbidity rate, 20.32/100000) in 2005 in Turkey (1). It is considered that the increased rates of human brucellosis may be due to improvement in registration as it may be due to insufficiency of eradication programs. Brucellosis is a multisystem disease that may present with a broad spectrum of clinical manifestations and complications, including central nervous system (CNS) or peripheral nervous system known as neurobrucellosis. Neurobrucellosis is a rare but serious complication of brucellosis in children. Clinical presentation of neurobrucellosis is quite heterogenous including meningitis, encephalitis, This article is protected by copyright. All rights reserved.
3
Accepted Article
myelitis, neuritis, radiculopathy, mycotic aneurysms, and brain abscess. Rarer neurological manifestations are Guillain-Barre´ syndrome, isolated intracranial hypertension, papilledema, optic neuropathy, diabetes insipidus, pituitary abscess, cerebral venous thrombosis, and subdural hemorrhage (2, 3). The aim of this study is to describe clinical, laboratory, neuroradiological findings and treatment of a cohort of pediatric patients with neurobrucellosis. Material and method Dr. Sami Ulus Maternity and Children’s Health and Diseases Training and Research
Hospital is a referral and tertiary care community hospital in Turkey. Patients between 1 months and 18 years of age with brucellosis who attended to department of pediatric infectious diseases between January 2005 and January 2011 were retrospectively reviewed. The diagnosis of brucellosis was established by serum agglutination test (SAT) titer ≥1/160, Coombs (agglutinin) test titer ≥1/160, serum enzyme-linked immunosorbent assay (ELISA)
positivity for Brucella and/or isolation of Brucella species from the blood in a patient with clinical symptoms and signs compatible with brucellosis. In all patients, neuroimaging techniques, including computed tomography (CT) and/or magnetic ressonance imaging (MRI) were performed at the onset of illness. Neurobrucellosis was defined in a brucellosis patient (except one patient with isolated neuropsychiatric symptoms) who had any neurological symptom/sign and the presence of at least one of the following criteria: (1) lymphocytic pleocytosis, increased protein, and decreased glucose level in the cerebrospinal fluid (CSF); (2) isolation of Brucella species from CSF and/or presence of anti-Brucella antibodies in CSF at any titer; or (3) findings of CNS disease in cranial MRI or CT. Demographic data, medical and epidemiological history, physical examination findings, CSF laboratory test results, anti-
brucellosis treatment regimen, the period of follow-up and outcome of the patients were recorded. Control CSF examinations were performed to only one patient.
This article is protected by copyright. All rights reserved.
4
Accepted Article
The cells in CSF were counted by Thoma cytometer slide. In biochemical examination
of CSF, protein and glucose levels were measured with standard methods. Cerebrospinal fluid was tested by serial tube dilution from 1:4 to 1:512 by tube agglutination. Brucella abortus 99 antigen (Pendik Veterinarian Research Institute, Istanbul, Turkey) was used for serological tests. Blood and CSF cultures were analyzed by using an automated BacTAlert system (Organon Technica, Durham, NC, USA). If no growth was detected with the usual 7 day protocol of the microbiology laboratory, incubation was maintained for 14 days. Results
Of 74 brucellosis patients, seven (9.4%) were diagnosed with neurobrucellosis and
five of them were male. The mean patient age was 12 years (range: 5-15 years). CSF findings of the patients with neurobrucellosis are demonstrated in Table 1. Neurological or neuropsychiatric symptoms/signs, duration of symptom(s) before the diagnosis, diagnostic tests for brucellosis, diagnostic criteria for neurobrucellosis and treatment duration are summarized in Table 2. All patients except the fourth patient had diagnostic criteria listed above. These patients presented with meningitis and meningoencephalitis. The third and fifth patients with CSF antibody positivity had cranial nerve palsies. The second patient had vasogenic eudema on imaging modality on admission. One of the two patients who had positive blood culture for Brucella presented with ataxia. The fourth patient who had not CSF findings was diagnosed as vocal tic. Control CSF examination findings of the patient 3 were demonstrated in Table 3. All patients except the second patient (because she was under eight years old,
trimethoprim sulfamethoxazole was replaced by doxycycline) were treated with doxycycline
(4 mg/kg/d, per orally), ceftriaxone (100 mg/kg/d, intravenously) for 21 days, gentamicin (5 mg/kg/d, intravenously) for 14 days, doxycycline (4 mg/kg/d, per orally) and rifampin (20 mg/kg/d, per orally) for at least 8 weeks. No adverse reaction was observed and no relapses
This article is protected by copyright. All rights reserved.
5
Accepted Article
and mortality occurred during the treatment except the second patient was lost to follow up. Patients with ataxia and diplopia recovered without sequelae. Patient with eighth cranial nerve palsy had bilateral hearing loss as a sequelae and cochlear implantation was performed. Discussion
Although headache, inattention and mental depression are common complaints in
people with brucellosis, invasion of the nervous system is rare. There are few pediatric neurobrucellosis series in English literature. Data found in the literature are generally restricted to case reports and case series. Neurobrucellosis was reported as 2.2% in a large report of pediatric brucellosis (4). The higher rate (9.4%) of neurobrucellosis in the present report might be related to the referral of most complicated brucellosis patients to our center. The clinical presentation of neurobrucellosis cases in our series was mostly meningitis or meningoencephalitis similarly to other reported pediatric series (5, 6). Headache was the most common symptom of neurobrucellosis in the present study. It is thought that, CSF
examination should be performed in the presence of headache in pediatric brucellosis cases. Neurobrucellosis may present with psychiatric symptoms such as agitation, personality disorder, depression, psychosis and epilepsy (7). These were relatively better defined in adult patients. Patient presented with chronic cough was diagnosed as tic disorder as an unusual presentation of neurobrucellosis in this study, this patient was previously reported as a case
report. He recovered dramatically with anti-brucellosis treatment (8). Cranial nerve involvements are among the major complications of neurobrucellosis.
Although the acoustic nerve was described as the most frequently involved cranial nerve, it is reported that sixth and seventh cranial nerves might also be affected more than other cranial nerves in neurobrucellosis (2). In a recent adult report consisting of 48 neurobrucellosis cases, cranial nerve involvement was reported as 19%. One patient was left with a sequela of peripheral facial paralysis and two patients with sensorineural hearing loss in this report (9).
This article is protected by copyright. All rights reserved.
6
Accepted Article
Sixth and eight nerve involvements were observed in our series. The patient presented with diplopia due to sixth nerve involvement in acute stage recovered completely. The other patient with eight nerve involvement presented in the late of the disease had sensorineural hearing loss as a sequel. This patient was also reported previously as a case report (10). The under-diagnosed or overlooked neurobrucellosis had an unfavorable outcome in this patient. Ataxia is rarely (1-4%) reported in neurobrucellosis (2, 9). Ataxia was observed in one patient in this report. He recovered completely with anti-brucellosis treatment. Because the signs and symptoms of neurobrucellosis are not pathognomonic, the
clinical diagnosis should be confirmed on bacteriological or serological tests. It is reported that automated continuously monitored blood culture systems such as Bactec (BD Diagnostics, Sparks, MD, USA) and BacTAlert (bioMerieux, Durham, NC, USA) give higher yields than the conventional culture method and expedite the detection of bacterial growth (majority recovered within 1 week). There is no need to incubate bottles longer than 10–14
days in these culture systems (11). Although culture method is the gold standard, the growth rate is low and this method is time consuming. Antibodies to Brucella are present in CSF in the majority (12). Diagnostic agglutination titer in CSF varies in different studies. Any titer detected in CSF was accepted as diagnostic in some studies. Brucella tube agglutination with
Coombs test in CSF has been reported sensitive and spesific by using a cut off of ≥ 1:8 in a recent study (9). Unfortunately, CSF Brucella antibody tests were not avaliable in all of our patients because of the retrospective nature of the study. Radiological findings of neurobrucellosis are variable and may mimic other infectious
or inflammatory conditions. Imaging studies might be normal despite positive clinical findings (13). MRI examination of our patients, except the second patient, presented with normal findings. The second patient had vasogenic eudema on cranial CT and MRI on
This article is protected by copyright. All rights reserved.
7
Accepted Article
admission. Follow-up cranial imaging couldn’t be performed because this patient lost to follow-up.
Because Brucella spp. are intracellular pathogens, treatment of brucellosis should be
based on prolonged chemotherapy with a combination of agents that are capable of penetrating the cells, otherwise treatment failure or relapse may occur. The treatment of neurobrucellosis consists of the combination of two or three drugs which cross the blood-brain barrier. The primary drugs of choice are doxycycline, rifampin, trimethoprim-sulfamethoxazole, ciprofloxacin, and ceftriaxone. It has been questioned that neurobrucellosis as a CNS infection, can be treated with oral antibiotics alone. On the other hand suitability of ceftriaxone that does not accumulate in phagocytes for the treatment of brucellosis. Ceftriaxone diffuses into the CSF well and have good in vitro activity against Brucella spp. In a multicenter study, the efficacy of ceftriaxone, rifampin, and doxycycline was compared the regime of trimethoprim-sulfamethoxazole, rifampin, and doxycycline in 215 adult patients with brucellar meningitis or meningoencephalitis. It has been found that ceftriaxone-based regimens are more successful and require shorter therapy than the oral treatment protocol (14). The duration of the treatment of neurobrucellosis has been recommended a minimum of 6 to 8 weeks, and possibly longer, depending on the clinical response by World Health Organization. In the present study the duration of therapy was individualized, the patients were treated
with
a combination
of doxycycline or trimethoprim
sulfamethoxazole, rifampicin, gentamicin and ceftriaxone for 8-24 weeks based on their clinical follow-up findings. It is generally recommended that the duration of
neurobrucellosis treatment should be determined on basis of the CSF response. The antibiotics of one of the our patients had been stopped based on the clinical evaluation combined with the normalization of CSF profiles.
This article is protected by copyright. All rights reserved.
8
Accepted Article
In conclusion, neurobrucellosis should be kept in mind in patients with any
neurological diseases who live in endemic areas for brucellosis. It should be also kept in mind that cranial imaging can be normal in neurobrucellosis. Early diagnosis and combination treatment are critical to prevent neurological sequela. References
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Yýllýðý. Ankara: Saðlýk Bakanlýðý; 2004. Available at:http://www.saglik.gov.tr/TR/belge/12952/istatistik-yillýklarý.html. 2. Gül HC, Erdem H, Bek S. Overview of neurobrucellosis: a pooled analysis of 187 cases. Int J Infect Dis 2009; 13:339-343. 3. Sturniolo G, Mondello P, Bruno S, et al. Neurobrucellosis associated with syndrome of inappropriate antidiuretic hormone with resultant diabetes insipidus and hypothyroidism. J Clin Microbiol 2010;48:3806–3809.
4. Tanir G, Tufekci SB, Tuygun N. Presentation, complications, and treatment outcome of brucellosis in Turkish children. Pediatr Int. 2009; 51:114-119. 5. Al-Eissa. YA. Clinical and therapeutic features of childhood neurobrucellosis. Scand J Infect Dis 1995; 27: 339-343.
6. Lubani MM, Dudin KI, Araj GF, Manandhar DS, Rashid FY. Neurobrucellosis in children. Pediatr Infect Dis J 1989;8:79-82. 7. Sheybani F, Sarvghad MR, Bojdi A, Naderi HD. Brucellar psychosis. Arch Iran Med 2012; 15:723-725.
8. Bayhan GI, Tanir G, Ertan U, Bodur S. A case of vocal tic: an unusual presentation of neurobrucellosis. East Mediterr Health J 2013;19:393-395. 9. Güven T, Ugurlu K, Ergonul O, et al. Neurobrucellosis: clinical and diagnostic features.
Clin Infect Dis 2013;56:1407-1412. This article is protected by copyright. All rights reserved.
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10. Oz FN, Tanir G, Simsek G, Gürcan Kaya N, Akin I. A case of underdiagnosed Brucella
meningitis presented with hearing loss. Inf Dis Clin Practice 2013;21:136-138. 11. Araj GF. Update on laboratory diagnosis of human brucellosis. Int J Antimicrob Agents 2010; 36:12-17.
12. Mantur BG, Akki AS, Mangalgi SS, Patil SV, Gobbur RH, Peerapur BV. Childhood brucellosis: a microbiological, epidemiological and clinical study. J Trop Pediatr 2004;50:153-157. 13. Al-Sous MW, Bohlega S, Al-Kawi MZ, Alwatban J, McLean DR. Neurobrucellosis: clinical and neuroimaging correlation. Am J Neuroradiol 2004;25:395-401. 14. Erdem H, Ulu-Kilic A, Kilic S. Efficacy and tolerability of antibiotic combinations in
neurobrucellosis: results of the Istanbul study. Antimicrob Agents Chemother 2012;56:1523-1528.
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Accepted Article
Table 1. CSF findings of the patients with neurobrucellosis Case
Presence CSF of cells protein (/mm3) (mg/dL)
CSF/Blood glucose ratio
CSF culture
1
17
22
0.57
Negative
2
19
27
0.89
Negative
3
82
233
0.14
Negative
4
0
23
0.68
Negative
5
61
58
0.56
Negative
6
49
33
0.50
Negative
7
33
139
0.32
Negative
Accepted Article
Table 2. Neurological or neuropsychiatric symptoms/signs, duration of symptom(s) before the diagnosis, diagnostic tests, diagnostic criteria and treatment duration for neurobrucellosis Case
Age (years) /sex
Diagnosis
Neurological or neuropsychiatric symptom/sign
Duration of symptom(s) before the diagnosis of neurobrucellosis 2 Months
1
12/M
Brucella meningitis
Headache
2
5/F
Brucella meningitis
2 Months
3
13/M
Brucella meningitis
Afebril convulsion, right upper and lower limb hypertonicity, optic disc pallor at right Headache, hearing loss
4
11/M
Neuropsychiatric disorder
Vocal tic
2 Months
5
14/F
Brucella meningoencephalitis
Headache, diplopia, left abducens nerve palsy
3 Weeks
6
14/M
Brucella meningitis
Fever, headache, neck rigidity
1 Week
7
15/M
Brucella meningitis
Fever, headache, ataxia
1 Week
15 Months
Diagnostic test for brucellosis
Diagnostic criteria for neurobrucellosis
Treatment duration
Brucella IgM, IgG positivity, Brucella Coombs agglutination positivity at a titer of 1/640 Brucella IgG positivity, Brucella Coombs agglutination positivity at a titer of 1/160 Brucella IgG positivity, Brucella Coombs agglutination positivity at a titer of 1/160, SAT positivity at a titer of 1/1280
Lymphocytic pleocytosis
8 weeks
Lymphocytic pleocytosis and cranial MRI finding (vasogenic edema)
Lost to follow up
Lymphocytic pleocytosis, increased protein, and decreased glucose level in CSF, CSF Brucella agglutination positivity at a titer of 1/80 None
24 weeks
Lymphocytic pleocytosis, increased protein level in CSF, CSF Brucella agglutination positivity at a titer of 1/20 Lymphocytic pleocytosis, increased protein level in CSF
16 weeks
Lymphocytic pleocytosis, increased
8 weeks
Brucella IgM positivity Brucella SAT positivity at a titer of 1/1280
Brucella SAT positivity at a titer of 1/1600, blood culture yielded Brucella spp. Brucella SAT positivity at a titer of
24 weeks
Lost to follow up
Accepted Article
1/640, blood culture yielded Brucella spp.
protein level in CSF
Accepted Article
Table 3. The CSF Findings and Serum Tube Agglutination Test Results in CSF and Blood During the Anti-brucella Treatment of the Patient 3.
Months of treatment
CSF Findings WBC/mm3 (% lymphocyte)
Brucella reciprocal titers
Protein (mg/dl)
Glucose (mg/dl)
CSF
Serum
Initial
82 (% 90)
233
15
1/80
1/1280
Second month
74 (%70)
152
24
1/40
1/1600
Third month
19 (%100)
131
48
1/80
1/640
Fourth month
10 (%100)
93
42
1/40
1/640
Sixth month
10 (%100)
78
53
1/20
1/160
