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Neurobrucellosis is an inflammatory disease caused by the invasion of Brucella spp. to the central nervous system (CNS). The pathogenesis of the disease is not well characterized; however, for Brucella to gain access to the brain parenchyma, traversing of the blood-brain barrier (BBB) must take place. To understand the CNS determinants of the pathogenesis of B. abortus, we have used the in vitro BBB model of human brain microvascular endothelial cells (HBMEC) to study the interactions between B. abortus and brain endothelial cells. In this study, we showed that B. abortus is able to adhere and invade HBMEC which was dependent on microtubules, microfilaments, endosome acidification and de novo protein synthesis. After infection, B. abortus rapidly escapes the endosomal compartment of HBMEC and forms a replicative Brucella-containing vacuole that involves interactions with the endoplasmic reticulum. Despite the ability of B. abortus to invade and replicate in HBMEC, the bacterium was unable by itself to traverse HBMEC, but could traverse polarized HBMEC monolayers within infected monocytes. Importantly, infected monocytes that traversed the HBMEC monolayer were a bacterial source for de novo infection of glial cells. This is the first demonstration of the mechanism whereby B. abortus is able to traverse the BBB and infect cells of the CNS. These results may have important implications in our understanding of the pathogenesis of neurobrucellosis. [ABSTRACT FROM AUTHOR]

Brucellosis is a zoonotic infection and has endemic characteristics. Neurobrucellosis is an uncommon complication of this infection. The aim of this study was to present unusual clinical manifestations and to discuss the management and outcome of a series of 18 neurobrucellosis cases. Initial clinical manifestations consist of pseudotumor cerebri in one case, white matter lesions and demyelinating syndrome in three cases, intracranial granuloma in one case, transverse myelitis in two cases, sagittal sinus thrombosis in one case, spinal arachnoiditis in one case, intracranial vasculitis in one case, in addition to meningitis in all cases. Eleven patients were male and seven were female. The most prevalent symptoms were headache (83%) and fever (44%). All patients were treated with rifampicin, doxycycline plus trimethoprim-sulfamethoxazole or ceftriaxone. Duration of treatment (varied 3-12 months) was determined on basis of the CSF response. In four patients presented with left mild sequelae including aphasia, hearing loss, hemiparesis. In conclusion, although mortality is rare in neurobrucellosis, its sequelae are significant. In neurobrucellosis various clinical and neuroradiologic signs and symptoms can be confused with other neurologic diseases. In inhabitants or visitors of endemic areas, neurobrucellosis should be kept in mind in cases that have unusual neurological manifestations.

Implantable cardioverter-defibrillator endocarditis is a rare and potentially life threatening complication of brucellosis of difficult management for clinicians. We report an unusual case of pacemaker-related endocarditis due to Brucella melitensis in a patient with previous history of neurobrucellosis. Our patient was admitted to a hospital with severe swelling of his pacemaker pocket implanted 8 years earlier for sick sinus syndrome. Although pocket site cultures were positive for Brucella but blood cultures were not and serologic titer by the Rose Bengal test was positive. Transesophageal echocardiography showed two vegetations on the pacemaker leads. The patient was treated with doxycycline, rifampin and gentamicin with full recovery and the entire pacemaker apparatus was surgically explanted. Interestingly, two year prior this admission, the patient presented with meningoencephalitis diagnosed with neurobrucellosis proven by positive growth of Brucella mellitensis from the CSF. The patient was treated with doxycycline, rifampin and gentamicin with full recovery and the pacemaker had been removed. Reports of Brucella infection of prosthetic implants and devices have increased over the past decade. Consequently, potential relapsing of the disease and occupational exposure to Brucella should be considered in the differential diagnosis and management of cardiac device infection.

Background: Brucellosis is an important multisystemic disease with many different clinical symptoms, and its early diagnosis and treatment are possible. Neurobrucellosis (NB) is a rare but serious finding of brucellosis. Brucella can be seen as meningitis and encephalopathy, and it can cause cranial nerve pathologies, vascular syndromes, myopathy, spinal diseases, and psychiatric disorders. In NB, vascular syndromes secondary to inflammation are rarely seen. Here, we present nine young patients with vascular and nonspecific neuropsychiatric findings who had NB as the etiology of stroke., Methods: Nine patients who were admitted to our Neurology Clinic between 2012 and 2017 for various reasons in whom brucellosis was found in the etiology were retrospectively studied. The patients' symptoms, physical examination, laboratory and radiographic findings, treatments, and treatment responses are discussed., Results: Of the nine patients who presented to our clinic in the 4-year period, five were female. The average age was 49 years. Five patients had small vessel vasculitis, three had great vessel vasculitis, and one had meningoencephalitis and pons abscess. Two patients had granuloma, and one had an aneurysm., Conclusions: We aimed to present our cases due to the fact that this disease should be kept in mind in the differential diagnosis of patients with stroke and similar neuropsychiatric findings.

Background: Brucellosis is the most common zoonotic infection in the world. Brucellosis with nervous system involvement is known as 'neurobrucellosis' (NB). The diagnosis of NB is difficult because its clinical manifestations are non-specific and the sensitivity of routine culture tests is low., Methods: Next-generation sequencing (NGS) of cerebrospinal fluid (CSF) was used to detect pathogens in patients with clinically suspected central nervous system (CNS) infections at a tertiary referral center in China between June 1, 2016 and June 1, 2017. The clinical characteristics and NGS results of patients with the diagnosis of NB were reviewed in this study., Results: Four patients were rapidly diagnosed with NB using NGS of the CSF in patients with clinically suspected CNS infections, although the clinical manifestations varied dramatically between these patients. NGS of the CSF revealed that the sequence reads identified that corresponded to Brucella species ranged from 11 to 104, with genomic coverage ranging from 0.043% to 0.4%. Rapid diagnosis led to prompt treatment with the appropriate antibiotics., Conclusions: This study demonstrates the power of NGS of the CSF coupled with a bioinformatic pipeline in the diagnosis of NB., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Neurobrucellosis (NB) is a rare complication of brucellosis. NB presents with avariety of clinical manifestations, and the symptoms are always atypical. Our aim was to analyze the demographic characteristics, clinical manifestations, laboratory findings, imaging findings, treatments and outcomes of patients with NB., Material and Method: We retrospectively reviewed the data from 17 patients with NB hospitalized at the Chinese People's Liberation Army General Hospital between 1 January 2005 and 31 October 2016., Results: The following symptoms were recorded: 10/17 (59%) patients had fever, and 9/17 (53%) patients had a disorder affecting urination and defecation. Involvement of the cranial nerves was documented in 12/17 (71%) patients. The positivity rates of the tests were as follows: serum standard tube agglutination (STA), 15/17 (88.2%); cerebrospinal fluid STA, 10/17 (59%). The radiologic findings were categorized into four types: normal, white matter changes, vascular insult and inflammatory changes. Patients were treated with different combinations of rifampicin, doxycycline, ceftriaxone sodium and sulphamethoxazole for a total of six months. Two (12%) patients deteriorated, and two (12%) patients were lost to follow-up. The remaining patients (76%) were cured, but sequelae occurred in six patients., Conclusions: NB should be kept in mind in patients with autonomic dysfunction, especially disorders of urination and defecation. Hearing loss due to vestibulocochlear nerve injury seems to be typical for NB. The high incidence of sequelae may be related to a long disease course and the involvement of the central nervous system. Early detection, diagnosis and treatment could decrease mortality and sequelae.

Background: Brucellosis is a chronic bacterial disease caused by members of the genus Brucella. Among the classical species stands Brucella neotomae, until now, a pathogen limited to wood rats. However, we have identified two brucellosis human cases caused by B. neotomae, demonstrating that this species has zoonotic potential., Cases Presentation: Within almost 4 years of each other, a 64-year-old Costa Rican white Hispanic man and a 51-year-old Costa Rican white Hispanic man required medical care at public hospitals of Costa Rica. Their hematological and biochemical parameters were within normal limits. No adenopathies or visceral abnormalities were found. Both patients showed intermittent fever, disorientation, and general malaise and a positive Rose Bengal test compatible with Brucella infection. Blood and cerebrospinal fluid cultures rendered Gram-negative coccobacilli identified by genomic analysis as B. neotomae. After antibiotic treatment, the patients recovered with normal mental activities., Conclusions: This is the first report describing in detail the clinical disease caused by B. neotomae in two unrelated patients. In spite of previous claims, this bacterium keeps zoonotic potential. Proposals to generate vaccines by using B. neotomae as an immunogen must be reexamined and countries housing the natural reservoir must consider the zoonotic risk.

Neurobrucellosis manifesting as optic neuritis is a rare disease in childhood. We report a case of neurobrucellosis in a 11 year old girl leading to visual impairment and headache. Physical examination revealed mild oedema of right tibiotarsic joint and optic neuritis. Investigations showed CSF pleocytosis and a Brucella serum agglutination titer of 1/640. Complete reversal of the symptoms was observed after appropriate antibiotic treatment. To our knowledge only four cases of neurobrucellosis manifesting with visual impairment in childhood are previously reported in literature. [ABSTRACT FROM AUTHOR]

Brucella spp. should be considered in the differential diagnosis of acute meningitis of children living in areas where brucellosis is endemic. [ABSTRACT FROM AUTHOR]

A 55-year-old male presented with fever, stupor, aphasia, and left hemiparesis. A history of head trauma 3 months before was also reported. Cranial magnetic resonance imaging revealed slight contrast enhancement of lesions under the right frontal skull plate and right frontal lobe. Because of deterioration in nutritional status and intracranial hypertension, the patient was prepared for burr hole surgery. A subdural empyema (SDE) recurred after simple drainage. After detection of Brucella species in SDE, craniotomy combined with antibiotic treatment was undertaken. The patient received antibiotic therapy for 6 months (two doses of 2 g ceftriaxone, two doses of 100 mg doxycycline, and 700 mg rifapentine for 6 months) that resulted in complete cure of the infection. Thus, it was speculated that the preexisting subdural hematoma was formed after head trauma, which was followed by a hematogenous infection caused by Brucella species.

A diagnosis of brucellosis can be difficult because routine culture and serological methods exhibit variable sensitivity and specificity. We present the use of a metagenomic next- generation sequencing assay to diagnose a case of neurobrucellosis from cerebrospinal fluid, resulting in the institution of appropriate antibiotic treatment and a favorable clinical outcome., (© The Author 2017. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Brucellosis is the most frequent bacteria zoonosis in the world, with more than half a million new cases each year [1]. It is also the most significant zoonos in the edge of the Mediterranean Sea [2]. This zoonosis is capable of affecting humans and cause polymorphic clinical manifestations. In Morocco, the southern regions are the main affected areas [3]. We are reporting the observation of a 17-year-old male patient, who presented a febrile meningeal syndrome for 9 months without sensitivo-motor deficit. Tuberculosis is frequently evoked in such clinical presentations because Morocco is an endemic country, brucellosis is therefore often forgotten. The results of lumbar puncture, magnetic resonance imaging (MRI) and especially serology aided to conclude to a neuro-brucellosis. The outcome was favourable with antibiotic therapy.

Objectives: To present a case of co-occurrence of neurobrucellosis and cerebral venous sinus thrombosis., Methods: Case report., Clinical Presentation:  We presented 49-year-old Caucasian domicile female-farmer with a history of headache, weakness, and vomiting for a period of three months. Also, she had significant papilledema. We diagnosed rare co-morbidity of neurobrucellosis (confirmed after ELISA-test in serum samples and CSF analysis of pleocytosis/increase in protein/decrease in glucose level) in the setting of cerebral venous thrombosis developed in left sigmoid/left transverse sinus (confirmed after MRV of brain). Favorable outcome was achieved by applying protracted polymicrobial antibiotic therapy and heparin., Discussion: It may be challenging to diagnose neurobrucellosis, especially in patients with atypical presentation and abortive clinical forms. The co-morbidity of neurobrucellosis and cerebral venous sinus thrombosis is uncommon. However, it provides a possibility of brucella-colonization in cerebral venous sinuses as a potential hidden link between them., Conclusion: Patients with severe and persistent headache, as well as other neurological symptoms/signs should be considered for neurobrucellosis in endemic, but also in brucella non-endemic regions due to migrations. According to literature survey, this co-occurrence of neurobrucellosis and cerebral venous sinus thrombosis is third one reported from Europe.

Inflammation has long been implicated as a contributor to pathogenesis in neurobrucellosis. Many of the associated neurocognitive symptoms of neurobrucellosis may be the result of neuronal dysfunction resulting from the inflammatory response induced by Brucella abortus infection in the central nervous system. In this manuscript, we describe an immune mechanism for inflammatory activation of microglia that leads to neuronal death upon B. abortus infection. B. abortus was unable to infect or harm primary cultures of mouse neurons. However, when neurons were co-cultured with microglia and infected with B. abortus significant neuronal loss occurred. This phenomenon was dependent on TLR2 activation by Brucella lipoproteins. Neuronal death was not due to apoptosis, but it was dependent on the microglial release of nitric oxide (NO). B. abortus infection stimulated microglial proliferation, phagocytic activity and engulfment of neurons. NO secreted by B. abortus-activated microglia induced neuronal exposure of the "eat-me" signal phosphatidylserine (PS). Blocking of PS-binding to protein milk fat globule epidermal growth factor-8 (MFG-E8) or microglial vitronectin receptor-MFG-E8 interaction was sufficient to prevent neuronal loss by inhibiting microglial phagocytosis without affecting their activation. Taken together, our results indicate that B. abortus is not directly toxic to neurons; rather, these cells become distressed and are killed by phagocytosis in the inflammatory surroundings generated by infected microglia. Neuronal loss induced by B. abortus-activated microglia may explain, in part, the neurological deficits observed during neurobrucellosis., (© 2017 Wiley Periodicals, Inc.)

Brucellosis is a multisystem zoonotic disease. We report an unusual case of neurobrucellosis with seizures in an immunocompromised patient in Saudi Arabia who underwent renal transplantation. Magnetic resonance imaging of the brain showed diffuse white matter lesions. Serum and cerebrospinal fluid were positive for Brucella sp. Granuloma was detected in a brain biopsy specimen.

Several species of Brucella are known to be zoonotic, but B. neotomae infection has been thought to be limited to wood rats. In 2008 and 2011, however, B. neotomae was isolated from cerebrospinal fluid of 2 men with neurobrucellosis. The nonzoonotic status of B. neotomae should be reassessed.

The innate immune system is essential for the detection and elimination of bacterial pathogens. Upon inflammasome activation, caspase-1 cleaves pro-IL-1β and pro-IL-18 to their mature forms IL-1β and IL-18, respectively, and the cell undergoes inflammatory death termed pyroptosis. Here, we reviewed recent findings demonstrating that Brucella abortus ligands activate NLRP3 and AIM2 inflammasomes which lead to control of infection. This protective effect is due to the inflammatory response caused by IL-1β and IL-18 rather than cell death. Brucella DNA is sensed by AIM2 and bacteria-induced mitochondrial reactive oxygen species is detected by NLRP3. However, deregulation of pro-inflammatory cytokine production can lead to immunopathology. Nervous system invasion by bacteria of the genus Brucella results in an inflammatory disorder termed neurobrucellosis. Herein, we discuss the mechanism of caspase-1 activation and IL-1β secretion in glial cells infected with B. abortus. Our results demonstrate that the ASC inflammasome is indispensable for inducing the activation of caspase-1 and secretion of IL-1β upon infection of astrocytes and microglia with Brucella. Moreover, our results demonstrate that secretion of IL-1β by Brucella-infected glial cells depends on NLRP3 and AIM2 and leads to neurobrucellosis. Further, the inhibition of the host cell inflammasome as an immune evasion strategy has been described for bacterial pathogens. We discuss here that the bacterial type IV secretion system VirB is required for inflammasome activation in host cells during infection. Taken together, our results indicate that Brucella is sensed by ASC inflammasomes mainly NLRP3 and AIM2 that collectively orchestrate a robust caspase-1 activation and pro-inflammatory response.

We present a diagnostically challenging case of a 61-year-old man presenting with progressive weakness and intermittent low-grade fever., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Central nervous system involvement is a serious complication of brucellosis with various incidence and various clinical presentations., Patients and Methods: Hospitalized patients in University Clinical Centre, Clinic for Infectious diseases in Prishtina, with laboratory-confirmed brucellosis, were analyzed, a brucellosis-endemic region. Among the 648 confirmed cases with brucellosis during the period 1991- 2013, 82 patients (12.65%) were diagnosed with neurobrucellosis. The clinical manifestations in patients with neurobrucellosis were evaluated and compared with brucellosis patients., Results: The major presentations among the brucellosis patients were headache, fever, sweating, nausea, weight loss and arthralgia, while from CNS predominant complains were: headache, vomiting, tremor, low back pain, hearing loss and visual disturbance. The mean age of 82 neurobrucellosis patients was 31.46 years with age distribution 12-71 years, from them 5 (6.1%), younger than 16 years, with a non-significant predominance of women (53.65%). The most common neurological findings were radiculopathies of legs (41.46%) neck rigidity (46.34%), agitation (25,6%), behavioral disorders (18.3%), disorientation (19.5%) and stroke (1.22%). Cranial nerves were involved in 20 of 82 patients (24.4%). Neurological consequences were evidenced in 5 (6.1%) patients. Three patients leave hospital with consequences of peripheral facial paresis, two with sensorineural hearing loss and one with left hemiparesis. Headache, nausea and vomiting and weight loss are significantly (p<0.001) more frequent complains in neurobrucellosis patients compare to patients with brucellosis. On the other hand, as regard to the physical findings and complications, meningeal signs and splenomegaly are significantly more frequent in neurobrucellosis (p<0.01) whereas the hepatomegaly and lymphadenopathy were more frequent (p<0.01) in brucellosis patients. Different significant correlations were observed among specific complains too., Conclusions: Our findings in regard to the specific associations of physical and clinical features in brucellosis patients in Kosovo, may serve as an indication for neurobrucellosis. In endemic areas for brucellosis patients complaining in radiculopathies, persistent headache, facial palsy, hearing loss or presenting stroke without risk factors, should be considered for screening for neurobrucellosis., Competing Interests: • Conflict of interest: none declared.

Brucellosis is a zoonotic disease causing serious public health problems in countries of the Middle-East and developing countries like India. Neurobrucellosis is one of the devastating complications of this re-emerging zoonosis. The objective of this review was to identify the neurological manifestations of Brucellosis in an Indian population and bring into light the effective modalities used for treating neurobrucellosis. A systematic review of the scientific literature reported in accordance with the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines was conducted. Three databases (PubMed, IndMed, and ScienceDirect) were used to analyze retrospectively case reports of sufficient quality for data extraction (from the last 15 years, 2002-2016), and relevant literature was reviewed. Most of the cases had a definite history of exposure to Brucella through occupational contact with cattle, drinking raw milk, or living near unhygienic abattoir or even trips to epidemic areas outside India. The common presentations include fever, meningitis, brisk deep-tendon reflexes, extensor plantars, sensory deficit usually below the twelfth thoracic vertebral level, weakness of lower limbs, ocular signs of papilledema, and retrobulbar neuritis. The usual systemic findings associated were hepatosplenomegaly and weight-loss. Neurobrucellosis needs to be kept in mind in the differential diagnosis of fever of unknown origin involving neurological symptoms and systemic involvement. Prognosis is good if there is a combination of antibiotics, each with different mechanisms of action given in full dose. Suitable measures for its prevention are also suggested.

Background: Neurobrucellosis is a disease consisting of a wide spectrum of complications such as peripheral neuropathy, cranial nerve involvement, ataxia, meningeal irritation, paraplegia, seizures, coma, and even death. The vestibulocochlear nerve seems to be the most commonly affected cranial nerve (10%). We present a patient with neurobrucellosis whose auditory perception and speech intelligibility skill performances improved after cochlear implantation., Case Report: A 35 year-old woman was admitted to another hospital 2 years ago with the symptoms of headache, nausea, and altered consciousness, who was finally diagnosed with neurobrucellosis. She developed bilateral profound sensorineural hearing loss during the following 6 months. There was no benefit of using hearing aids. After successful treatment of her illness, she was found to be suitable for cochlear implantation. After the operation, her auditory perception skills improved significantly with a Categories of Auditory Performance (CAP) score of 5. According to clinical observations and her family members' statements, her Speech Intelligibility Rating (SIR) score was 3. Her speech intelligibility skills are still improving., Conclusion: Our case report represents the second case of hearing rehabilitation with cochlear implantation after neurobrucellosis. Cochlear implantation is a cost-effective and time-proven successful intervention in post-lingual adult patients with sensorineural hearing loss. Early timing of the surgery after appropriate treatment of meningitis helps the patient to achieve better postoperative results.

Brucellosis is a multisystem disease with various clinical symptoms. Neurobrucellosis is a rare but serious manifestation of brucellosis. A 60-year-old man with a previous diagnosis of brucellar spondylitis presented with sudden onset of aphasia and numbness of the right upper extremity. Cerebral angiography showed diffuse narrowing and dilatation on the distal branches of both the anterior cerebral artery (ACA) and the left middle cerebral artery (MCA) which indicated cerebral vasculitis, and the patient's Brucella agglutinin titer was 1:1280. After combined antimicrobial and steroid therapy was started, the patient's condition improved significantly, and he was discharged after 1 month. Antimicrobial therapy was continued for 16 months on an outpatient basis, and the last Brucella agglutinin titer was 1:40. To our knowledge, this is the first case of relapsed neurobrucellosis with vasculitis in Korea to have been treated successfully.

Background: Brucellosis is a multisystem disease that may present with a broad spectrum of clinical manifestations and complications. Neurobrucellosis is an uncommon and serious complication of pediatric brucellosis., Methods: We describe seven cases of neurobrucellosis., Results: Ataxia (one patient), diplopia (one patient) and hearing loss (one patient) were among the neurological signs 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., Conclusion: Neurobrucellosis should be kept in mind in patients with any neurological or neuropsychiatric diseases who live in endemic areas of brucellosis., (© 2014 Japan Pediatric Society.)

Abstract: Brucellosis is a common and multisystemic zoonotic infectious disease. Central nervous system involvement is rarely seen in brucellosis, with an incidence of 0.5–25%. The aim of this report is to underline the importance of brucellosis, which is an endemic infection in our country, during the diagnostic evaluation of stroke. [Copyright &y& Elsevier]

Summary: Central nervous system involvement is a serious complication of brucellosis; data found in the literature are generally restricted to case reports and case series. In this study we pooled the data from Turkish medical practice in order to gain a thorough understanding of the subject. A search of Turkish publications on chronic neurobrucellosis was made using both Turkish and international databases. A total of 35 publications were analyzed and 187 neurobrucellosis cases were evaluated. Headache, fever, sweating, weight loss, and back pain were the predominant symptoms, while meningeal irritation, confusion, hepatomegaly, hypoesthesia, and splenomegaly were the most frequent findings. The major complications in patients were cranial nerve involvement, polyneuropathy/radiculopathy, depression, paraplegia, stroke, and abscess formation. Antibiotics were used in different combinations and over different intervals. The duration of antibiotic therapy reported ranged from 2 to 15 months (median 5 months). The mortality was 0.5% with suitable antibiotics. Neurobrucellosis may mimic various pathologies. For this reason, a thorough evaluation of the patient with probable disease is crucial for an accurate diagnosis and proper management of the disease. [Copyright &y& Elsevier]