The microbiological diagnosis of tuberculous meningitis: results of Haydarpasa-1 study.

We aimed to provide data on the diagnosis of tuberculous meningitis (TBM) in this largest case series ever reported. The Haydarpasa-1 study involved patients with microbiologically confirmed TBM in Albania, Croatia, Denmark, Egypt, France, Hungary, Iraq, Italy, Macedonia, Romania, Serbia, Slovenia, Syria and Turkey between 2000 and 2012. A positive culture, PCR or Ehrlich-Ziehl-Neelsen staining (EZNs) from the cerebrospinal fluid (CSF) was mandatory for inclusion of meningitis patients. A total of 506 TBM patients were included. The sensitivities of the tests were as follows: interferon-γ release assay (Quantiferon TB gold in tube) 90.2%, automated culture systems (ACS) 81.8%, Löwenstein Jensen medium (L-J) 72.7%, adenosine deaminase (ADA) 29.9% and EZNs 27.3%. CSF-ACS was superior to CSF L-J culture and CSF-PCR (p <0.05 for both). Accordingly, CSF L-J culture was superior to CSF-PCR (p <0.05). Combination of L-J and ACS was superior to using these tests alone (p <0.05). There were poor and inverse agreements between EZNs and L-J culture (κ = -0.189); ACS and L-J culture (κ = -0.172) (p <0.05 for both). Fair and inverse agreement was detected for CSF-ADA and CSF-PCR (κ = -0.299, p <0.05). Diagnostic accuracy of TBM was increased when both ACS and L-J cultures were used together. Non-culture tests contributed to TBM diagnosis to a degree. However, due to the delays in the diagnosis with any of the cultures, combined use of non-culture tests appears to contribute early diagnosis. Hence, the diagnostic approach to TBM should be individualized according to the technical capacities of medical institutions particularly in those with poor resources.

Outbreak of West Nile virus infection among humans in Serbia, August to October 2012.

We describe the first reported outbreak of West Nile virus (WNV) infection in humans in Serbia in August to October 2012 and examine the association of various variables with encephalitis and fatal outcome. Enzyme-linked immunosorbent assay (ELISA) was used for detection of WNV-specific IgM and IgG antibodies in sera and cerebrospinal fluid. A total of 58 patients (mean age: 61 years; standard deviation: 15) were analysed: 44 were from Belgrade and its suburbs; 52 had neuroinvasive disease, of whom 8 had meningitis, while 44 had encephalitis. Acute flaccid paralysis developed in 13 of the patients with encephalitis. Age over 60 years and immunosuppression (including diabetes) were independently associated with the development of encephalitis in a multivariate analysis: odds ratio (OR): 44.8 (95% confidence interval (CI): 4.93­408.59); p=0.001 (age over 60 years); OR: 10.76 (95% CI: 1.06­109.65); p=0.045 (immunosuppression including diabetes). Respiratory failure requiring mechanical ventilation developed in 13 patients with encephalitis. A total of 35 patients had completely recovered by the time they were discharged; nine patients died. The presence of acute flaccid paralysis, consciousness impairment, respiratory failure and immunosuppression (without diabetes) were found to be associated with death in hospital in a univariate analysis (p<0.001, p=0.007, p<0.001 and p=0.010, respectively).

Imported parasitic infections in Serbia.

BACKGROUND: Travel to the tropics is associated with a risk of parasitic infection, which is increasing in parallel with the rise in travel to these areas. We thus examined the prevalence and trend in the occurrence of parasitic infections in Serbian travelers. METHODS: A retrospective analysis of the medical records of all travelers returning from tropical and subtropical areas, who presented at the Institute for Infectious and Tropical Diseases in Belgrade between January 2001 and January 2008, was performed. RESULTS: Of a total of 2440 travelers, 169 (6.9%) were diagnosed with a parasitic infection, including malaria in 79, intestinal parasites in 84 (pathogenic species in 30 and non-pathogenic in 54), filariasis in four, and visceral leishmaniasis and fascioliasis in one patient each. Importantly, of the whole series only 583 (23.9%) were symptomatic, of which 19.4% were found to be infected with a parasite. The single pathogenic parasite occurring in asymptomatic patients was Giardia intestinalis. CONCLUSIONS: Parasitic infection causing symptomatic disease among travelers returning from tropical areas to Serbia is not infrequent. In view of the expected increase in travel to the tropics, diagnostic protocols for tropical parasitic diseases should take these data into account.

Seasonality of trichinellosis in patients hospitalized in Belgrade, Serbia.

A retrospective study of the course and outcome of trichinellosis in a series of 50 patients hospitalized at the Institute for Infectious and Tropical Diseases in Belgrade between 2001 and 2008 was performed. Clinical diagnosis of trichinellosis was based upon the patients' clinical history, symptoms and signs, and eosinophilia. The occurrence of cases showed a strong seasonality (P < 0.0001). The incubation period ranged between one and 33 days. The mean time between onset of symptoms and admission was nine days. Family outbreaks were the most frequent. Smoked pork products were the dominant source of infection (76%). Fever was the most frequent clinical manifestation (90%), followed by myalgia (80%) and periorbital edema (76%). 43 patients were examined serologically and 72% of them had anti-Trichinella antibodies. Eosinophilia and elevated levels of serum CK and LDH were detected in 94, 50 and 56% of the patients, respectively. All patients responded favorably to treatment with mebendazole or albendazole, but eight developed transient complications. Trichinellosis remains a major public health issue in Serbia.

The prognosis of highly active antiretroviral therapy (HAART) treated HIV infected patients in Serbia, related to the time of treatment initiation.

BACKGROUND: With the introduction of highly active antiretroviral treatment (HAART) an impressive improvement in patient survival and quality of life has bee observed. However, the optimal timing of initial HAART is still under consideration. OBJECTIVE: To investigate the prognosis of HAART treated patients in Serbia, related to the timing of HAART initiation. STUDY DESIGN: A series of 563 patients on HAART was retrospectively analyzed to investigate treatment response and survival. RESULTS: After a mean of 6 years (range 1-14) of treatment with PI-based and/or NNRTI-based regimens, a favorable response was achieved in 72.4%, treatment failure occurred in 7.9%, while 19.7% had a dissociative immunological/virological response. If treatment was initiated during primary HIV infection it took a shorter time to achieve a favorable response than in patients who began HAART in chronic HIV infection (2.7+/-2.2 years vs. 6.9+/-2.7 years, P<0.01). A higher proportion of patients with primary HIV infection then those treated in the chronic phase achieved a favorable response to HAART (88.4% vs. 71.9%, P=0.045). Patients who initiated HAART when their CD4 cell counts were below 200 cells/microL needed longer treatment for favorable response (8 years vs. 6 years, log rank P<0.01). Forty-seven (8.3%) patients died. The overall estimated survival was 13 years. Patients older then 40 and IVDU were more likely to die during HAART (OR 2.6, 95% CI 1.1-5.9, P=0.016, and OR 2.0, 95% CI 1.0-3.7, P=0.02, respectively). However, reaching and maintaining undetectable viremia was an independent predictor of longer survival (OR 11.3, 95% CI 4.6-27.7, P<0.01). CONCLUSION: Reaching and maintaining undetectable viremia during HAART predicted longer survival, even if sub-clinical immunodeficiency remained.

[Neurologic manifestations in trichinosis]. / Neuroloske manifestacije u toku trihinoze.

Neurologic manifestations are present in about 10-20 percent of patients with trichinosis. They could be a serious diagnostic problem in the absence of corresponding epidemiological data and typical symptoms and signs of the disease. In untreated patients the mortality rate is about 50%. Several pathogenic mechanisms are responsible for the neurological complications in trichinosis: obstruction of brain blood vessels by larvae, cysts or granulomas, toxic vasculitis with secondary thrombosis and haemorrhages, granulomatous inflammation of the brain parenchyma and allergic reaction. Neurotrichinosis is manifested with clinical symptoms and signs of meningitis, encephalitis, polyradiculoneuritis, poliomyelitis, myastenia gravis, paresis and paralysis, with the clinical picture of systemic disease of the connective tissue involving the nervous system and, extremely rare, as a sinus thrombosis. Thus, the broad spectrum of neurological lesions in trichinosis is, probably, the results of the fact that Trichinella spiralis larvae, during haematogenic dissemination has no special affinity for particular parts of the nervous system. We present five patients with encephalitis and focal cerebral lesions in trichinosis. In one patient the neurologic manifestations were the only sign of the disease. We believe that all pathogenic mechanisms mentioned above, were involved in the onset of neurological manifestations in our patients. The diagnosis of the disease was based on the clinical picture, epidemiological data, microscopic identification of larvae in the muscular tissue, the presence of antibodies against Trichinella spiralis in cerebrospinal fluid (with preserved blood brain barrier) and in serum confirmed by IIF method, computerised tomography and magnetic resonance imaging of the brain, eosinophilia in the peripheral blood picture. One patient died, and in the remaining patients the course of the disease was favourable; they were discharged from the hospital with minimal neurologic sequelae.

[Significance of bromide levels in evaluation of the hemato-encephalic barrier during acute viral meningitis]. / Znacaj bromidnog kolicnika za procenu funkcionog stanja hematoencefalne barijere u toku akutnih virusnih meningitisa.

INTRODUCTION: Inflammatory diseases of the CNS are associated with increased permeability of blood-brain barrier due to vasculitis of cerebral blood vessels leading to regional ischaemia and necrosis. Many substances pass easily from the serum into the CSF through inflamed and damaged blood-brain barrier. Bromide partition test is one of the parameters for evaluation of the blood-brain barrier integrity during CNS inflammatory diseases. As early as 1929 Walter published a monograph on blood-brain barrier accentuating the value of bromide partition test for evaluation of the functional status of blood-brain barrier. In healthy individuals bromide partition test usually ranges from 2.9-3.5. In most patients with TB meningitis bromide partition test remains below 1.6 while it is usually higher in patients with serous meningitis of other aetiologies. However, the low bromide partition test may associate also some other viral and other serous meningitides accompanied with severe lesions of the blood-brain barrier, resulting in increased passage of sodium bromide from the serum into the CSF, so that the serum/CSF ratio is lower. The aim of th study was to calculate and analyze the results of bromide partition test in patients with acute viral meningitis and hyperproteinorachia above 0.70 g/l and to calculate and analyze the results of bromide partition test in patients with TB and parasitic meningitis. The results of bromide patirion tests were compared with results of other parameters for evaluation of the blood-brain barrier function. METHOD: Titration method was used to determine the serum sodium bromide and CSF ratio. Sodium bromide oxidation into sodium bromate was the principle, where addition of potassium iodide is followed by release of equivalent amount of elementary iodide. Iodide is titrimetrically evidenced with thyosulphate, with starch as an indicator. In addition to bromide partition test functional condition of blood-brain barrier was also evaluated by albumin coefficients, albuminorachia and total proteinorachia. RESULTS: In 6 of 30 patients (20%) with acute viral meningitis the bromide partition ratio was below 1.6, suggesting severe damage of blood-brain barrier in these patients: albumin coefficients exceeded 16.7 (mean = 24.7), albuminorachia was over 0.90 (mean = 1.38 g/l), and total proteinorachia over 3.0 g (mean = 3.1 g/l). The aetiology was confirmed in all patients: lymphocyte choriomeningitis virus in 5, COX B1 in one. Values of bromide partition test were higher on follow-up examination, and values of other parameters decreased, suggesting restitution of blood-brain barrier. The results are given in Table 1. Most severe damage of blood-brain barrier was evidenced in patients with lymphocyte choriomeningitis. Parameters for evaluation of functional condition of blood-brain barrier in patients with lymphocyte choriomeningitis and TB meningitis with most severe damage of the barrier, were compared. The results are given in Table 2. No differences between the compared parameters were found, i.e. no difference in the severity of blood-brain damage. Bromide patition test values were below 1.6 in all patients with TB meningitis and in 3 of 5 patients with parasitic meningitis. DISCUSSION: Numerous studies have shown that bromide patition test value during TB meningitis was usually below 1.6. This is probably due to hypersensitivity reaction of the meninges to tuberculin which is located intrathecally and leads to blood-brain barrier damage. Use of antituberculous drugs does not affect the bromide partition test values in early stages of the disease. In all of our 15 patients with TB meningitis the bromide partition test values were below 1.6, coinciding with reference reports. However, we also measured bromide partition test values below 1.6 in 6 (20%) of 30 patients with acute viral meningitis with proteinorachia above 0,70 g/l (ABSTRACT TRUNCATED).

[Neural manifestations in Lyme disease (Lyme borreliosis of the nervous system)]. / Nervne pojave u Lajmskoj bolesti (Lajm-borelioza nervnog sistema).

The involvement of the nervous system is common during Lyme's disease, and the term neuroborreliosis has been established. All structures of the nervous system, from meninges to periferial nerves, can be involved. Neurological manifestations are most common in the second stage (dissemination). The article deals with the most important neurological manifestations, as well as with the contemporary pathogenetic considerations and therapy. Eleven patients with neuroborreliosis who were treated at Dr. Kosta Todorovitsh Institute of Infectious and Tropical Diseases, are reviewed. Five of them had acute meningoencephalitis, of whom two had concurrent neuritis; one patient had Banawart's syndrome with arthralgias, arthritis and fatigue syndrome; two patients had neuritis; one had bilateral facial palsy; two had chronic fatigue syndrome.

[Pulmonary manifestations of acquired immunodeficiency syndrome (AIDS)]. / Plucne manifestacije sindroma stecene imunodeficijencije (AIDS-om).

The lungs are the principal target organ in the infectious complications of acquired immunodeficiency syndrome (AIDS) and this predisposition to infections is not the regional manifestation of systemic immunologic deficiency induced by human immunodeficiency virus (HIV) only, because HIV also affects lung's own complex system of local defense mechanisms. It was demonstrated that pulmonary host defenses were compromised by.direct infection of alveolar macrophages with HIV and decreased production of solubile factors by lymphocytes derived from bronchoalveolar lavage fluid was shown. The most common infectious causative agents are facultative intracellular pathogens including Pneumocystis carinii, Cryptococcus neoformans, Mycobacterium tuberculosis and cytomegalovirus, which reflects the specific defects of cell-mediated immunity. AIDS patints have, in addition, an increased incidence of infections with capsulated bacteria such as Haemophilus influenzae and Sterptococcus pneumoniae which are associated typically with the impairment of the humoral immune response. High-grade pathogens such as M. tuberculosis tende to reactivate early in the progression of immunodeficiency whereas low-grade pathogens such as P. carinii only emerge when the defect is more advanced. The profound immunodeficiency in AIDS patients means that clinical features may be quite atypical and blunted.

[Lactates in the cerebrospinal fluid in patients with bacterial and viral meningitis--significance in differential diagnosis]. / Laktati u likvoru bolesnika sa bakterijskim i virusnim meningitisom--diferencijalno dijagnosticki znacaj.

Lactate concentrations were determined in the cerebrospinal fluid of patients with purulent, tuberculous and viral meningitis. The control group consisted of 10 patients with meningism (the presence of the meningeal syndrome with a normal cytobiochemical finding of the cerebrospinal fluid). The enzymatic kinetic method of the firm "Behringer" was used. In all the patients with purulent meningitis lactate values were elevated (above 6.2 mmol/l), and the highest values (above 15.0 mmol.l) were found in the patients who also developed respiratory failure. The lactate values in the cerebrospinal fluid of patients with purulent meningitis were higher in statistical significance than in all other examined groups of patients (p less than 0.01). The lactate values were in correlation with the total number of leukocytes (r = 0.78, p less than 0.01) and with the percent of polimorphonuclear leukocytes in the cerebrospinal fluid (r = 0.80, p less than 0.01). Elevated lactate values (above 2.95) were also found in all the patients who had tuberculous meningitis and statistically they differed significantly from the cerebrospinal fluid values of the patients with viral meningitis and meningism (p less than 0.01). There was no difference in the cerebrospinal fluid lactates of patients with viral meningitis and meningism (p greater than 0.05). Elevated lactate values were also found in 2 patients who had paraneoplastic meningitis and in 3 patients with cerebral cysticercosis and hydrocephalus, but without meningitis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Clinical expirience in the treatment of purulent meningitis and sepsis with Ceftriaxon]. / Klinicka iskustva sa primenom cefriaksona u lecenju gnojnih menigitisa u sepsi.

Our expirience in the treatment of purulent meningitis and sepsis with third generation of cephalosporin--Cephtriaxon--are presented. In the last two years 13 of 44 patients suffering from purulent meningitis were treated with Cephtriaxon. They were all succesfuly cured without complications and recurrence. The time of CSF normalisation was from 8-17 days, depending on the aethyological agent of meningitis. Cephtriaxon is the drug of choice for E. coli and Hemophilus influence meningitis. We achiewed good results in the treatment ob sepsis, and ten of these cases are presented. Our Staphylococcus aureus showed good susceptibility to Cephtriaxon, which is the reason of the good therapeutical results. The analysis of antibacterial activity of Cephtriaxon in bacteria isolated from blood and CSF cultures, revealed that 80 per cent of isolated bacteria were highly susceptible.

[Acute meningitis without cutaneous manifestations caused by varicella zoster virus--intrathecal synthesis of specific antibodies]. / Akutni meningitis izazvan varicella zoster virusom bez kutanih manifestacija--intratekalna sinteza specificnih antitela.

The results of virusologic and cytobiochemical evaluation of CSF and serum samples of four patients with acute viral meningitis (AVM), most probably induced by varicella zoster virus (VZV), are reported. In no case VZV infection was not cutaneously manifested. Aetiologic diagnosis was established according to the presence of specific anti VZV AVM, in spite of their presence in the sera. On samples detected by indirect enzyme immunoassay (EIA). Four different antibody indexes were used to prove that the antibodies were intrathecally synthesized. Other viral antibodies (HSV, mumps) were not evident in the CSF samples of the patients with VZV avm, in spite of their presence in the sera. On the other hand, anti VZV antibodies could not be identified in the CSF samples of the controls (AVM of other aetiology, meningism) in spite of their presence in the sera. A possible aetiologic link between anti VZV antibodies presence in the CSF samples and some neurologic syndromes is discussed.

[Cerebellitis during Mycoplasma pneumoniae infection]. / Cerebelitis u toku infekcije Mycoplasmom pneumoniae.

Mycoplasma pneumoniae is the primary cause of respiratory system diseases in school children and young adults. Most often an infection of the upper respiratory airways is in question, with or without pharyngitis, while clinically manifest pneumonia occurs in only 3-10% of patients. However, multisystemic manifestations of Mycoplasma pneumoniae infections can also occur, usually during the first 14 days after the start of respiratory symptomatology, but can also occur as isolated in some cases, with no prior respiratory illness, nor its later occurrence. In our patient there came to a development of pneumonia, exudative pleuritis, sinusitis and cerebellitis. The duration of the disease was protracted, but recovery was complete, without sequelae. The etiological diagnosis was set retrospectively on the basis of the dynamics of the titer of complement fixating antibodies. Mycoplasma pneumoniae should be considered as a possible etiological agent of various clinical syndromes.

[Neurolues--clinical characteristics, diagnosis and therapy]. / Neurolues--klinicke karakteristike, dijagnoza i terapija.

A female patient with neurolues was presented in this paper. The disease started 25 years after primoinfection by neurologic disturbances which corresponded to classic neurolues with the signs of meningovascular and parenchymatous disease. The diagnosis was confirmed by positive serologic tests, computerized brain tomography--whereby syphilomas were found in the brain and by histopathologic survey of one of peripheral syphilomas. Antibiotic therapy with high penicillin doses was initiated but without more significant clinical effects, it only led to negativization of serologic tests. The patient died after two months. Serologic tests to syphilis should be temporarily repeated in all patients suspective of neurolues, in order to initiate or repeat the previously employed therapy.