METHODS

Cecilia Makiwane Hospital, Mdantsane, Eastern Cape, Republic of South Africa.

OBJECTIVE

To assess the role of the semi-automated Roche COBAS AMPLICOR(TM)Mycobacterium tuberculosis PCR test in the diagnosis of tuberculous meningitis (TBM).

METHODS

Eighty-three specimens of cerebrospinal fluid (CSF) were collected prospectively from 69 patients with suspected TBM. The COBAS AMPLICOR TB PCR test was compared with the manual AMPLICOR(TM)TB PCR test, clinical and cerebrospinal fluid (CSF) findings, direct ZN smear and radiometric TB culture.

RESULTS

CSF from 7/40 (17.5%) patients treated for TBM were positive by TB COBAS AMPLICOR(TM). The sensitivity of the test was not significantly different (p=0.375) from the manual TB AMPLICOR(TM)PCR test. The comparative sensitivities of the TB COBAS AMPLICOR(TM)PCR and the manual AMPLICOR PCR for detecting cases of definite and probable TBM from CSF collected within 9 days of commencing antituberculosis treatment were 40% and 60% respectively. All 29 patients not treated for TBM were negative by COBAS AMPLICOR(TM), giving a specificity of 100%.

CONCLUSIONS

The COBAS AMPLICOR(TM)TB PCR test is a rapid and highly specific diagnostic test for TBM. However, there was a non-significant trend favouring slightly greater sensitivity using the manual AMPLICOR(TM)TB PCR test.

The results of a Dot immunobinding assay (Dot Iba) for the detection of mycobacterial antigen in the cerebrospinal fluid (CSF) of 45 patients with tuberculous meningitis (TBM) were compared with the results of a polymerase chain reaction (PCR) for the detection of Mycobacterium tuberculosis. In eight patients with culture proven TBM, Dot-Iba gave positive results, while PCR yielded positive results only in six patients. The overall sensitivities of Dot-Iba and PCR in 37 patients with culture negative (probable) TBM were 75.67% and 40.5% respectively. Dot-Iba, in contrast to PCR is a rapid and relatively easier method. More importantly, Dot-Iba is suitable for the routine application for the laboratory diagnosis of TBM and therefore best suited to laboratories in the developing world.

Tuberculous meningitis (TBM) is a common presentation of extrapulmonary tuberculosis. TBM is associated with many complications. However, concurrent syringomyelia and intradural extramedullary tuberculoma occurring in a patient treated for TBM is rare. Only one such case has been reported earlier. A 27-year-old woman presented with paraparesis of 2 months duration. She had been treated for TBM 8 months earlier. She was found to have an extensive syringomyelia from C2 to the conus medullaris and an intradural extramedullary tuberculoma at the lower thoracic levels. At surgery, a thick, granulomatous lesion was found in the intradural extramedullary plane. Following excision of the granulomatous lesion, a syringostomy was done. The patient was treated with antituberculous drugs and steroids. Six months after treatment, there was no significant change in her neurological status. Concurrent syringomyelia and intradural extramedullary tuberculoma should be entertained in the differential diagnosis when a patient presents with myelopathy following TBM. The pathogenesis of syringomyelia in this condition is discussed.

BACKGROUND

Tuberculous meningitis (TBM) is the most common form of neurotuberculosis and the fifth most common form of extrapulmonary TB. Early diagnosis and prompt treatment are the cornerstones of effective disease management. The accurate diagnosis of TBM poses a challenge due to an extensive differential diagnosis, low bacterial load and paucity of cerebrospinal fluid (CSF) especially in children.

RESULTS

We describe the utility of ELISA and qPCR for the detection of Mycobacterium tuberculosis (M. tb) proteins (GlcB, HspX, MPT51, Ag85B and PstS1) and DNA for the rapid diagnosis of TBM. CSF filtrates (n = 532) derived from children were classified as 'Definite' TBM (M. tb culture positive, n = 29), 'Probable and Possible' TBM (n = 165) and 'Not-TBM' including other cases of meningitis or neurological disorders (n = 338). ROC curves were generated from ELISA and qPCR data of 'Definite' TBM and Non-Tuberculous infectious meningitis (NTIM) samples and cut-off values were derived to provide ≥ 95% specificity. devR qPCR, GlcB, HspX and PstS1 ELISAs showed 100% (88;100) sensitivity and 96-97% specificity in 'Definite' TBM samples. The application of these cut-offs to 'Probable and Possible' TBM groups yielded excellent sensitivity (98%, 94;99) and specificity (98%, 96;99) for qPCR and for GlcB, HspX and MPT51 antigen ELISAs (sensitivity 92-95% and specificity 93-96%). A test combination of qPCR with GlcB and HspX ELISAs accurately detected all TBM samples at a specificity of ~90%. Logistic regression analysis indicated that these tests significantly added value to the currently used algorithms for TBM diagnosis.

CONCLUSIONS

The detection of M. tb GlcB/HspX antigens/devR DNA in CSF is likely to improve the utility of existing algorithms for TBM diagnosis and also hasten the speed of diagnosis.

Recent increases in the dosages of the essential antituberculosis agents isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA) for use in children recommended by World Health Organization have raised concerns regarding the risk of hepatotoxicity. Published data relating to the incidence and pathogenesis of antituberculosis drug-induced hepatotoxicity (ADIH), particularly in children, is reviewed. Amongst 12,708 children receiving chemoprophylaxis, mainly with INH, but also other combinations of INH, RMP and PZA only 1 case (0.06%) of jaundice was recorded and abnormal liver functions documented in 110 (8%) of the 1225 children studied. Excluding tuberculous meningitis (TBM) 8984 were children treated for tuberculosis disease and jaundice documented in 75 (0.83%) and abnormal liver function tests in 380 (9.9%) of the 3855 children evaluated. Amongst 717 children treated for TBM, however, jaundice occurred in 72 (10.8%) and abnormal LFT were recorded in 174 (52.9%) of those studied. Case reports document the occurrence of ADIH in at least 63 children. Signs and symptoms of ADIH were frequently ignored in the recorded cases. ADIH can occur in children at any age or at any dosage of INH, RMP or PZA, but the incidence of.ADIH is is considerably lower in children than in adults. Children with disseminated forms of disease are at greater risk of ADIH. The use of the higher dosages of INH, RMP and PZA recently recommended by WHO is unlikely to result in a greater risk of ADIH in children.

Tuberculous meningitis (TBM) remains difficult to diagnose. We prospectively evaluated a diagnostic algorithm for TBM in 205 HIV-negative patients with meningitis and a low CSF glucose. Patients were classified as having TBM or bacterial meningitis (BM) by two diagnostic methods: logistic regression method (LRM) and classification and regression tree (CART). We performed analyses of TBM versus BM and TBM versus non-TBM in all patients and in patients with microbiologically confirmed diagnoses. Diagnostic sensitivities for TBM were 99% (LRM) and 87% (CART). For BM, diagnostic sensitivities were 81.5% (LRM) and 86.5% (CART) in the primary analysis and 86.5% (LRM) and 74% (CART) in the secondary analysis. In microbiologically confirmed cases, similar rates were achieved. These figures are superior to microbiological confirmation rates in routine laboratories and support the use of this algorithm in high-prevalence TB settings with limited diagnostic facilities. Validation in an HIV-endemic setting is required.

This study was planned to compare the adenosine deaminase (ADA) levels and polymerase chain reaction (PCR) in cerebrospinal fluid (CSF) as a rapid method to diagnose tuberculosis meningitis (TBM). Fifty-four adult patients with suspected TBM and 37 controls were included in this study. The median ADA level was 21U/L of most likely TBM, 14U/L of unconfirmed TBM and 5U/L of controls. PCR for Mycobacterium tuberculosis was positive in 12 out of 27 most likely TBM cases, 5 out of 27 unconfirmed TBM cases and 3 out of 37 controls. Using a cut off level of >10U/L, CSF-ADA had a sensitivity of 92.5% and specificity of 97% for the diagnosis of TBM. PCR for M. tuberculosis had a sensitivity of 44.5% and specificity 92% in the most likely TBM cases. This study shows that CSF-ADA is a more sensitive indicator than PCR for the diagnosis of M. tuberculosis.

Tuberculous meningitis (TBM) leads to death or disability in half the affected individuals. Tools to assess severity and predict outcome are lacking. Neurospecific biomarkers could serve as markers of the severity and evolution of brain injury, but have not been widely explored in TBM. We examined biomarkers of neurological injury (neuromarkers) and inflammation in pediatric TBM and their association with outcome.

Blood and cerebrospinal fluid (CSF) of children with TBM and hydrocephalus taken on admission and over 3 weeks were analyzed for the neuromarkers S100B, neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP), in addition to multiple inflammatory markers. Results were compared with 2 control groups: patients with (1) a fatty filum (abnormal filum terminale of the spinal cord); and (2) pulmonary tuberculosis (PTB). Imaging was conducted on admission and at 3 weeks. Outcome was assessed at 6 months.

Data were collected from 44 patients with TBM (cases; median age, 3.3 [min-max 0.3-13.1] years), 11 fatty filum controls (median age, 2.8 [min-max 0.8-8] years) and 9 PTB controls (median age, 3.7 [min-max 1.3-11.8] years). Seven cases (16%) died and 16 (36%) had disabilities. Neuromarkers and inflammatory markers were elevated in CSF on admission and for up to 3 weeks, but not in serum. Initial and highest concentrations in week 1 of S100B and NSE were associated with poor outcome, as were highest concentration overall and an increasing profile over time in S100B, NSE, and GFAP. Combined neuromarker concentrations increased over time in patients who died, whereas inflammatory markers decreased. Cerebral infarcts were associated with highest overall neuromarker concentrations and an increasing profile over time. Tuberculomas were associated with elevated interleukin (IL) 12p40, interferon-inducible protein 10, and monocyte chemoattractant protein 1 concentrations, whereas infarcts were associated with elevated tumor necrosis factor α, macrophage inflammatory protein 1α, IL-6, and IL-8.

CSF neuromarkers are promising biomarkers of injury severity and are predictive of mortality. An increasing trend suggested ongoing brain injury, even though markers of inflammation declined with treatment. These findings could offer novel insight into the pathophysiology of TBM.

BACKGROUND

Movement disorders may appear during tuberculous meningitis (TbM).

OBJECTIVE

To investigate the variety of movement disorders seen in TbM and consider possible pathogenic mechanisms.

METHODS

We established two diagnostic categories for TbM: definite and probable. All patients were examined clinically and with laboratory tests, computed tomographic scan, or magnetic resonance imaging.

METHODS

A university hospital in Quito, Ecuador.

RESULTS

Thirty of 180 consecutively studied patients with TbM developed movement disorders. Twenty-four months after treatment was completed, we determined a prognosis for the patients. Seven patients had chorea, three dystonia, and 20 tremor. One of the patients with tremor also had myoclonus and one with dystonia had tremor. The average age of the patients with chorea was lower than that of the patients with dystonia and tremor. Two patients with chorea, one with dystonia, and three patients with tremor died. The patients with chorea and dystonia had more severe disease. We found little correlation between the type, distribution, or severity of abnormal movements and the computed tomography scan or magnetic resonance image findings.

CONCLUSIONS

Tremor is the most common movement disorder seen in the course of TbM. Chorea is more frequently found in young children. Deep vascular lesions are more common among patients with movement disorders.

Twenty children from 2 months to 7 years (mean age 2.74 years +/- 1.62) diagnosed to have tuberculous meningitis (TBM) were evaluated for serial serum sodium levels and osmolality of cerebrospinal fluid (CSF), serum and urine on admission and the results compared with 20 age and nutritionally matched controls, and these investigations repeated on day 3 and day 10. Mean serum sodium levels (130.7 +/- 6.26 mEq/L), and osmolality of CSF (272.0 +/- 7.0 mOsm/kg) and serum (275.5 +/- 6.09 mOsm/kg) were significantly lower (p < 0.001) than in controls. Hyponatremia was detected in 65% of cases on admission, 47% on day 3 and in 30.8% on day 10. All the patients with hyponatremia had biochemical evidence of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) on admission. Incidence of SIADH gradually decreased to 41.2% on day 3 and 15.4% on day 10. In some of the cases serum sodium levels and osmolality of serum and CSF took about 3 weeks to return to normal. CSF osmolality was lower than concomitant serum osmolality in patients as well as in controls. In patients with SIADH, CSF osmolality followed the same trend as serum values and returned to normal in 2-3 weeks. Overall mortality was 25%. Two out of 3 patients who expired during first 3 days had SIADH but in those cases who survived there was no correlation with degree of meningeal inflammatory changes or ultimate outcome. SIADH is commonly associated with TBM and should be diagnosed early in order to modify the fluid therapy in these cases.(ABSTRACT TRUNCATED AT 250 WORDS)

METHODS

In view of paucity of studies on predictors of hyponatremia in tuberculous meningitis (TBM) and its influence on outcome, this study was undertaken.

OBJECTIVE

To study the frequency, predictors and prognosis of hyponatremia in TBM.

METHODS

In this prospective hospital based study, 76 patients with TBM (definite 18 and probable 58) were enrolled. The severity of meningitis was graded as I-III and hyponatremia as severe (<120mEq/L), moderate (120-129mEq/L) or mild (130-134mEq/L). Hospital death was noted and functional outcome was assessed by modified Rankin Scale (mRS) on discharge.

RESULTS

34 (44.7%) TBM patients had hyponatremia (mild 3, moderate 23 and severe 8). Hyponatremia was due to cerebral salt wasting in 17, syndrome of inappropriate secretion of antidiuretic hormone in 3 and miscellaneous causes in 14 patients. Hyponatremia was related to GCS score and basal exudates. Outcome of TBM was related to duration of hospitalization, GCS score, focal deficit, mechanical ventilation, severity of TBM, age and comorbidities. Cerebral salt wasting was related to severity of TBM.

CONCLUSIONS

Hyponatremia occurred in 44.7% of TBM patients. Cerebral salt wasting was the commonest cause of hyponatremia and was related to the severity of TBM.

OBJECTIVE

To investigate the clinical features, laboratory test results, imaging data, and prognostic predictors of tuberculous meningitis (TBM) in adults.

METHODS

We retrospectively reviewed 108 adult patients with a diagnosis of TBM over a 6-year period. Patients were divided into "definite" and "probable" groups, depending on the diagnosis made by (1) positive culture, or polymerase chain reaction, of Mycobacterium tuberculosis (TB) from the cerebrospinal fluid (CSF); or (2) the isolation of TB elsewhere, or chest radiography consistent with active pulmonary TB, or imaging studies of the brain consistent with TBM, or clinical improvement on treatment. These two groups were compared for their clinical features, images, laboratory test results, and 9-month mortality rates to identify prognostic predictors.

RESULTS

Compared with the "probable" group (n = 62), the "definite" group (n = 46) had a higher mortality rate (50.0%vs. 30.6%, p = 0.041) and more consciousness disturbance (78.3%vs. 51.6%, p = 0.005), hydrocephalus (63.4%vs. 40.7%, p= 0.029) and isolation of TB from extra-CSF specimens (41.3%vs. 22.6%, p = 0.037). Old age (p = 0.002), consciousness change (p = 0.032), and hydrocephalus (p = 0.047) were poor prognostic indicators in the "definite" group as assessed by univariate analysis. Severity of TBM at admission and delayed anti-TB therapy resulted in a poor prognosis for all patients. Multiple logistic regression analysis showed that old age and hydrocephalus were independent factors for mortality. Adjunctive steroid therapy over 2 weeks improved survival in both the "definite" (p = 0.002) and "probable" (p = 0.035) groups, but more than 4 weeks of use had no significant effect on mortality. Steroid treatment, therefore, may improve the outcome of patients with TBM.

CONCLUSIONS

Old age, advanced stage of TBM at admission, hydrocephalus, and positive TB culture or polymerase chain reaction of CSF are factors associated with a poor prognosis for TBM. Early diagnosis and treatment, including short term steroid use, are mandatory for clinical care of adult patients with TBM.

BACKGROUND

Tuberculous meningitis (TBM) is the most severe form of extrapulmonary tuberculosis and causes high mortality and morbidity. Isoniazid resistance is strongly predictive of death in patients with TBM.

METHODS

In the present study, using polymerase chain reaction (PCR) and Genotype MTBDRplus line-probe assay, we investigated the drug resistance in patients with TBM living in Southwest China.

RESULTS

Our results showed that only one-third of patients with TBM had a positive result for Mycobacterium tuberculosis culture from cerebrospinal fluid (CSF). PCR-based detection of M. tuberculosis DNA in CSF is not only an alternative diagnostic approach for TBM but also can be further used for the detection of drug resistance when combined with the MTBDRplus assay, the results of which were consistent with the classic drug susceptibility test. However, it further provided the molecular profile of the mutations can be conducted much faster than the classic drug susceptibility test can (1 day vs 30-40 days, respectively). In the studied 30 CSF samples from patients with TMB, we found a rate of 64.29% for isoniazid resistance, 39.29% for rifampicin resistance, and 32.14% for multidrug-resistant tuberculosis, which is relatively higher than the reported resistance in pulmonary tuberculosis. However, the molecular profile indicated that the most frequently observed mutations in the rpoB and katG genes are also responsible for drug resistance in TBM.

CONCLUSIONS

Our data suggest that the MTBDRplus line-probe assay is capable of detecting drug resistance for the CSF samples that have a PCR-positive result. We recommend PCR-based diagnosis and drug resistance test as routine assays for patients with suspected TBM.

BACKGROUND

Tuberculous meningitis (TBM) is the most severe form of infection caused by Mycobacterium tuberculosis, causing death or disability in more than half of those affected. The aim of this review is to examine recent advances in our understanding of TBM, focussing on the diagnosis and treatment of this devastating condition.

METHODS

Papers on TBM published between 1891 and 2014 and indexed in the NCBI Pubmed. The following search terms were used: TBM, diagnosis, treatment and outcome.

RESULTS

The diagnosis of TBM remains difficult as its presentation is non-specific and may mimic other causes of chronic meningoencephalitis. Rapid recognition of TBM is crucial, however, as delays in initiating treatment are associated with poor outcome. The laboratory diagnosis of TBM is hampered by the low sensitivity of cerebrospinal fluid microscopy and the slow growth of M. tuberculosis in conventional culture systems. The current therapy of TBM is based on the treatment of pulmonary tuberculosis, which may not be ideal. The combination of TBM and HIV infection poses additional management challenges because of the need to treat both infections and the complications associated with them.

RESULTS

The pathogenesis of TBM remains incompletely understood limiting the development of interventions to improve outcome. The optimal therapy of TBM has not been established in clinical trials, and increasing antimicrobial resistance threatens successful treatment of this condition. The use of adjunctive anti-inflammatory agents remains controversial, and their mechanism of action remains incompletely understood. The role of surgical intervention is uncertain and may not be available in areas where TBM is common.

CONCLUSIONS

Laboratory methods to improve the rapid diagnosis of TBM are urgently required. Clinical trials of examining the use of high-dose rifampicin and/or fluoroquinolones are likely to report in the near future.

CONCLUSIONS

The use of biomarkers to improve the rapid diagnosis of TBM warrants further investigation. The role of novel antituberculosis drugs, such as bedaquiline and PA-824, in the treatment of TBM remains to be explored. Human genetic polymorphisms may explain the heterogeneity of response to anti-inflammatory therapies and could potentially be used to tailor therapy.

OBJECTIVE

Cerebrospinal fluid (CSF) hypoglycorrhachia and elevated protein is well-described in bacterial meningitis, but evidence for its differential diagnostic value in tuberculous meningitis (TBM) is lacking. We aimed to assess the diagnostic utility of CSF glucose, CSF to serum glucose ratio and CSF protein in children with suspected TBM.

METHODS

We describe CSF glucose and protein values as well as CSF to serum glucose ratios in a prospective evaluation of TBM suspects seen at Tygerberg Children's Hospital, Cape Town, South Africa, from January 1985 to January 2014.

RESULTS

Of 615 TBM suspects, 88 (14%) had microbiologically confirmed TBM, 381 (62%) 'probable' TBM and 146 (24%) 'non-TBM'. Mean absolute CSF glucose concentration was significantly lower in the microbiologically confirmed (1.87 ± 1.15 mmol/L) and 'probable' TBM (1.82 ± 1.19 mmol/L) groups compared to non-TBM (3.66 ± 0.88 mmol/L). A CSF glucose concentration of <2.2 mmol/L diagnosed TBM with sensitivity 0.68 and specificity 0.96. Sensitivity using a CSF to serum glucose ratio of <0.5 was 0.90. Mean CSF protein was significantly elevated in the microbiologically confirmed TBM (1.91 ± 1.44 g/L) and 'probable' TBM (2.01 ± 1.49 g/L) groups compared to the non-TBM (0.31 ± 0.31 g/L). A CSF protein >1 g/L diagnosed TBM with sensitivity 0.78 and specificity 0.94.

CONCLUSIONS

Absolute CSF glucose values of <2.2 mmol/L and protein values of >1 g/L differentiated between TBM and non-bacterial meningitis with good specificity, although sensitivity was poor. A CSF to serum glucose ratio is more informative than the absolute value.

Active-oxygen species generated on a copper complex play vital roles in several biological and chemical oxidation reactions. Recent attention has been focused on the reactive intermediates generated at the mononuclear copper active sites of copper monooxygenases such as dopamine β-monooxygenase (DβM), tyramine β-monooxygenase (TβM), peptidylglycine-α-hydroxylating monooxygenase (PHM), and polysaccharide monooxygenases (PMO). In a simple model system, reaction of O2 and a reduced copper(I) complex affords a mononuclear copper(II)-superoxide complex or a copper(III)-peroxide complex, and subsequent H(•) or e(-)/H(+) transfer, which gives a copper(II)-hydroperoxide complex. A more reactive species such as a copper(II)-oxyl radical type species could be generated via O-O bond cleavage of the peroxide complex. However, little had been explored about the chemical properties and reactivity of the mononuclear copper-active-oxygen complexes due to the lack of appropriate model compounds. Thus, a great deal of effort has recently been made to develop efficient ligands that can stabilize such reactive active-oxygen complexes in synthetic modeling studies. In this Account, I describe our recent achievements of the development of a mononuclear copper(II)-(end-on)superoxide complex using a simple tridentate ligand consisting of an eight-membered cyclic diamine with a pyridylethyl donor group. The superoxide complex exhibits a similar structure (four-coordinate tetrahedral geometry) and reactivity (aliphatic hydroxylation) to those of a proposed reactive intermediate of copper monooxygenases. Systematic studies based on the crystal structures of copper(I) and copper(II) complexes of the related tridentate supporting ligands have indicated that the rigid eight-membered cyclic diamine framework is crucial for controlling the geometry and the redox potential, which are prerequisites for the generation of such a unique mononuclear copper(II)-(end-on)superoxide complex. Reactivity of a mononuclear copper(II)-alkylperoxide complex has also been examined to get insights into the intrinsic reactivity of copper(II)-peroxide species, which is usually considered as a sluggish oxidant or just a precursor of copper-oxyl radical type reactive species. However, our studies have unambiguously demonstrated that copper(II)-alkylperoxide complex can be a direct oxidant for C-H bond activation of organic substrates, when the C-H bond activation is coupled with O-O bond cleavage (concerted mechanism). The reactivity studies of these mononuclear copper(II) active-oxygen species (superoxide and alkylperoxide) will provide significantly important insights into the catalytic mechanism of copper monooxygenases as well as copper-catalyzed oxidation reactions in synthetic organic chemistry.

There is paucity of studies on cytokines in tuberculous meningitis (TBM) and their relation with clinical and radiological changes; therefore this study was undertaken. 16 TBM patients diagnosed on the basis of clinical, CSF and radiological criteria were included. They were subjected to TNF-alpha, IL-6, IL-8, IL-10, IL-1beta, and IL-12p70 estimation in CSF. The cytokine levels were also estimated in 10 controls. Initial clinical examination, stage of TBM and MRI findings (infarct, hydrocephalus, tuberculoma and exudates) were recorded. The patients were treated with 4 drugs antitubercular (RHZE) therapy and after 3 months clinical examination, cytokine levels, and radiological studies were repeated. Outcome was defined by Barthel index score at 3 months into poor, partial and complete recovery. The patient's age ranged between 10 and 50 years, 5 were females. At 3 months, all the patients were clinically followed up and 14 underwent repeat MRI. 10 patients improved, 1 remained stable and 5 deteriorated. There was worsening with respect to tuberculoma in 3, infarction in 2 and exudate in 1 patient. TNF-alpha was expressed in 32% patients, IL-6, IL-10, IL-1beta and IL-8 were significantly expressed in patients and declined after 3 months following treatment. The cytokine levels did not correlate with stage of meningitis, outcome and radiological deterioration or improvement.

OBJECTIVE

Hydrocephalus is the most common complication of tubercular meningitis (TBM). Relieving hydrocephalus by ventriculoperitoneal (VP) shunt placement has been considered beneficial in patients in Palur Grade II or III. The role of VP shunt placement in those of Grade IV is controversial and the general tendency is to avoid its use. Some authors have suggested that patients in Grade IV should receive a shunt only if their condition improves with a trial placement of an external ventricular drain (EVD). In the present study, the authors assessed the outcome of VP shunt placement in patients in Grade IV TBM with hydrocephalus to examine the factors predicting outcome and to determine whether a trial with an EVD is absolutely necessary prior to shunt placement.

METHODS

Ninety-five consecutive cases of TBM with hydrocephalus in which the patients underwent VP shunt placement were retrospectively analyzed, and direct VP shunts were placed whenever possible. An EVD was placed first only in the presence of deranged blood parameters. Outcomes were assessed both in the short and long term.

RESULTS

The mean patient age was 17.5 years (range 1-55 years). Fifty-two patients underwent direct VP shunt placement, and the remaining 43 received EVDs first. Overall, 33 and 45% of patients had favorable short- and long-term outcomes, respectively. Age older than 3 years and duration of altered sensorium < or = 3 days were predictive of a favorable short-term outcome. Glasgow Coma Scale score at presentation was predictive of long-term outcome. Of the patients who did not improve with placement of an EVD prior to VP shunt insertion, 24 and 18% had favorable short- and long-term outcomes, respectively; this was not significantly different from the outcome in the patients who underwent direct VP shunt placement.

CONCLUSIONS

Direct VP shunt placement is an effective option in patients with Grade IV TBM with hydrocephalus. Age and duration of altered sensorium are predictive of short-term outcome, while Glasgow Coma Scale score at presentation predicts long-term outcome. Ventriculoperitoneal shunts should be considered even in patients who do not improve with an EVD.

BACKGROUND

Tuberculous meningitis (TBM) is the most lethal form of Mycobacterium tuberculosis infection, which has a high rate of neurological complications and sequelae.

OBJECTIVE

Our study offers a real-world infectious disease clinic perspective, being thus representative for the clinical environment of developing countries.

METHODS

We performed a retrospective analysis of the 127 adult and 77 pediatric cases diagnosed with TBM in the Infectious Disease Hospital of the School of Medicine of Iasi, Romania between 2004-2013.

RESULTS

Definite diagnosis of TBM was established in 31% of children but in only 20% of adults (p = 0.043). A contact with an individual with pulmonary tuberculosis was documented in 30% of children vs. 13% of adults (p = 0.0007). Coma occurred in 19% of patients (similar in children and adults); other consciousness abnormalities were seen in 27% of children and in 72% of adults (p = 0.000001). Cranial nerve palsies occurred prior to therapy in 9% of cases (12% vs 7% of children and adults, respectively, p>0.05), and developed 2-7 days after treatment initiation in 10% (12 vs 9%). CSF cultures were positive for M. tuberculosis in 24% of patients (31% vs. 20%, p>0.05). Overall mortality was 7.35%, similar for children and adults. Yet, permanent neurological sequelae, which were seen in 23% of patients occurred significantly more frequent in children vs. adults (36% vs. 14%, respectively, p = 0.0121). In conclusion, our retrospective analysis on a significant number of cases of TBM identified striking differences between children and adults: while children were in an earlier stage at the admission, they associated a higher frequency of neurological sequelae and miliary pattern, and they were more likely to have normal CSF protein levels and positive cultures of CSF.

OBJECTIVE

To assess the relative accuracy of dynamic spiral computed tomography (CT) compared with tracheobronchography, in a population of ventilator dependent infants with suspected tracheobroncho-malacia (TBM).

METHODS

Paediatric intensive care unit in a tertiary teaching hospital.

METHODS

Infants referred for investigation and management of ventilator dependence and suspected of having TBM were recruited into the study. Tracheobronchography and CT were performed during the same admission by different investigators who were blinded to the results of the other investigation. The study was approved by the hospital research ethics committee, and signed parental consent was obtained.

RESULTS

Sixteen infants were recruited into the study. Fifteen had been born prematurely, and five had cardiovascular malformations. In 10 patients there was good or partial correlation between the two investigations, but in six patients there was poor or no correlation. Bronchography consistently showed more dynamic abnormalities, although CT picked up an unsuspected double aortic arch. Radiation doses were 0.27-2.47 mSv with bronchography and 0.86-10.67 mSv with CT.

CONCLUSIONS

Bronchography was a better investigation for diagnosing TBM and in determining opening pressures. Spiral CT is unreliable in the assessment of TBM in ventilator dependent infants. In addition, radiation doses were considerably higher with CT.

Class IV-G (A/C) diffuse lupus nephritis and tubulointerstitial (TI) nephritis in a 31-year old woman was studied by light, immunofluorescence (IF), and electron microscopy (EM), to determine the pathogenesis of the TI lesions. The light microscopic findings showed peritubular capillaritis in the interstitium, with ruptures in the capillary structure, lysis of the surrounding tubular basement membrane (TBM), extravasated red blood cells (RBCs), the infiltration of neutrophils and mononuclear cells, and edema. The IF study revealed IgG, IgA, IgM, C1q, C3, and C4 depositions along the TBM, on the capillary walls, and in the interstitium proper. The EM study disclosed the deposition of immune complexes in the TBM, the capillary wall, and the interstitium proper. Based on these findings, the TI nephritis in this patient was considered to be due to peritubular capillaritis secondary to the immune complex depositions in the capillary wall of the interstitium.

BACKGROUND

The stage of tuberculous meningitis (TBM) at presentation is strongly associated with prognosis.

OBJECTIVE

To compare different staging systems for TBM in predicting outcome.

METHODS

The associations of different staging systems with neurological outcome were assessed using clinical, diagnostic and outcome data of 554 TBM children admitted to Tygerberg Children's Hospital from January 1985 to April 2005.

RESULTS

The refined Medical Research Council (MRC) scale after 1 week (84%, 95%CI 81-88) had the highest discriminatory power in predicting neurological morbidity. The Glasgow Coma Score (GCS) on admission, GCS after 1 week, the 'refined' MRC scale on admission and Tygerberg Children's Hospital (TCH) staging method all had excellent discriminatory powers in predicting outcome. Improvement of staging after 1 week occurred in children who did not have signs of raised intracranial pressure (P = 0.004) or brainstem dysfunction on admission (P = 0.030).

CONCLUSIONS

The 'refined' MRC scale 1 week after diagnosis showed the best association with neurological outcome after 6 months of treatment. The excellent discriminatory power of the TCH scale and its simplicity of use make it the ideal scale for use in resource-poor settings.

METHODS

Tuberculous meningitis (TBM) is the commonest form of neurotuberculosis in the Indian subcontinent. Rapid laboratory confirmation of TBM is important for the institution of early treatment and to avoid associated morbidity and mortality. The polymerase chain reaction (PCR) is the most widely applied alternative rapid diagnostic technique for TBM.

OBJECTIVE

To evaluate the efficacy of an in-house developed IS6110 uniplex PCR (uPCR) in the diagnosis of TBM.

METHODS

A prospective, blinded study was conducted in a large sample base of 677 cerebrospinal fluid samples from 677 patients with clinically suspected TBM.

RESULTS

All culture-positive samples (n = 136) were positive (100%) by the PCR assay. The assay was found to be positive in 70% (n = 541) of the samples with a clinical diagnosis of TBM. The assay had an observed sensitivity of 76.37% (negative predictive value 59.90%) and a specificity of 89.18% (positive predictive value 94.69%). A diagnostic accuracy of 80% (kappa 0.57) was seen in patients with a clinical diagnosis of TBM. Statistical significance was observed, as patients with a clinical diagnosis of TBM were found to be 9.38 times more likely to be PCR-positive (OR 9.38, chi2 = 149.94, P < 0.001).

CONCLUSIONS

The performance of the in-house IS6110 uPCR assay merits its use as a sensitive and specific tool for the rapid diagnosis of TBM.

We produced an autoimmune glomerulotubular nephropathy in Swiss-Webster mice using human glomerular antigen in Freund's complete adjuvant. The disease is associated with circulating antibody to both mouse and human glomerular basement membranes (GBM) and tubular basement membranes (TBM). All mouse IgG subgroups are deposited initially in a linear pattern along the GBM and TBM. IgG deposition remains linear, while that of the other subgroups assumes a granular GBM pattern with continued linear TBM deposits. Despite tissue deposition of antibody capable of C-3 fixation, no C-3 is found in vivo along the GMB or TBM, nor is there C-3 fixation in vitro. This appears to be related to spatial limitations of IgG molecule attachment to basement membranes. A unique ultrastructural lesion of the GMB developed, characterized by periodic expansions of the lamina rara externa to form a beaded pattern. Eluate of nephritic kidneys contained all subgroups of IgG, but mainly IgG1 fixed in vitro to mouse kidney and in vivo when injected intravenously into normal mice. Fixation of other IgG subgroups in vivo may have resulted from antibody formation to abnormally formed GBM, thereby accounting for the peculiar ultrastructural findings and tissue fixation characteristics of the eluted immunoglobulin. Abnormal proteinuria without glycosuria or lysozymuria developed in test animals as compared to controls. Our model is similar in certain aspects to previously described models of Stebley nephritis, but differs because of the total involvement of TBMs, unique ultrastructural lesions, and dissimilarity to other reports of this model in mice.