Ronald van Toorn

Tuberculous meningitis: more questions, still too few answers

Tuberculous meningitis is especially common in young children and people with untreated HIV infection, and it kills or disables roughly half of everyone affected. Childhood disease can be prevented by vaccination and by giving prophylactic isoniazid to children exposed to infectious adults, although improvements in worldwide tuberculosis control would lead to more effective prevention. Diagnosis is difficult because clinical features are non-specific and laboratory tests are insensitive, and treatment delay is the strongest risk factor for death. Large doses of rifampicin and fluoroquinolones might improve outcome, and the beneficial effect of adjunctive corticosteroids on survival might be augmented by aspirin and could be predicted by screening for a polymorphism in LTA4H, which encodes an enzyme involved in eicosanoid synthesis. However, these advances are insufficient in the face of drug-resistant tuberculosis and HIV co-infection. Many questions remain about the best approaches to prevent, diagnose, and treat tuberculous meningitis, and there are still too few answers.

MRI to demonstrate diagnostic features and complications of TBM not seen with CT.

BackgroundComputed tomography (CT) findings in children with tuberculous meningitis (TBM) often do not explain the clinical presentation and may even be normal. Magnetic resonance imaging (MRI) has the potential to diagnose TBM with greater sensitivity than CT and also to detect more infarcts.AimThe aim of this study was to determine whether MRI demonstrates features and complications of TBM not present on CT.Materials and methodsRetrospective, blinded evaluation and comparison of CT and MRI findings in children with TBM were performed.ResultsOf 30 children included, MRI demonstrated eight more with basal enhancement and four more with infarctions. Overall, MRI demonstrated an additional 104 sites of infarction (of a total 172) than CT. Of these, 89 were acute and visualized only on diffusion-weighted image. MRI showed five more patients with unilateral and two more with bilateral basal ganglia infarcts than CT as well as 19 brainstem infarcts. Hydrocephalus was equally detected by MRI and CT.ConclusionMRI is superior to CT for diagnosing TBM (by detecting basal enhancement in more patients) and prognosis (by detecting many more infarcts in strategic locations). The role of CT is defined for the acute setting in detecting hydrocephalus for surgical management.

The changing profile of pediatric meningitis at a referral centre in Cape Town, South Africa.

BACKGROUNDnPediatric meningitis remains a common cause of childhood morbidity and mortality in developing countries. Knowledge of the causative organisms in a region is of importance in guiding empiric antibiotic regimes and immunization schedules assisting decisions on primary health-care interventions.nnnMETHODSnThis retrospective review of 557 meningitis cases represents a third pediatric survey conducted over a 3-year period (January 2007 to December 2009) at the same institution and after an interval of 14 years. Cases were identified using cerebrospinal fluid results. Demographic and laboratory variables were collected and meningitis was classified as aseptic/viral, bacterial, septic, tuberculous meningitis (TBM) or fungal.nnnRESULTSnThe commonest form of bacterial meningitis was TBM diagnosed in 22% (nu2009=u2009126) of children. Streptococcus pneumoniae 4% (nu2009=u200923) and Klebsiella pneumoniae 3% (nu2009=u200917) were the next commonest causes of bacterial meningitis diagnosed. Haemophilus influenzae meningitis occurred in <1% (nu2009=u20093) of cases with a median age of 3 months. Aseptic meningitis remains the commonest category. Human immunodeficiency virus (HIV) testing was requested in 43% (nu2009=u2009241) of cases; 8% (nu2009=u200946) were positive.nnnCONCLUSIONnTBM remains the commonest cause of pediatric bacterial meningitis in the Western Cape. It is concerning that the percentage of TBM cases out of the total study population has more than doubled compared with that in previous surveys. The low prevalence and young age of H. influenzae meningitis cases confirm the benefits derived from H. influenzae type b (Hib) vaccination.

Tuberculous Meningitis-Related Optic Neuritis: Recovery of Vision With Thalidomide in 4 Consecutive Cases

Blindness is an uncommon but devastating complication of tuberculosis meningitis. The main causes are chronically raised intracranial pressure (hydrocephalus and/or tuberculomas) or direct involvement of the optic chiasm or optic nerves by the basal arachnoiditis (inflammation and/or compression). Antituberculosis therapy combined with corticosteroids and control of intracranial pressure constitutes the mainstay of therapy for tuberculous meningitis. Despite these treatment measures, some patients develop blindness, mainly as a result of progressive optochiasmatic arachnoiditis. This led us to explore the role of adjuvant thalidomide therapy, and we describe the dramatic recovery of vision in 4 consecutive cases. Clinical recovery was accompanied by marked radiological improvement on magnetic resonance imaging (MRI) of the brain.

Value of early follow-up CT in paediatric tuberculous meningitis.

Background: The value of CT in the diagnosis of tuberculous meningitis (TBM) in children is well reported. Follow-up CT scanning for these patients is, however, not well described and, in particular, the value of early follow-up CT has not been addressed for children with TBM. Objective: To assess the value of early follow-up CT in children with TBM in identifying diagnostic, prognostic and therapeutically relevant features of TBM. Materials and methods: A retrospective 4-year review of CT scans performed within 1 week and 1 month of initial CT in children with proven (CSF culture-positive) and probable TBM (CSF profile-positive but culture-negative) and comparison with initial CT for the diagnostic, prognostic and therapeutic CT features of TBM. Results: The CT scans of 50 children were included (19 “definite” TBM; 31 “probable” TBM). Of these, 30 had CT scans performed within 1 week of the initial CT. On initial CT, 44 patients had basal enhancement. Only 24 patients had contrast medium-enhanced follow-up scans. Important findings include: 8 of 29 patients (who were not shunted) developed new hydrocephalus. New infarcts developed in 24 patients; 45% of those who did not have infarction initially developed new infarcts. Three of the six patients who did not show basal enhancement on initial scans developed this on the follow-up scans, while in seven patients with pre-existing basal enhancement this became more pronounced. Two patients developed hyperdensity in the cisterns on non-contrast medium scans. Eight patients developed a diagnostic triad of features. Three patients developed CT features of TBM where there was none on the initial scans. Conclusions: Early follow-up CT is useful in making a diagnosis of TBM by demonstrating features that were not present initially and by demonstrating more sensitive, obvious or additional features of TBM. In addition, follow-up CT is valuable as a prognostic indicator as it demonstrates additional infarcts which may have developed or become more visible since the initial study. Lastly, follow-up CT has therapeutic value in demonstrating hydrocephalus, which may develop over time and may require drainage. We advise routine follow-up CT in patients with suspected TBM within the first week of initial CT and optionally at 1xa0month.

Magnetic resonance imaging of miliary tuberculosis of the central nervous system in children with tuberculous meningitis

BackgroundTuberculous meningitis (TBM) is closely associated with miliary tuberculosis and a pathogenetic relationship is suspected, although it has been proposed that the two processes are unrelated.ObjectiveTo describe miliary tuberculosis of the central nervous system (CNS) on MRI in children with TBM.Materials and methodsA retrospective descriptive study of 32 paediatric TBM patients referred for MRI. The presence of miliary nodules in the CNS was recorded. Lesions were categorized according to their distribution, enhancement pattern, size and signal characteristics.ResultsA miliary distribution of nodules was present in 88% of patients. All patients with a miliary distribution had leptomeningeal nodules and 18% of these patients had deep parenchymal nodules in addition. At least one tuberculoma with central T2 hypointensity was identified in 39% of patients.ConclusionThe high prevalence of miliary leptomeningeal nodules in the CNS of children with TBM is significant because it points to a pathogenetic relationship that has long been suspected on epidemiological grounds. Our findings challenge the concept that miliary tuberculosis is only an incidental finding in TBM patients and suggest that it plays an integral part in the pathogenesis.

Cerebral infarction and neurodevelopmental outcome in childhood tuberculous meningitis.

INTRODUCTIONnCerebral infarction is an important cause of neurological sequelae in childhood tuberculous meningitis (TBM).nnnAIMnTo investigate neurodevelopmental outcome and development of motor sequelae in TBM-related cerebral infarction.nnnMETHODSnA group of 64 children with TBM and computerized tomographic (CT) evidence of infarction were compared with regard to motor sequelae and neurodevelopmental outcome, with 54 children with TBM but no radiological evidence of infarction. The association between infarct number, size, location and outcome was investigated in the infarct group. Selected covariates were entered into a multivariate model to better understand the independent contribution of each factor on neurodevelopmental outcome.nnnRESULTSnAn association was found between the presence, number and size of hemispheric infarcts and motor handicap on follow-up. Location of single basal ganglia infarcts, however, did not correlate with motor outcome. The Griffiths general developmental quotient (GQ) was significantly lower in children with bilateral (p<0001) and unilateral multiple infarcts (p=0.0239) compared to those without infarcts. The GQ of children with unilateral single infarcts was not significantly lower than those without infarction (p=0.2282).nnnCONCLUSIONnInfarct characteristics should be taken into account when neurodevelopmental outcome is prognosticated in TBM. Young age, unilateral multiple or bilateral infarction on CT at 1 month, advanced stage of TBM and the interaction term stage x Glasgow coma score are the best predictors of neurodevelopmental outcome at 6 months.

Update on the Diagnosis and Management of Tuberculous Meningitis in Children

Tuberculous meningitis (TBM), the most devastating manifestation of tuberculosis, is often missed or overlooked because of nonspecific symptoms and difficulties in diagnosis. It continues to be an important cause of neurologic handicap in resource-poor countries. Owing to the suboptimal performance of diagnostic tests of TBM, diagnosis relies on thorough history, clinical examination, and relevant investigations. The development of affordable, accurate diagnostic tests for TBM in resource-poor settings remains a priority. Short intensified treatment is safe and effective in both human immunodeficiency virus (HIV)-infected and HIV-uninfected children. Treatment of tuberculous hydrocephalus depends on the level of the cerebrospinal fluid obstruction. Corticosteroids reduce risk of neurodisability and death in HIV-uninfected children. Thalidomide should be considered in children compromised by tuberculosis abscesses and tuberculous-related optochiasmic arachnoiditis. In resource-poor countries, home-based TBM treatment after initial in-hospital stabilization is feasible in carefully selected patients. Early diagnosis and treatment of TBM is the single most important factor determining outcome.

The conundrum of iron in multiple sclerosis – time for an individualised approach

Although the involvement of immune mechanisms in multiple sclerosis (MS) is undisputed, some argue that there is insufficient evidence to support the hypothesis that MS is an autoimmune disease, and that the difference between immune- and autoimmune disease mechanisms has yet to be clearly delineated. Uncertainties surrounding MS disease pathogenesis and the modest efficacy of currently used disease modifying treatments (DMTs) in the prevention of disability, warrant the need to explore other possibilities. It is evident from the literature that people diagnosed with MS differ widely in symptoms and clinical outcome - some patients have a benign disease course over many years without requiring any DMTs. Attempting to include all patients into a single entity is an oversimplification and may obscure important observations with therapeutic consequences. In this review we advocate an individualised approach named Pathology Supported Genetic Testing (PSGT), in which genetic tests are combined with biochemical measurements in order to identify subgroups of patients requiring different treatments. Iron dysregulation in MS is used as an example of how this approach may benefit patients. The theory that iron deposition in the brain contributes to MS pathogenesis has caused uncertainty among patients as to whether they should avoid iron. However, the fact that a subgroup of people diagnosed with MS show clinical improvement when they are on iron supplementation emphasises the importance of individualised therapy, based on genetic and biochemical determinations.

Iron Status in Children With Recurrent Episodes of Tumefactive Cerebral Demyelination

Iron is a vital element in the multifactorial initiation of myelination. It is required for cholesterol and lipid biosynthesis, both key components of myelin. Iron also plays an important role in energy production by mitochondrial oxidative metabolism which occurs in myelin-producing oligodentrocytes at a higher rate than in any other cell. Iron deficiency can, therefore, result in decreased oligodendrocyte survival and defective myelination. This led us to investigate iron status in 2 consecutive children with multiple sclerosis who presented with recurrent episodes of tumefactive demyelination. Testing revealed nonanemic iron deficiency in both patients. Discontinuation of iron supplementation in both children resulted in recurrent decreased iron parameters which can indicate mutations in proteins responsible for regulation of iron uptake. Further studies are warranted to explore the association of low iron in children presenting with recurrent episodes of tumefactive demyelination.