Priscilla Springer

Twenty Years of Pediatric Tuberculous Meningitis: A Retrospective Cohort Study in the Western Cape of South Africa

OBJECTIVE. Tuberculous meningitis is the most severe extrapulmonary complication of tuberculosis, with high morbidity and mortality rates. The objective of this study was to assess the relationship between presenting clinical characteristics and outcome of pediatric tuberculous meningitis. PATIENTS AND METHODS. We present a retrospective cohort study of all of the children diagnosed with tuberculous meningitis in a large university hospital in South Africa between January 1985 and April 2005. We compared demographic, clinical, and diagnostic characteristics with clinical outcome after 6 months of treatment. RESULTS. We included 554 patients. Common characteristics on admission were young age (82%; <5 years), stage II or III tuberculous meningitis (97%), nonspecific symptoms existing for >1 week (58%), poor weight gain or weight loss (91%), loss of consciousness (96%), motor deficit (63%), meningeal irritation (98%), raised intracranial pressure (23%), brainstem dysfunction (39%), and cranial nerve palsies (27%). Common features of tuberculous meningitis on computed tomography scan of the brain were hydrocephalus (82%), periventricular lucency (57%), infarctions (32%), and basal meningeal enhancement (75%). Clinical outcome after 6 months was as follows: normal (16%), mild sequelae (52%), severe sequelae (19%), and death (13%). All of the patients diagnosed with stage I tuberculous meningitis had normal outcome. Factors associated with poor outcome in univariate analyses were as follows: African ethnicity, young age, HIV coinfection, stage III tuberculous meningitis, absence of headache and vomiting, convulsions, decreased level of consciousness, motor deficits, cranial nerve palsies, raised intracranial pressure, brainstem dysfunction and radiographic evidence of hydrocephalus, periventricular lucency, and infarction. Ethnicity, stage of disease, headache, convulsions, motor function, brainstem dysfunction, and cerebral infarctions were independently associated with poor outcome in multivariate logistic regression analysis. CONCLUSIONS. Tuberculous meningitis starts with nonspecific symptoms and is often only diagnosed when brain damage has already occurred. Earlier diagnosis will improve outcome significantly. We were able to identify presenting variables independently associated with poor clinical outcome.

Adjunctive Thalidomide Therapy for Childhood Tuberculous Meningitis: Results of a Randomized Study

Childhood tuberculous meningitis is associated with serious long-term sequelae, including mental retardation, behavior disturbances, and motor handicap. Brain damage in tuberculous meningitis results from a cytokine-mediated inflammatory response, which causes vasculitis and obstructive hydrocephalus. Thalidomide, a potent tumor necrosis factor α inhibitor, was well tolerated and possibly showed some clinical benefit in children with tuberculous meningitis during a pilot study. The purpose of the present study was to assess the effect of adjunctive thalidomide in addition to standard antituberculosis and corticosteroid therapy on the outcome of tuberculous meningitis. Thalidomide (24 mg/kg/day orally) or placebo was administered in a double-blind randomized fashion for 1 month to patients with stage 2 or 3 tuberculous meningitis. The study was terminated early because all adverse events and deaths occurred in one arm of the study (thalidomide group). Thirty of the 47 children enrolled received adjunctive thalidomide, of whom 6 (20%) developed a skin rash, 8 (26%) hepatitis, and 2 (6%) neutropenia or thrombocytopenia. Four deaths (13%) occurred in patients with very severe neurologic compromise at baseline; two deaths were associated with a rash. Motor outcome after 6 months of antituberculosis therapy was similar in the two groups, even though the thalidomide group showed greater neurologic compromise on admission. In addition, the mean IQ of the two treatment groups did not differ significantly (mean IQ thalidomide group 57.8 versus mean IQ control group 67.5; P = 16). These results do not support the use of adjunctive high-dose thalidomide therapy in the treatment of tuberculous meningitis. (J Child Neurol 2004;19:250-257).

Long-term follow up of childhood tuberculous meningitis

The purpose of the present study was to determine the long-term outcome of 76 children (40 females and 36 males) diagnosed and treated with modern antituberculosis drugs. The median age of the children on admission was 29.5 months and on follow-up 9 years. Antituberculosis therapy consisted of daily isoniazid (20 mg/kg), rifampicin (20 mg/kg), ethionamide (20 mg/kg), and pyrazinamide (40 mg/kg) for 6 months. Twenty-three children received daily prednisone (2-4 mg/kg) for the first month of treatment. Raised intracranial pressure was actively monitored and treated. Patients with non-communicating hydrocephalus received ventriculo-peritoneal shunts shortly after admission while communicating hydrocephalus was treated with oral acetazolamide (100 mg/kg/day) and furosemide (1 mg/kg/day) in 3-4 divided doses. Communicating hydrocephalus that did not respond to this regimen within the first month of treatment also underwent ventriculo-peritoneal shunting. Only 20% of children were functionally completely normal at follow-up. Main areas of functional deficit were cognitive impairment (80%), poor scholastic progress (43%), and emotional disturbance (40%). Twenty-five per cent of children had evidence of motor impairment, but all could walk and only 5 of 76 children (6% of total) were unable to run. One child was blind but no child had sensori-neural deafness. It was concluded that these disabilities in children from mainly deprived socioeconomic backgrounds have serious implications for their future social, academic, and career prospects. A high index of suspicion of TBM in high tuberculosis incidence communities will help prevent the morbidity documented in this study.

Vascular endothelial growth factor and blood-brain barrier disruption in tuberculous meningitis

Background: Tuberculous meningitis (TBM) is characterized by disruption of the blood-brain barrier (BBB), cerebral edema and increased intracranial pressure (ICP). Vascular endothelial growth factor (VEGF) is a potent vascular permeability factor and a mediator of brain edema. Aims: To investigate whether in children with TBM disruption of the BBB relates to VEGF production and to assess the effect of corticosteroids on Mycobacterium tuberculosis-induced VEGF production by mononuclear leukocytes. Methods: Blood and CSF samples were collected from 26 children with stage 2–3 TBM and 20 controls. All patients received antituberculous and adjuvant corticosteroid therapy. Children were evaluated by ICP recording, computerized tomography scanning and outcome assessment at 6 months follow-up. BBB disruption was quantified by cerebrospinal fluid (CSF)-serum albumin ratios. VEGF concentrations were measured by enzyme-linked immunosorbent assay. In vitro human monocytic THP-1 cells were stimulated with M. tuberculosis sonicate or culture supernatant, and VEGF production was measured in the presence or absence of corticosteroids. Results: CSF VEGF concentrations were significantly higher in TBM patients than in the controls and correlated with mononuclear cell counts (r = 0.64; P = 0.001) and CSF-serum albumin ratio (r = 0.49; P = 0.015). CSF VEGF did not significantly correlate with elevated ICP. In vitro induction of VEGF production by M. tuberculosis sonicate or culture supernatant could be completely abrogated by corticosteroid treatment. Conclusions: Inflammatory cells secrete VEGF during TBM. CSF VEGF correlates with BBB disruption. Inhibition of VEGF may explain part of the clinical effect of adjuvant corticosteroid therapy in TBM.

The Role of Aspirin in Childhood Tuberculous Meningitis

Arterial stroke is the main cause of poor outcome in childhood tuberculous meningitis. Aspirin has an antithrombotic action at low dose and anti-ischemic and anti-inflammatory properties, which are dose-related. The aim of the study was to explore the possible benefits of aspirin in children with tuberculous meningitis. A total of 146 consecutive children with a diagnosis of probable tuberculous meningitis were studied. Patients were randomized into 3 groups: (1) placebo group, (2) low-dose aspirin group, and (3) high-dose aspirin group. Twenty-nine additional patients who received aspirin before admission were excluded from the randomized study, but continued on low-dose aspirin. Aspirin, irrespective of dose, did not show any significant benefit regarding morbidity (hemiparesis and developmental outcome) and mortality. Aspirin was well tolerated, but 1 death was probably related to aspirin. The fact that the outcome of the high-dose aspirin group compared favorably with the other treatment groups despite younger age and more severe neurological involvement at baseline needs further investigation.

Adjunctive thalidomide therapy of childhood tuberculous meningitis: Possible anti-inflammatory role.

The objective of this study was to determine the safety and tolerability of the immunomodulatory agent thalidomide as adjunct therapy in children with tuberculous meningitis. Children with stage 2 tuberculous meningitis received oral thalidomide for 28 days in a dose-escalating study, in addition to standard four-drug antituberculosis therapy, corticosteroids, and specific treatment of complications such as raised intracranial pressure. Clinical and laboratory evaluations were carried out. Fifteen patients (median age, 34 months) were enrolled. Thalidomide was administered via nasogastric tube in a dosage of 6 mg/kg/day, 12 mg/kg/day, or 24 mg/kg/day. The only adverse events possibly related to the study drug were transient skin rashes in two patients. Levels of tumor necrosis factor-α in the cerebrospinal fluid decreased markedly during thalidomide therapy. Clinical outcome and neurologic imaging showed greater improvement than that experienced with historical controls. Thalidomide appeared safe and well tolerated in children with stage 2 tuberculous meningitis and could have important anti-inflammatory effects. These promising results have led us to embark on a randomized, double-blind, placebo-controlled trial of the efficacy of thalidomide in tuberculous meningitis. (J Child Neurol 2000;15:497-503).

Coagulant and fibrinolytic status in tuberculous meningitis

Background: The long-term neurologic sequelae of childhood tuberculous meningitis (TBM) mainly result from ischemia owing to cerebral vasculitis. Deep vein thrombosis occurs in adults with pulmonary tuberculosis owing to hypercoaguability. The present study aimed to investigate coagulation status during acute childhood TBM. Methods: Coagulation status, including the natural anticoagulants, antithrombin, protein C and protein S; procoagulant FVIII; fibrinolytic factors, tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1) as well as anticardiolipin antibodies (ACA), was determined in 16 children with TBM before and during treatment. Results: A prothrombotic profile was found as expressed by a decrease of anticoagulant (protein S) and increase of the procoagulant (factor VIII) activity. Raised PAI-1 and normal tissue plasminogen activator values indicated deficient fibrinolysis. This hypercoagulable state was more pronounced in stage 3 patients than in stage 2 patients. The bleeding time on admission ranged from 1.2 to 10 minutes [mean 4.2 minutes]. The mean platelet count on admission was 577.9 ± 188.6 × 109/L and increased further during the course of the treatment. Conclusions: The hypercoagulable state in childhood TBM is comparable to that described in adults with pulmonary tuberculosis and may further increase the risk for infarction. Therapeutic measures that reduce the risk for thrombosis could therefore be potentially beneficial in childhood TBM.

Longitudinal developmental profile of children from low socio-economic circumstances in Cape Town, using the 1996 Griffiths Mental Development Scales

BACKGROUND: The Griffiths Mental Development Scales (GMDS) have not been standardised in South African children Neurodevelopmental scores of infants from deprived environments decline with age, but there is no evidence on how young South African children from such backgrounds perform on serial assessments. AIM: To describe the longitudinal developmental profile of infants from low socio-economic backgrounds at Tygerberg Childrens Hospital by comparing the GMDS scores performed at 10 - 12 months and 20 - 22 months. METHODS: Infants born to HIV-uninfected women attending the public service programme were recruited from a vaccine study in Cape Town, South Africa. The GMDS 0 - 2 years and a neurological examination were performed between 10 and 12 months and between 20 and 22 months. RESULTS: Thirty-one infants (14 girls, 17 boys) were assessed. Their mean (standard deviation (SD)) age was 11.6 (0.8) months and 21.0 (0.5) months at the first and second assessments, respectively. The mean (SD) general quotient decreased significantly from 107.3 (11.7) to 95.0 (11.0) (p<0.001). All sub-quotients decreased significantly except for locomotor. The hearing and language sub-quotient was most affected, with a decrease in mean quotients from 113.0 to 93.2 (p<0.001). There was no evidence of intercurrent events to explain the decline. INTERPRETATION: Scores on the GMDS of this group of children from low socio-economic backgrounds were normal at 11 months and, other than locomotor, decreased significantly at 21 months, with language the most affected. Further research is needed to determine the specific reasons for the decline.

Familial-Environmental Risk Factors in South African Children With Attention-Deficit Hyperactivity Disorder (ADHD): A Case-Control Study.

We investigated familial and environmental risk factors in a cohort of South African children diagnosed with attention-deficit hyperactivity disorder (ADHD). A prospective, hospital-based case control study was conducted comprising 50 children diagnosed with ADHD and 50 matched non-ADHD controls. The adjusted effect of familial-environmental risk factors on ADHD was determined by systematic assessment. Birth complications, parental psychiatric disorder, maternal ADHD, early childhood trauma, and nonmaternal child care were significant risk factors for ADHD. Prolonged breastfeeding was found to be protective. In a multivariable logistic regression model, 5 criteria (birth complications, breastfeeding <3 months, at least 1 parent with tertiary education, presence of parental psychiatric disorder, and nonmaternal primary caregiver) differentiated ADHD from non-ADHD controls with a sensitivity and specificity of 74% and 86%, respectively. We found a correlation between certain familial and environmental risk factors and ADHD. A 5-criterion multivariable logistic regression model may offer clinical guidance in ADHD diagnosis.CITATION: Van Dyk, L. et al. 2015. Familial-Environmental Risk Factors in South African Children With Attention-Deficit Hyperactivity Disorder (ADHD): A Case-Control Study. Journal of Child Neurology, 30(10):1327–1332, doi:10.1177/0883073814560630.

Tuberculous Meningitis: Barriers to Adherence in Home Treatment of Children and Caretaker Perceptions

INTRODUCTION In-hospital treatment of children with tuberculous meningitis (TBM) is not a feasible option in many resource-poor countries. Home-based treatment has shown to be a viable alternative. Adherence is an important factor determining success of treatment. OBJECTIVE Identify possible barriers to adherence of home-based treatment and caretaker perception of the disease. METHOD A qualitative study consisting of 11 in-depth semi-structured interviews was performed based on principles of the health belief model. RESULTS Barriers of adherence identified include poor understanding of the disease and transmission route, difficulty with medication administration and side effects, lack of access to the health-care facility, long waiting times and hidden costs of transportation. Caretakers showed good appreciation of the adverse effects of noncompliance and benefits obtained from taking treatment in the home environment. CONCLUSION Improved doctor-patient communication, information brochures, structural changes to hospital settings, provision of financial and peer support all contribute to optimal TBM home-based treatment.