In accordance with previous studies, this study found that decreased LOC, brainstem dysfunction and radiological infarction on CT are risk factors for poor long-term neurological outcome in children with TBM.
Detection of brainstem dysfunction is challenging but of utmost importance in comatose children with TBM both to guide therapy and to support outcome prediction. Brainstem dysfunction may lead to sensory and motor deficits, cranial nerve palsies, loss of consciousness, dysautonomia, and respiratory failure. There is often an overlap between the signs of raised ICP/hydrocephalus and brainstem dysfunction which necessities the need for neuro-imaging. A further complicating factor for accurate diagnosis is the fact that CT has a low sensitivity at diagnosing brainstem ischemia.
Similar to previous TBM outcome studies, this study also identified a trend towards poorer outcomes in younger children. Studies have shown that tuberculous stroke in young children have worse cognitive outcomes.[11] One explanation is that the classical signs of TBM are often absent in young children, and symptoms and signs tend to be non-specific. It has been shown that the younger the child, the less specific the signs and symptoms are of meningitis.[21] This invariably leads to diagnostic delays with a higher likelihood of advanced (severe) TBM disease. In addition, the first few years of life are a particularly important period of critical brain development and any injury during this period is likely to have irreversible longtime consequences. A key difference between young children and teenagers is that young childhood stroke results primarily in a changed ability to achieve, rather than lose, functional independence. The extent and severity of deficits across motor, sensory, cognitive, social, and behavioural domains may not be apparent in the short-term and it is likely that the development outcome in this group may even be worse. The mechanisms of infarction in TBM is not well understood and several varying pathogeneses have been suggested including (but not limited to) vasculitis, arterial thrombosis, and vascular proliferation. Perforating artery infarcts occurring in the middle cerebral artery (MCA) territory play an important role in TB stroke and the smaller diameter of such vessels in young children may increase vulnerability to vessel stenosis and eventually occlusion.[22] Despite infarctions being an important predictor of outcome in TBM, no effective therapeutic strategy is agreed on for their prevention. Both corticosteroids and aspirin have been evaluated, and to date neither have been shown to be an effective preventive therapy against infarctions.[23–27]
An interesting finding from the study is the poorer outcome in TBM children with left hemispherical stroke. This can be attributed to the fact that subcortical structures and mechanisms, specifically the basal ganglia and thalamus, actually underlie speech and language processing. There are only few studies in the literature that have investigated language outcomes after childhood stroke; none of them included children with TBM. In some of the studies the side of the lesion did not influence language, while others reported that considerable language or verbal memory difficulties were observed in left hemisphere lesions.[28] Haemodynamic differences have been demonstrated between the right and left carotid artery circulations,[29] In a study of premature babies followed up until 2 years of age, increased left cerebral blood flow velocity was associated with a better Bayley Mental Developmental Index score, with a postulation that adequate left cerebral blood flow velocity is especially important for language development.[30] Although our study did not demonstrate increased frequency of left-sided infarctions, there was significant association with worse IQ, indicating the importance of adequate left cerebral blood flow to the dominant hemisphere for later development, including language. Studies also show that bilateral cerebral infarction negatively impacts on neuroplasticity; a finding which explains the poorer outcome in study TBM children with bilateral cerebral infarcts.
Few controlled prospective studies exist regarding hydrocephalus outcomes; in their absence, largely retrospective studies must be used to evaluate the long-term consequences of hydrocephalus and its treatments. Tuberculous hydrocephalus (raised intracranial pressure), a very common complication of TBM, was not a predictor of poor developmental outcome in our study. This can be ascribed to the fact that most cases of tuberculous hydrocephalus communicating (non-obstructive) and responsive to diuretic therapy. A study at our institution utilizing transcranial Doppler imaging and serial lumbar CSF opening pressures at baseline, 3 days and 7 days, found that intracranial pressure normalized within 7 days after initiation of acetazolamide and furosemide in children with communicating hydrocephalus.[31]
There are limited data to guide standardized long-term neurocognitive management of both adults and children with TBM, partly due to the heterogeneity of assessment methods.[32] Other than for motor and sensory impairment, various standardized tools to assess neurodevelopment, neurocognition, functional ability and behavior have been proposed.[33] It is essential that standardized tools should be used in prospective studies, including comprehensive assessment of language development in young children, in order to build a body of data to inform evidence-based guidelines. What is undisputed, is that the long-term management of TBM in children is multidisciplinary and should be initiated as soon as possible to ensure better outcomes and quality of life.
Limitations of this study included a very small HIV-positive sample size which can be attributed to lack of HIV testing during the early period of the study. Accurate determination of treatment initiation time in TBM is notoriously difficult to assess as it relies on caregiver recall as well as the fact that the initial symptoms and signs of TBM are often subtle and non-specific. This was thus not assessed, which may have resulted in possible confounding. The study was conducted at a single site only which could have affected the generalizability of our findings. Outcomes relating to radiological infarction was assessed using only baseline CT imaging and small infarctions may have gone undetected. Only a sub-set had neuroimaging available for analysis. In addition, approximately 25% of children who have TBM without evidence of radiological infarction have been shown to develop new infarcts or enlargement of infarcts at 1 month of age.[34] This may have led to an underestimation of the number of infarcts. High resolution structural MRI is superior at identifying even small stroke lesions, but relating the size of lesions to clinical impairment and functional outcome is difficult especially since small lesions of the subcortical white matter or the brainstem can produce disproportionate clinical disturbances. The study focused purely on DQ/IQ as outcome measurement and the associations thus identified were non-specific to other outcome measures such as behaviour profiles and sensory impairments. Despite the abovementioned limitations, to the best of our knowledge, the study represents the largest data set (spanning 3 decades), to date, of cognitive outcome data in children with TBM. Additionally, only probable and definite TBM cases (according to TBM research case definition stipulations) were included.