Expanding the Horizons of mTOR Inhibitors for Treating Subependymal Giant Cell Astrocytomas with Obstructive Hydrocephalus

Dear Editor,Recently, Weidman et al. [1], from the Hospital for Sick Children, Toronto, published an interesting article on the role of mTOR inhibitors (mTORi), in the management of obstructive hydrocephalus (OH) associated with subependymal giant cell astrocytoma (SEGA) in patients of tuberous sclerosis. The authors should be congratulated for this intrepid step taken in the treatment of OH due to SEGA, with mTORi exclusively. This situation might be otherwise considered for an emergency cerebrospinal fluid (CSF) diversion in the neurosurgical community [1].The classical indications for surgery in SEGA have been the following: OH, increasing lesion size, hemorrhagic and cystic degeneration. OH can be dealt with definitive surgery, removing the SEGA with or without CSF diversion. The complications and the requirement of the CSF diversions following removal of the SEGA may be high (approximately 50%) as reported in the previous literature (prior to 2009, as per the study quoted by the authors). This led the authors to consider exclusive medical management with mTORi in patients harboring SEGA with OH, thereby avoiding the surgery.We like to reiterate the fact that surgical results have improved in the recent times, owing to the technological advances, especially with the endoscopic resections. Recently, the use of minimally invasive stereotactic-guided ablations, using either lasers or radiofrequency thermocoagulations, have revolutionized the treatment of the lesions arising from critical structures deep inside the brain with minimal morbidity and excellent outcomes [2-4]. On the contrary, Desai et al. [2], in another recently published study, successfully managed 3 patients of SEGA using laser ablation with no morbidity and excellent outcomes. Here, the authors performed surgery (stereotactic laser ablation with endoscopic septum pellucidotomy) for patients of tuberous sclerosis, harboring SEGA in the vicinity of foramen of Monroe, in the absence of hydrocephalus. They advocated prophylactic surgery to prevent development of hydrocephalus in the future. None of the patients in their series required a CSF diversion during the follow-up. This is contrary to the approach propounded by Weidman and colleagues [1]. However, the sample size was extremely small and the other important aspect was that none of these patients had hydrocephalus preoperatively. The surgery was performed preemptively to avoid the future development of OH [2].Weidmann et al. [1] have used ventricular dimensions for defining the hydrocephalus and accordingly classified moderate/severe ventriculomegaly as hydrocephalus. As per the criteria used which is not even validated, 8 patients had hydrocephalus; 5 of them had headache, nausea, and vomiting; and only 3 patients showed papilledema. Presence of papilledema is a definite sign of raised intracranial pressure, thereby reducing the effective sample size. There is no mention regarding the periventricular lucency (indicating transependymal flow), shape of the frontal horns, patency of the subarachnoid space, dilatation of the optic nerve sheath, and fullness of the brain on MRI brain. The diagnosis of hydrocephalus is therefore dependent on multiple factors and not just the ventricular dimensions as categorized by the authors. All these factors have a significant bearing in considering surgical treatment of the hydrocephalus. There is also no mention regarding the grading and the status of the papilledema in the follow-up [1]. Therefore, nearly 50% of the patients labelled as hydrocephalus might not be based on fair definition of the hydrocephalus. The authors do not make any mention regarding the patients undergoing surgery for SEGA with OH during the study period, thereby leading to a selection bias.The other critical aspect which needs to be addressed is the duration of the onset of the therapeutic benefit of mTORi from its initiation. The authors mention the symptomatic improvement was immediate in one of the patients; therefore, it was decided to continue the medical therapy despite severe hydrocephalus. This finding needs to be validated in a large patient pool and cannot be generalized, in view of the risk of progressive papilledema leading to visual deterioration. The other aspect which needs to be addressed is the time of onset of action, in terms of reduction of tumor size. The documentation of visual acuity/fields and fundus findings after the initiation of the therapy with mTORi and during the follow-up period would have been more appropriate.The other limitation of this study is the prolonged therapy with mTORi. It is currently a matter of debate on the duration of such therapy and also the associated risk of tumor regrowth following stopping of these medications. The prolonged therapy may not be economically feasible in resource limited countries. Hence, a one-time surgery using minimally invasive techniques may be more economical considering the cost of prolonged therapy with mTORi [5].Although this study shows promising results, it is marred by the small sample size and lack of an appropriate design. We are of the opinion that the use of mTORi in patients without OH may be more appropriate with our current understanding. The recommendation on the use of mTORi in patients of SEGA with OH should be considered with extreme caution. Well-designed studies involving patients with SEGA and OH undergoing medical management with mTORi in future should be awaited prior recommending stand-alone medical therapy for this subgroup of patients.The authors have no conflicts of interest to disclose.The authors did not receive any funding.Concept and drafting: Ramesh S. Doddamani, Rajesh Kumar Meena, Raghu Samala, and Mohit Agrawal. Critical review and editing the draft: Ramesh S. Doddamani, Sarat P. Chandra, and Manjari Tripathi.

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