Pediatric gliomatosis cerebri mimicking tubercular encephalitis.

Gliomatosis cerebri (GC) is a diffuse infiltrating glial neoplasm of astrocytic origin. GC in children is rare and difficult to diagnose, often presenting with a variety of signs and symptoms that may mimic myriad conditions. We discuss here the presentation and diagnosis of GC in a child who was initially treated on lines of tubercular encephalitis, with transient clinical relief and disappearance of enhancing component of the disease on magnetic resonance imaging. In this report, we highlight the limitations of clinical presentation and neuroimaging as well as the essential role of histological evaluation for the diagnosis of GC in children. Also is highlighted a more benign and protracted clinical course following radiotherapy in a subset of patients, with Ki index <10%, thereby stressing earliest possible diagnosis. A new prognostic classification can also be proposed for pediatric GC based on various parameters. Since these are rare cases, a combined effort is required for this.

Introduction

Gliomatosis cerebri (GC) was first described by Nevin[1] in 1938. GC is a diffuse glial neoplasm of astrocytic origin that is infiltrating and involving at least 3 cortical lobes.[2] Although it is exceedingly rare, GC can occur in children with a length of survival spanning from 6 months to 3 years.[3] However, a more benign presentation of GC is sometimes seen.[4] This case highlights the need for keeping the possibility of GC in mind when diffuse lesions show a slow response to standard treatment and an earlier tissue diagnosis in such cases. Radiotherapy leads to increased survival in this subset of patients.[5]

Case Report

A 12-year-old male presented to a pediatrician with a 1-month history of altered mental status complaining of a headache, neck pain, nausea/vomiting, and vision loss. Neurologic examination revealed bilateral papilledema and decreased visual acuity with right sided hemiparesis. Magnetic resonance imaging (MRI) showed extensive white matter edema in the right temporal and parietal lobes with an enhancing component in the right mesial temporal lobe, mimicking a tubercular granuloma [Figure 1]. Cerebrospinal fluid (CSF) showed albumino-cytologic dissociation and cultures were negative for viral, bacterial, and fungal agents. The child was started on alternating triple therapy (ATT) and intravenous dexamethasone for suspected tubercular encephalitis and appeared to improve clinically showing some interval improvement of the white matter edema on MRI. The strange finding on follow-up MRI was the disappearance of enhancing component on this treatment [Figure 2]. However, as the child relapsed, he was referred to us after 6 months. Repeat MRI again showed the absence of any enhancing component and presence of significant edema involving all three lobes and deep nuclei of the brain. Hence, a decision was taken to obtain a tissue diagnosis by right frontal craniotomy and biopsy. Stereotactic biopsy was not done in view of the absence of any enhancing component and financial constraints. Histopathology revealed round to oval cells with subpial, perineuronal and perivascular spread and mild pleomorphism. Focal oligodendroglial cells were also seen. There was no necrosis, brisk mitosis and microvascular proliferation. The cells were positive for glial fibrillary acidic protein. CD68 and CD45 were absent. Ki index was 6–8%. The child was treated with three-dimensional conformal whole brain radiation therapy – 5400 cGy/30 fractions over 6 weeks. The child has shown consistent and progressive improvement since after then.

Figure 1

Contrast-enhanced magnetic resonance imaging depicting an enhancing component in right mesial temporal lobe, mimicking a tubercular granuloma

Figure 2

Follow-up contrast-enhanced magnetic resonance imaging, after 3 months of steroid therapy and alternating triple therapy, showing disappearance of enhancing component

Discussion

GC in children is rare and difficult to diagnose, often presenting with a variety of signs and symptoms that may mimic encephalitis and other diffusely infiltrative conditions.[6] Because tuberculosis is endemic in India and central nervous system involvement very frequent, these similar presentations can confound a diagnosis of GC and delay crucial treatment. Both GC and tubercular encephalitis can present with a headache, vomiting and seizures as well as other often vague or site specific neurologic signs. MRI is the imaging modality of choice for GC; however, both conditions are represented as hyperintense lesions on T2-weighted and fluid-attenuated inversion recovery images with variable contrast enhancement rendering imaging studies rather nonspecific.[7] The relative preservation of the blood-brain barrier is the most likely reason for nonenhancement on postcontrast T1-weighted images in most of the cases. Neoplastic cells are rarely identified in the CSF of patients with GC; although, in the absence of malignant cells, normal CSF studies may be useful in ruling out viral, bacterial and fungal etiologies. Evidence of inflammation including pleocytosis and/or increased protein concentrations in CSF may point toward a diagnosis of tubercular involvement. However, the diagnosis of GC or exclusion thereof requires radiologic-pathologic correlation. The most confusing aspect of this case was the disappearance of enhancing component after starting ATT, which was probably due to steroids.

Obtaining tissue for pathologic review is ultimately necessary to confirm the diagnosis of GC. In children, a biopsy might be delayed in favor of treatments for inflammatory encephalitis. These treatments include steroids and anticonvulsants, which unreliably mask symptoms of GC falsely confirming a diagnosis of tubercular encephalitis. As GC cannot be excluded in these patients without a biopsy, the physician must risk either delaying treatment in a child with GC or performing an unnecessary invasive brain biopsy on a child with other pathologies. This case report highlights the fact that when there is a slow clinico-radiological improvement after starting ATT and in view of extensive edema involving all the three lobes, histological evaluation should be done as early as possible. In GC, the glioma cells migrate through the normal parenchyma, collect just below the pial margin (subpial spread), surround neurons and vessels (perineuronal and perivascular satellitosis), and migrate through the white matter tracts (intrafascicular spread).[8] This may reflect the glial cell's reacquisition of primitive migratory behavior, leading to the spread of individual tumor cells diffusely over long distances and into disparate brain regions. The widespread involvement of near-normal-looking astrocytes has led some neuropathologists to conclude that accurate diagnosis cannot be made without a histopathologic study of the entire brain. Although most patients with GC undergo disease progression within 1 year, early diagnosis and treatment with radiation have been shown to benefit patient outcomes.[9] There is a small subset of patients with a favorable outcome and increased survival after radiotherapy. The most important prognostic indicator is Ki-67 index. Kim et al.[4] reported that the tumor Ki-67 labeling index was the only predictor of survival in patients with GC, with increased survival, especially if the Ki-67 index is below 10%.[4]

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Conflicts of interest

There are no conflicts of interest