The child was developmentally normal till 10 months of age when she presented to a hospital outside with fever and seizures. MRI brain showed subtle T2/Flair hyperintensities in bilateral frontal lobes. She was diagnosed with acute encephalitis syndrome and empirically treated with intravenous acyclovir and ceftriaxone. After the illness, the child was noted to have developmental delays predominantly in socio-cognitive and motor milestones. Neuroimaging on follow-up showed post-encephalitic changes with gliosis in bilateral frontal regions. She was started on rehabilitation therapy and began gaining developmental milestones; however, she was later lost to follow-up.
At 12 years of age, she was admitted to our hospital with a respiratory infection. On assessment, she was found to have a global developmental delay. She could walk but not run and needed help climbing up and down the stairs. Her language and cognitive milestones were more significantly affected than her motor milestones. On clinical examination, there was no facial dysmorphism or neurocutaneous markers. Her general examination was normal. Neurological examination showed mild hypertonia and hyperreflexia of all four limbs. The child developed seizures after hospitalization which needed multiple antiseizure medications (ASM) for management. MRI brain showed an area of gyral swelling, hyperintensity, and patchy enhancement in the right high parietal lobe along with bilateral frontal and left temporal lobe gliosis attributed to previous illness (Fig. 1). CSF analysis revealed elevated proteins with 4 lymphocytes. The child was managed with ceftriaxone and ASM, with both seizures and respiratory complaints settling.
Legend: (Images at first presentation– clinical presentation of respiratory infection and seizures) Axial T2 weighted images (a to c) and post gadolinium T1 fat saturated images (d to f) show area of gyral swelling, hyperintensity and patchy enhancement (arrowheads) in right high parietal lobe. In addition, there are large areas of gliosis involving both frontal lobes and left temporal lobe (arrows). Note that the regions of gliosis show no post gadolinium enhancement
A month later, she was readmitted with right focal seizures in the form of twitching of eyes, persistent right-sided gaze, and jerking of the right upper limb. MRI brain demonstrated increased in ill-defined cortical-based enhancing lesions in the right temporoparietal region with diffuse pachymeningeal thickening (Fig. 2). Clinico-radiological differential diagnosis of tumefactive demyelination and chronic encephalitic infections were considered. Blood counts, HIV testing, and immunoglobulin profile were normal. CSF cell count and biochemistry were inconclusive. CSF-PCR for Burkholderia pseudomallei and HSV type 1&2 were negative. Anti-aquaporin-4 antibody and anti-myelin oligodendrocyte glycoprotein antibody were negative. Given the persistent seizures, a trial of intravenous methylprednisolone pulse therapy was given and her seizures gradually decreased. As there was a favorable clinical response, oral steroids were started which were later tapered off.
Legend: (Images after one month– clinical presentation with status epilepticus) Axial T2 weighted images (a to c) and post gadolinium T1 fat saturated images (d to f) show increase in gyral swelling, hyperintensity and enhancement (arrowheads) in right parietal lobe which has extended to involve the right temporal lobe along with diffuse pachymeningeal thickening. Stable areas of gliosis involving both frontal lobes and left temporal lobe (arrows) are noted
On follow-up, she presented with loss of previously attained milestones and seizures. MRI brain repeated at this stage showed an increase in the extent and severity of gliosis involving bilateral frontal, left temporal, and right parietal-temporal lobes spreading to the opposite hemisphere via the corpus callosum. There was also the presence of new gyral enhancement involving the gliotic regions in both frontal lobes along with persistent pachymeningeal thickening. These bilateral frontal changes were suggestive of a tumor-like lesion or a chronic granulomatous lesion (Fig. 3). As the investigations done so far were inconclusive, a ‘lesional’ brain biopsy was considered. Histopathology of the brain biopsy tissue revealed microglial infiltration suggestive of inflammation (Fig. 4a and b). Viral PCR and immuno-histochemistry performed on the tissue were strongly positive for HSV type 1 (Fig. 4c). The child received intravenous acyclovir and steroids for 21 days. After starting acyclovir, there was an improvement in her clinical condition and the seizures were controlled as well.
Legend: (Images after 2 months of initial presentation– clinical presentation with neuro-regression) Axial T2 weighted images (a to c) show increase in extent and severity of gliosis involving both frontal lobes, left temporal lobe and right parietal-temporal lobes (arrows). Post gadolinium T1 fat saturated images (d to f) show reduction in enhancement in right parieto-temporal lobe but presence of new gyral enhancement involving the gliotic regions in both frontal lobes along with persistent pachymeningeal thickening (arrowheads)
Legend: Hematoxylin and Eosin (H&E) stained section of neural parenchyma at 400x magnification, exhibiting chronic inflammation characterized by a dense lymphocytic infiltrate and surrounding histiocytic infiltration Hematoxylin and Eosin (H&E) stained section of neural parenchyma at 400x magnification, exhibiting histiocytic aggregates showing vague, ill-defined granulomatous inflammatory changes IHC HSV, brain, 400x: Focal positive staining in neurons, demonstrating viral inclusions and cytopathic changes indicative of Herpes simplex virus encephalitis
Given the unusually persistent picture of the viral encephalitis, an underlying genetic immunodeficiency patho-mechanism was considered, and an extensive immunodeficiency workup was initiated. The T cell and B cell total and subset populations were normal and immunoglobulin levels were also within normal ranges. The immunoglobulin functional assay couldn’t be performed due to logistic issues. Since the immunoglobulin workup was inconclusive, clinical exome sequencing (CES) was performed. CES revealed heterozygous micro-deletion in chromosome 22, suggestive of DiGeorge syndrome (DGS). While the child did not have any craniofacial features suggestive of DiGeorge syndrome, she did have a history of recurrent respiratory infections indicative of the underlying immunodeficiency. Also, the computed tomography thorax done at 12 years of age for respiratory complaints did not show a thymic shadow. 2D ECHO was performed to rule out any cardiac defects and showed a normal study. There was no parental consanguinity and the parents are phenotypically normal and asymptomatic. However, genetic testing was not done for the parents due to logistic reasons. Since no other specific clinical manifestations of DGS were present in this patient, CES helped us establish the diagnosis.
The child was continued on oral acyclovir prophylaxis and started regaining milestones slowly (Table 1). MRI brain was repeated after 6 months of acyclovir therapy and demonstrated a significant reduction in the size of the lesion (Fig. 5). At 2 years follow-up, the child is seizure-free, walking with some support, and speaking in short sentences.
Legend: (Images on follow-up)Axial T2 weighted images (a to c) show increase in volume loss and gliosis involving both frontal lobes, left temporal lobe and right parietal-temporal lobes (arrows). Post gadolinium T1 fat saturated images (d to f) complete resolution of enhancement in right parieto-temporal lobe and reduction in thickness of gyral enhancement in the gliotic regions in both frontal lobes (arrowheads)