A 17‐year‐old male with chronic epilepsy status post remote functional hemispherectomy

Access at https://isn-slidearchive.org/?col=ISN&fol=Archive&file=ID-1981812.svs. A 17-year-old male with infant-onset epilepsy refractory to multiple antiseizure medications had a history of right functional hemispherectomy performed at 6 months of age after demonstration of seizure activity localized to the right frontal lobe. A brain MRI performed at 4 months of age revealed a mildly enlarged right lateral ventricle but was otherwise unremarkable. Pathology from the surgical specimen reportedly identified a focal cortical dysplasia. Follow-up visits over the years showed that the patient was nonverbal and wheelchair-dependent, with left homonymous hemianopsia and spasticity, but the epilepsy was mostly controlled with only rare brief seizures. At 17 years of age, he was found unresponsive and pronounced dead at home. Recent clinical history included a respiratory illness accompanied by vomiting, fever, and fatigue. A complete autopsy was performed, and bronchopneumonia of the left lung was established as the likely cause of death. Gross examination of the brain revealed asymmetric cerebral hemispheres due to reduced volume of the right hemisphere, which contained a large area of cavitation spanning the frontal and temporal lobes and sparing the basal ganglia and thalamus, consistent with the history of functional hemispherectomy (Figure 1) (Box 1). Histopathological examination of sections from both hemispheres showed numerous haphazardly arranged astrocytes with eosinophilic ameboid to granular cytoplasmic inclusions (Figure 2A,B), variably distributed throughout all layers of the neocortex, and not present in deep gray matter structures. The inclusions were positive for GFAP (Figure 2C) and negative for NeuN (Figure 2D), OLIG2, PU.1, PAS, and neurofilament. There were increased numbers of corpora amylacea, highlighted by PAS. Hyaline protoplasmic astrocytopathy. Hyaline protoplasmic astrocytopathy (HPA) is a rare, underrecognized, and incompletely understood neuropathologic entity, with fewer than 70 cases reported in the literature, including both surgical and autopsy specimens [1]. First described by Alois Alzheimer in 1910 under a different designation [2], HPA has been associated with epilepsy, particularly in the setting of Aicardi syndrome, neurodevelopmental disorders, and less commonly, dementia. Histopathologically, HPA is characterized by hyaline ameboid to granular astrocytic inclusions, mostly juxtanuclear, distributed throughout all cortical layers. The affected astrocytes are often enlarged and haphazardly oriented, and the inclusions are sharply demarcated and eosinophilic, distinguished from corpora amylacea or neuronal storage material by their cellular localization. Inset of Figure 2B shows a reproduction of Alzheimer's original publication showing abnormal ameboid astrocytes. The hyaline astrocytes are rarely reported in the superficial white matter, hippocampus, and basal ganglia, and are absent in other deep gray matter, cerebellum, brainstem, or spinal cord [3]. An association between HPA and focal cortical dysplasia (FCD) has been described in a series of patients with chronic seizures [3], and has been illustrated in a case presented at the 2008 American Association of Neuropathologists Diagnostic Slide Session (Case 5; https://neuro2.pathology.pitt.edu/dss/year/2008). This relationship is relevant to the present case, in which the original hemispherectomy specimen was diagnosed as containing focal cortical dysplasia, although HPA was not reported at that time. The immunoprofile of the inclusions is variable among reported cases. While many cases show weak or negative GFAP staining, others, including the present case, demonstrate clear GFAP positivity. Stains that have been variably reported as positive in HPA include SOX9, filamin A, alphaB-crystallin, catalase, and carbonic anhydrase I [1], which highlight the unclear composition of the astrocytic inclusions and the absence of a unique marker for HPA. While early reports focused on strong filamin A labeling and proposed HPA to represent a pathologic process in the filaminopathy spectrum, later series showed more variable staining in inclusions and noted that reactive astrocytes can also express filamin A in some patients [1]. Furthermore, proteomic studies identified catalase and carbonic anhydrase I as the most differentially expressed proteins in the inclusions, and no pathogenic FLNA mutations have been detected in HPA patients [1]. Ultimately, the diagnosis of HPA is morphologic, based on the characteristic cytoplasmic inclusions and their distribution within the cortex. Despite the unclear pathogenesis, awareness and recognition of HPA is important to distinguish it from mimics such as inclusion disorders that may occur in the context of epilepsy. Claire Voyles, Elliot Stalter, Melissa M. Blessing, and Osorio Lopes Abath Neto collected data. Claire Voyles and Osorio Lopes Abath Neto drafted the manuscript. Claire Voyles, Elliot Stalter, Melissa M. Blessing, and Osorio Lopes Abath Neto reviewed and edited the draft, and approved the final submitted version. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.