J Neurol DOI 10.1007/s00415-014-7486-5 LETTER TO THE EDITORS Hippocampal dysplasia with balloon cells: case report and discussion on classification Fabio Rogerio • Marcia Elisabete Morita • Ana Carolina Coan • Carlos Alberto Mantovani Guerreiro • Helder Tedeschi • Roland Coras Luciano de Souza Queiroz • Ingmar Blu¨mcke • Fernando Cendes • Received: 29 July 2014 / Revised: 29 August 2014 / Accepted: 30 August 2014 Ó Springer-Verlag Berlin Heidelberg 2014 Dear Sirs, The International League Against Epilepsy (ILAE) has proposed a classification for focal cortical dysplasia (FCD), in which lesions with cortical dyslamination, dysmorphic neurons and balloon cells are considered as Type IIB. Blurring of gray–white matter junction and subcortical hyperintense T2/FLAIR signal are the main MRI findings of FCD Type IIB [1]. This classification, however, focuses mainly on neocortical alterations. Here, we report a case of hippocampal dysplasia with balloon cells (HD-bc) and discuss its valuation based on ILAE classification. A 12-year-old boy presented with short daily episodes of epigastric pain over 4 years, subsequently followed by episodes of confusion and oral automatisms identified as seizures. There was no history of perinatal complications, acquired deficits, febrile seizures or head trauma. Physical and neurological exams were normal. Electroencephalography showed interictal epileptiform discharges over the right temporal region. MRI revealed increased volume of F. Rogerio and M. E. Morita contributed equally to the manuscript. F. Rogerio (&) L. de Souza Queiroz Department of Pathology, State University of Campinas, UNICAMP, 13083-970 Campinas, SP, Brazil e-mail: [email protected] L. de Souza Queiroz e-mail: [email protected] M. E. Morita A. C. Coan C. A. M. Guerreiro H. Tedeschi F. Cendes Department of Neurology, State University of Campinas, Campinas, Brazil e-mail: [email protected] A. C. Coan e-mail: [email protected] right hippocampus with T2-weighted hyperintense signal (Fig. 1). Neuropsychological testing showed normal intelligence quotient and bilateral language representation. Based on these findings and refractoriness to four antiepileptic drugs (AEDs), a temporal lobectomy was performed. After 1 year of follow-up, he initially reported auras only and has been seizure-free for 6 months on AEDs. On neuropathological examination, hematoxylin and eosin-stained (H&E) paraffin sections (5 lm) showed cell loss, gliosis and scattered balloon cells in CA4. The remaining neurons were dysmorphic with occasional cytoplasmic vacuolization. Both cell types were distributed throughout the dentate gyrus hilum, where sparse perineuronal inflammatory infiltrates were noted. Dentate granular layer showed abnormally large neurons (Fig. 1). CA1 showed reduced pyramidal cell density and gliosis. There were no signs for neoplasia or acute inflammation. CA2 and CA3 evaluation was hampered by tissue disruption. The morphological findings based the diagnosis of HD-bc. HD-bc is uncommon; however, it may be underdiagnosed. To our knowledge, four cases were previously C. A. M. Guerreiro e-mail: [email protected] H. Tedeschi e-mail: [email protected] F. Cendes e-mail: [email protected] R. Coras I. Blu¨mcke Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany e-mail: [email protected] I. Blu¨mcke e-mail: [email protected] 123 J Neurol Fig. 1 Hippocampal dysplasia with balloon cells in a 12-year-old boy. Neuroimaging and pathological findings. Preoperative T1- (a) and T2-weighted (b) coronal MRI images showing enlargement of the right hippocampus with hypointense signal in T1 and hyperintense signal in T2 images with preservation of the external borders of the hippocampus. c–g Hematoxylin and eosin-stained (H&E) sections from CA4. c–f Dysmorphic neurons (enlarged and with irregular distribution of Nissl substance). c Panoramic view of CA4. Dentate gyrus (DG) is partially shown on the left. Note decrease in cell number in CA4, where only scattered abnormal neurons (d–f) are observed, some with cytoplasmic vacuolization (f). g Balloon cell (enlarged rounded cell, with glassy eosinophilic cytoplasm and vesicular nucleus; arrow) on gliotic background. h Immunohistochemistry for vimentin (1:100, Dako, M0725) highlights accumulation of intermediate filaments in the peripheral cytoplasmic region and thin processes of a balloon cell. i H&E section from CA4 showing 123 focal inflammatory infiltrate. Predominance of histiocytes (j) and T-lymphocytes (k) is shown by immunostaining for CD68 (1:1,000, Dako, M0814) and CD3 (1:100, Dako, A0452), respectively. l– m H&E sections from the dentate gyrus. l Granule cell dispersion. m Abnormally large granule cells with vesicular nuclei and prominent nucleoli. In addition (not shown), immunohistochemistry for neuronal markers [NeuN (1:1,000, Millipore, MAB377) and MAP2 (1:500, Invitrogen, MAB3418)] disclosed pyramidal and granule cell loss. SMI-32 (1:2,000, Covance, SMI-32R) immunostaining depicted cytoplasmic accumulation of nonphosphorylated neurofilament in both CA4 dysmorphic neurons and dentate granule layer. Onco-fetal antigen CD34 (1:100, Dako, M7165) was observed in endothelial cells only. CD20 (1:100, Dako, M0755)-positive lymphocytes were not detected. Cellular proliferation, as inferred from Ki-67 labeling (1:500, Dako, M7240), was low (\1 %). Bars 1 cm (a, b); 250 lm (c); 50 lm (d–i); 30 lm (j, k); 100 lm (l); 25 lm (m) J Neurol reported and all showed additional histological findings of hippocampal sclerosis (HS; neuronal depletion, gliosis and granule cell dispersion) [2–4]. Nevertheless, neuronal cytoplasmic vacuolization was described only in our case. Cytoplasmic vacuoles in neurons are observed in lesions of tuberous sclerosis complex (TSC), which also display scattered inflammatory infiltrates [5, 6]. However, our patient showed neither clinical nor imaging features of TSC. The pathophysiological mechanism underlying the present morphological findings is debatable. It might be hypothesized that the vacuolization and inflammatory foci are due to dysfunctional hippocampal circuitry and/or developmental abnormalities. Association of dysmorphic neurons and balloon cells with neuronal loss and gliosis suggests a developmental disorder. Indeed, balloon cells may coexpress neuronal and glial markers, and are considered incompletely developed cells [1]. A distinctive MRI feature in our patient was hippocampal enlargement and heterogeneous hypointense T1 and hyperintense T2 signal with preservation of external borders. The abnormally enlarged granule cells observed on neuropathological examination might contribute to such enlargement. The T2 hyperintensity is similar to MRI pattern seen on neocortical FCD Type IIB [1] and appears to correlate with detection of balloon cells exclusively in CA4. We believe that such neuroimaging features are relevant for the differential diagnosis between FCD and other hippocampal lesions. We faced the following diagnostic dilemma to classify this patient: FCD Type IIB or HS as part of dual pathology? We favor the first possibility due to the presence of balloon cells. Even though microscopic features of HS were observed, dual pathology would not be suitable as it refers to HS associated with a second principal brain lesion [1]. Recognition and clinical follow-up of similar cases will be essential to (1) determine whether treatment response and prognosis of patients with FCD in archicortex are similar to those in neocortex and (2) consider a specific classification for HD-bc. Conflicts of interest Dr. Rogerio, Dr. Morita, Dr. Coan, Dr. Tedeschi, Dr. Coras, Dr. Queiroz, Dr. Blu¨mcke and Dr. Cendes report no disclosures. Dr. Guerreiro received honoraria from serving on the scientific advisory board of Jansen-Cilag, GSK, Novartis, Abbott and UCB pharmaceutical companies. Ethical standards The present case report is in accordance with the standards of the local ethical committee. References 1. 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