Epilepsy Meet Am Soc Stereotact Funct Neurosurg, Snowbird, Utah, 1999 Stereotact Funct Neurosurg 1999;73:88–94 Surgical Management of Intractable Epilepsy in Children with Hemophilia David John Yeh Mark Lee Yong D. Park Joseph R. Smith Alton L. Lightsey, Jr. Departments of Surgery (Neurosurgery), Neurology (Child Neurology) and Pediatrics (Hematology and Oncology), Children’s Medical Center, Medical College of Georgia, Augusta, Ga., USA Key Words Hemophilia W Epilepsy W Intracranial hemorrhage W Hemispherotomy W Epilepsy surgery Abstract Intracranial hemorrhage occurs in 2–8% of patients with hemophilia and can result in neurologic sequelae including seizure disorders. There is a paucity of data concerning the surgical treatment of epilepsy in children with hemophilia. We review our experience with 2 children who developed medically refractory seizure disorders. Both children underwent hemispherotomy, at 18 months (case 1) and 13 years of age (case 2), respectively. Perioperative management included continuous factor replacement. Both children tolerated surgical intervention without complications or increased neurologic deficit. Case 2 showed a 90% reduction in seizure frequency, and case 1 is seizure free. Surgical management of intractable epilepsy in children with hemophilia is safe and effective. Copyright © 2000 S. Karger AG, Basel © 2000 S. Karger AG, Basel 1011–6125/99/0734–0088$17.50/0 Fax + 41 61 306 12 34 E-Mail karger@karger.ch Accessible online at: www.karger.com/journals/sfn www.karger.com David J. Yeh, MD Department of Surgery-Neurosurgery Medical College of Georgia, 1120 15th Street, BIW 348 Augusta, GA 30912 (USA), Tel. +1 706 721 3071 Fax +1 706 721 5551, E-Mail dyeh@mail.mcg.edu Downloaded by: University of Cambridge 131.111.164.128 - 1/7/2020 2:08:22 PM ABC Introduction Hemophilia is the X-linked inherited deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B) and occurs in approximately 1 in 5,000 male births [1]. Clinical findings associated with this bleeding disorder include prolonged perioperative bleeding and intracranial hemorrhage (ICH). In hemophilia A, the minimum level of factor VIII required for hemostasis is 30% of normal. Current treatment guidelines for these patients during surgical bleeding or life-threatening hemorrhage include intravenous infusion of factor VIII raising levels to 80–120% of normal. The half-life of factor VIII concentrates averages 9–18 h; thus, continuous infusion is often necessary [2]. ICH occurs in approximately 2–8% of patients with hemophilia and accounts for 25–35% of bleeding deaths in patients with factor VIII or IX deficiency, despite cryoprecipitate and factor replacement therapy [3]. The average age of onset of ICH has been reported to be between 14 and 16 years, with a range from 1 week to 74 years. The site of hemorrhage can be subarachnoid, intraventricular or intracerebral, or more commonly epidural or subdural [3, 4]. Arteriovenous malformation, cranial hemophilic pseudotumor (encapsulated hematomas) and spontaneous intraspinal hemorrhage are extremely rare forms of central nervous system bleeding in hemophilia also reported in the neurosurgical literature [5–7]. Objective and Methods Guidelines for surgical intervention in patients with severe hemophilia and ICH have been described [8–13]. ICH leads to chronic neurologic sequelae including seizures and intellectual and motor impairment in approximately 50% of survivors [5]. The proportion of these patients who will develop intractable epilepsy despite antiepileptic drugs (AEDs) is unknown. There is little documentation of the safety or efficacy of epilepsy surgery in the population of hemophiliacs with seizure disorders resulting from ICH. We reviewed 101 children evaluated in the Pediatric Hemophilia Center of Georgia, Augusta, Ga., born between January 1, 1980, and December 31, 1997, and identified 4 children who had suffered ICH with subsequent seizure disorders. Two children were managed surgically. Case 1 D.S. is a 24-month-old Caucasian male with severe hemophilia A (factor VIII !1%). He suffered 4 episodes of ICH at 5 weeks of age resulting in right-sided focal seizures. A ventriculoperitoneal shunt for obstructive hydrocephalus was placed at 3 months. At 7 months, he was diagnosed with infantile spasms (4/day) refractory to multiple AEDs. D.S. received prophylactic factor VIII (1,000 units, 3 times per week). On neurologic exam, D.S. had mild right hemiparesis. Denver testing showed mild developmental delays in motor and social activities. Ictal electroencephalogram (EEG) showed frequent bursts of polyspike waves over both hemispheres during spasms with a diffusely desynchronized background – Stereotact Funct Neurosurg 1999;73:88–94 89 Downloaded by: University of Cambridge 131.111.164.128 - 1/7/2020 2:08:22 PM Surgical Management of Intractable Epilepsy in Children with Hemophilia Fig. 1. T1-weighted (a, c, d) and FLAIR (b) magnetic resonance images showing multiple porencephalic cysts in the left hemisphere. Agenesis of the anterior corpus callosum was noted. an unlocalized pattern. [18F] Fluorodeoxyglucosepositron emission tomography (FDGPET) showed multiple photopenic regions within the left hemisphere with relatively normal areas in the left inferior frontal lobe, inferior parietal lobe and temporal lobe. The right hemisphere revealed normal FDG uptake. Plans were made for multiple left hemispheric corticectomies (lesionectomy) because the left central cortex and temporal lobe were relatively normal by magnetic resonance (fig. 1) and FDG-PET imaging in the presence of mild right hemiparesis. A left frontotemporal craniotomy was performed. Functional motor mapping demonstrated no movement in the right face, arm or hand despite maximal stimulation strength. Preresection electrocorticogram (ECoG) revealed diffuse multifocal spike activity over the opercular region as well as the postcentral gyrus and temporal neocortex. The corpus callosum was approached through the left frontal encephalomalacic cyst and was completely divided. Because ECoG over the left parietal and temporal lobes showed continuous epileptiform discharges, the hemispherotomy was completed (fig. 2). Stereotact Funct Neurosurg 1999;73:88–94 Yeh/Lee/Park/Smith/Lightsey Downloaded by: University of Cambridge 131.111.164.128 - 1/7/2020 2:08:22 PM 90 Fig. 2. Intraoperative photographs. Preresection labels indicate areas of frequent epileptiform discharges detected by ECoG. Postresection view after subpial hemispherotomy. Preoperatively, the patient was transfused factor VIII to 180% normal. The procedure lasted 8 h with 200 ml blood loss. Intraoperative factor levels were closely monitored and supplemented. Continuous factor infusion was titrated to maintain levels between 80 and 120% during postoperative days (POD) 1–4. Stress dose intravenous dexamethasone was given the night before surgery and over POD 1. Despite intravenous H2 receptor antagonist therapy, a small amount of upper gastrointestinal (UGI) bleeding developed on POD 1. The Stereotact Funct Neurosurg 1999;73:88–94 91 Downloaded by: University of Cambridge 131.111.164.128 - 1/7/2020 2:08:22 PM Surgical Management of Intractable Epilepsy in Children with Hemophilia Fig. 3. T2- (a, b) and T1-weighted (c, d) magnetic resonance images showing diffuse cystic encephalomalacic changes involving the right hemisphere. Dilation of the right lateral ventricle was noted. patient was transfused, and the bleeding episode resolved with conservative therapy. During POD 5–7, factor VIII levels were maintained at 60% with daily boluses. The patient was discharged on POD 8, resuming daily infusion of 1,000 units of factor VIII. Final surgical pathology reported diffuse astrocytic and subependymal gliosis with areas of focal glial scarring. Six months postoperatively, the patient remains seizure free without further neurologic deficit. Case 2 J.P. is a 13-year-old Caucasian male with severe hemophilia A and left hemiparesis secondary to intraparenchymal hematoma at 5 weeks of age which was surgically evacuated. At 6 years, he developed intractable generalized tonic-clonic seizures (30–40/day). Neuro- Stereotact Funct Neurosurg 1999;73:88–94 Yeh/Lee/Park/Smith/Lightsey Downloaded by: University of Cambridge 131.111.164.128 - 1/7/2020 2:08:22 PM 92 logical examination revealed a left hemianopsia and left spastic hemiparesis. Preoperative continuous video EEG monitoring revealed epileptiform activity involving the right and left frontal and vertex areas. MR revealed diffuse cystic encephalomalacia in regions supplied by the middle and anterior cerebral arteries with enlargement of the right lateral ventricle (fig. 3). Wada testing indicated left language dominance with appropriate asymmetry in object memory. Serial neuropsychological testing indicated a progressive decline in full intelligence quotient over 2 years prior to surgery. PET imaging revealed a loss of nearly all cortical metabolism in the right hemisphere with a small nidus of preserved activity in the right superior frontal lobe. Based on hemiparesis, right structural defect and seizure history, hemispherotomy was planned. A right frontotemporal-parietal craniotomy and an en bloc perisylvian corticectomy involving the temporal and frontoparietal operculum were performed. The remainder of the procedure was intraventricular. The dome of the amygdala was removed by subpial aspiration, and the hippocampus, parahippocampal gyrus and fornix were disconnected posteriorly. The corpus callosum was transected posteriorly to anteriorly, and the inferior cingulate gyrus was removed subpially. The subcallosal gyrus and posterior orbitofrontal cortex were removed by subpial dissection completing the hemispherotomy. Forty-five units/kg of recombinant factor VIII were infused the night prior to surgery. Postoperatively, the factor VIII activity level was maintained between 80 and 120% normal with continuous infusion titrated from a starting point of 2–4 units/kg/h. Postoperatively, the patient was placed on previous AEDs. Intravenous dexamethasone was given the night before surgery and tapered over 9 days. Postoperatively, the patient developed a subgaleal fluid collection, which appeared to be mixed cerebrospinal fluid (CSF) and hematoma on computerized tomography imaging. On POD 10, generalized tonic seizures, different than preoperative seizures, were observed. At discharge on POD 22, the patient was experiencing 1–2 seizures/day with complete resolution of the fluid collection. Thirteen months postoperatively, a 190% reduction in the number of seizures is observed (1/week). Neurological exam and neuropsychological testing reveal no new deficits. Results/Conclusion Four patients were identified who suffered ICH with a subsequent seizure disorder. One patient became seizure free and another patient was seen to have a chronic seizure disorder controlled with AEDs. Two patients had intractable epilepsy with diminished quality of life and were treated with hemispherotomy leading to excellent results. Complications seen included the development of mild UGI bleeding in case 1 and a subgaleal CSF/hematoma fluid collection in case 2. Both complications resolved with conservative therapy. Discharge disposition in case 2 was delayed by postoperative seizures which responded to titration of AEDs. We conclude that with close perioperative monitoring of factor VIII levels and aggressive factor replacement therapy, surgical intervention is a safe and effective alternative for treating intractable seizure disorders resulting from ICH in the hemophiliac population. Stereotact Funct Neurosurg 1999;73:88–94 93 Downloaded by: University of Cambridge 131.111.164.128 - 1/7/2020 2:08:22 PM Surgical Management of Intractable Epilepsy in Children with Hemophilia References 2 3 4 5 6 7 8 9 10 11 12 13 94 Hassouna HI: Laboratory evaluation of hemostatic disorders; in Penner JA, Hassouna HI (eds): Coagulation disorders II. Hematol Oncol Clin North Am 1993;7:1161. Lusher JM, Warrier I: Hemophilia A. 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