- Email: [email protected]
Prenatal Diagnosis of Hemimegalencephaly
Peer-Review Short Reports
Prenatal Diagnosis of Hemimegalencephaly Shih-Shan Lang1,2, Ethan Goldberg3, Deborah Zarnow4, Mark P. Johnson5, Phillip B. Storm1,2, Gregory G. Heuer1,2
Key words Cortical dysplasia - Fetal imaging - Hemimegalencephaly - Hemispherectomy - MRI - Neuronal migration -
- BACKGROUND:
In recent literature, there have been case reports of prenatal diagnosis of hemimegalencephaly, an extremely rare entity characterized by enlargement of all or portions of 1 cerebral hemisphere and intractable seizures. A unique case is presented of hemimegalencephaly of a fetus diagnosed in utero.
- METHODS:
Abbreviations and Acronyms HME: Hemimegalencephaly MRI: Magnetic resonance imaging From the 1Department of Neurosurgery, Hospital of the University of Pennsylvania; and 2Division of Neurosurgery, 3Division of Neurology, 4Department of Radiology, and 5Department of Surgery, Center for Fetal Diagnosis and Treatment, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA To whom correspondence should be addressed: Shih-Shan Lang, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2014). http://dx.doi.org/10.1016/j.wneu.2013.09.028 Journal homepage: www.WORLDNEUROSURGERY.org
A 27-year-old woman presented at 32 weeks’ gestation for fetal magnetic resonance imaging after an abnormal fetal ultrasound. Fetal magnetic resonance imaging showed hemimegalencephaly of the left cerebral hemisphere with abnormal gyration.
- RESULTS:
The patient was born via cesarean section at 39 weeks’ gestation. He had continuous infantile spasms and partial-onset seizures starting on day 1 of life, and electroencephalography showed burst suppression. The patient’s seizures were initially managed with antiepileptics, prednisolone, and a ketogenic diet; however, he was hospitalized multiple times because of status epilepticus. At 6 months of age, he underwent a successful anatomic left hemispherectomy.
- CONCLUSIONS:
In utero diagnosis of complex developmental brain anomalies allows a multidisciplinary approach to provide optimal prenatal patient treatment and parental counseling.
Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2014 Elsevier Inc. All rights reserved.
INTRODUCTION Hemimegalencephaly (HME) is a congenital brain malformation characterized by the overgrowth and enlargement of all or parts of a cerebral hemisphere; it can rarely involve the brainstem or cerebellar hemisphere (4, 5, 7, 8, 19-21, 23, 27, 39, 40). This disorder was first mentioned in the literature in the 1830s based on autopsy reports, but it was not described in clinical and pathologic detail until the 1960s (7, 8, 27, 36). HME can occur as part of a genetic syndrome, such as epidermal nevus syndrome, Proteus syndrome, or tuberous sclerosis, or it can occur in isolation (5, 9, 12, 14, 15, 20, 23, 38). The underlying pathogenesis is thought to be due to an abnormality in cortical development and neuronal migration and possibly an early disturbance in cellular lineage and differentiation (7, 9, 14, 20, 21, 29). Radiologically, HME manifests as an enlarged unilateral cerebral hemisphere with abnormal gyration and ventriculomegaly that can be evaluated by
ultrasound, computed tomography, or magnetic resonance imaging (MRI) (2, 4, 15, 17, 19, 20, 23, 33). Clinically, the enlarged cerebral hemisphere acts as a focus for seizures that are often intractable and poorly controlled with antiepileptic medications. In addition to epilepsy, patients typically have developmental delay and psychomotor retardation within the first few months of life (6, 17, 38, 40). For patients with intractable epilepsy, hemispherectomy is the surgical option for seizure control (6, 10, 16, 24, 25, 41, 42). Rare reports in the literature have focused on fetal imaging in patients with HME; however, in most cases, the diagnosis was made at autopsy (1, 29, 32-34). To our knowledge, we report the first case in the neurosurgery literature of prenatal diagnosis of HME and the outcome after hemispherectomy. CASE REPORT A 27-year-old, gravida 2, para 1 woman presented for a fetal MRI at 32 weeks’
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gestation after an abnormal ultrasound of the male fetus. Fetal MRI showed left HME (Figure 1). In prenatal consultation with the neurology and neurosurgery departments, it was proposed that the patient may be a suitable candidate for hemispherectomy when he reached approximately 10 kg body weight. The mother underwent an uncomplicated cesarean section at 39 weeks’ gestation and gave birth to a male infant weighing 3840 g. Immediately after birth, the patient began to have multiple seizure types, including infantile spasms and simple partial seizures. The patient was placed on 3 antiepileptic medications but continued to exhibit daily seizures. At 1 month of age, prednisolone was initiated with improvement of infantile spasms and resolution of hypsarrhythmia on electroencephalography. At 3 months of age, seizure frequency increased, and the patient started to have tonic seizures that progressed to status epilepticus requiring hospital admission. He was hospitalized on numerous occasions for increased seizure frequency (up to 25 per day) and intractable
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PEER-REVIEW SHORT REPORTS SHIH-SHAN LANG ET AL.
PRENATAL DIAGNOSIS OF HME
Figure 1. (AeC) Fetal magnetic resonance imaging. Axial single-shot, fast spin echo T2-weighted sequences show a markedly enlarged left cerebral
ictal emesis. At 5 months of age, he was started on a ketogenic diet but continued to have spasms with ictal emesis and partial seizures that progressed to focal motor status epilepticus on a near-daily basis. At 6 months of age, the patient was admitted for consideration of hemispherectomy. Family history was significant for an uncle with unspecified seizures. There were no genetic syndromes or history of seizures in the parents, grandparents, or the patient’s older sibling.
Imaging Fetal MRI was performed using a 1.5-tesla magnet with half-Fourier acquisition single shot turbo-spin echo, two-dimensional fast low angle shot, and echo planar imaging sequences obtained in orthogonal planes. MRI showed marked enlargement of the left cerebral hemisphere with abnormal gyration consistent with HME (Figure 1). Postnatal MRI was performed using a 3.0tesla magnet with the following sequences:
Figure 2. (AeC) Postnatal magnetic resonance imaging. Axial T2-weighted images confirm prenatal findings. The enlargement of the left cerebral hemisphere with abnormal gyration, absence of sulci, and hypointense
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hemisphere. The left lateral ventricle is dilated, and a thickened cerebral cortex with lissencephaly is seen.
sagittal three-dimensional T1 gradient echo with axial reformations; axial, sagittal, and coronal turbo-spin echo T2; axial fluid attenuated inversion recovery; arterialspin labeling perfusion; and susceptibilityweighted, diffusion-weighted, and diffusion tensor imaging. Postnatal MRI confirmed enlargement of the left cerebral hemisphere with abnormal gyration and absence of sulci (Figure 2). The white matter of the left cerebral hemisphere demonstrated hyperintense signal on T1-weighted MRI and
signal in the white matter are demonstrated. There is enlargement of the occipital horn and atrium of the left lateral ventricle.
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2013.09.028
PEER-REVIEW SHORT REPORTS SHIH-SHAN LANG ET AL.
hypointense signal on T2-weighted MRI. The occipital horn and atrium of the left lateral ventricle were disproportionally enlarged. Operation and Postoperative Course When the patient reached a safe weight to tolerate surgery, he underwent a staged left anatomic hemispherectomy. A complete left temporal lobectomy including amygdalohippocampectomy was performed en bloc following the vein of Labbé from the cavernous sinus to the transverse sinus. The frontal, parietal, and occipital lobes were partially removed. At this point in the operation, the patient had lost 2 full blood volumes, and it was determined that he would benefit from a staged procedure. After correction of the patient’s coagulopathy by resuscitation with fluids and blood products, the patient returned to the operating room 1 week later for completion of the left hemispherectomy. Postoperatively, the patient did not have any clinical seizure activity until postoperative day 5, when he experienced 2 self-resolving simple partial seizures. Neurologically, he was full strength (5/5) in his left upper extremity and bilateral lower extremities and antigravity (3/5) in his right upper extremity. He was discharged on his home antiepileptic regimen and a ketogenic diet with a plan to taper both treatments slowly over time. At his 1-year birthday (6.5 months postoperative) follow-up, the patient had been seizure-free since being discharged home after hemispherectomy. The patient continued to make developmental progress, being able to sit without assistance. He was also able to speak a few words, such as “dada,” and copied facial expressions and noises. Histopathology Histopathologic gross examination of the resected temporal lobe tissue revealed abnormal cortex lacking normal sulcation with a well-demarcated gray-white junction. Gross examination of the resected frontal, parietal, and occipital lobes revealed a thickened and nodular cortex. Microscopically, all 4 cortical lobe resections demonstrated lissencephaly and cortical dysplasia throughout the entire cortex. There was superficial undulation of the cortical ribbon with fused and buried sulci. Neurofilament antibodies showed
PRENATAL DIAGNOSIS OF HME
the increased thickness of the cortex (i.e., pachygyria) as well as prominent leptomeningeal heterotopias and white matter heterotopias. The cytoarchitecture was disorganized with a lack of neuronal lamination. Pyramidal and smaller neurons were dispersed across the cortex in misalignment; however, balloon cells and definitive giant neurons were not present. DISCUSSION HME is a rare developmental brain disorder characterized by the abnormal enlargement of the entire cerebral hemisphere or portions of it (4, 5, 7, 8, 19-21, 23, 27, 39, 40). More recently, there has been extensive research and literature has been published regarding the underlying genetic mutations and syndromic anomalies associated with this entity. HME can occur as an isolated case; however, it can also occur with neurocutaneous and other similar syndromes (5, 7, 12, 14, 15, 20, 38). In some cases, HME is thought to be caused by a somatic mutation or activation of components of the mammalian target of rapamycin (mTOR) pathway, including PI3K, AKT3, and mTOR itself (3, 28, 31, 37). The most common clinical presentation of affected patients is intractable epilepsy with severe developmental delay and psychomotor retardation typically starting from birth or within the first few months of life. Prenatal diagnosis of HME has been rarely reported (1, 22-25). When an anomaly is observed on routine fetal ultrasound, MRI should be performed to confirm the diagnosis and delineate better the degree of cortical malformation. Prenatal counseling from a multidisciplinary team can then proceed to determine the best medical and surgical options for epilepsy. For our patient, the neurology and neurosurgical consultants were able to give prenatal parental counseling on various medical treatment options and prepare the parents for the likely possibility of hemispherectomy. In addition, because the diagnosis was known at birth, medical therapy was able to be instituted at a very early age. Hemispherectomy is the surgical option for seizure control (6, 17, 20, 38). King et al. (25) reported the first case of a favorable outcome after hemispherectomy for HME. There are classically 2 types of hemispherectomy: anatomic and functional (10, 17, 35). Anatomic hemispherectomy is reported to
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have a higher rate of postoperative seizurefree outcomes over functional hemispherectomy in short-term and long-term follow-up (10, 13, 22, 35). However, anatomic hemispherectomy has a higher risk of intraoperative bleeding, postoperative coagulopathy from loss of multiple blood volumes, hydrocephalus, and superficial hemosiderosis (18, 26, 30, 43). Owing to complications of intraoperative blood loss leading to death, there has been a trend among neurosurgeons to favor the functional hemispherectomy technique (11, 13, 22, 35). Our patient experienced substantial intraoperative blood loss and needed a staged procedure to minimize morbidity and mortality. Virtually all reports in the literature suggest that regardless of which approach is taken, hemispherectomy is an effective surgery for intractable epilepsy from HME. CONCLUSIONS To our knowledge, we report the first case in the neurosurgery literature of a diagnosis of HME made in a patient in utero, who after birth underwent a successful hemispherectomy with excellent seizure control and improved developmental milestones. REFERENCES 1. Alvarez RM, Garcia-Diaz L, Marquez J, Fajardo M, Rivas E, Garcia-Lozano JC, Antiñolo G: Hemimegalencephaly: prenatal diagnosis and outcome. Fetal Diagn Ther 30:234-238, 2011. 2. Babyn P, Chuang S, Daneman A, Withers C: Sonographic recognition of unilateral megalencephaly. J Ultrasound Med 11:563-566, 1992. 3. Baek ST, Gibbs EM, Gleeson JG, Mathern GW: Hemimegalencephaly, a paradigm for somatic postzygotic neurodevelopmental disorders. Curr Opin Neurol 26:122-127, 2013. 4. Barkovich AJ, Chuang SH: Unilateral megalencephaly: correlation of MR imaging and pathologic characteristics. AJNR Am J Neuroradiol 11: 523-531, 1990. 5. Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB: Classification system for malformations of cortical development: update 2001. Neurology 57:2168-2178, 2001. 6. Battaglia D, Di Rocco C, Iuvone L, Acquafondata C, Iannelli A, Lettori D, Guzzetta F: Neuro-cognitive development and epilepsy outcome in children with surgically treated hemimegalencephaly. Neuropediatrics 30:307-313, 1999. 7. Bignami A, Palladini G, Zappella M: Unilateral megalencephaly with nerve cell hypertrophy. An
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anatomical and quantitative histochemical study. Brain Res 9:103-114, 1968.
Neuropathology suggests a disorder of cellular lineage. J Child Neurol 18:776-785, 2003.
8. Bignami A, Zappella M, Benedetti P: Infantile spasms with hypsarrhythmia. A pathological study. Helv Paediatr Acta 19:326-342, 1964.
22. González-Martínez JA, Gupta A, Kotagal P, Lachhwani D, Wyllie E, Lüders HO, Bingaman WE: Hemispherectomy for catastrophic epilepsy in infants. Epilepsia 46:1518-1525, 2005.
9. Boer K, Troost D, Spliet WG, Redeker S, Crino PB, Aronica E: A neuropathological study of two autopsy cases of syndromic hemimegalencephaly. Neuropathol Appl Neurobiol 33: 455-470, 2007. 10. Carreno M, Wyllie E, Bingaman W, Kotagal P, Comair Y, Ruggieri P: Seizure outcome after functional hemispherectomy for malformations of cortical development. Neurology 57:331-333, 2001. 11. Carson BS, Javedan SP, Freeman JM, Vining EP, Zuckerberg AL, Lauer JA, Guarnieri M: Hemispherectomy: a hemidecortication approach and review of 52 cases. J Neurosurg 84:903-911, 1996. 12. Cartwright MS, McCarthy SC, Roach ES: Hemimegalencephaly and tuberous sclerosis complex. Neurology 64:1634, 2005. 13. Cook SW, Nguyen ST, Hu B, Yudovin S, Shields WD, Vinters HV, Van de Wiele BM, Harrison RE, Mathern GW: Cerebral hemispherectomy in pediatric patients with epilepsy: comparison of three techniques by pathological substrate in 115 patients. J Neurosurg 100:125-141, 2004. 14. Crino PB: Molecular pathogenesis of focal cortical dysplasia and hemimegalencephaly. J Child Neurol 20:330-336, 2005. 15. DeLone DR, Brown WD, Gentry LR: Proteus syndrome: craniofacial and cerebral MRI. Neuroradiology 41:840-843, 1999. 16. Devlin AM, Cross JH, Harkness W, Chong WK, Harding B, Vargha-Khadem F, Neville BG: Clinical outcomes of hemispherectomy for epilepsy in childhood and adolescence. Brain 126:556-566, 2003. 17. Di Rocco C, Battaglia D, Pietrini D, Piastra M, Massimi L: Hemimegalencephaly: clinical implications and surgical treatment. Childs Nerv Syst 22:852-866, 2006. 18. Falconer MA, Wilson PJ: Complications related to delayed hemorrhage after hemispherectomy. J Neurosurg 30:413-426, 1969. 19. Fitz CR, Harwood-Nash DC, Boldt DW: The radiographic features of unilateral megalencephaly. Neuroradiology 15:145-148, 1978. 20. Flores-Sarnat L: Hemimegalencephaly: part 1. Genetic, clinical, and imaging aspects. J Child Neurol 17:373-384 [discussion 384], 2002. 21. Flores-Sarnat L, Sarnat HB, Davila-Gutierrez G, Alvarez A: Hemimegalencephaly: part 2.
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23. Griffiths PD, Welch RJ, Gardner-Medwin D, Gholkar A, McAllister V: The radiological features of hemimegalencephaly including three cases associated with proteus syndrome. Neuropediatrics 25:140-144, 1994. 24. Jonas R, Nguyen S, Hu B, Asarnow RF, LoPresti C, Curtiss S, de Bode S, Yudovin S, Shields WD, Vinters HV, Mathern GW: Cerebral hemispherectomy: hospital course, seizure, developmental, language, and motor outcomes. Neurology 62:1712-1721, 2004.
33. Romero XC, Molina FS, Pastor E, Amaya F: Hemimegalencephaly: 2D, 3D ultrasound and MRI correlation. Fetal Diagn Ther 29:257-260, 2011. 34. Sandri F, Pilu G, Dallacasa P, Foschi F, Salvioli GP, Bovicelli L: Sonography of unilateral megalencephaly in the fetus and newborn infant. Am J Perinatol 8:18-20, 1991. 35. Schramm J, Kral T, Clusmann H: Transsylvian keyhole functional hemispherectomy. Neurosurgery 49:891-900 [discussion 900-901], 2001. 36. Sims J: On hypertrophy and atrophy of the brain. Med Chir Trans 19:315-380, 1835. 37. Striano P, Zara F: Genetics: mutations in mTOR pathway linked to megalencephaly syndromes. Nat Rev Neurol 8:542-544, 2012.
25. King M, Stephenson JB, Ziervogel M, Doyle D, Galbraith S: Hemimegalencephaly—a case for hemispherectomy? Neuropediatrics 16:46-55, 1985.
38. Tinkle BT, Schorry EK, Franz DN, Crone KR, Saal HM: Epidemiology of hemimegalencephaly: a case series and review. Am J Med Genet A 139: 204-211, 2005.
26. Kossoff EH, Vining EP, Pillas DJ, Pyzik PL, Avellino AM, Carson BS, Freeman JM: Hemispherectomy for intractable unihemispheric epilepsy etiology vs outcome. Neurology 61:887-890, 2003.
39. Tjiam AT, Stefanko S, Schenk VW, de Vlieger M: Infantile spasms associated with hemihypsarrhythmia and hemimegalencephaly. Dev Med Child Neurol 20:779-798, 1978.
27. Laurence KM: A case of unilateral megalencephaly. Dev Med Child Neurol 6:585-590, 1964. 28. Lee JH, Huynh M, Silhavy JL, Kim S, DixonSalazar T, Heiberg A, Scott E, Bafna V, Hill KJ, Collazo A, Funari V, Russ C, Gabriel SB, Mathern GW, Gleeson JG: De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet 44:941-945, 2012. 29. Manoranjan B, Provias JP: Hemimegalencephaly: a fetal case with neuropathological confirmation and review of the literature. Acta Neuropathol 120: 117-130, 2010. 30. Mathew NT, Abraham J, Chandy J: Late complications of hemispherectomy: report of a case relieved by surgery. J Neurol Neurosurg Psychiatry 33:372-375, 1970. 31. Poduri A, Evrony GD, Cai X, Elhosary PC, Beroukhim R, Lehtinen MK, Hills LB, Heinzen EL, Hill A, Hill RS, Barry BJ, Bourgeois BF, Riviello JJ, Barkovich AJ, Black PM, Ligon KL, Walsh CA: Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 74: 41-48, 2012.
40. Trounce JQ, Rutter N, Mellor DH: Hemimegalencephaly: diagnosis and treatment. Dev Med Child Neurol 33:261-266, 1991. 41. Vigevano F, Bertini E, Boldrini R, Bosman C, Claps D, di Capua M, et al: Hemimegalencephaly and intractable epilepsy: benefits of hemispherectomy. Epilepsia 30:833-843, 1989. 42. Vigevano F, Di Rocco C: Effectiveness of hemispherectomy in hemimegalencephaly with intractable seizures. Neuropediatrics 21:222-223, 1990. 43. Vining EP, Freeman JM, Pillas DJ, Uematsu S, Carson BS, Brandt J, Boatman D, Pulsifer MB, Zuckerberg A: Why would you remove half a brain? The outcome of 58 children after hemispherectomy—the Johns Hopkins experience: 1968 to 1996. Pediatrics 100:163-171, 1997.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 12 June 2013; accepted 13 September 2013 Citation: World Neurosurg. (2014). http://dx.doi.org/10.1016/j.wneu.2013.09.028 Journal homepage: www.WORLDNEUROSURGERY.org
32. Ramirez M, Wilkins I, Kramer L, Slopis J, Taylor SR: Prenatal diagnosis of unilateral megalencephaly by real-time ultrasonography. Am J Obstet Gynecol 170: 1384-1385, 1994.
Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2014 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2013.09.028
Prenatal Diagnosis of Hemimegalencephaly Shih-Shan Lang1,2, Ethan Goldberg3, Deborah Zarnow4, Mark P. Johnson5, Phillip B. Storm1,2, Gregory G. Heuer1,2
Key words Cortical dysplasia - Fetal imaging - Hemimegalencephaly - Hemispherectomy - MRI - Neuronal migration -
- BACKGROUND:
In recent literature, there have been case reports of prenatal diagnosis of hemimegalencephaly, an extremely rare entity characterized by enlargement of all or portions of 1 cerebral hemisphere and intractable seizures. A unique case is presented of hemimegalencephaly of a fetus diagnosed in utero.
- METHODS:
Abbreviations and Acronyms HME: Hemimegalencephaly MRI: Magnetic resonance imaging From the 1Department of Neurosurgery, Hospital of the University of Pennsylvania; and 2Division of Neurosurgery, 3Division of Neurology, 4Department of Radiology, and 5Department of Surgery, Center for Fetal Diagnosis and Treatment, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA To whom correspondence should be addressed: Shih-Shan Lang, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2014). http://dx.doi.org/10.1016/j.wneu.2013.09.028 Journal homepage: www.WORLDNEUROSURGERY.org
A 27-year-old woman presented at 32 weeks’ gestation for fetal magnetic resonance imaging after an abnormal fetal ultrasound. Fetal magnetic resonance imaging showed hemimegalencephaly of the left cerebral hemisphere with abnormal gyration.
- RESULTS:
The patient was born via cesarean section at 39 weeks’ gestation. He had continuous infantile spasms and partial-onset seizures starting on day 1 of life, and electroencephalography showed burst suppression. The patient’s seizures were initially managed with antiepileptics, prednisolone, and a ketogenic diet; however, he was hospitalized multiple times because of status epilepticus. At 6 months of age, he underwent a successful anatomic left hemispherectomy.
- CONCLUSIONS:
In utero diagnosis of complex developmental brain anomalies allows a multidisciplinary approach to provide optimal prenatal patient treatment and parental counseling.
Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2014 Elsevier Inc. All rights reserved.
INTRODUCTION Hemimegalencephaly (HME) is a congenital brain malformation characterized by the overgrowth and enlargement of all or parts of a cerebral hemisphere; it can rarely involve the brainstem or cerebellar hemisphere (4, 5, 7, 8, 19-21, 23, 27, 39, 40). This disorder was first mentioned in the literature in the 1830s based on autopsy reports, but it was not described in clinical and pathologic detail until the 1960s (7, 8, 27, 36). HME can occur as part of a genetic syndrome, such as epidermal nevus syndrome, Proteus syndrome, or tuberous sclerosis, or it can occur in isolation (5, 9, 12, 14, 15, 20, 23, 38). The underlying pathogenesis is thought to be due to an abnormality in cortical development and neuronal migration and possibly an early disturbance in cellular lineage and differentiation (7, 9, 14, 20, 21, 29). Radiologically, HME manifests as an enlarged unilateral cerebral hemisphere with abnormal gyration and ventriculomegaly that can be evaluated by
ultrasound, computed tomography, or magnetic resonance imaging (MRI) (2, 4, 15, 17, 19, 20, 23, 33). Clinically, the enlarged cerebral hemisphere acts as a focus for seizures that are often intractable and poorly controlled with antiepileptic medications. In addition to epilepsy, patients typically have developmental delay and psychomotor retardation within the first few months of life (6, 17, 38, 40). For patients with intractable epilepsy, hemispherectomy is the surgical option for seizure control (6, 10, 16, 24, 25, 41, 42). Rare reports in the literature have focused on fetal imaging in patients with HME; however, in most cases, the diagnosis was made at autopsy (1, 29, 32-34). To our knowledge, we report the first case in the neurosurgery literature of prenatal diagnosis of HME and the outcome after hemispherectomy. CASE REPORT A 27-year-old, gravida 2, para 1 woman presented for a fetal MRI at 32 weeks’
WORLD NEUROSURGERY - [-]: ---, MONTH 2014
gestation after an abnormal ultrasound of the male fetus. Fetal MRI showed left HME (Figure 1). In prenatal consultation with the neurology and neurosurgery departments, it was proposed that the patient may be a suitable candidate for hemispherectomy when he reached approximately 10 kg body weight. The mother underwent an uncomplicated cesarean section at 39 weeks’ gestation and gave birth to a male infant weighing 3840 g. Immediately after birth, the patient began to have multiple seizure types, including infantile spasms and simple partial seizures. The patient was placed on 3 antiepileptic medications but continued to exhibit daily seizures. At 1 month of age, prednisolone was initiated with improvement of infantile spasms and resolution of hypsarrhythmia on electroencephalography. At 3 months of age, seizure frequency increased, and the patient started to have tonic seizures that progressed to status epilepticus requiring hospital admission. He was hospitalized on numerous occasions for increased seizure frequency (up to 25 per day) and intractable
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PEER-REVIEW SHORT REPORTS SHIH-SHAN LANG ET AL.
PRENATAL DIAGNOSIS OF HME
Figure 1. (AeC) Fetal magnetic resonance imaging. Axial single-shot, fast spin echo T2-weighted sequences show a markedly enlarged left cerebral
ictal emesis. At 5 months of age, he was started on a ketogenic diet but continued to have spasms with ictal emesis and partial seizures that progressed to focal motor status epilepticus on a near-daily basis. At 6 months of age, the patient was admitted for consideration of hemispherectomy. Family history was significant for an uncle with unspecified seizures. There were no genetic syndromes or history of seizures in the parents, grandparents, or the patient’s older sibling.
Imaging Fetal MRI was performed using a 1.5-tesla magnet with half-Fourier acquisition single shot turbo-spin echo, two-dimensional fast low angle shot, and echo planar imaging sequences obtained in orthogonal planes. MRI showed marked enlargement of the left cerebral hemisphere with abnormal gyration consistent with HME (Figure 1). Postnatal MRI was performed using a 3.0tesla magnet with the following sequences:
Figure 2. (AeC) Postnatal magnetic resonance imaging. Axial T2-weighted images confirm prenatal findings. The enlargement of the left cerebral hemisphere with abnormal gyration, absence of sulci, and hypointense
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hemisphere. The left lateral ventricle is dilated, and a thickened cerebral cortex with lissencephaly is seen.
sagittal three-dimensional T1 gradient echo with axial reformations; axial, sagittal, and coronal turbo-spin echo T2; axial fluid attenuated inversion recovery; arterialspin labeling perfusion; and susceptibilityweighted, diffusion-weighted, and diffusion tensor imaging. Postnatal MRI confirmed enlargement of the left cerebral hemisphere with abnormal gyration and absence of sulci (Figure 2). The white matter of the left cerebral hemisphere demonstrated hyperintense signal on T1-weighted MRI and
signal in the white matter are demonstrated. There is enlargement of the occipital horn and atrium of the left lateral ventricle.
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2013.09.028
PEER-REVIEW SHORT REPORTS SHIH-SHAN LANG ET AL.
hypointense signal on T2-weighted MRI. The occipital horn and atrium of the left lateral ventricle were disproportionally enlarged. Operation and Postoperative Course When the patient reached a safe weight to tolerate surgery, he underwent a staged left anatomic hemispherectomy. A complete left temporal lobectomy including amygdalohippocampectomy was performed en bloc following the vein of Labbé from the cavernous sinus to the transverse sinus. The frontal, parietal, and occipital lobes were partially removed. At this point in the operation, the patient had lost 2 full blood volumes, and it was determined that he would benefit from a staged procedure. After correction of the patient’s coagulopathy by resuscitation with fluids and blood products, the patient returned to the operating room 1 week later for completion of the left hemispherectomy. Postoperatively, the patient did not have any clinical seizure activity until postoperative day 5, when he experienced 2 self-resolving simple partial seizures. Neurologically, he was full strength (5/5) in his left upper extremity and bilateral lower extremities and antigravity (3/5) in his right upper extremity. He was discharged on his home antiepileptic regimen and a ketogenic diet with a plan to taper both treatments slowly over time. At his 1-year birthday (6.5 months postoperative) follow-up, the patient had been seizure-free since being discharged home after hemispherectomy. The patient continued to make developmental progress, being able to sit without assistance. He was also able to speak a few words, such as “dada,” and copied facial expressions and noises. Histopathology Histopathologic gross examination of the resected temporal lobe tissue revealed abnormal cortex lacking normal sulcation with a well-demarcated gray-white junction. Gross examination of the resected frontal, parietal, and occipital lobes revealed a thickened and nodular cortex. Microscopically, all 4 cortical lobe resections demonstrated lissencephaly and cortical dysplasia throughout the entire cortex. There was superficial undulation of the cortical ribbon with fused and buried sulci. Neurofilament antibodies showed
PRENATAL DIAGNOSIS OF HME
the increased thickness of the cortex (i.e., pachygyria) as well as prominent leptomeningeal heterotopias and white matter heterotopias. The cytoarchitecture was disorganized with a lack of neuronal lamination. Pyramidal and smaller neurons were dispersed across the cortex in misalignment; however, balloon cells and definitive giant neurons were not present. DISCUSSION HME is a rare developmental brain disorder characterized by the abnormal enlargement of the entire cerebral hemisphere or portions of it (4, 5, 7, 8, 19-21, 23, 27, 39, 40). More recently, there has been extensive research and literature has been published regarding the underlying genetic mutations and syndromic anomalies associated with this entity. HME can occur as an isolated case; however, it can also occur with neurocutaneous and other similar syndromes (5, 7, 12, 14, 15, 20, 38). In some cases, HME is thought to be caused by a somatic mutation or activation of components of the mammalian target of rapamycin (mTOR) pathway, including PI3K, AKT3, and mTOR itself (3, 28, 31, 37). The most common clinical presentation of affected patients is intractable epilepsy with severe developmental delay and psychomotor retardation typically starting from birth or within the first few months of life. Prenatal diagnosis of HME has been rarely reported (1, 22-25). When an anomaly is observed on routine fetal ultrasound, MRI should be performed to confirm the diagnosis and delineate better the degree of cortical malformation. Prenatal counseling from a multidisciplinary team can then proceed to determine the best medical and surgical options for epilepsy. For our patient, the neurology and neurosurgical consultants were able to give prenatal parental counseling on various medical treatment options and prepare the parents for the likely possibility of hemispherectomy. In addition, because the diagnosis was known at birth, medical therapy was able to be instituted at a very early age. Hemispherectomy is the surgical option for seizure control (6, 17, 20, 38). King et al. (25) reported the first case of a favorable outcome after hemispherectomy for HME. There are classically 2 types of hemispherectomy: anatomic and functional (10, 17, 35). Anatomic hemispherectomy is reported to
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have a higher rate of postoperative seizurefree outcomes over functional hemispherectomy in short-term and long-term follow-up (10, 13, 22, 35). However, anatomic hemispherectomy has a higher risk of intraoperative bleeding, postoperative coagulopathy from loss of multiple blood volumes, hydrocephalus, and superficial hemosiderosis (18, 26, 30, 43). Owing to complications of intraoperative blood loss leading to death, there has been a trend among neurosurgeons to favor the functional hemispherectomy technique (11, 13, 22, 35). Our patient experienced substantial intraoperative blood loss and needed a staged procedure to minimize morbidity and mortality. Virtually all reports in the literature suggest that regardless of which approach is taken, hemispherectomy is an effective surgery for intractable epilepsy from HME. CONCLUSIONS To our knowledge, we report the first case in the neurosurgery literature of a diagnosis of HME made in a patient in utero, who after birth underwent a successful hemispherectomy with excellent seizure control and improved developmental milestones. REFERENCES 1. Alvarez RM, Garcia-Diaz L, Marquez J, Fajardo M, Rivas E, Garcia-Lozano JC, Antiñolo G: Hemimegalencephaly: prenatal diagnosis and outcome. Fetal Diagn Ther 30:234-238, 2011. 2. Babyn P, Chuang S, Daneman A, Withers C: Sonographic recognition of unilateral megalencephaly. J Ultrasound Med 11:563-566, 1992. 3. Baek ST, Gibbs EM, Gleeson JG, Mathern GW: Hemimegalencephaly, a paradigm for somatic postzygotic neurodevelopmental disorders. Curr Opin Neurol 26:122-127, 2013. 4. Barkovich AJ, Chuang SH: Unilateral megalencephaly: correlation of MR imaging and pathologic characteristics. AJNR Am J Neuroradiol 11: 523-531, 1990. 5. Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB: Classification system for malformations of cortical development: update 2001. Neurology 57:2168-2178, 2001. 6. Battaglia D, Di Rocco C, Iuvone L, Acquafondata C, Iannelli A, Lettori D, Guzzetta F: Neuro-cognitive development and epilepsy outcome in children with surgically treated hemimegalencephaly. Neuropediatrics 30:307-313, 1999. 7. Bignami A, Palladini G, Zappella M: Unilateral megalencephaly with nerve cell hypertrophy. An
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 12 June 2013; accepted 13 September 2013 Citation: World Neurosurg. (2014). http://dx.doi.org/10.1016/j.wneu.2013.09.028 Journal homepage: www.WORLDNEUROSURGERY.org
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