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Best Cases from the AFIP

Hemimegalencephaly1
Editors Note.Everyone who has taken the course in radiologic pathology at the Armed Forces Institute of Pathology (AFIP) remembers bringing beautifully illustrated cases for accession to the Institute. In recent years, the staff of the Department of Radiologic Pathology has judged the best cases by organ system, and recognition is given to the winners on the last day of the class. With each issue of RadioGraphics, one or more of these cases are published, written by the winning resident. Radiologicpathologic correlation is emphasized, and the causes of the imaging signs of various diseases are illustrated.

David D. Broumandi, MD Ulrike M. Hayward, MD James M. Benzian, MD Ignacio Gonzalez, MD Marvin D. Nelson, MD History
A 9-lb 13-oz full-term male was delivered by cesarean section due to failure of labor to progress. He was born to a diabetic but otherwise healthy mother and at birth had spells of apnea, which were attributed to seizures. Computed tomography (CT) of the brain revealed a possible mass in the right hemisphere, and magnetic resonance (MR) imaging suggested right hemimegalencephaly. Although initially responsive to antiepileptic treatments, during the following several months the patient continued to experience seizures despite optimal trials of phenobarbital and Topamax (topiramate; Ortho-McNeil Pharmaceutical, Raritan, NJ). Serial electroencephalograms demonstrated continued right-sided epileptiform activity with minimal involvement of the left frontal region. At ten months of age, the patient was developmentally delayed and had an enlarged head circumference measurement of 47.4 cm. The patient had no focal neurologic decits, and no cutaneous abnormalities were noted.

Imaging Findings
At 10 months of age, the patient underwent follow-up MR imaging of the brain, which showed marked enlargement of the right cerebral hemisphere and ndings consistent with hemimegalencephaly (Fig 1). The right cerebrum was diffusely dystrophic with broadened gyri and a diffusely thickened cortical mantle, consistent with areas of pachygyria and polymicrogyria. The right lateral

Index terms: Brain, abnormalities, 10.144 Brain, enlarged, 10.144 Brain, volume, 10.144 RadioGraphics 2004; 24:843 848 Published online 10.1148/rg.243035135
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the Department of Radiology, Santa Barbara Cottage Hospital, Pueblo at Bath St, 0689, Santa Barbara, CA 93102-0689 (D.D.B., U.M.H., J.M.B.); and the Departments of Pathology (I.G.) and Radiology (M.D.N.), Childrens Hospital, Los Angeles, Calif. Received May 19, 2003; revision requested June 18 and received July 16; accepted July 17. Address correspondence to D.D.B. (e-mail: dbroumandi@sbch.org). RSNA, 2004

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Figure 1. Axial unenhanced (a) and contrast material enhanced (b) T1-weighted MR images show enlargement of the right cerebral hemisphere, cavitation in the region of the centrum semiovale (arrowhead), and diffuse gyral thickening (arrows) with diminished sulcation, a nding consistent with pachygyria. There are patchy, linear regions of increased signal intensity in the white matter of the right hemisphere. No pathologic enhancement is seen on the contrast-enhanced image (b).

Figure 2. (a) Axial unenhanced T1-weighted MR image obtained at the level of the basal ganglia shows an enlarged and dysmorphic right cerebral hemisphere. The right basal ganglia are poorly demonstrated. There is moderate mass effect anteriorly (arrow). (b) On a sagittal T1-weighted MR image obtained at the midline, the corpus callosum is poorly seen (arrowhead).

ventricle was dysmorphic with portions that were compressed (Figs 2, 3). The right globus pallidus, putamen, and thalamus were poorly demarcated, and the corpus callosum was small (Fig 2). The

cerebellum and brainstem appeared normal (Fig 3). The left cerebral hemisphere had a more normal gyral pattern; however, there were regions of thick gray matter and pachygyria in the left frontal lobe, consistent with cortical dysplasia. The imaging ndings were consistent with right hemimegalencephaly.

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Figure 3. Axial (a) and coronal (b) unenhanced T2-weighted MR images show enlargement of the right cerebral hemisphere. There is diffuse high signal intensity in the white matter, which correlates with histopathologic ndings of poor myelination and early cystic changes. The right lateral ventricle is compressed (arrow in b). The cerebellum is symmetrical and appears normal (arrowhead in b). Figure 4. Coronal section through the right frontal hemisphere (same orientation as in Fig 3b) shows broad gyri and a thick cortex, particularly in the frontal lobe (solid straight arrow). The occipital lobe has a more normal gyral pattern (arrowhead). The white matter is gliotic and shows areas of mucinous and cystic degeneration (curved arrow). The gray matter white matter junction is indistinct. The basal ganglia and thalami are small and poorly demarcated. Subventricular gray matter heterotopia is also noted (open arrow).

Pathologic Evaluation
Owing to the patients intractable seizures, a right hemispherectomy was performed for seizure control and prevention of progressive damage to the left hemisphere. The right hemisphere weighted 720 g. There was a diffusely abnormal gyral pattern with broad simple gyri and focal nodularity on the surface. Serial coronal sections revealed

short sulci and an irregularly thickened cortical band (Fig 4). There was a lateral sulcus that appeared short and markedly thickened, representing the sylvian ssure. The white matter was soft with friable cavitary regions. The right basal ganglia and thalami were poorly circumscribed. The cerebral commissures and internal capsule were thin. The ventricular system was compressed, and the ventricular wall was friable. Focal subventricular gray matter heterotopias were noted (Fig 4). The hippocampal formation was not distinguishable. In the occipital lobe, there were large areas of normal brain with intact architecture. Histologic sections revealed mild leptomeningeal brosis. The cortex was markedly thickened and dysplastic with poor lamination, subpial gliosis,

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Figure 5. (a) Low-power photomicrograph (hematoxylin-eosin stain) of the cerebral cortex shows a thickened cortex with poor neuronal lamination (between brackets). An increased number of neurons are present in the subcortical white matter (arrow). Large abnormal blood vessels with prominent perivascular spaces are also present in the white matter (arrowheads). (b) High-power photomicrograph (hematoxylin-eosin stain) shows poorly myelinated white matter containing scattered ectopic neurons (solid straight arrow), gliosis with hypertrophic changes (curved arrow), numerous Rosenthal bers (arrowheads), and vacuolar changes in the white matter. Focally scattered calcications are also present in the white matter (open arrow).

and scattered large neurons, many showing abnormal orientation (Fig 5). Focal areas with fusion of the molecular layers of adjacent gyri were present. The white matter was poorly myelinated and contained numerous scattered ectopic neurons, clusters and rows of hypertrophic astrocytes, and Rosenthal bers, represented by thick, elongated, brightly eosinophilic structures in a predominantly perivascular distribution (Fig 5). Rosenthal bers are found in conditions of longstanding gliosis, occasional tumors, and rare metabolic degenerative disorders. Areas of marked white matter vacuolation and cystic changes of varying degree were also noted. The histopathologic ndings conrmed the diagnosis of right hemimegalencephaly.

Discussion
Hemimegalencephaly or unilateral megalencephaly is a congenital disorder in which there is hamartomatous overgrowth of all or part of a cerebral hemisphere (1,2). The affected hemisphere may have focal or diffuse neuronal migration defects, with areas of polymicrogyria, pachygyria, and heterotopia. Hemimegalencephaly is a rare

disorder and was rst described by Sims in 1835 after reviewing 253 autopsies (3). Although the cause is unknown, it is postulated that it occurs due to insults during the second trimester of pregnancy, or as early as the 3rd week of gestation, as a genetically programmed developmental disorder related to cellular lineage and establishment of symmetry (1). Hemimegalencephaly may also be considered a primary disorder of proliferation wherein the neurons that are unable to form synaptic connections are not eliminated and are thus accumulated. Hemimegalencephaly differs from other cerebral dysgeneses because of its extreme asymmetry not corresponding to any normal stage of human brain development. No chromosomal abnormalities have been associated with hemimegalencephaly. There are three types of hemimegalencephaly (1). The isolated form, as in our case, occurs as a sporadic disorder without hemicorporal hypertrophy or cutaneous or systemic involvement. The syndromic form is associated with other diseases and may occur as hemihypertrophy of part or all of the ipsilateral body. It has been described in patients with epidermal nevus syndrome, Proteus syndrome, neurobromatosis type 1, hypermelanosis of Ito, Klippel-WeberTrenaunay syndrome, and tuberous sclerosis (2,4). Therefore, the syndromic type may follow a

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mendelian pattern of inheritance. The third and least common type is total hemimegalencephaly, in which there is also enlargement of the ipsilateral half of the brainstem and cerebellum. Affected patients may have macrocephaly at birth and in early infancy and often present with an intractable seizure disorder, hemiplegia, and severe developmental delay (2). Males and females are equally affected. Pregnancy is usually uncomplicated, but cesarean section may be required owing to cephalopelvic disproportion. Therefore, macrocephaly is often the rst presentation at birth (1). Hemimegalencephaly has a high mortality in infancy unrelated to surgery (5,6). A brain tumor may be suspected when there is rapid enlargement of the head in the rst months of life. Patients have been misdiagnosed as having obstructive hydrocephalus and undergone unnecessary ventriculoperitoneal shunting (1). In hemimegalencephaly, the clinical signs of intracranial hypertension such as separation of sutures, bulging fontanels, and the setting-sun sign of the eyes are absent. The latter is characteristic of increased intracranial pressure in infants, with both ocular globes deviated downward, the upper lids retracted, and the white sclerae visible above the iris. Epilepsy is the most frequent neurologic manifestation, occurring in greater than 90% of patients (1). Although progressive hemiplegia and hemianopia are common, some patients do not have focal motor decits (1). Hemimegalencephaly in association with neurobromatosis type 1 may be associated with a more favorable clinical course (2,4). The diagnosis of hemimegalencephaly can usually be made at cross-sectional imaging. At CT, asymmetry of the cranium may be evident with enlargement of all or part of a cerebral hemisphere and ipsilateral ventricle. There is often focal, small, or extensive calcication in the white and gray matter, and the white matter may have abnormally low attenuation representing heterotopia and dysplasia of neurons. MR is the imaging modality of choice. A characteristic nding is straightening of the ipsilateral frontal horn of the enlarged ventricle (2). However, the ipsilateral ventricle may be small in some patients. In this case, ventricular enlargement is less severe compared with that of the involved hemisphere. At MR imaging, the white matter shows heterogeneous but frequently high signal intensity and there is often distinction of areas of agyria, pachygyria, and/or polymicrogyria. The white

matter of the affected hemisphere may show advanced myelination for age (7). There is a roughly inverse relationship between the severity of the cortical and white matter abnormalities and the size of the cerebral hemisphere. Patients with agyria tend to have mild to moderate hemispheric enlargement, while those with polymicrogyria have more severe hemispheric enlargement (2,4). Prenatal and postnatal cranial sonography may reveal ventricular asymmetry and unilateral ventricular dilatation. Functional imaging with positron emission tomography has had good correlation with CT and MR imaging ndings and has disclosed functionally abnormal brain regions in the noninvolved hemisphere that appeared structurally normal at CT and MR imaging (8). The gross pathologic appearance correlates with the imaging ndings of enlargement of the affected cerebral hemisphere. The brain surface may show pachygyria and polymicrogyria. Microscopically, nerve cells are larger and less densely packed than in the normal side of the brain, and the number of glial cells is increased. Areas of polymicrogyria, neuronal heterotopia, and pachygyria occur. Histologically, there is no difference between focal cortical dysplasia and hemimegalencephaly. However, macroscopically, hemimegalencephaly involves the whole hemisphere, whereas focal cortical dysplasia is more limited (9). White matter may show areas of poor myelination, cystic change, and gliosis, which correspond to increased signal intensity on T2weighted MR images. Our patient had extensive gliosis, microcystic changes, and Rosenthal bers in the white matter resembling leukodystrophy. Such extensive white matter involvement is unusual in hemimegalencephaly. Delayed myelination was the extent of involvement described by Woo et al (10) in three patients with hemimegalencephaly. Syndromic hemimegalencephaly has a worse prognosis than the isolated type, and there is generally poor neurologic function in cases of hemimegalencephaly. Seizure control is the principal goal of therapy, and patients often require multiple antiepileptic medications that have adverse side effects. Hemispherectomy was rst performed for treatment of refractory epilepsy in 1978 and is considered the best therapeutic choice for patients with intractable seizures (5,6).

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Anatomic or functional hemispherectomy has also been performed with improvement in quality of life (11). Nevertheless, there is a high mortality and morbidity rate associated with hemispherectomy (5,6,12). Complications include subdural hematomas and hydrocephalus, often requiring surgical intervention and ventriculoperitoneal shunting. The age of the patient at the time of surgical intervention is an important factor in development of secondary hydrocephalus, with patients younger than 9 months being more at risk (12). The intracranial space left by resection of a large portion of the brain may be intraoperatively lled with Ringer lactate or may eventually become lled with cerebrospinal uid, but it remains vulnerable to infection and hemorrhage. In our case, the patient developed a large left-sided subdural hematoma a few days after right hemispherectomy. Surgical attempts at decompression failed to prevent progression of a left cerebral infarct due to the extensive intracranial bleeding, and the patient died.

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References
1. Flores-Sarnat L. Hemimegalencephaly. I. Genetic, clinical, and imaging aspects. J Child Neurol 2002; 17:373384. 2. Barkovich AJ, Chuang SH. Unilateral megalencephaly: correlation of MR imaging and pathologic 11.

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characteristics. AJNR Am J Neuroradiol 1990; 11:523531. Sims J. On hypertrophy and atrophy of the brain. Med Quir Trans 1835; 19:315380. Wolpert SM, Cohen A, Libenson MH. Hemimegalencephaly: a longitudinal MR study. AJNR Am J Neuroradiol 1994; 15:1479 1482. Vigevano F, Bertini E, Boldrini R, et al. Hemimegalencephaly and intractable epilepsy: benets of hemispherectomy. Epilepsia 1989; 30:833 843. Mathis JM, Barr JD, Albright AL, Horton JA. Hemimegalencephaly and intractable epilepsy treated with embolic hemispherectomy. AJNR Am J Neuroradiol 1995; 16:1076 1079. Yagishita A, Arai N, Tamagawa K, Oda M. Hemimegalencephaly: signal changes suggesting abnormal myelination in MRI. Neuroradiology 1998; 40:734 738. Rintahaka PJ, Chugani HT, Messa C, Phelps ME. Hemimegalencephaly: evaluation with positron emission tomography. Pediatr Neurol 1993; 9:21 28. Adamsbaum C, Robain O, Cohen P, Delalande O, Fohlen M, Kalifa G. Focal cortical dysplasia and hemimegalencephaly: histological and neuroimaging correlations. Pediatr Radiol 1998; 28:583590. Woo C, Chuang S, Becker L, et al. Radiologicpathologic correlation in focal cortical dysplasia and hemimegalencephaly in 18 children. Pediatr Neurol 2001; 25:295303. Carreno M, Wyllie E, Bingaman W, Kotagal P, Comair Y, Ruggieri P. Seizure outcome after functional hemispherectomy for malformations of cortical development. Neurology 2001; 57:331333. Di Rocco C, Iannelli A. Hemimegalencephaly and intractable epilepsy: complications of hemispherectomy and their correlation with the surgical techniquea report on 15 cases. Pediatr Neurosurg 2000; 33:198 207.