Epidermal Nevus Syndrome with Hemimegalencephaly: Neuropathological Study

Ryoichi Sakuta, MD, Hisashi Aikawa, MD, Sachio Takashima, MD and Shigeo Ryo, MD

A neuropathologic examination of a 5-year-boy with epidermal nevus syndrome and hemimegalencephaly revealed 1) left hemimegalencephaly with an increased volume of the white matter, and 2) cerebral polymicrogyria with pachy­gyria, heterotopic neurons and prominent astrogliosis. Golgi staining revealed hypertrophic neurons with increased dendrites and spines. The hemihypertrophy of the cerebral hemispheres seems to have contributed to an increased volume of the white matter with migration disorder, and may have been due to a disorder in the germinal cell prolifera­tion stage. Key words: Epidermal nevus syndrome, hemimegalencepholy, polymicrogyria, pochygyria, migration disorder.

Sakuta R, Aikawa H, Takashima S, Ryo S. Epidermal nevus syndrome with hemimegalencephaly: neuropathological study.

The epidermal nevus syndrome (ENS) is clinically charac­terized by several types of linear lesions of the skin with associated congenital anomalies including bony deformi­ties and/or central nervous system lesions [1]. Anumber of cases of ENS with hemimegalencephaly have been reported in the radiological and pathological literature [2-4]. However, the histological details of hemimegal­encephaly associated with ENS are largely unknown, except for the case reported by Choi and Kudo [3]. They suggested that the basic abnormalities were defects in speci~ic developmental events, such as neuronal migration and cortical differentiation. We report the neuropatho· logical, immunohistochemical and Golgi findings in a typical case of ENS with hemimegalencephaly.

CASE REPORT

The clinical characteristics of the patient including the histological findings for the skin lesion were reported

From the Department of Pediatrics, Nihon University School of Medicine, Tokyo (RS); Department of Pediatrics, Numazu City Hospital, Shizuoka (SR); Divisions of Ultrastructural Research (RS, HA) and Mental Retardation and Birth Defect Research (ST), National Institute of Neuroscience, NCNP, Kodaira, Tokyo.

Received for publication: November 16, 1990. Accepted for publication: May 27,1991.

Correspondence address: Dr. Ryoichi Sakuta, Division of Ultra­structural Research, National Institute of Neuroscience, NCNP, Kodaira, Tokyo 187, Japan.

Brain Dev 1991;13:260-5

previously [5]. A 5-year-old boy, the third child of unrelated Japanese parents, was born after a normal full-term pregnancy. At birth he was noted to have pig­mented nevi on the left forehead and left neck, and hemihypertrophy of the left side of the body. He devel­oped intractable seizures, mental retardation and right hemiparesis. His seizure pattern changed from early in­fantile epileptic encephalopathy to infantile spasms at 2 months of age. Electroencephalograms showed a burst-suppression pattern in the neonatal period, which subsequently changed to hypsarrhythmia. Computerized tomography of the brain showed left hemimegalencephaly with calcification. Histological examination of the pig­mented nevus on the neck revealed an acanthosis nigri­cans-like lesion. The boy unexpectedly developed severe generalized tonic-clonic seizures which were controlled within 1 hour of admission with diazepam and pheno­barbital. However, consciousness did not recover, and the pupils became fixed and dilated. He died 24 hours follow­ing admission.

Postmortem examination

A postmortem examination was carried out four hours after death but was limited to an examination of the brain. The brain was fixed in 10% formalin for three weeks. Sections of various regions were embedded in paraffm, and stained with hematoxylin-eosin, Luxol fast blue, Holzer, antisera against glial fibrillary acid­ic protein (GFAP) and synaptophysin, and Golgi stains.

Neuropathological fmdings

The unfixed brain weighed 1,550 gm, compared with a nonnal weight of about 1,300 gm. There was asymmetry of the cranium characterized by a larger left middle fossa. The cerebral hemispheres showed marked asymmetry, the left hemisphere being larger than the right one. The brain was swollen with herniation of the hippocampal unci and cerebellar tonsils. The leptomeninges were thick and slightly congested. The gyral fonnation of the right hemisphere was nonnal, but pachygyria and polymicro­gyria were evident in the frontal and parietal lobes of the left cerebral hemisphere. The pons, medulla and cerebel­lum were also asymmetric, being larger on the left side. The vessels of the circle of Willis and the cranial nerves were nonnal (Fig 1).

On coronal sectioning the right cerebral hemisphere was found to be nonnal, but the left hemisphere had thick gyri with many shallow sulci. There were multi­focal white color changes in the cortex and an increased volume of white matter, predominantly in the frontal and parietal lobes (Fig 2). The left side of the corpus callosum was large and the left lateral ventricle appeared to be replaced by spongy tissue. The basal ganglia and thalamus were displaced inferiorly. The left Sylvian fis­sure was incompletely fonned with a widely exposed insula. The left posterior and inferior horns of the lateral ventricles were slightly dilated. Both lateral ventricular walls were granular.

Light microscopic examination revealed marked cerebral hypertrophy with polymicrogyria in the cortex

Fig 1 Gross photograph of the cerebrum. Note left hemimegal· encephaly with cerebral polymicrogyria.

Fig 2 Coronal sections showing increased white matter volume predominantly in the frontal and parietal lobes (A, B, C). Note ob­struction of the left anterior homs of the lateral ventricles, and displacement of the basal ganglia and thalamus due to spongy and gliotic changes of subependymal areas of the caudate nucleus.

Sakuta et al: Epidermal nevus syndrome 261

and heterotopic neurons and prominent astrogliosis in the white matter of the left hemisphere (Fig 3A, B, C). The left megalencephalic hemisphere showed several kinds of polymicrogyria with an irregular neuronal arrangement, which in some areas formed 4 layer pattern. The sulci were shallow and adjacent cortices were fused, engulfmg

D

262 Brain & Development, Vol 13, No 4, 1991

meningeal vessels (Fig 4). The meningeal arteries were very large with thickened walls. Occasional leptomeningeal glioneuronal heterotopias were observed. The volume of the cerebral white matter was markedly increased and myelination had irregularly invaded into the cortex (Fig 3A, C). There were several areas with hypertrophic astro-

Fig 3 The left hemi­sphere showing a thick cortex with many shal­low sulci, with invasion of myelination into the cortex, and hypertro­phy of the frontal and parietal white matter (A, C), comparing with the right hemisphere (D). Marked gliosis appeared around the spongy lesions and white matter (C). (A, C, D: Luxol fast blue stain, B: Holzer stain)

Fig 4 The left frontal cortex showing poly microgyria with fused sulci. (HE x 100)

'. .. . . .. .'

.1'\ ' : ~ '. '. i

........ ~ ...• ". . . : :,. -.. -. :". ~

') .. ') ' . . '-- ",. •· .. S 1 • ',:,1 -r; , . . • • • • , .I • •• ., • . .. . ' .. . . . ' "f' . . ' • :- • ' . .. ii, ..

. . . - ".

Fig 5 Calcifications in periventricular white matter of the left frontal lobe. (HE x 100)

Fig 6 Spongy and gliotic changes with prominent vessels in sub· ependymal areas of the caudate nucleus. (HE x 100)

•

, . (

) (

I l

f -1 .j ,J.''''''

l' " ~'.I. .. , \. ~ .;.. . l' \

I \. .~.

t'

Fig 7 Hypertrophic astrocytes in spongy and gliotic lesions. (GFAPx 100)

0 •• , •

0

• • ,. • ~ .1

.. ' (

1

Fig 8 Heterotopic neurons remaining in the white matter. (Syn· aptophysin immunostaining x 150)

Fig 9 I"egulor neuronal amzngement (arrows) in various direc· tions in the frontal cortex. (Golgi x 40)

Sakuta et al: Epidermal nevus syndrome 263

cytosis and/or accumulation of macrophages. Calcification involving the perivascular space and vascular walls was prominent at periventricular sites (Fig 5). Some vessels showed fibrous thickening of their walls and narrowed or obstructed lumens (Fig 6). The putamen and caudate nucleus contained normal neurons, but were laterally displaced. The thalamus was not deformed. The globus pallidus had a reduced complement of neurons. Areas possibly representing the lateral ventricle were spongy with fibrous astrogliosis (Fig 7). The hippocampus had a tortuous and elongated granular layer. The inferior horn was large.

The midbrain showed symmetrical anatomical land­maIks associated with mild proliferation of astrocytes. The pons was normal. Granular cells were decreased in the cerebellum. The arcuate nucleus of the medulla ob­longata was absent on the right side. The junction of the medulla and spinal cord was normal. The left cerebellar hemisphere was normal with a regular neuronal arrange­ment and normal myelination.

Immunohistochemistry showed marked GFAP positive astrocytes in the cerebral cortex and white matter. Syn­aptophysin staining was demonstrated in the cerebral cortex and in the neuronal heterotopias in the white matter (Fig 8).

On Golgi staining of the frontal cortex, most pyramidal neurons were found to be arranged radially, but some were oriented obliquely and hOrizontally. A small number of neurons were upside-down. The soma was variable in size, but basal dendrites were short in small neurons and their branchings were irregular in most of the pyramidal and stellate neurons (Fig 9). Also identified in the deeper cortex were giant pyramidal and stellate neurons with large amounts of cytoplasm and thick dendrites. The large soma had a rounded or multipolar contour and the dendrites showed complex branchings with many spines.

DISCUSSION

The pathological features observed in this case included: 1) left hernimegalencephaly with cerebral polymicrogyria; 2) obstruction of the left anterior horns of the lateral ventricles, and displacement of the basal ganglia and thalamus due to spongy and gliotic changes involving subependymal areas of the caudate nucleus; 3) local calci­fication of the periventricular white matter of the left frontal lobe; 4) the absence of an arcuate nucleus in the left medulla oblongata; 5) decreased granular cells in the cerebellum; and 6) granular ependymitis.

Many neurologic abnormalities have been reported in association with ENS [6]. Fifty percent of patients have had severe to moderate neurologic involvement and most of them have exhibited electroencephalographic evidence of focal spike activity. The most common (40%) abnor­mality is mental retardation. Other abnormalities have

264 Brain & Development, Voli3, No 4, 1991

included focal and grand mal epilepsy, hyperkinesia, hemiparesis, quadriplegia, cranial nuclei abnormalities (mostly of the 6th, 7th and 8th nerves), cortical blindness and astrocytoma.

Fletcher [7] defmed megalencephaly as "proportio­nate enlargement of the whole brain, associated with the presence of a variable mental or nervous aberration." Recently, the accepted defmition has been a brain weigh­ing 2.5 standard deviations above the mean for the same age and gender. Dekaban and Sakuragawa [8] subdivided the megalencephalies into three main categories. Primary megalencephalies could be an isolated fmding or associ­ated with achondroplasia occurring on endocrine disturb­ances. Secondary megalencephalies are associated with a neurocutaneous syndrome or metabolic disorders, such as sphingolipidosis, mucopolysaccharidoses and leucodystro­phies (Canavan disease, Alexander disease, etc). The third group includes unilateral megalencephaly, which could be associated with hypertrophy of one side of the body. A variety of neuropathological changes have been described in hemirnegalencephaly including an abnormal cortical cytoarchitecture, non-specific nerve cell abnormalities, varying degrees of gliosis, large neurons and an excess number of neurons [9].

Neuropathologic examination of the brain in patients with ENS has only rarely been reported. Mollica et al [10] described a newborn infant who had a large epider­mal nervus and who died 36 hours postnatally. Autopsy revealed a leptomeningeal hemangioma. Holden and Dekaban [11] found an arachnoid cyst overlying a dys­genetic cerebral cortex in one child and cortical atrophy in another child. A case reported by Meyerson [12] showed a low grade astrocytoma localized in the hypo­thalamus. Our case showed marked hypertrophy of the cerebral white matter with spongy and gliotic changes around the lateral ventricular areas, but did not show neoplasms.

The pathological features of reported cases of hemi­megalencephaly show a wide spectrum. Bignami et al [13] reported polymicrogyri with prominent fusion of the molecular cortical layers. Laurence [9] reported disorganization of the cytoarchitecture of the gray matter, swollen distorted nerve cells arranged in irregular layers with large vacuolated ganglion cells and gliosis of the white matter. Large neurons have been described: a three­fold increase in size of neurons, a three-fold increase in nuclear volume and a six-fold increase in nucleolar volume [14]. Also noted have been generalized proliferation of neurons and hypertrophy of the white matter (diffuse gangliocytoma) [15]; blurred demarcation of the cortex and white matter, ectopic neurons in the white matter, scattered giant bizarre neurons, astrocytosis and large atyp­ical neurons in subjacent white matter [16], lissencephaly [16], and pachygyria [17-20]. Robin et al [21], on elec­tron microscopy, found glial abnormalities consisting of

hyperplasia with giant astrocytes and Rosenthal fibers. Golgi staining revealed many giant neurons whose peri­karya were covered by perisomatic processes. The dendritic tree was reported to be complex. Our case has typical features of white matter hyperplasia and polymicrogyria with pachygyria, similar to some of the case reports of hemimegalencephaly.

Pachygyria, agyria, lissencephaly and neuronal hetero­topias have been described in association with disturbances of neuronal migration. In our case, migration disorders may have occurred at 3-5 months of gestation, and the spongiosis accompanied by calcification and gliosis may have been secondary to disturbances of the microcircula­tion. The hemihypertrophy of the cerebral hemispheres contributed to the hypertrophy of white matter with migration disorders, but the etiology remains unknown.

Bignami et al [14] reported a 30% increase in DNA content and a 300% increase in protein in the affected hemisphere. Manz et al [19] also reported a 40% increase in DNA, a 56% increase in RNA and a 66% increase in protein, and suggested heteroploidy of chromosomal DNA, and increased transcription and translation in the hemimegalic hemisphere. In our case some pyramidal and stellate neurons were hypertrophic with an increased number of dendrites and spines. Recently, a cell line was established from a continuous culture of human cerebral cortical neurons obtained from a patient with unilateral megalencephaly [22]. The cells displayed a mature neuronal morphology with neurons with long, extensively branched processes with spines and varicosities in the presence of a nerve growth factor. The cells stained posi­tively for neurofilament protein and neuron-specific enolase, but were negative' for glial markers. This neuronal cell line may facilitate characterization of the unique pathogenesis in hemimegalencephaly which comprises overgrowth of neurons and myelin sheaths.

ACKNOWLEDGMENTS

We thank Professor Masahiko Okuni (Department of Pediatrics, Nihon University School of Medicine, Tokyo) for his suggestion and advice on this work.

REFERENCES 1. Solomon LM, Fretzin DF, Dewald RL. The epidermal nervus

syndrome. Arch Dermatol 1968;97:273-85. 2. Levin S, Robinson RO, Aicardi J, et al. Computed tomogra­

phy appearance in the linear sebaceous nevus syndrome. Neuroradiology 1984;26:469-72.

3. Choi BH, Kudo M. Abnormal neuronal migration and glio­matosis cerebri in epidermal nevus syndrome. Acta Neuro­pathol (Berl) 1981;53:319-25.

4. Robain 0, Floquet CH, Heldt N, Rozenberg F. Hemimegal­encephaly: a clinicopathological study of four cases. Neuro­pathol Appl Neurobiol 1988; 14: 125-35.

5. Sakuta R, Aikawa H, Takashima S, Yoza A, Ryo S. Epider­mal nevus syndrome with hernimegalencephaly: a clinical report of a case with acanthosis nigricans-like nevi on the face and neck, hemimegalencephaly, and hemihypertrophy of the body. Brain Dev (Tokyo) 1989; 11:191-4.

6. Solomon LM, Esterly NB. Epidermal and other congenital organoid nevi. Curr Probl Pediatr 1975;6: 3-56.

7. Fletcher HM. A case of megalencephaly. Transactions of the Pathological Society of London 1900; 51: 230-2.

8. Dekaban AS, Sakuragawa N. Megalencephaly. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology. Vol 30. Amsterdam: North Holland, 1977:647-60.

9. Laurence KM. A case of unilateral megalencephaly. Dev Med Child Neurol 1964;6:585-90.

10. Mollica F, Pavone L, Nuciforo G. Linear sebaceous nevus syndrome in a newborn. Am J Dis Child 1974; 128:868-71.

11. Holden KR, Dekaban AS. Neurological involvement in nevus lateris and nevus linearis sebaceus. Neurology 1972;22: 879-87.

12. Meyerson LB. Nevus unius lateralis, brain tumor, and dience­phalic syndrome. Arch Dermatol 1967; 95 :501-4.

13. Bignami A, Zappella M, Benedetti P. Infantile spasms with hypsarrhythmia. A pathological study. Helv Paediatr Acta 1964; 19:326-42.

14. Bignami A, Palladini G, Zappella M. Unilateral megalence­phaly with nerve cell hypertrophy. An anatomical and quantitative histochemical study. Brain Res 1968; 9: 103-14.

15_ Dom F, Brucher JM. Hamartoblastome (gangliocytoma diffuse) unilateral de l'ecorce cerebrale. Rev Neurol (Paris) 1969; 120:307-18.

16. Townsend 11, Nielsen SL, Malamud N. Unilateral megalence­phaly: hamartoma or neoplasm? Neurology 1975;25: 448-53.

17. Tijiam AT, Stevanko S, Schenk VMD, Vlieger de M. Infantile spasms associated with hemihypsarrhythmia and hemimegal­encephaly. Dev Med Child NeuroI1978;20:779-98.

18. Fitz CR, Harwood-Nash DC, Boldt DW. The radiographic features of unilateral megalencephaly. Neuroradiology 1978; 15:145-8.

19. Manz HJ, Phillips TM, Rowden G, McCulloch DC. Unilateral megalencephaly, cerebral cortical dysplasia, neuronal hyper­trophy and heterotopia: cytomorphometric, fiuorometric, cytochemical and biochemical analysis. Acta Neuropathol (Berl) 1979;45:97-103.

20. King M, Stephenson JBP, Ziervogel M, Doyle D, Galbraith S. Hemimegalencephaly. A case for hemispherectomy. Neuro­pediatrics 1985; 16:46-55.

21. Robin 0, Chiron C, Dulac O. Electron microscopic and Golgi study in a case of hemimegalencephaly. Acta Neuro­path 01 1989;77:664-6.

22. Gabriele YR, Lynda DH, Jeffrey SN, Karen C, Solomon HS. Human cortical neuronal cell line: establishment from a patient with unilateral megalencephaly. Science 1990; 248: 603-5.

Sakuta et al: Epidermal nevus syndrome 265