Background-Linear epidermal nevus syndrome and linear sebaceus nevus syndrome are rare neurocutaneous syndromes characterized by epidermal nevi, epilepsy, and mental retardation. Pathologic descriptions of the central nervous system findings in such patients are rare.
Design.-We examined the clinicopathologic features of 2 patients with linear epidermal nevus syndrome and 1 with nevus sebaceus syndrome who underwent surgical resections for chronic epilepsy in a tertiary referral center with a high volume of epilepsy surgery.
Results.-Patients included 3 females, aged 11 months (patient 1), 8 years (patient 2), and 2 1/2 years (patient 3) at the time of surgery. The duration of seizures prior to surgery was 11 months, 6 years, and 28 months, respectively. Two patients had epidermal nevi involving the head region (patients 1 and 3), and 1 had a nevus sebaceus of Jadassohn (patient 2); patient 2 had a choristoma, and patient 3 had
a dermoid cyst in the eye region. Patient 1 demonstrated hemimegalencephaly radiographically. Histologic examination of resected cortical tissue in patients 1 and 2 demonstrated severe diffuse cortical dysplasia characterized by a disorganized cortical architectural pattern, a haphazard orientation of cortical neurons, and increased molecular layer neurons. Gyral fusion was seen in patient 1. Pial glioneuronal hamartomas were observed in patient 1. Prominent cortical astrocytosis was seen in patients 1 and 2, and foci of microcalcification were evident in patient 1. Cortical dysplasia was milder in patient 3 and consisted of an increased number of molecular layer neurons. Neuronal heterotopia was observed in all 3 patients.
Conclusion.-The spectrum of neuronal migration abnormalities in the setting of these syndromes may be variable in terms of its histologic phenotypic manifestations.
(Arch Pathol Lab Med. 1999;123:301-305)
Neurocutaneous syndromes include a wide variety of disorders, which are characterized by congenital dysplastic abnormalities involving both the skin and the nervous system. Many of these syndromes are associated with chronic epilepsy. The most commonly encountered neurocutaneous syndromes include tuberous sclerosis, Sturge-Weber syndrome, and a subset of patients with neurofibromatosis type I. There are, however, a number of less commonly encountered neurocutaneous syndromes that are associated with chronic epilepsy. Linear sebaceus nevus syndrome was first recognized in 1962 by Feuerstein and Mims1 as a condition characterized by a triad of findings, including seizures, mental retardation, and linear sebaceus nevus of Jadassohn. Subsequently, the types of congenital skin lesions that have been described in this setting have been expanded to include a variety of epidermal nevi and resulted in the designation of epidermal nevus syndrome, coined in 1968 by Solomon et al.2 Since the earliest cases, these syndromes have been reported in the literature associated with a variety of central nervous system symptomatologies and abnormalities. Relatively few studies have documented the specific neurohistopathology in tissue removed from these patients.
This study examines 2 patients with linear epidermal nevus syndrome and 1 with nevus sebaceus syndrome who underwent surgical resection for intractable epilepsy. The clinicopathologic features of these cases are described with particular regard to the histopathology.
REPORT OF CASES
The patient is an 11-month-old female infant who presented at 1 day of age with myoclonic jerks in both arms. A computed tomographic scan performed at that time showed right hemimegalencephaly. The child was a product of a pregnancy complicated by toxemia, which was treated with antihypertensive medications, and a cesarian section, performed because of macrocephaly (head circumference 40 cm at birth). An epidermal nevus was appreciated at birth over the midline facial region and off to the right side of the forehead with a linear extension down the midline bridge of the nose and the philtrum. In addition, a white, bandlike lesion was noted on the surface of the tongue. A position emission tomographic scan showed evidence of hypometabolism throughout the right hemisphere with a focus of increased metabolism in the right occipital lobe region. Despite anticonvulsive medication, seizures persisted at a frequency of 10 to 15 per day. On examination, the infant was noted to be developmentally delayed and showed left hemiparesis and decreased vision in both eyes. Her head circumference at 7 months of age was 49 cm (approximately 4 SD above the mean). At 11 months of age, she underwent a right hemispherectomy. Postoperatively, the patient was seizure-free for approximately 3 months, at which time she developed recurrent seizures. Increasing head size and ventricular size prompted placement of a right frontal ventriculoperitoneal shunt with redo right frontal disconnection.
The patient is an 8-year-old girl who presented with seizures at age 2 months. She was the product of a full-term uncomplicated pregnancy and delivery. A left facial nevus sebaceus of Jadassohn was excised at 1 year. Seizures persisted despite antiepileptic medication. On examination, the patient was noted to be severely developmentally delayed; she was able to follow only simple commands, had a vocabulary of approximately 10 to 20 words, and had poor fine motor coordination. A magnetic resonance imaging study showed evidence of cortical dysplasia involving the left inferior temporal and left occipital lobes and an arachnoid cyst in the left middle cranial fossa (Figure 1). A position emission tomographic imaging study showed extensive hypometabolism in the left hemisphere, which was most severe in the temporal and occipital lobe regions. A left ptosis and dermoid cyst overlying the left upper conjunctiva were also seen. The patient underwent excision of the left occipital and temporal lobes, including amygdala and hippocampus. The patient has been completely free of seizures for 7 months postoperatively.
The patient is a 2 1/2-year-old girl who was delivered about 1 month premature by cesarean section. She was noted at birth to have an epidermal nevus overlying the right scalp and a bulbar dermoid cyst involving the lateral canthus of the right eye. The nevus was surgically excised during infancy. She began having seizures, which were refractory to a variety of medications, at approximately 2 months of age. A magnetic resonance imaging study showed pachygyria involving the right temporal lobe and evidence of cortical dysplasia in the right parietal-occipital region. A position emission tomographic scan demonstrated hypermetabolism in the right temporal lobe. On examination, the child was noted to be severely developmentally delayed. She underwent right temporal lobectomy. Postoperatively, she continued to have intractable seizures on antiepileptic medication and continued to demonstrate significant developmental delay. A magnetic resonance imaging study performed approximately 2 years after the initial surgery showed evidence of residual right parietal-occipital cortical dysplasia.
The histopathologic findings in patients 1 and 2 are quite similar. Both resection specimens demonstrated diffuse severe cortical dysplasia. The cortical dysplasia was characterized by loss of the normal 6-layer architecture of cortex, including focal loss of obvious lamination and haphazard orientation of neurons within the cortex (Figures 2 and 3). In particular, cortical layers 2 and 4 did not appear to be well formed. Both patients showed focal evidence of increased molecular layer neurons. Balloon cells and prominent neuronal cytomegaly were not observed. Foci of microcalcification were noted in both gray and white matter parenchyma; calcifications tended to be more perivascular in distribution in patient 1. Several small pial glioneuronal hamartomas were also noted in patient 1 (Figure 4). In both cases, increased numbers of neuronal cells were observed in the deep white matter, constituting neuronal heterotopia. Areas of gyral fusion were seen in patient 1. Focal areas of leptomeningeal fibrosis and chronic inflammation, possibly related to invasive monitoring were seen. Subpial gliosis was observed in both cases. Areas of mild perivascular atrophy involving white matter vessels were more pronounced in patient 2. A glial fibrillary acidic protein immunostain (1:600 dilution, Dako Corporation, Carpinteria, Calif) highlighted a marked degree of reactive astrocytosis in both gray and white matter in both cases (Figure 5).
Cortical dysplasia was also observed in patient 3 and consisted primarily of increased numbers of molecular layer neurons (Figure 6). Focal heterotopic neurons, situated deep within the white matter, were also seen. Distortion of the cortical architecture and lamination, balloon cells, and neuronal cytomegaly were not observed. Focal meningeal fibrosis, chronic perivascular inflammation, and subpial gliosis were observed in patient 3.
Cortical dysplasia (neuronal migration abnormality, microdysgenesis) represents a group of malformative disorders of the cortex related to derangements in neuronal migration, most of which occur in the first 2 trimesters of gestation. Although there is general agreement with regard to the inclusion of certain lesions under the general heading of cortical dysplasia, inclusion of certain extracortical lesions is debated. Gross pathologic findings associated with dysplasia have included abnormalities of gyration and sulcation, including agyria, pachygyria, polymicrogyria, and laminar and nodular heterotopias. More subtle forms of dysplasia are often only evident upon microscopic examination. The spectrum of histologic findings in the setting of dysplasia has been well described in the literature in recent years. Most commonly these forms of dysplasia consist of a disruption of the normal cortical architecture, particularly with respect to neurons, although glial cells may participate in the dysplastic process.3-8
It is well recognized that cortical dysplasias are assocated with chronic epilepsy. Work in recent years has shown an association of cortical dysplasia with certain low-grade neoplasms that frequently arise in this setting, including gangliogliomas, dysembryoplastic neuroepithelial tumors, glial-neuronal hamartomas, and, most recently, pleomorphic xanthoastrocytomas.9-15 These neoplasms have a number of features in common, including a generally benign clinical course, low rates of cell proliferation, a generally young age of presentation, temporal lobe predisposition, and evidence of glial and neuronal differentiation. The association of cortical dysplasias with phakomatoses has also been long recognized. In particular, the association of neuronal migration abnormalities with tuberous sclerosis and neurofibromatosis type I has been well documented.4,16-22 Although less commonly encountered than tuberous sclerosis and neurofibromatosis type I, descriptions of cortical dysplasia associated with epidermal nevus syndrome suggest more than a casual relationship. In 1975, Solomon and Esterly23 retrospectively reviewed the clinical findings in 60 patients with epidermal nevus syndrome (including 6 patients with nevus sebaceus), many of whom were previously described in the literature. Fifty percent of the patients examined in their series had severe to moderate neurologic involvement.23 The most common clinical neurologic findings included mental retardation 40% and epilepsy in approximately 33%. Other less commonly observed neurologic abnormalities included evidence of hydrocephalus and cortical atrophy, hyperkinesia, partial or hemiparesis, cranial nerve disorders, cerebral hemangiomas and vascular malformations, and, rarely, tumors. Specific descriptions of the histopathologic findings in these cases, however, have been only sparsely reported in the literature.
In 1974, Mollica et al24 reported autopsy findings in a newborn infant with linear sebaceus nevus syndrome. Autopsy examination of the brain demonstrated a leptomeningeal hemangioma; however, pathologic description of the rest of the brain parenchyma was not offered. Holden and Dekaban25 in 1972 described 2 cases in which biopsy material was examined; 1 case demonstrated an arachnoid cyst overlying dysgenetic cortical tissue and the other case showed evidence of cerebral atrophy. More recently, a number of studies have documented examples of hemimegalencephaly in these patients.26-29 One of the 3 patients in our series had radiographic evidence of hemimegalencephaly. Examination of brain tissue from these patients revealed a variety of pathologic findings consistent with neuronal migration abnormalities. Vigevano et al27 described the absence of cortical neuronal layering, neuronal cytomegaly, neuronal heterotopias, and prominent gliosis in 2 hemispherectomy patients. The one patient described by Robain et al28 demonstrated evidence of so-called bizarre giant cells and atypical neuronal cells, often arranged in columns. Increased numbers of glial fibrillary acidic protein-positive astrocytic cells were noted in both gray and white matter. In addition, subependymal nodules of predominantly astrocytic cells were observed. In 3 cases autopsied by Pavone and colleagues29 in 1991, areas of pachygyria, sometimes associated with polymicrogyria, were noted in the affected hemisphere. Heterotopic white matter nodules, severely disturbed cortical cytoarchitecture (including neuronal cytomegaly), and prominent large astrocytes were also seen. Heterotopic neurons were observed within the white matter with increased astrocytosis and foci of mineralization. Histologic evaluation of brain tissue examined in a 3-month-old patient with epidermal nevus syndrome also documented a marked astrocytic proliferation and heterotopic gray matter within the centrum semiovale accompanied by neuronal cytomegaly.26
The histologic findings in 2 of the 3 patients in our series demonstrate pathologic features that overlap with those previously reported. In particular, marked cortical architectural disorganization and prominent astrogliosis of both gray and white matter were seen. Additionally, increased numbers of neurons were seen within the deep white matter, as were foa of microcalcification. In contrast to several of the previously reported studies, neuronal cytomegaly was not a prominent feature in any of the 3 patients in this series. Additional features that appeared to be unique to the patients in our series included the presence of increased numbers of molecular layer neurons in all 3 cases and foci of pial glioneuronal hamartomatous ectopic foci. In 1 of our 3 cases, increased numbers of molecular layer neurons was the only notable dysplastic abnormality observed.
Although not observed in any of the patients in our series, rare examples of tumor associated with epidermal nevus and nevus sebaceus syndromes have also been documented.30-34 Four of the 5 tumors described in this setting were gliomas, including 1 optic nerve glioma and 1 gliomatosis cerebri. The fifth tumor involved a choroid plexus papilloma. Choi and Kudo34 hypothesized that in addition to the neuronal migration abnormalities commonly encountered in this syndrome, an abnormality in the proliferative activity of astroglial cells may also occur in a subset of these patients, which may account for the increased risk of tumorigenesis. This is entirely unexpected, given the association of many of the other neurocutaneous syndromes with tumors.
The experience in the literature with regard to surgical outcome in patients with nevus syndromes, chronic epilepsy, and hemimegalencephaly has been somewhat limited. Vigevano and DiRocco35 reported no evidence of seizures after surgery in 3 such patients. In this series, 2 of the 3 patients had persistent seizures following surgery. Surgery appears to be helpful in a subset of patients with epidermal nevus syndrome, but not all cases are amenable to surgical control. Perhaps in some patients, the pathology is more extensive than the excised area or is predominantly but not exclusively confined to one side. Jahan et al36 recently reported bilateral cortical dysplasia in a 7-month-old girl with hemimegalencephaly at autopsy; this suggests that the dysplasia is not necessarily confined to the hemisphere that appears grossly abnormal.
The specific mechanisms underlying the development of nevus syndromes and the cortical dysplasias associated with these syndromes are largely not well understood. It has been hypothesized that epidermal nevus syndrome may be due to an autosomal dominant lethal mutation that survives by mosaicism.37 A somatic mutation may evolve early in embryogenesis that involves only parts of the body that develop from the mutated cell/cells. A variety of factors may come into play in the development of migrational defects, including abnormalities involved in neuronal cell proliferation, differentiation, programmed cell death, neuronal and glial interactions, and defects in cell division to name a few. Whether the abnormalities associated with epidermal nevus syndrome are the result of a single defect, perhaps a genetic mutation, or are the manifestation of multiple defects has yet to be discerned.
The authors thank Denise Egleton for her assistance in the preparation of this manuscript.
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Accepted for publication October 9, 1998.
From the Departments of Anatomic Pathology (Dr Prayson), Neurology (Drs Kotagal and Wyllie), and Neurosurgery (Dr Bingaman), Cleveland (Ohio) Clinic Foundation.
Reprints: Richard A. Prayson, MD, Department of Anatomic Pathology (L25), Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195.
Copyright College of American Pathologists Apr 1999
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