Periventricular heterotopia and epilepsy Peter R. Huttenlocher, MD; Sasidharan Taravath, MD; a n d Saeid Mojtahedi, MD Article abstract-We report a family with nodular subependymal masses of heterotopic gray matter occurring in six members in four generations. Only female members of the family are affected, and there is a high rate of spontaneous abortion, consistent with X-linked dominant inheritance, and lack of viability in affected males. Both in this family and in sporadic cases of subependymal heterotopias there is a high frequency of convulsive disorders, suggesting that epilepsy may be the major clinical manifestation of this developmental defect. NEUROLOGY 1994;44:51-55 Neuronal migration in the embryonic CNS is a complex process of outward radial movement of neuronal and glial precursor cells from the periventricular proliferative zone to the cortical plate. This migration may be arrested at various stages, giving rise to heterotopias. Heterotopic gray matter may occur in subcortical regions, as in lissencephaly, where entire populations of neurons that normally form the upper cortical layers remain below the cortical plate. Less severe defects include laminar bands of heterotopia and islands of heterotopic neurons in the subcortical white matter.l Another form of heterotopic gray matt e r occurs in a periventricular location, in the region of the original g e r m i n a l m a t r i x . P e r i v e n t r i c u l a r (subependymal) heterotopias are nodular masses, u p t o 2 cm in size, that protrude into the ventricular lumen. They are a prominent component of the migratory disorder of tuberous sclerosis2 but may occur as isolated defects in otherwise normal brains. Reports of the latter type were primarily as incidental autopsy f i n d i n g F or as abnormalities on imaging studies of the brain.6-s There are few reports that address the clinical findings in such cases, and there is no information about genetic factors. We studied a large family in which six members in four generations have n o d u l a r subependymal heterotopias, indicating that this developmental defect m a y be genetically determined. Patient reports. The family was initially referred to the Tuberous Sclerosis (TSc) Clinic a t the University of Chicago. A diagnosis of TSc had been made elsewhere. However, none of the affected family members had the skin, renal, or cardiac lesions of TSc. Four of six family members with subependymal heterotopias on brain imag- ing studies had a history of prolonged tonic-clonic seizures that responded well to therapy with standard anticonvulsant agents. Cognitive impairments were absent or mild. Strokes have occurred in at least two and most likely three affected family members (patients 1, 3, and 5), including an apparent embolic stroke in a 19-year-old. Only female members of the family are affected (figure 1).There is a high incidence of spontaneous abortion, with 11 miscarriages in five affected women. Affected women have nine live daughters and only two sons. The inheritance pattern is suggestive of X-linked dominant transmission with fetal death in affected males. The family is of Irish-Swedish origin. In addition to this family, we studied one other patient with similar periventricular heterotopias on MRI who also presented with a seizure but whose family history is negative (patient 7). Patient 1. This 71-year-old woman has a history of multiple strokes since age fifty. She has a mild right hemiparesis but otherwise is remarkably intact neurologically. Cerebral angiogram a t age 69 showed left carotid artery occlusion. She subsequently had a left carotid endarterectomy. Imaging studies of the brain showed multiple, bilateral cortical and subcortical lesions consistent with infarcts. In addition, there were bilateral nodular subependymal gray matter heterotopias. She has a history of Sydenham's chorea in childhood, negative for seizures. She has three daughters, including patients 2 and 3. She has also had three miscarriages. Patient 2. This 48-year-oldwoman had onset of generalized tonic-clonic seizures at age eighteen. She at first had frequent recurrences, but has had complete seizure control since age 46 on carbamazepine monotherapy. Her neurologic examination was normal. MRI of the brain showed nodular periventricular heterotopias (figure 2). The patient has one daughter (patient 4).She has a history of three miscarriages. From the Departments of Pediatrics, Neurology, and Radiology, The University of Chicago, Chicago, IL. Supported by funds from the Illinois Tuberous Sclerosis Association. Received May 4, 1993. Accepted for publication in final form July 8, 1993. Address correspondence and reprint requests to Dr. Peter R. Huttenlocher, University of Chicago, Department of Pediatrics, 5841 South Maryland Avenue, MC/3055, Chicago, IL 60637. January 1994 NEUROLOGY 44 51 Stroke Case Ii ;Ttl”rpr: *$IF case Ill Stroke 5 Miscarriages Seizures I eizuren Seizures 1 0 OJa Neonatal Hemorrhaoic Dlsease Case VI Stillborn Figure 1. Family pedigree showing affected females in three generations and large numbers of miscarriages. lesions. The patient has also had five miscarriages. Patient 4. This 26-year-old woman had a single generalized tonic-clonic seizure a t age twenty-four. She is presently receiving phenytoin therapy, without seizure recurrence. Her medical history is unremarkable, except for migraine. A head CT showed multiple nodular periventricular heterotopias. She had a normal EEG. The patient has two children. A 5-year-old son is clinically normal and had a normal brain MRI. A 2-year-old daughter (patient 6) has periventricular heterotopias on MRI. Figure 2. Brain MRI. TI-weightedimage showing periventricular heterotopias in patient 2 (arrows). Patient 3. This 45-year-old woman has had generalized tonic-clonic seizures since age four. The seizures have recurred as frequently as once per week, and some have been prolonged, including status epilepticus. Present therapy includes phenytoin and primidone. At age 41, she developed a right hemiparesis. Subsequent brain MRI showed a large area of encephalomalacia in the left temporal lobe as well as multiple small lesions in the subcortical white matter with increased signal on T2.The white matter lesions have been variously interpreted as strokes and areas of demyelination. In addition, the MRI showed extensive nodular periventricular heterotopias. An MRI of the spinal cord was normal, as were visual and somatosensory evoked potentials, spinal fluid examination including measurement of immunoglobulin G, and serum values for antigenic protein C, protein S, and antithrombin 111. An EEG showed epileptiform discharges arising independently from both temporal regions, more marked on the left, a s well as bitemporal and frontal slowing of background rhythms. The patient has three daughters, including patient 5. She had one son who died a t age 7 days due to multiple systemic hemorrhages. Autopsy did not reveal any brain 52 NEUROLOGY 44 January 1994 Patient 5. This 21-year-old woman had a generalized tonic-clonic seizure a t age 5 years. She had one recurrence a t age 18, and has been seizure-free since then on phenobarbital therapy. At age 19 years, she had sudden onset of left hemiparesis. A cerebral angiogram showed a thrombus in the right middle cerebral artery (MCA). MRI of the brain showed a large infarct in the right MCA territory a s well a s extensive nodular periventricular gray matter heterotopias (figure 3). No source of an embolus was found. An EEG 3 days after the stroke showed a slow-wave focus in the right temporal and frontal regions but no epileptiform discharges. Serum antigenic protein C was deficient in the heterozygote range (52%; normal range, 80% to 120%). At age 19, the patient had a still-born girl with a nuchal cord. She recently had a clinically normal boy who has not as yet had an imaging study of the brain. Patient 6. This 2-year-old girl has a history of surgery for patent ductus arteriosus. She is developing normally and has not had seizures. Her head circumference is at the 25th percentile. At age 21 months she had an MRI of the brain as part of a family study. This showed an irregular contour of the lateral walls of the lateral ventricles due to small nodular masses that were isointense to the gray matter. The nodular gray matter heterotopias were somewhat less extensive than those found in other affected family members. Patient 7. The patient is a 26-year-old man who is unrelated to the large family. He was well until age 25, when he had a single generalized tonic-clonic seizure, CT and MRI of the brain were obtained a s part of a seizure workup. These showed extensive bilateral nodular periventricular heterotopias (figure 4). A diagnosis of TSc was considered, and the patient was referred to the TSc Clinic a t the University of Chicago for further evaluation. A neurologic examination and examination of the skin Table. Reported cases of nodular periventricular heterotopia ~ Reference N Sex Seizures MR Comments Present cases, familial 6 6F 4 0 Strokein 2 or 3; many miscarriages Present case, sporadic Zimmerman et a16 Smith e t aI7 Barkovichand Kjos8 1 1M 1 0 2 2F 2 0 6 Unknown 5 8 2M,6F I Martin-Araguz e t all4 1 1F 1 Total 24 3M,15F 20 0 2 Hypoplasia (mild) of corpus callosum in I 0 2 MR Mental retardation. Figure 3. Brain MRI. Proton-density image, patient 5. Periventricular heterotopias are indicated by small arrows. There also is a large infarct involving the right frontoparietal cortex, internal capsule, and periventricular heterotopic tissue (large arrow). Figure 4. Brain MRI. TI-weightedimage showing periventricular heterotopias (arrows) in patient 7. and eyes were normal. He had normal EEG, renal ultrasound, and echocardiogram. There was no family history of seizures or of the skin lesions of TSc. A cousin had Down’s syndrome. Head CTs of both parents were normal. Discussion. Nodular periventricular heterotopias and seizures are common findings in TSc. This diag- nosis was entertained initially in the present cases. However, the findings on imaging studies of the brain excluded TSc. The periventricular heterotopias in the present cases are more diffuse, imparting an irregular outline to the lateral walls of the body of the lateral ventricles. Calcifications have not occurred in these lesions, in contrast to the subependyma1 heterotopias of TSc, which are almost always calcified past infancy. Periventricular heterotopias of TSc have heterogeneous signal intensity on MRI,S,1° whereas the lesions in the present cases always had signal characteristics of cortical gray matter. None of the present cases showed tumors near the foramina of Monro or the cortical-subcortical tubers that are typical of TSca2Mental retardation did not occur in the present cases; the major clinical resemblance to TSc is the occurrence of seizures. Although there is evidence of vertical transmission of the disorder in the large family reported here, the pattern of inheritance appears to be that of an Xlinked dominant gene with lack of viability in affected males rather than autosomal dominant inheritance as occurs in TSc. However, autosomal dominant inheritance cannot be excluded on the basis of this single pedigree. We also studied an apparently sporadic male patient with similar nodular periventricular heterotopias (patient 7). Dominant or Xlinked dominant inheritance in this patient are ruled out by normal imaging studies of the brain in the parents. Family studies in other cases are needed to confirm the inheritance patterns and to determine the proportion of cases with genetic transmission. No genetic information is provided for previously reported cases of periventricular heterotopias, but review of published reports indicates an excess of affected females (table). The largest series reported to date, by Barkovich and Kjos,B contains six females and only two males (table). Although there have been several pathologic reports of cases with nodular periventricular heterotopias, these had insufficient clinical data for delinJanuary 1994 NEUROLOGY 44 53 in the present cases are glial in nature derives some eation of a clinical syndrome. Greenfield3provided an support from the fact that there is no zone of white illustration of a pathologic specimen with the typical matter interposed between the nodular heterotopias nodular lesions but did not give a clinical history for and the ventricular lumen. Such a band of white the patient. There are reports of nodular periventricumatter tends to form in defects of neuronal migralar heterotopias in association with other develoption, such as laminar (band) heter0topias.l mental defects of brain including hydrocephalus, agenThe occurrence of strokes early in life in three afesis of the corpus callosum, micropolygyria, and fected family members studied by us raises the quesmegalen~ephaly.~ Meschede11J2and Virchow13 protion of whether stroke is part of the syndrome of vided early descriptions of widespread subcortical hetperiventricular heterotopia. We did not find any reerotopias. Histologic examination demonstrated ocports of strokes in cases of periventricular heterotopias currence of neurons and glia in such malformations.12 other than in the family we studied. Stroke in this Recent radiologic studies provide some clinical infamily is probably related to a separate genetic defect. formation in addition to the imaging findings. Zimmerman et a16 briefly reported two unrelated girls The family reported here appears to provide the first proof of genetic transmission of periventricular heterowith nodular gray matter densities protruding into the lateral ventricles. Both had histories of seizures topias. This malformation now needs to be considered since childhood. Smith et al,7 in a survey that inin families with epilepsy in multiple generations. cluded six imaging centers, identified six cases with Addendum. A family i n which a mother and bilateral subependymal nodules, including one with daughter both had periventricular heterotopias and autopsy confirmation of ectopic gray matter. Five of seizures has recently been reported. l8 the six had a history of seizures; in one, the periventricular heterotopias were an incidental finding in a References tumor patient studied for possible CNS metastases. This report does not provide further details, such as 1. Livingston JH, Aicardi J . Unusual MRI appearance of difthe sex of the patients or the family history. Martinfuse subcortical heterotopia or double cortex in two children. J Neurol Neurosurg Psychiatry 1990;53:617-620. Araguz et all4 reported a single case with seizures as 2. Stefansson K, Wollmann RL, Huttenlocher PR. Lineages of the only clinical manifestation. Barkovich and Kjoss cells i n t h e central nervous system. In: Gomez MR, ed. recently reported eight patients with subependymal Tuberous sclerosis. 2nd ed. New York: Raven Press, 1988: gray matter heterotopias, most of whom had both 75-87. complex partial a n d generalized tonic-clonic 3. Adams J H , Corellis JAN, Duchen LW, eds. Greenfield's neuropathology. 4th ed. New York: John Wiley and Sons, seizures. These cases, as well as the ones reported 1984~411-413. here, suggest a high association between periventric4. Friede RL. Developmental neuropathology. 2nd ed. New ular nodular heterotopias and epilepsy (table). The York: Springer-Verlag, 1989:333-335. seizures have been generalized tonic-clonic in most 5 . Crome L, Stern J. Pathology of mental retardation. 2nd ed. Edinburgh: Churchill Livingstone, 1972:141. of the reports that specified seizure type. 6. Zimmerman RA, Bilaniuk LT, Grossman RI. Computerized Seizure disorder as the only clinical manifestation tomography in migratory disorders of human brain developof a cerebral migratory defect is somewhat unexment. Neuroradiology 1983;25:257-263. pected, since mental retardation is a major finding in 7. Smith AS, Weinstein MA, Quencer RM, et al. Association of most other migratory disorders, including heterotopic gray matter with seizures. MR Imaging Radiology 1988;168:195-198. lissencephaly, laminar heterotopias, and TSc. How8. Barkovich AJ, Kjos BO. Gray matter heterotopias: MR charever, Meencke and Janz15J6reported subtle migraacteristics and correlation with developmental and neurotory disorders or microdysgenesis in a large proporlogic manifestations. Radiology 1992;182:493-499. tion of cases with primary generalized epilepsy, and 9. Inoue Y, Nakajima S, Fukuda T, et al. Magnetic resonance images of tcberous sclerosis. Neuroradiology 1988;30:379-384. suggested that these may be causally related to the 10 Braffman BH, Bilaniuk LT, Naidich TP, et al. MR imaging seizure disorder. The migratory disorder in our cases of tuberous sclerosis: pathogenesis of this phakomatosis, use appears to be much more extensive. Nevertheless, of aadopentetate dimadumine, and literature review. Neusufficient normal cortical architecture seems to be asroradioiogy 1992;183:227-238. sembled for the development of normal cognitive 11. Meschede F. Uber Neubildung grauer Hirnsubstanz in den Wandungen der Seiten-Ventrikel und iiber eine bisher nicht functions. The ectopic cells left behind in the perivenbeschriebene, durch Hyperplasie grauer Corticalsubstanz tricular (germinal matrix) zone may be predomibedingte Structur-Anomalie der Hirnrinde. Psychiat u Psynantly glia, as in the subependymal nodules of T S C . ~ chisch Gerichtl Med 1864;1:481-505. Gressens et all7 recently reported that, in the mouse, 12. Meschede F. Ein neuer Fall von abnormen Einlagerungen a late group of cells forms in the germinal matrix grauer Hirnsubstanz innerhalb der Medullarsubstanz des grossen Gehirns. Virchows Arch 1866;37:567-570. near term, after the completion of neuronal birth and 13. Virchow R. Heterotopie der grauen Substanz. Virchows Arch migration, and migrates to the upper (supragranu1867;38:138-142. lar) layers of cerebral cortex, where these cells form 14. Martin-Araguz A, Moreno-Martinez JM, Garrido-Carrion A, cortical astrocytes. In the mouse, damage to this cell Esteban-Alonso F. Heterotopic gray matter: an infrequent cause of epilepsy. Arch Neurobiol (Madr) 1989;52:140-143. population appears to affect neuronal function and 15. Meencke H-J, Janz D. Neuropathological findings in prisurvival. A migration disorder that starts late in demary generalized epilepsy: a study of eight cases. Epilepsia velopment, during t h e l a t e second a n d third 1984;25:8-21. trimesters, could therefore lead to a pure population 16. Meencke H-J, Janz D. The significance of microdysgenesia in primary generalized epilepsy: a n answer to considerations of arrested glia. The possibility that the heterotopias 54 NEUROLOGY 44 January 1994 Periventricular heterotopia and epilepsy Peter R. Huttenlocher, Sasidharan Taravath and Saeid Mojtahedi Neurology 1994;44;51 DOI 10.1212/WNL.44.1.51 This information is current as of January 1, 1994 Updated Information & Services including high resolution figures, can be found at: http://www.neurology.org/content/44/1/51.full.html Citations This article has been cited by 10 HighWire-hosted articles: http://www.neurology.org/content/44/1/51.full.html##otherarticles Permissions & Licensing Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions Reprints Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1994 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. 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