KISEP J Korean Neurosurg Soc 36 : 13-17, 2004

Clinical Article Relationship between Cavum Septum Pellucidum and Epilepsy

Ki - Young Choi, M.D., Jong - Pil Eun, M.D., Ha - Young Choi, M.D. Department of Neurosurgery, Research Institute of Clinical Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Korea

Objective : The authors study a relationship between the presence of cavum septum pellucidum(CSP) and the development of epilepsy by comparing the presence of CSP, which has been known to be a normal variation, in normal control group and epilepsy patients. Methods : This study included 377 patients with epilepsy and 252 controls without epilepsy. Of epilepsy patients, 168 patients underwent surgery due to intractability and 209 patients was on medication of antiepileptic drugs. Control group had only headache and no visible lesion in MRI. Of 168 surgical patients, 102 patients had temporal lobe epilepsy and 66 patients had extratemporal lobe epilepsy. Ninty five patients showed a neuronal migration disorder in histopathologic findings. Definition of "CSP" and "partial CSP" was followed by Pauling's classification. Results : CSP was present 8.2% of epilepsy patients and 1.6% of control group(p<0.01). CSP was detected in 11.3% of patients with surgical treatment and in 5.7% of patients with medical treatment. CSP was noticed in 8.9% of temporal lobe epilepsy, in 15.2% of extratemporal lobe epilepsy, in 13.7% of patients with neuronal migration disorder, and in 8.2% of patients with no neuronal migration disorder. Conclusion : Presence of CSP is statistically higher in epilepsy patients than in control group. This results indicates that the presence of CSP may not be a simple normal variation, and it can be considered a developmental anomaly that may contribute to epileptogenesis.

KEY WORDS : Cavum septum pellucidum·Epilepsy.

Introduction close from the posterior part starting the 6th month of gesta- tion26). It remains as a small slit but usually becomes to close eptum pellucidum refers to a thin translucent plate of two completely around the 2nd month of birth as brain develops. S laminae that parallels interhemispheric fissure. It forms However CSP can be occurred on an acquired basis. Higher the medial wall of both lateral ventricles and extends from the presence of CSP in boxers than that of ordinary people indicates lamina terminalis to the splenium of the corpus callosum. It is that CSP can be occurred even by repeated brain damage5,14,19). postero-inferior to the corpus callosum and antero-superior to Investigation into presence of CSP was started by autopsy the fornix and hippocampal commissure. Lateral aspect of at the initial period, and subsequently continued by means of septum pellucidum is a triangular shape with its base locating pneumoecephalography, computed tomography(CT) and magnetic anteriorly and with its apex locating posteriorly. Septum pell- resonance image(MRI). But, it failed to attract attention on a ucidum is part of the limbic system and play as a relay station clinical basis and CSP has been considered as normal variation. connecting the hypothalamic autonomic system to hipocampus, Recently, research was conducted for patients with psychotic amygdala, habenula and brain stem reticular formation3,23,25). disorders such as schizophrenia and mood disorder compared A cavity between two leaflets of septum pellucidum is called with normal control groups11,15,16,21) regarding presence of CSP cavum septum pellucidum(CSP), and it can be also called the but none was made for epilepsy patients with control groups. fifth ventricle because it is filled with cerebrospinal fluid(CSF). As CSP was observed frequently in MRI of epilepsy patients, But the cavity is not connected to leptomeningeal or ventricular we have launched this investigation on the idea that existence of spaces4). CSP normally exists in the fetal period but begins to CSP may have an impact on epileptogenesis.

Received：February 27, 2004 Accepted：April 28, 2004 Address for reprints：Jong-Pil Eun, M.D., Department of Neu- Materials and Methods rosurgery, Research Institute of Clinical Medicine, Chonbuk National University Medical School and Hospital 634-18 Geumam-dong, Deok jin-gu, Jeonju 561-712, Korea hree hundred and seventy seven epilepsy patients were Tel : 063) 250-1580 , Fax : 063) 277-3273 T included for this study. Out of them, 168 patients under- E-mail : [email protected] went operation due to intractable epilepsy from May 1998 to

VOLUME 36 July, 2004 13 Cavum Septum Pellucidum and Epilepsy

June 2003 and According to the classification of Pauling22), when the leaves could be traced, of the septum were separated by at least 2mm from the rostral- and the remain- superior attachment to the corpus callosum to the caudal- ing 209 were ou- inferior attachment to the collumns of the fornix, it was tpatients on me- defined as “CSP”. When two laminae were partly connected dication for epil- or divided and length from anterior to posterior was longer eptic seizures. than width, it was defined as “partial CSP”(Fig. 1, 2). Epilepsy pat- Additionally, when signal intensity in CSP was different from ients caused by that in cerebrospinal fluid of both lateral ventricles, it were head trauma, tu- excluded from this research even though there was a cavity. mors, parasite and Pearson’s χ2 and Fisher's extract test of SPSS were used for vascular malfor- a statistical analysis. mation which were not related to epil- Results Fig. 1. Cavum septum pellucidum on axial T1-weighted magnetic resonance image. epsy that broke out in course of brain s epilepsy patients recorded CSP presence of 8.2% development were A (31/377) and control groups posted 1.6%(4/252) respec- excluded from this tively, epilepsy patients showed significantly higher ratio(p<0.01). study. With partial CSP presence standing at 13%(49/377) for epilepsy Control groups patients and 10.7%(27/252) for control groups, epilepsy patients included 252 who have more partial CSP than control groups, but there was no have come to hos- statistical significance(p=0.389). pital for headache Presence of CSP reached 11.3%(19/168) for epilepsy patients from January 2001 who underwent operation and 5.7%(12/209) for patient who did to June 2003 and not, and thus those who underwent operation showed higher had no visible les- presence ratio(p=0.060). Presence of partial CSP amounted to ion in MRI. 14.9%(25/168) for patients who underwent operation and Epilepsy patients 11.5%(24/209) for patients who did not(p=0.330). Of patients were composed of who underwent operation, temporal lobe epilepsy patients stood 220 males (58.4%) at 8.8%(9/102) and extratemporal lobe epilepsy patients

Fig. 2. Partial cavum septum pellucidum on and 157 females commanded 15.2%(10/66), showing higher presence ratio axial T1-weighted magnetic resonance (41.6%), and 30.3 (p=0.206) in terms of presence by lesion. As patients who were image. ±11.9 years old diagnosed as neuronal migration disorder in biopsy accounted on average, while control groups were made up of 133 males for 13.7%(13/95), and patients who were not reached 8.2% (52.8%) and 119 females (47.2%), and 44.3±12.6 years old on (6/73), patients with neuronal migration disorder showed higher average. Of patients who underwent operation for epilepsy, presence ratio of CSP(p=0.268). In terms of presence of partial there were 102 patients (60.7%) with temporal lobe epilepsy CSP, temporal lobe epilepsy patients accounted for and 66 patients (39.3%) with extratemporal lobe epilepsy. In 11.8%(12/102) and extratemporal lobe epilepsy patients held biopsy, 95 patients (56.5%) were diagnosed as neuronal 19.7%(13/66) and thus extratemporal lobe epilepsy patients migration disorder and 73 patients (43.5%) were not. showed higher presence of partial CSP(p=0.158). Patients with MRI scans were obtained on a 1.5 Tesla imager (Siemens neuronal migration disorder showed a 12.6%(12/95) and Magnetom Vision, Erlangen, Germany). T1-weighted images patients who were not accounted for 17.8%(13/73)(p=0.350). In were acquired using spin echo technique with a repetition epilepsy patients, CSP presence by age stood at 16.7%(3/18) time(TR) 520msec, echo time(TE) 12 msec in axial and from 1 to 10, 8.8%(5/57) from 11 to 20, 10.7%(13/121) from 21 coronal, and sagittal planes. T2-weighted images were obtained to 30, 5.4%(6/112) from 31 to 40 and 5.8%(4/69) from 41 and with a RT of 4600msec and TE of 99msec. The thickness of the older(p=0.365). By sex, control groups' CSP presence was contiguous slices were defined as 5mm. The number of 1.5%(2/133) for male and 1.7%(2/119) for female, while that of excitation(NEX) was 2. epilepsy patients was 8.2%(18/220) for male and 8.3%(13/157)

14 J Korean Neurosurg Soc 36 KY Choi, et al. for female, showing similar presence in both control groups and discrepancy between investigation result is that there is a epilepsy patients. difference between definition and investigation method of CSP According to the investigation result on presence of CSP or and the number of targeted groups, but presence of CSP is partial CSP, CSP showed statistically higher ratio in epilepsy usually around 2%, based on large or complete CSP. patients than in control groups. In terms of the location of the On CSP presence of patients with brain disease, there are a epileptogenic zone and pathologic substrate, patients with group of researchers who have made the comparative study on extratemporal lobe epilepsy or neuronal migration disorder schizophrenia and control groups. They reported that patients showed higher ratio. Presence of CSP by age and sex was and control groups showed a similar CSP presence when size of highly observed in patient groups but both cases had no statis- width of CSP was not taken into consideration15,16,21), and tical significance(Table 1). deemed partial CSP as anatomical normal variation. Nopoulos 21) Table 1. Incidence of cavum septum pellucidum in control and patient groups et al studied 44 schizophrenic patients without CSP and 10 Absent(N,%) Partial(N,%) Complete(N,%) Total(N) patients with CSP. In this study, the schizophrenic patients with Control 221(87.7%) 27(10.7%) 4(11.6%) 252 abnormal CSP showed volume reduction in the left temporal Patients 297(78.8%) 49(13.0%) 31(18.2%)* 377 lobe, as well as a less severe decrease in total brain tissue. This Operation 124(73.8%) 25(14.9%) 19(11.3%) 168 finding may reflect developmental abnormality of hippocampus NMD 70(73.7%) 12(12.6%) 13(13.7%) 95 No NMD 54(74.0%) 13(17.8%) 6(18.2%) 73 and corpus callosum in schizophrenic patients with CSP. TLE 81(79.4%) 12(11.8%) 9(18.8%) 102 There are some reports that CSP were more common in ETLE 43(65.1%) 13(19.7%) 10(15.2%) 66 retarded populations5,21,28). They explained that the CSP serves No Operation 173(82.8%) 24(11.5%) 12(15.7%) 209 as a marker or cerebral dysfunction manifested by neurode- * : p<0.01 NMD : neuronal migration disorder, TLE : temporal lobe epilepsy, ETLE : extra temporal lobe epilepsy, N : number velopmental abnormalities. In our study, epilepsy patients presence of partial CSP was Discussion slightly higher than control groups, but there was no statistical significance. On the other hand, presence of CSP stood at 8.2% n this study, presence of CSP showed a statistically higher for patient groups and 1.6% for control groups and statistically I ratio in epilepsy patients. It implies that existence of CSP in significant difference was observed accordingly. epilepsy patients could have implications for epileptogenesis in Akiyama et al1) observed CSP from 71 patients (2.6%) by a previously unknown form. According to other studies on CSP analyzing CT of 2722 patients. Of those who were observed to presence of normal people, the rates of CSP in CT were repor- have CSP, 16 patients (22.5%) were those who showed ted to reach 1.3~3.3%4,20,25). By MRI studies, they reported CSP symptoms of clinical epileptic seizure and 22 patients (31.0%) in 1.1% to 84.8%2,10,11,15,16,22)(Table 2). Classifying the size of the were those who did not have the symptoms but showed abn- width of CSP, Shunk27) announced that CSP presence stood at ormal findings in electroencephalography. Bruyn8) said that 30 16.3% when it was less than 2mm-wide, 8.4% when it was less to 50% of people with CSP were found to show epileptic seizure than 3mm-wide, 5.4% when it was less than 4mm-wide and and 15% were known to have psychosis, dementia and personality 0.3% when is more than 5mm-wide. The reason why there is a changes. Two leaflets of septum pellucidum become fused by Table 2. Incidence of CSP in normal persons rapid growth of hippocampal Autors Number Incidence Imaging Definition of CSP alveoli and corpus callosum in Bae et al. 1000 1.3% CT Not discribed process of brain maturation, and Degreef et al. 46 15.2% MRI Visible space between SP abnormal forma-tion of this 2.2% Width > 3mm in coronal view Nopoulous et al. 95 58.7% MRI More than 1 slice in coronal view structure can hamper fusion of (1mm slice thickness) septum pellucidum, thereby 1.1% More than 6 slices leading to presence and continued Kim et al. 28 10.7% MRI With >3mm in axial view existence of CSP. Aldur et al. 500 2.8% MRI Space between SP (entire length) Septum pellucidum itself cannot Pauling et al. 814 2.1% MRI Space between SP (entire length) Kwon et al. 47 84.8% MRI More than 1 slice in coronal view cause epilepsy because it does not (1.5mm slice thickness) consist of pyramidal cells, so that 8.7% More than 4 slices it can be thought that epilepsy which Choi et al. 252 1.6% MRI Space between SP (entire length) occurred in patients with CSP is CT : computed tomography, MRI : magnetic resonance image, SP : septum pellucidum, CSP : cavum septum pellucidum attributable to abnormality in the

VOLUME 36 July, 2004 15 Cavum Septum Pellucidum and Epilepsy limbic system related to the formation of CSP or other lobe epilepsy than in patients with temporal lobe epilepsy and accompanying abnormality in neuronal development. According also higher in patients with neuronal migration disorder than in to our study on the relationship between presence of CSP and patients without neuronal migration disorder. This leads to a epilepsy, presence of CSP stood at 8.2% for patient groups and conclusion that CSP is not a simple normal variation but related 1.6% for control groups, and 13.7% for patients with neuronal to occurence of epilepsy in some portions, and CSP should be migration disorder and 8.2% for patients without neuronal considered a developmental anomaly that may contribute to migration disorder. From this, authors think that patients with epileptogenesis. More sophisticated study should be continued CSP may show symptoms of epilepsy in tandem with other by increasing the number of patient groups and control groups. abnormality in neuronal dev-elopment. In this study, presence of CSP stands at 11.3% for patients who References underwent operation and 5.7% for patients whose seizure is well- 1. Akiyama K, Sato M, Sora I, Otsuki S, Wake A, Fukui H, et al : A study controlled by medication and this indicates intractable epilepsy of incidence and symptoms in 71 patients with cavum septi pellucidi. No To Shinkei 35 : 575-881, 1981 patients have higher presence ratio (p<0.06). This can be 2. Aldur MM, Gurcan F, Basar R, Aksit MD : Frequency of septum interpreted that existence of CSP may have influence on effect of pellucidum anomalies in non-psychotic population : a magnetic resonance imaging study. Surg Radiol Anat 21 : 119-123, 1999 antiepileptic drugs, but it is necessary to study further on this. 3. Andy OJ, Stephan H : The septum in the human brain. J Comp Neurol In our study on CSP presence according to the location of the 133 : 383-410, 1968 epileptogenic zone and the presence of the neuronal migration 4. Bae BH, Kim JH, Oh KC, Kim YS, Park BH : Computed tomography in the diagnosis of cavum septum pellucidum. Korean J Radiol 17 : disorder, patients with extratemporal lobe epilepsy and patients 193-197, 1981 with neuronal migration disorder had more CSP even though 5. Bodensteiner JB, Schaefer GB, Craft JM : Cavum septi pellucidi and cavum vergae in normal and developmentally delayed populations. J there was no statistical significance. From the above results, it Child Neurol 13 : 120-121, 1998 can be suggested that existence of CSP is abnormality in 6. Bogdanoff B, Natter HM : Incidence of cavum septum pellucidum in adults : a sign of boxer's encephalopathy. Neurology 39 : 991-992, 1989 neuronal development associated with brain diseases such as 7. Boyar B, Ildan F, Bagdatoglu H, Cetinalp E, Karadayi A : Unilateral schizophrenia, mental retardation, epilepsy, and so on. hydrocephalus resulting from occlusion of foramen of Monro : a new There are some studies that agenesis of septum pellucidum, procedure in the treatment : stereotactic fenestration of the septum pellucidum. Surg Neurol 39 : 110-114, 1993 one of other abnormalities in neuronal development associated 8. Bruyn GW : Handbook of Clinical Neurology, Vol 30. Amsterdam, with presence of septum pellucidum, is related to epileptic Elsevier North-Holland, 1977, pp299-366 13) 9. Butt W, Havill D, Daneman A, Pape K : Hemorrhage and cyst seizure. Harenko et al noted that of nine patients with agenesis development in the cavum septi pellucidi and cavum Vergae. Report of of septum pellucidum, two are related to epileptic seizure. three cases. Pediatr Radiol 15 : 368-371, 1985 Agenesis of septum pellucidum is very rare innate or acquired 10. Corsellis JA, Bruton CJ, Freeman-Browne D : The aftermath of boxing. Psychol Med 3 : 270-303, 1973 abnormality that lateral ventricles are connected into one 11. Degreef G, Lantos G, Bogerts B, Ashtari M, Lieberman J : Abnor- because there is no septum pellucidum. This can be occurred to malities of the septum pellucidum on MR scans in first-episode 10) 24) schizophrenic patients. Am J Neuroradiol 13 : 835-840, 1992 boxers , patients with Tourette syndrom , and patients after 12. Farruggia S, Babcock DS : The cavum septi pellucidi : its appearance neuroendoscopic surgery21), the fetus exposed to anticonvulsant and incidence with cranial ultrasonography in infancy. Radiology 139 : during gestational ages18). It is known that genetic background 147-150, 1981 13. Harenko A, Toivakka E : Agenesis of septum pellucidum as a clinical comes from injury of nerves stemming from hypoperfusion and finding. Acta Neurol Scand 43 : 47-48, 1967 infection at a time when septum pellucidum forms around 7 to 8 14. Jordan BD, Jahre C, Hauser WA, Zimmerman RD, Zarrelli M, Lipsitz 17) EC, et al : CT of 338 active professional boxers. Radiology 185 : 509- weeks of pregnancy . Usually 2 or 3 per 100,000 are reported 512, 1992 to have agenesis of septum pellucidum, but in our study, this 15. Kim CE, Shin SE, Kang MH, Lim MK : Preliminary MRI study of abnormality have not shown from control groups but had a cavum septi pellucidi in schizophrenia. J Korean Neuropsychiatr Assoc 37 : 509-514, 1998 relatively higher ratio of 0.8%(3/377) from epilepsy patients. 16. Kwon JS, Shenton ME, Hirayasu Y, Salisbury DF, Fischer IA, Dickey However, the figure cannot be deemed general because the CC, et al : MRI study of cavum septi pellucidi in schizophrenia, affective disorder, and schizotypal personality disorder. Am J Psy- number of patient groups is small. chiatry 155 : 509-515, 1998 17. Lau KY, Tam W, Lam PK, Wood BP : Radiological cases of the month. Septo-optic dysplasia (De Morsier syndrome). Am J Dis Child Conclusion 147 : 71-72, 1993 18. Lindhout D, Omtzigt JG, Cornel MC : Spectrum of neural-tube defects ccording to our study, presence of CSP showed statis- in 34 infants prenatally exposed to antiepileptic drugs. Neurology 42 : 111-118, 1992 A tically higher ratio in epilepsy patients than in control 19. Moseley IF : The neuroimaging evidence for chronic brain damage due groups. It is found to be higher in patients with extratemporal to boxing. Neuroradiology 42 : 1-8, 2000

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