Informative Value of Magnetic Resonance Imaging and EEG in the Prognosis of Infantile Spasms

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1 Epilepsi, 43(3): , 2002 Blckwell Publishing, Inc. Interntionl Legue Aginst Epilepsy Informtive Vlue of Mgnetic Resonnce Imging nd EEG in the Prognosis of Infntile Spsms *Sem Sltik, Nci Kocer, nd *Aysin Dervent *Deprtment of Neurology, Division of Child Neurology, nd Deprtment of Rdiology, Division of Neurordiology, Istnbul University, Cerrhps Medicl Fculty, Istnbul, Turkey Summry: Purpose: To investigte the informtive vlue of EEG nd crnil mgnetic resonnce imging (cmri) in the prognosis of infntile spsms (ISs); 86 ptients with ISs were included in this study. Methods: All cses hd epileptic spsms, psychomotor retrdtion, nd hypsrrhythmi in t lest one of their EEGs. cmris nd lbortory tests necessry for etiologic dignosis were completed in ll cses. Ptients were followed up periodiclly both cliniclly nd by video-eegs for >1 yer. Clinicl informtion ws ctegorized on the bsis of four spheres s epilepsy, psychosocil development, motor development, nd overll clinicl condition, with ech ctegory being evluted under three levels of involvement s good, moderte, nd severe, depending on selected prmeters. A similr scle ws pplied for the EEG results nd for the cmri findings. Clinicl prmeters were correlted to EEG nd cmri results, by Spermn test. Other sttisticl tests used were Kruskl Wllis 2 nd Mnn Whitney U nlysis s multiple comprison by post hoc Bonferroni correction. Results: A severe overll clinicl course ws observed in 64% of ptients, wheres this incidence ws 58% nd 44% in the EEG follow-up nd cmri prmeters, respectively. In regrd to prognosis, significnt correltion ws determined between the clinicl nd the EEG course. This reltion ws the most prominent in psychosocil developmentl prmeters nd lest prominent in the motor development. cmri findings, however, were correlted only with motor development. Conclusions: cmri nd repeted EEG recordings, especilly when ssessed together, my provide complementry informtion regrding the prognosis in ISs. Key Words: Infntile spsms Electroencephlogrphy Mgnetic resonnce imging Prognosis Hypsrrhythmi. Infntile spsms (ISs), one of the most common epileptic syndromes in infncy, is chrcterized by trid composed of clusters of spsms, distinctive EEG pttern, clled hypsrrhythmi, nd n rrest or regression in psychomotor development (1 3). Ptients with ISs generlly hve poor neurologic prognosis, s intellectul outcome deteriortes, nd seizures often persist (4); however, minority my preserve norml intelligence nd even disply cdemic performnce (5). This study in group of ptients with ISs questioned the prognostic informtive vlue of cmri nd seril EEGs s compred with the clinicl course of the disese. METHODS A totl of 86 ptients with epileptic spsms, psychomotor developmentl dely, nd hypsrrhythmi in t lest one of the seril EEGs ws included in the study. There were eight (9.3%) cryptogenic nd 78 (90.7%) Revision ccepted November 28, Address correspondence nd reprint requests to Dr. S. Sltik t Acibdem cddesi No. 146, Tibs Prk Sitesi H Blok Dire: 9, Uskudr, Istnbul, Turkey. E-mil: sltik@ixir.com TABLE 1. Ptient distribution in clinicl severity scles No. of pts %of pts SF (none or >50% decrese in seizure frequency) Moderte (between 50 nd 74% decrese in seizure frequency ( 75% decrese in seizure frequency) PSD (no development in cognitive nd ffective rections, utism inc.) Moderte (<50% of pp. ge) ( 50% of pp. ge) MD (no development) Moderte (>50% of pp. ge) ( 50% of pp. ge) OCC (t lest one of these prmeters is severe) Moderte (ll three prmeters moderte or two moderte, one good) (Three prmeters good or two good, one moderte) SF, seizure frequency; PSD, psychosocil development; MD, motor development; OCC, overll clinicl course; inc, included; pp, pproprite. 246

2 PROGNOSIS IN INFANTILE SPASMS 247 FIG. 1. Bilterl fst dischrges s n indictor of severe course in the EEGs of n infnt with nesidioblstosis nd infntile spsms: (), t 10 months, nd (b), t 22 months throughout the evolution into Lennox Gstut syndrome. symptomtic cses, s described in the Interntionl Clssifiction of Epilepsies nd Epileptic Syndromes (6) with mle/femle rtio of 1.75/1. Clinicl evlution protocol Follow-up exmintions, fter the dignostic procedures completed, were crried on monthly bsis within the initil 3 months, followed by once in 3 months during the first yer nd once in 6 months, lter. The shortest follow-up period ws 1 yer, the longest ws until 10 yers of ge. Men ge of the ptients ws 34.6 ± 21.5 months, the medin ge ws 29.5 months t the lst visit. Clinicl evlutions of the ptients included specific informtion regrding the seizure frequency (SF), motor development (MD) nd mentl nd psychosocil development (PSD) during the initil nd follow-up visits. After detiled exmintion of the initil video-eegs, ll documented prtil seizures nd epileptic spsms of the infnt were shown to the prents during nother visit, nd common semiologic understnding nd nming of the seizure types ws chieved. Seizure types were lter ssembled under single ctegory for sttisticl resons. Developmentl milestones were determined by Denver II (7) screening test. Prmeters s eye contct nd following objects, communictive smiling, reching objects, nd responsive utterings were crefully noted within the context of PSD. A rting scle ws djusted for frequency nd severity of seizures, s for psychosocil nd for motor performnces; nd differences throughout the initil visit to the ltest one were noted. A common clinicl follow-up prognostic scle (good, moderte, severe) ws lter developed on the bsis of evolutionry scles for ech individul modlity (Tble 1). EEG recordings nd the evlution protocol EEGs of 2-h durtion during sleep nd wking, synchronized with video monitoring ws conducted by 32-chnnel digitl mchine. A totl of 386 video-eegs (men, 4.5 ± 2.6 per individul) recorded with regulr intervls from the onset of the disese to the lst followup visit were evluted by the uthors. EEG prmeters included were presence of sleep spindles, hypsrrhythmi, bilterl fst dischrges (8), nd epileptogenic foci fter disppernce of hypsrrhythmi, s well s sym- FIG. 2. Asymmetric hypsrrhythmi with depression on the right hemisphere leds, s mrker of severe course from n infnt (11-month-old) with hypoxic ischemic encephlopthy nd bilterl clstic lesions in the crnil mgnetic resonnce imging, lrger on the right.

3 248 S. SALTIK ET AL. FIG. 3. EEG smple of n epileptic spsm (A) followed by n ictl pttern (B) predominnt on T3 with extension to djcent regions (s mrker for severe course). Cliniclly, right-sided motor seizure in 10-month old infnt, with bilterl pchygyri in the crnil mgnetic resonnce imging. metry of sleep spindles nd of hypsrrhythmi. Presence of interhemispheric symmetry in the bckground ctivity, if not hypsrrhythmic, s well s dditionl ictl ptterns nd vrious bnorml rhythms lso were noted. Those were considered s ccessory criteri for clssifiction of EEGs with in-between fetures of severity levels. (Exmple: An EEG tht could not be clerly rted s good or moderte ws clssified s moderte if focl ictl ptterns would exist.) See smple EEGs showing dignostic indictors of vrious severity scles in Figs A conclusive formt for video-eeg dt ws then completed on the bsis of those prmeters. Finl stge of this evlution process ws the production of severity scle similr to tht of the clinicl outcome (Tble 2). Evlution protocol for cmris A totl of 103 cmris ws vilble with t lest one for ech ptient nd repeted exmintions to follow either the mturtionl chnges of the brin or to void dignostic suspicion. They were evluted by two independent neurordiologists, nd the following prmeters were noted: presence of lesion, its locliztion, its distribution (rnging from + to ++++), presence of white (subcorticl, deep) nd gry mtter (cortex, deep nuclei) involvements, nd morphology of corpus cllosum nd cerebrl ventricles, enlrgement of subrchnoid spce, diffuse cerebrl or cerebellr trophy, nd pttern of myelintion nd its ppropriteness for ge. A severity scle prepred on the bsis of these cmri prmeters is seen in Tble 3. Figures 5 nd 6 illustrte some exmples of different levels of involvement. No EEG or cmri dt were included in the study if the ptient ws tking drenocorticotropic hormone (ACTH) or ws within 6 months fter tretment becuse of the reported side effects of the drug (9,10). Sttistics Rting results of SF, PSD, MD, nd overll clinicl course (OCC) were correlted to EEG nd cmri rtings individully by Spermn correltion nlysis. Medin vlues for ech severity level in clinicl prmeters (SS, PSD, MD, OCC, individully) nd corresponding EEG groups were compred by Kruskl Wllis 2 nlysis. Mnn Whitney U test ws performed to ssess significnce mong group differences nd by post hoc Bonferroni correction. Similr procedures were performed for cmri findings. RESULTS A severe OCC ws detected in 64% (Tble 1) of ptients of whom seven (8.13%) died during the evlution period. A prognostic profile indicting severity ws prominent in the EEGs of 58% of ptients (Tble 2), wheres 44% reveled such degree of involvement in their cmris (Tble 3) versus 25.5% with no remrkble cmri chnges. A strongly positive correltion ws found between ll prmeters of clinicl course (SF, PSD, MD, OCC) nd EEG rtings for severity (Tble 4). Comprison of group differences of medin vlues reveled tht the most significnt reltion existed between PSD nd EEG. Subgroups of severity levels strictly corresponded for PSD nd EEG course. Although significntly relted in globl evlution, SF ws rted moderte in the EEG FIG. 4. EEG smples indicting good course in n infnt with tuberosclerosis. A: Hypsrrhythmi t ge 4 months. B: Presence of sleep spindles long with bilterl spike-wve dischrges, t 8 months, with vigbtrin. C: Orgnized non rpid-eyemovement sleep, stge 2, with well-developed sleep spindles, t 3 yers, receiving vigbtrin.

4 PROGNOSIS IN INFANTILE SPASMS 249 TABLE 2. EEG follow-up scle nd the incidence of ptients Course of EEG: No. of pts : 50 (58.1% of pts) or moderte (s determined by ccessory criteri nd lter plced in other groups) Moderte: 26 (30.2% of pts) : 10 (11.6% of pts) subgroup with severe chnges. MD ws the modlity with lest significnt reltion with the degree of severity in the EEG (Tble 5). Correltive nlyses of clinicl-severity subgroups, however, showed tht MD ws the only prmeter significntly relted to cmri chnges (Tble 6). As is shown by the medin vlues of clinicl prmeters corresponding to ech cmri severity subgroup, MD ws good in ptients with norml cmri findings, nd it ws the worst in the group with severe imging findings (Tble 7). DISCUSSION Description Bilterl fst dischrges present Asym hyps cont Asym hyps mef Asym hyps fe+slsp Abs/sym Sym hyps cont + sl sp bs/sym Sym hyps mef + sl sp bs/sym Sym hyps cont + sl sp sym Sym hyps mef + sl sp sym Sym hyps fe+slsp bs/sym Sym hyps fe+slspsym Sym hyps no e sym, symmetricl; hyps, hypsrrhythmi; cont, continuous, mef, multiple epileptogenic foci; sym, symmetricl; fe, focl epileptogenic ctivity; bs, bsent; sl, sleep; sp, spindle; e, epileptogenic ctivity;, chnged to. See EEG recordings nd the evlution protocol, in Methods. Our results suggest tht mentl nd communictive skills re the most consistently ffected behviorl spects of the infnt with IS, wheres seizures my decrese or increse in the time course. Only 22% of our ptients hve reltively good PSD, which is not fr from the results of similr studies (5,11). Contributions of ggressive use of ntiepileptic mediction (AEDs) long with the introduction of newer gents my ply role in this fct; however, mturtionl chnges in neuronl excitbility my be even more effective. A question my emerge t tht point: Is it epilepsy tht bers more future risks for the child, or is it the cognitive involvement? Nevertheless, it is obvious tht mngement should be directed to ll behviorl modlities. However, the generl pproch to the ptient with IS, t lest in our country, hs been directed minly to seizure control nd to motor rehbilittion to lesser extent. Physicins frequently overlook the cognitive nd psychosocil impirment of the child until it becomes very evident to the fmily, by the ner-school ges. Numerous EEG findings hve been evluted nd discussed regrding their prognostic vlue in IS (9,12 17). Presence of physiologic bckground ctivity nd sleep spindles within hysprrhythmic periods hs been proposed s indicting good prognosis in one study (18), wheres controversil reports in reltion to the spindles exist (19,20). Our study ws not designed to question the informtive vlue of sleep spindles in the prognosis; rther, both presence nd interhemispheric symmetry of those physiologicl elements were included s prmeters contributing to the clssifiction of ny EEG under good ctegory in ddition to other relevnt dt. Hypsrrhythmi with prominent interhemispheric symmetry (if the nonhypsrrhythmic hemisphere lcked physiologic ctivities nd showed depression in the bckground ctivity s the difference in the mplitudes ws >50%), bilterl fst dischrges (suggestive of Lennox Gstut syndrome) were ctegorized s criteri for severe prognosis (21). Asymmetric hypsrrhythmi seems relible sign of lesionl involvement (12), nd when the bioelectricl ctivity is definitely depressed, the lesion is locted solely or predominntly in the non- or lesshypsrrhythmic hemisphere. A prmeter included s evidence for good prognosis, in this study, ws the erly disppernce of hypsrrhythmi fter tretment, fct reported erlier (1,5). Our results reveled tht 58% of our cses hd trend towrd mlignncy in their EEGs, nd 11% hd good course. Those results were sttisticlly correlted with the clinicl course of the ptient nd very strictly corre- FIG. 5. Exmple of moderte degree of involvement in crnil mgnetic resonnce imging (3-yer-old boy with hypoxic ischemic encephlopthy): Bioccipitl subcorticl gliotic lessions, prominent in T 2 - weighted imge. A: T 1 -weighted imge. B: T 1 -weighted imge.

5 250 S. SALTIK ET AL. FIG. 6. Exmple for severe degree of involvement in crnil mgnetic resonnce imging (2-yer-old girl with hypoxic ischemic encephlopthy): Biprieto occipitl subcorticl lessions nd ventriculr enlrgement. Note the mssive pthologic signls of cerebellum with pil hemosiderin deposit. A: Axil T 2 -weighted imge. B: Coronl T 2 -weighted imge. lted with the cognitive behvior. Although EEG hs been populr mens of serch for the epilepsy in IS nd the underlying pthophysiology (17,19,20) its reltion to other modlities of well-being seems to deserve ttention. In 33 (80.5%) of 41 ptients with very poor psychosocil performnce, the EEGs showed consistent progress towrd mlignncy, nd none towrd good prognosis. Negtive impct of the persistence of diffuse epileptogenic ctivity on the cognitive functions leding to mentl deteriortion hs been reported before (22), where hypsrrhythmi my be considered bioelectricl sttus seizing the yet immture brin nd leding to irreversible functionl chnges, in this sense. Another probbility, however, my be the direct effect of the primry etiologic fctor on those modlities. Becuse IS is frequently consequence of severe pre- or perintl dmge to the brin, s well s on developmentl or metbolic bnormlities, there my not be enough reson to expect norml cognitive functioning. A positive reltion between decrese in the severity of hypsrrhythmi nd the SF hs been reported (23). A similr observtion s 85.7% of severe EEG course in contrst to 3.5% good course ws detected in ptients with intrctble seizures in our study. However, no significnt difference in the seizure prognosis ws existent between EEG groups with good nd with moderte courses. Results were suggestive of possibility for TABLE 3. Ptient groups ccording to cmri findings nd incidences Degree of Inv N: % of pts Description : 38: 44.2% Moderte: 13: 15.1% Mild Norml: 35: 40.7% Lesion +++/++++, sv trophy nd vol loss, delyed myelintion, deep white nd gry mtter inv. Lesion in two lobes, +/++, trophy nd vol loss, delyed myelintion Norml cmri or lesion in one or two lobes, no trophy/vol loss, norml myelintion sv, severe; vol, volume; inv, involvement; cmri, crnil mgnetic resonnce imging. better prognosis of epilepsy independent of the EEG chnges in time, lthough the probbility of lter developing epilepsy cn not be excluded. Another positive but less significnt reltion ws encountered between MD nd the EEG course of the ptients with IS. This reltion ws most prominent in the cses with severe motor deteriortion. Mlignnt EEG chnges were seen in 80% of tht group. The EEG my serve s n indirect tool minly by reflecting the negtive effects of either diffuse or unilterl involvement of the brin on MD by mens of the symmetry or the bsence of physiologic phsic or bckground ctivities. Crnil MRI hs distinctive plce in etiologic dignosis in IS. A differentition in prognostic consequences depending on the type of brin lesion ws reported, nd the best prognosis ws ttributed to the group with norml cmri findings (24). No vilble dt in regrd to the prognostic informtive vlue of cmri outside the etiologic perspective exists in the relted field. The presence or bsence of TABLE 4. Correltion of clinicl follow-up prmeters nd EEG course Clinicl prmeters EEG course (no. of pts) Moderte SF (r s, 0.44; p < 0.001) Moderte PSD (r s, 0.51; p < 0.001) 33 8 Moderte MD (r s, 0.40; p < 0.001) 28 7 Moderte OCC (r s, 0.49; p < 0.001) Moderte Spermn Correltion Anlysis test; SF, seizure frequency; MD, motor development; PSD, psychosocil development; OCC, overll clinicl course.

6 PROGNOSIS IN INFANTILE SPASMS 251 TABLE 5. Comprison of medin vlues for clinicl severity rtings nd EEG groups Clinicl prmeters SF (medin) PSD (medin) MD (medin) OCC (medin) EEG groups Moderte p Moderte b b b Moderte Moderte c Moderte b Moderte severe c b bc b bc p < p < p < 0.01 p < Pired letters (i.e., b) indicte significnt differences within groups shring similr letters. Kruskl Wllis 2 test. lesions nd their extensiveness in the cmri, rther thn type, nd lso the severity of destruction ws scored in this study, nd no sttisticlly significnt correltion ws found between the level of involvement in the cmri nd the questioned clinicl prmeters, except with MD (Tble 4). In our ptients with preserved motor functioning (27%), there were no or mild involvements in the cmris in 74%. Motor performnce in ll the symptomtic cses ws ffected in strict concordnce with the underlying primry disese, s to its severity nd extensiveness of the cmri lesions. Apprent independence of the clinicl prmeters such s cognitive nd seizure condition of the ptients from the cmri-relted scles my be relted to vrious resons. First, purely biochemicl bnormlities without imging findings s well s presence of lesions undetectble with vilble technicl stndrds my ply importnt roles in the prognostic profile of certin group of ptients with IS. Second, interfering frequent spontneous or drug-fcilitted infections (i.e., ACTH, TABLE 6. Correltion of clinicl follow-up prmeters nd cmri involvements Clinicl prmeters cmri involvement (no. of pts) Moderte Mild Norml SF (r s, 0.10; p > 0.05) Moderte PSD (r s, 0.07; p > 0.05) Moderte MD (r s, 0.45; p < 0.001) Moderte OCC (r s, 0.19; p > 0.05) Moderte Spermn correltion nlysis test. TABLE 7. Comprison of medin vlues for clinicl severity rtings nd cmri involvements Clinicl prmeters cmri involvement Moderte Mild Norml SF (medin) Moderte Moderte Moderte Moderte PSD (medin) Moderte Moderte Moderte MD (medin) p Moderte OCC (medin) indictes significnt group differences (Mnn Whitney U test s multiple comprison by post hoc Bonferroni correction). significnt in Kruskl Wllis 2 test. benzodizepines), poor feeding or hygienic cre, delyed dignosis, nd mlprctice hve been some of our observtions complicting the clinicl course, in our settings. Finlly, becuse IS hs very heterogeneous chrcter on both clinicl nd lbortory grounds, it is not very unlikely tht quite different results might be chieved in different methodologic settings. Although mximl ttention to be precise nd objective in the design nd interprettion of the results ws pid in this study, unvoidble complexities my still be brriers for more conclusive decisions. Finlly, when the results re briefly summrized, cmri findings in ptients with IS seem to be relted to the MD, wheres the EEG chnges nd their evolution in time pprently hve informtive vlue regrding especilly the psychosocil development nd, in decresing order, the seizure outcome nd the MD of the infnt. Results indicte tht vluble informtion regrding the prognosis of n individul ptient with IS my be gined erly in the clinicl course of the disese when the cmri nd repeted EEG dt re crefully exmined nd interpreted from n integrtive perspective. Any mens for mngement of the well-known severe consequences of the syndrome my, therefore, be reched erlier. Acknowledgment: We thnk Omer Uysl (Ph.D.), for the sttistics in this study. REFERENCES 1. Commission on Clssifiction nd Terminology of the Interntionl Legue Aginst Epilepsy. Proposl for revised clssifiction of epilepsies nd epileptic syndromes. Epilepsi 1989;30: Chiron C, Dulc O, Bulteu C, et l. Study of regionl cerebrl blood flow in West syndrome. Epilepsi 1993;34: Jevons PM, Livet MO. West syndrome: infntile spsms. In: Roger J, Bureu M, Drvet C, et l., eds. 2nd ed. Epileptic syndromes in infncy, childhood nd dolescence. London: John Libbey, 1992: Vigevno F, Fusco L, Cusmi R, et l. The idiopthic form of West syndrome. Epilepsi 1993;34: Riikonen R. Long term outcome of West syndrome: study of dults with history of infntile spsms. Epilepsi 1996;37: Commission on Peditric Epilepsy of the Interntionl Legue Aginst Epilepsy. Workshop on infntile spsms. Epilepsi 1992; 33:195.

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