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1 Seizure 18 (2009) Contents lists vilble t ScienceDirect Seizure journl homepge: Frequency nd ptterns of MRI bnormlities due to sttus epilepticus Trcey A. Millign, *, Amir Zmni b, Edwrd Bromfield Deprtment of Neurology, Brighm nd Women s Hospitl, Boston, MA 02115, United Sttes b Deprtment of Rdiology, Brighm nd Women s Hospitl, Boston, MA, United Sttes ARTICLE INFO ABSTRACT Article history: Received 12 October 2007 Received in revised form 7 July 2008 Accepted 11 July 2008 Keywords: Seizure Sttus epilepticus MRI Epilepsy Bckground: MRI chnges due to sttus epilepticus (SE) often suggest combintion of cytotoxic nd vsogenic edem, but it is uncler why only certin ptients hve MRI chnges. Objectives: To determine the frequency of MRI chnges due to SE nd the ssocited ptient chrcteristics. Methods: We reviewed records for demogrphics, medicl history, nd MRI chnges ttributble to seizures of ll ptients dmitted to Brighm nd Women s Hospitl or Msschusetts Generl Hospitl for SE from 1/1999 to 7/2003 nd who hd MRI during dmission. Results: Ten (11.6%) of the eighty-six ptients identified hd MRI bnormlities likely due to seizures. Four, two with pre-existing epilepsy nd two with extrtemporl structurl lesions, hd foclly incresed signl on T2 nd diffusion-weighted imging (DWI) in the hippocmpus ipsilterl to the seizure focus. One, with elevted levels of clozpine, hd incresed signl on T2 weighted imges nd vribly restricted diffusion in the splenium. Five hd gyrl distribution of restricted diffusion nd incresed signl on T2 weighted imges; they hd complex medicl comorbidities nd possible hypoperfusion or hypoxi ssocited with SE. Conclusions: Among ptients with SE who hd MRI chnges, those with previous epilepsy or extrtemporl structurl lesions showed incresed diffusion in the hippocmpus nd my hve selective hippocmpl vulnerbility to seizure-induced hyperexcitbility. Ptients with hyperintense signl in the corticl gry mtter hd episodes of possible hypoperfusion or hypoxi. ß 2008 British Epilepsy Assocition. Published by Elsevier Ltd. All rights reserved. 1. Introduction Visible cerebrl chnges, notbly incresed blood flow, due to seizure ctivity were first described by Horsley in 1892: I hd the opportunity of witnessing n epileptic fit in ptient t the time of n opertion in which the motor region, so-clled, ws exposed nd electriclly stimulted. In tht cse, the cortex ws... distinctly hyperemic during the ttck. 1 Reversible hyperperfusion nd mild edem hve lso been noted with cute seizures during ngiogrphy 2 trnsient hypodensities were noted on erly CT, 3 nd the first MRI report ws in 1986, 4 with reversible findings noted in Since then there hve been mny cse reports, smll series, nd niml studies showing reversible nd irreversible MRI findings. In ddition to loclized hyperperfusion, reported chnges include contrst enhncement, incresed T2 fluid-ttenuted inversion recovery (FLAIR), nd diffusionweighted imging (DWI) signl, nd vrible degree of reduction * Corresponding uthor. Tel.: ; fx: E-mil ddress: tmillign@prtners.org (T.A. Millign). in the pprent diffusion coefficient (ADC). 5 9 The imging findings ssocited with SE my reflect the mny physiologic chnges tht cn occur during SE, including cerebrl edem, hyperperfusion, nd ltertion of the blood brin brrier. The prevlence of these chnges fter either SE or isolted seizures is unknown. The im of this study is to explore the frequency, imging chrcteristics, nd clinicl correltes of MRI chnges ttributble to SE. 2. Mterils nd methods Adults dmitted with dignosis of SE or seizure to Brighm nd Women s Hospitl or Msschusetts Generl Hospitl from Jnury 1999 to July 2003, nd who hd undergone brin MRI during their hospitliztion were identified through reserch ptient dt registry. Ptients with SE due to hypertensive encephlopthy, eclmpsi, or cute encephlitis were excluded. A dignosis of SE ws met if the seizure lsted longer thn 30 min or if the ptient hd intermittent seizure ctivity for longer thn 30 min without regining bseline function. Chrts of ll ptients meeting the bove criteri were reviewed for clinicl dt /$ see front mtter ß 2008 British Epilepsy Assocition. Published by Elsevier Ltd. All rights reserved. doi: /j.seizure

2 T.A. Millign et l. / Seizure 18 (2009) including ge, sex, dignoses, history of epilepsy, timing of initil nd follow-up MR imging, nd EEG findings. Permission for this serch nd chrt review ws obtined from the Institutionl Review Bord. If n MRI bnormlity ws reported s possibly due to seizures, neurordiologist (AZ) visully reviewed the imges; no volumetric mesurements were. MRI bnormlities were ttributed to SE if they did not pper to represent strokes or tumors, nd their loction corresponded to the EEG bnormlity or seizure semiology. MR imging ws with Signl 1.5-T system (GE Medicl Systems, Milwukee, WI). Sgittl nd trnsverse T1- weighted imges (repetition time, 600 ms; echo time 25 ms), FLAIR (repetition time, ,000 ms; echo time, ms; inversion time, ms) nd trnsverse T2-weighted imges (repetition time, ms; echo time, ms; EC = 1) were cquired with 5-mm contiguous sections. 78/86 ptients (91%) of ptients received DWI s well. Acquisition prmeters for DWI included repetition time of ,000 ms, echo time of ms, nd mximum b vlue of 1221 s/mm 2. Sttisticl nlyses were using Fisher s exct test. 3. Results Sixteen of eighty-six ptients hd MRI reports listing seizures s possible cuse of MRI bnormlities. Six were excluded, one due to n cute stroke, one due to tumor ner the region of interest nd 4 becuse of suspected encephlitis. The remining 10 (11.6%) were identified s hving MRI chnges ttributble to SE. Ptients with nd without such chnges did not differ with regrd to ge, sex, etiology of SE, history of epilepsy, or time to MRI (Tble 1). In the other 76 ptients, 64 (84.2%) showed bnormlities. Ischemic stroke ws the most common finding in 11 (14.5%), followed by tumor in 10 (13.2%), chronic stroke in 10 (13.2%), nonspecific white mtter chnges in 8 (10.5%), possible encephlitis in 7 (9.2%), noxic chnges in 5 (6.6%), intrcerebrl hemorrhge, vsculr mlformtions, old contusions nd multiple sclerosis in two ech (2.6%), nd possible hypertensive leukoencephlopthy, genesis of the corpus cllosum, srcoidosis, bscess, nd diffuse trophy in one ptient ech (1.3%). Five of the ten ptients hd history of epilepsy. Of the remining 5, 2 developed epilepsy, 1 died, nd the other 3 were lost to follow-up. All hd focl seizures, 3 with left, 5 with right, nd 2 with bihemispheric onset; 4 hd secondry generliztion. Ictl EEGs were obtined in 7; in the other 3, seizures were observed cliniclly, while EEG the sme dy showed periodic lterlized epileptiform dischrges (PLEDs) in 2, nd postictl focl slowing in one whose EEG ws 2 dys lter (Tble 2). Of these 10 ptients, 3 required phrmcologiclly induced com to tret SE (ptients 2, 3 nd 9). Initil MRI ws in <24 h in 5 nd up to 11 dys fter onset in the others. Follow-up MRI ws obtined for the nine surviving ptients. Three ptterns of MRI chnge were identified (Fig. 1, Tble 3). The first consisted of incresed DWI signl in the hippocmpus ipsilterl to the side of seizure onset (ptients 1, 6, 7, nd 10). One ptient lso hd T2 prolongtion in the ipsilterl insul nd thlmus (ptient 10). Three hd reduced intensity in the hippocmpus on ADC mpping, consistent with restricted diffusion. Three of these ptients hd previously dignosed epilepsy, two with extrtemporl vsculr mlformtions nd one with hippocmpl sclerosis. The other ptient lter developed epilepsy nd mesil temporl sclerosis (ptient 7). The second pttern ws gyrl distribution of restricted diffusion nd T2 prolongtion, seen in five ptients (2, 3, 5, 8, nd 9). Chnges were lso seen in the ipsilterl thlmus (ptients 2, 3, 8 nd 9) nd the contrlterl cerebellum (ptient 8); ll 3 with ADC mpping hd reduced corticl signl. All 5 hd possible hypoperfusion nd/or hypoxi ischemi ssocited with SE (2 with cute myocrdil infrction, 1 episodic hypotension, 1 episodic hypoxi, nd 1 ipsilterl subclvin stel syndrome), compred to one of the ptients with other ptterns of MRI chnge (p = 0.05) nd 22/54 without MRI chnge due to SE (p = 0.28). Three ptients showed improvement on follow-up imging. The third pttern seen ws of restricted diffusion in the splenium. This ptient hd elevted levels of clozpine nd bitemporl SE. MRI becme norml fter the ptient discontinued clozpine nd strted tretment with ntiepileptic drugs. 4. Comment MRI findings ttributble to SE my provide insight into the mechnism of SE nd ssocited neuronl dmge. The hippocmpl pttern hs been reported previously rrely with extrtemporl epilepsy This is the chnge most frequently Tble 1 Chrcteristics of ll ptients nd ptients with chnges on MRI due to sttus epilepticus Chrcteristic Ptients without chnges Ptients with chnges Totl number Demogrphics Sex, M 36 5 Sex, F 40 5 Men ge (rnge) 52 (19 86) 44 (22 83) Hx of epilepsy 22 5 Men dys from onset until MRI Primry etiology Vsculr 15 2 Low AED level 12 3 Tumor 10 0 Unknown 6 2 Infection 8 ETOH/benzodizepine withdrwl 8 0 Epilepsy (with no provoking fctors identified) 6 1 Toxic metbolic 3 2 Anoxi 5 MS 0 1 Mitochondril 2 Chnges seen could not be definitively ttributed to seizures P-vlue >0.05 for ll comprisons.

3 106 T.A. Millign et l. / Seizure 18 (2009) Tble 2 Chrcteristics of ptients with MRI findings due to sttus epilepticus Age (yer)/sex Seizure type Durtion EEG Etiology/relevnt history 1 52/F SPS (phsi) nd CPS 1 dy Left temporl lobe seizures Low AED level, History of occipitl AVM resection 2 41/F CPS with secondry 21 dys Posterior qudrnt seizures, Vsculr generliztion bilterl independent 3 22/M CPS with secondry 54 dy Left hemisphere seizures Unknown (drug nd/or lcohol buse suspected) generliztion 4 42/F CPS >1 dy (overll durtion unknown) Bitemporl seizures Toxic metbolic, bipolr disorder; EEG to evluted subcute chnge in mentl sttus 5 52/M SPS (R motor) 1 dy Post-ictl left hemisphere slowing Unknown in the next month developed subclvin stenosis 6 55/M SPS (R motor) with 4 dys R hemisphere seizures nd PLEDs Cvernous ngiom with intrctble epilepsy secondry generliztion 7 45/M GTC <1 dy R PLEDs No cute precipitnt; history of multiple sclerosis 8 36/M GTC <1 dy R hemisphere seizures Low AED levels 9 83/F L motor with secondry generliztion 2 4 dys R PLEDs Unknown; found unresponsive nd lst seen 2 dys prior; hyperclcemic 10 44/F CPS 4 dys R frontl seizures Dibetes with cute hypoglycemi nd history of epilepsy CPS: complex prtil seizure; GTC: generlized tonic clonic; SPS: simple prtil seizure; AED: ntiepileptic drug; HC: hippocmpus; PLEDs: periodic lterlized epileptiform dischrges. Epilepsy prior to SE. seen in niml models of SE. 16 In humns, fter prolonged nonfebrile or febrile seizures, the hippocmpus cn initilly become enlrged nd hyperintense, nd lter trophy. Neuropthologicl exmintion cn show hippocmpl sclerosis, 17 The hippocmpl bnormlities my reflect the vulnerbility of the hippocmpus to excitotoxic dmge, or to immedite or delyed neuronl deth through necrosis nd poptosis. 18 The corticl MRI pttern ws seen in ptients with possible hypoperfusion or hypoxi. Focl SE hs previously been shown to produce MRI chnges in the neocorticl region corresponding to Fig. 1. (A) Axil DWI during episode of focl SE in 52-yer-old womn with history of left occipitl AVM resection nd epilepsy who presented with episodic phsi nd confusion. There is restricted diffusion in the left hippocmpus. (B) Axil DWI during focl motor SE showing restricted diffusion in the right hippocmpus in 55-yer-old mn with right prietl cvernous ngiom nd mediclly intrctble epilepsy. (C) Axil DWI showing expnded nd hyper-intense splenium in 52-yer-old womn during SE chrcterized by bitemporl seizures nd chnge in mentl sttus. (D) Axil DWI showing gyrl pttern of restricted diffusion nd ipsilterl thlmic chnge in n 83-yer-old womn with left hemisphere seizures nd hypotension. (E) Axil DWI imges showing E1 gyrl pttern of restricted diffusion nd E2 crossed cerebellr dischisis in 36-yer-old mn with epilepsy who presented with hypoxi nd recurrent right hemisphere SE.

4 T.A. Millign et l. / Seizure 18 (2009) Tble 3 MRI findings Initil MRI Follow-up MRI Timing DWI ADC signl Are of incresed T2 signl Timing DWI T2 Hippocmpus Neocorticl gry mtter Thlmus Cerebellum Other 1 <24 h Yes # Left 2 weeks Slight Slight 1 month N N 2 <24 h Not Not Bilterl Bilterl frontl nd insul, left prietl, right cingulte 2 weeks Less hyperintense in corticl regions, thlmus unchnged 3 11 dys Yes # Bilterl diffuse Bilterl 6 months N N 4 UK Yes # Splenium 10 weeks N N 5 2 dys Yes Not Left insul nd cortex 1 week Less hyperintense 6 1 dy Yes # Right Left 1 yer Hippocmpl sclerosis 7 1 dy Yes # Right 1 yer Hippocmpl sclerosis, left cerebellr stroke 8 <12 h Yes # Right diffuse Right Left Right cudte Not 9 1 dy Yes # (except thlmus) Bilterl occipitl, R temporl Right 3 dys ADC incresed Unchnged 10 8 dys Yes " Right Right insul Right 1 week Less hyperintense Incresed + incresed signl in left cerebellum UK, unknown, severl MRIs were obtined with the sme finding prior to EEG nd chnge in tretment. the zone of seizure onset, with reversible diffusion s well s perfusion chnges in nonconvulsive SE In some cses, focl trophy results. 22 Signl chnges were seen not only in the res primrily involved in seizure ctivity but lso in those remote from but functionlly connected to the epileptogenic cortex, including the ipsilterl thlmus (ptients 2,3, 8, 9, nd 10) nd contrlterl cerebellum (ptient 8, ptient 6 hd contrlterl cerebellr stroke nd ptient 10 hd contrlterl cerebellr chnges on repet imging). Similr thlmic chnges hve been seen in niml models 23 nd cse reports, 21,24 though the specific involved nuclei hve not been determined; contrlterl cerebellr chnges re more esily explined by known corticocerebellr connections. 21 This pttern my be ssocited with reduced energy supply. With either the corticl or hippocmpl pttern, incresed DWI nd decresed ADC signl my represent cytotoxic edem, nd T2 prolongtion nd incresed signl on DWI without decresed ADC my represent vsogenic edem. Lminr necrosis from the originl injury is possible, but seems unlikely in tht chnges were reversible mong those imged week or more lter. On the other hnd, the sme chrcteristics tht predispose these neuronl popultions to necrosis my predispose them to the temporry supply-demnd mismtch cused by SE. These two processes rise the possibility of developing neuroprotective strtegies tht trget excitotoxic nd substrte mismtch mechnisms similr to those being investigted in neuroprotection fter stroke. With further understnding of the MRI chnges induced by seizures, MRI could be used s surrogte mrker for evluting potentilly neuroprotective gents nd strtegies. The third pttern, tht of signl increse in the splenium, hs been reported in vrious situtions, including bitemporl seizures, 27 ntiepileptic drug withdrwl, 28 nd osmotic or metbolic injury of vrious types. 29,30 This lesion my represent different nd s yet undefined mechnism of seizure-induced injury. In ptient 4, elevted levels of clozpine my hve contributed, presumbly by cusing SE, but direct neurotoxic effects cnnot be ruled out. The splenium my be prticulrly visible on DWI becuse of high myelin wter frction (believed to represent wter trpped between the lipid bilyers), mking DWI of the splenium prticulrly sensitive for restricted free wter motion in toxic metbolic conditions nd sttes of excitotoxicity such s SE. Limittions of this study include vribility in the timing nd sequence of initil nd follow-up MRI nd in clinicl follow-up. Also, some ptients dmitted in SE, primrily those with known epilepsy, did not receive MR imging; therefore, the overll frequency of MR chnges my be underestimted. Although our relince on the forml MRI report to screen studies for detiled review could lso hve resulted in missing some ptients whose imges showed subtle seizure-induced chnges, the neurordiologists t our institutions were well wre of such chnges, prticulrly those tht were not explined by the clinicl history prt from SE. The frequency of MRI bnormlities ws similr to peditric series. 31 However tht study did not specificlly mention ny bnormlities due to SE lone. As seen in Tble 1, we could not find ny clinicl vribles tht relibly distinguished ptients with MRI chnges from those without. However, vribility in mitochondril reserve, presumbly on genetic bsis, might explin these differences. In summry, we found MRI chnges ttributble to SE in 11.6% of cses, nd these chnges seemed to correlte with seizure locliztion nd underlying pthology. The differences in the observed MRI ptterns nd their clinicl correltes my provide insight into the mechnisms of SE-relted neuronl injury nd suggest mens of trgeting neuroprotective strtegies. Conflicts of interest The uthors hve reported no conflicts of interest.

5 108 T.A. Millign et l. / Seizure 18 (2009) Competing interests The uthors hve no competing interests. Acknowledgements Funding: Supported by Brighm nd Women s Hospitl Institute for the Neurosciences Trining Grnt. References 1. Horsley V. The origin nd set of epileptic disturbnce. Br Med J 1892;1: Lee SH, Goldberg HI. Hypervsculr pttern ssocited with idiopthic focl sttus epilepticus. Rdiology 1977;125: Rumck CM, Guggenheim MA, Fsules JW, Burdick D. Trnsient positive postictl computed tomogrphic scn. J Peditr 1980;97: Stone JL, Hughes JR, Brr A, Tn W, Russell E, Crowell RM. Neurordiologicl nd electroencephlogrphic fetures in cse of temporl lobe sttus epilepticus. Neurosurgery 1986;18: Krmer RE, Luders H, Lesser RP, Weinstein MR, Dinner DS. Trnsient focl bnormlities of neuroimging studies during focl sttus epilepticus. Epilepsi 1987;28: Henry TR, Drury I, Brunberg JA, Pennell P, McKeever PE, Beydoun A. Focl cerebrl mgnetic resonnce chnges ssocited with prtil sttus epilepticus. 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