The onset of Rasmussen syndrome is usually between the ages of about 18 months and ICyears with a mean of i years: and development is usually normal ...
Rasmussen's encephalitis
Among the causes of intractable epilepsy RasmussenSi encephalitis must rank high on the list.antl the condition has become increasingly familiar to thoscbtreating chiltlrcn with seizuw tlisorders.The syndrome is certainly well defined. with fits starting in childhood, folloivcd by progressive heniiplegia and dementia, tlie foriner usually responding poorly to treatment. Histological examination of biopsy material, or at autopsy.confirms t he presence of inflammatory changes i n the affecbtecl Iiemisphcre,but this is not the elid ofthestory'. The condition was first recognized i n 19.41' when a boy aged 7 years developed right-sided seizures and slight weakness of the right arm.and a cortical biopsy showed evidance of encephalitis.Thc hemiplegia progressed. and a few years later was accompanied by a hemianopia. -4hemisplierectoniy was performed at the age of 22 years. Histological examination showed perivascular inflammation antl glial nodules. T h i Rasmussen et aI.:$ reported three patients with intractable focal seiztrrers. a slowly progressive neurological tleteriora'tion, cortical atrophy mainly in t h r perisylvian region. antl histological evitleiire of an inflammatory proccss.The question was whether these findings were primary orsccontlary The onset of Rasmussen syndrome is usually between the ages of about 18 months and ICyears with a mean of i years: and development is usually normal before the onset of the epilepsy. In just over half the patients this takes the form of epilcpsia partialis continua.The occuri'ence of fits can fluctuate spontaneously. and there can be evidence of 1)ilateral epileptic foci'. Thr condition is frequently progressive over many years,but can stabilize at any time,and death is rare. I n a iwiew of 48 patients with Rasmussen syndrome.', 23 had a history of infections or inflammatory episodes within 6 months of the onset of epileptic fits, probably most often of viral aetiology: but with no obvious history of immunodcficiency. Fourteen had generalized tonic-clonic seizures. 12 had simple partial seizures with motor maiiifestations.and 12 had complex partial seizures. Simple partial seizures also occasionally occurred with postural signs suggesting involvement ofthe supplementary motor area,such as conjugate deviation of the head antl eyes. visual symptoms. and somatosensory symptoms. O f t l i e 48 patients. 27 had epilepsia partialis eontinua, always i n association with other seizure patterns. antl nine presented with writhing or chorcriform movements.t,tiree of them being \vrongly diagnosed as having Sydenham's chorea. The clinical co~rrsewas divided into t1ireestages:before the development of a fixed Iieniiplegia. from this development to the end of the neurological deterioration, and during the stable state with no progress of neurological symptoms and signs. Symptoms included: homonyinous hemianopia. 49%:
sensory tlcfects. 29%:tlysartliria. 29'%):dysphasia. 18%: and psychiatric abnoriiialitics sucli as pcrsoiiality chrigw and destructive behaviour. 17%. Surgery was ~)rrformetli n all 48. but c*ortic-ectornydid not control seizures or pievent tleteiioration. Sistwn had a liemispherectomy when the neuivlogical state had stabilizctl.nnt1 it was found that a fuiictionally complete but anatomically subtotal IiciiiispIiri.ectoi~i~:to avoid the compliration of Iiacmosidcrosis. was Iwst .This did riot aggravatc t he c.ontlition. and usudly al)olishctl seizures and arirstcd tletcrioration.
Histology and aetiologs Typical pathological findings consiat of I)ci*ivamilarIymphocytic cuffiiig.~~roliferatioii of microglial ~iorlr~lrs.nc~i~i~onal loss. antl gliosis.iii the affected Iieiiiisl,here".Thc niicroglial nodules are associated wit h frequent non-speci tic. neiironophagia. mostly of nietliuin-sized pyraniitlal cells o f t lie external pyramitlal layer: antl they occur particularly n w i ' pcrivabcular ruffs of lymphocytes and moiioc~tcAs.l'liei~is sonie evidence of spongiosis along with thesr inflammatory changcs.l)ut this is iiot so witlespreatl as i n the sp(ingiform ence~~halo~~athics:and there can he a niarltetl gliosis of the molccular layer covcrinp the cavitatetl eortes. Lesions sewn to rxtciicl in a coiiflucwt rather t han a mukifocal nianni4. Such results obviously raise the possibility of a virus infcction. Searches for possible herpes virus genes in tissues fi-om patients with Itasinussen syndrome can be equivocal, and no evidence of virions has bern fountI.\'inters and FaridI' found lo\\ levels of cytomegalovirus (ChlV) and Epsteiii-Barr virus genes i n brain tissuc. from both those with and those without encephaiitis, suggesting that these viruses do not cause tliib type ofencephalitis. Two children were reported by Harvey ct al.!' who during the early stages of Hasmubsen's enreptialitis deve~opetlacute uveitis on the same sidr as tlie brain patliologyl'his raises the possibility ofthe infertion spreading to the brain.antl the history of another child was published by Fukuda ct al.'". describing the tlevelopinent of loralized encrphalitis a montli after an operation for residual cataract.due to chronic uveitis on the same side.Tests.iiiclutliiig those for possible virus i n f k tioiis. WIV however negative. Nore persuasive were the findings of Power et at.". I n IO patients with clinical and patIiologic*al findings coriipati1)le~ with a diagnosis of Rasmussen syndronie. i n sit 11 Iiybritlizution with a biotinylatetl CAI\' DSA probe done on brain biopsy speciniens tlenionstratcd CN\' genomic material i n seven of them.\vhile in 46 controls this was only present i n two. Probes for herpes simples virus antl for hepatitis I3 virus were negative. suggesting that W\' was a likely c.ause.\Valter and
Reiic41a'2 rvpoi-tctl t u o patients with focal lesions that on in Iiybritlizatioii \\it11 biotin-~abei~etI Ds.4 piul)es. foIlo\vctl by tletrIction wit11 avidi~i-alI;aliiie phosphatase coinpleses. stlo\\etl Epstei n- ~ a r rvi i'us genoi/ie i n i ntra tiuciea I* central cores within tticenceplialiticitifiltt~ktiotis;but tlie clinical diagnosis of Rasniussen syndrome is oljen to doubt. .Atkins et a].]:{ stut~ied10biopsy and dsrction specimens from seven patients with this syiitlromc. using biotinyldetl tlouble-straiitle(1 DSA probcs to CJlC HS\:antl EB\:antl \vwe unable to itlentif\. any evitlencr of viral material using tlirse tecliniques.Tliis cwtninly suggests that a viral infection.is not tlietr could be a genetithe only cause of tlie c~tici~plialitis.birt cally tleterininetl predisposition triggered by a viritl illness.or a combination of sricli an illness antl tin abnormal immunr response. Hoivcvcr i n tlie futuir tlic. tecliniques of genomic amplificatiott may I)(. the most srritablr to yevcal the prcsence ofa virus". The. possil)le link bet \\pen Rasniussdn syntli-oine antl autoimmunity is suggested in a number of ways. During efforts to raise atitibotlics to recombinant glittaniate receptors. histological features like those of Ramussen's cncephnlitis were found in tlie 1)rains of rabbits imni(inizet1 ivith CluR3 protcin:aiitl a correlation has bceii shown 1)itween this form of eiiceplialitis antlseruin aritibotlies to ( W R 3 protcin.The transient reduction of the seruni titres of (;luK3 antibodies by i'epeated plasma rschanges i n a child with this condifion may have been the cause of the tleci*eascof seizures and iniprovpnient i n neurologiral function. 1fso.tIiissuI)ports tlie idea that GluR3 is an autoantigen antl that t ~ i iaiitoinitniine process may untlerlie this disease. Fort his to happen !he blood--brain occur after barrier \vou~dIiare t o be tIamage:etI.w~iictiicoiiit~ injuries arid infections1" "'.This could bc the first ofthree in&pelitleiit events \\ liicli could start antl Iwpetuate the disease ~~i~oe~~ss.Seeoiitlly tlicre \ v o ~ l t lIiii~cto be the presence or abilit y to produce the C:luR3 or related antibodSes.antl finally the piwenee or display of G'luR3 on the neuron/in a form that can be accessed by the immune system.This eomplicatetl niotlel is consistent with tile rarity ofthis (Iisease". Ifit is some form of aut oini m i n e process rnninly tli twted agaiiist Glu R3. specific antibody therapy. plasmaplioresis to reniovb only GluR3 protein. or oral tolerimtion with ( J u R 3 pro!ein. may provide effective long-term tlicrapy".Apart from the fact that theC'SF shows no consistent inflammatory response. esaniination of the systemic stid CSF irntnune responses fdils to indicate evi(letice of either ongoing or tleficietit immuiie rcactivityIY. ~ o n e v e ras . t~iscusset~. tiiere may ~ ) an e i jimunogenetieally tleterniinerl susc.eptibility for some viral infectious process. possibly linked with the HLA system]!'. Apparent dual pathologies liave been iq)ortecIi:2t'. for esainple histological evidenceofan inflammatory process and of a neural migration tlefect.Tliis could be a chance finding. hut it is possible that the latter lesiori 'may have caused seizures that tlisruptcd the blood-l)raiii barrier. Then at1 immune response could have resulted from tlie tle~clopment ofantibodiesagairist GlitR3 proteins. A possible cause for the intractable epilepsy is an axonal sprouting and synaptogcnesis. \vhicli can occur as a consequence of seizure-intlucetl ticoronal loss.This. i n the fututv. may have therapeutic implications. with t h r developnieiit of inhibitors of these phenomena", X genetic disposition to seizures may \veil also contribute t o intractable epilepsy1!'. sitti
Diagnosis Tlic differeiitial diagnosis. \vlien their: is illtractable epilepSyis from cortical tlysplasias. b rai ti t u innu rs. antl degenerative cortical grey tiiattcr diseases, especially spongiform rncel)haloputhies antl prioii diseases. although no prionrelated protein has been found i n cortical or cerebellar amyIoid pIaclucsi; and \vhen there is epilepsia partialis continua this is paiticiilarly suggestive of these conditions. antl of some forms of ineriiiigoence~~lialitis.or of mitochontlrial eiireplialopnthies". Initially the diagnosis of this syntlrorne will be a clinic~lone i n a patient presenting with intractable focal seizures, Iiemiplegia. and dementia. I n Rasinussen s y n dronie the ('SF is either normal or shonrs a 1y1npIiocytosi~.Tl~e EEG usually shows ~ateraiiket~ lion-epileptic ant1 epileptiform abnorma1ities:but not al\wys.The lack ofelectroclinical correlations in a few patients can be striking. antl certainly the EEC findings support tlie contention that lesions n1a.y not be confined to one hcrnisplierv.hut can be more diffuse". Seui.oradiological investigations. i ncluding CT scans antl inagiletic rcsoi1aiicc imaging. will usually but not always.confirm the focal nature o f t he responsible cerebral lesion antl its extent,'". as weII as IieIp to monitor progress". Sometimes a brain biopsy may be rieetletl t o demonstrate the exact pat hology esl)eciially if there is no epilepsia partialis continua early i n the illtiess nor clear evidence of deterioration. However it can be difficult t o tlecitle if this is justifiahle, as too large a biopsy iniiy liave a detrimental effect on the conclition.and too small a one may give a false-negative result. - Maglietic resoiiance spectroscopic imaging. using the relative resonance intensity of S-acetylaspartate antl creatine. can show rvitlence of neuvonal loss or tlaniage within tlie brain.sonictinies in areas that appear normal on conventional magnetic resonance imaging'-'. This may help iii tlie early detection of brain (lainape antl i n monitoring progression antl the response t o treatment oftliis disease. Using this tech~iiclue there was no significant incir?asc of lactate resonance intensity, cicept i n two patients with epilepsia partialis continua, indicating t,liat this results from tlie scizutas rather than froin thedisease itself. Sometimes i n uiitloubtetl Rasiiiussen syntlrorne the CSF and magnetic resonance imaging can he norma1,and Burke et aI."' record onesucii patient.
Treatment The theories on aetiology have led to a number of clifferetit tliempies. In view ofthe possibility ofa viral aetiologpantiviral agents such as gaiiciclovir antl zitlovutline can be tried. DeToletlo antl Sinith2i gave zidovudine to a patient \vitli this condition \vliose seizures had not responded to any antiepileptic tlrrigs.which is often tlie case.'l'liis was given for 62 tlays,antl then stopped because of granulocytopcnia ...\ftc.r. a few weeks the seizures stopped antl the paticntk condition ceased t o deteriorate for 21 months. Partial fits involving the other hemisphere recurred, but it was not possible to wsuiiie the zidovudine. I t could be that, rather than Iiaving a direct antiviral action, the drug suppresses IgC: and IgM; if an autoimmune mechanism is involved. I t is also a worry that the disease spread after treatment was stopped. so tliat it may liave only h e n symptomatic. Xndrews et aLGhave tried the effect of iapeated plasmaplieresis on four children with pathologically confirmed KasiniissenB encephalitis. In three of thcni, in which it was
assessed,tliere \Yere elevated levels of GluH3 antibodies.Tliree of them sho\vctl dramatic. transient responses with reduced seizure fi-equency antl improved symptoms and signs:but one only improved marginally. These results suggest that circulating substances. such as autoantibodies, can bc harmful in some of those affected 1)y the disease: and that it may well be itn aiitoinimune condition. So plasmaphoresis can sometimes be useful. esprcially \vhcn arute deterioration occurs, for example with status cpilepticus.ant1 it can Iielp i n the assessment of residual function in the damaged hemisplierc before surgical resection by revealing potentially useful function i n the diseased cortex. Iiiimiinosiil)pressant therapy with steroids antl initnunoglobulins can result i n fewer seizures and some improvement i n neurological findings. Steroids. although reported to be effective i n suppressing epilepsy partialis continua,only slightly improved motor or cognitive deficits. High dose steroids. for csamplc. were given i n three intravenous infusions of 400mg/m2 inet Iiylpredisolone, one every other day, follo\vetl by oral prednisone 2mg/kg/day. or Iiydrorortisone lOnig/kg/clay, reduced progressively over 3 to 24 months*. Chinchilla et al.' treated eight patients 11 itli Hasmussen syndrome with high doses of steroids, inclutling pulses of niethylprednisolone antl prctlnisone i n decreasing doses. I n seven t ~ i e r \\'as c a t~ecreaseoft~ieel)i~epsy and tileneuro~ogica~ symptoms within 6 months: but only five of them. i n whom steroid treatment had been started less than 15 months after tlheonset of cpilcpsia partialis coiitinua.cx~~crieiice~l a lasting effect. Even these had periodic transient i.elapses.Three possibilities are suggested to esplain the action of thr steroids. They may act as antiepileptic drugs, they may protect and repair the blood-brain barrier. or they may have antiinflammatory or ii~imunosuppir?ssi\.eeffects. Sineteen patients with the syndrome were treated by Hart et aI.?!' with intravenous immunoglobdins. high-dose steroids. or both.Ten of the 17 who received steroids,and 8 of the 9 given immunoglobulins, had some reduction of seizure frequency, but improvement in their hemiparesis was slight.Therc was no definite correlation between the duration of the disease antl the effect of treatment. Side effects of steroids. such as fluid retention, were common. I t is suggested that if intravenous gammaglobdin is sometimes successful this niay be due'to a non-specific blockade of endogenous antibody synthesis. and to a decline of autoantibodies, as tlcmonstratetl in the treatment of autoiinrnune th roin bocy topenia 's''. Wise et aLR'treated a 14-year-old girl with Rasmussen syndrome with intravenous gammaglobulin every four months for 46 months. During this time there was no progression in motor and cognitive signs, or in the incidence of seizures; and although the mechanism of their action is obscure it may \veil be related to the modification of an immunological disoider. Krauss et al.(1996) reported a patient with a pretlominantly left-sided encephalitis, seizures, and language impairment, findings compatible with a diagnosis of ltasmussen's encephalitis. Other possible diagnoses were excluded, but there were unusual features: the onset at 15 years of age was late,symptoms progressed in adult life,and altliough cerebral involvement \vas asymmetrica1,it was bilateral.Also the benefit from immunosuppression was very marked, for esample with intermittent intravenous cy(:lophosplianiide.as an alternative t o steroitls.Thcre were no autoantibodies detected t o
the glutamate receptor subunits GluRl. CluRZ, and (4luK3. This absence suggests that this form of chronic encephalitis may have iiiultiple caiises. Intraventricular alpha interferon has been tried with impro\-ement and no adverse sidc effects':'. Its mode of action is uncertain, but it may corrcct subtle immune defects. or reduce a viral antigen load. \vhich may illlow cffectivc viral c+wance.As there was no evidence of a viral infection in the child treated with interferon. the former action seems more likely. and suggests that iiniiiuiic-iiietliatctl mec.lianisrns do contribute to the patliogenesis. I n a condition that usaally has a rc~lentlesslyprogrrssive course it may be necessary to consider more radical trcatment. Surgical excision of the afrectetl part of the brain may be possible,or a hen~isphei-crtoniy.I t is easier to tleeitle on the latter if there is already a motlerate to severe heniianopia and Iiemiplegii". mid if the non-dominant liemisphere i h irivoIved:'".r\s has already been statc(1.a functionally complete but anatomically subtotal liemisplicirrtoiiiy may give the best results". Tivel ve children with this sy iitli~omc un(lerwcnt hcmisph(vxtorny.and were followd up for an average of 9. I5 yearb by Vining et d.:l'i.Kady operation is favoured i n vie\\+of the very poor prognosis antl the fact that a suc*c.i~ssfiil outcome can lead t o the child resuming a moir normal life: and niay help to prevent the tlementiaoften associated with the t ' c p ~ t c ~ seizures. l Especially iii young cliildipn. after the t l a m a ~ ~ t l liemisphere is removed. it may be easier for ncurological functions to transfer to the good Iicniisphcre and dcvelop more effectively.
Conclusions It asmu ssen sy ntI rome
\v i I I ril rely 1) resen t sew 1.C. diagnost i tt tlifficulties. with its triad of epilepsy. heniiplcgia and tlementia: but some special test niay be neetletl. and i n certain circumstances even a brain biopsyThe aetiology ofthe condition is open to doubt: is Hasmusscn syndrome due to ii virus infection, or an autoinimunc disorder, or both? Treatment with antiepileptic drugs is unsatisfactory, hut the course of the illness ran be influenced by a number of therapies based on putative causcs.Thesc include antiviral and ininiunosuppressant tIiera1)y plasmaphoresis. antl alpha interferon. I t is often necessary to consider surgeryantl the best option seems t o be a functionally coinplcte but anatomically subtotal licmisplierectorn): This should be consitlered early i n the courseoftliedisease ratherthan laterifthebest outcomeis to be obtained.
References 1.Antel JI? RasniiissetiT.(1996) Rasniussrii'seiirqhditis and tlir new Iiat.i\'euro/ogy4&9-11. 2. RasniussenTR.( 1991)Clironic eiireplialitis and seixums:historiral ic Eticrplinlit in n t i t / int rcxluctioii.I n:Andertnann Fedit or.(%h Ep i / ~ p yHua . tti i(.s.wti b Syti drotti P. 0sford: 1311t t e r\vo rt I1 Heineniann.1) 1-4.
