Journal ofNeurology, Neurosurgery, and Psychiatry 1996;61:151-156

Startle provoked epileptic seizures: features in 19patients

Mark R A Manford, David R Fish, Simon D Shorvon

AbstractObjectives-To define the clinical charac-teristics of a group of patients with startleprovoked epileptic seizures (SPES).Methods-Nineteen patients were identi-fied during the course of a larger study ofclinical seizure patterns. A witnessedseizure account was obtained in allpatients; interictal EEG in 18, video-EEG-telemetry in eight, CT in 18, andhigh resolution MRI in eight.Results-The onset of SPES was in child-hood or adolescence in 14 of 19 patients. Itwas preceded by exclusively spontaneousseizures in nine patients and SPES hadbeen replaced by exclusively spontaneousseizures in two patients. Sudden noisewas the main triggering stimulus andsomatosensory and visual stimuli werealso effective in some patients. The clini-cal seizure pattern involved asymmetrictonic posturing in 16 of 19 patients. Focalneurological signs were present in ninepatients, mental retardation in six, and 10were clinically normal. Ictal scalp EEGshowed a clear seizure discharge in onlyone patient with a tonic seizure pattern;over the lateral frontal electrodes con-tralateral to the posturing limbs. BrainCT showed a porencephalic cyst in threepatients, focal frontal atrophy in one, andgeneralised atrophy in one. Brain MRIwas undertaken in five normal subjectsand three neurologically impairedpatients, six with normal CT. It showed aporencephalic cyst in one patient. In sixpatients, there were dysplastic lesions.They affected the lateral premotor cortexin three patients and the perisylvian cor-tex in three patients, one with bilateralperisylvian abnormality.Conclusions-SPES are more frequentthan is generally appreciated. They maybe transient and occur relatively com-monly without fixed deficit, by contrastwith previous reports. The imagingabnormalities identified in those withoutdiffuse cerebral damage suggest thatSPES are often due to occult congenitallesions and that the lateral premotor andperisylvian cortices are important in thisphenomenon.

(3 NeurolNeorosurg Psychiatry 1996;61:151-156)

Keywords: epilepsy; startle; magnetic resonance imag-ing; frontal lobe; dysplasia

A major issue in the understanding of seizuremechanisms lies in the factors determining thetransition from interictal state to seizure andthose controlling termination of seizure activ-ity. For most patients, the occurrence ofepileptic seizures is sporadic and unforesee-able. In about 5% of patients, however, spe-cific triggers for the epilepsy have beenidentified,' the commonest being photosensi-tivity. These cases provide an opportunity toexplore factors involved in generation ofseizures. Some patients have seizures precipi-tated by startle stimuli, which are known as"startle provoked epileptic seizures" (SPES).The stimuli can be sensory stimuli of variousmodalities, most commonly noise, but only in aspecific context; the same stimulus that trig-gers a seizure if unexpected, will have no effectif the patient is forewarned. We have found 65previously reported cases of SPES'-7; they areusually considered rare.8 The patientsdescribed mostly had severe epilepsy, oftenassociated with moderate to severe fixed neu-rological handicaps, representing diffuse neu-rological damage. The purpose of this paper isto present the clinical and investigational find-ings of a further 19 patients. Only some of thecurrent series were affected by fixed neurologi-cal deficit, others had no neurological signsand were of normal intelligence. The secondgroup affords the opportunity of trying tolocalise the region responsible for startle sensi-tivity without the confounding factor of wide-spread damage that is often associated withfixed neurological deficit.

MethodsPATIENT SELECTIONNineteen patients with SPES were identifiedduring the course of a larger study of 252patients, investigating the clinical features offrontal and temporal lobe epilepsies. In thatstudy,9 potential cases were identified by retro-spective selection and ongoing surveillance ofhospital records. The criterion for inclusionwas evidence of frontal or temporal lobe partialseizure onset as defined by: (1) a demonstrablestructural lesion on CT or MRI; (2) an ictalEEG recording suggesting electrographic focalseizure onset; (3) an interictal EEG showinglocalised paroxysmal spike activity; (4) ictalclinical features suggestive of focal epilepticactivity according to current concepts.'0

PATIENTS' SEIZURE DESCRIPTIONSAll patients were interviewed using a speciallydesigned questionnaire. An open section was

Wessex NeurologicalCentre, SouthamptonGeneral Hospital,Tremona Road,Southampton,Hampshire S016 6YD,UKM R A ManfordEpilepsy ResearchGroup, Institute ofNeurology, QueenSquare, London,WC1N 3BG, UKS D ShorvonD R FishCorrespondence to:Dr M R A Manford, WessexNeurological Centre,Southampton GeneralHospital, Tremona Road,Southampton, HampshireS016 6YD, UK.Received 13 June 1995and in final revised form9 April 1996Accepted 11 April 1996

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used to collect details of the sequence ofseizure manifestations, followed by a closedquestionnaire to ensure completeness and todefine the timing characteristics of theseizure for example, seizure frequency anddiurnal variation. In all cases the patient's sub-jective account and an objective account wereobtained; from an eye witness only in 11patients and also from video-EEG-telemetryin eight. Patients with SPES had seizuresoccurring consistently, but not necessarilyexclusively, immediately after an unexpectedsensory stimulus but not if the same stimuluswas anticipated. In 17 of 19 patients a historyof startle sensitivity was elicited spontaneouslyin the open section of the questionnaire. In allpatients verification of the history was soughtfrom an observer; the frequency, consistency,and spontaneous reporting of SPES left littledoubt that the phenomenon was genuine, evenin those in whom it was not seen on video-EEG-telemetry.

EEG ANALYSISA median of two EEGs was available for eachpatient. For the eight patients who had under-gone video-EEG-telemetry, additional longperiods of interictal recording were available.The locations of up to the first 100 spikes wereassessed on available interictal EEGs for eachpatient. These included all available spikes in17 patients. Other EEG manifestations wereassessed qualitatively. Spikes were definedaccording to conventional criteria" and classi-fied according to location. Video-EEG-tele-mery recordings were made with 24 channelEEG and computerised recordings, using thestandard 10-20 system. Ictal scalp EEGs wereavailable for nine of the 19 patients, eight withsimultaneous video recording.

NEUROIMAGINGAbnormalities on CT were localised using atemplate technique'2 1 based on the atlas ofTalairach et al. i-i Abnormalities on MRI werelocalised directly from anatomical landmarksvisible on the scan. Eight patients underwenthigh resolution MRI, including six with nor-mal CT. A 1.5 Tesla Signa machine (GEMedical systems, Milwaulkee, Wisconsin) wasused and standard axial and sagittal seriesobtained with T2 and Ti weighting. In addi-tion, a series of 124 contiguous, 1-5 mm, pro-ton density, coronal sequences was obtainedwith techniques described previously,'5 allow-ing reformatting in any plane for optimal visu-alisation of structural abnormalities.

ResultsCLINICAL CHARACTERISTICSNineteen patients were identified with SPES,7-5% of the whole series. A congenital aetiol-ogy was postulated for 11 patients; on the basisof retardation or neurological signs since birthin six, and purely from the dysplastic nature ofthe imaging abnormalities in five. In onepatient, severe meningitis in the first fewmonths of life was thought to be the cause andin another SPES were seen after treatment for a

pineal tumour at the age of 10. Table 1 showsthe clinical characteristics and results of interic-tal EEG and neuroimaging. Table 2 shows theclinical seizure characteristics and ictal EEG.Patients were divided into two groups; patients1-9 had fixed neurological deficits and patients10-19 had no fixed deficit. There was no evi-dence that patients with clinical signs had a dif-ferent pattern of epilepsy in terms of age ofonset, seizure frequency, severity, or responseto treatment.The onset of startle sensitivity was in child-

hood or adolescence in 14 patients, but in fivepatients not until adult life. Nine patients hadhad seizures unrelated to startle stimuli forsome years before startle sensitivity developed;in one patient, epilepsy started at the age of oneyear but startle sensitivity only supervened inassociation with an exacerbation of her epilepsyand a change in her seizure pattern at the age of25. In five patients the seizure pattern preced-ing the onset of startle sensitivity was similar tothat seen subsequently, except that seizureswere spontaneous. In four patients develop-ment of sensitivity to startle was associated withnew ictal manifestations. Pathological startleresponse had disappeared by the time of inter-view in two patients and it occurred, therefore,during only part of the course of many patients'epilepsy history. In all except one patient, iden-tical seizures could occur spontaneously or beprecipitated by startle at different times; theproportion of spontaneous versus triggeredattacks varied widely between patients. Theother patient was one of six who reported a sec-ond seizure type that was never induced bystartle. Thus in no patient were seizures exclu-sively associated with startle stimuli.

SEIZURE CHARACTERISTICS (TABLE 2)Seizures tended to occur with high frequency;all patients had, at some point, experiencedmore than one seizure in a day and 10 had hadmore than 10 a day. Seizures were usually brief,only four patients reporting habitual SPES last-ing more than one minute. In 16 patients theseizures evolved into tonic motor activity,which was focal in 14. Five had a focalsomatosensory onset before tonic posturing,but in the others there were no earlier specificsymptoms. Three patients had very differentseizure patterns; absence with no focal features;generalised tonic clonic with no focal features,and complex absence with giggling, thenbehavioural automatisms. These were allpatients without fixed deficit. Clinical seizurepatterns were otherwise similar in the twogroups.

All patients' seizures could be triggered bysudden, unexpected noise, but other sensorymodalities were more variable in their effect.Six could have a seizure triggered bysomatosensory stimuli-for example, an unex-pected tap on the shoulder or by catching aparetic foot. Visual stimuli such as suddenmovement in the visual field were reported tobe effective in three patients, but they were lessreproducible in their effect than sudden noise.No patient reported a seizure in response totaste or smell.

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Table 1 Clinical characteristics ofpatients with SPES

Age at Age at onset Intelligence Appearance ofAge at onset of of starle (u scale IQ Intenctal EEG Features of high resolution

Case internvew epilepsy response or estimate) Clinical signs spikes CTIMRI MRI Aetiology

1 14 7 7 Mild Left hemiparesis Rare right Right frontal atrophy N/A Abscess ageretardation parietotemporal 5 months

2 20 1 3-5 74 Left hemiparesis None Right frontoparietal N/A Congenitalporencephalic cyst

3 20 8 8 91 Left hemiparesis None Right frontocentral N/A Congenitalporencephalic cyst

4 7 3-5 7 Moderate Right hemiparesis N/A N/A Left frontopartietal Congenitalretardation porencephalic cyst

5 31 12 12 75 Left hemiparesis None Right frontopartietal N/A Congenitalporencephalic cyst

6 24 16 18 Moderate Bitemporal visual Bifrontal Generalised atrophy N/A Pinealomaretardation field defect age 1

7 42 11 Uncertain 80 Pseudobulbar None Normal Bilateral opercular Congenitalpalsy microgyria

8 34 6-5 Uncertain Low average Left Babinski None Normal Right lateral frontal Congenitalresponse cortical thickening

9 55 44 44 93 Bilateral optic None Normal Normal Possibleatrophy from congenitalcongenital rubella

10 13 1 1 1 1 91 None None Mild hemiatrophy Mild hemiatrophy Congenitalwith markedperisylvian atrophy

11 58 14 14 High average None Occasional bifrontal Normal Normal Unknown12 20 2 months Uncertain 85 None Widespread Normal Right perisylvian Congenital

atrophy anddysplasia

13 31 2-5 Uncertain High average None Rare right Normal Right lateral frontal Congenitalfrontotemporal migration defect

14 31 1 25 84 None Bifrontal Normal Right frontal Congenitalmigration defect

15 18 7 13 Low average None Left temporal and Normal N/A Unknownbifrontal spikes

16 50 20 33 84 None Rare centrotemporal Normal N/A Unknown17 29 19 23 88 None None Normal N/A Unknown18 45 7 17 84 None Bifrontal Normal N/A Unknown19 53 13 22 Average None Bitemporal Normal N/A Unknown

N/A = Not available.

Table 2 Seizure characteristics ofpatients with SPES

Average Maximum Tendencyseizure number in to Diurnal Clinical pattern of Seizure Postictal

Case frequency 1 day cluster variation starde provoked seizures duration recovery time Ictal EEG features

1 1/day 3 - No pattern Focal tonic 10-30 s < 10 s N/A2 1-4/day 400 + Most nocturnal Focal tonic 30-60 s 30-60 s N/A3 7-12/y 2 - No pattern Focal somatosensory 2-5 min 5-20 min N/A

then focal tonic4 > 10/day 20 - Only waking Generalised tonic 10-30 s 1-5 min N/A5 1-4/day 12 - Only waking Focal somatosensory <10 s 30-60 s N/A

then focal tonic6 5-10/day 40 + Most waking Generalised tonic 30-60 s 1-5 min N/A7 1-4/mth 10 + No pattem Focal tonic 30 s 10-30 s Single widespread

slow wave at onset8 > 10/day 100 - Most nocturnal Focal somatosensory 10-30 s 30-60 s Muscle artefact

then focal tonic9 1-4/day 30 - No pattern Generalised tonic 30-60 s 10-30 s Muscle artefact10 1-4/day 6 - No pattern Focal tonic 10-30 s 10 s Muscle artefact11 1-6/y 100 + Only waking Focal tonic 10-30 s <10 s Left frontal 16 Hz12 1-4/day 6 - Only waking Focal somatosensory 10-30 s 10-30 s Muscle artefact

then focal tonic13 5-10/day 75 - No pattern Epigastric then focal tonic 10-30 s <10 s Muscle artefact14 1-4/day 4 - Most day Generalised tonic 10-30 s 30-60 s N/A15 > 10/day 80 + Only waking Absence <10 s <10 s Generalised spike

and wave16 7-12/y 20 + No pattern Absence with automatisms 1-2 min 2-5 min N/A

and laughter17 1-4/day 6 - Most waking Epigastric sensation 10-30 s 10-30 s Muscle artefact

then focal tonic18 7-12/y 4 + Most waking Generalised tonic clonic 2-5 min 20-60 min N/A19 1-6/y 8 + Most nocturnal Focal somatosensory 30-60 s 5-10 min N/A

then focal tonic

N/A = Not available.

Seizures were generally refractory to med-ical treatment; patients had received a medianof four antiepileptic drugs and only fourpatients reported a moderate benefit from anyof the agents received. In two patients this wasclobazam, in one clonazepam, and in one car-bamazepine.

EEG CHARACTERISTICS (TABLE 1)Interictal scalp EEG was available in 18patients. It showed spikes in only 10 and slowwave abnormalities in 12. It was normal infive. In patients with neurological signs, inter-ictal spikes were identified in two and were

bifrontal and parietotemporal. In the fourpatients with hemiparesis and porencephaliccysts, slow waves were generalised or wide-spread over one hemisphere. In three otherpatients with abnormal signs there were slowwaves and these were pericentral, bifrontal,and generalised. Eight patients with no fixeddeficit had spikes, more than in the clinicallyabnormal group. This may reflect selectionbias, as patients without gross lesions on neu-roimaging more often underwent video-EEG-telemetry with long periods of interictal EEGrecording. Sites of spikes varied considerablywithin patients and between patients, involv-

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ing frontal, central, and temporal regions andusually they were not highly localised. Therewere slow waves in five patients with no signs;generalised in one, bifrontal in one, andlocalised in three. Two patients with the mostpronounced slow wave abnormalities had dys-plastic lesions on MRI but the slow wavesseemed to be more diffuse than the scanabnormality.An ictal scalp EEG recording was available

in nine patients, six patients in the group withno signs. The ictal EEG onset was obscuredby artefact in seven patients. In one patientthere was clear 12-16 Hz activity at the leftmid-frontal electrode (F3) at the onset of theseizure, contralateral to the direction of headturning and to the predominant side of postur-ing. In patient 15, an absence was recordedfortuitously on routine EEG and was accom-panied by a generalised spike and wave dis-charge, phase reversing at the mid-frontalelectrodes. She reported similar seizures inresponse to startle and a second seizure typesuggesting a focal onset that occurred less

Figure 1 MRI ofunilateral perisylvianatrophy in patient 10.

Figure 2 MRI ofbilateral perisylvianatrophy in patient 7 withopercular syndrome.

often. These seizures started with staring, pal-lor, and dysphasia, followed by a Jacksonianspread of tingling from her left hand and thenshe would turn her head to the right and occa-sionally rotate in circles for up to two minutes.Her interictal EEG showed occasional focalleft anterior temporal and bifrontal spikes andthis, combined with the clinical seizure pat-tern, suggested a localisation related epilepsy,despite the generalised EEG dischargerecorded during her absence. In two patients,in whom there was no clear ictal onset of scalpEEG, there were postictal changes; unilateral,pericentral slow waves in one patient andwidespread slowing in the other.

IMAGING CHARACTERISTICS (TABLE 1)In all patients with a hemiparesis, a poren-cephalic cyst or pronounced focal atrophy wasseen in the contralateral hemisphere. In onepatient with only reflex asymmetry, one withbilateral optic atrophy, and one with pseudo-bulbar palsy, CT was normal. One patientwith no clinical deficit had mild hemiatrophyon CT; in all the others with no signs, CT wasnormal.

High resolution MRI was performed on sixpatients with normal CT, and in the patientwith mild hemiatrophy on CT. Five of thesehad no signs, one an extensor plantarresponse, and one pseudobulbar palsy.Abnormalities on MRI were seen in sixpatients and seemed to fall into two overlap-ping patterns, both consistent with a dysplasticaetiology. In three patients there was perisyl-vian atrophy associated with thickening of theperisylvian grey matter. This was predomi-nantly anterior and unilateral in two patients(fig 1), with maximal involvement of thefrontal component of the perisylvian region. Inthe other it was bilateral, with narrowing of theperisylvian region (fig 2), in association withpseudobulbar palsy, and closely resembles thebilateral opercular pattern previouslydescribed on MRI'6 and pathologically.'7 Thesecond pattern, frontal dysplasia, was seen inthree patients. In two of these there was sub-cortical nodular heterotopia in associationwith cortical dysplasia. In the first patient (fig3) the cortex overlying heterotopia appearedas normal on MRI but pathological examina-tion confirmed the presence of focal corticaldysplasia. After resection of the abnormalregion and adjacent cortex this patient has hadone seizure in two years of follow up, havingpreviously had several seizures a day. In thesecond patient, there was a similar but moresevere appearance on MRI, this time associ-ated with thickening of the lateral and mesialfrontal cortices. The third patient had justthickening of the lateral frontal cortex, withoutheterotopia. There was no pathological verifi-cation in these patients.The anatomical localisation of abnormal tis-

sue remains difficult because of the wideextent of atrophy in some patients and the dif-ficulty in defining the limits of cortical dyspla-sia. In the patients with unilateral perisylviandisease and those with porencephalic cysts, themaximal involvement seemed to be frontopari-

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Startle provoked epileptic seizures: features in 19 patients

Figure 3 MRI of lateralfrontal dysplasia in patient13.

etal. In the opercular syndrome involvementwas extensive and probably included all threelobes. In the four patients in whom the lesionwas restricted to one lobe this was alwaysfrontal and never temporal.

DiscussionThe selection methods in this series favouredpatients with frontal lobe epilepsy and thismay have contributed to the high frequency ofSPES-7-5%. Frontal lobe epilepsy is, how-ever, common in the general epilepsy popula-tion.18 Moreover, our findings show that SPESare relatively common without fixed deficit (10of 19 of our patients compared with only fiveof 65 patients reported previously) and the fre-quency is probably underestimated.8 It is possi-ble to miss SPES because they are a transientphenomenon in a patient's seizure history, asillustrated both in this and most previous stud-ies.2-4 6 7 19 20 Although typically starting inchildhood, SPES may not occur until adultlife, even if associated with a congenital MRIabnormality. The clinical ictal features of pre-viously reported patients were similar-56 of65 with a tonic seizure onset. Seizures aremost consistently triggered by noise in allstudies and other modalities seem to be lesseffective, but this may merely reflect the rela-tive potency of noise to cause startle in normalpeople. The refractoriness of these seizures tomedical treatment is well recognised and ouruncontrolled results are similar to others infinding benzodiazepines of some benefit.2'No patients reported had previously under-

gone MRI. Brain MRI was not available inevery patient with negative CT in this study,but the similarity of clinical and ictal features,in those with and without MRI, suggests thatthis was not a major source of bias. The identi-fication of dysplastic lesions in six of seven

patients in whom it was undertaken meansthat this type of pathology is likely to beimportant. It is consistent with the increasing

recognition of cortical dysplasia as an impor-tant cause of partial epilepsies.22 This repre-sents a move away from previous views, inwhich SPES were commonly attributed toperinatal insult and in which the commonestabnormalities on CT were porencephalic cystsand centrotemporal hypodensity, consistentwith the findings in our subgroup with a fixeddeficit. Porencephaly, underlying some of themore severely affected patients' epilepsy, isalso thought to have a dysplastic basis.22

Scalp EEG is recognised to have limitedvalue in SPES. The ictal EEG often shows justa vertex spike, which may represent muscleartefact, rather than abnormal cortical activ-ity.8 Patients with Down's syndrome may be adistinct subgroup, as they more often haveabsence seizures and spike-and-wave on theEEG.'9 Our patient with absences did not,however, have Down's syndrome.Our data showed the brunt of frontal lobe

pathology to be lateral frontal but previouspatients have shown lesions mainly in themesial frontal lobes on CT, especially the sup-plementary motor area. All the previouslyreported patients with CT had fixed deficitsand the imaging modality was less sensitive,unable to detect subtle dysplasia. This differ-ence in location of lesion may be explained bythe results of the only intracranial EEG studyin SPES. Although seizure discharges weremost commonly seen arising from the mesialfrontal lobes, it was rare for them not toinvolve both mesial and lateral frontal struc-tures, making it difficult to discern a puremesial frontal or pure lateral frontal seizuretype.2

There is no current measure of startle sensi-tivity in these patients, except the generationof seizures. Because seizures almost invariablyoccur both with and without startle sensitivity,the two components are dissociable and theirneurological substrates may also, therefore, bespatially separated. We speculate that thejunction of polymodal sensory connectionsand limbic inputs may provide the substratefor this response selective for unexpected stim-uli in various modalities. Cortical regions thatmight fulfil these criteria include the perisyl-vian region, SMA, and especially lateral pre-motor cortex, which is involved in the sensoryguidance of movement.23-26 The phenomenonseems to be due to a variable abnormalitysuperimposed on a fixed defect, as the underly-ing lesion is usually congenital and yet theeffect is transient in the patient's history.

We thank Dr Mark Cook and Dr John Stevens for their helpwith neuroimaging and Mrs Catherine Scott for her help in theanalysis of telemetry recordings. This work was supported byAction Research.

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