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Original article with video sequencesEpileptic Disord 2011; 13 (2): 125-32

Epilepsy in adult patientswith Down syndrome:a clinical-video EEG study

Aglaia Vignoli 1, Elena Zambrelli 1, Valentina Chiesa 1,Miriam Savini 1, Francesca La Briola 1, Elena Gardella 1,Maria Paola Canevini 1,2

1 Centro Epilessia, Azienda Ospedaliera San Paolo, Milano2 Dipartimento di Medicina Chirurgia e Odontoiatria, Università degli Studi di Milano,Italy

Received May 13, 2010; Accepted February 28, 2011

ABSTRACT – Patients with Down syndrome are now living longer and theoverall prevalence of epilepsy is increasing, however, full characterisationof epilepsy in adult age is still incomplete. We describe the electrocli-nical characteristics of epilepsy in 22 adult patients with Down syndrome(11 males, 11 females), with a mean age of 46 years (range: 28-64 years),followed at the Epilepsy Centre, San Paolo Hospital in Milan. Mean age atepilepsy onset was 36.8 years (range: 6-60 years). Nine out of 22 patientshad focal epilepsy, while nine had late-onset myoclonic epilepsy. In fourpatients, epilepsy was unclassified. The EEG pattern of our patients wascharacterised by a progressive slowing of the background activity withsharp-and-slow waves with frontal predominance. In the patients diagnosedwith late-onset myoclonic epilepsy, the EEGs showed generalised polyspikewaves. Three subjects had an episode of myoclonic status epilepticus at thebeginning or in the course of the disorder. After the first descriptions of late-onset myoclonic epilepsy by Genton and Paglia (1994), this is one of thelargest patient cohorts reported. Our data confirm that epilepsy in adult

nts peculiar electroclinical characte-early as prompt, effective treatmenteo sequences]

ilepsy, late-onset myoclonic epilepsy

(Smigielska-Kuzia et al., 2009; Aryaet al., 2011).In DS, a bimodal distribution of

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patients with Down syndrome preseristics which should be recognizedmay be beneficial. [Published with vid

Key words: Down syndrome, adult, ep(LOMEDS), focal seizures

Down syndrome (DS) (trisomy 21)is the most frequent chromoso-mal cause of mental retardation,

pileptic Disord, Vol. 13, No. 2, June 2011 125

orrespondence:. Vignolientro Epilessia,zienda Ospedaliera San Paolo,ia Di Rudinì 8,0142 Milano, Italyaglaia.vignoli@ao-sanpaolo.it>

with a frequency rate of about 1in 700 births (Sherman et al., 2007).The prevalence of epilepsy in sub-jects with DS is reported to rangefrom 1% to 13%, higher than in thegeneral population but lower thanin patients with mental retardation

seizure onset has been described:the first peak of incidence duringearly childhood and the second inmiddle age (Moller et al., 2001). Theprevalence of epilepsy in patientswith DS has also been reported toincrease with age, with a prevalence

1

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. Vignoli, et al.

f 46% in subjects over 50 years of age (Mc Vickert al., 1994). Since life expectancy for subjects withS has increased in the last decades, a larger overallroportion of them now have epilepsy.eculiar electroclinical patterns and epileptic syn-romes have been recorded in adult patients with DS:

ocal epilepsies, reflex seizures (auditory stimulus) andyoclonic epilepsy associated with dementia (Genton

nd Paglia, 1994), defined as “Late-onset myoclonicpilepsy in Down syndrome” (LOMEDS) (Mollert al., 2001). The electroclinical features of LOMEDSre massive myoclonic jerks on awakening andeneralised tonic-clonic seizures, with generalisedolyspikes/spikes and waves on EEG and progressiveementia, usually preceding epilepsy onset (Crespelt al., 2007; Menéndez, 2005). Recently, Ferlazzo et al.escribed a group of DS patients with a peculiar typef Lennox-Gastaut syndrome, characterised by latenset and high incidence of reflex seizures (Ferlazzot al., 2009).n this study, we examined the electroclinical findings,pilepsy characteristics, relationship between seizurenset and cognitive decline and response of seizures

o drug therapy in a cohort of patients with DS, evalu-ted over a 14-year period at a single regional centre.he accompanying video documents seizure semio-

ogy in two patients.

atients and methods

e retrospectively analysed all patients diagnosedith DS and epilepsy, aged more than 18 years,

ollowed at our Centre between January 1995 andecember 2009. The clinical diagnosis of DS basedn typical somatic features was confirmed by cytoge-etic analysis. Seizures were categorised according to

he proposed classification of epileptic seizures andpilepsy by the Commission on Classification and Ter-inology of the ILAE, 2001 (Engel, 2001).

atients were seen at least twice a year, with video-EEGolygraphic recording and neurological examination.ideo-EEG polygraphic recordings were performeduring wakefulness using a digital EEG System

Micromed, Treviso). Scalp electrodes were posi-ioned according to the international 10/20 systemith EMG electrodes for deltoid muscles. Neuro-

adiological and neuropsychological findings wereecorded when available. The presence and charac-

26

eristics of cognitive deterioration and behaviouralroblems were screened through parental/caregiver

nterview, focusing on the description of differentehavioural patterns, including frequency and rela-

ionship with seizure onset. At the onset of cognitiveeterioration, the patients were screened for otheredical conditions which could cause such decline

MrwpoN1

e.g. thyroid dysfunction, metabolic disorders).he information for each patient was tabulated withemographic data and full details of epilepsy diagno-is, age at seizure onset, seizure type and frequency,nd parental/caregiver interviews were included,ogether with antiepileptic drugs used and responseo treatment. Data obtained from video-EEG record-ngs, brain MRI or CT scans, and neuropsychologicalndings were also included.

esults

e identified 22 adult patients with epilepsy and DS (11ales, 11 females) with a mean age of 46 years (range:

8-64 years). Complete evaluation of the patientsas not possible, as two were lost at follow-up and

wo died.he mean age at epilepsy onset was 36.8 years (range:-60 years). According to the proposed ILAE classifi-ation (2001), 12 patients had generalised tonic-cloniceizures, seven had focal seizures, and two had toniceizures, in one of them the tonic seizures were trig-ered by sudden noise (reflex seizures). Nine patientsad myoclonic seizures, predominantly involving thepper limbs, often occurring after awakening. Of

hose who had myoclonic seizures, one patient hadyelid myoclonia (see video sequence 1; figure 1).f the three patients who had myoclonic status epilep-

icus, the status occurred at epilepsy onset in twoatients. In both of these subjects myoclonic statuspilepticus was easily controlled with i.v. valproate.ine of 22 patients had focal seizures and a tempo-

al origin was identified in some patients. Nine werelassified as LOMEDS and in four patients the epilepsyas unclassified. The mean age at epilepsy onset inatients with LOMEDS was 50.2 years and in most of

hem cognitive decline preceded any obvious seizurenset by about 6-18 months (5/9 subjects) or occurredt seizure onset (4/9 subjects).n most subjects, cognitive deterioration was tooapid for neuropsychological testing. When cognitivevaluation could be performed, the presence of mem-ry deficits, spatial-temporal disorientation and verbaluency impairment was detected. Parents and/or care-ivers also reported loss of previously achieved dailybilities, mental slowing, behavioural disturbancesuch as irritability, and increased stereotyped move-ents.

Epileptic Disord, Vol. 13, No. 2, June 2011

ost of our patients were treated using monothe-apy: eight with valproate, five with levetiracetam, oneith phenobarbital, one with primidone and one withhenytoin. Five patients were on polytherapy becausef drug resistance.euroimaging (CT scan and/or MRI) was performed for

9 of 22 patients. Brain atrophy was found in seven sub-

E

Down syndrome and epilepsy in adults

High pass filter: 1,600 Hz Low pass filter: 70 Hz Gain: 0200 µV/cm

Fp2 F8

Fp2 F4

G2 G2

Fp1 F3

F8 T4

F4 C4

F3 C3

C3 P3

P3 O1

T5 O1

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Dels+ Dels

eog+ eog-

EKG+ EKG-

C4 P4

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Fz Cz

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Fp1 F7

F7 T3

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jlgIIntsifIpm(ca

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MS 39 yrs 200 µV/cm 20 sec

MKR+ MKR-

igure 1. Diffuse polyspike waves related to eyelid myoclonia.

ects, associated with hydrocephalus in four, ischaemicesions in one and an arachnoidal cyst in another. Basalanglia calcifications were detected in three subjects.n eight patients the result was unremarkable.n all patients, EEGs showed a slow and poorly orga-ised background activity. This pattern is recognised

o be typical of subjects with DS. We observed progres-ive slowing of the dominant background activity withncreasing age. Theta activity was predominant overronto-temporal regions in most patients (figure 2).n all except one patient with LOMEDS, bilateralolyspike-wave discharges were recorded (figure 3),ostly associated with myoclonic jerks in upper limbs

see video sequences 2 and 3; figure 4). The main clini-al, EEG and neuroradiological findings of the patientsre described in table 1.

iscussion

n recent decades, people with DS have lived for longernd this may be ascribed to improvements in medi-al care (Glasson et al., 2002). For this reason, clinicalomplications in adult patients with DS are becominguch more frequent.

pileptic Disord, Vol. 13, No. 2, June 2011

n our sample of adult patients with DS, two mainroups of epilepsy syndromes were identified: focalpilepsy, with a prevalent onset in adolescence oroung adulthood, and LOMEDS, with a typical onsetfter the fifth decade (in five patients the onsetas in the fifth decade and in four in the sixthecade). Regarding the patients with DS and focal

pcordai

pilepsy, the mean age of epilepsy onset was 25.7 years.n all except two, epilepsy onset occurred at a youngge. In this group of patients, epilepsy was some-imes drug-resistant and continued lifelong withoutny clear cognitive decline. No particular neuroradi-logical picture was evident in this group of patients.ecently, Ferlazzo et al. (2009) described a peculiar pre-entation of Lennox-Gastaut syndrome in DS. In ourample, two patients had tonic seizures, but none ofhem were diagnosed with Lennox-Gastaut syndromeince the complete syndromic features, including mul-iple seizure types, characteristic EEG pattern andehavioural disturbances, were not evident.ince the first description of LOMEDS, characterisedy myoclonic epilepsy associated with dementia withnset during or after the fifth decade in DS (Gentonnd Paglia, 1994), few patients with this peculiar syn-rome have been described in small case series

Moller et al., 2001; De Simone et al., 2006; Larner,007; Genton, 2007; Crespel et al., 2007). In our groupf adult patients with DS and epilepsy, nine subjectsere shown to fulfill the criteria for the diagnosis of

OMEDS, which represents, to our knowledge, theargest reported cohort of patients to date.

ith regard to the clinical characteristics of these

127

atients, we observed that the cognitive decline pre-eded any obvious seizure onset by about 6-18 monthsr occurred at seizure onset in most cases. As alreadyeported (Deb et al., 2007), the early symptoms ofementia in DS patients may be difficult to recognizend the caregivers often have a crucial role in detect-ng the primary behavioural changes presented in the

128 Epileptic Disord, Vol. 13, No. 2, June 2011

A. Vignoli, et al.Ta

ble

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Epileptic Disord, Vol. 13, No. 2, June 2011 129

Down syndrome and epilepsy in adults

Tab

le1.

(Co

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1

A. Vignoli, et al.

PP 46 yrs 100 µV/cm 20 sec

Fp2 F8

Fp2 F4

Fp1 F3

F8 T4

F4 C4

F3 C3

C3 P3

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T5 O1

pB02+ pB02- Non Presente

MKR+ MKR-

C4 P4

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T4 T6

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Fp1 F7

F7 T3

T3 T5

Figure 2. Slow background activity with sharp-and-slow waves with frontal predominance.

Fp2 F8

Fp2 F4

Fp1 F3

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F4 C4

F3 C3

C3 P3

P3 O1

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MKR+ MKR-

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RLC 61 yrs 100 µV/cm 20 sec

igure 3. Diffuse slow activity with generalised polyspike waves

30

atients. It is noteworthy that the most frequent signsf dementia reported by the caregivers in our sam-le were loss of previously achieved daily abilities,ental slowing, and behavioural disturbance such as

rritability and increased stereotyped movements. Thelinicians should regard such early symptoms with sus-icion and ask for further investigations with video

plTaaIn

atient with LOMEDS.

Epileptic Disord, Vol. 13, No. 2, June 2011

olygraphic EEG recording and neuroradiological eva-uation in order to diagnose LOMEDS.he electroclinical pattern of LOMEDS was found inll patients and was characterised by slow backgroundctivity and diffuse spike waves or polyspike waves.n a few cases, it was possible to record myoclo-ias, mainly involving upper limbs. Neuroradiological

E

Down syndrome and epilepsy in adults

GA 45 yrs 100 µV/cm 20 sec

Fp2 F8

Fp2 F4

Fp1 F3

F8 T4

F4 C4

F3 C3

C3 P3

P3 O1

T5 O1

MKR+ MKR-

C4 P4

P4 O2

Fz Cz

Cz Pz

T4 T6

T6 O2

Fp1 F7

F7 T3

T3 T5

DELd+ DELd-

DELs+ DELs-

F ation in a patient with LOMEDS.

icvoogIdcDsdgtDAIpamsdptde

DNs

Legends for video sequencesVideo sequence 1Video-EEG recording (EEG is not presented)obtained after a generalised tonic-clonic seizure ina patient aged 39 years. Several eyelid myocloniawere recorded lasting 3-4 seconds, related to diffusepolyspike waves.

Video sequence 2Video-EEG recording of a 45-year-old patient pre-senting recurring myoclonic jerks involving both

R

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igure 4. Myoclonic seizure induced by intermittent light stimul

nvestigations in patients with LOMEDS showed onlyerebral atrophy, probably related to senility. As pre-iously reported (De Simone et al., 2006) and also inur experience, antiepileptic treatment with valproater levetiracetam can promptly control myoclonic andeneralised tonic-clonic seizures in these patients.t is well known that the clinical picture of cognitiveecline in DS is very similar to that of dementia inlassic Alzheimer disease, although onset is earlier inS. Neurophysiological analysis of myoclonus in DS

howed the same characteristics present in Alzheimerisease (Wilkins et al., 1984), as did the neuropatholo-ical examination performed in a few cases. However,he incidence of epileptic seizures and myoclonus inS patients is about eight times greater than that inlzheimer patients (Evenhuis, 1990).

t is important to recognize the specific electroclinicalattern of LOMEDS in order to start early treatment andchieve a prompt control of the seizure disorder whichay avoid further cognitive decline. Since myoclonic

eizures may involve not only the upper limbs but alsoifferent parts of the body, as demonstrated in ouratients with eyelids myoclonias, the full characterisa-

ion of these patients reported here should extend the

pileptic Disord, Vol. 13, No. 2, June 2011

escription of clinical presentation and EEG pattern ofpilepsy in adult patients with DS. �

isclosure.one of the authors has any conflict of interest or financial

upport to disclose.

d

Dw2

Dic

arms.

Video sequence 3The same patient showed myoclonias induced byintermittent light stimulation.

eferences

rya R, Kabra M, Gulati S. Epilepsy in children with Downyndrome. Epileptic Disord 2011; 13: 1-7.

respel A, Gonzalez V, Coubes P, Gelisse P. Senile myoclonicpilepsy of Genton: two cases in Down syndrome with

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ementia and late onset epilepsy. Epil Res 2007; 77: 165-8.

eb S, Hare M, Prior L. Symptoms of dementia among adultsith Down’s syndrome: a qualitative study. J Intell Disab Res

007; 51: 726-39.

e Simone R, Daquin G, Genton P. Senile myoclonic epilepsyn Down syndrome: a video and EEG presentation of twoases. Epileptic Disord 2006; 8: 223-37.

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