SHORT COMMUNICATION

ADHD and Epilepsy in children with Tourette Syndrome: a triplecomorbidity?R Rizzo (rerizzo@unict.it)1, M Gulisano1, PV Calì1, P Curatolo2

1.Section of Child Neuropsychiatry, Department of Pediatrics, Catania University, Catania, Italy2.Section of Child Neuropsychiatry, Department of Neurosciences, University Tor Vergata, Rome, Italy

CorrespondenceR Rizzo, Department of Paediatrics, Catania Univer-sity, Via Santa Sofia 78, 95123, Catania.Tel: +393402647099 |Fax: +39095495673 |Email: rerizzo@unict.it

Received3 June 2010; revised 2 July 2010;accepted 9 July 2010.

DOI:10.1111/j.1651-2227.2010.01951.x

Tourette Syndrome (TS) is an inherited neurodevelopmen-tal disorder most commonly diagnosed in childhood orearly adolescence, characterized by multiple motor tics andone or more phonic tics, which last for more than a year.Tics may be simple or complex in nature and vary in num-ber, frequency and severity over time. TS is not a unitarycondition and can be disaggregated into more homo-geneous symptom components. With a prevalence of about1%, TS is no longer considered a rare condition. TS has amultifactorial aetiology, in which genetic, immunologicaland hormonal factors interact to establish vulnerability. TSis associated with several comorbid disorders which areoften the major source of impairment for affected children.Comorbidity between TS and ADHD is high even if thegenetic relationship between ADHD and TS has not beenfully established (1). The comorbidity of TS and epilepsy israrely reported. In this paper, we report a series of eightyoung patients with TS who were followed up for at least7 years, presenting comorbid mild ADHD symptoms andeasily controlled seizures.

Our series includes eight patients (seven males and onefemale) with a median age of 14.8 years (range 10–17) withdefinite diagnosis of TS according to Diagnostic and Statis-tical Manual of Mental Disorders-IV-Text Revised(DSM-IV-TR) criteria, assessed at the Neuropediatric Unitof Catania University, Italy, and followed up for a periodof at least 7 years. Full personal and family historieswere obtained with particular reference to epilepsy andTS-related disorders. For the definition of epilepsy, weconsidered the presence of at least two afebrile seizures;for the ADHD definition, we considered excessive inat-tention, hyperactivity and impulsivity either alone or incombination.

All the patients underwent a complete physical and neu-rological examination, routine laboratory examinations,awake electroencephalogram (EEG) and cerebral magneticresonance imaging (MRI).

Patients’ assessment was carried out using the NationalHospital Interview Schedule for Gilles de la Tourette Syn-drome, the Yale Global Tic Severity Rating Scale (YGTSS),the physician rated Diagnostic Confidence Index. The Con-ners’ Parents Scale, Child Behaviour Checklist and DSM-IV-TR criteria were used to evaluate the severity of ADHDand to define its subtype. Psychiatric comorbidities werealso evaluated by the following scales: the Children’s Yale-Brown Obsessive Compulsive Scale, the Wechsler Intelli-gence Scale for Children, the self-report Child DepressionInventory and the Multidimensional Anxiety Scale forChildren.

Clinical findings of our eight patients are summarized inTable 1. Soft neurological signs such as incoordination andclumsiness were present in three patients.

There was a positive family history for either tics or TS infour patients. All the patients had a typical onset of TS,presenting firstly motor tics at the age of 6.4 years (range6–10 years), followed by vocal tics at the age of 9.8 years(range 8–13 years). One of them presented also obsessivecompulsive disorder. Neuropsychological findings showeda normal IQ in six of eight patients.

Three patients had mild tics and did not require any medi-cations. TS was pharmacologically treated in five patientswho presented high YGTSS’ scores (>20) with severeimpairment in their daily life; three patients received pim-ozide and two risperidone, obtaining an improvement of thesymptoms and a reduction in YGTSS’ score (p value: 0.005).All of them are still under pharmacological treatment.

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A positive family history for idiopathic epilepsy was pres-ent in four patients. Seizure onset was characterized by par-tial complex seizures in four patients, generalized tonicclonic seizures in three and childhood absence epilepsy inone. Seizures began after 4 years (range 5–9) and precededthe tic onset in all patients except for two. MRIs were nor-mal in all the samples.

All the patients had a prompt response to the first anti-epileptic drug treatment. At the last follow-up, after at least7 years (range 7–10 years), seven patients were seizure-freewithout medications; only one showed sporadic seizuresand was still under valproic acid.

Six patients presented ‘combined ADHD’ type and twopredominantly hyperactive ⁄ impulsive ‘ADHD-H’ type. Twoof them showed behavioural disorders characterized byaggressiveness. All the patients showed Conners’ scorehigher than 12 (range 27–41). Non pharmacological treat-ment including cognitive behavioural therapy and familysocial interventions obtained an improvement of ADHDsymptoms.

We describe eight young patients with TS with easily con-trolled seizures, ADHD and soft neurological signs. TS, likeepilepsy, is often associated with behavioural phenotype(Rickards 1995) (2).

ADHD is a frequent comorbidity of TS children. In epi-demiologic samples, the reported prevalence of ADHD inTS is 55% (3).

In our series, ADHD symptoms typically preceded theonset of the tics. Patients with TS + ADHD showed cogni-tive impairment and behavioural problems compared topure TS because of the malfunctioning ADHD can cause.Furthermore, when ADHD is present, clumsiness and lackof coordination are frequently reported (4).

Comorbidity of TS and ADHD may reflect a commonneurobiological substrate. Studies of the motor characteris-tics of the ADHD associated with TS has revealed uniqueanatomical and neurobehavioural differences (5). A

significant loss of the normal globus pallidus asymmetry inthe patients with TS or in the patients with ADHD hasbeen reported. However, poor inhibitory control and volu-metric reductions in fronto-striatal circuits appear to becore features of ADHD, whereas reduced volumes of thecaudate nucleus together with activation and hypertrophyof prefrontal regions seem to be core features of TS (6).Diffusion tensor imaging of adult patients with TS haveshown a decrease of fractional anisotropy (FA), increasedradial diffusivity in corticostriatal tracks and a significantreduction in FA in corpus callosum fibres. In patients withADHD, there was a significant reduction in FA in cortico-striatal tracks too (7). Moreover, abnormal level of dopa-mine and glutamate has been reported in both conditions(8).

There are some anecdotal case reports in the literaturethat documented the association between TS and epilepsy;the majority of them describe epilepsies or tics whose onsetsare subsequent to other diseases.

Neville et al. (2001) described early onset epilepticauditory and visual agnosia with spontaneous recoveryassociated with TS. However, only two authors describeda triple comorbidity of idiopathic epilepsy, TS and ADHD(9).

Eapen et al. (10) reported a 3-year-old hyperactive boywho presented at the age of 5 complex partial seizures trea-ted with sodium valproate, with moderate improvement ofseizures; in the following years, a diagnosis of TS was made.

Diamond et al. (11) reported a 30-year-old male patientwho had TS, ADHD and complex partial epilepsy whosetics responded to vagal nerve stimulation.

The dopamine system is altered in idiopathic generalizedepilepsy; basal ganglia and dopamine dysfunction may beinvolved in different ways in the different type of benign epi-lepsy and may be related both to seizures expression andpoor cognitive performances such as processing speed andattention (12). In animal models, glutamate and GABA

Table 1 Clinical features of eight patients with TS, ADHD and seizure

Patient SexAge(years)

Seizureonset(years)

Familyhistoryseizure

Seizurestype EEG abnormalities

Ticsonset(years)

Familyhistoryof Tic

Neurologicalexamination

Followup Treatment

IQ

YGTSS

ConnersADHDtypeTIC EPI ATT AED onset follow up

1 M 10 5 + CPS 3-cycles ⁄ sec generalized

spike waves

6 ) Incoordination,

clumsiness

+ ) PIM VPA 48 38 25 31 C

2 M 17 9 ) GTCS Frontal spikes 6 + Incoordination + ) RIS VPA 97 42 30 27 C

3 M 16 8 ) CPS Occipital right spikes 10 + – + ) – VPA 95 39 30 28 H

4 M 13 4 ) GTCS Centro temporal spikes 7 ) Incoordination,

clumsiness

+ ) – VPA 90 20 – 30 C

5 M 16 6 ) GTCS Generalized spikes 7 ) – + ) RIS VPA 68 35 30 32 C

6 F 14 7 + CAE 3-cycles ⁄ sec generalized

spike waves

8 + – + ) – ETS 95 15 – 41 C

7 M 15 7 + CPS Centro temporal spikes 7 ) – + ) PIMFLU LVT 92 45 28 36 C

8 M 17 5 + CPS Frontal spikes 7 + – + + – VPA 100 15 – 38 H

GTCS = Generalised Tonic Clonic Seizures; CPS = Complex Partial Seizures; CAE = Childhood Absence Epilepsy; IQ = Intelligence Quotient; ADHD = Attention

Deficit Hyperactivity Disorder; C = combined; H = Hyperactivity; YGTSS = Yale Global Tic Severity Scale; ATT = Anti-Tourette Therapy; AED = Anti-Epilepsy Drug;

PIM = Pimozide; RIS = Risperidone; FLU = Fluoxetine; VPA = Valproic Acid; LEV = Levetiracetam; ETS = Ethosuccimide.

Rizzo ADHD, epilepsy and Tourette syndrome

ª2010 The Author(s)/Acta Pædiatrica ª2010 Foundation Acta Pædiatrica 2010 99, pp. 1894–1896 1895

perturbations in the thalamocortical network have beenshown to play a role (13).

Moreover, human studies have shown that there aregenetic modifications in the metabotropic glutamate recep-tor 4 (14).

Although the relationship between TS, ADHD and epi-lepsy is not fully understood, an increased dopamine- andglutamate-mediated excitatory activity could explain theoccurrence of the symptoms.

The pharmacological treatment of patients affected by TSplus ADHD and epilepsy is a challenge. Tic medications,such as typical and atypical neuroleptics, can lower seizurethreshold and induce epileptiform EEG discharges. In thesecases, treatment with topiramate or levetiracetam could beeffective. (15).

Patients with a triple comorbidity could benefit from atreatment with an anti-epileptic drug, such as topiramate orlevetiracetam.

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15. Martinez-Granero MA, Garcia-Perez A, Montanes F. Leveti-racetam a san alternative therapy for Tourette syndrome.Neuropsychiatr Dis Treat 2010; 6: 309–16.

ADHD, epilepsy and Tourette syndrome Rizzo

1896 ª2010 The Author(s)/Acta Pædiatrica ª2010 Foundation Acta Pædiatrica2010 99, pp. 1894–1896