1. ADHD and epilepsy What should we know? Sergio Aguilera, M.D.
Pediatric Neurology Unit
Department of Pediatrics
Complejo Hospitalario de Navarra
Pamplona, Spain

2. ADHD and epilepsy
Should we be aware of epilepsy in patients with ADHD?
How can we identify children with ADHD at risk of epilepsy?
Should we perform an EEG in every patient with ADHD?
Is the use of psychostimulants safe in patients with ADHD and epilepsy?
During this conference I will focus on main topics related to ADHD and epilepsy by answering to these questions: 1,2,3,4
Let’s start with a special case report that illustrates these main topics

3. Sleep video-EEG recording without AED or MPH
Case report
Boy, 9-yo
Inattentive> fidgetiness, impulsivity evident from 5-yo
Normal IQ
ADHD inattentive subtype, DSM-IV-TR
No familial history of ADHD or epilepsy
12 hours after first dose of MPH-OROS (0.6 mg/kg)
At sleep, tonic-clonic seizure lasting 15 min
Complete recovery 2 hours later
Next day interictal awake EEG: generalized slow spike-wave discharges predominantly on both centro-temporal regions
Conventional cerebral MRI normal
This is the case of a 9-yo boy recently diagnosed with ADHD inattentive subtype following DSM-IV criteria, whose behavioral symptoms were evident from 5-yo and academic performance worsened during the last year. His IQ was normal. There was no familial history of ADHD or seizures. Twelve hours after the first dose of long-lasting methylphenidate he presented a T-C seizure lasting almost 15 minutes. He completely recovered. Awake EEG was performed next day and revealed epileptiform discharges on both C-T regions. Cerebral MRI was normal. An EEG during sleep showed that epil. discharges were present in more than 85% of the sleep record…
Sleep video-EEG recording without AED or MPH

4. Sleep video-EEG recording with AED and MPH: normal
Case report
Subclinical idiopathic epilepsy with centro-temporal spikes
Continuous spike-wave during slow sleep (CSWS): deleterious effects on cognition and behavior
Valproic acid+clobazam reverted CSWS
MPH 50/50 was added 6-mo later with favorable effects on attention and academic performance
No changes in IQ in 2 years, no seizures, still on valproic acid
In spite of he never had seizures before, ‘just ADHD’, EEG suggested a electric pattern similar to BECS (benign epilepsy with centrotemporal spikes). Then, MPH probably acted as a trigger. But an uncommon electroencephalographic complication was present: CSWS, which by itself produces a deleterious effect on cognition and behavior if persists long time. Half of the cases of CSWS are idiopathic and age-related, typically during school age. Treatment with at least 2 AEDs is mandatory and it usually reverts CSWS within several weeks. IQ must be revised periodically in order to assess cognitive decline, but this was not the case. Academic achievement remained low but MPH was added again and favorable effects were recorded
Sleep video-EEG recording with AED and MPH: normal

5. What should have been done?
Must epilepsy or subclinical epileptiform discharges be ruled out in all patients with ADHD?
Perform an EEG in every patient with ADHD?
Avoid psychostimulants in patients with ADHD and EEG abnormalities?
After this clinical case, additional questions raises:1,2,3
The answer to the first question is yes, but only if clinical data suggests it. In this case the only relevant information was that there was no familial history of ADHD, so the etiology was not clear and subclinical epilepsy could be there…but…is it enough to perform an EEG in this patient before treatment? Academic performance was declining in last year but cognitive abilities were right and this decline it is usually found in ADHD patients along the school years. Finally, subtle absence seizures were not probably mistaken in this boy because of the location-related origin of his epilepsy
Second question: no, but depends on several clinical aspects that I will explain now
Third question: no, but caution if an EEG has been performed and abnormalities are found
Let’s see what conclusions can be taken from different studies on these topics… ?

6. Should we be aware of epilepsy in patients with ADHD?
The prevalence of ADHD in childhood is 5-9%
Epilepsy affects 0.5-1% of children and adolescents
ADHD tends to co-occur with epilepsy at rates 1-77%
The prevalence of ADHD in childhood is from 5 to 9% depending of different studies
The prevalence of epilepsy is much lower
Different studies have found that ADHD tends to co-occur with epilepsy with differing results that can be attributed to methodologies

7. Antiepileptic drugs+epilepsy Antiepileptic drugs+ADHD
In this population-based study including more than quarter million children, epilepsy had a prevalence of 0.5%. Prevalence for ADHD was much higher taking into account that the study is pharmacy-based on electronic records. What is interesting in this study is that almost one third of children with epilepsy also had ADHD, but only 1% of patients diagnosed with ADHD also had epilepsy…So just bad luck with our case?
Primary-physician (MHS database) and pharmacy-based electronic records (insurances)
284,419 children
Mean age 9.4y SD2.3, 51%males
Antiepileptic drugs+epilepsy
Antiepileptic drugs+ADHD
Epilepsy: 0.5% (55% males)
ADHD: 12% (75% males)
Epilepsy+ADHD: 0.2%
27% epilepsy had ADHD
1% ADHD had epilepsy

8. ADHD in patients with epilepsy
38% ADHD in 175 children with epilepsy>6m (Dunn et al., 2003)
31% ADHD in 75 children with new-onset epilepsy vs. 6% of general population (McDermott&Akrishnaswami, 1995)
High frequency attributed to:
Type of epilepsy: idiopathic, generalized, absences, partial seizures, encephalopathy
Side effects of antiepileptic drugs
Effect of chronic seizures or epileptiform discharges on memory, learning and processing speed
Psychosocial factors
Exploring the presence of ADHD in children with epilepsy, most studies are hospital-based so it is easy to think that high rates of ADHD may be related to severe cases of epilepsy, that presented with cerebral lesions or cognitive sequelae. But in new-onset cases with idiopathic epilepsy the frequency of ADHD is also high. This high frequency is attributed in the literature to a wide range of factors as: …

9. 80% of children with active epilepsy had a DSM-IV-TR behavioral disorder and/or cognitive impairment (IQ <85)
N=85
Of the 60% of children who met diagnostic criteria for a DSM-IV-TR disorder, only one-third had previously been diagnosed
This is a very interesting prospective community-based study of neurobehavioral comorbidities in 85 children with ACTIVE epilepsy collected from schools, it means they HAVE seizures. What is relevant for our topic and for our case: they detected that 15% of children with active epilepsy had a diagnosis of ADHD BEFORE the onset of seizures. After the onset of seizures, the percentage raised to 33%, a similar rate as previous hospital-based studies. They concluded that other factors than seizures are related to the presence of ADHD, as psychosocial factors or underlying common pathophysiological mechanisms.

10. Some recent studies have focused on brain images in children with ADHD with or without epilepsy (seizures).
Saute et al. (2014) have studied cortical thickness in children with epilepsy and ADHD, children with epilepsy without ADHD, and controls. They found that children with epilepsy and ADHD exhibited of decreased cortical thickness that was bilateral and widespread, compared to children with epilepsy without ADHD. These anatomical abnormalities were evident early in the course of epilepsy suggesting the presence of antecedent neurodevelopmental changes

11. They suggest that ADHD in epilepsy or alone share a common origin
N=17 ADHD+EPIL
N=15 ADHD-
N=15 controls
Working memory tests
fMRI
No differences in tests results or pattern activation between ADHD+ and ADHD-
They suggest that ADHD in epilepsy or alone share a common origin

12. Epilepsy in patients with ADHD
History of ADHD 2.5-fold more common in new-onset seizures than controls (Hesdorffer et al., 2004)
Pathological findings on EEG without seizures: ADHD (6%) vs. aged-matched children (3%) (Richer et al., 2002)
If sleep EEG is included: 28% abnormal in ADHD vs. 7% in wake EEGs (Millichap et al., 2011)
General population: Rolandic spikes (2%) are related to seizures in <10% (Holtman et al., 2006)
If we focus on the presence of epilepsy in patients with ADHD, first we have to recognize two main situations:
ADHD plus seizures: as in Reilly et al. study, others have found a history of ADHD more common in new-onset seizures than controls
ADHD plus epileptiform discharges on EEG records, but without seizures: epic discharges are frequent in ADHD patients, more evident when sleep EEG is recorded.
This abnormalities in EEG are not always related to epilepsy. In the general population, rolandic discharges are related to seizures in only 10% of the cases. Another question is what is the risk of seizures when I start psychostimulants in my patient with rolandic discharges and ADHD. It is not clear.

13. In patients with ADHD and epil
In patients with ADHD and epil. discharges but without seizures, abnormalities in EEG appear in most of the cases on centro-temporal regions or frontal (like in our patient). These patients are at low risk of developing seizures (<10%) but it is known that discharges can produce specific deficits in response inhibition, leading these patients more prone to impulsivity. However, these results are not found in other studies, that showed more inattentive subtype of ADHD in children with epil. discharges without seizures (Dunn et al.).
It is difficult to know if psychostimulants can trigger seizures in these cases. Then, based in our experience, we choose atomoxetine instead, or start AEDs at low doses associated with short-acting MPH. If discharges during sleep are frequent (>50%), treatment is different as prognosis is poor in untreated patients with CSWS
Holtmann et al.,2003, 2006: ADHD+rolandic spikes without epilepsy: more impulsive and more deficits in response inhibition (CPT and Stroop tests) than ADHD-

14. Suggested indications to perform an EEG in ADHD
Attention disorders with: Episodic altered awareness, daydreaming, confused state, memory lapses (transient cognitive impairments related to generalized>focal discharges) Millichap et al., 2011; Loo&Barkley, 2005
Motor focal deficits in detailed neurological examination
Low IQ and/or autism
Cognitive decline
Aggressive behavior in outbursts
Unexplained absence of improvement with drugs ???
Febrile seizures during infancy (5% risk of idiopathic epilepsy )*
Relatives with epilepsy (8% heritability)
Absence of relatives with ADHD? (our case report…)
Routine EEG is probably not indicated in the evaluation of all children with ADHD (AAP Practice Guidelines, 2001) but some indications are useful in the clinical practice based on experience.
The most accepted indication by different authors is…it must include Wake andSleep EEG

15. Stimulants for ADHD and epilepsy
MPH improve ADHD symptoms in 70-85% of children with well-controled epilepsy
Seizure exacerbation has been reported with MPH, but no randomized controlled trials
Retrospective, open-label and controlled trials do not support that MPH increases seizures frequency
MPH is useful in difficult-to-treat epilepsies (Fosi et al., 2013)

16. Medication for ADHD and EEG
Stimulants and other drugs used in ADHD do not seem to exacerbate EEG abnormalities found in children with ADHD

17. Stimulants for ADHD with epileptiform discharges
Risk of seizures is not well established
Always perform a sleep EEG during sleep (night or after deprivation)
Depends on type of discharges
Frequent generalized discharges are more prone to seizures
Use of AEDs in children without seizures is controversial
Use of levetiracetam may improve discharges and also cognition in some studies
Low doses of stimulants do not increase epileptiform discharges but it is not clear if also do not affect the risk of a seizure
Some authors recommend short-acting MPH at low doses in non- treated ADHD+epilepsy with AEDs

18. Conclusions We must be aware of epilepsy in children with ADHD
There are some clinical clues that may help to differentiate ADHD+ from ADHD-epilepsy but are not well studied
The use of AEDs in patients with ADHD and epileptiform discharges is controversial and must be individualized
The routine EEG is not indicated in the diagnosis of ADHD
MPH is safe in patients with ADHD+epilepsy well-controlled with AEDs
MPH short-acting at low doses may be an option if no AEDs are used in the same patient, always with informed consent of the parents