1. Cognition in new onset epilepsy in children and adults
Nicole Taylor, PhD, C.Psych
Antonina Omisade, PhD, R.Psych.

2. Faculty/Presenter Disclosure
Faculty: Nicole Taylor, Antonina Omisade
No conflicts to disclose

3. New Onset Epilepsy Terms and Definitions
New Onset (NOE) vs. Newly Diagnosed Epilepsy (NDE):
NOE is an subset of NDE – onset of seizures within the past year.
NDE is a broader category that may represent people who have had seizures for years, but were only recently diagnosed.
Pohlmann-Eden, B (2011). Conceptual relevance of new onset epilepsy. Epilepsia 52(Suppl 4), 1-6.

4. Why is New Onset Epilepsy Special?
Most of what we know about cognitive dysfunction in epilepsy comes from studying people with chronic seizures;
Causes are multi-factorial, dynamic and interactive:
Determining the causes of cognitive deficits becomes more complex with longer duration of epilepsy, as the number of factors affecting cognition increases. In later stages of chronic epilepsy, it is impossible to attribute cognitive deficits to a specific cause without serial assessments.

5. Why is New Onset Epilepsy Special?
Etiology of cognitive deficits in epilepsy is multi-factorial. Dynamic factors include (i) active epilepsy (seizures and interictal discharges), (ii) AEDs and (iii) psychiatric co-morbidities.
Factors contributing to cognitive deficits are not independent. In addition to dynamic factors, age of onset, individual reserve capacity and age- and sex-related plasticity are important moderating variables.
Witt, J.-A. & Helmstaedter, C. (2015). Cognition in the early stages of adult epilepsy. Seizure, 26, (Review)

6. Why is New Onset Epilepsy Special?
It is impossible to attribute cognitive deficits to a specific cause without serial assessments, ideally starting prior to initiation of treatment.
Untreated NOE population is the key to understanding cognitive dysfunction and trajectories in epilepsy.
Determining the causes of cognitive deficits becomes more complex with longer duration of epilepsy, as the number of factors affecting cognition increases. In later stages of chronic epilepsy, it is impossible to attribute cognitive deficits to a specific cause without serial assessments.

7. Why is New Onset Epilepsy Special?
Etiology of cognitive deficits in epilepsy is multi-factorial. Dynamic factors include (i) active epilepsy (seizures and interictal discharges), (ii) AEDs and (iii) psychiatric co-morbidities.
Factors contributing to cognitive deficits are not independent. In addition to dynamic factors, age of onset, individual reserve capacity and age- and sex-related plasticity are important moderating variables.
Witt, J.-A. & Helmstaedter, C. (2015). Cognition in the early stages of adult epilepsy. Seizure, 26, (Review)

8. Goals of Presentation Review what we know about cognition in NOE:
Cognitive profile at onset
Trajectory over time
Current recommendations regarding cognitive assessment of patients with NOE
Local practice
Unanswered questions

9. NOE in ChiLdren
What do we know?

10. NOE and Cognition in Children: What do we know?
Neuropsychological / Cognitive Findings in NOE
Attention, reaction time, visual memory
Mild generalized cognitive impairment in intelligence, language, attention, executive functioning, and psychomotor speed
Examination of new learning, memory, and attention revealed poor attention, visualmotor speed
Academic problems / use of educational services prior to epilepsy onset*

11. NOE and Cognition in Children: What do we know?
Behavioral and Psychiatric Factors*
Higher than expected rates of behavior problems (32% in the clinical or at-risk range) in the 6 months before the first recognized seizure.
45% with DSM-IV Axis I disorders before the first recognized seizure (ADHD, depression and anxiety).
Elevated rate of lifetime-to-date (DSM-IV) Axis I disorders (depressive disorders, anxiety disorders, ADHD).
In a population-based study, children with a spontaneous unprovoked seizure were 2.5 times more likely to meet DSM- IV criteria for ADHD before the first seizure.
Behavioral and Psychiatric Factors
The most common findings (albeit based on retrospective review) are findings of ACADEMIC and / or BEHAVIORAL PROBLEMS predating the onset of the first seizure.

12. NOE and Cognition in Children: What do we know?
Neuroimaging
Baseline abnormalities in cortical and subcortical anatomy, white matter integrity, and ventricular volumes, suggestive of antecedent brain anomalies
Baseline abnormalities are related to cognitive and behavioral findings
Longitudinal findings show altered patterns of brain development after baseline (i.e. slowed white matter expansion and gray matter tissue loss)

13. NOE and Cognition in Children: What do we know?
Cognitive Phenotypes in NOE
Associations between epileptic syndrome and specific cognitive dysfunctions
In NOE, unique cognitive phenotypes were identified representing variations in the presence, type, and degree of neuropsychological compromise. Hermann et al. (2016)
Cognitive phenotypes were independent of epilepsy syndrome
but were associated with neurobiological measures of brain structure (quantitative volumetrics) and features of family environment and early neurodevelopment

14. NOE and Cognition in Children: What do we know?
Early Medical Risk Factors for Neuropsychological Deficit:
Multiple seizures
Use of AEDs
Epileptiform activity on the initial EEG
Symptomatic/cryptogenic etiology
Absence epilepsy
Unknown or unclassifiable epilepsy etiology
Genetic epilepsy
Unknown semiology of seizures
Idiopathic Generalized Epilepsy

15. NOE and Cognition in Children: What do we know?
Early Neuropsychological Risk Factors for poor Outcomes:
Children having preexisting behavior / academic problems more likely to exhibit poor neuropsychological outcomes at 1 year
In FLE, worse neuropsychological outcomes at “Time 0” associated with poorer prognosis for epilepsy management as well as even poorer neuropsychological functioning at 1 year Matricardi et al (2016)

16. WISC Composite scores in:
Group 1 (drug-resistant FLE at 1 year) Group 2 (good seizure control on monotherapy)
A) Time 0
B) Time 1
S. Matricardi et al. (2016). Epilepsy & Behavior, 55, 79–83

17. NOE and Cognition in Adults
What do we know?

18. NOE and Cognition in Adults: What do we know?
Subtle cognitive deficits are already present at the time of first seizure (Witt & Helmstaedter, 2015):
Psychomotor speed
Attention/ “Executive functions”
Memory
Deficits are present in absence of visible MRI lesions
People with “symptomatic” epilepsies tend to have more severe deficits than those with cryptogenic or idiopathic epilepsies.
Correlated with lower education and frequent GTC seizures (Witt & Helmstaedter, 2012).
Of course, a “clean” MRI does not mean that there is no brain pathology; findings differ greatly depending on the field strength, imaging techniques, and even who interprets the images.
NOTE: “Symptomatic, cryptogenic and ideopathic” is outdated terminology.

19. NOE and Cognition in Adults: What do we know?
To date, only SANAD study has evaluated trajectory of cognitive dysfunction over time (12 months):
Patients with epilepsy had worse cognitive performance at baseline and worse change scores compared to controls on tasks of processing speed, memory, and verbal fluency.
“Change” was characterized mainly by a lack of practice effects or subtle losses.
Baker, G., Taylor, J., & Aldenkamp, A.P. (2011). Newly diagnosed epilepsy: Cognitive outcome after 12 months.
Epilepsia 52(6),

20. NOE and Cognition in Adults: What do we know?
To date, only SANAD study has evaluated trajectory of cognitive dysfunction over time (12 months):
In general, seizure freedom did not predict better cognitive outcomes on most measures. There was also no significant difference in change scores depending on seizure type, except with regard to immediate verbal recognition and recall, which showed greater decline in patients with generalized seizures.
Topiramate was associated with greater declines on figure recognition memory, delayed story recall, verbal fluency and information processing.
- SANAD study is not informative about the causes and mechanisms of different cognitive trajectories. Specifically, since all patients were treated with AED’s after the baseline assessment, it is impossible to differentiate AED effects from epilepsy effects or pathology. One exception is topiramate, which was associated with significant declines in areas that have been shown to suffer as a result of this drug.
Baker, G., Taylor, J., & Aldenkamp, A.P. (2011). Newly diagnosed epilepsy: Cognitive outcome after 12 months.
Epilepsia 52(6),

21. NOE and Cognition in Adults: What do we know?
Cognitive problems are under-reported by NOE (seizures <12 months) and NDE patients:
Focus on controlling seizures and adjusting to diagnosis.
Fig. 1 Prevalence of objective and subjective cognitive deficits in
untreated patients with newly diagnosed epilepsy (n = 247)
Witt & Helmsaedter, 2012.
. Assessment performed using EpiTrack (attention and EG) and short form of VLMT
The EpiTrack [14, 15] is a 12- to 15-min assessment tool focusing on attention and executive functions. Six subtests assess response inhibition, visuo-motor speed, mental flexibility, visual motor planning, verbal fluency, and working memory. Based on the subtest results an agecorrected total score is calculated.
The interval for mild impairment is 26–28 points, corresponding to a performance of[1 and B2 standard deviations (SD) below the average performance of the normative sample. The cut-off for marked impairment, i.e.,[2 SD below the normative sample, is B25 points

22. Recommendations
Cognitive, behavioral, and academic problems should be screened at diagnosis, before initiation of medication treatment.
Consideration of a core uniform battery used across epilepsy centers to meet clinical and research goals.
Triplett & Asato (2015): pilot feasibility trial of a brief cognitive and behavioral screening (CNS Vital Signs computer-based screen, and Strengths & Difficulties parent questionnaire) in children with new- onset epilepsy
In pediatric cases, a history of academic problems and / or behavioral and psychiatric problems may indicate later cognitive impairment. Should consider increased prioritization in these cases.
Triplett & Asato: computerized cognitive battery and behavioral questionnaire
- tolerated and well received by children and their parents
time efficient for clinical use with the potential to detect early cognitive and behavioral difficulties related to epilepsy
identified abnormal cognitive profiles in 32% of epilepsy sample, and identified significantly higher emotional symptoms symptom count in epilepsy.
- However, unclear whether use of this screening method in monitoring for disease- or treatment-related changes is successful – under further study.

23. Recommendations Baseline cognitive screening :
Disentangle effects of pathology, seizures, AED’s and psychiatric comorbidities on cognition;
Identify potential biomarkers;
Help guide treatment decisions;
Provide counseling to patients to ameliorate any functional effects of cognitive problems;
Monitor the course of the disease and effects of treatment.
Screening should be offered regardless of subjective complaints.
Biomarkers: does presence of cognitive dysfunction early in the disease process predict seizure recurrence, worse seizure management and worse NP and psychological outcomes in the future?
Subjective complaints may not be the best way to determine who needs an assessment due to high rates of under-reporting of cognitive deficits.

24. Approach to NOE in Halifax
Brief (2-hour) baseline assessment is offered to:
All NOE patients within one month of initiation of AED’s;
Individuals after their first clearly-unprovoked seizure,
Patients who were seen after their first seizure are only seen again if they have another seizure
NOE patients are re-assessed after 2 years.
Individuals with major cognitive deficits or functional complaints are referred for a complete neuropsychological assessment.

25. Questions to be Addressed
The developmental course of epilepsy, including NOE needs further research in order to better understand the impact of factors such as :
Age of onset (are there critical stages of brain maturation that lead to specific alterations of brain organization impacting on developmental course?)
Seizure frequency and type, extension of epileptic focus, occurrence of secondarily generalized seizures, and duration of epilepsy
Trajectory of cognitive dysfunction and its clinical significance re: seizure management and functional outcomes

26. Questions to be Addressed
The cause of cognitive problems at (and even before) the time of the first seizure is unclear:
Underlying common pathology?
Some form of bi-directional relationship?
Cognition in new onset vs. newly diagnosed epilepsy:
SANAD study – mean duration of seizures prior to diagnosis was 5 years.
In adult studies, age ranges are large:
Implications for etiology of epilepsy, etc.
Elderly populations are under-represented
Role of “cognitive reserve” factors:
Current research: Whatley et al. (Halifax)
The finding that cognitive-behavioral deficits may precede seizure onset [26], raises the question of whether there is a bidirectional relationship between the cognitive deficits and epilepsy. It is clear that people with epilepsy have a higher risk of cognitive deficits. But do people with cognitive impairment also have a higher risk of developing epilepsy?
To date, most studies looking at epilepsy patients in the early stages, focus on people who are newly-diagnosed, and not those with new-onset epilepsy. Within the newly-diagnosed cohorts, duration of epilepsy ranges from 92 days to 7 years (SANAD study, mean duration is 5 years). As such, these studies to not tell us much about new-onset epilepsy per se.
Age of onset ranges on average between 27 and 71 years in adult studies, and age is strongly connected to etiology. Early and late onset epilepsies are different entities when it comes to pathology and its effects on the maturing vs. ageing brain. In fact, patients with epilepsy starting after the age of 60 tend to demonstrate greater cognitive impairment than younger individuals.

27. Halifax First Seizure Clinic Winnipeg Epilepsy Surgery Group
Acknowledgements
Halifax First Seizure Clinic
Winnipeg Epilepsy Surgery Group
Dr. Bernhard Pohlmann-Eden
Karen Legg, RN-NP
Dr. Ben Whatley
Dawnette Benedict-Thomas (Psychometrist)
Dr. Fran Booth and Pediatric Neurology Team
Kristi MacDonald (Psychometrist)