Psychiatric Comorbidity in
Pediatric and Adult Epilepsy
John M. Pellock, MD
Professor and Chairman, Division of Child Neurology
Children’s Hospital of Richmond at VCU
Virginia Commonwealth University/Medical College of
Virginia Hospitals
Richmond, Virginia
OBJECTIVES
1)
2)
3)
Appreciate the occurrence of
neuropsychiatric comorbidities
associated with epilepsy
Understand how psychiatric
comorbidities influence the quality of life
in persons with epilepsy
Discuss appropriate treatment needs of
persons with epilepsy and depression
John M. Pellock, MD
Professor and Chairman, Division of Child Neurology
Virginia Commonwealth University/ Medical College of Virginia
Children’s Hospital of Richmond
Richmond, Virginia
Dr Pellock has received grants/research support in excess of $10,000 and is a paid consultant as listed below. All grants, research
support, consultant fees and honoraria are paid to Virginia Commonwealth University or the physician practice plan (MCV Physicians).
Dr Pellock has NO equity, stock or any other ownership interest in any of these companies.
Company
NIH/NINDS
Advisory Board
Consultant
Research
YES
YES
CDC/HRSA
YES
Catalyst
Eisai
YES
YES
YES
YES
GlaxoSmithKline
YES
YES
King Pharmaceuticals
YES
KV Pharmaceuticals
YES
Marinus Pharmaceuticals
YES
Neuropace
YES
YES
Lundbeck
YES
YES
YES
Pfizer
YES
YES
YES
Questcor
YES
YES
YES
Sepracor
YES
YES
Sunovion
YES
UCB Pharmaceuticals
YES
YES
YES
Upshur Smith
YES
YES
YES
Valeant
YES
Epilepsy - Definition
• Seizure – disturbances in the electrical activity
of the brain
• Epilepsy – two or more unprovoked seizures
separated by at least 24 hours
• Epilepsy is a spectrum of disorders
• Many different types of seizures
• Many causes
• Many syndromes and types of epilepsy
Institute of Medicine of the National Academies,
2012
Seizure Type versus
Epileptic Syndrome
• A seizure is determined by the patient’s behavior
and EEG pattern during the ictal event
• An epileptic syndrome is defined by:
– seizure type(s)
– natural history
– EEG (ictal and interictal)
– Response to treatment
– Etiology
GENERALIZED EPILEPSIES
LOCALIZATION-RELATED EPILEPSIES
Juvenile
absence
epilepsy
Primary reading
epilepsy
Benign childhood
epilepsy with
centrotemporal spikes
Idiopathic or
Cryptogenic
Childhood
absence
epilepsy
Childhood
epilepsy
with occipital
paroxysms
BMEI
Symptomatic or
Cryptogenic
Chronic
progressive
epilepsia partialis
continua of
childhood
EME
EIEE
Neonatal
Seizures
Severe myoclonic
epilepsy in infancy
Epilepsy with continuous spikewaves during slow-wave sleep
Acquired epileptic
aphasia
Epilepsia 1999;40:531.
Epilepsy with
grand-mal
seizures on
awaking
Epilepsy with
specific modes
of activation
BNFC
BNC
Temporal, frontal, parietal, or occipital lobe epilepsies
-symptomatic
-cryptogenic
Juvenile
myoclonic
epilepsy
West
syndrome
Lennox Gastaut
syndrome
Epilepsy with
myoclono-astatic
seizures
Epilepsy
with myoclonic
absences
EME: Early Myoclonic Encephalopathy
EIEE: Early Infantile Epileptic Encephalopathy
BNFC: Benign Neonatal Familial Convulsions
BNC: Benign Neonatal Convulsions
BMEI: Benign Myoclonic Epilepsy in Infancy
Magnitude
• 2.2 million people in the United States and more
than 65 million people worldwide have epilepsy;
• 150,000 new cases of epilepsy are diagnosed in
the United States annually;
• 1 in 26 people in the United States will develop
epilepsy at some point in their lifetime;
• Children and older adults are the fastest-growing
segments of the population with new cases of
epilepsy;
• Epilepsy is the fourth most common neurological
disorder in the United States after migraine,
stroke, and Alzheimer’s disease
Institute of Medicine of the
National Academies, 2012
Psychogenic Nonepileptic
Seizures
• Terminology
– Hysteria, pseudoseizures (pejorative)
PNES or non-epileptic seizures (preferred)
• Psychological profile
– Significant depression (> 50%)
– Anxiety disorder (> 50%)
• Posttraumatic stress disorder (22%-100%)
• Includes sexual abuse
• Rapid diagnosis associated with better outcome
Dickinson,Looper: Epilepsia, 2012
Paroxysmal Nonepileptic Events in
Children and Adolescents
• PNEs in 15.2% of those monitored
• 2 months to 5 years: 26 patients
– Stereotypical movements, hypnic jerks, parasomnias,
Sandifer (GER)
• 5-12 years: 61 patients
– Conversion disorder (psychogenic seizures),
inattention/daydreaming, stereotyped movements,
hypnic jerks, paroxysmal movements (15 with
concomitant epilepsy)
• 12-18 years: 48 patients
– Conversion disorder (40/83%; 9 concomitant
epilepsy)
Kotegal, Pediatics, 2002
Not All Seizures Are Epilepsy Also Applies to the Military
Rochelle Caplan, MD
Psychogenic Nonepileptic Seizures in US Veterans.
Salinsky M, Spencer D, Boudreau E, Ferguson F. Neurology 2011;77(10): 945–950
OBJECTIVES: Psychogenic nonepileptic seizures (PNES) are frequently encountered in
epilepsy monitoring units (EMU) and can result in significant long-term disability. We reviewed
our experience with veterans undergoing seizure evaluation in the EMU to determine the time
delay to diagnosis of PNES, the frequency of PNES, and cumulative antiepileptic drug (AED)
treatment. We compared veterans with PNES to civilians with PNES studied in the same EMU.
METHODS: We reviewed records of all patients admitted to one Veterans Affairs Medical
Center (VAMC) EMU over a 10-year interval. These patients included 203 veterans and 726
civilians from the university affiliate. The percentage of patients with PNES was calculated for
the veteran and civilian groups. Fifty veterans with only PNES were identified. Each veteran
with PNES was matched to the next civilian patient with PNES. The 2 groups were compared
for interval from onset of the habitual spells to EMU diagnosis, cumulative AED treatment, and
other measures. RESULTS: PNES were identified in 25% of veterans and 26% of civilians
admitted to the EMU. The delay from onset of spells to EMU diagnosis averaged 60.5
months for veterans and 12.5 months for civilians (p < 0.001). Cumulative AED treatment
was 4 times greater for veterans with PNES as compared to civilians (p < 0.01). Fifty-eight
percent of veterans with PNES were thought to have seizures related to traumatic brain
injury. CONCLUSIONS: The results indicate a substantial delay in the diagnosis of PNES in
veterans as compared to civilians. The delay is associated with greater cumulative AED
treatment.
Epilepsy Currents, 2012
Epilepsy and
Neurological Comorbidity
• Approximately 30% of patients with epilepsy
have significant neurological comorbidity
– MR, CP, autism, prior stroke, major head trauma,
encephalitis
• Conversely, epilepsy is more common in those
with these neurological impairments or prior
neurological insults
– MR, CP, autism, prior stroke, major head trauma
• The more severe the neurological comorbidity,
the higher the frequency of epilepsy
National Profile of Childhood Epilepsy
2007 survey: 977 of 91,605 reported epilepsy/seizures
Epilepsy/seizure prevalence higher in lower income families
Children with epilepsy/seizures
 Depression (8 vs 2%)
 Anxiety (17 vs 3%)
 ADHD (23 vs 6%)
 Conduct problems (16 vs 3%)
 DD (51 vs 3%)
 ASD (16 VS 1%)
 Headache (14 vs 5%)
Epilepsy/seizure group poorer education, social outcome
Russ, Larson, Halfon: Pediatrics, 2012
Psychiatric Comorbidities with
Epilepsy
• Frequent finding: lifetime prevalence of
depression and anxiety disorders 30%-35%
• Associated with worse response to AEDs
and surgery and worse medication tolerance
• Affective disorders increase the completed
suicide risk by 32-fold
Bateman, et al, Ep Currents, 2012
Prevalence of Psychiatric Disorders
In epilepsy (range)
In the general
population (range)
Depression
11-60%
2.0-4.0%
Anxiety
Psychosis
19-45%
2-8%
2.5-6.5%
0.5-0.7%
ADHD
25-30%
2.0-10.0%
Kanner, Epilepsia 2003;44(5):3-8.
Prevalence of Psychiatric and Behavioral
Comorbidities
• Population-based, retrospective
study
Prevalence
20
– Incident cases of epilepsy
(1980-1995)
– Rochester, MN
– DSM-IV diagnosis: 51%
(69/104)
– Without mental retardation
and/or pervasive developmental
disorder: 40.4% (44/109)
• Children with newly diagnosed
epilepsy frequently exhibit
comorbid psychiatric or
behavioral disorders
15
Prevalence (%)
• Prevalence
17%
12%
10%
10
5
0
ADHD
Mood
Adjustment
Disorder
Disorder
Hedderick E, et al. Ann Neurol. 2003;54(suppl 7):S115. Abstract E12.
ADHD and Childhood Epilepsy
• ADHD in children
– Up to 87% have >1 additional psychiatric disorder
• ADHD and epilepsy
– Predominately inattention type
– Differential diagnosis
• Medical effect
• Nocturnal seizures
• Absence or complex partial seizures
– Comparison with ADHD seen in psychiatric clinics
• Children with epilepsy more inattentive
• Equal male:female ratio
Dunn D, et al. Dev Med Child Neurol. 2003;45:50-54.
Semrud-Clikeman M, Wical B. Epilepsia. 1999;40:211-215.
Epilepsy and Attention Deficit
Hyperactivity Disorder (ADHD)
Prevalence
•
•
•
•
ADHD
Epilepsy
ADHD in epilepsy
ADHD in patients with epilepsy
treated with AED
5%
1%
20%
30%
Impulsive-Aggressive Spectrum
ADHD
Bipolar Spectrum
Spectrum
Cluster B
Personality Disorders
Borderline
Personality
Disorders
Sexual
Compulsions
Impulsivity and
Aggression
Tourette/
OCD
Developmental
Disorders
Autism
Spectrum
Disorders
Impulse
Control
Substance
PTSD
Disorders
Use
Disorder
Salpekar, 2005
Social Outcome - Results
CAE patients (%)
JRA patients (%)
Odds ratio (CI)
No high school grad
36
14
3.7 (1.3-10.4)
Special classes
16
3
5.7 (1.1-40.5)
Repeated a grade before
diagnosis
20
3
7.6 (1.4-52.8)
Ever considered a
behavior problem
41
10
6.4 (2.2-19.9)
Unplanned pregnancy
34
3
19.3 (2.3-426.1)
Psychiatric or emotional
problems
54
31
2.6 (1.1-5.9)
Unskilled laborer
53
16
5.9 (1.6-24.0)
Manager or professional
0
29
undefined
Not employed in area of
training
50
14
5.7 (1.2-33.9)
Wirrell et al, 1997.
Juvenile Myoclonic Epilepsy
• 1st described in 1867
• Triad
• Myoclonic, absence, tonic clonic
seizures
• Normal development
• 3.5 - 6 Hz multispike and wave
• Onset pre- to post-puberty (12-18 years)
• F=M
• ~ 2% - 5% of all patients with epilepsy
Ethosuximide, Valproic Acid, and Lamotrigine in Childhood Absence Epilepsy
Glauser TA, et al. NEJM 362;9, March 4, 2010
Psychiatric Comorbidities
and Epilepsy:
Is It the Old Story of the
Chicken and the Egg?
Kanner, Ann Neurol, 2012
Epilepsy Curr. 2012 Sep-Oct; 12(5): 201–202.
Hospitalization for Psychiatric Disorders Before and After Onset of Unprovoked
Seizures/Epilepsy.
Adelöw C, Andersson T, Ahlbom A, Tomson T. Neurology 2012;78:396–401
[PubMed]
OBJECTIVE: To study hospitalization for psychiatric disorders before and after onset of
unprovoked epileptic seizures/epilepsy. METHOD: In this population-based case-control study,
the cases were 1,885 persons from Stockholm with new onset of unprovoked seizures from
September 1, 2000, through August 31, 2008, identified in the Stockholm Epilepsy Register.
Controls, in total 15,080, were randomly selected from the register of the Stockholm County
population. Odds ratios (ORs) were calculated to assess the risk of developing unprovoked
epileptic seizures before and after hospitalization for a psychiatric diagnosis defined as a
psychiatric hospital discharge diagnosis using International Classification of Disease codes
from the Swedish Hospital Discharge Registry. RESULTS: The age-adjusted OR (95%
confidence interval) for unprovoked seizures was 2.5 (1.7–3.7) after a hospital
discharge diagnosis for depression, 2.7 (1.4–5.3) for bipolar disorder, 2.3 (1.5–3.5) for
psychosis, 2.7 (1.6–4.8) for anxiety disorders, and 2.6 (1.7–4.1) for suicide attempts. The
risk of developing unprovoked epileptic seizures was highest less than 2 years before
and up to 2 years after a first psychiatric diagnosis. CONCLUSION: The increased rate of
psychiatric comorbidity predating and succeeding seizure onset indicates a bidirectional
relationship and common underlying mechanisms for psychiatric disorders and epilepsy.
Epilepsy, Suicidality, and Psychiatric Disorders: A Bidirectional Association
Dale C. Hesdorffer, PhD,1 Lianna Ishihara, PhD,2 Lakshmi Mynepalli, MSc,3, David J. Webb, MSc,4 John
Weil, MD,5 and W. Allen Hauser, MD1,6
Objective: A study was undertaken to determine whether psychiatric disorders associated with suicide are
more common in incident epilepsy than in matched controls without epilepsy, before and after epilepsy
diagnosis.
Methods: A matched, longitudinal cohort study was conducted in the UK General Practice Research
Database. A total of 3,773 cases diagnosed with epilepsy between the ages of 10 and 60 years were
compared to 14,025 controls matched by year of birth, sex, general practice, and years of medical records
before the index date. We examined first diagnosis of psychosis, depression, anxiety, and suicidality in each of
the 3 years before and after the index date and annual prevalence of suicide. Referent diagnoses were
eczema and acute surgery. The incidence rate ratio (IRR) was calculated for each year in the study period; the
prevalence ratio (PR) was calculated for suicidality.
Results: The IRR of psychosis, depression, and anxiety was significantly increased for all years before
epilepsy diagnosis (IRR, 1.5–15.7) and after diagnosis (IRR, 2.2–10.9) and for suicidality before epilepsy
diagnosis (IRR, 3.1–4.5) and 1 year after diagnosis (IRR, 5.3). The PR was increased for suicide attempt
before epilepsy onset (PR, 2.6–5.2) and after onset (PR, 2.4–5.6). Eczema and acute surgery were both
associated with epilepsy in the first and third year after diagnosis.
Interpretation: Epilepsy is associated with an increased onset of psychiatric disorders and suicide
before and after epilepsy diagnosis. These relations suggest common underlying pathophysiological
mechanisms that both lower seizure threshold and increase risk for psychiatric disorders and suicide.
ANN NEUROL 2012;72:184–191
Epilepsy and Psychiatric Disorders:
A Bidirectional Relation
• With epilepsy, significantly higher risk for developing:
– Psychosis
– Depression
– Anxiety disorders
– Suicidality
• With psychiatric disorders, significantly higher risk for
developing epilepsy
• Psychiatric disorders not simply a reaction to
psychosocial obstacles!
Hesdorffer, Ann Neurol, 2012
Psychiatric Disorders and Epilepsy
Bidirectional Relation:
Neurobiological/Pathogenesis
• Neurotransmitters: serotonin,
norephinephrine, dopamine, glutamate,
GABA
• Endocrine: hyperactive hypothalamicpituitary-adrenal axis producing high
cortisol
• Inflammatory mechanisms
Kanner, Annals of Neurology, 2012
Psychiatric Comorbidities with
Epilepsy
• Persons with epilepsy need screening
throughout lifetime, particularly with
– Medication changes
– Life changes
– Pregnancy/postpartum
• A barrier to successful epilepsy
management
• A public health challenge
Bateman, et al, Ep Currents, 2012
Epilepsy, AEDs and Suicidality
(FDA Alert; January 2008)
AEDS: Suicidal thoughts/behavior risk: 0.43 vs. 0.22 (pbo)
- Estimated 2.1/1000 more patients on AEDs vs. PBO
- Not specific to single drug or class
Recommendations: Class warning.
- Balance risk for suicidality with clinical need for AED
- Be aware of possibility of emergence or worsening of
depression, suicidality, or unusual changes in behavior
- Inform patients, their families, and caregivers of the potential.
Symptoms such as anxiety, agitation, hostility, mania and
hypomania may be precursors to emerging suicidality.
Suicide rate increased in epilepsy
Suicide rate increased in adolescents
Antidepressants: Suicidality in Adolescents
 Depression …. “the common cold of psychiatry”
 Prevalence in children 2.4%; adolescents 8.3%
 Adolescent suicide increased 4x since 1950
 Therapy: medication and behavioral/cognitive/psychoanalysis
 FDA 10/15/2004 Black Box Warning: Antidepressants increase
suicidal thinking and behavior (suicidality) in children
 Must balance risk/benefit and closely monitor clinically
 Subsequent decrease in adolescent SSRI Rx by 22%;
suicide increased 14%
Gibbons et al (2007) AJ Psych
Twenty Leading Causes of Death Highlighting Suicide
Among Persons Ages 10 Years and Older,
United States, 2006
In 2006, suicide was ranked as the 11th
leading cause of death among persons
ages 10 years and older, accounting for
33,289 deaths.
Among 15- to 24-year olds, suicide accounts for 12% of all deaths annually
Second leading cause of death among 25-34 year olds; third leading cause
among 15- to 24-year-olds
www.cdc.gov/violenceprevention
Epilepsy and Suicidality
Encompasses
• Completed suicide
• Suicide attempt
• Suicidal ideation
More frequent in epilepsy vs general population
• Mean 11.5% deaths in chronic epilepsy patients
• 3x suicide causing death
• Bidirectional relationship (suicidality 5x risk
epilepsy)
Kanner, 2009
AEDs and Suicidality
FDA Alert
Questions Remain –
1) Assessment based on “spontaneous reports”
2) Risk associated with all AEDs, but significant
with only TPM and LTG
-Adding 3 additional LTG studies lost significance
-VPA and CBZ demonstrated “small protective effect”
3) Most epilepsy trials adjunctive therapy
4) Geographic differences
Consider results with caution
Epilepsy and Suicidality
• History of attempt strongest predictor
– 34.8% attempts, later successful
– 46.2% successful with prior attempts
• Comorbid psychiatric disorders increased risk 14x
– Mood – 32x
– Anxiety – 12x
• Risk greatest 1st 6 months following diagnosis of
epilepsy
Kanner, 2009
Epilepsy and Suicidality
Recommendations
Identify psychiatric disorders
Neurologists not expected to manage
Most frequent associated risks:
Current or past history of mood/anxiety disorder
Family psyche history of mood disorder; particularly
suicidal behavior
Past suicide attempts
Document Assessment
?Format
Referral
Kanner, 2009
Willmore, Pellock, 2009
Medication Effects on Seizures
• Increase in seizures with antidepressants:
amoxapine, maprotiline, clomipramine,
bupropion
• Protective effect for unprovoked seizure: SSRIs
(unless toxic)
Fluoxetine, citalopram: protective effect
(animal models)
• High risk de novo seizures: 2nd generation antipsychotics: clozapine, olanzapine, quetiapine
• Stimulants: no seizure increase, unless toxic
Kanner, Annals of Neurology, 2012
Long-Term Mortality in Childhood-Onset Epilepsy
Matti Sillanpää, M.D., Ph.D., and Shlomo Shinnar, M.D., Ph.D.
From the Departments of Pediatric Neurology and Public Health, University of Turku and Turku University Hospital —
both in Turku, Finland (M.S.); and the Departments of Neurology, Pediatrics, and Epidemiology and Population Health
and the Comprehensive Epilepsy Management Center, Montefiore Medical Center, Albert Einstein College of Medicine,
Bronx, NY (S.S.).
ABSTR ACT
Background
There are few studies on long-term mortality in prospectively followed, well-characterized cohorts of children with epilepsy.
We report on long-term mortality in a Finnish cohort of subjects with a diagnosis of epilepsy in childhood.
Methods
We assessed seizure outcomes and mortality in a population-based cohort of 245
children with a diagnosis of epilepsy in 1964; this cohort was prospectively followed for 40 years. Rates of sudden,
unexplained death were estimated. The very high autopsy rate in the cohort allowed for a specific diagnosis in almost all
subjects.
Results
Sixty subjects died (24%); this rate is three times as high as the expected age- and sex-adjusted mortality in the general
population. The subjects who died included 51 of 107 subjects (48%) who were not in 5-year terminal remission (i.e., ≥5
years seizure-free at the time of death or last follow-up). A remote symptomatic cause of epilepsy (i.e., a major neurologic
impairment or insult) was also associated with an increased risk of death as compared with an idiopathic or cryptogenic
cause (37% vs.12%, P<0.001). Of the 60 deaths, 33 (55%) were related to epilepsy, including sudden, unexplained death in
18 subjects (30%), definite or probable seizure in 9 (15%), and accidental drowning in 6 (10%). The deaths that were not
related to epilepsy occurred primarily in subjects with remote symptomatic epilepsy. The cumulative risk of sudden,
unexplained death was 7% at 40 years overall and 12% in an analysis that was limited to subjects who were not in longterm remission and not receiving medication. Among subjects with idiopathic or cryptogenic epilepsy, there were no
sudden, unexplained deaths in subjects younger than 14 years of age.
Conclusions
Childhood-onset epilepsy was associated with a substantial risk of epilepsy-related
death, including sudden, unexplained death. The risk was especially high among children
who were not in remission. (Funded by the Finnish Epilepsy Research Foundation.)
N Engl J Med, 2010 Dec 23;363(26): 2522-9
Long-Term Mortality in
Childhood-Onset Epilepsy
Sillampaa M and Shinnar S. N Engl J Med 2010;363:2522-9
Long-Term Mortality in
Childhood-Onset Epilepsy
Sillampaa M and Shinnar S. N Engl J Med 2010;363:2522-9
Epilepsy: Quality of Life
• Patient's concerns
– Memory
– Fear of seizures
– “I’m depressed”
– “Just don’t feel right”
– Mortality
• Parents’ concerns
– Behavior
– Cognition
Epilepsy: Quality of Life
• Array of challenges to daily living
– Vary with severity of epilepsy
– Change with age
• Negative effects can be severe and involve
family
–
–
–
–
–
Social relationships
Academic achievement
Employment
Housing
Independent functioning
• Family support community services critical
IOM, 2012
Epilepsy:
Cross-Cutting Themes
•
•
•
•
•
A common and complex neurological disorder
Often affects quality of life
Whole-patient perspective needed
Effective treatments available but access falls short
Data needed to improve epilepsy knowledge and
care and to inform policy
• Strengthen health professionals education
• Bolster education efforts for people with epilepsy
and their families
• Eliminate stigma
Institute of Medicine of the National
Academies, 2012
Improve Quality of Life
• Living with epilepsy is about much more than
seizures. For people with epilepsy, the
disorder is often defined in practical terms,
such as challenges in school, uncertainties
about social and employment situations,
limitations on driving a car, and questions
about independent living. At the same time,
they are faced with health care and
community services that are often
fragmented, uncoordinated, and difficult to
obtain.
IOM, 2012
Epilepsy and
Comorbid Behavioral Disorders
• Comorbid behavioral disorders are
common in both children and adults with
epilepsy
• Comprehensive management of epilepsy
is more than just controlling seizures
• Clinicians caring for patients with epilepsy
must be sensitive to these common and
often treatable comorbid conditions
Pellock, JCN, 2002