Psychiatric Comorbidity in Pediatric and Adult Epilepsy

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Psychiatric Comorbidity in Pediatric and Adult
Epilepsy

• John M. Pellock, MD
• Professor and Chairman, Division of Child
  Neurology
• Childrens Hospital of Richmond at VCU
• Virginia Commonwealth University/Medical College
  of Virginia Hospitals
• Richmond, Virginia

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OBJECTIVES
1) Appreciate the occurrence of neuropsychiatric
comorbidities associated with epilepsy 2) Underst
and how psychiatric comorbidities influence the
quality of life in persons with
epilepsy 3) Discuss appropriate treatment needs
of persons with epilepsy and depression
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John M. Pellock, MD Professor and Chairman,
Division of Child Neurology Virginia Commonwealth
University/ Medical College of Virginia Childrens
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 Advisory Board Consultant Research
NIH/NINDS   YES YES
CDC/HRSA     YES
Catalyst YES YES  
Eisai YES YES YES
GlaxoSmithKline   YES  
King Pharmaceuticals   YES  
KV Pharmaceuticals   YES  
Marinus Pharmaceuticals   YES YES
Neuropace   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  
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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
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Seizure Type versus Epileptic Syndrome

• A seizure is determined by the patients 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

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GENERALIZED EPILEPSIES
LOCALIZATION-RELATED EPILEPSIES
Juvenile absence epilepsy
Primary reading epilepsy
10 year-old
Benign childhood epilepsy with centrotemporal
spikes
Juvenile myoclonic epilepsy
Childhood absence epilepsy
Epilepsy with grand-mal seizures on awaking
Idiopathic or Cryptogenic
1 year-old
Childhood epilepsy with occipital paroxysms
BMEI
1 month-old
Epilepsy with specific modes of activation
BNFC BNC
West syndrome
EME
EIEE
Temporal, frontal, parietal, or occipital lobe
epilepsies -symptomatic
-cryptogenic
Lennox Gastaut syndrome
Neonatal Seizures
Epilepsy with myoclono-astatic seizures
Chronic progressive epilepsia
partialis continua of childhood
Severe myoclonic epilepsy in infancy
Epilepsy with myoclonic absences
Symptomatic or Cryptogenic
Epilepsy with continuous spike- waves during
slow-wave sleep
Acquired epileptic aphasia
EME Early Myoclonic Encephalopathy EIEE Early
Infantile Epileptic Encephalopathy BNFC Benign
Neonatal Familial Convulsions BNC Benign
Neonatal Convulsions BMEI Benign Myoclonic
Epilepsy in Infancy
Epilepsia 199940531.
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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 Alzheimers disease

Institute of Medicine of the National Academies,
2012
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Psychogenic Nonepileptic Seizures

• Terminology
• Hysteria, pseudoseizures (pejorative)
• PNES or non-epileptic seizures (preferred)
• Psychological profile
• Significant depression (gt 50)
• Anxiety disorder (gt 50)
• Posttraumatic stress disorder (22-100)
• Includes sexual abuse
• Rapid diagnosis associated with better outcome

Dickinson,Looper Epilepsia, 2012
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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
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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
201177(10) 945950 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 lt 0.001). Cumulative AED treatment was 4 times
greater for veterans with PNES as compared to
civilians (p lt 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
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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

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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
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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
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Prevalence of Psychiatric Disorders
In epilepsy (range) In the general population (range)
Depression 11-60 2.0-4.0
Anxiety 19-45 2.5-6.5
Psychosis 2-8 0.5-0.7
ADHD 25-30 2.0-10.0
Kanner, Epilepsia 200344(5)3-8.
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Prevalence of Psychiatric and Behavioral
Comorbidities

• Population-based, retrospective study
• Incident cases of epilepsy (1980-1995)
• Rochester, MN
• Prevalence
• 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

Prevalence
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12
10
Prevalence ()
ADHD Mood Adjustment
Disorder Disorder
Hedderick E, et al. Ann Neurol. 200354(suppl
7)S115. Abstract E12.
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ADHD and Childhood Epilepsy

• ADHD in children
• Up to 87 have gt1 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 malefemale ratio

Dunn D, et al. Dev Med Child Neurol.
20034550-54. Semrud-Clikeman M, Wical B.
Epilepsia. 199940211-215.
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Epilepsy and Attention Deficit Hyperactivity
Disorder (ADHD)

• Prevalence
• ADHD 5
• Epilepsy 1
• ADHD in epilepsy 20
• ADHD in patients with epilepsy treated with
  AED 30

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Impulsive-Aggressive Spectrum
ADHDSpectrum
Bipolar Spectrum
Tourette /OCD
Cluster B Personality Disorders
Developmental Disorders
Borderline Personality Disorders
Autism Spectrum Disorders
Sexual Compulsions
Impulse Control Disorders
SubstanceUse Disorder
PTSD
Salpekar, 2005
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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.
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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

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Ethosuximide, Valproic Acid, and Lamotrigine in
Childhood Absence Epilepsy
Glauser TA, et al. NEJM 3629, March 4, 2010
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• Psychiatric Comorbidities and Epilepsy
• Is It the Old Story of the Chicken and the Egg?

Kanner, Ann Neurol, 2012
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Epilepsy Curr. 2012 Sep-Oct 12(5) 201202.
Hospitalization for Psychiatric Disorders
Before and After Onset of Unprovoked
Seizures/Epilepsy. Adelöw C, Andersson T, Ahlbom
A, Tomson T. Neurology 201278396401
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 (1.73.7) after a
hospital discharge diagnosis for depression, 2.7
(1.45.3) for bipolar disorder, 2.3 (1.53.5) for
psychosis, 2.7 (1.64.8) for anxiety disorders,
and 2.6 (1.74.1) 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.
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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, 1.515.7) and after
diagnosis (IRR, 2.210.9) and for suicidality
before epilepsy diagnosis (IRR, 3.14.5) and 1
year after diagnosis (IRR, 5.3). The PR was
increased for suicide attempt before epilepsy
onset (PR, 2.65.2) and after onset (PR,
2.45.6). 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 201272184191
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Epilepsy and Psychiatric DisordersA
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
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Psychiatric Disorders and EpilepsyBidirectional
Relation Neurobiological/Pathogenesis

• Neurotransmitters serotonin, norephinephrine,
  dopamine, glutamate, GABA
• Endocrine hyperactive hypothalamic-pituitary-adre
  nal axis producing high cortisol
• Inflammatory mechanisms

Kanner, Annals of Neurology, 2012
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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
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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

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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/psyc
  hoanalysis
• 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
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Twenty Leading Causes of Death Highlighting
Suicide Among Persons Ages 10 Years and Older,
United States, 2006

•                                                 
                                                    
                                                    
                   
• 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

In 2006, suicide was ranked as the 11th leading
cause of death among persons ages 10 years and
older, accounting for 33,289 deaths.
www.cdc.gov/violenceprevention
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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

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AEDs and SuicidalityFDA Alert

• Questions Remain
• Assessment based on spontaneous reports
• 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
• Most epilepsy trials adjunctive therapy
• Geographic differences
• Consider results with caution

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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

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Epilepsy and SuicidalityRecommendations

• 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
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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
  anti-psychotics clozapine, olanzapine,
  quetiapine
• Stimulants no seizure increase, unless toxic

Kanner, Annals of Neurology, 2012
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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, Plt0.001). 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
long-term 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 23363(26) 2522-9
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Long-Term Mortality in Childhood-Onset Epilepsy

• Sillampaa M and Shinnar S. N Engl J Med
  20103632522-9

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Long-Term Mortality in Childhood-Onset Epilepsy
Sillampaa M and Shinnar S. N Engl J Med
20103632522-9
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Epilepsy Quality of Life

• Patient's concerns
• Memory
• Fear of seizures
• Im depressed
• Just dont feel right
• Mortality
• Parents concerns
• Behavior
• Cognition

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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
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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
44
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
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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
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