Psychiatric Comorbidity in Pediatric and Adult Epilepsy

John M. Pellock, MDProfessor and Chairman, Division of Child Neurology

Children’s Hospital of Richmond at VCUVirginia Commonwealth University/Medical College of

Virginia HospitalsRichmond, Virginia

OBJECTIVES

1) Appreciate the occurrence of neuropsychiatric comorbidities associated with epilepsy2) Understand how psychiatric comorbidities influence the quality of life in persons with epilepsy3) Discuss appropriate treatment needs of

persons with epilepsy and depression

Company Advisory Board Consultant ResearchNIH/NINDS

  YES YESCDC/HRSA

    YESCatalyst

YES YES  Eisai YES YES YESGlaxoSmithKline   YES  King Pharmaceuticals

  YES  KV Pharmaceuticals   YES  Marinus Pharmaceuticals   YES YESNeuropace   YES  Lundbeck YES YES YESPfizer YES YES YESQuestcor YES YES YESSepracor YES YES  Sunovion   YES  UCB Pharmaceuticals YES YES YESUpshur Smith YES YES YESValeant   YES  

John M. Pellock, MDProfessor and Chairman, Division of Child Neurology

Virginia Commonwealth University/ Medical College of VirginiaChildren’s Hospital of Richmond

Richmond, VirginiaDr 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.

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

BNFCBNC

EME EIEE

Neonatal Seizures

BMEI

Westsyndrome

Childhood absenceepilepsy

Benign childhoodepilepsy with

centrotemporal spikes

Childhood epilepsy

with occipital paroxysms

Temporal, frontal, parietal, or occipital lobe epilepsies-symptomatic -cryptogenic

Chronic progressive

epilepsia partialiscontinua ofchildhood

Severe myoclonic epilepsy in infancy

Epilepsy with continuous spike-waves during slow-wave sleep

Acquired epilepticaphasia

Epilepsywith myoclonic

absences

Lennox Gastautsyndrome

Epilepsy with myoclono-astatic

seizures

GENERALIZED EPILEPSIES

Epilepsy with specific modes

of activation

Epilepsy with grand-mal

seizures on awaking

Juvenilemyoclonicepilepsy

Juvenileabsenceepilepsy

LOCALIZATION-RELATED EPILEPSIES

Primary readingepilepsy

Idiopathic orCryptogenic

Symptomatic orCryptogenic

EME: Early Myoclonic Encephalopathy EIEE: Early Infantile Epileptic EncephalopathyBNFC: Benign Neonatal Familial ConvulsionsBNC: Benign Neonatal ConvulsionsBMEI: Benign Myoclonic Epilepsy in InfancyEpilepsia 1999;40:531.

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 MilitaryRochelle 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 familiesChildren 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 19-45% 2.5-6.5%

Psychosis 2-8% 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 – 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

0

5

10

15

20

ADHD Mood AdjustmentADHD Mood Adjustment Disorder DisorderDisorder Disorder

Pre

vale

nce

(%

)P

reva

len

ce (

%)

17%17%

Hedderick E, et al. Ann Neurol. 2003;54(suppl 7):S115. Abstract E12.

PrevalencePrevalence

12%12%

10%10%

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 5%

• Epilepsy 1%

• ADHD in epilepsy 20%

• ADHD in patients with epilepsy treated with AED 30%

Impulsivity andAggression

Impulse Control

Disorders

Bipolar Spectrum

Cluster B Personality Disorders

ADHDSpectrum Tourette /

OCD

Developmental Disorders

SubstanceUse

Disorder

Sexual Compulsions

Impulsive-Aggressive Spectrum

Borderline Personality Disorders Autism

Spectrum Disorders

PTSD

Salpekar, 2005

Social Outcome - ResultsCAE 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 EpilepsyJuvenile Myoclonic Epilepsy• 1st described in 18671st described in 1867

• TriadTriad

• Myoclonic, absence, tonic clonic Myoclonic, absence, tonic clonic seizuresseizures

• Normal developmentNormal development

• 3.5 - 6 Hz multispike and wave3.5 - 6 Hz multispike and wave

• Onset pre- to post-puberty (12-18 years)Onset pre- to post-puberty (12-18 years)

• F = MF = M

• ~ 2% - 5% of all patients with epilepsy~ 2% - 5% of all patients with epilepsy

Glauser TA, et al. NEJM 362;9, March 4, 2010

Ethosuximide, Valproic Acid, and Lamotrigine in Childhood Absence Epilepsy

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 AssociationDale 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 EpilepsyBidirectional Relation:

Neurobiological/Pathogenesis

• Neurotransmitters: serotonin, norephinephrine, dopamine, glutamate, GABA

• Endocrine: hyperactive hypothalamic-pituitary-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 epilepsySuicide 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

                                                                                                                     

                                                 Among 15- to 24-year olds, suicide accounts for 12% of all deaths annuallySecond leading cause of death among 25-34 year olds; third leading cause among 15- to 24-year-olds

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.

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 SuicidalityFDA 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 therapy4) 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 SuicidalityRecommendations

Identify psychiatric disordersNeurologists not expected to manage

Most frequent associated risks:Current or past history of mood/anxiety disorderFamily psyche history of mood disorder; particularly

suicidal behaviorPast suicide attempts

Document Assessment?FormatReferral

Kanner, 2009Willmore, 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 anti-psychotics: clozapine, olanzapine, quetiapine

• Stimulants: no seizure increase, unless toxic

Kanner, Annals of Neurology, 2012

Long-Term Mortality in Childhood-Onset EpilepsyMatti 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 ACTBackgroundThere 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.MethodsWe assessed seizure outcomes and mortality in a population-based cohort of 245children 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.ResultsSixty 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 long-term remission and not receiving medication. Among subjects with idiopathic or cryptogenic epilepsy, there were nosudden, unexplained deaths in subjects younger than 14 years of age. ConclusionsChildhood-onset epilepsy was associated with a substantial risk of epilepsy-relateddeath, including sudden, unexplained death. The risk was especially high among childrenwho 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

Sillampaa M and Shinnar S. N Engl J Med 2010;363:2522-9

Long-Term Mortality in Childhood-Onset Epilepsy

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