Neurological Risk at Younger Ages

2012 AAIM Triennial

Paul J. Nittoli, MDMassMutual Financial Group

John Schoonbee, MBChBSwiss Re

Presentation Objectives

• Discuss risk stratification of seizure disorders for both disability and life underwriting: clinical, diagnostic, treatment, and lifestyle factors

• Discuss mortality assessment in Multiple Sclerosis: risk implications of clinical features, diagnostic findings, and disease-modifying medication use

Brief History of Epilepsy

• 4500-1500 BC: described in Ayurvedic literature (‘apasmara’ = loss of consciousness)

• 1000 BC: described in a Babylonian tablet as supernatural

• 400 BC: Hippocrates’ monograph disputes supernatural cause

• 130-200 AD: Galen theorized it a brain disorder with manifestations governed by the moon (‘lunatics’)

• 1494: Malleus Maleficarum links seizures with witchcraft

• 1800s: John Harvey Kellogg (of corn flake fame) attributed epilepsy to masturbation

Temkin. The Falling Sickness: A history of Epilepsy from the Greeks to the Beginnings of Modern Neurology. 2nd ed. 1971. The Johns Hopkins University Press

Seizure Disorders: Defining Terms

• “an excessive and disorderly discharge of central nervous system tissue on muscle”– John Hughlings Jackson MD, 1870

• Motor (convulsive)

• Sensory

• Autonomic

• Psychic

• Epilepsy: A) 2 unprovoked seizures 24 hrs apart; B) 1 seizure within the context of a predisposing cause

Seizure Disorders: Defining Terms

• Partial (focal) seizures – focal onset• Simple – no alteration of consciousness

• Complex – impaired consciousness

• Generalized seizures – bilateral onset, presumption of impaired consciousness

• Secondary generalization of partial seizures

• Absence (petit mal)

• Tonic +/- clonic (grand mal)

• Juvenile seizure disorders

• Pseudoseizures

Electroencephalogram

• “excessive and disorderly discharge” of cortical neurons

• Anticonvulsants are most effective at blocking propagation of neural activity from the seizure focus

• Asymptomatic interictalspikes may be present

• Absence of epileptiformdischarges does not rule out a seizure disorder

Alternative AED Uses

• Valproic acid: psychiatric, analgesic

• Carbamazepine: psychiatric, analgesic

• Gabapentin: psychiatric, analgesic, menopausal sx

• Lamotrigine: psychiatric, analgesic

• Topiramate: psychiatric, analgesic, substance abuse, obesity

• Levetiracetam: psychiatric, autism, Tourette syndrome

• Primidone: essential tremor, LQTS

• Phenobarbital/ethosuximide/phenytoin: AED only

Seizure Recurrence after AED

Withdrawal• Poor prognostic factors

• Abnormal (sleep-deprived) EEG• Abnormal brain MRI• Poor control with monotherapy• Certain epileptic syndromes (JME)• FHx of seizure disorder• <2-5 years seizure-free on treatment

» 65-75% of pre-adolescents (≤12yo) & 60% of adults who are seizure-free x several years (mean 3 yrs) and w/o negative indicators will remain seizure-free off AEDs)

Neurology 1996;47:600

• Risk windows for relapse in children• 50% during 1st 3-6 months• 60-80% within 1st year• >80% within 1st 5 years

Nonpharmacologic Seizure

Management• Surgery

• Usually done for intractable epilepsy• Generalization improvement• Focal seizures often not ameliorated and may worsen• Residual neurological deficits• Best outcomes: unilateral temporal or hippocampal loci

• Vagal nerve stimulation• Palliative not curative• Partial seizures

• Ketogenic diet• Failure of AED control• Mimics starvation – little or no carbs (Crisco)• Effectiveness: 1/3-1/3-1/3

Occupational and Lifestyle

Precautions

• Motor vehicle operation

• Water• Swimming

• Bathing

• Boating

• Heights

• Fire (esp. cooking-related burns)

• Power tools

• Sports

Epileptic Syndromes - Infancy

• Seizures within 24-48 HOL are often indicative of severe cerebral insult (less common are benign familial & idiopathic neonatal convulsions – begin 48-72 HOL and remit by 2-6 mos)

• Simple febrile seizure• Ages 6mos-5yo, <15 min duration, recurrent in 1/3

• 2x risk for epilepsy c/w general population risk

• West Syndrome/Infantile Spasm• Recurrent trunk/limb flexion “salaam seizures”

• Hypsarrhythmia (severely disordered EEG)

• Remit by 4-5 yo but may have residual mental impairment or seizure disorder

Epileptic Syndromes - Childhood

• Lennox-Gastaut syndrome – poor px

• Rolandic epilepsy• Benign childhood epilepsy w/ centrotemporal spikes

• Onset 5-9yo, disappears during adolescence

• Auto Dom, control w/monotherapy

• Absence (petit mal) seizures• 3Hz spike-and-wave pattern diagnostic

• Complex seizure disorder

• Good AED response; nearly ½ develop GTCS

Epileptic Syndromes - Adolescence

• Most common window of clinical presentation

• Idiopathic seizures

• Juvenile myoclonic epilepsy• Peak incidence 12-18 yrs

• Complex seizure disorder in most

• Control w/low dose monotherapy

• Lifelong seizure risk

Epileptic Syndromes - Adulthood

• Idiopathic

• Trauma

• Intracranial mass lesions

• Intracranial vascular lesions (blood isepileptogenic)

• Infections

• Metabolic encephalopathies

• Substance abuse

Pseudoseizures

• Psychogenic nonepileptic seizures

• 20-50% of referrals to tertiary epilepsy centers

• Somatoform disorder vs. factitious

• Typically begin in adolescence but incidence in all ages; 70% female

• Dx by video-EEG monitoring (gold std), provocative techniques, and CPK measurement

Epilepsy-related Mortality

• Japanese population of an epilepsy center (1765); 43 deaths over an 8-year period– Accidents 30% (drowning & head injury)

– SUDEP 23%

– Status epilepticus 16%

– Suicide 14% (all temporal lobe epilepsy)

– Other 16%Fukuchi T, et al. Epilepsy Res 2002;51:233.

• Other community-based studies in Western countries show most of the mortality in accidents and “other” (CNS tumors, vascular disease, pneumonia)Lhatoo SD, et al. Epilepsia 2005;46 s11:36

Status Epilepticus

• Continuous seizures for >1 hour

• Neuronal death: combination of systemic and

CNS- specific factors (intraneuronal calcium)

• Mortality increases with age

• Frequently the initial presentation in children

• Mortality risk is defined by age, etiology, and

ability to achieve control (<5% mortality directly

attributable to SE)

Sudden Unexpected Death in

Epilepsy (SUDEP)• Defined as SUD with or without evidence of a seizure in

a person without identified status epilepticus or toxicological, traumatic, anatomical cause

• Cardiopulmonary etiologies postulated

• Low incidence in community-based cohort: 0.35-2.7/1000 p-yrsLhatoo SD, et al. Epilepsia 2005;46 s11:36

• Risk factors• Males, age 20-40

• Frequent GTC seizures, polytherapy

• Treatment noncompliance

• AlcoholHesdorffer DC, et al. Epilepsia 2011;52:1150

Mohanraj R, et al. Lancet Neurol

2006;5:481

• 890 newly dx 8/91 => 5/01; f/up until 10/03

• Age-gender match to general population

(Scotland) ; avg age 31

• Overall SMR 1.42 (n=890;d=93)• Tx non-responders SMR 2.54 (n=318; d=42)

• Tx responders SMR 0.95 (n=462;d=41)

• Tx unknown response (n=110;d=10)

• Chronic epilepsy data not shown• Unsuccessful tx w/1-9 meds (median 3)

• Treatment response not recorded

Survival Newly-Dx Epilepsy by

Lesion on Brain Imaging

60

65

70

75

80

85

90

95

100

0 2 4 6 8

Years

% S

uviv

al

Cryptogenic

Symptomatic

Mohanraj R, et al. Lancet Neurol 2006;5:481

Strauss D, Shavelle R, et al. JIM

2003;35:155• CA Dept. of

Developmental Services– 80,682 persons, ages 5-65

yo: 47K w/epilepsy out of 506K total [p-yrs], 266 epilepsy deaths out of 1523 total

– No assist for gait/stairs; ≤moderate MR; no “degenerative illnesses” or “idiopathic epilepsy”(presumably genetic)

– Epilepsy prevalence 10X general population

MR EDR

Epilepsy w/o Events <12

mos

111% 0.3

Epilepsy w/ Event <12

mos (not GTC)

237% 3.0

GTC <12 mos 293% 5.3

Status epilepticus <12

mos

371% 6.4

CDDS pop w/o epilepsy

c/w CA gen’l pop

171% 1.1

Approach to Epilepsy Risk

Assessment• Age

• Occupation/Avocation/MVR

• Seizure type• Focal vs. generalized

• Simple vs. complex

• Seizure Control• Frequency

• Number of AEDs in use

• Altered neuroanatomy• Brain injury/depressed skull fx

• Encephalitis

• SDH/AVM

• CVA

Magnetic Resonance Imaging

• Protons in water align

with the magnetic field of

the MRI coils

• A radiofrequency pulse

causes precession about this alignment

• After the pulse is turned

off, the protons “relax” to

their previous alignment

• Different tissue types

“relax” at different rates

MRI Terminology

• T1 – fat light, H2O dark (blackholes-MS/lacune; white-WMH); used with Gd contrast (active MS plaque)

• T2 – H2O light, fat dark (top right); white-MS plaque,lacune, WMH

• T2 FLAIR – free H2O dark, edema fluid light (bottom right)

• DWI – diffusion-weighted imaging (+) from minutes up to 2 weeks after acute ischemia

What can cause T2 Lesions on MRI?

• Demyelinating Disease

• Infectious illness

• Migraines

• Ischemic disease

• Neurofibromatosis

• Small vascular anomalies

• Unidentified Bright Objects

Multiple Sclerosis

• Lesions separated by space & time– Clinical exam – attack = neuro disturbance ≥

24hrs

– MRI – Gd/T1 or T2

– Lumbar puncture/CSF – oligoclonal IgGbands in CSF

• If suspicion of MS without meeting full criteria → clinically isolated syndrome (CIS)

MS – Signs & Symptoms

• Sensorimotor deficits (many CNS areas)

• Ataxia (parietal lobe/cerebellum/brainstem)

• Neurogenic bladder (multiple CNS areas)

• Internuclear ophthalmoplegia (abbrev. INO; brainstem)

• Facial pain/tic douloureux/trigeminal neuralgia (brainstem; trigeminal nerve)

• Lhermitte sign (cervical spinal cord)

• Cognitive impairment (50% eventually; diffuse cerebral disease)

• Optic neuritis (20% initial sx; optic nerve)

MS – Clinical Subtypes

MS Treatment

• Steroids

• Interferon (IFN)– beta-1a (2 preps, A & R), beta-1b (B)

• Other Immune Modulator – glatiramer acetate (C)

• Lymphocyte Sequestration – fingolimod

• ?mechanism – teriflunomide, BG-12

• Monoclonal Antibody – natalizumab

• Immunosuppressive Agent – mitoxantrone

Oral cladribine development withdrawn by Merck

What Is the Impact of MS on Mortality?

• Uncommon disease(s) + variable clinical course +

expect decades of life after onset = need for large cohort

followed for many years to estimate and categorize risk

• Danish study Onset 1948-86 122,373 p-yr

MS + CIS gen’l pop controls

– SMR from onset = 3.25

– EDR from onset = 13.0/1000 p-yr

– Median survival time from onset = 30 yrs

– Median survival time from diagnosis = 25 yrs(Brønnum-Hansen. Neurology. 1994;44:1901)

(Pokorski RJ. JIM. 1997;29:100)

Underwriting MS – Forks in the Road

• Diagnosis

Indefinite Definite

CIS/ON Early Stage Late Stage

MS – Unfavorable Prognosis =

High Risk

• Immobility- think paralysis or quadriplegia

• Primary or secondary progression

• Brain atrophy & cognitive decline

• Multiple black holes on MRI

• Renal function

• Suicide/MDD/substance abuse

• “novel therapy”• Bee stings, cobra venom, pregnant cow milk

• Chronic cerebrospinal venous insufficiency (CCSVI)

MS – Favorable Prognosis = Better Risk

• ♀ (higher prevalence; better outcomes)

• Younger age @ onset (pivot = 40yo)*

• Low relapse rate in early disease (first 2 years)*

• Complete recovery after relapse*

• Sensory/CN/ON as initial sx (motor/cerebellar worse pxas initial sx)*

• Lower lesion burden & accretion by MRI*

• EDSS = 0-3, 5 yrs after dx

• Response to disease-modifying MS drugs

(*early stage prognostic factors > Scott. Neurology. 2000;55:689.)

Kurtzke Expanded Disability Status Scale

• 10 point scale ranging from no disability (0.0) to death (10.0)

• “Functional systems” used for scores < 4.0

• “Cerebral” = cognition & mood

• Emphasizes ambulation

• Key breakpoints

– 3.0 moderate disability, fully ambulatory

– 6.0 at least unilateral ambulatory assist

– 7.0 wheelchair-dept; indept transfers

Generally, disability correlates with risk(Kurtzke. Neurology. 1983;33:1444.)

EDSS & Mortality

• Canadian study - MS clinic - diagnosis 1972-1985 - insured controls

# EDSS Death MR

1394 0.0-3.5 33 1.60

789 4.0-7.0 58 1.84

165 ≥7.5 24 4.44

2384 115 2.00

(Sadovnick. Neurology. 1992;42:991)

ABCR Drugs – Positive Factors

• In the short-term, they have been shown to reduce relapse-related EDSS progression; frequency of relapses; and MRI characteristics of inflammation

• IFNβ1a vs. placebo in delaying CDMS after CIS w/+MRI: CHAMPS Trial (Jacobs. NEJM. 2000;343:898) RR=0.56 p=0.002

• Other ABCR trials reduce progression to CDMS by ~30%

• For u/w purposes, ABCR drugs are equivalent

IFN Reduces RRMS => SPMS Progression

Trojano M. Ann Neurol. 2007;61:300.

• Observational, non-randomized study, median f/u 5.7 yrs (up to 7 yrs)

• 1103 treated

• 401 untreated (refused; contraindicated; early drug d/c; no relapses in 2yrs & EDSS<3)

• Various ABR drugs

• End points: Secondary progressive dz; stable EDSS 4 or 6

SP EDSS 4 EDSS 6

HR-progression from first visit to end point

0.38

p<0.0001

0.70

p=0.0174

0.60

p=0.0304

Shirani A, et al. JAMA 2012;308(3):247Derfuss T, et al. JAMA 2012;308(3):290

• Well designed observational study failed to show IFN reduced disability progression over a long term (>5yrs)– IFN-treatment group

– 2 untreated groups• Contemporary untreated• Historical untreated

• Caveats– Bias against tx of benign disease

– Underpowered

• IFN reduction in long-term disability, “although plausible, remains unproven”

ABCR Caveats

• Need 6-12 months to determine efficacy• Barriers to Use

– Injection-site reactions– Depression– Flu-symptoms– Fatigue– Headache

• Adherence to therapy– Adherence = acceptance + persistence + compliance– 60-75% adhere for 2-5 yr (IFN)– Adherence rates similar to insulin for type 2 diabetes– Majority who discontinue do so in the first 2 yrs (ABCR)– Other studies show first 6 mos indicative of persistence

(Costello. Medscape J Med. 2008;10:225)

(Tremlett HL. Neurology. 2003;61:551)

% Developing MS vs. MRI Lesion at Presentation

69

82

4

12

0

10

20

30

40

50

60

70

80

90

CIS & abnl MRI CIS & nl MRI

5 years

10 years

Sailer et al. Neurology

1999;52:599

MS Risk After Optic Neuritis Based on MRI Lesion Load

• Cumulative Probablility of MS vs. Lesions at Dx

0

10

20

30

40

50

60

70

80

90

0 Lesions 1-2 Lesions 3+ Lesions

5Years

10Years

15Years

ON Study Group. Arch Neurol. 2008;65:727.

MS Risk After Optic Neuritis Based on MRI Lesion Load

• Conditional Probablility of MS vs. Lesions at Dx

0

5

10

15

20

25

30

35

40

45

0 lesions 1+ lesions

0-5Years

6-10Years

11-15Years

ON Study Group. Arch Neurol. 2008;65:727.

Approach to MS Risk Assessment

• MRI

• Lesion burden & accretion

• Black holes

• Relapse rate

• Frequency

• Proximity to pre-lapse baseline

• Clinical subtype

• EDSS – 3 & 6 are important scores

• Disease-modifying therapy

• Response to treatment

• Medication choice

• Markers of high risk