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AntiEpileptic Drugs Related

Rash Jaichat Mekaroonkamol, MD.

Contents

Adverse effect of AED 1

Pathogenesis and cross sensitivity 2

Predisposing factors and In vitro

assessment

3

Management 4

Lancet Neurol 2012; 11: 792–802

Lancet Neurol 2012

Expert Rev. Neurother. 886 10(6), (2010)

Adverse reactions

CNS

AED

Non-CNS

• Most common

• Occur during

initiation of Tx

• Dose-related

• Reversible

• Common

• Idiosyncratic - Rash

- Hepatotoxicity

- Hematologic

- Renal effect

- Metabolic and

endocrine

• 120 adult (Age > 18 years)

• descriptive cross sectional hospital

based study

Dose related

Hussein A, et al. OMJ. 25, 17-21 (2010)

Idiosyncheratic

N=45 N=42 N=35 N=38

10%

Hussein A, et al. OMJ. 25, 17-21 (2010)

Types of skin reactions

Herbert AA, Ralston JP.. J Clin Psychiatry. 2001;62 (Suppl 14):22-26

Specific reactions to

anticonvulsant drugs

Herbert AA, Ralston JP.. J Clin Psychiatry. 2001;62 (Suppl 14):22-26

Specific reactions to

anticonvulsant drugs

Herbert AA, Ralston JP.. J Clin Psychiatry. 2001;62 (Suppl 14):22-26

AED related rash

Benign

Rash

SCARs

• Morbilliform

/ measles-

like rashs

• SJS

• TEN

• DRESS

Benign Skin Rash

• Skin rash extremely common

complications of AED

– Phenytoin/carbamazepine: 7-12%

– Lamotrigine: 8-10%

• Morbilliform rashes usually occur within

3-8 wk of drug initiation, more likely to

occur when AEDs are started rapidly

• Usually be discontinued to minimize risk

for a severe skin reaction

– Resolve within 1-2 weeks after

discontinuing

Epilepsia 1999

• Retrospective study

• 1,890 outpatients with epilepsy

• Aged >/= 16 years: 1,649 (87%)

• 15 AEDs

• Subgroup analysis

– Non-AED predictors

– with another AED rash

– without another AED rash

NEUROLOGY 2007;68:1701–1709

• Phenytoin 5.9%

• Lamotrigine 4.8%

• Carbamazepine 3.7%

• Topiramate <1%

• Valproate 0.7%

• Levetiracetam 0.6%

• Gabapentin 0.3%

NEUROLOGY 2007;68:1701–1709

262/1649 = 15.9%

AED predictors

NEUROLOGY 2007;68:1701–1709

AED predictors

NEUROLOGY 2007;68:1701–1709

OR 3.1 (1.8-5.1)

AED predictors

NEUROLOGY 2007;68:1701–1709

4.1% vs 2.4%

• AED-related allergy without rash

was not a predictor of AED rash

– Hepatitis 42/1,649 = 2.5%

– Fever 31/1,649 = 1.8%

• The mean time to appearance of a

rash was 18.1 (± 10.5)days after

starting an AED.

NEUROLOGY 2007;68:1701–1709

A valuable finding was that the

risk of AED linked rash is

approximately five-times more

likely in patients who have had a

previous AED rash (8.8%) than

those who did not (1.7%)

NEUROLOGY 2007;68:1701–1709

Cross-sensitivity of skin rashes

• Cross-sensitivity among aromatic AEDs

(CBZ, LTG, OXC, PHT, PB) is said to

occur in 40–58% of patients

• High as 80% in an in vitro assay

• Specific cross-sensitivity among CBZ,

PHT, and PB may be at least partially

explained by the “hapten hypothesis”

• LTG: P-I concept

Neurology 71 November 4, 2008

CBZ, PHT, and PB

LTG

Neurology 71 November 4, 2008

• 3793 outpatients

• 3.61% (137/3793)

of patients

experienced a skin

rash

• Cross-reactivity

rates between

certain AEDs are

high, especially

CBZ and PHT

X.-q. Wang et al. Seizure 19 (2010) 562–566

X.-q. Wang et al. Seizure 19 (2010) 562–566

X.-q. Wang et al. Seizure 19 (2010) 562–566

AED related rash

Benign

Rash

SCARs

• Morbilliform

/ measles-

like rashs

• SJS

• TEN

• DRESS

Harr and French Orphanet Journal of Rare Diseases 2010

Histology: SJS

• Early

– Perivascular mononuclear inflammatory infiltrate

comprised primarily of T-lymphocytes.

– at the dermoepidermal junction, with lymphocytes

clustered around dying basal keratinocytes

("satellitosis")

• As the lesions progress

– frank subepidermal vesiculation develops, with full

thickness epidermal necrosis.

• Fully developed SJS

– full thickness epidermal detachment with splitting

above the basement membrane, minimal inflammatory

infiltrate, and normal immunofluorescence.

Arch Dermatol. 1992

Histology: TEN

• The histopathology of TEN is similar in

SJS.

• In addition – abnormalities of the underlying sweat ducts have

been described in TEN, including lymphocytic

infiltration, basal cell hyperplasia, and necrosis

J Cutan Pathol. 1995

DRESS

British Journal of Dermatology 2007

British Journal of Dermatology 2007

AED induced SCARs

• Different ethnic populations may have

dissimilar risks regarding the

development of AED-SCARs due to

various genetic backgrounds

• CBZ-induced SJS/TEN

– 59 cases per 100,000 new users per year in

Taiwan.

– 2 cases of 100,000 new exposures a year

have been reported in the United States

– much higher in South-East Asian countries

than in Western countries

Allergol Int 2010

• Retrospective study

• 6-year period from January 2003 to

December 2009

• At 2 clinical branches of Chang

Gung Memorial Hospital

• 154 patients with AED induced

SCARs

Neurology December 6, 2011

• CBZ and PHT were the most common causative

AEDs

– SJS/TEN (67.8%)

– DRESS (43.6%)

• No SCARs case was caused by nonaromatic AEDs

Neurology December 6, 2011

• Average latent period in AED-induced SJS/TEN or

DRESS was about 20 days ( DRESS has a longer)

• Average doses for tolerant controls were much

higher

Neurology December 6, 2011

AED-SCARs are not associated with the

AED dose or exposure duration

Neurology December 6, 2011

Most of the patients were well tolerant to nonaromatic

AEDs, especially VPA.

Prognosis of AED-SCARs

Neurology December 6, 2011

• The overall mortality rate was 6.49%

(10/154)

– TEN: 50%

– SJS-TEN: 20%

– SJS: 1%

– DRESS: 7.7%

• PHT was the major AED to cause

mortality(8/10 deaths) PHT-SCARs

had more complicated

J Investig Allergol Clin Immunol 2013

Epilepsy Currents, Vol. 6, No. 2 (March/April) 2006

AED

AED

Predisposing factors

• HLA-B 1502

– SJS/TEN induced by CBZ, PHT

• HLA-A 3101

– CBZ-ADR in Japanese

• CYCP2C19*2

– SCARs from PH

• HLA-B 4001

• HLA-B 5801 Protective AED-SJS/TEN

HLA-B 1502

Screening for HLA-B*1502 has been

recommended by the U.S. Food and

Drug Administration (FDA) prior to

starting CBZ in patients with

ancestry from these populations

since December 2007

HLA-B 1502

Epilepsia 2010

• 31 case: 10 AED-SJS, 21 AED-MPE

• 50 control: at least 3 months

• Age 10-45 years

• Exclude patients who developed SJS after

simultaneous use of more than one drug

• As soon as, they developed cutaneous adverse

reactions, all medications were withdrawn

Epilepsia, 49(12):2087–2091, 2008

• HLA-B 1502

– CBZ-SJS: 100% sensitivity, 80% specificity

43% PPV, 100% NPV

– PHT-SJS: 100% sensitivity, 82% specificity

33% PPV, 100% NPV

Epilepsia, 49(12):2087–2091, 2008

Epilepsia, 54(7):1307–1314, 2013

• 55 case: SJS/TEN

• 275 control: at least 3 months

• Age 6-77 years

Epilepsia, 54(7):1307–1314, 2013

Epilepsia, 54(7):1307–1314, 2013

Phenytoin

Lamotrigine

Epilepsia, 54(7):1307–1314, 2013

Protective AED-SJS/TEN

• CYP2C19, a member

of cytochrome P450

enzymes

• plays an essential

role in bioactivating

and detoxifying

pathways of aromatic

AED

• most common variant

resulting in poor

metabolizer are

CYP2C19*2(0.27) and

CYP19*3(0.02)

Pediatr Allergy Immunol 2013

Toxic metabolite

Pediatr Allergy Immunol 2013

0-18 yr

Pediatr Allergy Immunol 2013

• CYP2C19*2 variant

– SCARs from phenobarbital

• 42% sensitivity, 77% specificity, 65% PPV, 47% NPV

In vivo assessment

• Patch tests

• Late intradermal reading

• 10 subjects (7 females, 3 males),

• Age 8 to 42 years (mean age, 21.50 ± 10.99 yr)

• Performed 23.50 ± 40.45 months (range, 1 to 120) after

the adverse reaction

Current Pharmaceutical Design, 2006

• 34 control group subjects (23 females, 11males)

• Age from 7 to 55 years (mean age 24.56 ±12.04 years)

Current Pharmaceutical Design, 2006

Patch positive

Contact Dermatitis 2010: 62: 47–53

Drug Safety 2009; 32 (5)

• The PPV of the test in optimal

conditions was as high as 80–90%

depending on the drug tested.

• It should be performed 2–6 months

after recovery from the date of the

ADR for best results

Drug Safety 2009; 32 (5)

In vitro assessment

Lymphocyte transformation tests

• 10 subjects (7 females, 3 males),

• Age 8 to 42 years (mean age, 21.50 ± 10.99 yr)

• Performed 23.50 ± 40.45 months (range, 1 to 120) after

the adverse reaction

Current Pharmaceutical Design, 2006

• 34 control group subjects (23 females, 11males)

• Age from 7 to 55 years (mean age 24.56 ±12.04 years)

Current Pharmaceutical Design, 2006

LTT positive

Positive responses to aromatic anticonvulsants were

observed in 9 (26.5%) of the 34 control group subjects

Mol Diagn Ther 2009

• Sensitivity of the LTT and the LTA

seem to be around 70% and 90%

• However, the lack of a gold-

standard diagnostic test to prove

drug culpability

• Timing: 5 weeks to 1 year

Mol Diagn Ther 2009

Treatment of AED-SCARs

1. Supportive care

2. Corticosteroids

3. IVIG

4. Combination therapy of IVIg and

systemic corticosteroids

Ciclosporin, TNF antagonists (Infliximab,Etanercept),

Plasmapheresis, cyclophosphamide

IVIG for TEN

• anti-Fas potential of pooled human IVIG

in vitro

• total IVIG doses of more than 2 g/kg may

be of greater benefit

IVIG for TEN

British Association of Dermatologists 2012

Neurology December 6, 2011

1. Corticosteroids

– 84.42% for SJS/TEN and DRESS

2. Supportive care: 14.94%

3. IVIG: 0.65%

4. Combination therapy of IVIg and systemic

corticosteroids: 6.49%

Prognosis of AED-SCARs

Neurology December 6, 2011

• The overall mortality rate was 6.49%

(10/154)

– TEN: 50%

– SJS-TEN: 20%

– SJS: 1%

– DRESS: 7.7%

Pediatr Allergy Immunol 2013

TAKE HOME MESSAGE

• PHT and CBZ are the two drugs which most

frequently cause sensitivity

• Cross-sensitivity among aromatic AEDs occur

in 40-58%

• Rarely nonaromatic AEDs induced SCARs

• Most of the patients with AED-rashs were well

tolerant to nonaromatic AEDs, especially VPA.

• CBZ- and PHT-induced SJS, but not MPE, is

associated with HLA-B∗1502 allele in Thai

population

• In vivo and in vitro assesment lack of validated

studied

• Treatment are controversial

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