Complications of Antiepileptic Drugs - Block 1

Question 1

What are the types of Dermatologic Drug Reactions?

Answer 1

Irritant: topical
Allergic: topical or systemic route

Question 2

What kind of hypersensitivity is SJS/TEN?

Answer 2

Type 4: Delayed cell-mediated

Question 3

What are the types of drug eruptions?

Answer 3

Question 4

What are Severe Cutaneous Adverse Reactions to Drugs (SCARs)? Types?

Answer 4

Skin reactions accompanied by fever are generally more serious systemic disorders:
1. Dress
2. SJS
3. TEN

Question 5

What is DRESS?

S/s

Answer 5

characterized by an extensive skin rash and fever
S/S: 2-8 weeks

• mortality rate is very high

Question 6

What causes DRESS?

Answer 6

Exact pathogenesis is still unknown:
1. Mutations in genes encoding drug detox enzymes have a higher risk of DRESS
2. Reactivation of human herpes virus (Epstein barr and HHV6 and 7)
3. Ethnic predisposition with certain human leukocyte antigen (HLA) alleles

Question 7

What is the proposed diagnostic marker for DRESS?

Answer 7

HHV-6

Question 8

What is the relationship between carbamazepine and DRESS?

Answer 8

Chinese, Koreans, Japanese, & Europeans who express the HLA serotype (HLA-A*3101) have a higher risk of developing DRESS

Question 9

What are presentation of DRESS?

Answer 9

Latency: later onset of fever, malaise, lymphadenopathy
Cutaneous and mucosal: maculopapular eruption -> coalescing erythema
* Target-like lesions
* Facial edema
* > half BSA

(50% of patients have mucosal involvement, but it is mild in comparison to SJS/TEN)

Question 10

What are the lab presentation of DRESS?

Answer 10

1. Fever ≥101.3
2. Lymphadenopathy
3. Hematologic abnormalities (Eosinophilia, leukocytosis, lymphocytosis, atypical lymphocytes)
4. Liver, kidney, lung, heart abnormalities

Question 11

What is the diagnostic approach to DRESS?

Answer 11

1. New drug treatment (especially high-risk drugs/AEDs) within the last 2-8 weeks
2. Presenting with systemic involvement

Question 12

What are we looking for in DRESS through the assessment of drug causality?

Answer 12

1. Prolonged latency
2. Drugs that have been stopped can still be suspected
3. Exposure to high-risk drugs
4. Unlikely culprit if drug was taken for less than 2 weeks or more than 3 months
5. Risk for drug accumulation can increase risk for DRESS (RENAL DOSING!)

Question 13

What are the high risk drugs that cause DRESS?

Answer 13

Aromatic AED:
1. Carbamazepine
2. Phenytoin
3. Lamotrigine
4. Oxcarbazepine
5. Phenobarbital

1.

Question 14

What is the tx goals for DRESS?

Answer 14

Identify and dc causative drug

Question 15

What is the tx for DRESS?

Answer 15

ID and withdrawal of causative drug
* Avoid introduction of new drugs like aromatice drugs)

Supportive: Fluid, electrolyte, nutritional support, gentile skin care

Question 16

What are examples of nonaromatic agents?

Answer 16

1. VA
2. Topiramate
3. Gabapentin
4. Keppra

Question 17

Monitoring of DRESS Tx?

Answer 17

1. Clinical, lab, imaging
2. Timely consultation with specialists

Question 18

What is mild DRESS? How do you treat it?

Answer 18

No organ involvement or mild liver involvement:
* Liver transaminases <3x ULN
* Tx symptoms

Tx for pruritis:
* Topical corticosteroids (high potency) BID-TID until resolution: Clobetasol, betamethasone

Question 19

What is severe DRESS? How do you treat it?

Answer 19

• Lungs (dyspnea, abnormal CXR, hypoxemia)
• Kidneys (SCr > 1.5xbaseline & proteinuria or hematuria)

Tx: Glucocorticoids
* Moderate to high dose prednisone oral 0.5 to 1 mg/kg/day or equiv until clin improvement and normalization of labs
* Then slowly taper over at least 8-12 weeks
* alt. reg. -> methylprednisolone IV 200-500 mg daily x 2-4 days followed by prednisolone PO 1 mg/kg/day tapered over 8-12 weeks
* Systemic GCC may increase infection

Question 20

What are the 2nd line for DRESS?

Answer 20

Cyclosporine have limited evidence

Question 21

How do we prevent DRESS?

Answer 21

1. Educate survivors on avoidance of offending drug
2. Record drug allergy
3. Avoid unnecessary drug tx
4. Genetic screening for HLA alleles

Question 23

What is SJS and TEN? How do they differ?

Answer 23

Severe cutaneous adverse reactions that causes extensive necrosis and detachment of the epidermis: mucous membrane affected >90% of patients at ≥2 sites
* Medical emergency
* Type 4 rx

Question 24

RF of EN?

Answer 24

1. HIV
2. Connective tissue dx
3. Malignancy
4. Older adults

Question 25

What medications cause SJS/TEN?

Answer 25

**Strong:** Lamotrigine, Carbamazepine, Phenytoin, sulfonamides, phenobarbital **Associated:** Oxcarbazepine **Low risk:** Levetiracetam

Question 26

What is the protopathic bias?

Answer 26

Meds used to tx initial symptoms of SJS/TEN (e.g. cold/flu meds, abx) are erroneously implicated

Question 27

What is timing of onset fro SJS/TEN?

Answer 27

Between 1 week to 1 month prior

Question 28

Describe the mechanisms of SJS/TEN?

Answer 28

1. Genetic predisposition 2. Drug antigen presentation 3. T-cell mediated response and immune dysregulation 4. Release of cytotoxic mediators, death signals, and keratinocyte death

Question 29

What are the pharmacogenomics associated with SJS/TEN?

Answer 29

* HLA B*1502 / carbamazepine - in Han Chinese, Thai, and Malay populations * carriers of HLA B*1502 are at higher risk of phenytoin-induced SJS/TEN. * Screening is recommended in Asian ancestry prior to initiating tx

Question 30

What are the presentations of SJS/TEN?

Answer 30

**Prodromal:** * Malaise * Fever * Myalgia * Sore throat * Conjunctivitis **Cutaneous lesions:** * Initially – exanthematous rash * Start on face and thorax – then spread symmetrically * Early lesions – ill-defined, purpuric spots, 2-ring targets, and flaccid bullae

Question 31

What are the later signs of SJS/TEN?

Answer 31

* Extensive, sheet-like detachment and erosions occur * Nikolsky sign is positive * Edematous erythema on palms and soles * Skin tenderness

Question 32

What are Extracutaneous involvement and complications of SJS/TEN?

Answer 32

1. Mucosal involvement: oral cavity 2. Eye involvement: conjunctival hyperemia 3. Bacteremia and sepsis 4. GI involvement 5. Liver injury 6. Hematologic abnormalities

Question 33

How do we diagnose SJS/TEN?

Answer 33

Dx must be suspected in anyone who presents with tender, extensive, mucocutaneous rash Drug causality assessment: **Latency:** 1-4 weeks of rx **Drug notoriety:** drugs most frequently associated with SJS/TEN Skin biopsy, labs, imaging

Question 34

What occurs in the Acute, progressive phase of SJS/TEN?

Answer 34

1. Fluid/electrolyte imbalances 1. Increased metabolic demands 1. Sepsis 1. Hypothermia 1. Organ decompensation 1. Death **From dx arrest, the skin re-epithelizes over 7-21 days**

Question 35

What occurs during the first initial in-hosptial eval of SJS/TEN?

Answer 35

1. ID and withdrawal of offending drug 2. Assess severity/prognosis (SCORTEN) 3. Pts with > 10% BSA detachment -> specialized units (e.g. burn / ICU)

Question 36

How do you use SCORTEN?

Answer 36

1. 0-1 dx not rapidly progressing may be treated in non-specialized wards. 2. More severe disease >1 should be in ICU or burn unit

Question 37

What is the supportive care for SJS/TEN?

Answer 37

1. Wound care 2. Fluid and electroly mgmt 3. Nutritional support 4. Temp mgmt (lower temp to prevent higher caloric expenditure) 5. Pain control 6. Ocular care (CCS eye drops) 7. Infection prevention

Question 38

How should we montior and treat superinfection associated with SJS/TEN?

Answer 38

Prophylactic systemic antibiotics cannot be advised: * Sterile handling is essential * Silver sulfadiazine should be AVOIDED if EN suspected to be from sulfonamides * Silver nitrate and silver impregnated nanocrystalline gauze **Monitoring:** * Repeated cultures of skin, blood, catheters, gastric, and any other tubes Q 48 hrs * Ab choice based on culture

Question 39

What are examples of adjunct tx for SJS/TEN? Are they commonly used?

Answer 39

Adjunctive pharmacologic therapies No established pharmacologic treatment but can be beneficial: 1. Cyclosporine 2. Alt: etanercept Systemic corticosteroids is not recommended, as well as, combo IVIG plus systemic CS

Question 40

What is the cornerstone of SJS/TEN tx?

Answer 40

Supportive care

Question 41

Is systemic CS recommended for TEN/SJS?

Answer 41

No, increases the risk for sepsis and protein catabolism, and decrease rate of epithelialization in patients with extesive skin detachment

Question 42

How do you prevent SJS/TEN?

Answer 42

1. Educate survivors about avoiding causative drugs 2. Re-exposure may be fatal 3. Update med records/allergy lists