difficult case of fever rash

1. Difficult Case of Fever & Rash Andrew Dionne, MD Dan Onion, MD Roy Miller, MD

3. PMH: Type 2 Diabetes, Mild hypertension, Bipolar Affective Disorder Meds: Glucophage, Tegretol, recently discontinued a beta-blocker Allergy: Penicillin Lives in area with her teenage son, works as a secretary, smokes 1 ppd, no alcohol Family history notable for CAD, BPAD Case Presentation

4. Initial exam Alert, oriented Pulse 120 (sitting & standing), BP 140/90 supine & fell to 95 systolic with standing HEENT, Cardiac, Lung Exams normal Abdomen with mild RLQ tenderness Extremities no edema Skin maculopapular rash confluent on upper arms, chest, back, knees Neuro normal Case Presentation

5. Initial Laboratory Data WBC 4,000 with 48 polys, 30 bands, 17 lymphs Hgb 11.3, HCT 33.7; plt 215,000 Electrolytes, BUN/Cr WNL; glucose 120 Protein 6.7 (Alb 3.0), AST 112, ALT 93, Alk Phos 181, Bili 0.6 Blood, Urine & Vaginal Cultures were ordered Imaging Chest X-Ray was normal Pelvic U/S was normal Head CT was normal Case Presentation

6. Was admitted with a diagnosis of toxic shock syndrome vs. viral illness (mono, hepatitis) Started on IV cefazolin and clindamycin Blood, urine, & vaginal cultures had no growth One dose of IVG was given Patient had no clinical improvement with continued fevers, postural hypotension; rash worsened and edema, then anasarca, came on Left axillary lymphadenopathy developed Case Presentation

7. Further Lab Work revealed WBC fell to 3600 then increased to 13,000 H/H increased to WNL Plt count increased to >500K PT 15.6, INR 1.4, PTT 31 TSH 7.40, FT4 normal Alk Phos, AST, ALT remained 2x normal; GGTP 618 CPK 3, ESR 10, Tegretol 6.6, RPR NR, Monospot (-) Repeat Blood Cx were negative Case Presentation

8. On hospital day #7, Tegretol and Glucophage were discontinued Gallium scan done to r/o abscess was negative Because of elevated LFTs, RUQ U/S was done and came back negative; CT Abd/Pelvis (-) Because of prolonged sinus tach and orthostasis, an echocardiogram was performed and showed small pericardial effusion but normal LV size and function Case Presentation

9. Diagnosis of small vessel vasculitis considered Repeat ESR 5 Immune Survey WNL except IgG, IgA slightly low, C3 high ANA, RF (-); P-ANCA, C-ANCA, Antimit AB sent out (and came back negative) Biopsy of rash done from 2 sites Intraepidermal pustular dermatitis Dermatology and rheumatology consults placed Case Presentation

10. Further study brought about consideration of anticonvulsant hypersensitivity syndrome Patient started on IV then PO steroids on hospital day #11 Steady clinical improvement of edema, pruritus, rash, and hypotension Case Presentation

11. Anticonvulsant Hypersensitivity Syndrome AKA Dilantin Hypersensitivity Syndrome, Pseudolymphoma syndrome Reported primarily with phenytoin, carbamazepine, and phenobarbital Between 1/1000 and 1/10,000 exposures First described by Chaiken et al in 1950 Increased risk with race and family history Onset of symptoms delayed with 1st exposure- 2 weeks to 3 months

12. Phenytoin Carbamazepine Phenobarbital Primidone Lamotrigine Valproic Acid Ethosuximide Dapsone Sulfasalazine Sulfonamides Allopurinol Diltiazem Mexiletine Minocycline Terbinafine Anticonvulsant Hypersensitivity SyndromeCausative Medications

13. Fever 90-100% Rash 90% Lymphadenopathy 70% Periorbital/Facial Edema 25% Hepatitis 50-60% Hematologic abnormal. 50% Multi-organ involvement 60% Myalgia, arthralgia 20% Pharyngitis 10% Anticonvulsant Hypersensitivity SyndromeClinical Findings

14. Viral diseases Hepatitis Influenza CMV, EBV HIV Collagen Vascular Dis. Kawasaki Syndrome Lymphoma Syphilis Porphyria Anticonvulsant Hypersensitivity SyndromeDifferential Diagnosis Hypereosinophilic syndrome Toxic Shock Syndrome Other drug reactions Erythema multiforme Toxic Epidermal Necrolysis Serum sickness

15. Anticonvulsant Hypersensitivity SyndromeDermatologic Findings Begins as patchy, macular erythema Dusky, confluent, pruritic papular rash Edema, esp. on face Differentiates from other drug rashes Sterile follicular pustules May progress to erythema multiforme or toxic epidermal necrolysis

16. Anticonvulsant Hypersensitivity SyndromeOther Findings Lymphadenopathy Localized or generalized Lymphoid hyperplasia May be atypical cells similar to lymphoma Small number have coexistant or subsequently develop lymphoma- “pseudo-pseudolymphoma syndrome” Hepatitis Most common cause of death; Mortality 18-40% LFTs may continue rise after off med, take up to 1 year to resolve

17. Anticonvulsant Hypersensitivity SyndromeOther Findings Hematologic Leukocytosis with atypical lymphs Eosinophilia Coombs (-) hemolytic anemia Immunologic Ig, ESR, Complement usually normal Other Nephritis, pancreatitis, pneumonitis Polyarteritis nodosa, myopathy, myocarditis Hypo- and hyperthyroidism

18. No relation to drug dosage or levels One theory proposed like graft-versus-host disease, i.e. lymphocytes have altered recognition of “self” Others say due to circulating autoantibodies Shear and Spielberg, 1988 suggested due to a toxic metabolite ? Related to HHV-6 infection Anticonvulsant Hypersensitivity SyndromePathophysiology

19. Anticonvulsants metabolized by cytochrome p450 to arene oxide metabolite Metabolite detoxified by epoxide hydrolase Enzyme may be lacking or mutated in some people Toxin may cause direct cell death or trigger autoimmune response In vitro enzyme testing can be performed but not readily available Anticonvulsant Hypersensitivity SyndromePathophysiology

20. Primary therapy is discontinuation of offending medication prior to significant organ involvement Supportive care with O2, IVF, etc Treat rash with topical steroids, wet wraps, antihistamines IV steroids widely used and felt to be helpful but not clinically proven 0.5-2 mg/kg daily Anticonvulsant Hypersensitivity SyndromeTreatment

21. May take weeks to months for symptoms and lab abnormalities to improve Patient should be warned never to use anticonvulsants Even small doses can lead to immediate, life-threatening reactions Consider warning bracelet if prone to status epilepticus ? Follow closely for lymphoma Warn family members about risk Anticonvulsant Hypersensitivity SyndromeFollow-Up