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					Difficult Case of Fever & Rash

Andrew Dionne, MD
Dan Onion, MD
Roy Miller, MD
Case Presentation
• 33 year old woman presented to local health
  center with fever, rash, and orthostatic
• Seen 2 weeks prior in the ER for menorrhagia and
  orthostasis, received hydration
• 5 days prior to admission, developed fever to 105F
  at home and mild headache; took antihistamine
• 12 hours later developed rash which lasted until
  going to her doctor’s office
Case Presentation
• 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
• 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
• 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
• 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
• 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
• On hospital day #7, Tegretol and Glucophage were
• 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
Case Presentation
• Diagnosis of small vessel vasculitis considered
   – Repeat ESR 5
   – Immune Survey WNL except IgG, IgA slightly low, C3
   – 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
• 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
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
Anticonvulsant Hypersensitivity Syndrome
Causative Medications

•   Phenytoin           •   Dapsone
•   Carbamazepine       •   Sulfasalazine
•   Phenobarbital       •   Sulfonamides
•   Primidone           •   Allopurinol
•   Lamotrigine         •   Diltiazem
•   Valproic Acid       •   Mexiletine
•   Ethosuximide        •   Minocycline
                        •   Terbinafine
Anticonvulsant Hypersensitivity Syndrome
Clinical Findings

•   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 Syndrome
Differential Diagnosis

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

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

• 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 Syndrome

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

• 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,
• IV steroids widely used and felt to be helpful but
  not clinically proven
   – 0.5-2 mg/kg daily
Anticonvulsant Hypersensitivity Syndrome

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