54 year old male with HIV, fever, altered mental status

1. Brian Crabtree, MD PGY-3 Maine ACP Conference 2013 September 28, 2013 54 year old male with HIV, fever, altered mental status

2. Identification and Chief Complaint 54 year old Cuban American man with a history of HIV positivity, schizoaffective disorder, glaucoma, recent diagnosis of ankylosing spondylitis presents with three days of fevers and chills, worsening headache and confusion.

3. History of Present Illness Mr. B was in his usual state of health until four days before admission when he reports developing low grade fevers and night sweats with generalized malaise. Over the next two days he developed a worsening headache, confusion and ataxia. His significant other brought him to the ED by car for failure to improve and worsening mental status.

4. Review of Systems General: +malaise, +fever, no weight loss HEENT: +headache, no photophobia, +ulcer on lip for the last week, no visual changes CV: no chest pain, no DOE, no orthopnea Respi: no cough, no SOB GI: +nausea, no vomiting, no bowel changes, no abdominal pain GU: +polydipsia and polyuria, no dysuria Neuro: no focal weakness, no sensory deficits or paresthesias Skin: no rashes, no jaundice Psych: +somnolence, +confusion, no hallucinations, delusions MSK: +neck stiffness, +low back pain, no joint pain

5. Past Medical History Active Problem List 1. Fever 2. AMS HIV – diagnosed in 1990s, currently on antiretroviral therapy, most recent CD4 count 369 with low viral load (30) Schizoaffective disorder – diagnosed in his mid twenties and on valproic acid Anklyosing spondylitis – HLA-B27 positive, diagnosed in the last year History of uveitis and glaucoma Gilbert’s disease Chronic Hepatitis B carrier Hyperlipidemia

6. Past Medical History Active Problem List 1. Fever 2. AMS PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B HIV – diagnosed in 1990s, currently on antiretroviral therapy, most recent CD4 count 369 with low viral load (30) Schizoaffective disorder – diagnosed in his mid twenties and on valproic acid Anklyosing spondylitis – HLA-B27 positive, diagnosed in the last year History of uveitis and glaucoma Gilbert’s disease Chronic Hepatitis B carrier Hyperlipidemia

7. Past Surgical History Active Problem List 1. Fever 2. AMS PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B Tonsillectomy Rectal fistula repair

8. Social History Active Problem List 1. Fever 2. AMS PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B Mr. B was born in Cuba and moved to the United States at age 9. He is homosexual with a long term partner. He was sexually active in New York City in the 1980’s and was diagnosed with HIV in the early 1990’s. He has a history of drug use including cocaine and acid. Minimal current alcohol use, history of social tobacco use. He moved to southern Maine in 2009 to run a kennel with his partner. He is on disability for his schizoaffective disorder.

9. Medications and Allergies Active Problem List 1. Fever 2. AMS PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B Ritonavir 100mg cap daily Atazanavir 300mg cap daily Emtricitabine-tenofovir 200-300mg tab daily Valproic acid 500mg 3 tabs at bedtime Perphenazine 16mg tab twice daily Bupropion 450mg XR once daily Pravastatin 20mg tab daily Etodolac 400mg tab twice daily Loratadine 10mg tab daily as needed Dorzolamide-timolol solution one drop twice daily Loteprednol etabonate 0.5% solution once daily

10. Physical Examination Active Problem List 1. Fever 2. AMS PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B T 39.7 HR 107 RR 20 142/88 97% O2 General: drowsy, poor attention, orientedx3 HEENT: PERRL, EOMI, +1cm ulcer on left lower lip, +nuchal rigidity CV: regular rhythm, normal rate, normal S1 and S2 without murmurs Respi: good air movement, clear to auscultation Abd: soft and nontender, normal bowel sounds, no organomegaly Ext: no peripheral edema, good pulses Neuro: cranial nerves 2-12 tested and intact, 5/5 strength throughout, normal reflexes, negative Kernig and Brudzinski signs, normal tone, normal sensation

11. Initial Lab Testing Active Problem List 1. Fever 2. AMS PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B CBC: WBC 7.0, Hb 13.2, Hct 37.2, Plt 177 BMP: Na 122, K 3.8, Cl 84, CO2 24 BUN 10, Cr 1.2, Glu 109 UA/sediment: pH 5.0, negative leukocytes and nitrites, +urobilinogen, no casts, 3-5 RBCs, occasional WBCs

12. Differential Diagnosis Active Problem List 1. Fever 2. AMS 3. Hypo-natremia PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B Infectious: Sepsis of any origin, meningoencephalitis, brain abscess Autoimmune: CNS vasculitis, Still’s disease Malignancy: Lymphoma, leukemia Environmental: Heat stroke Toxins: Neuroleptic malignant syndrome, salicylate overdose, serotonin syndrome, anticholinergic toxicity, sympathomimetic toxicity Metabolic: Thyrotoxicosis

13. Chest X ray

14. CT Head

15. MR Brain

16. Clinical Course in the ED Active Problem List 1. Fever 2. AMS 3. Hypo-natremia PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B Lumbar puncture was attempted six times and was finally successful. The patient remained febrile. Results of lumbar puncture showed: WBC 206/mm3 with 86% lymphocytes Glucose 52 mg/dL Protein 91 mg/dL No RBCs Gram stain negative Blood cultures were taken and empiric acyclovir was initiated.

17. Interpreting CSF Active Problem List 1. Fever 2. AMS 3. Hypo-natremia PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B Results of lumbar puncture showed: WBC 206/mm3 with 86% lymphocytes Glucose 52 mg/dL Protein 91 mg/dL No RBCs Gram stain negative

18. Differential Diagnosis for Aseptic Meningitis Active Problem List 1. Aseptic Meningitis 2. Hypo-natremia PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B Viral – enteroviruses, arboviruses, HSV, HIV, measles, mumps, VZV, CMV, EBV Bacterial – Parameningeal abscess, Leptospirosis, Listeria, Brucella, Coxiella, Borrelia, TB, Syphilis, Rickettsia, Ehrlichia Fungal – Crypotococcus, coccidiodes, histoplasma Parasitic – Toxoplasmosis, taenia solium Infectious

19. Differential Diagnosis for Aseptic Meningitis Active Problem List 1. Aseptic Meningitis 2. Hypo-natremia PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B Drug Induced – Ibuprofen, TMP-SMX, other NSAIDs, Azathioprine, Lamotrigine, IVIg, monoclonal antibodies Malignancies – Lymphoma, leukemia, metastases Autoimmune – Sarcoidosis, Systemic Lupus Erythematosis, Behcet’s, vaccine reaction Non-Infectious

20. Clinical Course Active Problem List 1. Aseptic Meningitis 2. Hypo-natremia PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B The patient was admitted to the hospital floor on a hospitalist team. Neurology and infectious disease were consulted. The patient continued having fevers >38ºC multiple times per day for three days. Vancomycin and ceftriaxone were added empirically, but he continued to have fevers that would respond to acetaminophen. His mental status continued to fluctuate and he continued to have back pain and stiff neck.

21. Clinical Course

22. Work-up for Aseptic Meningitis Active Problem List 1. Aseptic Meningitis 2. Hypo-natremia PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B Infectious workup: Blood and CSF cultures – negative at 48 hours CSF Cryptococcal antigen: negative T-spot: negative T pallidum Ab: negative Lyme IgG and IgM Ab: negative CSF HSV PCR: negative CSF arbovirus panel: negative CD4 count: 342 HIV viral load: 30 copies/mL Rheumatologic workup: ESR: 22 CRP: 0.56

23. Work-up for Aseptic Meningitis Active Problem List 1. Aseptic Meningitis 2. Hypo-natremia PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B Drug Induced Aseptic Meningitis – - Most common offending medications include ibuprofen, other NSAIDs, lamotrigine. - Difficult to test for and is often a diagnosis of exclusion. Diagnosis depends on causal relation with drug administration and is confirmed with pharmacologic challenge testing where medication is given and clinical response is monitored.

24. = ibuprofen administration

25. Drug-Induced Aseptic Meningitis Active Problem List 1. Drug-induced Aseptic Meningitis 2. Hypo-natremia PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B First described in 1978 in a 26 year old female with lupus who developed meningitis while taking ibuprofen. The diagnosis was confirmed with challenge testing. Body of evidence regarding drug-induced aseptic meningitis (DIAM) is largely based on case reports A 2006 review article reviewed 71 cases of NSAID-induced meningitis. 61% of cases had an underlying connective tissue disease HIV has been mentioned as a predisposing condition as well Exact incidence is unknown History and Epidemiology

26. Drug-Induced Aseptic Meningitis Active Problem List 1. Drug-induced Aseptic Meningitis 2. Hypo-natremia PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B Clinical Features Rodriguez, SC. Characteristics of meningitis caused by ibuprofen: report of 2 cases and review of the literature. Medicine (Baltimore) 2006 Jul; 85(4) 214-20.

27. Drug-Induced Aseptic Meningitis Active Problem List 1. Drug-induced Aseptic Meningitis 2. Hypo-natremia PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B Thought to be a type III hypersensitivity reaction against the drug or metabolite One suggested mechanism is hypersensitivity to the drug as a hapten with an CSF-protein which would explain the limitation of the inflammation to only the central nervous system. Some patients have idiosyncratic reactions to only one NSAID while others have been described as having reactions to several drugs within the class Proposed Mechanism

28. Drug-Induced Aseptic Meningitis Active Problem List 1. Drug-induced Aseptic Meningitis 2. Hypo-natremia PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B CSF evidence of meningitis with neutrophil or lymphocyte predominance, usually elevated protein and normal glucose Exclude infectious causes There must be temporal relationship between a known offending agent and symptoms Symptoms should resolve rapidly after withdrawing offending agent Can be confirmed with challenge testing, though no evidence based protocol exists Diagnosis

29. Drug-Induced Aseptic Meningitis Active Problem List 1. Drug-induced Aseptic Meningitis 2. Hypo-natremia PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B Discontinue offending agent Use other drugs in the class with caution Consider workup for underlying autoimmune condition Management

30. Follow-up with patient Active Problem List 1. Drug-induced Aseptic Meningitis 2. Hypo-natremia PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B Ibuprofen was discontinued and both ibuprofen and etodolac were placed on the patient’s allergy list. Empiric antibiotics were discontinued as well. The patient had no further fevers once ibuprofen was discontinued and delirium improved over the next 24 hours. Did well for six months, then began developing ataxia of hands, cognitive slowing, fixed dilated right pupil, tremor. He was diagnosed with Parkinsonism by neurology and it is unclear if this is related to psychotropic medications, HIV or underlying Parkinson disease.

31. Take Home Points from Case Active Problem List 1. Drug-induced Aseptic Meningitis 2. Hypo-natremia PMH 1. HIV 2. Schizo-affective disorder 3. Akylosing spondylitis 4. Chronic Hepatitis B Drug-induced aseptic meningitis is a syndrome that can be clinically indistinguishable from bacterial meningitis but should be suspected in a patient on commonly offending agents (NSAIDs, TMP-SMX, lamotrigine, azathioprine, IV Ig) especially in those with underlying connective tissue disease. Ibuprofen and other NSAIDs are widely used drugs and it is important for physicians to be aware of the potentially severe side effects

32. References Mandell, Douglas, and Bennett. Principles and Practice of Infectious Disease. Seventh Edition. 2010 Jolles, Stephen. Drug Induced Aseptic Meningitis – Diagnosis and Management. Drug Safety 2000 Mar; 22(3): 215-226. Moreno-Ancillo, A. Ibuprofen-Induced Aseptic Meningoencephalitis Confirmed by Drug Challenge. J Investig Allergol Clin Immunol 2011; Vol 21(6): 484-487. Rodriguez, SC. Characteristics of meningitis caused by ibuprofen: report of 2 cases and review of the literature. Medicine (Baltimore) 2006 Jul; 85(4) 214-20. Lee, RZ, Ibuprofen-induced aseptic meningoencephalitis. Rheumatology. 2002 41(3): 353-355.