Download Without guile: a case of drug-induced aseptic meningitis in a patient

Without guile: a case of drug-induced
aseptic meningitis in a patient with
idiopathic CD4 lymphocytopenia
LT Benjamin S. Vipler, MD, Associate, Walter Reed National Military Medical Center, Bethesda, MD.
CPT Jason J. Nam, MD, Associate, Madigan Army Medical Center, Tacoma, WA.
LCDR Andrew G. Letizia, MD, Walter Reed National Military Medical Center, Bethesda, MD.
Christina M. Schofield, MD, FACP, Madigan Army Medical Center, Tacoma, WA.
MAJ David M. Callender, MD, FACP, Walter Reed National Military Medical Center, Bethesda, MD.
Disclosures
• The views expressed in this case are those of the author and do not
necessarily reflect the official policy or position of the Departments of the
Army, Navy, Defense, nor the US Government.
• I have no financial disclosures.
Chief Complaint
• Shaking
• Fever
• Neck pain
History of Present Illness
• 62 year old African-American man
– Idiopathic CD4+ lymphocytopenia (ICL)
– Diabetes mellitus type II
– Psoriatic arthritis
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Fever, rigors, then headache, posterior neck pain/stiffness
Acute onset, 12 hours prior to being seen in ER
“I never get headaches”
Exacerbation of chronic polyathralgias
History of Present Illness Continued
• Started on trimethoprim/sulfamethoxazole (TMP/SMX) for pneumocystis
prophylaxis
– Last CD4+ count 120 (cells/µl) one month earlier
– First pill of TMP/SMX was that morning
• Dose administered 3 hours prior to symptoms
What is Idiopathic CD4+ Lympho(cyto)penia
• Defined by CDC in 1992 (also called “severe unexplained HIV-seronegative
immune suppression” by WHO)
– Decreased CD4 T lymphocytes
• <300 cells/µl OR
• <20% of total T cells
– 2 separate lab draws ≥6 weeks apart
– No evidence of HIV-1 or HIV-2
– Absence of defined immunodeficiency or T cell lowering therapy
• Not sexually transmitted
• No gender predilection
• No clear age of onset
Walker et al. Curr Opin Rheumatol 18 (4): 389–95.
What is Idiopathic CD4+ Lympho(cyto)penia
• Some evidence on BM biopsy of decreased T cell precursors
– Similarities seen in CVID patients with low CD4 cell counts
• Asymptomatic to severely ill
• Similar illnesses as HIV infected patients
• Treatment focused on prophylaxis
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No guidelines for ICL
Extrapolated from HIV
Pneumocystis
More frequent cervical cancer screening
Walker et al. Curr Opin Rheumatol 18 (4): 389–95.
Past Medical History
• ICL
– Diagnosed 2002
– Multiple bone marrow biopsies unrevealing
• Chronic recurrent fevers without underlying infectious etiologies
– Not associated with headache or neck pain
• Recurrent pneumonia
• Moderate to severe plaque psoriasis
– Psoriatic arthritis
• Multiple unprovoked pulmonary emboli
– Lifelong anticoagulation
Past Medical History Continued
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Morbid obesity
Diabetes mellitus type II
Hypertension
Hyperlipidemia
GERD
Left elbow surgery after trauma
Excisional lymph node biopsy
Past Medical History Continued
• Similar episode of current presentation “years ago”
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Same symptoms
Body habitus prohibited acquisition of spinal fluid
Treated empirically for meningitis
Required ICU admission for “coma” per wife
Recovered
Circumstances surrounding this episode unknown
Medications
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Loratidine 10mg
Lisinopril 40mg
Glipizide XL 10mg
Triamterene/HCTZ 37.5/25mg
Nifedipine 30mg
Atorvastatin 40mg
Esomeprazole 40mg
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Vitamin B12
Vitamin C
Insulin
Metformin XR 500mg twice daily
Acetaminophen with codeine
Morphine
Fentanyl (transdermal) 125mcg/hr
Vital Signs
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BMI 47
Temp: 39.1° C (102.4° F)
HR 93, regular
BP 115/48
RR 20
SpO2 98%, room air
Pain score 7/10
Physical Examination
• Awake, alert, oriented. Well developed. No acute distress
– Occasional shivers. No rigors observed
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Mucosa moist. Oropharynx without erythema/exudates
No nystagmus. Mild conjunctivitis
Neck flexion to 60 degrees, then limited by pain in the poster neck
Posterior neck slightly tender. No significant lymphadenopathy
Normal respiratory depth, rhythm and effort
– Slightly increased rate to low 20s
• Lungs clear to auscultation without wheezes/rhonchi/crackles.
Physical Examination continued
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Regular rate and rhythm
II/VI early systolic murmur at left upper sternal border
Soft, nontender, nondistended, without peritoneal signs
Normoactive bowel sounds. No bruits
Extremities with limited joint mobility.
– No increased warmth in any particular joint.
• Scattered hyperpigmented plaques
– Consistent with known psoriasis
• Cranial nerves II-XII intact.
• Brudzinski sign negative. Kernig sign difficult to perform with arthropathy
Labs
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AST 18
ALT 18
Alk phos 111
Total bili 0.3
Total protein 7.4
Albumin 3.9
– Lipase 30
– INR 1.5
– Anion gap 13
– Lactate 2.4
– UA negative
– Cardiac enzymes negative
Imaging / Diagnostics
Initial Assessment/Plan
• Sepsis with potential CNS source
– IV fluid resuscitation
– Empiric meningitis coverage for an immunocompromised host
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Ampicillin
Ceftriaxone
Vancomycin
Acyclovir
– TMP/SMX held
Hospital Course
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High fevers continued despite broad spectrum antimicrobials
Blood and urine cultures no growth to date
Influenza PCR negative
Cryptococcus serum antigen negative
Body habitus prevented lumbar puncture until hospital day (HD) 3
Head CT obtained prior to LP
– Negative
Spinal Fluid Analysis
• Tube #3
– Color/appearance: pink, hazy
– WBC: 219 cells per mm3
• PMN: 90%
• Lymph: 2%
• Mono: 8%
– RBC: 5040 cells per mm3
• Peripheral blood contamination
• WBC corrects to 207 cells per mm3
– Glucose: 50 mg/dL
– Protein: 56 mg/dL
Spinal Fluid Analysis Continued
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Gram stain: no organisms
Arbovirus panel negative
Cytomegalovirus negative
Varicella zoster negative
Cryptococcus negative
Enterovirus negative
Herpes simplex 1&2 negative
Bacterial and fungal cultures negative
Hospital Course
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High fevers continued
On HD 4, patient found altered with global aphasia
Transferred to intensive care unit
Intubated for airway protection
Neuroimaging with CT and MRI did not reveal cause
Hospital Course
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Condition improved with supportive care
Extubated the following day
Last fever noted just prior to ICU transfer
Antimicrobials weaned
– Acyclovir discontinued HD 5
– Ampicillin, vancomycin discontinued HD 6
– Ceftriaxone discontinued HD 10
Hospital Course
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On HD 7, started on dapsone for pneumocystis prophylaxis
Developed a fever to 38.4° C (101.2° F)
Dapsone abruptly discontinued
Did not have fever recurrence for the duration of hospitalization
Hospital Course
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On HD 7, started on dapsone for pneumocystis prophylaxis
Developed a fever to 38.4° C (101.2° F)
Dapsone abruptly discontinued
Did not have fever recurrence for the duration of hospitalization
Diagnosis:
Hospital Course
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On HD 7, started on dapsone for pneumocystis prophylaxis
Developed a fever to 38.4° C (101.2° F)
Dapsone abruptly discontinued
Did not have fever recurrence for the duration of hospitalization
Diagnosis: drug-induced aseptic meningitis (DIAM) due to sulfa drugs
Hospital Course
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On HD 7, started on dapsone for pneumocystis prophylaxis
Developed a fever to 38.4° C (101.2° F)
Dapsone abruptly discontinued
Did not have fever recurrence for the duration of hospitalization
Diagnosis: drug-induced aseptic meningitis (DIAM) due to sulfa drugs
– Dapsone, a sulfone, is structurally similar to sulfamethoxazole, a sulfonamide
Discussion
• DIAM is often associated with NSAIDs, antiepileptics, and other drugs
– Diagnosis of exclusion
– Well-documented with TMP-SMX
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Most frequently cited antibiotic
Rapidly progressive
Blood brain barrier
Therapeutic levels in CSF for 15 hours
First reported case in 1983, first reported in an HIV patient in 1994
Associated with autoimmune diseases and immunodeficiency/immunosuppression
Repplinger et al. Am J Emerg Med (2011) 29,242.e3-242.e5.
Thea et al. Infect Dis Clin North Am 1989;3:553-70.
Dudley et al. Antimicrob Agents Chemother 1984;26:811-4.
Discussion
• Fever, headache, meningismus, mental status changes
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Confusion, coma, seizure
ICU admission
Intubation
Global aphasia
• Generally responds to withdrawal of offending agent
• Continued/repeat ingestion has been shown to worsen symptoms
Capra et al. Intensive Care Med. (2000) 26: 212-214.
Repplinger et al. Am J Emerg Med (2011) 29,242.e3-242.e5.
Harrison et al. Clin Infect Dis. 1994;19:431-4.
Discussion
• Proposed mechanism of action
– Direct toxicity
– Immunologic
• Hypersensitivity reaction
• Immune complex deposition
• Auto-antibody induction
• CSF analysis
– Elevated protein
– Elevated WBC
– Normal or borderline glucose
• Not reliable in differentiating from partially treated bacterial meningitis
Von Reyn et al. Ann Intern Med 99: 342-344.
River et al. J Neurol Neurosurg Psychiatry. 57: 705-708.
Carillo et al. Rev Neurol 23 (119): 142-144.
Capra et al. Intensive Care Med. (2000) 26: 212-214.
Trimethoprim-induced aseptic meningitis in a
patient with AIDS: case report and review
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41 year old HIV+ treated with TMP-SMX for pneumocystis
Suffered DIAM within hours of his first dose
Promptly discontinued and symptoms resolved in 72 hours
On day 14, treatment with TMP/Dapsone attempted
– Dapsone given
– 4 hours later, TMP given
– 4 hours later, pt had recurrence of DIAM
• Dapsone and TMP discontinued
• 48 hours later patient returned to neurologic baseline
• Felt to be due to TMP, as patient was followed on Dapsone pneumocystis
prophylaxis for 6 months without issue
Harrison et al. Clin Infect Dis. 1994;19:431-4.
Conclusion
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DIAM in a patient with ICL
Supported by use of sulfone antibiotic
Aseptic nature does not denote a benign course
Bacterial meningitis should remain high on differential diagnosis
Resources
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Walker UA, Warnatz K (July 2006). “Idiopathic CD4 lymphocytopenia”. Curr Opin Rheumatol
18 (4): 389–95.
Thea D, Barza M. Use of antibacterial agents in infections of the central nervous system.
Infect Dis Clin North Am 1989;3:553-70.
Dudley MN, Levitz RE, Quintiliani R, et al. Pharmacokinetics of trimethoprim and
sulfamethoxazole in serum and cerebrospinal fluid of adult patients with normal meninges.
Antimicrob Agents Chemother 1984;26:811-4.
Capra C, Monza GM, Meazza G, et al. Trimethoprim-sulfamethoxasole-induced aseptic
meningitis: case report and literature review. Intensive Care Med 2000;26(2): 212-4.
Repplinger MD, Falk PM. Trimethoprim-sulfamethoxazole-induced aseptic meningitis. Am J
Emerg Med (2011) 29,242.e3-242.e5.
Von Reyn CF (1988) Recurrent aseptic meningitis due to sulindac. Ann Intern Med 99. 343344.
River Y, Averbuch-Heller L, Weinberger M, Meiner Z, Mevorach D, Schlesinger I, Argov Z
(1994) Antibiotic induced meningitis. J Neurol Neurosurg Psychiatry. 57: 705-708.
Carrilo F, Cubero A, Hernandez Gallego J Jimenez Santana P (1995) Recurrence of
meningoencephalitis induced by cotrimoxazole. Rev Neurol 23 (119): 142-144.
Harrison MS, Simonte SJ, Kauffman CA. Trimethoprim-induced aseptic meningitis in a patient
with AIDS: case report and review. Clin Infect Dis. 1994;19(3):431-4.
PRN Slides
Healthy Individual with TMP/SMX DIAM
Capra et al. Intensive Care Med. (2000) 26: 212-214.
HIV patient withTMP/SMX DIAM
*
*and dapsone
Harrison et al. Clin Infect Dis. 1994;19:431-4.
CSF
Bacterial
Aseptic
• Appearance
• Appearance
– Cloudy
– Clear
• Pressure
• Pressure
– 18-30
– 9-18
• WBC
– 100-10,000 polys
• Glc
– <45
• TP
– 100-1000
• WBC
– <300 polyslymphs
• Glc
– 50-100
• TP
– 50-100
BM Bx
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2003
– NORMOCELLULAR MARROW WITH MILD ERYTHROID AND MEGAKARYOCYTIC
DYSPLASIA AND MEGALOBLASTOID CHANGES
• This marrow is very small and hence, it is difficult to render a more definitive diagnosis.
This marrow was compared with the previous marrow (NB02-200), which shows more
severe leukopenia and thrombocytopenia, however, the rest of the marrow is more or
less similar to the current marrow. The dysplasia does not show any increase in number
or severity of changes. The presence of megaloblastoid changes and giant
metamyelocytes suggest a B12 and/or folic acid deficiency. Close clinical follow-up and
clinicopathologic correlation may be warranted.
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2007
– NORMOCELLULAR BONE MARROW WITH TRILINEAGE HEMATOPOIESIS AND
INCREASED MONOLOBATED MEGAKARYOCYTES
• Significant morphologic evidence of dysplasia is limited to the megakaryocytic lineage
with greater than ten percent of megakaryocytes with hypo/monolobation. Significant
erythroid dysplasia is not apparent. An evolving myelodysplastic disorder cannot be
excluded. Correlation with cytogenetic studies and B12/folate levels is recommended.