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Case Presentation Cryptococcal Meningitis
A 29-year-old female presented with severe frontal headache, vomiting, and neck stiffness for one week. A lumbar puncture revealed cryptococcal meningitis. She was started on amphotericin B and fluconazole for induction and consolidation therapy. Monitoring showed worsening anemia and kidney injury from the amphotericin B treatment. The patient's symptoms improved but serial lumbar punctures and cultures were needed to ensure sterilization of the cerebrospinal fluid and check for potential drug resistance before completing the full antifungal treatment course.
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Case Presentation Cryptococcal Meningitis
- 1.
- 2. GENERAL DATA • MsXX • 29 year old female • Swazi • Unemployed
- 3. CHIEF COMPLAINT 21/11/17 •Severe frontalheadache, not relieved by analgesia and vomiting for about 1 week.
- 4. PRESENT ILLNESS • Severefrontal headache not relieved by analgesics, accompanied by vomiting and neck stiffness. In addition, patient has oral thrush. • RVD positive, but not on treatment, not clear why • No history of any chronic diseases • Travel hx: nil • VITALS; • T: 36.4 • P: 67 • BP: 125/71 • RBS: 6.6
- 5. PHYSICAL EXAM GE; •Chronically ill-looking,confused with slurred speech •Dehydrated, Mild pallor •Oral thrush, Pruritic rash on trunk •CVS: S1S2-N, no added sounds •RESP: GAEB •ABD: SNT, no organomegally
- 6. • CNS: • Lethargic,slurred speech, gait disturbance • Brudzinki’s sign + ..Neck stiffness • Kernig’s sign +
- 7. PLAN • LP; CSF CryptoAg, microscopy, India ink, Zeihl-Neelson, culture • Bloods; FBC, U E & Cr • Manage as bacterial meningitis • Trace results in the ward; adjust Rx • Consult dermatologist in ward
- 8. OPD PRESCRIPTION 21/11/17 •Rocephin 2g IV stat • Panado 1g PO TDS x3D
- 9. LAB FINDINGS 21/11/17TESTRESULT NORMAL RANGE UNITS WBC 6.28 3.60 – 9.60 x10*3/uL RBC 4.14 4.20 – 5.40 x10*6/uL Hb 12.0 12.0 - 15.0 g/dl MCV 84.7 82.0 – 97.0 FL Platelet 182 150 – 450 x10*9/l Creatinine 46 53 - 97 mmol/L BUN 2.1 2.9 – 9.3 mmol/L Na 129 136-144 mmol/L K 3.3 3.5 – 5.5 mmol/L Ca 2.33 2.10 – 2.55 mmol/L
- 10. • Plasmodium FalcipurumAg……. Negative • VDRL/RPR???
- 11. CSF findings 21/11/17 MICROSCOPIC; Clearsupernatant appearance WBC; 0-2 /HPF RBC; 0-3/HPF INDIA INK; scanty ZEIHL NEELSON; No AFB seen GRAM STAIN; Yeast cells <5 CRYPTOCOCCAL antigen; out of stock CULTURE: pending
- 12. CSF analysis cont…. componentresult Normal range units chloride 125 120 - 130 mmol/L glucose 2.4 2.2 – 3.9 Mmo/L
- 13. DIAGNOSIS • Cryptococcal meningitis •Oral candidiasis • Pityriasis rosea • RVD pre-ART
- 14. MANAGEMENT 21/11/17 •Amphotericin B 50mgIV in 5% dextrose saline over 4-6 hrs x14D •IV N/S 1L Q12H •Nystatin susp 1m QID •Paracodeine 1G PO TDS 22/11/17 •CTX 960 mg PO BD •Consult VCT
- 15. Derma prescription • Emmulsifyingointment x7D • 1% hydrocortisone cream BD x7D • Allergex 4mg nocte x7D
- 16. 23/11/17 test RESULT NORMALRANGE UNITS WBC 3.50 3.60 – 9.60 x10*3/uL RBC 3.61 4.20 – 5.40 x10*6/uL Hb 10.4 12.0 - 15.0 g/dl MCV 83.6 82.0 – 97.0 FL Plateletes 121 150 – 450 x10*9/l Creatinine 56 53 - 97 mmol/L BUN 2.2 2.9 – 9.3 mmol/L Na 137 136-144 mmol/L K 2.9 3.5 – 5.5 mmol/L Ca 2.31 2.10 – 2.55 mmol/L
- 17. • A; Anemia Hypokalemia • P; KCl600mg PO OD Fefol 2 tabs BD
- 18. 30/11/17 test RESULT NORMALRANGE UNITS WBC 11.51 3.60 – 9.60 x10*3/uL RBC 2.84 4.20 – 5.40 x10*6/uL Hb 8.5 12.0 - 15.0 g/dl MCV 86.0 82.0 – 97.0 FL Plateletes 154 150 – 450 x10*9/l Creatinine 170 53 - 97 mmol/L BUN 10.7 2.9 – 9.3 mmol/L Na 136 136-144 mmol/L K 2.9 3.5 – 5.5 mmol/L Ca 2.03 2.10 – 2.55 mmol/L ALP 94 38- 126 U/l GGT 86 7 - 50 U/l
- 19. PLAN • A; • AKI •Anemia • P; • Hydration: IVI NS 1L 8Hrly • Repeat bloods on Monday 04/11, FBC, KFT, LFT, electrolytes
- 20. Patient condition update •Well oriented • No neck stiffness • No headache • No vomiting • Jaundice +
- 21. 04/12/17- Ampho B,D12 test RESULT NORMAL RANGE UNITS WBC 8.01 3.60 – 9.60 x10*3/uL RBC 2.49 4.20 – 5.40 x10*6/uL Hb 7.6 12.0 - 15.0 g/dl MCV 86.4 82.0 – 97.0 FL Plateletes 188 150 – 450 x10*9/l Creatinine 221 53 - 97 mmol/L BUN 31.1 2.9 – 9.3 mmol/L Na 124 136-144 mmol/L K 5.6 3.5 – 5.5 mmol/L Ca 2.23 2.10 – 2.55 mmol/L ALP 291 38- 126 U/l GGT 243 7 - 50 U/l HBsAg negative
- 22.
- 23. INTRODUCTION • Although thegenus Cryptococcus contains more than 50 species, C neoformans and C gatti are considered principal pathogens. • Cryptococcal neoformans is an encapsulated yeast, first described in 1984, by a pathologist, Busse. • The most serious infections usually develop in patients with defective cell mediated-immunity.
- 24. PATHOGENESIS • C neoformanscan cause an asymptomatic pulmonary infection, followed later by the development of meningitis. • Following inhalation through the respiratory tract, the yeast spores are transmitted into the pulmonary alveoli, where they are phagocytosized by alveolar macrophages. • If confined to the lungs, it can cause pneumonia, poorly defined mass lesions, pulmonary nodules, and rarely, pleural effusion. • The organism disseminates hematogenously and has a propensity to localize to the central nervous system (CNS).
- 25. Why the CNS? •It is uncertain, but a number of hypotheses have been proposed: • The CSF is a favorable growth medium. In the serum, the organism activates the alternative complement pathway, but complement activity in the CSF is very low. • Dopamine levels in the CNS may promote cryptococcal virulence by serving as a substrate for melanin production by the organism. • Production of mannitol by the organism may contribute to brain edema and inhibit phagocyte function
- 26. EPIDEMIOLOGY • GLOBALLY, • ~957,900cases of CCM yearly, with more than 600,000 deaths. • majority among patients with AIDS and a CD4 count <100 cells/microL. • region with the highest number of estimated cases in 2006 was sub-Saharan Africa (720,000 cases; range, 144,000 to 1.3 million), • followed by South and Southeast Asia (120,000 cases; range, 24,000 to 216,000)
- 27. • MBABANE GOVTHOSP 2016/17 OCT NOV DEC JAN FEB MAR APR MAY JUN JUL AUG SEP w18 5 4 2 1 0 2 0 1 3 1 2 3 w12 2 1 0 0 1 0 2 1 0 0 2 2
- 28. DIAGNOSIS • CCM suspectedin patients with advanced HIV infection (CD4 cell count <100 cells/microL) who have isolated fever and headache. • Initial evaluation includes a careful history, neurologic exam, and serum cryptococcal antigen.
- 29. • LP toobtain CSF • CSF analysis; Cryptococal culture - cream-colored mucoid colonies India ink staining - typical round encapsulated yeast organisms • Cryptococcal antigen (CrAg) - latex agglutination, sandwich enzyme-linked immunosorbent assay (ELISA) and lateral flow assay (LFA)
- 30. MANAGEMENT • The initialpreferred approach to the patient with CCM includes; induction phase; combination antifungal therapy with amphotericin B plus flucytosine. consolidation phase; fluconazole.
- 31. MONITORING • During therapy,patients should be monitored for recurrence of clinical symptoms that may suggest increased intracranial pressure, relapse of infection (from lack of adherence or drug resistance), adverse events related to antifungal therapy, and immune recovery syndromes secondary to antiretroviral therapy (ART).
- 32. Intracranial pressure • frequentmonitoring is needed for individuals with evidence of increased ICP (defined as ICP>20 cmH2O) and persistent symptoms. • Some individuals are asymptomatic, therefore, difficult to assess clinically. • ICP should be measured at the time of initial LP, if the patient has persistant symptoms, and when repeat fungal cultures are obtained after 2 weeks of induction therapy. • LP, which leads to transient improvement in ICP, can be life-saving.
- 34. Drug resistance testing •resistance considered if the CSF has not been sterilized after two weeks, or if a patient has relapsing infection. • A cryptococcal isolate be evaluated for changes in the minimum inhibitory concentration (MIC) against the antifungal agent that is being administered. • a threefold increase in MIC from the pre-treatment isolate to the on- treatment isolate would suggest emerging drug resistance. • An absolute MIC of >16 mcg/mL for fluconazole or >32 mcg/mL for flucytosine for a single isolate may also be suggestive of drug resistance
- 35. Adverse events • AmphotericinB deoxycholate is frequently associated with electrolyte disturbances, anemia, renal insufficiency, and infusion site reactions, such as drug fever and rigors. • daily monitoring of serum creatinine and electrolytes • Some require significant amounts of K and/or Mg supplementation during therapy and hydration with NS during amphotericin B infusions.
- 36. • Flucytosine ismainly associated with gastrointestinal intolerance. Laboratory abnormalities include elevations in aminotransferases, anemia, leukopenia, and thrombocytopenia. • Fluconazole is generally well tolerated; patients occasionally may develop rash or abnormal aminotransferases.
- 37. Sterilization of cerebrospinalfluid • LP is repeated for fungal culture after two weeks of induction antifungal therapy to confirm sterilization of the cerebrospinal fluid (CSF), even among patients who have clinically improved. • The opening pressure should also be measured at that time
- 39. Lipid based AmphoB • UWHC guidelines; The newer lipid-based formulations of amphotericin B are less likely to cause elevations in serum creatinine than conventional amphotericin B deoxycholate (AmB). • Available studies indicate comparable efficacy. • The lipid-based formulations are usually used as second-line agents because they are much more expensive than the conventional formulation.
- 42. TAKE HOME MESSAGE •Patients with advanced HIV infection (CD4 cell count <100 cells/microL) who have isolated fever and headache; suspect CCM. • LP and CSF analysis to confirm diagnosis. Serum latex agglutination may also be used • Monitoring of patient symptoms and drug adverse effects is very crucial during management. • Lipid based Ampho B formulations have comparable efficacy with less side effects…but expensive. • Combination of Ampho B with flucytosine leads to faster and increased sterilization of CSF from crypto Ag.
- 44. REFERENCES • Cox, GM and Perfect, J R, 2017. Clinical management and monitoring during antifungal therapy of the HIV-infected patient with cryptococcal meningoencephalitis. Extracted from UpTodate, 10/12/17. • Goshman, L. 2009. UWHC Guidelines For the Use Of Lipid-Based Amphotericin B Products In Adults and Children. Guidelines developed by UWHC Center for Drug Policy (CDP) • Rolfes MA, et. al. 2015. The effect of therapeautic lumber puncture on acute mortality from cryptococcal meningitis. Clin infection 2014, 59 1607-14. • Sloan D, Dlamini S, Paul N, Dedicoat M. 2008. Treatment of acute cryptococcal meningitis in HIV infected adults, with an emphasis on resource-limited settings. Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD005647. DOI: 10.1002/14651858.CD005647.pub2. • Viviani ET. AL., 1994. Lipid-based amphotericin B in the treatment of cryptococcosis. Springer Link. 22: 137.https://doi.org/10.1007/BF01739025
Editor's Notes
- #8 Patients with toxoplasmosis may also have focal findings, such as specific hand weakness, while patients with cryptococcal meningoencephalitis usually have cranial neuropathies. Patients with tuberculosis meningitis may also have other clues to the diagnosis, such as cough, hemoptysis, and an abnormal chest x-ray. Patients with secondary syphilis with aseptic meningitis usually have normal mentation and a disseminated maculopapular rash.
- #16 DERMA priscription::: Emmulsifying ointment 1% hydrocortisone cream BD Allergex 4m nocte
- #20 WBC?
- #25 People with AIDS, organ transplantation, corticosteroid rx, with sarcoidosis, reticuloendothelial malignancy
- #26 The organism is is primarily transmitted via the respiratory route, but not directly from human to human.
- #27 CSF is a favorable growth medium as it lacks the factors present in serum that inhibit cryptococcal growth The basis for the tropism for the CNS is uncertain, but
- #28 Although the incidence of CCM has declined in patients who have access to ART), cryptococcal disease remains a leading cause of mortality in the developing world where access to ART is limited and HIV prevalence remains high.
- #31 THROUGH IMMUNO DIAGNOSTIC TECHNIQUES Importance of neuroimaging — Prior to a lumbar puncture (LP), patients suspected of having increased intracranial pressure and/or CNS mass lesions must have neuroimaging (eg, computed tomography [CT] scan or magnetic resonance imaging [MRI]).
- #32 Cryptococcal meningoencephalitis is a serious opportunistic infection that is seen among patients with untreated AIDS.
- #34 Persistant behavior disturbance, gait, vomiting, Increased ICP has been associated with persistently positive cultures and an increased risk of mortality.
- #35 In sum, 248 individuals with human immunodeficiency virus (HIV)-associated cryptococcal meningitis, screened for the Cryptococcal Optimal ART Timing (COAT) trial in Uganda and South Africa, were observed. Individuals received an LP to diagnose meningitis, and subsequent therapeutic LPs were recommended for elevated ICP (&gt;250 mmH2O) or new symptoms. We compared survival, through 11 days, between individuals receiving at least 1 therapeutic LP with individuals not receiving therapeutic LPs.
- #36 not been sterilized after two weeks of combination therapy,
- #37 Amphotericin B —is associated with renal insufficiency, hypocalcemia, hypophosphatemia, and hypokalemia. Thus, patients treated with amphotericin B should have daily monitoring of serum creatinine and electrolytes. Many patients require significant amounts of potassium and/or magnesium supplementation during therapy and hydration with normal saline during amphotericin B infusions. Itraconazole is associated with significant gastrointestinal intolerance and pedal edema and requires drug monitoring due to significant differences in bioavailability from person to person.
- #39 Raised ICP should be considered an urgent medical issue requiring prompt intervention. Acute mortality from cryptococcal meningoencephalitis with underlying HIV infection ranges from 6 to 16 percent in resource-available environments [16,34,36-38].
- #41 64 patients with a first episode of HIV-associated CCM were randomised to initial treatment with: amphotericin B (0·7 mg/kg daily); amphotericin B plus flucytosine (100 mg/kg daily); amphotericin B plus fluconazole (400 mg daily); or triple therapy with amphotericin B, flucytosine, and fluconazole. Our primary endpoint was fungicidal activity, measured by the rate of reduction in CSF cryptococcal colony-forming units (CFU) from serial quantitative CSF cultures on days 3, 7, and 14 of treatment.
- #43 Fro Oxford academic
- #44 Six studies are included in the review. Five of the studies compared antifungal treatments and one study addressed lowering intracranial pressure. This study was stopped early due to excess adverse effects. policy makers and national departments of heath should consider procuring this drug for HIV treatment programmes.
- #45 policy makers and national departments of heath should consider procuring this drug for HIV treatment programmes.