An Approach to Cryptococcal Meningitis in the HIV + Patient. Dr Renusha Narismulu

Transcription

1 An Approach to Cryptococcal Meningitis in the HIV + Patient Dr Renusha Narismulu

2 Case Presentation 24 year old female P/C 2/12 history of intermittent headache PMH: RVD +, CD4 92, not on HAART PTB on tx for 4/12 PSH: nil Social: non contributory

3 Physical Examination Vitals normal Apyrexial T=36.8 C Some cervical adenopathy CNS: GCS 15/15, - FNS, - meningism Resp: clear CVS: BP 120/75, PR 72, no abnormalities Abd: SNT, -HSM, -ascites

4 LP Results Polys: 0 Lymphs: 5 Protein: 0.49 Glucose: 2.2mmol India Ink + CLAT +

5 Cryptococcal Meningitis Cryptococcus neoformans Weathered pigeon droppings ( serotypes B and C ) Eucalyptus tree debris ( serotypes A and D ) Inhalation of fungus Silent haematogenous spread to brain Dense basilar arachnoiditis Meningoencephalitis at presentation

6 Neuropathology Meningeal invasion by budding yeast forms Fulminant cases: invasion of brain parenchyma along Virchow Robin Spaces. Clusters of budding yeasts develop within the basal ganglia coalescing to form cryptococcomas.

7 India Ink Stain

8 The Culprits

9 Symptoms Headache, nausea, staggering gait, confusion, irritability,blurred vision, dementia NB: fever and nuchal rigidity often lacking Papilloedema 1/3 CN palsies asymmetrical in ¼ of cases Deepening coma Signs of brainstem compression

10 Differential in the HIV + patient with chronic meningitis TB CNS lymphoma Toxoplasmosis Histoplasma capsulatum Nocardia Candida Aspergillus sp

11 Syphilis HIV

12 Diagnosis LP Non AIDS related CCM : increased protein, pleocytocis, decreased sugar AIDS related CCM : normal CSF cell count and chemistry in up to 50% Opening pressure elevated in 2/3 of patients Cryptococcal antigen: highly sensitive and specific CLAT : high specificity, suitable for rapid diagnoses.

13 Radiology CT Scan Contrast enhancement of meninges MRI is more effective in diagnosing cryptococcomas

14 Management Treating the infection Managing symptoms related to raised intracranial pressure Prophylaxis

15 Treatment Amphotericin B for at least 2/52 IVI (0.7 1mg/kg/day) Has been given via intrathecal injection Parenteral polyene AB Binds to ergosterol ( a fungal membrane component ) S/E include chills, rigors, fever, pulmonary oedema, phlebitis, seizures and vomitting GFR decreased in 80 % of patients but this is usually reversible

16 5-Flucytosine Used in addition to Ampho B in fulminant cases S/E include bone marrow toxicity, DIH, enterocolitis and diarrhoea

17 Fluconazole 400mg 8/52 ( 600mg to 800mg if patient on TB treatment ) Inhibits demethylase enzyme Good CSF penetration

18 Drug Recommendations/Comments Amphotericin B Gold standard for initial therapy. Intrathecal amphotericin should only be used in cases refractory to standard IV amphotericin +/- flucytosine. Fluconazole Drug of choice for maintenance therapy.all azoles should be avoided during pregnancy. If a women has active cryptococcosis during pregnancy, consider a switch to IV amphotericin B.

19 Flucytosine Can be used in combination with amphotericin for initial therapy. This combination is favoured in severe cases characterized by increased ICP or change in mental status. Therapy should be monitored with peak levels drawn 2 hrs after oral dose ( mcg/ml). No IV formulation.

20 Treatment Related Toxicity Monitor for treatment related toxicity on biweekly schedule during the induction phase and weekly on consolidation phase. Amphotericin B: electrolyte imbalances, renal insufficiency, anaemia, acute infusionrelated toxicity. Liposomal formulation less nephrotoxic (AmBisone)

21 5-FC: severe colitis, leucopoenia, thrombocytopenia, rash, or hepatitis. Dosage should be reduced for cytopaenias or colitis and levels monitored to limit toxicity. Addition of 5-FC to Amphotericin B provides only marginal benefit at most. Azoles:liver toxicity.

22 Raised Intracranial Pressure Opening CSF pressure on LP > 20cm/H2O Normal opening CSF pressure 10cm/H20 NB LP must be done with patient lying on their side. Symptoms: headache, mental obtundation, Papilloedema, CN palsies.

23 Management of Raised ICP If ICP >25 cm/h20 and signs of cerebral oedema present, do daily LP to reduce pressure until patient is improved. If clinical signs of cerebral oedema do not improve after about 2 wks of daily LPs, consider placement of a lumbar drain or ventriculoperitoneal shunt. Patients with hydrocephalus may or may not have increased ICP and rarely have cerebral oedema.

24 Management of elevated intracranial pressure in HIV-infected patients with cryptococcaldisease Focal neurological signs or obtunded Normal opening pressure Radiographic imaging before lumbar puncture to identify mass lesions that may contraindicate lumbar puncture Initiate medical therapy, with followup lumbar puncture at 2 weeks

25 Opening pressure >25cmH2O Follow-up for elevated pressure Lumbar drainage sufficient to achieve closing pressure <20 cm H2O or 50% of initial opening pressure Repeated drainage daily until opening pressure is stable

26 If elevated pressure persists Lumbar drain Ventriculoperitoneal shunt

27 Invasive Management in Raised Intracranial Pressure Therapeutic lumbar puncture: maintain closing CSF pressure at approximately 10cm/H2O, can drain up to 20 millilitres CSF. Lumbar drain Ventriculoperitoneal Shunt Ommaya Reservoir

28 ommaya reservoir.jpg

29 The Role of Drugs in Raised Intracranial Pressure Acetazolamide : Carbonic Anhydrase Inhibitor, decreases rate of absorbtion of CSF from the choroid plexus. Corticosteroids : of benefit in marked cerebral oedema or imminent risk of herniation but may accelerate meningitis. Mannitol : not useful in the setting of cryptococcal meningitis The use of all of these agents remain controversial.

30 Maintenance Therapy Fluconazole, mg po lifelong Itraconazole, 200 mg po bid lifelong uncommonly used in place of fluconazole for maintenance therapy. Multiple drugdrug interactions require caution when prescribing this medication. Amphotericin B, 1 mg/kg iv 1 3 times a week lifelong

31 Discontinuation of maintenance therapy In the pre-haart era, risk of relapse was 4% in those on maintenance therapy but up to 37-60% in those who discontinued therapy. Patients should remain on maintenance therapy until they are asymptomatic, have had >6 months with CD4 > on HAART and have completed initial course of antifungal therapy. If after discontinuation of maintenance therapy, the CD4 falls to < , reinitiate maintenance therapy.

32 Immune Reconstitution Reactions Following initiation of HAART Enhanced but partially reconstituted pathogen-specific, cell-mediated immunity and induction of proinflammatory cytokines, leading to an exaggerated inflammatory reaction. Worsening meningitis with elevated ICP Lymphadenitis Sterile abscess Cavitation of pulmonary lesions.

33 Antifungal Resistance Testing Should be limited to patients with multiple recurrences or disease in the setting of adherence to standard therapy.

34 Whats New? Vaccine : working on a cryptococcal capsular polysaccharide vaccine US FDA currently conducting trials using the new drug Mycograb, human genetically recombinant antibody to fungal heat shock protein 90.

35 What can we do better? Low threshold for LP in the HIV positive patient presenting with headache. Ensuring treatment given correctly with regards to time frame and dosages. Being more aggressive in managing raised intracranial pressure.