An Approach to Cryptococcal Meningitis in the HIV + Patient

Dr Renusha Narismulu

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

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

LP Results

• Polys: 0• Lymphs: 5• Protein: 0.49• Glucose: 2.2mmol• India Ink +• CLAT +

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

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.

India Ink Stain

The Culprits

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

Differential in the HIV + patient with chronic meningitis

• TB• CNS lymphoma• Toxoplasmosis• Histoplasma capsulatum• Nocardia• Candida• Aspergillus sp

• Syphilis• HIV

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.

Radiology

• CT Scan• Contrast enhancement of meninges• MRI is more effective in diagnosing

cryptococcomas

Management

• Treating the infection• Managing symptoms related to raised

intracranial pressure• Prophylaxis

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

• 5-Flucytosine• Used in addition to Ampho B in fulminant

cases• S/E include bone marrow toxicity, DIH,

enterocolitis and diarrhoea

• Fluconazole• 400mg 8/52 ( 600mg to 800mg if patient on

TB treatment )• Inhibits demethylase enzyme• Good CSF penetration

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.

• 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 (50-100 mcg/mL). No IV formulation.

Treatment Related Toxicity

• Monitor for treatment related toxicity on bi-weekly schedule during the induction phase and weekly on consolidation phase.

• Amphotericin B: electrolyte imbalances, renal insufficiency, anaemia, acute infusion-related toxicity.

• Liposomal formulation less nephrotoxic (AmBisone)

• 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.

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.

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.

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 follow-up lumbar puncture at 2 weeks

• 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

• If elevated pressure persists

• Lumbar drain• Ventriculoperitoneal

shunt

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

ommaya reservoir.jpg

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.

Maintenance Therapy

• Fluconazole, 200–400 mg po lifelong• Itraconazole, 200 mg po bid lifelong

uncommonly used in place of fluconazolefor maintenance therapy. Multiple drug-drug interactions require caution when prescribing this medication.

• Amphotericin B, 1 mg/kg iv 1–3 times a week lifelong

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 >100-200 on HAART and have completed initial course of antifungal therapy.

• If after discontinuation of maintenance therapy, the CD4 falls to <100-200, reinitiate maintenance therapy .

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.

Antifungal Resistance Testing

• Should be limited to patients with multiple recurrences or disease in the setting of adherence to standard therapy.

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.

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.