1. Cryptococcosis: Management of Raised Intracranial Pressure
Prof. David W. Denning
The University of Manchester, UK

2. Intended Learning Outcomes
To understand the pathophysiology of raised intracranial pressures in cryptococcal meningitis
To be aware of the benefit of serial lumbar punctures in the management of raised ICP
To be aware of the deleterious effect of glucocorticoids in patients with cryptococcal meningitis

3. Increased intracranial pressure
Defined as CSF pressure (supine) >25cm H2O
Pathophysiology
Not completely understood
Hypotheses
Cytokine-induced inflammation
Increased vascular permeability
Cerebral oedema
Yeast clogging arachnoid villi
Impaired resorption of CSF
Raised mannitol in CSF, produced by C. neoformans
Cerebral oedema is not a significant component of cryptococcal meningo-encepahalitis. Mannitol levels are raised but nothing like as high as levels that are used in the treatment of raised ICP from other causes. The best analogy for raised ICP in CM is benign intracranial hypertension. This is treated with repeated lumbar punctures and occasionally shunting.
Pappas et al. Clin Infect Dis. 2005; 40 (3):
Denning et al Am J Med, 1991, vol. 91:267-72

4. Increased intracranial pressure
Intracranial pressure correlates with CSF fungal burden
Clumped yeast cells impairs CSF outflow
CSF production = 450 mL daily.
Volume of CSF is only 150 mL.
Intracranial hypertension is associated with increased morbidity and mortality
Faster resolution of ICP if combination Amphotericin B and 5FC used.
Loyse et al. AIDS. 2010; 24(3): 405–410.

5. Complications of raised ICP
Reduced consciousness - increasing risk from aspiration, low calorie and fluid intake
Early (and sometimes delayed) death
Visual loss (16-32%)
Due to persistent papilledema
? Direct invasion by Cryptococcus
Hearing loss (7-17%)
In addition to hearing and visual loss, vertigo and impaired thinking are also relatively common complications of CM, but not obviously attributable to raised ICP.
Bicanic & Harrison. British Medical Bulletin. 2004; 72 (1): 99–118
Okun & Butler. Arch Ophthalmol. 1964;71(1):52-57

6. Corticosteroids, mannitol & acetazolamide are not recommended for management of increased CSF pressure
Beardsley et al., N Engl J Med 2016; 374:

7. Association between therapeutic LP & acute mortality
Only 1 LP
[Diagnostic LP]
Rolfes et al. Clin Infect Dis 2014; 58 (11);

8. Management of raised ICP
Document closing pressure after first LP, if possible. If >25 cm H2O, the patient will definitively need a second therapeutic LP - next day if semi- conscious or worse.
Repeated lumbar punctures until CSF pressures and symptoms are stable for >2 days (i.e. CSF pressure <25cm H20). Use amphotericin B and 5FC if possible.
If after after 10 days of repeated LPs, the opening pressure is still >25cm H20, consider shunting.
Lumbar or ventricular-peritoneal shunt is required if obstructive hydrocephalus develops or if CSF pressure is still high (>25cm H20).

9. Shunts Lumbar shunt and drain Ventriculo-peritoneal shunt
A lumbar drain is inserted using aseptic conditions using the same approach as an LP, but with an epidural set. This is then connected to a sterile reservoir, and hung at the correct height next to the patient. The patient has to lie flat, until it is removed. It make be in for days and if it does not resolve raised ICP, a VP shunt is required.

10. Summary
Raised intracranial pressure in CM contributes to death and blindness after CM
As CSF drainage is blocked by yeast cells, mechanical drainage is required
Mortality is reduced with 2 or more lumbar punctures
Corticosteroid therapy is detrimental, and other medical strategies are ineffective.

11. END