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

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

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): 480-482. Denning et al Am J Med, 1991, vol. 91:267-72

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.

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

Corticosteroids, mannitol & acetazolamide are not recommended for management of increased CSF pressure Beardsley et al., N Engl J Med 2016; 374:542-554

Association between therapeutic LP & acute mortality Only 1 LP [Diagnostic LP] Rolfes et al. Clin Infect Dis 2014; 58 (11); 1607-1614

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).

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.

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.

END