Cryptococcus may present with several different clinical patterns. Often, the infection is subclinical. It appears that exposure to C neoformans and subsequent sensitization without the appearance of clinical illness is not uncommon. Organs that may be sites of clinically apparent infection most commonly include the lung, CNS, skin, bone, and prostate, but others may be affected as well. Simultaneous dissemination to multiple sites may be observed. For instance, AIDS patients with overwhelming immunosuppression and cryptococcal meningitis have been described with skin lesions due to C neoformans (Manfredi et al 1996). Some of these lesions may mimic molluscum contagiosum (Manfredi et al 1996). Cryptococcal meningitis is estimated to account for 40% to 86% of the estimated cases of symptomatic cryptococcal infection. The frequency of disseminated infection in the setting of cryptococcal meningitis is highlighted by the occurrence of abnormal chest radiograph opacities compatible with cryptococcal lung infections in 25% of patients with cryptococcal meningitis (Hay et al 1980) and by the relatively high frequency with which the organism can be isolated from blood.
Cryptococcal meningitis generally progresses slowly; it is seldom explosive in onset. Patients with cryptococcal meningitis most commonly complain of headache, usually frontal or temporal in location. Headache is not invariable and the combination of headache and fever occur together in only 67% to 82% of some large series of AIDS patients with cryptococcal meningitis. However, a recent study of nearly 300 HIV-infected persons with cryptococcal meningitis found that headache occurred in 99% (Day et al 2013). Neck stiffness was observed in approximately 70%. Mental status changes and alterations of level of consciousness are frequent. Nausea or emesis is present in about 45% of cases, whereas photophobia and features of meningeal irritation are remarkably uncommon for meningitis in general, occurring in less than a third of cases. Seizures occur in 4% to 18%, and cognitive impairment or alterations in sensorium occur in 17% to 24%. Episodes of transient loss of consciousness may be the heralding symptom (Wilbur and Heyborne 2009). Cranial neuropathies are seen in up to 15%. Focal neurologic deficits occur in 5% to 15% of cases. Dizziness, cerebellar ataxia, and syncope have also been noted as presenting features (Kovacs et al 1985; Zuger et al 1986; Chuck and Sande 1989; Clark et al 1990; Rozenbaum and Goncalves 1994). Mesencephalic abscesses complicating cryptococcal meningitis have resulted in a clinical presentation mimicking Parkinson disease (Bouffard 2003).
Visual symptoms may occur in up to 21% of cases and neuro-ophthalmic findings in up to 33% (Jabs et al 1989; Rozenbaum and Goncalves 1994). Impaired visual acuity may be the presenting manifestation in some patients (Okun and Butler 1964). Visual symptoms may include transient, abrupt, or progressive loss of visual acuity in 1 or both eyes due to increased intracranial pressure (Denning et al 1991), necrotizing optic neuropathy from cryptococcal infiltration (Ofner and Baker 1987; Cohen and Glasgow 1993), or compression of the optic nerve with vascular compromise (Lipson et al 1989). Diplopia may be intermittent or persistent and may be associated with cranial neuropathies, skew deviation, internuclear ophthalmoplegia, and nystagmus (Friedman 1991; Keane 1991; 1993; Fay and Strominger 1999; Sadun et al 1999). Papilledema occurs in 1.5% to 12% of cases (Jabs et al 1989; Rozenbaum and Goncalves 1994). Visual field deficits may be homonymous, bitemporal, or altitudinal (Friedman 1991; Golinki et al 1991; Garrity et al 1993). Visual symptoms may be the first indication of recurrent cryptococcal meningitis in AIDS patients on maintenance antibiotic therapy (Golnik et al 1991).
Psychiatric symptoms may also be presenting features of cryptococcal meningitis. Psychosis (Clark et al 1990) and behavioral changes (Saag et al 1992) have been noted. Mania as an isolated presenting symptom has been described in 2 patients, one of whom responded to successful therapy of his meningitis with complete resolution of the manic syndrome (Johannessen and Wilson 1988). In some cases, no signs of neurologic disease are present and diagnosis results from evaluation of systemic symptoms (Zuger et al 1986; Rozenbaum and Goncalves 1994).
Analogous to the immune reconstitution inflammatory syndrome (IRIS) that occurs following the administration of highly active antiretroviral therapy in HIV-infected patients with tuberculosis and progressive multifocal leukoencephalopathy, a similar disorder may be observed in cryptococcal infection (Jenny-Avital and Abadi 2002). IRIS typically occurs within 3 months of the initiation of highly active antiretroviral therapy (Broom 2006). IRIS takes 2 forms, “paradoxical” cryptococcal IRIS is a worsening of symptoms that occurs in individuals with established disease, and “unmasking” cryptococcal IRIS is the unexpected development of de novo cryptococcal meningitis following the initiation of antiretroviral therapy (Nunnari et al 2013). Distinguishing IRIS from recurrent disease may be difficult (Nunnari et al 2013). In one review of the disorder, 13% of 101 AIDS patients with cryptococcal meningitis receiving HAART developed IRIS (Sungkanuparph et al 2009); an increased baseline serum cryptococcal antigen was a risk factor. In another review, the median CD4 count at the time of diagnosis of cryptococcal meningitis was 25 cell/ml and at the time of IRIS 197 cells/ml (Skiest et al 2005). The underlying illness, eg, cryptococcal meningitis, may be inapparent until brought to light by the restoration of an effective immune response (Broom 2006). The development of increased intracranial pressure in HIV-infected patients being treated for cryptococcal meningitis may be the consequence of IRIS (Jenny-Avital and Abadi 2002; York 2005).