Fulminant cryptococcal meningoencephalitis with adrenal involvement in an immunocompetent patient: a clinicopathologic correlation

Abstract

Cryptococcus meningoencephalitis (CM) is the most frequently encountered manifestation of cryptococcosis. We report the case of a previously healthy, human immunodeficiency virus (HIV)-negative 65-year-old man who presented with 3 days of severe holocranial headache followed by sudden psychomotor agitation, confusion, and disorganized speech, without improvement after midazolam, requiring endotracheal intubation. Initial neuroimaging suggested inactive neurocysticercosis. Early cerebrospinal fluid (CSF) analysis showed lymphocytic pleocytosis with negative India ink but positive cryptococcal antigen (latex agglutination), and subsequent testing confirmed Cryptococcus neoformans . The patient received fluconazole and amphotericin B and underwent therapeutic lumbar punctures for intracranial pressure control, with opening pressures decreasing from 25 to 13 cmH ₂ O and transient clinical improvement. Despite this response, he experienced sudden deterioration and died. Autopsy revealed diffuse cerebral edema and granulomatous adrenal involvement. This case illustrates the potential fulminant course of cryptococcal meningoencephalitis in immunocompetent individuals and reinforces the importance of early recognition and aggressive intracranial pressure management.

CLINICAL VIGNETTE

A 65-year-old previously healthy, human immunodeficiency virus (HIV)-negative male presented with 3 days of severe holocranial headache unresponsive to analgesics, progressing to agitation and confusion. He received midazolam without improvement, required intubation, and was transferred to our service. On admission, he was hemodynamically stable but deeply comatose (RASS -5), non-responsive, mechanically ventilated, with absent brainstem reflexes, no motor response to pain, and globally depressed reflexes.

Initial laboratory work-up showed preserved renal and hepatic function (Cr 0.67 mg/dL, ALT 14 U/L, AST 12 U/L, bilirubin 1.56 mg/dL, INR 1.12), normal electrolytes—including sodium (137 mEq/L)—, normal inflammatory markers (CRP 0.48 mg/L), and a complete blood count without cytopenias (Hb 12 g/dL, leukocytes 13,950/µL, platelets 240,000/µL). There was no history of diabetes mellitus, alcohol use, chronic kidney disease, chronic liver disease, malignancy, autoimmune disease, or prior use of corticosteroids or other immunosuppressive therapies. Serologies for HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) were repeatedly negative. Head computed tomography (CT) showed two punctate calcifications compatible with inactive neurocysticercosis, without hydrocephalus or mass effect ( Figure 1 ). Brain magnetic resonance imaging (MRI) could not be performed due to the need for sedation and limited availability of anesthesiology.

Figure 1.

Computed tomography image showing nodular calcifications in the right superior frontal gyrus and in the left thalamus.

On the day after admission, the first lumbar puncture revealed lymphocytic pleocytosis (298 cells/mm ³ ; 91% lymphocytes), mildly elevated protein (53 mg/dL), low glucose (cerebrospinal fluid [CSF]-to-serum ratio 0.34), negative India ink staining, and positive cryptococcal antigen (latex agglutination). Opening pressure was not measured during the initial lumbar puncture, despite being a standard component of CSF evaluation. This omission, along with the lack of fundoscopy, limited early recognition of ICH and may have delayed optimal management.

On the 2nd day after admission, a repeat lumbar puncture confirmed cryptococcal infection with positive India ink staining, positive cryptococcal antigen, and culture growing Cryptococcus neoformans , establishing the diagnosis.

Antifungal therapy began on the 3rd day after admission with oral fluconazole (800 mg/day) and amphotericin B deoxycholate at a dose of 0.8 mg/kg/day, administered for 1 day due to limited availability. Therapy was switched to liposomal amphotericin B at a dose of 3 mg/kg/day the following day. Therapeutic lumbar punctures were performed on the 3rd and 4th days after admission; however, opening pressures were not measured. Another lumbar puncture on the fifth day showed an opening pressure of 25 cm H ₂ O, reduced to 15 cm H ₂ O after CSF drainage. He improved clinically and was extubated later that day. After extubation, he reported intermittent headaches over the year preceding the major episode, initially responsive to analgesics. However, it remains uncertain whether symptoms truly began 3 days before admission or represented exacerbation of a preexisting condition. On the following day, lumbar puncture showed an opening pressure of 13 cm H ₂ O

The patient remained clinically stable. No metabolic or systemic cause for deterioration was identified (no laboratory evidence of sepsis, hepatic or renal failure, coagulopathy, or metabolic derangement; serum sodium 145 mEq/L). He was transferred to the ward, but during the following night he was found in agonal breathing and pulseless and died despite resuscitation having been attempted.

Autopsy revealed diffuse cerebral edema without herniation, multifocal granulomatous meningitis, and necrotizing adrenalitis containing C. neoformans , consistent with severe CM complicated by ICH and adrenal involvement ( Figures 2 and 3 ). Table 1 presents the chronological history of clinical presentation, diagnostic findings, and interventions

Figure 2.

Typical aggregates of encapsulated Cryptococcus neoformans at adrenal glands highlighted by periodic acid-Schiff (PAS) staining.

Figure 3.

Typical aggregates of encapsulated Cryptococcus neoformans at the cerebral sulci highlighted by PAS staining.

Table 1. Chronological history of clinical presentation, diagnostic findings, and interventions.

Timeline	Clinical events and findings	Diagnostic data	Interventions/management
Three days before admission	Severe holocranial headache unresponsive to analgesics	–	–
Day of admission	Sudden psychomotor agitation, confusion, disorganized speech; no response to midazolam given externally; intubated before transfer; arrived sedated and ventilated	CT : two punctate calcifications suggestive of inactive neurocysticercosis; no hydrocephalus	Airway secured at outside facility
Day after admission	Clinically stable under sedation	LP #1: 298 cells/mm 3 (91% lymphocytes), protein 53, CSF-to-serum glucose ratio 0.34, India ink negative; positive cryptococcal antigen (latex agglutination) no opening pressure measured ; no culture obtained	Supportive care
Second day after admission	Clinically stable under sedation	LP #2: 2 cells/mm 3 , protein 119, elevated lactate, CSF-to-serum glucose ratio 0.30, India ink staining positive , positive cryptococcal antigen (latex agglutination), culture positive for Cryptococcus neoformans	Diagnosis confirmed
Third day after admission	Clinically stable under sedation	Labs: no renal/hepatic failure, no coagulopathy LP #3	Started oral fluconazole (800 mg/day) amphotericin B deoxycholate (0.8 mg/kg/day);
Fourth day after admission	Clinically stable under sedation	LP #4	Amphotericin B deoxycholate switched to liposomal amphotericin B (3 mg/kg/day)
Fifth day after admission	Improved responsiveness	LP #5: opening pressure 25 cmH 2 O → decreased to 15 cmH 2 O after drainage	ICP control; extubated later that day
Sixth day after admission	Awake; reported intermittent headaches over the previous year	LP #6: opening pressure 13 cmH 2 O	Continued antifungal therapy
Seventh day after admission	Clinically stable	Labs: sodium 145 mEq/L; no metabolic derangements	Supportive care
Following night (Seventh →Eighth day)	Found in agonal breathing, pulseless; death despite CPR		Resuscitation attempted
Postmortem		Autopsy: diffuse cerebral edema without herniation; multifocal granulomatous meningitis; necrotizing adrenalitis with Cryptococcus neoformans

Abbreviations: CPR, cardiopulmonary resuscitation; CSF, cerebrospinal fluid; CT, computed tomography; ICP, intracranial pressure; LP, lumbar puncture.

FROM PRESENTATION TO RESOLUTION: LESSONS LEARNED

What is the expected clinical presentation of CM?

Cryptococcal meningoencephalitis is a brain infection caused by C. neoformans (80% of cases) and Cryptococcus gattii (20% of cases). ^{1 2} Approximately 20% of infections occur in immunocompetent patients. ³ Both C. neoformans and C. gattii are encapsulated yeasts acquired via inhalation, with subsequent hematogenous dissemination and tropism for the central nervous system, and C. gattii more frequently affecting immunocompetent patients. ^{4 5}

The clinical presentation in immunocompetent individuals is variable. Most patients develop subacute meningoencephalitis with headache, lethargy, and behavioral or cognitive changes. Fever is present in ∼ 50% of cases. ⁶ Symptoms are typically subacute and may precede hospital admission by weeks to months, contributing to delayed diagnosis. In our case, although acute deterioration prompted hospital admission, the patient retrospectively reported intermittent headaches for up to 12 months prior, suggesting a prolonged subclinical course that may have contributed to delayed diagnosis. A retrospective cohort study demonstrated longer diagnostic delay in immunocompetent patients, with an average of 68 days from symptom onset to diagnosis, and a trend toward higher mortality. ⁷

What determines prognosis in CM across immune states?

Cryptococcal meningoencephalitis, although classically associated with immunosuppression, also affects immunocompetent individuals. In these patients, prognosis may be equally severe or worse, often related to delayed diagnosis and a higher inflammatory burden. Outcomes remain variable across immune states.

In our case, the patient was immunocompetent but infected with C. neoformans . Multicenter studies show that among HIV-negative patients, mortality reaches up to 27% at 90 days; in HIV-positive patients, global mortality rates range from 24 to 47% within 10 weeks. ^{8 9} Combination therapy with liposomal amphotericin B and flucytosine is associated with improved survival; however, flucytosine was unavailable in our institution, which may have contributed to the unfavorable outcome.

Overall, CM carries a guarded prognosis regardless of immune status. Initial neurological severity and early initiation of antifungal therapy remain the key determinants of outcome. Warning signs such as opening pressure above 25 cm H ₂ O and altered mental status are linked to higher mortality. ⁷ These features were present in our case. Adrenal involvement was identified at autopsy but likely represented a secondary factor rather than the primary mechanism of sudden deterioration; unfortunately, pre-mortem cortisol was not measured, which is a limitation.

Why can sudden death occur even after clinical improvement in immunocompetent CM?

Similar cases of sudden death after clinical improvement in immunocompetent patients with CM have been reported as presented in Table 2 . An Australian case described the unexpected death of a 22-year-old man, and a Nepali case reported the death of a 29-year-old woman. ^{1 10}

Table 2. Comparison of reported sudden deterioration in immunocompetent patients with cryptococcal meningitis.

Case/Study	Patient characteristics	Key clinical features	Diagnostic findings	Treatment	Outcome
Tu and Byard, 2021 1	Immunocompetent; 22-year-old male, previously healthy	Two-and-a-half-week generalized headache worsened by bending; vomiting began three days before admission; mild fever and neck stiffness, no focal deficit	Chest X-ray: right perihilar mass “toluroma”; LP: numerous C. neoformans .	Not mentioned	Sudden death after transient improvement
Regmi et al., 2023 10	Immunocompetent, 29-year-old female, no comorbidities; former smoker, occasional alcohol use.	Intermittent headaches with vomiting for 3 months, worsening over 20 days; fever unrecorded; no initial meningeal signs (no neck stiffness or Kernig's sign).	Head MRI showed a ring-enhancing lesion in the left lentiform nucleus with an eccentric nodule, initially suggestive of neurocysticercosis. CSF: < 5 cells, protein 50 mg/dL, glucose 30 mg/dL. India ink positive for C. neoformans ; CrAg positive. The opening pressure was 12 cm of H 2 O. Later opening pressure > 35 cm H 2 O.	Treatment included liposomal amphotericin B (3 mg/kg/day) and oral fluconazole (800 mg/day), as flucytosine was unavailable. CSF drained twice for ICP > 35 cm H 2 O.	Died on ICU day 7 after sudden deterioration; outcome contrasts with favorable prognosis reported in some immunocompetent cases
Ecevit et al., 2006 11	9 Immunocompetent adults treated at the University of Florida (1997–2005), highlighting poor prognosis and high morbidity in this population. Most (89%) were younger than 60 years	Headache was the most common initial symptom (89%), but never isolated. Other complaints included fever, weakness/anorexia, lethargy, and visual disturbances. Diagnosis was often delayed, with a median of 44 days from symptom onset.	Gadolinium-enhanced MRI was more sensitive than CT, showing leptomeningeal enhancement (100%), cerebral edema (89%), hydrocephalus (67%), and cerebral infarcts (44%). CSF often showed elevated opening pressure (> 15.5 cm H 2 O) and low glucose.	Standard treatment included amphotericin B and 5-flucytosine. ICP managed with repeated LPs, lumbar drains, or permanent shunts	Mortality 44%, cerebral infarcts had 100% mortality. All survivors had permanent sequelae (blindness, deafness, memory loss, severe depression). Three had paradoxical deterioration due to exaggerated immune response.
Oliveira et al, 2026	Immunocompetent; 65- year-old, HIV-negative	Acute neurological decline after 3-day headache; transient improvement after ICP control	CT suggestive of inactive neurocysticercosis; CSF India ink +; culture + for C. neoformans	Amphotericin B deoxycholate → liposomal amphotericin B; flucytosine unavailable; serial LPs	Sudden deterioration and death; autopsy with diffuse edema and adrenal involvement

Abbreviations: CPR, cardiopulmonary resuscitation; CSF, cerebrospinal fluid; CT, computed tomography; HIV, human immunodeficiency virus; ICP, intracranial pressure; ICU, intensive care unit; LP, lumbar puncture; MRI, magnetic resonance imaging.

A study from the University of Florida evaluated 9 immunocompetent patients with CM and found a mean time to diagnosis of 44 days from symptom onset. Most were initially misdiagnosed as having primary headaches. Mortality was 44%, and 3 patients worsened despite an initial response to therapy, with cerebral infarcts, increased cystic lesions, and diffuse cerebral edema. ¹¹

Sudden death in apparently immunocompetent patients with CM is largely driven by severe ICH and an exuberant inflammatory response, both often exacerbated by delayed diagnosis. ^{1 10}

What laboratory methods and neuroimaging findings support the diagnosis?

Laboratory diagnosis relies on microscopic, antigen-based, and culture methods. India ink staining has limited sensitivity and may yield false-negative results. Culture provides definitive species identification. Antigen detection tests, including latex agglutination and lateral flow assay, are the most sensitive methods. Limited access to these tools may delay diagnosis and worsen outcomes. In our institution, cryptococcal antigen titers were not available at presentation.

Neuroimaging findings vary according to disease stage and host immune response. Common abnormalities include hydrocephalus and signs of ICH. Additional findings, particularly on MRI, include dilation of perivascular spaces and leptomeningeal enhancement. Parenchymal involvement may manifest as pseudocysts or cryptococcomas, and cerebral infarcts may occur due to secondary vasculitis. ^{5 10} Calcifications, as observed in this patient, are not typical of cryptococcal infection and likely represent unrelated prior pathology.

What is the current recommended treatment?

The 2024 Global Guideline for the Diagnosis and Management of Cryptococcosis recommends:

• Induction: liposomal amphotericin B (3–4 mg/kg/day) plus flucytosine (100 mg/kg/day) for 2–6 weeks.

  • ○ Alternative: amphotericin B deoxycholate (0.7–1 mg/kg/day). if liposomal formulation unavailable.

  • ○ If flucytosine unavailable: fluconazole 800–1,200 for 2 weeks

• Consolidation: fluconazole 400–800 mg/day for 8 weeks.

• Maintenance: fluconazole 200 mg/day for 12 months.

Intracranial pressure control is critical and should be measured at initial lumbar puncture, and pressures ≥ 25 cm H ₂ O should be promptly managed with CSF drainage. ¹² Opening pressures were not measured initially in this case, which may have contributed to delayed recognition of ICH and poor outcome.

Funding Statement

Funding The authors declare that they did not receive funding from agencies in the public, private, or non-profit sectors to conduct the present study.

TEACHING POINTS.

1. Cryptococcal meningoencephalitis can affect immunocompetent individuals and often presents with severe neurological symptoms due to delayed diagnosis. Initial neurological severity is the strongest mortality predictor.

2. Clinical suspicion must remain high, particularly in the presence of signs of intracranial hypertension (ICH), a key prognostic factor that requires prompt recognition and management.

3. Cryptococcal antigen testing is the most sensitive diagnostic method; latex agglutination follows. India ink has limited sensitivity and false negatives. Culture provides definitive diagnosis.