Cryptogenic neuropsychiatric presentations diagnostic delay in Cryptococcus gattii meningoencephalitis at a regional Australian tertiary hospital

Clinical record

Case 1

A 70‐year‐old man was admitted for investigation of confusion, agitation and falls. His history included a mechanical aortic valve and post‐traumatic stress disorder. He was a retired paramedic and police officer. He had previously camped in a red‐gum forest on the Murray River. His wife reported 8 months of intermittent nausea, vomiting and headaches and 12 months of fluctuating memory impairment, confusion and paranoia. Investigation by his general practitioner and a geriatrician had not revealed a cause for a suspected early onset dementia. Investigation included thyroid function testing, vitamin B12, cortisol, syphilis serology, and brain magnetic resonance imaging (MRI). Computed tomography scan of the brain was normal. The initial working diagnosis was delirium due to urinary tract infection and hyponatraemia (129 mmol/L; reference interval [RI], 135–145 mmol/L). Psychotic symptoms and falls prompted neurology consultation. A lumbar puncture showed a low opening pressure at 4 cmH₂O (RI, 6–20 cmH₂O), cerebrospinal fluid pleocytosis (260 × 10⁶/L; RI, < 5 × 10⁶/L), and abnormal protein (> 2.5 g/L; RI, 0.15–0.45 g/L) and glucose levels (0.1 mmol/L; RI, 2.8–4.4 mmol/L). India ink staining was positive and cryptococcal antigen detected (titre, 1:2560). Cryptococcus gattii was cultured. Brain MRI showed no cryptococcomas. Chest x‐ray identified suspected right upper lobe pulmonary cryptococcosis, for which he is in radiological follow‐up with bronchoscopic biopsy being considered. An immunodeficiency workup, including full blood examination, T cell flow cytometry, and human immunodeficiency virus (HIV) serology, was unremarkable. He received induction therapy with liposomal amphotericin B and flucytosine for 5 weeks. He continues on oral fluconazole 800 mg daily for consolidation, with at least 12 months of eradication therapy planned. At discharge, his confusion, headache and psychotic symptoms had resolved.

Case 2

A 39‐year‐old man with a history of attention deficit/hyperactivity disorder (ADHD) was brought to hospital by police because of acute behavioural disturbance. A few days of fever and headache were noted (Box). Following resolution of pyrexia and headache and improvement in mental status, he was discharged with a provisional diagnosis of a psychotic episode. A lumbar puncture was not performed. One month later, the patient presented with ongoing headache and altered conscious state. He had been withdrawn and less responsive for one week, with reduced intake and new urinary incontinence. On admission he was hypertensive and hyponatraemic (129 mmol/L; RI, 135–145 mmol/L) (Box). Meningoencephalitis was considered unlikely in the absence of systemic symptoms or meningism. However, a lumbar puncture demonstrated intracranial hypertension and a cryptococcal antigen titre of 1:2560 (Box). Culture subsequently confirmed C. gattii. Liposomal amphotericin B and oral flucytosine were commenced. He was transferred to a neurosurgical centre for external ventricular drain and subsequently ventriculoperitoneal shunt placement. At the end of his 6‐week induction, inpatient rehabilitation was required for his high falls risk (impaired gait and impulsivity). Despite significant improvement to his mental state, his cryptococcal meningoencephalitis was complicated by an acquired brain injury, with deficits in higher level attention, memory, and flexible thinking. He was prescribed a minimum of 12 months of fluconazole therapy. As of late 2021, he is ambulant without a gait aid, is independent with personal and domestic activities of daily living, and is currently working up to 4 hours per week.

Discussion

Cryptococcal meningoencephalitis is an invasive fungal infection occurring especially in immunocompromised hosts. C. gattii, endemic to Australia, frequently causes meningoencephalitis in immunocompetent patients, and is associated with eucalypts but not birdlife, unlike the globally more common Cryptococcus neoformans.1 Cryptococcal meningoencephalitis is treated with a 2–6‐week induction phase of amphotericin B and flucytosine followed by prolonged fluconazole therapy (consolidation and eradication).2 Early diagnosis, via cerebrospinal fluid examination with cryptococcal antigen testing, is essential; diagnostic delay is associated with increased mortality3 and poorer neurological outcomes.4 The median time from onset to diagnosis is over one month,4,5 and diagnostic delay occurs more commonly with immunocompetent patients.6,7 Although classically presenting with subacute or chronic headache, anorexia and fever, presentations vary and fever is frequently absent.8 Psychiatric and neurological symptoms are common. Classical meningism is uncommon.9,10 Psychiatric presentations may include aggression, behavioural and personality change, visual hallucinations or insomnia.10 Cryptococcal meningoencephalitis may mimic decompensation of pre‐existing psychiatric illness.5,9 Neurological presentations may include altered conscious state, visual disturbance, hearing loss or impaired verbal expression.11 Common misdiagnoses include migraine, stroke and sinusitis.6 Mass lesions without fever can mimic malignancy.12 Altered mental status in cryptococcal meningoencephalitis can also be mistaken for stimulant drug use.9 These cases highlight the importance of lumbar puncture and consideration of cryptococcal disease in patients with unexplained subacute or chronic cognitive, neurological or psychiatric symptoms, even without fever. We believe there is a need for improved awareness in the medical community of cryptococcal meningoencephalitis and its clinical presentations.