Cryptococcal Meningitis With Acute Psychotic Confusion in a Sarcoid Patient

Sir: Cryptococcosis is a systemic fungal disease, usually caused by Cryptococcus neoformans, often transmitted by inhalation of dust or contaminated soil. The diagnosis of cryptococcal meningitis is difficult because of its various presentations. Non–HIV-contaminated patients may present brief mental confusion, coma, subacute or chronic meningitis, encephalitis, focal brain or spinal cord lesions, or mental changes.^1–3 Sarcoidosis is an idiopathic granulomatous illness. While any organ may be involved, 90% of patients develop pulmonary disease. Sarcoidosis is associated with deficient cell-mediated immunity, because of sequestration of CD4 cells in sarcoid granulomas, anergy, and reversal of the CD4/CD8 ratio.⁴ Concurrent cryptococcal disease in sarcoid patients is not rare, even in the absence of immunosuppressive therapy, and it may be misdiagnosed as neurosarcoidosis.

Case report

Mr. A, a single, 27-year-old unemployed man, was admitted to the Medical Emergency Department at University Hospital Centre of Angers in November 2004, for nonspecific behavior disorders, which had been gradually worsening over a period of more than 1 year, and included, over the previous 24 hours, complete mutism, prostration, and two episodes of vomiting.

Mr. A used to have a moderate consumption of cannabis but stopped it when he was diagnosed with sarcoidosis in May 2004 (microscopic lesions of lymphadenopathy were typical, containing noncaseating epithelioid cell granulomas). Tuberculosis and brucellosis had been excluded. Mr. A had not been treated with steroids. He exhibited progressive social and professional withdrawal and showed increasing negligence of his personal hygiene, evoking a diagnosis of early schizophrenia. Since September 2004, Mr. A had suffered with neck pain, episodes of generalized contractures in the limbs (which resolved spontaneously), and insomnia. On November 1, 2004, his psychotic-like behavior disorders had resulted in his first hospitalization in a psychiatry department, although no specific diagnosis was made. He remained in bed and continually complained of diffuse pain. He did not have any hallucinations or delusional ideas, but his affective contact was strange, and his answers poor and sometimes inappropriate. Medical (including neurologic) examinations and standard blood tests revealed no abnormalities, except for a blood C-reactive protein (CRP) level of 38 mg/dL, attributed to sarcoidosis. An emergency brain computed tomography (CT) scan found no abnormalities. Urinary screening for drugs was negative. Twenty-four hours after being admitted to the hospital, he became asymptomatic and was discharged.

When Mr. A was admitted a second time, on November 10, 2004, he had a fever of 38.7°C and confusion, with disorientation in time and space. His answers were short and poor. He was hyperactive, with a mood disorder, alternating rapidly between euphoria and apathy. He complained of abdominal pain and had a distended bladder. On examination, he was found to have binocular diplopia and meningeal signs. Blood tests showed hyponatremia (127 mmol/L) and an inflammatory syndrome, with increased white blood cells (20,000 cells/mL), a blood CRP level of 59 mg/mL, and a high level of angiotensin convertase (44 U/L). There was hypogammaglobulinemia (IgG of 645 ng/dL). A lumbar puncture was performed, following another brain CT scan, which showed clear cerebrospinal fluid (CSF), increased CSF protein (1.14 g/dL), low CSF glucose (< 0.1 mmol/L), and 70 nucleated cells (78% polynuclear neutrophils, 12% lymphocytes). A diagnosis of cryptococcal infection was confirmed by the presence of Cryptococcus neoformans on direct microscopy (staining with Chinese ink) and culturing. HIV-1 and -2 serologies were negative, despite the low CD4 lymphocyte count (228 cells/mL). The other serologies performed on the CSF specimen (herpes simplex virus, chicken pox/herpes zoster virus, cytomegalovirus, and Epstein-Barr virus) were also negative. A brain magnetic resonance imaging (MRI) scan showed contrast being taken up in the meninges and signs of meningitis, but no dilatation of the ventricles or any abscess. This MRI scan allowed a diagnosis of neurosarcoidosis to be excluded. Immediate treatment was started with IV amphotericin B, which was very quickly effective, with a complete disappearance of the confusion, the mood disorder, the hyperactivity, and the behavior disorders. The treatment was continued by mouth for 4 months. The improvement continued throughout the regular follow-up, which lasted 1 year. His social reinsertion was shown by his quickly finding a job and friends.

We here report the case of a young adult with sarcoidosis who presented with fluctuating acute cryptococcal meningitis and psychotic confusion. He also presented with progressive social withdrawal over 1 year and nonspecific behavior disorders that were misinterpreted as the early phase of hebephrenic schizophrenia. A search of the literature for related case reports was conducted on MEDLINE, with cryptococcosis, psychosis, confusional meningitis, and sarcoidosis as keywords.

Sarcoidosis is considered an independent risk factor for cryptococcal infection due to the immunosuppression generally associated with it.^4,5 The most frequent manifestations of cryptococcosis in sarcoid patients are fever (69%), headache (54%), meningismus (54%), nausea and vomiting (31%), anorexia (23%), and decreased level of consciousness (23%).⁶ The principal differential diagnosis is neurosarcoidosis with overlapping clinical and laboratory features. However, cranial nerve palsies (especially of the facial and optic nerves) are more common in neurosarcoidosis (72%) than in cryptococcal meningitis (11%). Neurosarcoid patients less frequently present with signs suggesting infectious meningitis: only 12% have meningismus, 19% fever, and 24% headache. The CSF profile is similar in neurosarcoidosis and cryptococcal meningitis, but hypogly-corrhachia is much more common in cryptococcal meningitis.^6,7

Cryptococcal meningitis with confusional psychosis before meningeal signs are present is rare in non–HIV-infected patients⁸ and usually mimics mood disorders (hypomania).^9,10 This type of pseudopsychiatric history may be due to meningeal cryptococcosis with normal pressure hydrocephalus.¹¹ Laboratory investigation of the CSF, such as an Indian ink smear and fungal cultures, to detect the infective organism, and the latex agglutination test to detect the streptococcal antigen, are invaluable aids for making the correct diagnosis.¹² The test of choice for the diagnosis in HIV-negative patients is CSF cryptococcal antigen titer, which is positive in 97% of cases. Eighty-seven percent of HIV-negative patients with cryptococcal meningitis also have a positive serum cryptococcal antigen.⁴ For our patient, both acute meningitis and chronic social isolation were successfully treated with specific antifungal treatment. During the 1-year follow up, we noted a sustained improvement of all his mental functions.

This case underlines the necessity of making a careful search for subtle systemic and neurologic signs, in order to exclude organic brain syndromes, before embarking on psychiatric treatment for apparent psychosis. In particular, cryptococcal meningitis in sarcoid patients should be excluded before neurologic disturbances by obtaining CSF samples, even when MRI findings suggest neurosarcoidosis.^4,13