Abstract
Cryptococcal species are the most common fungal pathogens to cause meningitis worldwide. The majority of cases are caused by Cryptococcus neoformans and occur in immunocompromised hosts, while Cryptococcus gattii causes most fungal meningitis in immunocompetent hosts. To date, non-neoformans, non-gattii species of Cryptococcus remain rare causes of human disease, and their clinical courses and preferred treatment regimens remain poorly characterized. We present the case of an otherwise immunocompetent woman with subacute meningoencephalitis diagnosed with Papiliotrema laurentii (formerly Cryptococcus laurentii) meningitis, who, despite successful fungal eradication, developed hydrocephalus. To our knowledge, this represents the first case of P. laurentii meningitis in an immunocompetent host leading to hydrocephalus, illustrating the diagnostic and therapeutic challenges that remain for atypical fungal meningitis.
Keywords
Introduction
Cryptococcal meningitis affects more than 150 000 persons worldwide each year and is the most common cause of fungal meningitis. 1 Cryptococcus neoformans causes the majority of these cases and predominantly affects HIV-infected individuals. Serologic studies suggest up to 3% of HIV/AIDS patients to be infected. 2 Cryptococcus gattii is a less frequent cause of fungal meningitis, but often occurs in immunocompetent hosts. 3 Non-neoformans, non-gattii cryptococci were thought to be rare human pathogens until recently, when evidence emerged that such species can cause clinical disease in immunocompromised hosts. Papiliotrema laurentii has been shown to cause cutaneous disease, fungemia, central nervous system infection, and other infectious syndromes. 4 The first case of P. laurentii meningitis was reported in 1998, and to date, only 5 cases have been identified, 2 of which occurred in HIV-negative patients.5-10 To date, there have been no reported cases of communicating hydrocephalus caused by P. laurentii. We report a unique case of P. laurentii in an immunocompetent host, and what we believe to be the first reported case of hydrocephalus resulting from P. laurentii infection.
Case Presentation
A 57-year-old, non–HIV-infected female with a past medical history of well controlled hypertension, intermittent asthma not on medication, and stage 2 chronic kidney disease presented with gradual onset of progressive memory loss and gait instability over 3 months. On initial presentation, a computed tomography (CT) scan of her head was performed, which was unremarkable. Lumbar puncture revealed normal opening pressure; cerebrospinal fluid (CSF) analysis was significant for a leukocyte count of 105/mcL with a lymphocytic predominance (83%), a high protein of 193 mg/dL, a low glucose of 16 mg/dL, a positive cryptococcal antigen, and fungal culture performed by LabCorp grew P. laurentii. She was initially treated with liposomal amphotericin B and flucytosine for 2 weeks and was discharged on fluconazole maintenance therapy after resolution of her symptoms. Unfortunately, she was unable to adhere to therapy after discharge and her symptoms, including altered mental status, difficulty ambulating, falls, and urinary incontinence, recurred, at which point she returned for evaluation. Table 1 includes a detailed timeline of her second presentation.
Case Timeline of Second Hospitalization.
Clinical Findings
On this presentation, she was hypertensive to 163/126 mmHg and other vitals were within normal limits. On physical examination, she was alert and oriented to person and place but not to time or situation. Her neck was supple, without meningismus, and she had no rashes. Her gait was narrow-based and tentative. She demonstrated full strength in all extremities without sensory or cranial nerve deficits.
Diagnostic Assessment
CT of the head showed ventriculomegaly, suggesting acute hydrocephalus. A lumbar puncture yielded 18 mL of clear fluid, with an elevated opening pressure of 25.5 mmHg. CSF analysis was remarkable for elevated protein and low glucose, but normal white blood cell count (Table 2). A brain magnetic imaging (MRI) scan demonstrated ventriculomegaly and periventricular hyperintense signal on T2 flair, which was consistent with a diagnosis of acute hydrocephalus (Figure 1).
CSF Results [Normal Values].
(Herpes simplex virus [HSV]-1, HSV-2, human herpes virus 6, human parechovirus, Streptococcus spp., Escherichia coli, cytomegalovirus, varicella zoster virus, Epstein-Barr virus, Haemophilus influenzae, Neisseria meningitis, Listeria monocytogenase, C. neoformans/gattii).
MRI Brain demonstrating communicating hydrocephalus and periventricular T2 hyperintensities. Panel A: T2 Axial, Post-Gadolinium; Panel B: T1, Sagittal, Post-Gadolinium.
Therapeutic Intervention
She was started on fluconazole 400 mg daily to continue maintenance therapy. She underwent external ventricular drain (EVD) placement and was transferred to the Neurological Intensive Care Unit. A ventriculoperitoneal shunt (VPS) was subsequently placed for long-term management of her hydrocephalus. Her symptoms significantly improved after VPS placement. Given dramatic improvement in symptoms after VPS placement and bland CSF studies with negative culture and cryptococcal antigen, it was determined that hydrocephalus was the etiology for her symptom recurrence as opposed to relapse of P. laurentii infection. She was discharged on oral fluconazole 400 mg with close follow-up with neurosurgery and infectious disease in the outpatient setting.
Follow-Up and Outcomes
The patient followed up with neurosurgery in the clinic 1 month after discharge and with infectious disease at 2 and 3 months after discharge. She remained without neurological symptoms at these visits and reported improved appetite and energy levels. She was transitioned to oral fluconazole 200 mg at the 2-month visit and was given the choice of either continuing lifelong therapy or discontinuing therapy after 1 year followed by antigen monitoring every 3 months for another year.
Discussion
Hydrocephalus is a condition defined by the symptomatic accumulation of CSF. 11 Communicating hydrocephalus is caused by decreased reabsorption of CSF, which leads to CSF accumulation in the ventricular system and resultant enlargement of all the ventricles. 12 This is in contrast to non-communicating hydrocephalus, where obstruction of CSF flow leads to enlargement of the ventricles upstream and spares the ventricles downstream of the obstruction. 13 The patient in this vignette presented with urinary incontinence, dementia, and gait abnormality characteristic of hydrocephalus.12,14,15 The elevated opening pressure on lumbar puncture and her preceding infection make her clinical syndrome consistent with a post-infectious communicating hydrocephalus rather than normal pressure hydrocephalus. Neuroimaging and lumbar puncture are 2 modalities used to confirm the diagnosis of hydrocephalus. Characteristic MRI findings include ventriculomegaly with periventricular hyperintensities, which was observed in this case. Lumbar puncture can provide symptomatic relief and CSF studies can help elucidate an etiology.13,16,17
Cryptococcal meningitis, which usually occurs in immunocompromised patients, such as those living with HIV/AIDS, can lead to hydrocephalus as the fungal polysaccharide clogs the arachnoid villi and prevents CSF reabsorption. 17 Another possible mechanism of CSF outflow obstruction is reactive edema from the neural inflammatory response to cryptococcosis.17,18 In addition to hydrocephalus, intracranial hypertension and acute neurological deterioration also occur, and result in death if not treated rapidly. 17
Management of hydrocephalus is the mainstay of treatment of cryptococcal meningitis. This consists of CSF diversion, which can take the form of a VPS, EVD (both of which this patient received), or endoscopic third ventriculostomy. 17 In inoperable patients, treatment with acetazolamide and/or serial lumbar punctures may be pursued, however, these interventions are less efficacious.
To date, no cases of hydrocephalus due to P. laurentii have been reported. Therefore, the initial suspicion was that this case represented a relapse of the initial infection. However, repeat CSF analysis ruled out active infection and confirmed the diagnosis of communicating hydrocephalus.
It remains undetermined how this patient became infected with such a rare pathogen or why she suffered such a severe complication. This patient was HIV-negative, had no prior history of compromised immunity or immunodeficiency, and was not receiving any immunomodulatory drugs. Although the literature suggests that roughly 20% of cryptococcal meningitis cases occur in HIV-negative patients, most of those patients had an underlying immune-related risk factor such as hematologic malignancy, Cushing syndrome, sarcoidosis, chronic renal failure, and a variety of rheumatologic disease. 19 Indeed, most cases of cryptococcal meningitis in immunocompetent individuals are caused by C. gattii,3,20,21 which may also infect immunocompromised individuals and is becoming more prevalent in North America and in parts of China.21,22 Furthermore, P. laurentii meningitis is exceedingly rare in immunocompetent hosts. Most documented cases of P. laurentii infections occur outside the nervous system, including cutaneous infections, endophthalmitis, and fungemia.23-28 We only found 1 reported case P. laurentii meningitis in an immunocompetent individual; in that case, occupational exposure to bird droppings was presumed to be the predisposing condition. 7 Our patient reported no such exposure.
While an exhaustive immunologic work-up was not pursued for this patient, she had no history of recurrent, severe, or atypical infections that would suggest an underlying immunodeficiency. One theory as to why she may have become infected and suffered such a severe disease course is offered by a 2013 article by Rosen et al 29 which suggests that anti-granulocyte-macrocyte colony stimulating factor (α-GM-CSF) antibodies may be implicated in the pathogenesis of cryptococcal meningitis in immunocompetent individuals. A follow-up study by Saijo et al 30 in 2014 demonstrated α-GM-CSF antibodies in immunocompetent cryptococcal meningitis patients who tested positive for C. gattii but not in those who tested positive for C. neoformans. This suggests that α-GM-CSF antibodies may be a risk factor for meningococcal meningitis caused by C. gattii but not C. neoformans and may explain the predilection for C. gattii infection in immunocompetent individuals. An association between α-GM-CSF antibodies and P. laurentii has not been established. However, it is plausible that a similar mechanism predisposing patients with positive α -GM-CSF antibodies to C. gatti may also exist for P. laurentii. α-GM-CSF testing is not approved by the US Food and Drug Administration and is available on an investigational basis only; testing was offered to our patient, but she declined, so her α-GM-CSF status is unknown.
Footnotes
Acknowledgements
The authors thank Dr Francois Rollins, Dr Yosef Dastagirzada, Shawn Lockhart, and Mary Ann Kirkconnell Hall for their help with this work.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval
Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent
Verbal informed consent was obtained from the patient(s) for their anonymized information to be published in this article.
