Severe hyponatremia masking cryptococcal meningitis in a fingolimod-treated patient: a case report

Introduction

Cryptococcal meningitis is a life-threatening fungal infection with a high mortality rate, particularly when diagnosis is delayed (1,2). In individuals without human immunodeficiency virus (HIV) infection, immunosuppressive medications are important risk factors for this condition (1). Fingolimod is a sphingosine-1-phosphate receptor modulator used for the treatment of multiple sclerosis, and accumulating evidence suggests a strong association between fingolimod therapy and cryptococcal meningitis (3).

Cryptococcal meningitis may present without classic meningeal signs, which may delay diagnosis (4). In addition, hyponatremia is a common complication of cryptococcal meningitis and may contribute to encephalopathy, potentially complicating the diagnostic process (5).

We report a case of cryptococcal meningitis in a patient receiving long-term fingolimod therapy who presented with progressive encephalopathy and severe hyponatremia. Early cerebrospinal fluid (CSF) evaluation and prompt antifungal therapy resulted in successful treatment. This case highlights the importance of considering cryptococcal meningitis in patients receiving fingolimod, even in the absence of fever or meningeal signs, and avoiding attribution of encephalopathy solely to hyponatremia. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0110/rc).

Case presentation

A 77-year-old man with a history of multiple sclerosis receiving fingolimod for 15 years presented with a four-week history of low-grade fever and progressive confusion and disorientation. At baseline, he was independently ambulatory with a walker. However, following symptom onset, he developed increasing weakness and drowsiness and became bedbound 3 days prior to presentation. According to his family, he had no complaints of headache or neck pain. He had no known direct animal exposure or pet ownership, although possible environmental exposure to pigeons was noted. On presentation, his temperature was 37.4 ℃, blood pressure 164/85 mmHg, and heart rate 80 beats per minute. Physical examination revealed a lethargic appearance with disorientation to place but no meningeal signs. Baseline right lower extremity weakness due to multiple sclerosis was present but unchanged from his usual status. Because of generalized fatigue, he was unable to ambulate. Laboratory evaluation demonstrated lymphopenia 103/µL (normal range, 1,000–4,800/µL) and severe hyponatremia 117 mmol/L (normal range, 135–145 mmol/L). Thyroid-stimulating hormone and random serum cortisol levels were within the normal range. Urinalysis showed a high urine sodium 93 mmol/L (normal range, <30 mmol/L) and urine osmolality 738 mOsm/kg (range, 50–1,200 mOsm/kg), and serum osmolality was 245 mOsm/kg (range, 275–295 mOsm/kg), consistent with hypotonic hyponatremia. Head computed tomography revealed no evidence of intracranial hemorrhage or space-occupying lesions. CSF analysis showed clear fluid with mild lymphocyte-predominant pleocytosis: white blood cell count 10/µL (normal range, 0–5/µL), 79% lymphocytes, and mildly elevated protein 71 mg/dL (normal range, 15–45 mg/dL). Opening pressure was normal at 10 cmH₂O (normal range, 10–20 cmH₂O). CSF smear demonstrated encapsulated round yeast-like organisms (Figure 1). CSF cryptococcal antigen and CSF polymerase chain reaction were positive, and both CSF and blood cultures grew Cryptococcus neoformans (Figure 2), consistent with disseminated cryptococcosis with cryptococcal meningitis. Chest radiography revealed no pulmonary nodules, cavitary lesions, or hilar lymphadenopathy suggestive of pulmonary cryptococcosis. Chest computed tomography (CT) was not performed in this case.

Figure 1 Gram stain of cerebrospinal fluid demonstrating encapsulated yeast forms (original magnification ×50).

Figure 2 Gram stain of blood culture demonstrating encapsulated yeast forms (original magnification ×50).

Given that his multiple sclerosis had been clinically stable, fingolimod was immediately discontinued, and induction antifungal therapy with liposomal amphotericin B and flucytosine was initiated. For hyponatremia, a continuous infusion of 3% hypertonic saline was administered with close monitoring. Serum sodium increased to 124 mmol/L on hospital day 1, and the patient’s level of consciousness began to improve accordingly. During the first 3 days of hospitalization, his altered mental status gradually returned to baseline. Therefore, further neuroimaging with brain MRI was not pursued. Follow-up CSF examinations on hospital days 7 and 14 showed normal opening pressure and normalization of the cell count and protein levels. After completing 14 days of induction therapy, antifungal treatment was transitioned to oral fluconazole. The patient did not develop any major treatment-related complications, including clinically significant acute kidney injury or liver enzyme abnormalities attributable to liposomal amphotericin B. No recurrent fever or worsening neurological findings occurred during hospitalization, and the patient recovered without sequelae.

At the neurology follow-up visit one month after discharge, his lower extremity weakness remained stable. Given the recent severe opportunistic central nervous system infection, fingolimod was permanently discontinued, and no alternative treatment for multiple sclerosis was initiated. He continues to be followed regularly in the neurology clinic.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

This case highlights two important learning points. First, even in the absence of meningeal signs or fever, early lumbar puncture should be considered to evaluate for cryptococcal meningitis in patients receiving long-term fingolimod therapy. Second, cryptococcal meningitis is more frequently associated with severe hyponatremia than other central nervous system infections, which may be incorrectly attributed as the primary cause of encephalopathy. Clinicians should therefore consider evaluating potential underlying cryptococcal meningitis in immunocompromised patients.

The mortality of cryptococcal meningitis remains high at 10–25% and is often attributed to diagnostic delays and therapeutic challenges (2). As most cases occur in immunosuppressed patients, presenting symptoms are often nonspecific with classic meningeal symptoms occurring in only one-quarter of patients, which can lead to diagnostic challenges (4). Fingolimod has recently been recognized as important risk factors for this condition (6). It is a sphingosine-1-phosphate receptor modulator that causes functional T-cell suppression through lymphocyte sequestration and may facilitate cryptococcal reactivation (7). Growing evidence suggests a strong association between fingolimod therapy and cryptococcal meningitis (8).

In our case, the patient presented with only low-grade fever and progressive confusion without meningeal signs. Although only a mild elevation in body temperature and the absence of classic meningeal symptoms could have increased the risk of missed diagnosis, careful history taking, including identification of long-term fingolimod therapy and the progression of altered mental status reported by the patient’s family, helped guide the diagnostic evaluation.

Hyponatremia is a common complication of central nervous system infections and is typically caused by syndrome of inappropriate antidiuretic hormone secretion or cerebral salt wasting syndrome (5). In cryptococcal meningitis, a particularly strong association with hyponatremia has been reported (9). An observational study reported that hyponatremia occurred in approximately 42% of patients with cryptococcal meningitis, and severe hyponatremia has been associated with poor clinical outcomes (9). In chronic severe hyponatremia, neurological manifestations such as confusion may occur in up to 30% of patients and frequently contribute to altered mental status (10).

In the present case, the patient developed progressive confusion, followed by further acute deterioration. These findings suggest that hyponatremia secondary to cryptococcal meningitis may have contributed to worsening the patient’s encephalopathy. In immunocompromised patients presenting with subacute encephalopathy and severe hyponatremia, clinicians should avoid attributing altered mental status solely to hyponatremia and should consider cerebrospinal fluid evaluation to assess for underlying cryptococcal meningitis, even in the absence of fever or meningeal signs.

Conclusions

In patients receiving fingolimod who present with altered mental status and severe hyponatremia, clinicians should maintain a high index of suspicion for cryptococcal meningitis and consider early cerebrospinal fluid evaluation.

Acknowledgments

The authors would like to express their sincere gratitude to Jaellen Flores, a laboratory scientist at Kuakini Medical Center, for her assistance in providing Gram stain images of blood culture and cerebrospinal fluid specimens.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0110/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0110/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0110/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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