IDCases · 2025
Финголимод, связанный с криптококковым менингитом у пациента с множественным склерозом: доклад о деле и обзор литературы.
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Nakagawa Hidenori, Takagi Akari, Mitsueda Takahiro, Shirano Michinori
Аннотация
У 65-летней женщины с множественным склерозом появились головные боли и судороги. Культура цереброспиновой жидкости (CSF) указывает на неоформаны криптококка. Анализ литературы по 20 случаям криптококкового менингита показал, что головная боль является наиболее распространенным первоначальным симптомом, и все случаи были положительными для сыворотки и/или криптококковых антигенов CSF.
Оригинал публикации
Fingolimod-associated cryptococcal meningitis in a patient with Multiple Sclerosis: A case report and literature review.
A 65-year-old woman with Multiple Sclerosis treated with fingolimod developed headaches and convulsions. Cerebrospinal fluid (CSF) culture indicated Cryptococcus neoformans. A literature review of 20 cases of cryptococcal meningitis indicated that headache was the most common initial symptom, and all cases were positive for serum and/or CSF cryptococcal antigens.
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Introduction
Cryptococcus neoformans can cause potentially lethal disseminated infections including meningitis in both persons living with acquired immunodeficiency syndrome and in other immunosuppressed populations. The latest immunosuppressive therapies used to treat a wide range of autoimmune and inflammatory diseases may increase the risk of cryptococcal infections. We describe a woman with Multiple Sclerosis (MS) who developed cryptococcal meningitis. The patient was being treated with fingolimod, which inhibits lymphocyte migration from the lymph nodes and reduces peripheral blood lymphocyte count, a risk factor for cryptococcal infection.
Case presentation
We describe the case of a 65-year-old woman who experienced a 2-week course of gradually worsened unilateral headaches and anorexia. She presented to our hospital with an episode of loss of consciousness and newly onset convulsive seizure. Thirteen years prior, she presented with primary complaints of headaches and gait disturbances. She was diagnosed with relapsing/remitting MS based on brain magnetic resonance imaging (MRI), which initially revealed periventricular and juxtacortical T2 hyperintense lesions ( Fig. 1 ), followed by new right cerebral peduncle and left middle cerebellar peduncle lesions (3 months later). Oligoclonal bands were absent from the cerebrospinal fluid (CSF).
Brain MRI at the time of MS diagnosis (13 years ago), which revealed periventricular and juxtacortical T2 hyperintense lesions.
Twelve years ago, she started taking fingolimod as a disease-modifying treatment (DMT) for MS. Among the limited treatment options available at the time (i.e. interferon β-1a/1b and fingolimod), fingolimod was chosen over interferon β because a) she had a history of depression, for which interferon β is contraindicated due to possible exacerbation of depressive symptoms, and b) several factors including brain stem lesions and short interval between relapses suggested an active disease calling for higher efficacy therapy.
After the introduction of fingolimod, the patient has been clinically stable with mild disability at the Kurtzke Expanded Disability Status Scale (EDSS) score 1, without evidence of recurrence or progressive atrophy on brain MRI. Peripheral blood lymphocyte count remained at 400–600/µL, slightly below the reference range, a common side effect of fingolimod, but never below 200/µL, a criterion for discontinuing the drug. Because she was clinically stable, fingolimod was continued for 12 years without switching to other DMTs.
On examination upon this admission, she was afebrile. Laboratory tests revealed mild peripheral lymphopenia (520/uL). Head CT and brain MRI with and without gadolinium contrast enhancement showed no new lesions nor meningeal enhancement ( Fig. 2 ). Seizure was refractory to levetiracetam and fosphenytoin. Progressive headache and refractory seizure suggested a possible central nervous system infection. A CSF examination performed two days after hospitalization revealed an opening pressure of 14 cm H 2 O, a cell count of 15/µL (80 % mononuclear cells), 52 mg/dL protein, and 62 mg/dL glucose (174 mg/dL blood glucose).
Brain MRI on this admission, with no new lesions.
The CSF was positive for cryptococcal antigen (1:1024). Multiplex polymerase chain reaction (BioFire® FilmArray® Meningitis/Encephalitis Panel) was positive for Cryptococcus ; it was finally identified as C. neoformans using CSF culture. CSF myelin basic protein levels were marginally elevated at 111.5 pg/mL (reference: < 102 pg/mL); however, the IgG index remained within normal limits at 0.672 (reference: < 0.73). Adenosine deaminase (ADA) levels were within the normal range at 4.2 IU/L, and both Treponema pallidum antibody and oligoclonal bands were negative. Blood was also positive for cryptococcal antigen (1:1024); however, blood cultures were negative. Cryptococcal meningitis was diagnosed. Induction therapy with liposomal amphotericin B (5 mg/kg intravenously once daily) and flucytosine (25 mg/kg orally, four times a day) was started on hospital day 2. Her headaches subsided within a few days.
On hospital day 5, antiseizure medications were switched from intravenous to oral drugs, comprising levetiracetam, lacosamide and clobazam, and no recurrence of seizure was observed.
Four days after treatment initiation, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations increased to 158 U/L (reference range, 8–38) and 364 U/L (reference range, 4–44), respectively, and drug-induced liver injury was suspected. Considering the importance of treating cryptococcal meningitis, liposomal amphotericin B was continued as a key drug. Flucytosine and the antiepileptic drug, clobazam, which was more likely to cause liver dysfunction than levetiracetam and lacosamide (which were administered simultaneously), were discontinued. The AST and ALT concentrations gradually improved to 25 U/L and 42 U/L, respectively, over the 2 weeks after drug discontinuation. A follow-up CSF examination was performed 1 week and 2 weeks after treatment. C. neoformans was still positive in the first follow-up CSF culture; however, the CSF culture was negative 2 weeks after treatment. In general, fluconazole is proposed to add to liposomal amphotericin B as the induction treatment for cryptococcal meningitis in the absence of flucytosine. However, concerns arose regarding the addition of a new drug in the presence of liver dysfunction; therefore, we decided to continue treatment with liposomal amphotericin B alone.
Liposomal amphotericin B was continued for 4 weeks after a negative CSF culture (a total of 6 weeks; liver function improved in this time), followed by fluconazole (400 mg orally once daily) for 8 weeks as consolidation therapy, and fluconazole (200 mg orally once daily) for 1 year as maintenance therapy. She was treated for seizures with intravenous levetiracetam and fosphenytoin immediately after hospitalization, and after 5 days, treatment was switched to oral levetiracetam and lacosamide (oral clobazam was also started, but discontinued due to liver dysfunction, as described above). There was no recurrence of seizures. To treat MS, fingolimod was discontinued and replaced with an anti-CD20 monoclonal antibody, ofatumumab, because of its reliable efficacy and safety.
Discussion
Herein, we report the case of a 65-year-old woman who developed cryptococcal meningitis approximately 12 years after initiating fingolimod treatment for MS, which improved with antifungal treatment.
MS is an inflammatory-demyelinating disease of the central nervous system affecting 2.3 million people worldwide [1] . There is no curative treatment available for MS. Current therapeutic strategy aims at reducing the risk of relapses and disability progression.
Fingolimod (FTY720) is a sphingosine 1-phosphate (S1P) receptor modulator and oral DMT approved by the FDA in 2010 for the treatment of patients with relapsing–remitting MS. Fingolimod acts as an antagonist of S1P receptors on lymphocytes, inhibiting lymphocyte migration from the lymph nodes, and reducing peripheral blood lymphocyte counts. This suppresses the infiltration of autoreactive T cells into the central nervous system, which has an inhibitory effect on MS [2] .
The effects of fingolimod on MS have been well-evaluated. In a Phase III study of patients with relapsing–remitting MS, fingolimod was associated with substantially lower relapse rates and less disease progression on imaging than placebo [3] and interferon beta-1a (IFNβ-1a) [4] .
However, it has several adverse effects. Paradoxical worsening of MS disease activity can occur after discontinuation of fingolimod treatment at rates of 10–25 % [5] . A rapid reentry of lymphocytes into the CNS upon drug discontinuation is suggested as a possible mechanism of the "rebound" phenomenon. Fingolimod in patients with MS substantially increases the risk of infection, especially lower respiratory tract and herpes virus infections [6] . Opportunistic infections including progressive multifocal leukoencephalopathy and cryptococcal meningitis are considered rare adverse events with the use of fingolimod. C. neoformans infection, especially meningitis, is considered a rare adverse event of fingolimod treatment, with an estimated incidence of 8 per 100,000 patient-years (95 % confidence interval, 6.0–10.0) [7] . The exact mechanism of action of fingolimod and cryptococcal meningitis is unknown [7] . However, there are multiple case reports of fingolimod-associated cryptococcal meningitis in MS patients since 2015.
A literature review (as of 2024) revealed 19 case reports of cryptococcal meningitis in MS patients treated with fingolimod. Table 1 shows the clinical characteristics of the 20 patients, including this case [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] . Of the 20 patients, equal numbers of male and female cases were reported. The median patient age was 49 years (n = 19, range 21–67 years old), and the present case was the third-oldest. The median duration of fingolimod treatment was 5 years, and the present case developed cryptococcal meningitis after the longest period following the initiation of fingolimod treatment. The risk of cryptococcal meningitis tends to increase with the duration of fingolimod treatment; however, no definitive conclusions have been made [7] . Headache was the most common initial symptom in 85 % (17/20) of the patients; only 25 % (5/20) developed fever. Contrast-enhanced brain MRI indicated leptomeningeal enhancement in 47 % (9/19) of patients, consistent with cryptococcal meningitis, whereas 42 % (8/19) of patients had no new lesions (including the present case). The median serum lymphocyte and CD4-positive lymphocyte counts (at the time of cryptococcal meningitis diagnosis) both declined to 318/µL (n = 18, range 90–2390/µL) and 69/µL (n = 7, range 5–192/µL), respectively.
Table 1 Clinical features and parameters of published case reports of fingolimod-associated cryptococcal meningitis with Multiple Sclerosis. Table 1 Author Year Age Sex Duration of fingolimod use Initial symptoms MRI findings Serum lymphocyte (/µL) Serum CD4 (/µL) Serum CrAg (1: X) CSF CrAg (1: X) CSF opening pressure (cmH 2 O) CSF cell (/µL) CSF lymphocyte (or mononuclear cells) (/µL) CSF protein (mg/dL) CSF glucose (mg/dL) CSF culture treatment outcome reference Huang D 2015 50 Male 3y6m headache, somnolence, nausea, ataxia thalamic and corpus callosum lesion with mass effect, diffuse meningeal enhancement 500 ND 128 108 ND ND 308 217 23 positive liposomal amphotericin B + flucytosine (8w) -> fluconazole improved (8) Achtnichts L 2015 40s Male 2y headache, photophobia, lethargy multiple nonenhancing lesions 90 56 ND 2048 38 20 19 40 26.67 positive liposomal amphotericin B + flucytosine (2w) -> fluconazole improved (9) Ward MD 2016 67 Female 3y6m fever, dysarthria, diplopia, vomiting, confusion, cognitive changes multiple acute infarcts, intraparenchymal and sulcal contrast enhancement 2390 ND 40 positive ND ND 240 84 13 positive amphotericin B (4w) -> fluconazole dead (10) Grebenciucova E 2016 62 Male 3y headache, dizziness, confusion no change 336 ND ND positive ND 203 ND 117 48 positive liposomal amphotericin B + flucytosine (2w) -> fluconazole improved (11) Seto H 2016 63 Male 2y gaze palsy, facial paralysis, dysarthria, apraxia, muscle weakness, multiple cutaneous lesions no change 300 145 256 1024 16 74 67 323 ND negative liposomal amphotericin B + flucytosine (6w) -> fluconazole improved (12) Pham C 2017 61 Female 3y headache, neck pain, nausea, vertigo, weight loss leptomeningeal enhancement, fourth ventricle compression, cerebellar tonsillar herniation, obstructive hydrocephalus 120 5 positive positive ND ND ND ND ND ND liposomal amphotericin B + flucytosine (30d) -> fluconazole improved (13) Anene-Maidoh TI 2018 61 Female 4y10m headache, confusion, ataxia, seizure nd nd 69 positive positive 50 48 5 91 0 positive amphotericin B + flucytosine dead (14) Chong I 2019 40 Female 2y3m headache, generalized weakness, anorexia, hallucinations diffuse leptomeningeal enhancement 200 ND ND positive normal 22 8 142 7 positive amphotericin B + flucytosine (6w) improved (15) Kuruoglu T 2019 30 Male 5y headache, dysarthria ependymal surface hyperintensity, prepontine interpeduncular linear contrasts 620 192 ND ND ND 110 ND 114 4 positive liposomal amphotericin B + fluconazole (4w) -> fluconazole improved (16) Ma SB 2020 58 Male 7y headache, fever, confusion early cerebritis of bilateral parietal lobes, mild sulcal effacement, leptomeningeal enhancement 900 ND 2560 5120 29 62 62 101 40 positive amphotericin B + flucytosine (8w) -> fluconazole improved (17) Wienemann T 2020 49 Female 5y6m headache, fever, confusion, cough. generalized weakness no change 900 77 ND 160 normal 54 ND 146 normal positive liposomal amphotericin B+ fluconazole -> liposomal amphotericin B + flucytosine -> fluconazole improved (18) Baghbanian SM 2020 41 Female 5y headache, blurred vision, disorientation, meningeal signs, ataxia intraparenchymal right occipital enhancing lesion, leptomeningeal enhancement 250 ND ND positive 25 20 20 30 83 positive (india ink) amphotericin B + fluconazole (4w) improved (19) Kaur P 2020 34 Male 5y loss of consciousness, ataxia, generalized weakness, anorexia, nausea, vomiting no change nd 61 2560 ND 48 8 3 58.4 27 positive liposomal amphotericin B + flucytosine (4w) -> fluconazole improved (20) Cuascut FX 2021 48 Female 7y7m headache, nausea, emesis, photophobia, phonophobia, meningismus, confusion, diplopia, seizure leptomeningeal enhancement 210 ND ND 1024 55 99 6 76 15 positive amphotericin B + flucytosine -> fluconazole improved (21) Aoki R 2021 41 Male 6y headache, fever meningeal enhancement 177 ND 2048 256 ND 65 nd 123 27 positive liposomal amphotericin B + flucytosine (4w) -> fluconazole improved (22) Darazam IA 2022 39 Female 5y headache, fever, weakness, loss of consciousness no change 500 ND ND ND 32 20 ND normal normal positive liposomal amphotericin B + flucytosine (2w) -> fluconazole improved (23) Zhou DJ 2023 67 Male 6y headache, dysphasia, ataxia, confusion multiple parenchymal and leptomeningeal enhancement 100 ND ND 2560 40 71 50 80 20 positive ND ND (24) Nasir M 2023 21 Female 5y headache, photophobia, nausea, malaise no change 530 ND ND 100 33 < 5 ND 94 3 positive amphotericin B + flucytosine (2w) -> fluconazole improved (25) Singh R 2024 44 Male 8y headache, ataxia, confusion, photophobia, dysphasia leptomeningeal enhancement 250 ND ND ND ND 780 218 367 3 positive liposomal amphotericin B + flucytosine dead (26) Present Case 2024 65 Female 11y11m headache, anorexia, loss of consciousness, seizure no change 520 ND 1024 1024 14 15 12 52 62 positive liposomal amphotericin B + flucytosine (1w) -> liposomal amphotericin B (5w) -> fluconazole improved Abbreviations: CrAg; cryptococcal antigen, CSF; cerebrospinal fluid, ND; not done or not described.
Clinical features and parameters of published case reports of fingolimod-associated cryptococcal meningitis with Multiple Sclerosis.
Abbreviations: CrAg; cryptococcal antigen, CSF; cerebrospinal fluid, ND; not done or not described.
CSF findings include intracranial pressure greater than 25 cmH 2 O in 9 cases (median 33 cmH 2 O, range 25–55 cmH 2 O), whereas in the remaining 4 cases it was normal. CSF cells were only mildly elevated, with a median of 58/µL (n = 16). CSF protein concentration was elevated over 45 mg/dL in 16 out of 18 cases where specific values were given (median 97.5 mg/dL, range 30–367 mg/dL). CSF glucose concentration was reduced to median 21.5 mg/dL (n = 16). Cryptococcal antigen testing of serum or CSF was always positive if tested (n = 17). The fungal culture of CSF was positive for C. neoformans in all but one case. Most patients are treated with amphotericin B (liposomal or non-liposomal) and/or flucytosine as induction therapy, followed by fluconazole as consolidation and maintenance therapy. Although a minimal 2-week induction therapy for cryptococcal meningitis in non-HIV patients is recommended [27] , it has been reported that induction therapy for 6 weeks is associated with a lower risk of relapse when neurological complications (e.g., seizures) developed [28] , as in the present case. The recommended durations of consolidation and maintenance therapies are 8 weeks and 12 months, respectively [27] . The mortality rate was 16 % (3/19), which was the similar to or lower than in the previous studies on cryptococcosis-related mortality in various populations [29] .
Fingolimod-associated cryptococcal meningitis is a rare but potentially lethal infection if the diagnosis is delayed. Symptoms may be subtle and brain MRI may not show significant changes. A prompt diagnostic evaluation including lumber puncture is required; intracranial pressure is typically elevated. CNS lymphocyte elevation may be mild due to fingolimod. CNS fungal culture, which remains the standard method of diagnosis, is limited by prolonged time of organism growth. CSF cryptococcal antigen testing can be rapidly performed with high sensitivity and specificity. Treatment may take months to complete.
Consent
Written informed consent for publishing the case report was obtained from the patient.
Ethical approval
Written informed consent for publication was obtained from each participant, and ethical approval was waived.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Hidenori Nakagawa: Writing – original draft, Conceptualization. Michinori Shirano: Writing – review & editing, Supervision. Takahiro Mitsueda: Writing – review & editing. Akari Takagi: Writing – review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We would like to thank Editage ( www.editage.jp ) for English language editing.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
References
Associated Data
Data Availability Statement
All data generated or analyzed during this study are included in this published article.
Cryptococcus neoformans can cause potentially lethal disseminated infections including meningitis in both persons living with acquired immunodeficiency syndrome and in other immunosuppressed populations. The latest immunosuppressive therapies used to treat a wide range of autoimmune and inflammatory diseases may increase the risk of cryptococcal infections. We describe a woman with Multiple Sclerosis (MS) who developed cryptococcal meningitis. The patient was being treated with fingolimod, which inhibits lymphocyte migration from the lymph nodes and reduces peripheral blood lymphocyte count, a risk factor for cryptococcal infection.
Case presentation
We describe the case of a 65-year-old woman who experienced a 2-week course of gradually worsened unilateral headaches and anorexia. She presented to our hospital with an episode of loss of consciousness and newly onset convulsive seizure. Thirteen years prior, she presented with primary complaints of headaches and gait disturbances. She was diagnosed with relapsing/remitting MS based on brain magnetic resonance imaging (MRI), which initially revealed periventricular and juxtacortical T2 hyperintense lesions ( Fig. 1 ), followed by new right cerebral peduncle and left middle cerebellar peduncle lesions (3 months later). Oligoclonal bands were absent from the cerebrospinal fluid (CSF).
Brain MRI at the time of MS diagnosis (13 years ago), which revealed periventricular and juxtacortical T2 hyperintense lesions.
Twelve years ago, she started taking fingolimod as a disease-modifying treatment (DMT) for MS. Among the limited treatment options available at the time (i.e. interferon β-1a/1b and fingolimod), fingolimod was chosen over interferon β because a) she had a history of depression, for which interferon β is contraindicated due to possible exacerbation of depressive symptoms, and b) several factors including brain stem lesions and short interval between relapses suggested an active disease calling for higher efficacy therapy.
After the introduction of fingolimod, the patient has been clinically stable with mild disability at the Kurtzke Expanded Disability Status Scale (EDSS) score 1, without evidence of recurrence or progressive atrophy on brain MRI. Peripheral blood lymphocyte count remained at 400–600/µL, slightly below the reference range, a common side effect of fingolimod, but never below 200/µL, a criterion for discontinuing the drug. Because she was clinically stable, fingolimod was continued for 12 years without switching to other DMTs.
On examination upon this admission, she was afebrile. Laboratory tests revealed mild peripheral lymphopenia (520/uL). Head CT and brain MRI with and without gadolinium contrast enhancement showed no new lesions nor meningeal enhancement ( Fig. 2 ). Seizure was refractory to levetiracetam and fosphenytoin. Progressive headache and refractory seizure suggested a possible central nervous system infection. A CSF examination performed two days after hospitalization revealed an opening pressure of 14 cm H 2 O, a cell count of 15/µL (80 % mononuclear cells), 52 mg/dL protein, and 62 mg/dL glucose (174 mg/dL blood glucose).
Brain MRI on this admission, with no new lesions.
The CSF was positive for cryptococcal antigen (1:1024). Multiplex polymerase chain reaction (BioFire® FilmArray® Meningitis/Encephalitis Panel) was positive for Cryptococcus ; it was finally identified as C. neoformans using CSF culture. CSF myelin basic protein levels were marginally elevated at 111.5 pg/mL (reference: < 102 pg/mL); however, the IgG index remained within normal limits at 0.672 (reference: < 0.73). Adenosine deaminase (ADA) levels were within the normal range at 4.2 IU/L, and both Treponema pallidum antibody and oligoclonal bands were negative. Blood was also positive for cryptococcal antigen (1:1024); however, blood cultures were negative. Cryptococcal meningitis was diagnosed. Induction therapy with liposomal amphotericin B (5 mg/kg intravenously once daily) and flucytosine (25 mg/kg orally, four times a day) was started on hospital day 2. Her headaches subsided within a few days.
On hospital day 5, antiseizure medications were switched from intravenous to oral drugs, comprising levetiracetam, lacosamide and clobazam, and no recurrence of seizure was observed.
Four days after treatment initiation, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations increased to 158 U/L (reference range, 8–38) and 364 U/L (reference range, 4–44), respectively, and drug-induced liver injury was suspected. Considering the importance of treating cryptococcal meningitis, liposomal amphotericin B was continued as a key drug. Flucytosine and the antiepileptic drug, clobazam, which was more likely to cause liver dysfunction than levetiracetam and lacosamide (which were administered simultaneously), were discontinued. The AST and ALT concentrations gradually improved to 25 U/L and 42 U/L, respectively, over the 2 weeks after drug discontinuation. A follow-up CSF examination was performed 1 week and 2 weeks after treatment. C. neoformans was still positive in the first follow-up CSF culture; however, the CSF culture was negative 2 weeks after treatment. In general, fluconazole is proposed to add to liposomal amphotericin B as the induction treatment for cryptococcal meningitis in the absence of flucytosine. However, concerns arose regarding the addition of a new drug in the presence of liver dysfunction; therefore, we decided to continue treatment with liposomal amphotericin B alone.
Liposomal amphotericin B was continued for 4 weeks after a negative CSF culture (a total of 6 weeks; liver function improved in this time), followed by fluconazole (400 mg orally once daily) for 8 weeks as consolidation therapy, and fluconazole (200 mg orally once daily) for 1 year as maintenance therapy. She was treated for seizures with intravenous levetiracetam and fosphenytoin immediately after hospitalization, and after 5 days, treatment was switched to oral levetiracetam and lacosamide (oral clobazam was also started, but discontinued due to liver dysfunction, as described above). There was no recurrence of seizures. To treat MS, fingolimod was discontinued and replaced with an anti-CD20 monoclonal antibody, ofatumumab, because of its reliable efficacy and safety.
Discussion
Herein, we report the case of a 65-year-old woman who developed cryptococcal meningitis approximately 12 years after initiating fingolimod treatment for MS, which improved with antifungal treatment.
MS is an inflammatory-demyelinating disease of the central nervous system affecting 2.3 million people worldwide [1] . There is no curative treatment available for MS. Current therapeutic strategy aims at reducing the risk of relapses and disability progression.
Fingolimod (FTY720) is a sphingosine 1-phosphate (S1P) receptor modulator and oral DMT approved by the FDA in 2010 for the treatment of patients with relapsing–remitting MS. Fingolimod acts as an antagonist of S1P receptors on lymphocytes, inhibiting lymphocyte migration from the lymph nodes, and reducing peripheral blood lymphocyte counts. This suppresses the infiltration of autoreactive T cells into the central nervous system, which has an inhibitory effect on MS [2] .
The effects of fingolimod on MS have been well-evaluated. In a Phase III study of patients with relapsing–remitting MS, fingolimod was associated with substantially lower relapse rates and less disease progression on imaging than placebo [3] and interferon beta-1a (IFNβ-1a) [4] .
However, it has several adverse effects. Paradoxical worsening of MS disease activity can occur after discontinuation of fingolimod treatment at rates of 10–25 % [5] . A rapid reentry of lymphocytes into the CNS upon drug discontinuation is suggested as a possible mechanism of the "rebound" phenomenon. Fingolimod in patients with MS substantially increases the risk of infection, especially lower respiratory tract and herpes virus infections [6] . Opportunistic infections including progressive multifocal leukoencephalopathy and cryptococcal meningitis are considered rare adverse events with the use of fingolimod. C. neoformans infection, especially meningitis, is considered a rare adverse event of fingolimod treatment, with an estimated incidence of 8 per 100,000 patient-years (95 % confidence interval, 6.0–10.0) [7] . The exact mechanism of action of fingolimod and cryptococcal meningitis is unknown [7] . However, there are multiple case reports of fingolimod-associated cryptococcal meningitis in MS patients since 2015.
A literature review (as of 2024) revealed 19 case reports of cryptococcal meningitis in MS patients treated with fingolimod. Table 1 shows the clinical characteristics of the 20 patients, including this case [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] . Of the 20 patients, equal numbers of male and female cases were reported. The median patient age was 49 years (n = 19, range 21–67 years old), and the present case was the third-oldest. The median duration of fingolimod treatment was 5 years, and the present case developed cryptococcal meningitis after the longest period following the initiation of fingolimod treatment. The risk of cryptococcal meningitis tends to increase with the duration of fingolimod treatment; however, no definitive conclusions have been made [7] . Headache was the most common initial symptom in 85 % (17/20) of the patients; only 25 % (5/20) developed fever. Contrast-enhanced brain MRI indicated leptomeningeal enhancement in 47 % (9/19) of patients, consistent with cryptococcal meningitis, whereas 42 % (8/19) of patients had no new lesions (including the present case). The median serum lymphocyte and CD4-positive lymphocyte counts (at the time of cryptococcal meningitis diagnosis) both declined to 318/µL (n = 18, range 90–2390/µL) and 69/µL (n = 7, range 5–192/µL), respectively.
Table 1 Clinical features and parameters of published case reports of fingolimod-associated cryptococcal meningitis with Multiple Sclerosis. Table 1 Author Year Age Sex Duration of fingolimod use Initial symptoms MRI findings Serum lymphocyte (/µL) Serum CD4 (/µL) Serum CrAg (1: X) CSF CrAg (1: X) CSF opening pressure (cmH 2 O) CSF cell (/µL) CSF lymphocyte (or mononuclear cells) (/µL) CSF protein (mg/dL) CSF glucose (mg/dL) CSF culture treatment outcome reference Huang D 2015 50 Male 3y6m headache, somnolence, nausea, ataxia thalamic and corpus callosum lesion with mass effect, diffuse meningeal enhancement 500 ND 128 108 ND ND 308 217 23 positive liposomal amphotericin B + flucytosine (8w) -> fluconazole improved (8) Achtnichts L 2015 40s Male 2y headache, photophobia, lethargy multiple nonenhancing lesions 90 56 ND 2048 38 20 19 40 26.67 positive liposomal amphotericin B + flucytosine (2w) -> fluconazole improved (9) Ward MD 2016 67 Female 3y6m fever, dysarthria, diplopia, vomiting, confusion, cognitive changes multiple acute infarcts, intraparenchymal and sulcal contrast enhancement 2390 ND 40 positive ND ND 240 84 13 positive amphotericin B (4w) -> fluconazole dead (10) Grebenciucova E 2016 62 Male 3y headache, dizziness, confusion no change 336 ND ND positive ND 203 ND 117 48 positive liposomal amphotericin B + flucytosine (2w) -> fluconazole improved (11) Seto H 2016 63 Male 2y gaze palsy, facial paralysis, dysarthria, apraxia, muscle weakness, multiple cutaneous lesions no change 300 145 256 1024 16 74 67 323 ND negative liposomal amphotericin B + flucytosine (6w) -> fluconazole improved (12) Pham C 2017 61 Female 3y headache, neck pain, nausea, vertigo, weight loss leptomeningeal enhancement, fourth ventricle compression, cerebellar tonsillar herniation, obstructive hydrocephalus 120 5 positive positive ND ND ND ND ND ND liposomal amphotericin B + flucytosine (30d) -> fluconazole improved (13) Anene-Maidoh TI 2018 61 Female 4y10m headache, confusion, ataxia, seizure nd nd 69 positive positive 50 48 5 91 0 positive amphotericin B + flucytosine dead (14) Chong I 2019 40 Female 2y3m headache, generalized weakness, anorexia, hallucinations diffuse leptomeningeal enhancement 200 ND ND positive normal 22 8 142 7 positive amphotericin B + flucytosine (6w) improved (15) Kuruoglu T 2019 30 Male 5y headache, dysarthria ependymal surface hyperintensity, prepontine interpeduncular linear contrasts 620 192 ND ND ND 110 ND 114 4 positive liposomal amphotericin B + fluconazole (4w) -> fluconazole improved (16) Ma SB 2020 58 Male 7y headache, fever, confusion early cerebritis of bilateral parietal lobes, mild sulcal effacement, leptomeningeal enhancement 900 ND 2560 5120 29 62 62 101 40 positive amphotericin B + flucytosine (8w) -> fluconazole improved (17) Wienemann T 2020 49 Female 5y6m headache, fever, confusion, cough. generalized weakness no change 900 77 ND 160 normal 54 ND 146 normal positive liposomal amphotericin B+ fluconazole -> liposomal amphotericin B + flucytosine -> fluconazole improved (18) Baghbanian SM 2020 41 Female 5y headache, blurred vision, disorientation, meningeal signs, ataxia intraparenchymal right occipital enhancing lesion, leptomeningeal enhancement 250 ND ND positive 25 20 20 30 83 positive (india ink) amphotericin B + fluconazole (4w) improved (19) Kaur P 2020 34 Male 5y loss of consciousness, ataxia, generalized weakness, anorexia, nausea, vomiting no change nd 61 2560 ND 48 8 3 58.4 27 positive liposomal amphotericin B + flucytosine (4w) -> fluconazole improved (20) Cuascut FX 2021 48 Female 7y7m headache, nausea, emesis, photophobia, phonophobia, meningismus, confusion, diplopia, seizure leptomeningeal enhancement 210 ND ND 1024 55 99 6 76 15 positive amphotericin B + flucytosine -> fluconazole improved (21) Aoki R 2021 41 Male 6y headache, fever meningeal enhancement 177 ND 2048 256 ND 65 nd 123 27 positive liposomal amphotericin B + flucytosine (4w) -> fluconazole improved (22) Darazam IA 2022 39 Female 5y headache, fever, weakness, loss of consciousness no change 500 ND ND ND 32 20 ND normal normal positive liposomal amphotericin B + flucytosine (2w) -> fluconazole improved (23) Zhou DJ 2023 67 Male 6y headache, dysphasia, ataxia, confusion multiple parenchymal and leptomeningeal enhancement 100 ND ND 2560 40 71 50 80 20 positive ND ND (24) Nasir M 2023 21 Female 5y headache, photophobia, nausea, malaise no change 530 ND ND 100 33 < 5 ND 94 3 positive amphotericin B + flucytosine (2w) -> fluconazole improved (25) Singh R 2024 44 Male 8y headache, ataxia, confusion, photophobia, dysphasia leptomeningeal enhancement 250 ND ND ND ND 780 218 367 3 positive liposomal amphotericin B + flucytosine dead (26) Present Case 2024 65 Female 11y11m headache, anorexia, loss of consciousness, seizure no change 520 ND 1024 1024 14 15 12 52 62 positive liposomal amphotericin B + flucytosine (1w) -> liposomal amphotericin B (5w) -> fluconazole improved Abbreviations: CrAg; cryptococcal antigen, CSF; cerebrospinal fluid, ND; not done or not described.
Clinical features and parameters of published case reports of fingolimod-associated cryptococcal meningitis with Multiple Sclerosis.
Abbreviations: CrAg; cryptococcal antigen, CSF; cerebrospinal fluid, ND; not done or not described.
CSF findings include intracranial pressure greater than 25 cmH 2 O in 9 cases (median 33 cmH 2 O, range 25–55 cmH 2 O), whereas in the remaining 4 cases it was normal. CSF cells were only mildly elevated, with a median of 58/µL (n = 16). CSF protein concentration was elevated over 45 mg/dL in 16 out of 18 cases where specific values were given (median 97.5 mg/dL, range 30–367 mg/dL). CSF glucose concentration was reduced to median 21.5 mg/dL (n = 16). Cryptococcal antigen testing of serum or CSF was always positive if tested (n = 17). The fungal culture of CSF was positive for C. neoformans in all but one case. Most patients are treated with amphotericin B (liposomal or non-liposomal) and/or flucytosine as induction therapy, followed by fluconazole as consolidation and maintenance therapy. Although a minimal 2-week induction therapy for cryptococcal meningitis in non-HIV patients is recommended [27] , it has been reported that induction therapy for 6 weeks is associated with a lower risk of relapse when neurological complications (e.g., seizures) developed [28] , as in the present case. The recommended durations of consolidation and maintenance therapies are 8 weeks and 12 months, respectively [27] . The mortality rate was 16 % (3/19), which was the similar to or lower than in the previous studies on cryptococcosis-related mortality in various populations [29] .
Fingolimod-associated cryptococcal meningitis is a rare but potentially lethal infection if the diagnosis is delayed. Symptoms may be subtle and brain MRI may not show significant changes. A prompt diagnostic evaluation including lumber puncture is required; intracranial pressure is typically elevated. CNS lymphocyte elevation may be mild due to fingolimod. CNS fungal culture, which remains the standard method of diagnosis, is limited by prolonged time of organism growth. CSF cryptococcal antigen testing can be rapidly performed with high sensitivity and specificity. Treatment may take months to complete.
Consent
Written informed consent for publishing the case report was obtained from the patient.
Ethical approval
Written informed consent for publication was obtained from each participant, and ethical approval was waived.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Hidenori Nakagawa: Writing – original draft, Conceptualization. Michinori Shirano: Writing – review & editing, Supervision. Takahiro Mitsueda: Writing – review & editing. Akari Takagi: Writing – review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We would like to thank Editage ( www.editage.jp ) for English language editing.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
References
Associated Data
Data Availability Statement
All data generated or analyzed during this study are included in this published article.