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Observation
October 2015

Cryptococcal Meningoencephalitis in a Patient With Multiple Sclerosis Treated With Fingolimod

Author Affiliations
  • 1Department of Neurology, Cantonal Hospital of Aarau, Aarau, Switzerland
  • 2Department of Infectious Diseases, Cantonal Hospital of Aarau, Aarau, Switzerland
JAMA Neurol. 2015;72(10):1203-1205. doi:10.1001/jamaneurol.2015.1746

Fingolimod, the first oral drug approved for relapsing-remitting multiple sclerosis (MS), acts primarily by blocking the outlet of lymphocytes from the lymph nodes.1 Despite the resulting lymphocytopenia, the overall incidences of infections with fingolimod were similar to those in the control groups of the pivotal studies.2 Nevertheless, since the drug’s approval in 2010, few cases of serious infections have emerged under fingolimod treatment.3

To our knowledge, we report the first case of opportunistic cryptococcal meningoencephalitis ensued in an otherwise healthy patient with MS treated with fingolimod.

Report of a Case

A man in his 40s presented with throbbing bilateral, retro-orbital and temporal headache (numeric rating scale score, 7/10), photophobia, and lethargy lasting for 5 days. The patient had a 3-year history of relapsing-remitting MS and had been treated with fingolimod for 2 years. Neurological examination found no nuchal rigidity or focal neurological deficits. The patient was slightly dysarthric and lethargic but oriented. Laboratory test results displayed lymphocytopenia with a lymphocyte level of 400/uL (to convert to ×109 per liter, multiply by 0.001) compatible with continuous fingolimod treatment. The white blood cell count was 7200/µL (to convert to ×109 per liter, multiply by 0.001). Cerebrospinal fluid (CSF) findings were normal, except for mild hyperproteinorachia (Table). Brain computed tomography was unremarkable.

Table.  
CSF Findings on Repeated Examinations
CSF Findings on Repeated Examinations

Despite analgesic treatment, the headache worsened (numeric rating scale score, 10/10) over the following 2 days and was complicated by vomiting and fever. Multiple nonenhancing supratentorial and infratentorial white matter lesions were seen on magnetic resonance imaging (Figure, A). Escalation of pain medication resulted in headache relief on day 4, although analgesics discontinuation prompted a headache relapse with ataxic gait and disorientation on day 8. Repeated magnetic resonance imaging revealed new T2-weighted hyperintense supratentorial and infratentorial lesions without gadolinium enhancement (Figure, B). Lymphocytopenia worsened (lymphocyte level of 90/uL), with similar reductions of all lymphocyte subtypes (CD4, 56/uL; CD8, 24/uL; normal CD4:CD8 ratio) and no alterations in other leukocytes. Fingolimod was withdrawn. Cryptococcal meningoencephalitis was diagnosed based on antigen detection by latex agglutination in CSF and serum, as well as positive CSF culture (Table).

Figure.
Magnetic Resonance Imaging (MRI) Findings on Repeated Examinations
Magnetic Resonance Imaging (MRI) Findings on Repeated Examinations

A, On day 2, axial T2-weighted MRI shows multiple nonenhancing supratentorial and infratentorial (not shown) lesions (arrowheads). B, On day 8, new T2-weighted MRI lesions in the basal ganglia, again without gadolinium enhancement (arrowheads). Similar lesions were also identified in the pons and the mesencephalon (not shown). C, On day 28, gadolinium enhancement in the basal ganglia on T1-weighted MRI (arrowheads).

Because no therapeutic recommendations for the management of cryptococcosis in patients with MS exist, we followed the protocol for nonhuman immunodeficiency virus immunocompromised patients4: intravenous induction therapy with liposomal amphotericin B (4 mg/kg per day) plus flucytosine (100 mg/kg per day) for 2 weeks; oral consolidation with fluconazole, 400 mg, per day for at least 10 weeks; and oral maintenance with fluconazole, 200 mg, per day for at least 6 months. Elevated CSF pressure was managed by repetitive spinal taps. After 14 days of antifungal therapy, the patient was headache free. Cryptococcal antigen titer decreased, and the CSF culture result was negative (Table). However, slurred speech and cognitive deficits signaled clinical deterioration. Brain magnetic resonance imaging on day 28 identified breakdown of the blood-brain barrier in the basal ganglia (Figure, C). The condition was diagnosed as immune reconstitution inflammatory syndrome. No specific treatment was required. Moderate cognitive impairment persisted despite an intensive neurological rehabilitation program. An MS relapse occurred 9 months after fingolimod discontinuation and was treated with intravenous steroids. Shortly thereafter, therapy with glatiramer acetate was instituted. After normal cognitive assessment and negative cryptococcal antigen titers, fungal therapy was discontinued 13 months after initial presentation. Six months later (ie, 19 months after the cryptococcal meningoencephalitis), the patient was still symptom free.

Discussion

Opportunistic cryptococcosis is common among immunocompromised individuals with human immunodeficiency virus and leukemic or immunosuppressed transplant patients.5 We report here the first case, to our knowledge, of opportunistic cryptococcosis in an otherwise healthy patient with MS after 2 years of fingolimod treatment. Symptoms preceded pathological CSF findings by 1 week. In our patient, drug-induced lymphocytopenia and persisting headache were red flags that prompted a repeated spinal tap and testing for opportunistic infections. Discontinuation of fingolimod has led to immune reconstitution inflammatory syndrome. An antifungal treatment protocol for human immunodeficiency virus–negative immunocompromised patients has proven effective in this setting.

Our case report adds to the awareness of opportunistic infections with the novel MS drugs.

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Article Information

Corresponding Author: Lutz Achtnichts, MD, Department of Neurology, Cantonal Hospital of Aarau, Tellstrasse, 5001 Aarau, Switzerland (lutz.achtnichts@ksa.ch).

Conflict of Interest Disclosures: None reported.

Additional Contributions: We are mostly indebted to our patient who allowed us to publish his unique case. We are grateful to our colleagues in the Neurological Department of the Cantonal Hospital of Aarau and the Rehabilitation Clinics in Rheinfelden, Switzerland, who sensitively cared for the patient.

References
1.
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Francis  G, Kappos  L, O’Connor  P,  et al.  Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy. Mult Scler. 2014;20(4):471-480.
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Rosenstiel  PV, Gottschalk  R, Cappiello  L,  et al.  Long-term safety of fingolimod: interim evaluation of data from the longterms trial. Mult Scler Relat Disord. 2014;3(6):752.Article
4.
Perfect  JR, Dismukes  WE, Dromer  F,  et al.  Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(3):291-322.
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Sloan  DJ, Parris  V.  Cryptococcal meningitis: epidemiology and therapeutic options. Clin Epidemiol. 2014;6(6):169-182.
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