A 63-year-old man with a history of MS was referred to our hospital for a detailed investigation of an erythematous nodular lesion with ulceration present on his left mandible. Three months prior to referral, he developed a papular lesion on his left lower jaw, low-grade fever, lethargy, and muscle weakness. The cutaneous lesion had gradually increased in size and eventually developed into an ulcer. One month prior to this referral, lower-extremity muscle weakness and cognitive impairment worsened and he could not read or write correctly. He was referred to our dermatology department for an investigation of the cutaneous lesion.
The case had a 30-year history of MS with poor responses to disease-modifying therapy, and two years prior to referral, treatment with fingolimod had been started. Nifedipine, valsartan, clopidogrel, aspirin, and atorvastatin had also been administered for hypertension and coronary heart disease in his past medical history. Since the start of fingolimod treatment, his lymphocyte counts were approximately 500 /muL. He denied any recent travel or close contact with birds.
On examination, he was not in acute distress, but his speech was slow and his accent was flat. He had no fever. He had a normal blood pressure (122/64 mmHg) and heart rate (60 bpm). His respiratory rate and oxygen saturation were 16 per minute and 99% in room air, respectively. There was an erythematous multilocular lesion with ulceration that measured 5x3 cm on his left mandible (Fig. 1). There was slight neck stiffness. Cardiovascular, pulmonary, and abdominal examinations were normal. A neurological examination revealed left lateral gaze palsy, left central facial paralysis, slight dysarthria, and limb-kinetic apraxia. His muscle strength and tendon reflex of the upper extremities were normal and his bilateral lower-extremity muscle strength was 2/5 (an inability to overcome gravity). Positive findings for Babinski's reflex and foot clonus were seen bilaterally. These neurological findings, except for lower-extremity muscle weakness, were the same as they had been before referral.
To investigate the cause of the skin lesion, a skin biopsy was performed. The histopathology of the skin biopsy revealed no malignant cells. However, many yeast-like organisms with thick capsules were observed in the skin specimens and periodic acid-Schiff and Grocott staining were positive for these organisms (Fig. 2). C. neoformans was isolated and identified from a tissue culture. Both a tissue culture and polymerase chain reaction for Mycobacterium tuberculosis were negative.
Computed tomography (CT) of the chest revealed multinodular lesions in the left lung. Both staining and a culture of his sputum showed no pathogen growth. Bronchoscopy for lung nodular lesions was not performed. Fluid attenuated inversion recovery images of brain magnetic resonance imaging (MRI) showed multiple hyperintense oval lesions in the white matter. The same oval lesions observed by brain MRI performed one year prior to this episode were present. Therefore, these lesions were most likely due to MS.
A cerebrospinal fluid (CSF) examination yielded elevated white blood cell numbers (74 /muL) and protein (323 mg/dL), and the titer of cryptococcal antigen by latex agglutination of CSF was 1:1,024. The opening pressure of a lumbar puncture was 16 cm H2O. Mononuclear and polynuclear white cells in the CSF were present at 90% and 10% of overall white blood cells, respectively. However, gram staining, India ink staining and a culture of CSF showed no bacterial or fungal pathogens.
Repeated blood cultures were all negative for bacterial and fungal pathogens. Laboratory investigations, including liver enzyme levels, renal function and electrolytes, were all within the normal limits, but the titer of serum cryptococcal antigen was 1:256. White blood cell counts were 5,000 /muL (neutrophils 82%, lymphocytes 6%, monocytes 8%). Absolute lymphocyte counts were 300 /muL (CD4+ lymphocytes 145 /muL, CD8+ lymphocytes 113 /muL). Antigen and antibody tests for HIV were negative.
We reached a diagnosis of disseminated cryptococcal infection based on a tissue culture of the skin biopsy, and positive findings for CSF and the serum cryptococcal antigen test. After admission, the administration of fingolimod was stopped because of lymphocytopenia, which might have led to an immunocompromised state. Liposomal amphotericin B 300 mg/day (5 mg/kg/day) and flucytosine 4,000 mg/day (64 mg/kg/day) were administered for 6 weeks as induction therapy. Thereafter, consolidation therapy for 8 weeks with fluconazole 400 mg orally daily was administered.
Two weeks after the initiation of induction therapy, we repeated a CSF examination and observed a decrease in the number of white blood cells (49 /muL) and protein (177 mg/dL). After 4 weeks of induction therapy, the absolute lymphocyte counts returned to normal levels (1,239 /muL) and a follow-up study with chest CT showed diminished nodular lesions in the left lung. After 6 weeks of induction therapy, his cutaneous lesion had almost completely healed. However, the lower-extremity muscle weakness and cognitive impairment had only slightly improved, though no obvious exacerbation of MS was seen. He was transferred to a regional hospital for continuous care and rehabilitation.