ClinicSpeak: DMF & PML – more vigilance is needed

Are the three PML cases on Tecfidera the tail of the curve with more cases to come?

Hoepner et al. Progressive multifocal leukoencephalopathy during fumarate monotherapy of psoriasis. Neurol Neuroimmunol Neuroinflamm 2015; 2(3):e85.

Excerpt: In September 2013, a 69-year-old Caucasian man who was anti–JC virus (JCV) antibody positive was admitted to our hospital with slowly progressing right hemiparesis and aphasia lasting for approximately 6 months. Medical history revealed arterial hypertension, biological aortic valve replacement, and psoriasis vulgaris, treated with 3–6 tablets daily of dimethylfumarate (DMF; 120 mg)/ethylhydrogenfumarate (EHF; 95 mg) (Fumaderm) since December 2008 (table e-1 at Neurology.org/nn). No other immunosuppressive pretreatment had been given. In April/May 2013, the patient recognized a steadily progressing weakness of the right leg. In June 2013, an external diagnosis of ischemic stroke was made. An MRI scan  which was performed after deterioration of clinical symptoms, revealed a subcortical left hemispheric lesion; biopsy demonstrated macrophage-dominated inflammation, dysmorphic astrocytes, simian virus 40 positivity, and several p53- and MiB1-positive cells, suggestive of a JCV encephalitis. JCV DNA was detected in CSF at 2 different time points using a highly sensitive PCR protocol (September 24, 2013, 16 copies/mL; October 7, 2013, 42 copies/mL),1 leading to the diagnosis of progressive multifocal leukoencephalopathy (PML) in September 2013. Further diagnostic workup unmasked toxic bone marrow damage and an increased excretion of kappa light chains in urine without any evidence for a plasmocytoma. Taking into account the patient’s initial presentation with a slowly progressive paresis since April/May 2013 as well as the initial MRI scan, which is compatible with the PML diagnosis, we believe that the onset of PML was in April/May without preexisting leukopenia and only moderate lymphopenia (grade 2 lymphopenia: 724–738 cells/µL). Several weeks later, white blood cell count dropped to a minimum of 4,800 cells/µL with 288 cells/µL lymphocytes under continuous Fumaderm treatment. Fumaderm was discontinued, and treatment with mirtazapine (45 mg/day), mefloquine (250 mg/week), and levetiracetam (1,000 mg/day) was initiated.

Nieuwkamp et al. PML in a Patient without Severe Lymphocytopenia Receiving Dimethyl Fumarate.
N Engl J Med 2015; 372:1474-1476.

Excerpt: On July 18, 2014, a 64-year-old woman presented with a 2-week history of progressive apraxia. She had been receiving topical glucocorticoids and compounded delayed-release DMF (Psorinovo) for the treatment of psoriasis since June 2012. Magnetic resonance imaging (MRI) of the brain showed multiple subcortical white-matter lesions. Leukocyte and lymphocyte counts were normal before DMF treatment but reached a nadir of 4000 cells and 792 cells per cubic millimeter, respectively, in June 2014. Analysis of the cerebrospinal fluid showed normal levels of leukocytes, protein, and glucose. The patient was seronegative for the human immunodeficiency virus. At that time, a diagnosis of PML was considered. However, testing of the cerebrospinal fluid for JC virus DNA on polymerase-chain-reaction (PCR) assay was negative. Treatment with DMF was discontinued, and the patient received the diagnosis of atypical ischemic stroke.

Owing to progressive hemiparesis and somnolence, she was transferred to our hospital on August 14, 2014. Follow-up MRI showed a rapid and widespread dissemination of lesions suggestive of PML–immune reconstitution inflammatory syndrome (IRIS). Treatment with mefloquine, mirtazapine, and glucocorticoids was initiated. The patient’s condition continued to deteriorate, and she died on August 26, 2014. PML was confirmed on histologic analysis of brain tissue and positive results on PCR assay for JC virus DNA in brain tissue and cerebrospinal fluid.