The median age at diagnosis of PML was 43 years in survivors and 53 years in those who died. The mean time from PML symptom onset to diagnosis was 34 days in survivors and 54 days in those who died. Among 70 patients with brain MRIs, 29 of the survivors (54%) had unilobar PML extensions, compared with 2 (12%) of those who died.
Among the 38 survivors with at least 6 months of follow-up since PML diagnosis, 5 (13%) had mild disability as rated on the Karnofsky Performance Scale, 19 (50%) had moderate disability, and 14 (37%) had severe disability.
The findings suggest that earlier diagnosis through enhanced clinical vigilance and optimal management of PML might improve outcomes, Dr. Vermersch said.
Data on the first 35 confirmed cases of PML will be published in the May issues of the journal Neurology.
PML Presentation Can Be Subtle
PML usually presents as an aggressive disease with symptoms of visual, motor, language, neurobehavioral, and cognitive changes. Seizures also can occur. Dr. Kristen Babinski of New York University and her associates presented a case of PML that presented in a 26-year-old man being treated for multiple sclerosis whose only symptom of PML was subacute amotivational syndrome.
After his 42nd infusion of natalizumab, a brain MRI showed not only signals typical of multiple sclerosis but new abnormalities in the left frontal white matter. The patient’s brother reported that the patient had become depressed, unmotivated, nihilistic, hopeless, and cynical. An ultrasensitive quantitative polymerase chain reaction (PCR) analysis found JCV DNA in the patient’s cerebrospinal fluid. Findings on MR spectroscopy supported a PML diagnosis.
He stopped taking natalizumab and received treatment for PML. Seven months later, brain imaging shows no signs of PML and his cognitive function and mood have improved, Dr. Babinski said. The patient is being treated for multiple sclerosis with daily glatiramer acetate (Copaxone) injections, monthly infusions of IV immunoglobulin, and monthly methylprednisolone infusions, with 4-aminopyridine (Ampyra), mirtazapine (Remeron), and clonazepam for management of symptoms.
The case suggests that recommended yearly brain MRIs in patients on natalizumab are not frequent enough and that ultrasensitive quantitative PCR and MR spectroscopy may be useful to diagnose PML, Dr. Babinski said. Her institution now performs brain MRI every 6 months in these patients, she said.
Immunosuppressant History Is Relevant
A study of postmarketing data from 2,943 patients taking natalizumab for multiple sclerosis in Canada, Europe, and Australia identified no unknown safety concerns and confirmed that the risk for PML increases with longer use of natalizumab and with any prior use of immunosuppressive therapy.
The risk for PML was 0% in patients untreated for multiple sclerosis before starting natalizumab, 0.1% in patients who had taken one or more disease-modifying drugs, and 0.5% in patients previously treated with an immunosuppressive therapy for multiple sclerosis, reported Dr. Helmut Butzkueven of the University of Melbourne and his associates.
Mean annualized relapse rates on natalizumab therapy were lowest in the therapy-naive patients (0.17) and highest in patients with a history of immunosuppressive therapy (0.36) or those who had switched between glatiramer acetate and interferon therapy (0.29). The risk of serious adverse events was 0.3% in the therapy-naive group, 0.9% in patients on one or more disease-modifying drugs when starting natalizumab, and 1.3% in those with a history of immunosuppressive therapy.
The Food and Drug Administration recently updated the natalizumab (Tysabri) label to include new information about the risk for progressive multifocal leukoencephalopathy (PML) associated with use of the drug. Tysabri is approved to treat multiple sclerosis and Crohn’s disease.
The previous label had warned that using an immunosuppressive medication at the same time as Tysabri may increase the risk of developing PML. The label now includes a warning that taking an immunosuppressive drug at any point prior to taking Tysabri increases the risk for PML. The immunosuppressive drugs include mitoxantrone (Novantrone), azathioprine (Imuran), methotrexate, cyclophosphamide (Cytoxan), or mycophenolate (CellCept).
The updated label also includes a new table listing rates of PML by the number of Tysabri infusions.
Biogen Idec and Elan Pharmaceuticals, which comarket Tysabri, funded most of the studies. Except for Dr. Babinski, each of the presenters and some of their coinvestigators disclosed financial associations with Biogen Idec and other pharmaceutical companies.