Elsevier

The Lancet Neurology

Volume 9, Issue 4, April 2010, Pages 438-446
The Lancet Neurology

Rapid Review
Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases

https://doi.org/10.1016/S1474-4422(10)70028-4Get rights and content

Summary

Background

Treatment of multiple sclerosis with natalizumab is complicated by rare occurrence of progressive multifocal leukoencephalopathy (PML). Between July, 2006, and November, 2009, there were 28 cases of confirmed PML in patients with multiple sclerosis treated with natalizumab. Assessment of these clinical cases will help to inform future therapeutic judgments and improve the outcomes for patients.

Recent developments

The risk of PML increases with duration of exposure to natalizumab over the first 3 years of treatment. No new cases occurred during the first two years of natalizumab marketing but, by the end of November, 2009, 28 cases had been confirmed, of which eight were fatal. The median treatment duration to onset of symptoms was 25 months (range 6–80 months). The presenting symptoms most commonly included changes in cognition, personality, and motor performance, but several cases had seizures as the first clinical event. Although PML has developed in patients without any previous use of disease-modifying therapies for multiple sclerosis, previous therapy with immunosuppressants might increase risk. Clinical diagnosis by use of MRI and detection of JC virus in the CSF was established in all but one case. Management of PML has routinely used plasma exchange (PLEX) or immunoabsorption to hasten clearance of natalizumab and shorten the period in which natalizumab remains active (usually several months). Exacerbation of symptoms and enlargement of lesions on MRI have occurred within a few days to a few weeks after PLEX, indicative of immune reconstitution inflammatory syndrome (IRIS). This syndrome seems to be more common and more severe in patients with natalizumab-associated PML than it is in patients with HIV-associated PML.

Where next?

Diagnosis of natalizumab-associated PML requires optimised clinical vigilance, reliable and sensitive PCR testing of the JC virus, and broadened criteria for recognition of PML lesions by use of MRI, including contrast enhancement. Optimising the management of IRIS reactions will be needed to improve outcomes. Predictive markers for patients at risk for PML must be sought. It is crucial to monitor the risk incurred during use of natalizumab beyond 3 years.

Introduction

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral brain disease that is being increasingly recognised because of its occurrence in patients with multiple sclerosis treated with natalizumab.1, 2, 3, 4, 5, 6, 7, 8 Caused by reactivation of latent JC virus infection, the incidence of this complication was estimated to be 1:1000 (95% CI 0·2–2·8) from the experience in clinical trials that assessed the safety and efficacy of natalizumab for the treatment of patients with multiple sclerosis and patients with inflammatory bowel disease.1

After suspension of marketing to investigate the complication of PML, natalizumab was remarketed in June, 2006, by the US Food and Drug Administration and the European Medicines Agency. It was hoped that this efficacious drug might have a lower risk for PML than estimated from the clinical trial experience.9 The drug is approved for treatment of patients with multiple sclerosis who have failed other disease-modifying therapies or who have aggressive disease. Because cases of PML in clinical trials occurred with concomitant interferon beta therapy, natalizumab is recommended as monotherapy only. Clinical vigilance for new neurological complaints that might be early signs of PML and rapid evaluation with MRI scans and CSF analysis is recommended.

Between July, 2006, and November, 2009, 28 post-marketing cases of confirmed PML were reported. The first post-marketing case was diagnosed in July, 2008, although symptoms had started beforehand. In recent months, one to two cases per month have been reported, with 31 cases reported by the end of January, 2010.10 This Rapid Review summarises the clinical experience of the 28 cases up to the start of December, 2009, and provides new insights regarding clinical, diagnostic, and management concerns surrounding PML in patients with multiple sclerosis.

Section snippets

Incidence of PML

About 65 000 patients with multiple sclerosis have now been exposed to natalizumab therapy,11 with a cumulative experience of about 85 000 person-years (data on file, Biogen-Idec, MA, USA). With rapidly increasing median duration of exposure, the drug generally continues to be well tolerated and effective in most cases.9

The incidence of PML has increased with the duration of natalizumab use and is proportional to the duration of exposure in the first 3 years of use (figure). Although shorter

Clinical presentation and diagnosis

Clinical symptoms have drawn attention to the development of PML in all cases. It is not known how long the infection was present before symptoms occurred, but the time from the first symptoms attributable to the PML lesion(s) to diagnosis has been generally short, with a trend towards more rapid diagnosis with experience. Early diagnosis is important in limiting the degree of permanent brain damage before immune reconstitution can be accomplished.

The recommendation that new neurological

Treatment

In all but one case, either plasma exchange (PLEX) or immunoabsorption was used to rapidly remove natalizumab and to re-establish immune surveillance of the CNS (table 2).14 Although only a randomised trial could definitively establish the importance of this intervention, the aggressive nature of PML and the acknowledged role of immune reconstitution in its management mean that a study is unlikely to be undertaken. The only patient not treated with PLEX or immunoabsorption developed PML several

Immune reconstitution inflammatory syndrome

IRIS typically presents as a subacute progression and exacerbation of earlier symptoms of PML within days to a few weeks after PLEX (table 2). Such progression occurred in almost all cases. Development of enlarging MRI lesions or increased gadolinium enhancement on MRI scans supports the diagnosis of IRIS, but these scan changes are not necessary for diagnosis because inflammatory brain responses occur before MRI changes can be detected, and enhancement might be suppressed by corticosteroid use.

Outcomes

To date, eight of 28 confirmed cases of PML in the natalizumab post-marketing period have been fatal. This 71% survival rate is better than most reports suggest for PML, and probably reflects the early diagnosis achieved in these cases through clinical vigilance and the ability to achieve immune reconstitution. Many of the patients who survived had serious morbidity and substantial and permanent disability.

Prognosis is related to the location of lesions, with the most serious consequences

Future directions

The risk of PML increases with duration of natalizumab exposure, necessitating active monitoring of patients and continuous discussion of optimum use of this drug. Identification of high-risk populations is important. The relevance of monitoring JC virus activation in plasma, peripheral blood mononuclear cells, or urine to achieve risk stratification continues to be investigated. While one study suggests significant increases in titres of the virus in these compartments,19 reports of larger

Search strategy and selection criteria

We searched PubMed by use of the search terms “PML”, “JC virus”, “natalizumab”, “immune reconstitution syndrome”, and “multiple sclerosis” from 1996 to December, 2009. We analysed MedWatch reports of all reported cases of PML associated with natalizumab in the post-marketing era, prepared by Biogen-Idec staff and supplied to the US Food and Drug Administration and to the authors for review up to early January, 2010. These accounts are variable in detail and sometimes contain contradictory

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