Unusual natalizumab-associated progressive multifocal leukoencephalopathy starting in the brainstem

Abstract

we report on a 45-year-old German patient with relapsingremitting (RR) multiple sclerosis (MS) who was started on natalizumab (NAT) therapy in November 2007, because of ongoing disease activity despite interferon therapy. She had never been treated with immunosuppressants before. After she tested positive for anti-JCV (John Cunningham Virus)antibodies for the first time, she decided to discontinue NAT treatment in July 2011 (after 49 NAT infusions). At this time point, as well as during NAT therapy, she was clinically stable (EDSS 3.5). Six weeks later in August 2011, she developed new brainstem symptoms, with left facial and trigeminal nerve palsy, double vision and mild dysphagia. On magnetic resonance imaging (MRI), a large brainstem-midbrain lesion was seen (Fig. 1D). The symptoms were initially interpreted as MS relapse and treated with corticosteroids. After transient improvement, she deteriorated again and was seen for the first time at our hospital. Progressive multifocal leukoencephalopathy (PML) was diagnosed in September 2011 after detection of JCV DNA (31 c/ml in CSF, 5 c/ml in serum; EDSS 7.0). Subsequently, she developed severe immune reconstitution inflammatory syndrome (IRIS), deteriorated clinically (EDSS 9.5), and had to be transferred to the intensive care unit (ICU) for several weeks. Finally, she stabilized after repeated courses of high-dose iv glucocorticosteroids (GC) and iv immunoglobulins (IVIgG, 5 days a 0.4 g/kg body weight), as well as concomitant therapy with mefloquine and mirtazapine. Six months later, she had improved, but still showed severe ataxia and brainstem symptoms (EDSS 6.0). Retrospective analysis of all available MRI scans identified a small new-initially asymptomatic-T2 brainstem lesion as the first MRI manifestation of this patient’s PML in November 2010, which slowly progressed over 41 weeks until clinical PML presentation (Fig. 1A–D). Several aspects in this report are unusual: (1) brainstem PML is rare and has been reported in association with NAT therapy in MS patients only once so far [1]; (2) the longlasting pre-symptomatic phase of 41 weeks and clinical manifestation of PML only 6 weeks after NAT was discontinued; and (3) clinical improvement after combined therapy with GC and IVIgG. In this patient, a new, asymptomatic, non-contrast-enhancing T2 lesion appeared in the brainstem in November 2010 (Fig. 1B). Notably, before the MRI lesion was rated as important, the patient decided to stop NAT therapy in July 2011 due to fear of PML. At this time and during NAT treatment, the lesion was completely asymptomatic. The patient developed new brainstem symptoms only 6 weeks after discontinuation of NAT and showed a large brainstem-midbrain lesion on MRI at that time. Detailed retrospective MRI analysis identified that this large lesion had progressed over time from the small brainstem lesion 41 weeks before. NATassociated PML with a pre-symptomatic course up to 24 weeks has been reported, but not in the brainstem so far [2]. More recently, Yousry and colleagues [3] identified common MRI patterns of NAT-associated PML, which help in the early diagnosis of PML. Except for the unusual initial localization in the brainstem and size (\ 3 cm), all J. Havla (&) R. Hohlfeld T. Kumpfel Institute of Clinical Neuroimmunology, Ludwig-Maximilians-University, Medical Campus Grosshadern, Marchioninistr. 15, 81377 Munich, Germany e-mail: joachim.havla@med.lmu.de