A 32-year-old woman presented with multiple sclerosis (MS) in 2001, displaying typical MS features on MRI and in the CSF. The patient's clinical condition was relatively stable without major exacerbations on interferon beta-1a but MRI investigation in September 2007 noted a significant progression in lesions (figure, A) but without contrast enhancement, indicating no loss of blood-brain barrier (BBB) integrity. The patient commenced natalizumab immunotherapy in November 2007 (300 mg every fourth week). At this point, she presented with an Extended Disability Status Scale score estimated at 3.0 and complaint of some memory and concentration problems.
(A–G) MRIs showing aspects of the malignant transformation. The pretreatment scan (A) performed in September 2007 shows moderate multiple sclerosis inflammation without signs of current activity (no gadolinium + lesions). Images (B–G) show multifocal inflammation following the fifth infusion (May 2007) with T2-weighted sequences (B and D) and contrast-enhanced T1-weighted sequences (C and E) with transaxial (B and C) and sagittal (D and E) projections, respectively. Images F and G show the medulla at the same occasion with T2-weighted (F) and contrast-enhanced T1-weighted (G) sequences, respectively. (H–J) Immunostaining of brain biopsy for immunoglobulin (Ig)G, IgM, and complement C9, respectively. The brown staining shows significant infiltration of IgG (H) indicating blood-brain barrier disruption. IgM staining (I) was restricted to the blood vessel walls. Strong staining for complement C9 (red) was detected along blood vessel walls (arrows) with more diffuse staining seen in the surrounding tissue by the red staining used in this protocol.
The patient experienced slight chills and fever in conjunction with the fourth and following 2 natalizumab infusions with escalating intensity. Shortly after the sixth infusion, the patient was admitted to the hospital with progressive gait difficulties, ataxia, and reduced mental status. The MRI examination showed a considerable progression with both new hyperintense T2 lesions and multifocal areas of gadolinium enhancement (figure, B–G). Methylprednisolone was administered and PCR test results for JC virus in the CSF were negative. On arrival at the regional hospital, she was bed bound, tetraparetic, and uncommunicative, with depressed consciousness (Extended Disability Status Scale score 9.0). A new MRI scan displayed further progression of multifocal contrast-enhancing MS lesions (data not shown). Further CSF studies revealed no increased cell count or elevated CSF:serum albumin ratio. A brain biopsy showed a histologic picture of acute MS inflammation with infiltrating activated macrophages (data not shown) as well as signs of BBB breakdown with leakage of immunoglobulin (Ig)G but not IgM and also deposits of complement C9 around the vessel walls as well as diffusely in the tissue (figure, H–J). High levels of anti-drug antibodies (ADA) against natalizumab were detected (335 mg/L), predominantly of the complement-fixing subtype IgG3. The patient was treated with plasmapheresis and prepared for high-dose cytotoxic therapy with stem cell transfer with mobilization doses of cyclophosphamide (2 g/m2), but her condition did not improve sufficiently to allow therapy to proceed. The patient remained mostly comatose and a decision of purely palliative care was made. She died at her local hospital in June 2008.
Investigation into possible causes for the malignant transformation.
Analysis of tissue from the brain biopsy obtained before the onset of high-intensity immunotherapy showed features of acute MS inflammation, which were confirmed at autopsy. Extensive investigation regarding possible infectious agents did not reveal any sign of viral, bacterial, or fungal infection of the CNS. Antibodies for aquaporin-4 were not analyzed because we did not have clinical suspicions of neuromyelitis optica.
It is possible that the natalizumab ADA in this case exhibited an anti-idiotypic reactivity against ligands of very late activation antigen-4, vascular cell adhesion molecule-1, and fibronectin. However, treatment of vascular cell adhesion molecule-1–transfected cell lines and activated human vascular endothelial cells with patient serum did not show any anti-idiotypic effects (data not shown).
Discussion.
We describe an unusual case in which exacerbation of MS culminating in death occurred in conjunction with the development of neutralizing antibodies during treatment with natalizumab. Our case shows similarities with other cases reported in the literature of either paradoxical worsening during natalizumab treatment1 or as a rebound phenomenon after discontinuation of this treatment, but differs from them in the malignant course despite intense immunosuppressive treatment.2,–,4 To our knowledge, this is the first description of rebound neuroinflammation as a result of the development of natalizumab ADA.
The detected ADA titers were among the highest recorded among ADA-positive patients identified in Sweden (n = 57, data not shown) and were predominantly of the complement-fixing subtype IgG3.
Although it is possible that the described event could be a case of an unusually severe rebound inflammation, because the development of ADA rendered the patient functionally untreated, we propose that the immunologic response associated with the formation of ADA may have served as an adjuvant to this reaction. High-titer complement-fixing antibodies brought into close contact with the endothelium by lymphocytes bearing natalizumab-ADA complexes could have had a role in the widespread BBB breakdown, a hypothesis supported by the increasing intensity of infusion reactions preceding deterioration as well as by positive staining for complement C9 around blood vessels in the brain biopsy tissue.
In conclusion, we recommend that repeated moderate to severe infusion reactions in the beginning of natalizumab treatment should prompt the cessation of treatment and assessment for the development of natalizumab ADA. Such patients should be followed closely for deterioration in their disease course clinically and by MRI.
Footnotes
Author contributions: A. Svenningsson: study concept and design, patient management, interpretation of data, drafting/revising the manuscript, obtaining funding, study supervision and coordination. A.M. Dring: analysis and interpretation of data (dot blots, immunohistochemistry), drafting/revising the manuscript, preparing figures. A. Fogdell-Hahn: analysis and interpretation of data (ADA analysis), contribution of vital reagents/tools, revising the manuscript, preparing figures. I. Jones: analysis and interpretation of data (cell culture and transfections, immunofluorescence), revising the manuscript. E. Engdahl: analysis and interpretation of data (ADA analysis), revising the manuscript. M. Lundkvist: analysis and interpretation of data (ADA analysis), revising the manuscript. T. Brännström: analysis and interpretation of data (histology, immunohistochemistry), contribution of vital reagents/tools. J.D. Gilthorpe: study concept and design, analysis and interpretation of data, contribution of vital reagents/tools, drafting/revising the manuscript, study supervision and coordination.
Study funding: Financial support was provided through regional agreement between Umeå University and Västerbotten County Council on cooperation in the field of Medicine, Odontology and Health (ALF), the KI Foundation, and the Swedish Association of Persons with Neurological Disabilities (NHR).
Disclosure: A. Svenningsson has received unrestricted research grants from Biogen Idec, Bayer-Schering, and Baxter Medical as well as travel grants and consulting fees from Biogen Idec, Sanofi-Aventis, Merck Serono, and Baxter Medical. A.M. Dring reports no disclosures. A. Fogdell-Hahn has received unrestricted research grants from Biogen Idec, Merck Serono, and Sanofi-Aventis. I. Jones reports no disclosures. E. Engdahl has received unrestricted research grants from Merck Serono. M. Lundkvist has received unrestricted research grants from Biogen Idec and Sanofi-Aventis as well as consultant fees from Biogen Idec. T. Brännström and J.D. Gilthorpe report no disclosures. Go to Neurology.org for full disclosures.
- Received June 18, 2012.
- Accepted October 8, 2012.
- © 2013 American Academy of Neurology
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