Journal of the Neurological Sciences 339 (2014) 223–225
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Short communication
Catastrophic brain relapse in seronegative NMO after a single dose of natalizumab Joanna Kitley a, Nikos Evangelou b, Wilhelm Küker c, Anu Jacob d, M. Isabel Leite a, Jackie Palace a,⁎ a
Nuffield Department of Clinical Neurosciences, Oxford University Hospitals NHS Trust, University of Oxford, Oxford, UK Queen's Medical Centre, University of Nottingham, Nottingham, UK Department of Neuroradiology, Oxford University Hospitals NHS Trust, Oxford, UK d The Walton Centre for Neurology and Neurosurgery, Liverpool, UK b c
a r t i c l e
i n f o
Article history: Received 16 December 2013 Received in revised form 22 January 2014 Accepted 27 January 2014 Available online 4 February 2014 Keywords: Devic's disease Neuromyelitis optica NMO AQP4 Aquaporin-4 Natalizumab
a b s t r a c t Natalizumab, an effective treatment for MS, has been shown to exacerbate neuromyelitis optica (NMO) with aquaporin-4 antibodies, but whether this is the case in antibody negative NMO and atypical MS/NMO spectrum disorder overlap syndromes is unknown. We describe a patient with a relapsing optico-spinal demyelinating syndrome, negative for aquaporin-4 antibodies, who experienced a catastrophic brain relapse shortly after a single dose of natalizumab, highlighting that MS immunomodulatory drugs may worsen demyelination in patients with seronegative NMO and atypical MS/NMO overlap syndromes even if they are aquaporin-4 antibody negative. We summarise the treatments considered safe and effective in NMO, and those with potential to exacerbate disease. © 2014 Elsevier B.V. All rights reserved.
1. Introduction
1.1. Case report
Neuromyelitis optica (NMO) is a severe inflammatory disorder of the CNS, usually associated with aquaporin-4 antibodies (AQP4-Abs), and is now recognised as a distinct entity from multiple sclerosis (MS). Immunosuppression with agents such as azathioprine, mycophenolate mofetil, rituximab and/or prednisolone is essential to prevent recurrent attacks. Treatment of AQP4-Ab seronegative (sNMO) patients is less clear as it is not known whether these patients share common pathogenic mechanisms and it is difficult to differentiate sNMO from atypical MS with an optico-spinal phenotype. Immunomodulatory drugs effective in MS, such as beta-interferon and natalizumab, have been reported to exacerbate NMO with AQP4-Abs [1,13]. No similar exacerbations have been reported in sNMO patients. We describe a patient with a relapsing optico-spinal demyelinating syndrome, negative for AQP4-Abs, who experienced a severe relapse shortly after a single dose of natalizumab. Our case highlights that MS immunomodulatory drugs may worsen demyelination in patients with NMO/optico-spinal demyelinating syndromes even if they are AQP4-Ab negative.
A 31 year-old Caucasian woman presented in October 2008 with myelitis, followed after two weeks by severe right optic neuritis. Brain MRI was normal and there were several short lesions in the thoracic cord. Cerebrospinal fluid (CSF) was acellular and oligoclonal bands were negative. She made a good recovery from the myelitis but poor recovery in vision. Two months after disease onset, in December 2008, she developed numbness below the waist and became unable to walk. There was now longitudinally extensive transverse myelitis (LETM) on the spinal MRI. She made a good but incomplete recovery and was started on azathioprine 2.5 mg/kg/day and prednisolone 30 mg on alternate days. She remained well on treatment until a year later when she developed expressive dysphasia associated with a lesion in the left frontal lobe, and this was followed by two further severe myelitis attacks. Azathioprine was replaced with mitoxantrone but she continued to relapse and glatiramer acetate was commenced. Eleven months into treatment she had another severe LETM and optic neuritis. AQP4-Abs, tested on both a cell-based assay and flow cytometry were negative in sera on three separate occasions and also negative in CSF. Other autoantibodies including ANA, ENA, myelin-oligodendrocyte glycoprotein and antiphospholipid antibodies were negative and there were no systemic features to suggest a more widespread inflammatory disease such as Behçet's disease or sarcoidosis.
⁎ Corresponding author. Tel.: +44 1865 31900; fax: +44 1865 231870. E-mail addresses:
[email protected] (J. Kitley),
[email protected] (N. Evangelou),
[email protected] (W. Küker),
[email protected] (A. Jacob),
[email protected] (M.I. Leite),
[email protected] (J. Palace). 0022-510X/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2014.01.035
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J. Kitley et al. / Journal of the Neurological Sciences 339 (2014) 223–225
The decision was made to start natalizumab for atypical MS. Ten days after the first dose she developed confusion, hallucinations and quadriparesis. Brain MRI showed multiple T2 hyperintensities in both cerebral hemispheres and the corpus callosum with restricted diffusion, oedema and partial ring enhancement post-contrast (Fig. 1). There were also new lesions in the spinal cord (Fig. 1). Intravenous methylprednisolone was administered and she made some improvement but has been left with gait ataxia, expressive dysphasia and a degree of cognitive impairment. The diagnosis is now felt to be sNMO and rituximab treatment has been commenced. Following several relapses in the first 6 months of treatment, she has now remained well for a year. 2. Discussion Natalizumab has only rarely been used for the treatment of NMO, with two small case series showing on-going relapses [8,10]. In one [8], some patients developed callosal lesions similar to those seen in our case, albeit less severe. A severe brain relapse occurring in an NMO patient after three years of natalizumab treatment has also recently been reported [1]. Cognitive impairment and confusion were seen, and as with our case the patient was left with cognitive impairment. In our experience, clinically-apparent cognitive impairment is rare in NMO, although recent studies have demonstrated deficits on formal neuropsychological testing [3,4,16]. Our patient fulfils the current diagnostic criteria for NMO and although not all AQP4-Ab negative patients fulfilling these criteria have NMO, our patient clearly had a relapsing optico-spinal predominant disease with normal CSF and a brain MRI
not suggestive of MS. Of note, although our patient did have very active disease prior, they had a dramatic worsening clinically and on imaging shortly after natalizumab, suggesting this was the precipitating cause. Although early relapses following natalizumab treatment have been described in MS [5], these are rarely severe. Natalizumab is an anti-α4 integrin monoclonal antibody whose efficacy in MS is presumed to be related to inhibition of entry of autoreactive T cells into the CNS. Natalizumab appears to alter the balance of the immune system, with reports of increased serum levels of circulating B cells [11,14], a decrease in circulating T regulatory cells [16] and an increase in the number of pro-inflammatory cytokineproducing T cells such as IFN-γ, TNF and IL-17 [9]. Thus, there are theoretical reasons why it may exacerbate NMO. Seronegative NMO and atypical MS/NMO overlap cases represent a diagnostic challenge as there is no disease biomarker to guide treatment. In addition to natalizumab, other immunomodulatory drugs effective in MS have been reported to exacerbate NMO with AQP4-Abs. These include interferon [13], fingolimod [12] and alemtuzumab [15]. To our knowledge, there have been no previous reports of similar exacerbations in sNMO patients. However, as these drug-induced exacerbations can be catastrophic it is our practice to avoid their use in patients with sNMO or atypical MS/NMO overlap syndromes, in whom we prefer to use treatments considered to be effective for both MS and NMO such as rituximab, azathioprine or methotrexate (Table 1). There are also reports of NMO patients responding to glatiramer acetate [2,7] and intravenous immunoglobulin [6]; thus these treatments may also be useful in NMO though experience with their use is limited.
Fig. 1. Brain and spinal cord MRI appearances before and after natalizumab. The brain MRI scan 2 months' pre-treatment showed a large lesion in the left frontal lobe with a smaller subcortical lesion more posteriorly (i, ii) and there were no peri-ventricular lesions characteristic of multiple sclerosis (iii). Cord imaging revealed T2 high signal at the levels of C3/4 and T1/2 to T7 (iv), with no cord oedema or post-contrast enhancement. MRI scans performed 2 weeks' after the first natalizumab infusion showed multiple T2 hyperintensities in both cerebral hemispheres and the posterior aspect of the corpus callosum (v) with restricted diffusion (vi), surrounding oedema and partial ring enhancement post-contrast (vii). A new acute lesion was seen in the spinal cord at the level of T9 (viii), with oedema and post-contrast enhancement (ix).
J. Kitley et al. / Journal of the Neurological Sciences 339 (2014) 223–225 Table 1 Drugs to avoid and those to consider in NMO. Immunomodulatory therapies to avoid in seronegative NMO and atypical MS/NMO overlap cases β-interferon: multiple reports of exacerbation of NMO Fingolimod: isolated case report of severe NMO exacerbation Alemtuzumab: known to exacerbate autoimmune disorders and isolated report of severe NMO exacerbation Drugs to consider in seronegative NMO and atypical MS/NMO overlap cases Rituximab Azathioprine Methotrexate Mitoxantrone Intravenous immunoglobulin Glatiramer acetatea a Anecdotal case reports of efficacy in NMO and no reports to date of disease exacerbations.
Contributions and disclosures Joanna Kitley Contribution: Conception and design of study, acquisition, analysis and interpretation of data, drafting/revising the manuscript for content, and approved the final version. Disclosures: Dr Kitley has received support for scientific meetings from Biogen Idec, Novartis and Teva, speaker honoraria from Novartis and Terumo BCT and is supported by the NHS National Specialised Commissioning Group for Neuromyelitis Optica. Nikos Evangelou Contribution: Conception and design of study, acquisition, analysis and interpretation of data, drafting/revising the manuscript for content, and approved the final version. Disclosures: Dr Evangelou has received honoraria for participating in advisory boards for Bayer-Schering, Merck-Serono, and Novartis, and received funding for attending conferences from Novartis, BayerSchering, Biogen-Idec, and Merck-Serono. Wilhelm Küker Contribution: Conception and design of study, acquisition, analysis and interpretation of data, drafting/revising the manuscript for content, and approved the final version. Disclosures: Dr Küker reports no disclosures. Anu Jacob Contribution: Conception and design of study, acquisition, analysis and interpretation of data, drafting/revising the manuscript for content, and approved the final version. Disclosures: Dr Jacob is supported by the NHS National Specialised Commissioning Group for Neuromyelitis Optica.
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M Isabel Leite Contribution: Conception and design of study, acquisition, analysis and interpretation of data, drafting/revising the manuscript for content, and approved the final version. Disclosures: Dr Leite is involved in AQP4 and MOG antibody testing, is supported by the NHS National Specialised Commissioning Group for Neuromyelitis Optica and by the NIHR Oxford Biomedical Research Centre and has received speaking honoraria from Biogen Idec and travel grants from Novartis. Jackie Palace Contribution: Conception and design of study, acquisition, analysis and interpretation of data, drafting/revising the manuscript for content, approved the final version, and is the corresponding author. Disclosures: Dr Palace has received unrestricted grants and support for scientific meetings and scientific advisory honorariums from Merk Serono, TEVA, Biogen, Bayer Schering and Novartis, has held MS society grants, is a clinical lead for the UK DOH RSS and is supported by the NHS National Specialised Commissioning Group for Neuromyelitis Optica. References [1] Barnett M, Prineas J, Buckland M, Parratt J, Pollard J. Massive astrocyte destruction in neuromyelitis optica despite natalizumab therapy. Mult Scler 2012;18:108–12. [2] Bergamaschi R, Uggetti C, Tonietti S, Egitto M, Cosi V. A case of relapsing neuromyelitis optica treated with glatiramer acetate. J Neurol 2003;250:359–61. [3] Blanc F, Noblet V, Jung B, Rousseau F, Renard F, Bourre B, et al. White matter atrophy and cognitive dysfunctions in neuromyelitis optica. PLoS One 2012;7:e33878. [4] Blanc F, Zephir H, Lebrun C, Labauge P, Castelnovo G, Fleury M, et al. Cognitive functions in neuromyelitis optica. Arch Neurol 2008;65:84–8. [5] Centonze D, Furlan R, Gasperini C, Salvetti M, Battistini L. Early relapses after the first dose of natalizumab in active multiple sclerosis patients. Mult Scler 2008;14:1137–8. [6] Elsone L, Panicker J, Mutch K, Boggild M, Appleton R, Jacob A. Role of intravenous immunoglobulin in the treatment of acute relapses of neuromyelitis optica: experience in 10 patients. Mult Scler 2013 [Sep 2 [Epub ahead of print]]. [7] Gartzen K, Limmroth V, Putzki N. Relapsing neuromyelitis optica responsive to glatiramer acetate treatment. Eur J Neurol 2007;14:e12–3. [8] Jacob A, Hutchinson M, Elsone L, Kelly S, Ali R, Saukans I, et al. Does natalizumab therapy worsen neuromyelitis optica? Neurology 2012;79:1065–6. [9] Kivisakk P, Healy B, Viglietta V, Quintana F, Hootstein M, Weiner H, et al. Natalizumab treatment is associated with peripheral sequestration of proinflammatory T cells. Neurology 2009;72:1922–30. [10] Kleiter I, Hellwig K, Berthele A, Kumpfel T, Linker R, Hartung HP, et al. Failure of natalizumab to prevent relapses in neuromyelitis optica. Arch Neurol 2012;69:239–45. [11] Krumbholz M, Meinl I, Kumpfel T, Hohlfeld R, Meinl E. Natalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis. Neurology 2008;71:1350–4. [12] Min J, Kim B, Lee K. Development of extensive brain lesions following fingolimod (FTY720) treatment in a patient with neuromyelitis optica spectrum disorder. Mult Scler 2012;18:113–5. [13] Palace J, Leite MI, Nairne A, Vincent A. Interferon beta treatment in neuromyelitis optica: increase in relapses and aquaporin 4 antibody titers. Arch Neurol 2010;67:1016–7. [14] Putzki N, Baranwal M, Tettenborn B, Limmroth V, Kreuzfelder E. Effects of natalizumab on circulating B cells, T regulatory cells and natural killer cells. Eur Neurol 2010;63:311–7. [15] Qian P, Cross A, Naismith R. Lack of response to monoclonal antibody therapy in neuromyelitis optica. Arch Neurol 2011;68:1207–9. [16] Saji E, Arakawa M, Yanagawa K, Toyoshima Y, Yokoseki A, Okamato K, et al. Cognitive impairment and cortical degeneration in neuromyelitis optica. Ann Neurol 2013;73:65–76.
