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Interferon-β-related tumefactive brain lesion in a Caucasian patient with neuromyelitis optica and clinical stabilization with tocilizumab.

Harmel J, Ringelstein M, Ingwersen J, Mathys C, Goebels N, Hartung HP, Jarius S, Aktas O - BMC Neurol (2014)

Bottom Line: Under this treatment, the patient showed persisting relapse activity and finally presented with a severe episode of subacute aphasia and right-sided hemiparesis due to a large T2 hyperintensive tumefactive lesion of the left brain hemisphere and a smaller T2 lesion on the right side.Despite rituximab therapy two further LETM episodes occurred, resulting in severe neurological deficits.Therapeutic blockade of the interleukin (IL)-6 signalling pathway by tocilizumab was initiated, followed by clinical and radiological stabilization.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Neuromyelitis optica (NMO) is a severely disabling inflammatory disorder of the central nervous system and is often misdiagnosed as multiple sclerosis (MS). There is increasing evidence that treatment options shown to be beneficial in MS, including interferon-β (IFN-β), are detrimental in NMO.

Case presentation: We here report the first Caucasian patient with aquaporin 4 (AQP4) antibody (NMO-IgG)-seropositive NMO presenting with a tumefactive brain lesion on treatment with IFN-β. Disease started with relapsing optic neuritis and an episode of longitudinally extensive transverse myelitis (LETM) in the absence of any brain MRI lesions or cerebrospinal fluid-restricted oligoclonal bands. After initial misdiagnosis of multiple sclerosis (MS) the patient received subcutaneous IFN-β1b and, subsequently, subcutaneous IFN-β1a therapy for several years. Under this treatment, the patient showed persisting relapse activity and finally presented with a severe episode of subacute aphasia and right-sided hemiparesis due to a large T2 hyperintensive tumefactive lesion of the left brain hemisphere and a smaller T2 lesion on the right side. Despite rituximab therapy two further LETM episodes occurred, resulting in severe neurological deficits. Therapeutic blockade of the interleukin (IL)-6 signalling pathway by tocilizumab was initiated, followed by clinical and radiological stabilization.

Conclusion: Our case (i) illustrates the relevance of correctly distinguishing NMO and MS since these disorders differ markedly in their responsiveness to immunomodulatory and -suppressive therapies; (ii) confirms and extends a previous report describing the development of tumefactive brain lesions under IFN-β therapy in two Asian NMO patients; and (iii) suggests tocilizumab as a promising therapeutic alternative in highly active NMO disease courses.

No MeSH data available.


Related in: MedlinePlus

Disease course, MRI scans and therapy in a patient with AQP4-Ab-positive NMO. The figure depicts clinical relapses (diamonds), MRI findings (T2, FLAIR), and therapy data (methyl prednisolone (MP) 1000 mg i.v. 3–5 daily infusions; tocilizumab 8 mg/kg bodyweight once a month; rituximab 1000 mg i.v. (single infusion), IFN (interferon)-β1a 44 μg s.c. three times a week (Rebif®); IFN-β1b s.c. daily (Betaferon®, Betaseron®); methylpredisolone 250 mg i.v. once per month; azathioprine (AZA)). No relapses have occurred during therapy with tocilizumab (follow-up: 12 months). AQP: aquaporin, AZA: azathioprine, FLAIR: fluid attenuated inversion recovery, IFN: interferon, MP: methyl prednisolone, MRI: magnetic resonance imaging, MS: multiple sclerosis, NMO: neuromyelitis optica.
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Fig1: Disease course, MRI scans and therapy in a patient with AQP4-Ab-positive NMO. The figure depicts clinical relapses (diamonds), MRI findings (T2, FLAIR), and therapy data (methyl prednisolone (MP) 1000 mg i.v. 3–5 daily infusions; tocilizumab 8 mg/kg bodyweight once a month; rituximab 1000 mg i.v. (single infusion), IFN (interferon)-β1a 44 μg s.c. three times a week (Rebif®); IFN-β1b s.c. daily (Betaferon®, Betaseron®); methylpredisolone 250 mg i.v. once per month; azathioprine (AZA)). No relapses have occurred during therapy with tocilizumab (follow-up: 12 months). AQP: aquaporin, AZA: azathioprine, FLAIR: fluid attenuated inversion recovery, IFN: interferon, MP: methyl prednisolone, MRI: magnetic resonance imaging, MS: multiple sclerosis, NMO: neuromyelitis optica.

Mentions: A 47-year old Caucasian female patient had been diagnosed with MS in 1995 in an external hospital after four episodes of optic neuritis (ON) since 1989 and an episode of longitudinally extensive transverse myelitis (LETM) in 1995 (Figure 1). Cerebrospinal fluid (CSF)-restricted oligoclonal bands (OCBs) were repeatedly negative and brain MRI scans did not show any abnormalities (e.g. MRI performed in 2001, Figure 1). After an initial two months azathioprine treatment in 1995, which had to be discontinued because of side effects, repeated monthly intravenous (iv) steroid pulse treatments with 250 mg methylprednisolone (MP) were initiated and continued until April 2013. In 2001, after three further episodes of ON, subcutaneous IFN-β1b medication was added to the ongoing steroid pulse treatment. In 2005, subcutaneous IFN-β1b was switched to subcutaneous IFN-β1a (3 × 44 μg/week). During IFN-β therapy the patient still suffered from further relapses, most of them occurring between the years 2001 and 2005 (July 2002, February 2005, and April 2005). She recovered only partially from the relapses and accumulated fixed neurological deficits such as amaurosis of the right eye and impaired walking with an expanded disability status scale (EDSS) score of 4.0 in January 2012. Of note, there was no chronic progression between the relapses. In 2011 persisting disease activity prompted testing for serum AQP4 antibodies (by a cell-based assay; CBA [7]) which were found positive and confirmed the diagnosis of seropositive NMO. Following the patient’s wishes and in light of the reduced relapse rate since 2005 therapy with subcutaneous IFN-β1a was continued, together with the regular monthly steroid therapy (250 mg MP each) established since 1995. In January 2012, she suffered from a subacute aphasia and right sided hemiparesis and presented to our department. MRI imaging showed a large T2 hyperintensive, tumefactive lesion in the prefrontal white matter of the superior and middle frontal gyrus of the left hemisphere and smaller T2 lesions on the right side without clear evidence of a disturbed blood brain barrier (Figure 1). MR spectroscopy showed an unchanged choline peak and thus did not give a hint to a malignant process. Analysis of CSF was unremarkable with still no quantitative evidence for intrathecal immunoglobulin (Ig) synthesis or OCBs and a normal CSF white cell count. AQP4-Ab serum titre was 1:1000 (CBA). Furthermore, a time-of-flight MR-angiography showed no signs of vasculitis, and laboratory work-up revealed no clinical or serological evidence for connective tissue diseases. The patient received a high-dose methylprednisolone iv pulse and clinically improved. The follow-up MRI one month later showed a mild regression of the large T2 hyperintense lesion. We stopped IFN-β therapy and continued the already existing monthly steroid pulses (250 mg MP each) as the patient declined any additional medication at that time. However, two attacks of myelitis occurred in March 2013 and April 2013. Follow-up AQP4-Ab testing in April 2013 confirmed seropositivity (1:1000; CBA). The patient was treated with high-dose steroid iv pulse therapy and rescue plasmapheresis. Thereafter our patient agreed to an adaptation of therapy and the monthly steroid infusions were discontinued without tapering.Figure 1


Interferon-β-related tumefactive brain lesion in a Caucasian patient with neuromyelitis optica and clinical stabilization with tocilizumab.

Harmel J, Ringelstein M, Ingwersen J, Mathys C, Goebels N, Hartung HP, Jarius S, Aktas O - BMC Neurol (2014)

Disease course, MRI scans and therapy in a patient with AQP4-Ab-positive NMO. The figure depicts clinical relapses (diamonds), MRI findings (T2, FLAIR), and therapy data (methyl prednisolone (MP) 1000 mg i.v. 3–5 daily infusions; tocilizumab 8 mg/kg bodyweight once a month; rituximab 1000 mg i.v. (single infusion), IFN (interferon)-β1a 44 μg s.c. three times a week (Rebif®); IFN-β1b s.c. daily (Betaferon®, Betaseron®); methylpredisolone 250 mg i.v. once per month; azathioprine (AZA)). No relapses have occurred during therapy with tocilizumab (follow-up: 12 months). AQP: aquaporin, AZA: azathioprine, FLAIR: fluid attenuated inversion recovery, IFN: interferon, MP: methyl prednisolone, MRI: magnetic resonance imaging, MS: multiple sclerosis, NMO: neuromyelitis optica.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4301061&req=5

Fig1: Disease course, MRI scans and therapy in a patient with AQP4-Ab-positive NMO. The figure depicts clinical relapses (diamonds), MRI findings (T2, FLAIR), and therapy data (methyl prednisolone (MP) 1000 mg i.v. 3–5 daily infusions; tocilizumab 8 mg/kg bodyweight once a month; rituximab 1000 mg i.v. (single infusion), IFN (interferon)-β1a 44 μg s.c. three times a week (Rebif®); IFN-β1b s.c. daily (Betaferon®, Betaseron®); methylpredisolone 250 mg i.v. once per month; azathioprine (AZA)). No relapses have occurred during therapy with tocilizumab (follow-up: 12 months). AQP: aquaporin, AZA: azathioprine, FLAIR: fluid attenuated inversion recovery, IFN: interferon, MP: methyl prednisolone, MRI: magnetic resonance imaging, MS: multiple sclerosis, NMO: neuromyelitis optica.
Mentions: A 47-year old Caucasian female patient had been diagnosed with MS in 1995 in an external hospital after four episodes of optic neuritis (ON) since 1989 and an episode of longitudinally extensive transverse myelitis (LETM) in 1995 (Figure 1). Cerebrospinal fluid (CSF)-restricted oligoclonal bands (OCBs) were repeatedly negative and brain MRI scans did not show any abnormalities (e.g. MRI performed in 2001, Figure 1). After an initial two months azathioprine treatment in 1995, which had to be discontinued because of side effects, repeated monthly intravenous (iv) steroid pulse treatments with 250 mg methylprednisolone (MP) were initiated and continued until April 2013. In 2001, after three further episodes of ON, subcutaneous IFN-β1b medication was added to the ongoing steroid pulse treatment. In 2005, subcutaneous IFN-β1b was switched to subcutaneous IFN-β1a (3 × 44 μg/week). During IFN-β therapy the patient still suffered from further relapses, most of them occurring between the years 2001 and 2005 (July 2002, February 2005, and April 2005). She recovered only partially from the relapses and accumulated fixed neurological deficits such as amaurosis of the right eye and impaired walking with an expanded disability status scale (EDSS) score of 4.0 in January 2012. Of note, there was no chronic progression between the relapses. In 2011 persisting disease activity prompted testing for serum AQP4 antibodies (by a cell-based assay; CBA [7]) which were found positive and confirmed the diagnosis of seropositive NMO. Following the patient’s wishes and in light of the reduced relapse rate since 2005 therapy with subcutaneous IFN-β1a was continued, together with the regular monthly steroid therapy (250 mg MP each) established since 1995. In January 2012, she suffered from a subacute aphasia and right sided hemiparesis and presented to our department. MRI imaging showed a large T2 hyperintensive, tumefactive lesion in the prefrontal white matter of the superior and middle frontal gyrus of the left hemisphere and smaller T2 lesions on the right side without clear evidence of a disturbed blood brain barrier (Figure 1). MR spectroscopy showed an unchanged choline peak and thus did not give a hint to a malignant process. Analysis of CSF was unremarkable with still no quantitative evidence for intrathecal immunoglobulin (Ig) synthesis or OCBs and a normal CSF white cell count. AQP4-Ab serum titre was 1:1000 (CBA). Furthermore, a time-of-flight MR-angiography showed no signs of vasculitis, and laboratory work-up revealed no clinical or serological evidence for connective tissue diseases. The patient received a high-dose methylprednisolone iv pulse and clinically improved. The follow-up MRI one month later showed a mild regression of the large T2 hyperintense lesion. We stopped IFN-β therapy and continued the already existing monthly steroid pulses (250 mg MP each) as the patient declined any additional medication at that time. However, two attacks of myelitis occurred in March 2013 and April 2013. Follow-up AQP4-Ab testing in April 2013 confirmed seropositivity (1:1000; CBA). The patient was treated with high-dose steroid iv pulse therapy and rescue plasmapheresis. Thereafter our patient agreed to an adaptation of therapy and the monthly steroid infusions were discontinued without tapering.Figure 1

Bottom Line: Under this treatment, the patient showed persisting relapse activity and finally presented with a severe episode of subacute aphasia and right-sided hemiparesis due to a large T2 hyperintensive tumefactive lesion of the left brain hemisphere and a smaller T2 lesion on the right side.Despite rituximab therapy two further LETM episodes occurred, resulting in severe neurological deficits.Therapeutic blockade of the interleukin (IL)-6 signalling pathway by tocilizumab was initiated, followed by clinical and radiological stabilization.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Neuromyelitis optica (NMO) is a severely disabling inflammatory disorder of the central nervous system and is often misdiagnosed as multiple sclerosis (MS). There is increasing evidence that treatment options shown to be beneficial in MS, including interferon-β (IFN-β), are detrimental in NMO.

Case presentation: We here report the first Caucasian patient with aquaporin 4 (AQP4) antibody (NMO-IgG)-seropositive NMO presenting with a tumefactive brain lesion on treatment with IFN-β. Disease started with relapsing optic neuritis and an episode of longitudinally extensive transverse myelitis (LETM) in the absence of any brain MRI lesions or cerebrospinal fluid-restricted oligoclonal bands. After initial misdiagnosis of multiple sclerosis (MS) the patient received subcutaneous IFN-β1b and, subsequently, subcutaneous IFN-β1a therapy for several years. Under this treatment, the patient showed persisting relapse activity and finally presented with a severe episode of subacute aphasia and right-sided hemiparesis due to a large T2 hyperintensive tumefactive lesion of the left brain hemisphere and a smaller T2 lesion on the right side. Despite rituximab therapy two further LETM episodes occurred, resulting in severe neurological deficits. Therapeutic blockade of the interleukin (IL)-6 signalling pathway by tocilizumab was initiated, followed by clinical and radiological stabilization.

Conclusion: Our case (i) illustrates the relevance of correctly distinguishing NMO and MS since these disorders differ markedly in their responsiveness to immunomodulatory and -suppressive therapies; (ii) confirms and extends a previous report describing the development of tumefactive brain lesions under IFN-β therapy in two Asian NMO patients; and (iii) suggests tocilizumab as a promising therapeutic alternative in highly active NMO disease courses.

No MeSH data available.


Related in: MedlinePlus