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Department of Pediatrics, Toho University, Ohashi Medical Center, 2-22-36, Ohashi, Meguro, Tokyo, 153-8515, JapanDepartment of Pediatrics, Toho University, Sakura Medical Center, 564-1, Shimoshizu, Sakura, Chiba, 285-0841, Japan
Long-term management varies in patients with fulminant demyelinating diseases.
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Our fulminant MS patient had a tumefactive cervical lesion successfully treated with TCZ.
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TCZ decreased the relapse rate, oral PSL dose for relapse prevention, and the EDSS score.
Abstract
Fulminant demyelinating disease including acute disseminating encephalitis, multiple sclerosis (MS) variants, and neuromyelitis optica spectrum disorder (NMOSD) are often managed with similar acute treatment such as intravenous methylprednisolone and plasma exchange. On the other hand, long-term management varies. The choice of the drug is based on several factors including the activity and severity of the disease course. Tocilizumab (TCZ), which is a humanized anti-interleukin-6 receptor antibody, is one of the promising therapies for NMOSD because of decreasing the relapse rates and possibly the neurological disability. However, the efficacy of TCZ for MS with tumefactive lesion is unknown.
Here, we describe the clinical course of a 12-year-old Japanese boy who was diagnosed with fulminant MS with a tumefactive cervical lesion. Our case was refractory to aggressive immunosuppressive therapies and developed dependent on an intermediate dose of oral prednisolone (PSL) for relapse prevention. His neurological condition worsened with every attempt of tapering the PSL dose. Thus, we started treatment with tocilizumab, which allowed of tapering of the PSL dose without his symptom exacerbations, and effectively improved his Expanded Disability Status Scale score. Our findings may indicate that TCZ is effective for fulminant MS patients with a tumefactive cervical lesion.
Fulminant demyelinating diseases are often managed with similar acute treatments including intravenous methylprednisolone (IVMP) and plasma exchange (PE). However, long-term management varies. Tumefactive multiple sclerosis (MS), which is defined by the presence of a large (>2 cm) demyelinating lesion, is one of the fulminant demyelinating diseases (
We report a 12-year-old patient with fulminant MS with a tumefactive cervical lesion that was successfully treated with tocilizumab (TCZ), which is a humanized anti-interleukin-6 (IL-6) receptor antibody.
2. Case report
A 12-year-old Japanese boy presented the right upper limb weakness. He had no preceding infectious diseases or vaccinations. A week later, he was admitted to our hospital because of right hemiparesis and dyspnea. Neurological examination revealed right hemiplegia with extensor planter response, inability to elevate right rib cage, and no visual disturbance. The right upper extremity muscle strength was 2/5, and that of the right lower extremity was 3/5. Senses were normal. He was alert without any cognitive problems.
Blood and urine test results were unremarkable. A cerebrospinal fluid (CSF) examination revealed white cells 33 /μl comprised of 31 lymphocytes, protein 41 mg/dl, myelin basic protein 909 pg/ml (normal, <102 pg/ml), normal IgG index, and oligoclonal bands were negative. Autoantibody levels (anti-nuclear antibodies, anti-DNA antibodies, and anti-neutrophil cytoplasmic antibodies) were normal and serum anti-aquaporin-4 antibody (AQP4-IgG) and anti-myelin oligodendrocyte glycoprotein antibody were negative by cell-based techniques. Herpes simplex virus 1 and 2 (polymerase chain reaction in serum and CSF), cytomegalovirus, Epstein-Barr virus, varicella zoster virus, rubella virus, measles virus, human immunodeficiency virus, Mycoplasma pneumoniae, Treponema pallidum, and Borrelia garinii (ELISA in serum) were absent.
Brain magnetic resonance imaging (MRI) showed two lesions (Fig. 1). One lesion was in the right thalamus (Fig. 1, A, arrow) and the other was a cervical tumefactive lesion (>2 cm) with ring gadolinium (Gd)-enhancement (Fig. 1, B, arrowhead). The thoracic and lumbar spine MRI findings were normal.
Fig. 1Brain MRI at the onset. A: Axial T2-weighted image. B: Sagittal gadolinium (Gd)-enhanced T1-weighted image. C: Axial T2 weighted image. D: Coronal fluid-attenuated inversion recovery image. A: The image show a hyperintense lesion in the right thalamus (arrow). B: The image showed a cervical tumefactive lesion (>2 cm) with ring Gd-enhancement (arrowhead). C, D: The images showed a hyperintense lesion in cervical spine. The lesion is predominantly in the right side.
We diagnosed an inflammatory demyelinating disease and treated with IVMP (30 mg/kg/day) for 5 days, intravenous immunoglobulin (1 g/kg/day) for 2 days, four PEs, and intravenous cyclophosphamide (CPA) (500 mg/m2). However, his symptoms gradually progressed. Two weeks after starting these therapies, he developed complete paralysis and respiratory failure requiring mechanical ventilation. We maintained with a 3-day course of IVMP (30 mg/kg/day) 1x/month, intravenous CPA (500 mg/m2) 1x/month, and prednisolone (PSL) (30 mg/day [1.0 mg/kg/day]) through a nasogastric tube. Six weeks from the disease onset, his condition was stable: flaccid paralysis, respiratory failure, and visual disability (Expanded Disability Status Scale [EDSS] score: 9.5 points). The brain MRI, performed at 1-month intervals, revealed new disseminated lesions in the cerebrum, cerebellum, and optic nerves (Fig. 2, A2, B, C). Twelve courses of CPA (90 g in total) were completed at 1 year from the disease onset.
Fig. 2Serial brain MRI in the patient, a 12-year-old boy. A1-3: Coronal fluid-attenuated inversion recovery (FLAIR) image. B: Sagittal FLAIR image. C: Coronal gadolinium (Gd)-enhanced T1-weighted image with fat suppression. D: Axial Gd-enhanced T1-weighted image. A1: The image obtained at the onset show a hyperintense lesion in the right thalamus. A2, B, C: The images obtained at 3 months from the disease onset show the advent of new disseminated areas of hyperintensity in the cerebrum, cerebellum (A2), and the advent of a new Gd-enhanced lesion in optic nerve (arrow) (C). The cervical lesion is extending to the pons (B). D: The image obtained during the first tapering of prednisolone at 4 months from the disease onset show the advent of a new Gd-enhanced lesion (arrowhead). A3: The image obtained at 5 years from the disease onset show regression of the known lesions.
The oral PSL was tapered four times during the 2-year period from the disease onset (Fig. 3). His neurological conditions worsened with every attempt of tapering the PSL dose. In the first tapering at 4 months from the disease onset, his right upper extremity muscle strength worsened from 2/5 to 1/5, requiring PE because IVMP for 5 days was ineffective, and brain MRI revealed the advent of a new Gd-enhanced lesion (Fig. 2, D). We confirmed the diagnosis of MS and added intramuscular interferon β1a (INF-β1a) (30 μg) 1x/week. We considered the treatment with natalizumab rather than INF-β1a, but his parents disagreed with natalizumab because they concerned about opportunistic infections such as progressive multifocal leukoencephalopathy. In the second and third tapering, however, his limbs muscle strength also worsened, requiring PE, and brain MRI revealed the advent of new Gd-enhanced lesions. INF-β1a was discontinued after the third tapering at 1 year and 4 months from the disease onset, and IVMP switched to oral tacrolimus (3 mg/day, trough blood concentration 3.7–6.6 ng/ml) considering the side effects of long-term IVMP administration. During the fourth tapering, the brain MRI, performed at 1-month intervals, revealed the advent of a new Gd-enhanced lesion by chance without his symptoms exacerbations. We returned oral PSL to 30 mg/day and prevented exacerbations.
Fig. 3The clinical course of our patient and the therapeutic regimens. The oral PSL was tapered four times during the 2 years from the disease onset. After starting TCZ treatment, the dose of oral PSL was tapered from 30 to 10 mg/day and his EDSS score improved from 8.5 to 5.0 points without the advent of new Gd-enhanced lesions in brain MRI. CPA, cyclophosphamide; EDSS, expanded disability status scale; Gd, gadolinium; IL, interleukin; INF, interferon; IVIg, intravenous immunoglobulin; IVMP, intravenous methylprednisolone; MRI, magnetic resonance imaging; PSL, prednisolone; TCZ, tocilizumab.
Two years and 10 months after the disease onset, his serum levels of IL-6 (LSI Medience, Tokyo) increased to 8.84 pg/ml (normal, <2.41 pg/ml), whereas those of other pro-inflammatory cytokines including IL-1β and tumor necrosis factor alpha (TNFα) were normal. The patient and parents agreed to treatment with intravenous TCZ (8 mg/kg, at 4-week intervals) to reduce the oral PSL dose. One year and 6 months after starting TCZ treatment, we tapered the oral PSL from 30 to 10 mg/day and his EDSS score improved from 8.5 to 5.0 points (Fig. 3).
Five years from the disease onset, his conditions remained stable; he was able to walk independently and breathe spontaneously, and his visual acuity was 20/200 without loss of visual field. Brain MRI showed regression of the known lesions (Fig. 2, A3). Adverse events associated with TCZ were not observed.
3. Discussion
Clinical manifestations in tumefactive MS patients depend on the size and location of the tumefactive demyelinating lesion (TDL), which is more common in supratentorial area [1]. In our case, the upper cervical site of TDL predominantly extending to the right side (Fig. 1, C, D) may have affected the right pyramidal tract and phrenic nerve, resulting in right hemiplegia and reduced movement of the right rib cage.
To our knowledge, no patient with tumefactive MS treated with TCZ has been reported. The efficacy of TCZ for MS is inconsistent. One group reported a patient with rheumatoid arthritis (RA) and MS who was treated with TCZ for >5 years without exacerbations of MS (
). TCZ is one of the promising therapies for neuromyelitis optica spectrum disorder (NMOSD) because of decreasing the relapse rates and possibly the neurological disability. Araki et al. reported TCZ decreased the dose of oral PSL in four of seven NMOSD patients requiring an intermediate dose of PSL for relapse prevention (
). Our case developed on an intermediate dose of PSL for relapse preventation, and his serum level of IL-6 was increased. Therefore, we started TCZ treatment which allowed of tapering of the PSL dose and improved his EDSS score. There were no serious adverse events associated with TCZ including infusion-related reactions and infectious. Our patient was successfully treated with TCZ.
Atypical manifestations and disease course pose a therapeutic challenge. The acute managements of fulminant demyelinating diseases are similar, whereas the long-term management varies. The choice of the drugs is based on several factors including the activity and severity of the disease course. TCZ should be considered as a disease modifying therapy of tumefactive MS with dependence on an intermediate dose of PSL for relapse prevention and an increased serum IL-6 level.
Limitations include that the discontinuation of INF-β1a and/or the start with tacrolimus might have improved his conditions. In particularly, the discontinuation of INF-β1a may be effective because INF-β1a could worsen NMOSD. Our patient's serum AQP4-IgG levels remained negative despite serial testing. However, we could not exclude the diagnosis of NMOSD because some pediatric AQP4-IgG-seronegative patients become seropositive >3 years after the disease onset (
). In addition, we could not measure the IL-6 level in both serum and CSF before the start with immunotherapies. IL-6 plays an essential role in NMOSD pathogenesis, which has not been identified in tumefactive MS as yet.
4. Conclusion
TCZ treatment may have decreased the relapse rate, the oral PSL dose for relapse prevention, and the EDSS score in our fulminant MS patient with a tumefactive cervical lesion.
Funding
Supported by the Health and Labour Science Research Grants on Intractable Disease (Neuroimmunological Disease) and on The Promotion of Drug Development from the Ministry of Health, Labour and Welfare of Japan.
Ethics approval and consent to participate
This case report was approved by the Ethical Committee of Toho University, Ohashi Medical Center.
Consent for publication
Written informed consent for publication of this Case Report and any accompanying images was obtained from the patient and the patient's parents.
We thank Professor Takashi Sekine for clinical and administrative support, Dr. Toshiyuki Takahashi, Tohoku University Graduate School of Medicine for measuring antibodies against aquaporin-4 and myelin oligodendrocyte glycoprotein, and Dr. Hiroshi Terashima, National Center for Child Health and Development for advice.
References
Araki M.
Matsuoka T.
Miyamoto K.
et al.
Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study.
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