‘Natalizumab in paediatric multiple sclerosis and service implication’

The recent paper by Karenfort et al.1 in DMCN raises important issues in the treatment of multiple sclerosis (MS) in children, and not just the potential benefit of disease-modifying treatment (DMT), as illustrated by the following patient. A 7-year-old male presented to Alder Hey Children's Hospital with ataxia, double vision, and internuclear ophthalmoplegia. Magnetic resonance imaging (MRI) revealed multiple areas of high signal in the cerebral and cerebellar hemispheres and brainstem. Cerebrospinal fluid (CSF) analysis showed 10 monocytes, an elevated protein level, and positive oligoclonal bands. The differential diagnosis included acute disseminated encephalomyelitis or a clinically isolated syndrome. Recovery was complete following intravenous methylprednisolone; MRI 6 weeks after admission showed a new lesion in the cerebellum. Four months later the patient presented with cerebellar ataxia. MRI demonstrated new lesions in the cerebellar vermis and right cerebellar hemisphere; CSF showed no cells and positive oligoclonal bands. A probable diagnosis of relapsing-remitting MS was discussed with the family. Four separate clinico-radiological episodes occurred over the next 22 months. Disease-modifying treatment to prevent further relapses was discussed with the lead neurologist in multiple sclerosis (MB) at the local adult neurosciences tertiary centre. Glatiramer acetate was commenced at 11 years of age. The child was followed up in the paediatric neurology clinic, and by MB and the MS nurse specialist at the adult neuroscience centre. Two relapses occurred one and five months following the introduction of glatiramer acetate, and a third 13 months later in the brainstem and cervical cord. Glatiramer acetate was discontinued and 2 months later (aged 13y), he was commenced on monthly intravenous infusions of natalizumab (300mg). The patient has received natalizumab for 15 months and has experienced no further relapses. Neurological examination is normal and he attends a mainstream school. Brain MRI demonstrates an improvement compared with a pretreatment baseline scan and no new lesions. Antinatalizumab antibodies have not been detected. The patient remains under the care of the author (RA). Before 2004, the patient was also reviewed in the adult MS clinic; however, in 2004, following child protection guidelines, patients under 16 were no longer able to attend the adult neurosciences centre. Consequently, contact with the MS team has been by telephone and annual joint assessments by RA and MB at Alder Hey. Although MS occurs far less commonly, it is considered to be more aggressive with more frequent relapses in children than in adults.2,3 Our patient met historic and current diagnostic criteria for MS.4 Frequent relapses justified the use of DMT, initially with glatiramer acetate, despite UK guidance.5 A subsequent severe relapse in a new anatomical site prompted the introduction of second-line therapy with natalizumab, an α4β1-intergrin antagonist, recently licensed as monotherapy in 'highly active' MS. Our patient has tolerated natalizumab well and has been relapse-free with improved MRI appearances over 15 months on treatment. There have been only a few single case reports of natalizumab6,7 and a related drug, rituximab1 in children; although these early reports are encouraging caution is required because of the rare but serious side effects, including progressive multifocal leucoencephalopathy which has been reported in adults treated with these drugs. In the UK, the management of MS in children is not as structured as in adults, in part reflecting its relative rarity and atypical presentation as well as limited access to a specialist multidisciplinary service. Transition demands a planned and structured move from paediatric to adult care, which should include appropriate preparation and discussion before transfer to a new service for continuing care. Ideally, transitional care should be introduced from 13 or 14 years of age, similar to transitional clinics established in other areas, including epilepsy and cerebral palsy.8,9 The use of DMT is limited in children, because these have been no paediatric randomized clinical trials, the recommendation by the Association of British Neurologists that these drugs should only be used in patients aged over 18 years, and concern over their side effects. This is compounded by the fact that patients under 16 years cannot be seen in some adult units or Trusts. This is of particular concern with the importance of the early use of DMT to prevent relapses and reduce the risk of irreversible neurological disabilities. Young people with MS should be managed within multidisciplinary clinics involving paediatric neurologists and adult MS specialists to optimize their care, particularly with DMT. There are specific multiple sclerosis clinics (including 'Pediatric MS Centers of Excellence') in the US (http://www.nationalmssociety.org) which are multidisciplinary teams including both adult and paediatric specialists, with links to an adult MS centre. Transitional services for young people with MS are less well established in parts of Canada (http://www.mssociety.ca; Banwell B, Camfield P, personal communication 2009) and Europe (specifically, the Netherlands and Sweden; Brouwer O, Wide K, personal communication 2009), where teenagers and adolescents tend to be transferred directly to an adult MS clinic or service. It is hoped that further discussions in the UK will lead to similar dedicated joint, transitional, and multidisciplinary clinics for young people with MS, thereby addressing their needs and also the concerns raised by the National Services Framework10 and the MS Society of Great Britain.8

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