Treatment of children and adolescents with multiple sclerosis

The onset of multiple sclerosis is being increasingly recognized in children and adolescents. There are now approved immunomodulatory therapies for adults with multiple sclerosis. Treatment early in the disease course appears to have a greater impact on disease outcome, an issue of particular importance for children who face decades of multiple sclerosis disease activity. This review summarizes the multiple sclerosis therapies currently available, efficacy data available from studies of these medications in adults and limited information on the use of these medications in children. Future directions in multiple sclerosis therapeutics and specific issues relating to pediatric multiple sclerosis are discussed.     

Is multiple sclerosis a sexually transmitted infection?

It is proposed that multiple sclerosis may be transmitted chiefly by sexual contact. Arguments favouring this include: migration studies that suggest a transmissible agent in adolescence; clusters of multiple sclerosis which have occurred in low prevalence areas following entry of young males; the similarity of multiple sclerosis to tropical spastic paraplegia, a known sexually transmitted infection with resemblance to primary progressive multiple sclerosis; an increased rate in drug misusers; a similar age of onset and sex pattern to that found in sexually transmitted disease; increased incidence of multiple sclerosis in those using oral contraceptives; low multiple sclerosis rates in societies with a strict moral code; longitudinal shifts in sex prevalence that show an increase in women after the sexual revolution of the 1960s; and important exceptions to the worldwide distribution corresponding to countries with permissive attitudes to sex. Family, conjugal pair, twin, and adoption studies are compatible with an infectious cause of multiple sclerosis if this is sexually transmitted. It is not proposed that sexual transmission is the only cause but that inherited factors create a susceptibility to a sexually transmitted neurotropic agent. It is hoped this hypothesis might encourage a new direction of neurological research.     

Serum measles antibodies in multiple sclerosis

Serum haemagglutination inhibition/HI/antibody titres to measles virus were examined in 80 multiple sclerosis patients, their 20 sibs, in 990 healthy controls, and 25 control patients. The measles HI titres were significantly raised in the serum of multiple sclerosis patients compared with healthy controls. There was no statistical difference between the levels of HI antibody titres in multiple sclerosis patients and their sibs. The measles HI titres decreased significantly in older age groups of healthy controls, whereas an analogous drop was not found in the multiple sclerosis group. The levels of serum HI antibody titres did not correlate with the sex of patients with multiple sclerosis or the activity of the disease. In the CSF of six multiple sclerosis patients low titres of HI antibodies were detected, whereas none of eight control patients had measurable traces of measles antibodies in the CSF. The significance of these findings in the aetiology of multiple sclerosis is briefly discussed.     

Definite and suspected multiple sclerosis in children: long-term follow-up and magnetic resonance imaging findings

Twenty-five children at the ages of 3 to 18 years with an initial diagnosis of acute disseminated encephalomyelitis were followed in the Clinic of Child Neurology for a period of 2 to 8 years. In 10 children, there were data for clinically definite or laboratory-supported definite multiple sclerosis. The other 15 children in our study were considered as having suspected multiple sclerosis. Brain magnetic resonance imaging (MRI) performed in 15 children disclosed multiple hyperintense lesions on T2-weighted imaging in 13 children: 10 with definite multiple sclerosis and 3 with suspected multiple sclerosis. The clinical manifestations did not always correspond to the size and location of the MRI lesions of demyelination. Follow-up revealed normalization of the neurologic examination in 18 patients (72%) and abnormal neurologic findings in 7 patients (28%) (6 children with definite multiple sclerosis and 1 with suspected multiple sclerosis). Magnetic resonance imaging follow-up in children with definite multiple sclerosis disclosed a reduction in the size of the lesions in 3; enlargement or new lesions were established in the other 7 cases, and 2 cases were without clinical signs of new attacks. Correlation was done concerning the findings of the cerebrospinal fluid examination, transcranial magnetic stimulation, evoked potentials, computed tomography, and MRI. The role of MRI for an early diagnosis of multiple sclerosis in children is discussed. The dynamic follow-up of the pathologic changes is of prognostic significance for the course of the disease that could be a definite cessation of the process in acute disseminated encephalomyelitis cases or transition to multiple sclerosis.     

A reassessment of the risk of multiple sclerosis developing in patients with optic neuritis after extended follow-up.

One hundred and one of 146 patients presenting with isolated idiopathic optic neuritis, previously reviewed in 1978, were reassessed clinically, and retyped for HLA antigens and Factor B alleles, after a mean follow-up of 11.6 years. Fifty eight patients (57%) had developed multiple sclerosis at the time of reassessment in the present study, of whom 51 (88%) had clinically definite disease. This compared with 40% of the original group, in 1978, of whom 62% then had clinically definite multiple sclerosis. When the life-table method of analysis was used, the probability of developing multiple sclerosis was 75%, 15 years after the initial episode of optic neuritis. The frequencies of HLA-DR2 and the recently defined D-region antigen, DQw1, were significantly increased in patients with isolated optic neuritis and those who subsequently developed multiple sclerosis compared with normal controls, but neither allele appears to influence progression from optic neuritis to multiple sclerosis. Patients with optic neuritis who were HLA-DR3 positive had an increased risk for the development of multiple sclerosis (RR = 2.8) and this risk was further enhanced when DR3 occurred in combination with DR2 (RR = 6.7). The overall increased risk of developing multiple sclerosis for patients with this combination was 26 times that for the normal population. When the patients' original tissue-typing was considered BT 101 no longer influenced conversion of optic neuritis to multiple sclerosis. This may partly be explained by improved methods of tissue-typing, since not all BT 101 patients were subsequently found to be positive for HLA-DR2 or HLA-DQw1 and vice versa and by extended follow-up as multiple sclerosis conversion in HLA-DR2 negative individuals increased with time. All 101 patients were typed for Factor B alleles. No significant differences in frequencies were found between individuals with isolated optic neuritis or those who progressed to multiple sclerosis compared with the control population. Recurrent episodes of optic neuritis were associated with an increased risk for the development of multiple sclerosis in this study.     

Borrelia burgdorferi antibodies in patients with relapsing/remitting form and chronic progressive form of multiple sclerosis.

Sera of 106 multiple sclerosis patients and 103 closely matched controls were examined for Borrelia burgdorferi antibodies. The prevalence rate in multiple sclerosis patients was 14.2%, in controls 25.2%. Overall prevalence was 20.1%. Mean IgG antibody level was insignificantly higher in controls than in multiple sclerosis patients. Patients with a chronic progressive course of multiple sclerosis had an insignificantly higher mean borrelia antibody level, when compared with those suffering from relapsing/remitting form of disease.     

Tau, phospho-tau, and S-100B in the cerebrospinal fluid of children with multiple sclerosis

Axonal injury and glial activation are an early neuropathologic event in adults with multiple sclerosis. To investigate whether markers of axonal injury and glial activation are already elevated in the cerebrospinal fluid of children with multiple sclerosis, we studied the cerebrospinal fluid of 25 children with multiple sclerosis and 67 controls for the presence of tau, phospho-tau, and S-100B proteins using specific enzyme-linked immunoabsorbent assays. In general, tau, phospho-tau, and S-100B protein levels did not differ significantly between groups. However, in a subgroup of nine children with multiple sclerosis, all of whom had prominent clinical symptoms at the time of lumbar puncture and radiologic disease activity, tau protein levels were significantly elevated when compared with other controls. These data indicate that axonal injury is not restricted to adult multiple sclerosis but can already occur in children with multiple sclerosis.     

Acute optic neuritis: a prospective study of risk factors for multiple sclerosis.

Eighty two patients with isolated optic neuritis were studied prospectively to determine the frequency with which multiple sclerosis developed and the factors which increased its risk. Patients were followed for 6 to 264 months (mean, 57 months). Twenty six patients (32%) developed clinically definite or probable multiple sclerosis during the period of follow-up. Actuarial analysis predicted that 42% would develop multiple sclerosis by 7 years. Of those patients who developed multiple sclerosis, 92% had symptoms within 4 years of the first attack of optic neuritis. The highest incidence of multiple sclerosis occurred in the 21-40 year age group. There was an increased risk of MS in patients with HLA-DR2 and HLA-B7 tissue types. The frequency of HLA-DR4 was increased in patients with optic neuritis alone compared to controls and to patients with multiple sclerosis, but further studies are required to confirm this finding.     

Intravenous immunoglobulin and interferon: successful treatment of optic neuritis in pediatric multiple sclerosis

Optic neuritis is a common clinical condition that causes loss of vision. It can be clinically isolated or can occur as one of the manifestations of multiple sclerosis. Multiple sclerosis is a severe disabling demyelinating disease of the central nervous system, which is rare among children. The treatment of optic neuritis has been investigated in several trials, the results of which have shown that corticosteroids speed up the recovery of vision without affecting the final visual outcome. Treatment of neurologic disorders with intravenous immunoglobulin is an increasing feature of our practice for an expanding range of indications, including multiple sclerosis. Owing to its anti-inflammatory properties, intravenous immunoglobulin can be beneficial in the treatment of acute relapses and in the prevention of new relapses of multiple sclerosis. To our knowledge, there is only one experience of treatment of optic neuritis with intravenous immunoglobulin in multiple sclerosis, even if therapeutic trials are used in the therapy of multiple sclerosis. We report on a girl with optic neuritis and multiple sclerosis in whom treatment with intravenous immunoglobulin at first alone and subsequently associated with interferon achieved great improvement in visual acuity.     

Demyelinating optic neuritis in children

Acute demyelinating optic neuritis in children can occur in isolation or be associated with acute disseminated encephalomyelitis, multiple sclerosis, or neuromyelitis optica. Clinical features, neuroimaging, cerebrospinal fluid findings, and long-term prognosis were reviewed in 26 children diagnosed with optic neuritis at the first presentation of demyelinating disease. The risk factors for the subsequent diagnosis of multiple sclerosis were analyzed. The mean duration of follow-up was 6.2 years. To date, 6 children have been diagnosed with multiple sclerosis (23%). An abnormal brain magnetic resonance imaging, older age, oligoclonal bands in cerebrospinal fluid, and elevated immunoglobulin G index were associated with multiple sclerosis outcome. Children with monosymptomatic optic neuritis and an abnormal brain magnetic resonance imaging had a higher risk for multiple sclerosis. These children should be monitored closely for the subsequent diagnosis of multiple sclerosis and can be considered for early preventive therapy.     

The association between multiple sclerosis and infection with Epstein-Barr virus and retrovirus

B-lymphoblastoid cell-lines may develop spontaneously in mononuclear cells from patients with multiple sclerosis, an observation rarely seen in healthy individuals. Examination of such spontaneously established B-cell lines reveal the presence of Epstein-Barr virus and retrovirus particles. We have speculated that in predisposed individuals, a dual infection with retrovirus and late acquired Epstein-Barr virus plays an aetiological role in the development of multiple sclerosis. This hypothesis is supported by a number of observations, including the finding that infection with Epstein-Barr virus may be a prerequisite for developing multiple sclerosis. The association between multiple sclerosis and infection with Epstein-Barr virus and retrovirus is evaluated in this study.     

Increased prevalence and titer of Epstein-Barr virus antibodies in patients with multiple sclerosis

The prevalence and titer of serum antibodies to several Epstein-Barr virus (EBV) antigens were compared among patients with multiple sclerosis, healthy siblings of multiple sclerosis patients, patients with other neurological diseases, and healthy non-blood-related subjects. Serum-cerebrospinal fluid (serum-CSF) pairs were available on a selected number of multiple sclerosis and control subjects. An increased antibody response to EBV antigens was noted rather consistently in the sera of the multiple sclerosis group in comparison with the control groups. A greater number of reduced ratios of serum:CSF IgG antibody to EBV-capsid antigen and antibody to EBV-early antigen components than to adenovirus, a reference or control virus, were found in the multiple sclerosis group. Reduced ratios of these EBV antibodies were detected more frequently or showed a trend in this direction in multiple sclerosis patients compared with the group with other neurological diseases. Our findings extend the results of an earlier report and strengthen the association between EBV and multiple sclerosis.     

Multiple ring-enhancing lesions in a child with relapsing multiple sclerosis

The presence of ring-enhancing lesions in brain magnetic resonance images (MRIs) often raises the concern of an infectious etiology, although this radiographic finding is also seen in patients with multiple sclerosis. Multiple ring-enhancing lesions have been reported in adult patients diagnosed with multiple sclerosis but have not yet been reported in childhood multiple sclerosis. We report here a 14-year-old girl with recurrent neurologic symptoms. Her initial brain MRI showed multiple ring-enhancing lesions involving numerous white-matter fiber tracts. An extensive investigation for infectious etiologies was unrevealing. Studies of cerebrospinal fluid showed an elevated myelin basic protein and the presence of an oligoclonal band not seen in the serum. The results of electrophysiologic studies suggested a demyelinating process. The patient responded rapidly to high-dose corticosteroid treatment. However, she suffered a clinical relapse 3 months later, presenting with dysesthesia and weakness of the right arm. Repeat MRI showed multiple new active lesions. This case report illustrates that multiple ring-enhancing lesions in the brain MRI can be seen in children with multiple sclerosis and that multiple sclerosis should be considered as part of the differential diagnosis when encountering a pediatric patient with similar radiographic findings.     

Human herpesvirus 6 is latent in peripheral blood of patients with relapsing-remitting multiple sclerosis

Studies of the association between HHV-6 and multiple sclerosis are hindered by the difficulty in discriminating between latent and active infection. A follow up study was undertaken of patients with multiple sclerosis, searching peripheral blood mononuclear cells for molecular markers associated with HHV-6 latency and lytic replication. The results show that HHV-6 is latent and did not support systemic infection in patients with multiple sclerosis. Likewise, patients with multiple sclerosis did not show any evidence of active infection with other human herpesviruses HHV-7 and HHV-8.     

Concepts of viral pathogenesis of multiple sclerosis.

Viral infections have long been suspected to cause or modulate the pathogenesis of multiple sclerosis. Recently, two viruses in particular have been associated with multiple sclerosis: human herpesvirus-6 and a retrovirus termed multiple sclerosis-associated retrovirus, which is a member of the human endogenous retrovirus-9 family. Reports on the detection of human herpesvirus-6-encoded proteins in and around multiple sclerosis lesions are intriguing. Serological and polymerase chain reaction analyses looking for signs of reactivation of human herpesvirus-6 in multiple sclerosis patients are ambiguous, however. If human herpesvirus-6 does play a role as an initiator or amplifier of inflammatory lesions in some multiple sclerosis patients, these individuals might benefit from antiviral therapy.     

Epidemiology and natural history of multiple sclerosis: new insights

PURPOSE OF REVIEW: The cause of multiple sclerosis remains elusive. We review recent epidemiological studies of genetic and environmental factors that influence susceptibility to the disease and its clinical course. RECENT FINDINGS: Genetic advances strengthen the association of multiple sclerosis with the human leukocyte antigen (HLA)-DRB1 allele and interferon-gamma polymorphisms and suggest that apolipoprotein E alleles play an important role. In the environmental realm, nested case-control studies show that prior Epstein-Barr virus exposure is overrepresented in multiple sclerosis. Smoking has been associated with both risk of multiple sclerosis and progressive disease. Vitamin D deficiency might tie together environmental clues with higher multiple sclerosis prevalence rates; dietary vitamin supplementation is also associated with reduced multiple sclerosis risk. Natural history studies demonstrated dissociation between relapses and disease progression, facilitated the ability to distinguish neuromyelitis optica and related syndromes from typical multiple sclerosis, and spawned the exploration of large datasets to model long-term disease activity. SUMMARY: Our understanding of the contributions of specific genetic and environmental factors that contribute to multiple sclerosis has improved. Further refinements will eventually allow powerful longitudinal studies to assess genetic and environmental interactions with implications for prediction of individual disease susceptibility, clinical course, and response to therapy.     

Chlamydophila pneumoniae infection of the central nervous system in patients with multiple sclerosis

BACKGROUND: Chlamydophila pneumoniae has been postulated as an aetiological agent in the pathophysiology of multiple sclerosis. Previous studies show conflicting results. OBJECTIVE: To investigate patients with multiple sclerosis and other neurological diseases for evidence of past or present infection with C pneumoniae. METHODS: 19 patients with multiple sclerosis and 29 with other neurological diseases were studied. Evidence was sought for past or present infection with C pneumoniae using polymerase chain reaction (PCR) and cell culture of cerebrospinal fluid (CSF), and enzyme linked immunosorbent assay and microimmunofluorescence of serum. RESULTS: C pneumoniae was grown from the CSF of one patient with multiple sclerosis. PCR was negative in all cases. Anti-chlamydial antibodies were detected in the same proportion in each group. CONCLUSIONS: This study does not support the theory of an association between C pneumoniae and multiple sclerosis.     

Multiple sclerosis in North-West India

Fifty-four patients with multiple sclerosis from North-West India are described. This included two pathologically proven cases of multiple sclerosis. Five patients conformed to the definition of neuromyelitis optica (Devic's syndrome). This study is in agreement with the other series reported from Asia regarding the special clinical features of multiple sclerosis described from this part of the world. There is more common occurrence of visual impairment at onset, predominant involvement of optic nerves and spinal cord and higher incidence of classical neuromyelitis optica. There is no relationship of any or all cerebro spinal fluid abnormalities with the type of multiple sclerosis, duration of an attack and disability, except for the possible relation between the type of colloidal gold reaction pattern and the type of multiple sclerosis.     

Speed of information processing as a key deficit in multiple sclerosis: implications for rehabilitation

Speed of information processing was assessed in patients with multiple sclerosis and healthy controls using both an auditory and visual task designed to control for accuracy of performance across groups. After controlling for accuracy of performance, patients with multiple sclerosis were found to have significantly slower speed of information processing relative healthy controls, irrespective of the modality of stimulus presentation (auditory or visual). When given an adequate amount of time to process information, however, the patients performed similarly to controls. These results suggest that persons with multiple sclerosis experience deficits specifically in processing speed but not performance accuracy. Results are discussed in terms of rehabilitative guidelines for the cognitive improvement of persons with multiple sclerosis.