Introduction:

Adult MS patients have a relapsing- remitting (80%) and less frequently a primary- progressive course of the disease (20%) Reference Amato, Ponziani, Bartolozzi and Siracusa(1)). Children with MS have also a predominantly relapsing-remitting course. No reports on a primary-progressive course below the age of 10 years do exist. Even between 10 and 16 years of age a primary-progressive course of the disease is exceedingly rare Reference Simone, Carrara, Tortorella, Liguori, Lepore, Pellegrini, Bellacosa, Ceccarelli, Pavone and Livrea(2)). Children with MS have a longer disease duration until they enter a phase of secondary-progression compared to adults Reference Simone, Carrara, Tortorella, Liguori, Lepore, Pellegrini, Bellacosa, Ceccarelli, Pavone and Livrea(2,Reference Renoux, Vukusic and Mikaeloff3). Children with MS reach an expanded disability status scale (EDSS) 4 after a much longer time than adults (20.2 vs. 10.7 years), but are still significantly younger (median 31.6 years) than adults (median 41.1 years) when they suffer from significant disability Reference Simone, Carrara, Tortorella, Liguori, Lepore, Pellegrini, Bellacosa, Ceccarelli, Pavone and Livrea(2,Reference Renoux, Vukusic and Mikaeloff3). When children enter the phase of secondary progression they appear to follow the same time course as adults Reference Renoux, Vukusic and Mikaeloff(3)).

Children more often than adults present initially with more than one functional system involved Reference Noseworthy, Lucchinetti, Rodriguez and Weinshenker(4)). In a cohort of 132 patients reported by Pohl and colleagues 67% of children with MS had a polysymptomatic manifestation Reference Pohl, Hennemuth, von Kries and Hanefeld(5)). Cerebellar and brainstem symptoms in pediatric MS are more and pyramidal symptoms less frequent than in adults with MS Reference Simone, Carrara, Tortorella, Liguori, Lepore, Pellegrini, Bellacosa, Ceccarelli, Pavone and Livrea(2,Reference Pohl, Hennemuth, von Kries and Hanefeld5).

Children with MS have a higher relapse rate in the first 2 years, which in general correlates with a faster disease progression, than in adults Reference Gorman, Healy, Polgar-Turcsanyi and Chitnis(6)).

Before the age of 10 years a male preponderance exists. During and after puberty (between 15 and 16 years) several studies report a rise in the female/male ratio to 2.1:1 to 2.4:1, which is slightly higher compared to adults with MS Reference Simone, Carrara, Tortorella, Liguori, Lepore, Pellegrini, Bellacosa, Ceccarelli, Pavone and Livrea(2,Reference Pohl, Hennemuth, von Kries and Hanefeld5).

Of particular diagnostic relevance is the observation that children with MS often do not meet the McDonald MRI criteria for dissemination in space at the time of their first exacerbation or their MS diagnosis Reference Hahn, Shroff, Blaser and Banwell(7)).

This underscores the importance of other diagnostic features such as the presence of oligoclonal bands for an accurate diagnosis also in view of the broad differential diagnosis in pediatric MS. The most frequently considered differential diagnosis is acute dissem inated encephalomyelitis (ADEM). Clinical and neuroradiological features often do not permit a discrimination at the initial presentation. Although ADEM is regarded to be a monophasic disease, reports demonstrate the existence of biphasic or multi-phasic variants in children. ADEM presents rarely with oligoclonal IgG in cerebro-spinal fluid (CSF). Other important neuroimmu-nological diseases, which need to be considered, are neuromyelitis optica (NMO), the group of clinical isolated syndromes (e.g. transverse myelitis, opticus neuritis) in addition to rare neuromet-abolic diseases (e.g. Leber's hereditary optic neuropathy (LHON)). Most CSF studies in MS have been performed in adults. Little is known about the natural evolution from childhood to adulthood MS of CSF parameters such as albumin, protein, intrathecal IgG-and IgM- or a measles, rubella and varicella antibody synthesis -an important but still underappreciated feature of a chronic-neuroinflammatory disease.

We therefore studied the CSF of the first available lumbar puncture of 9 groups of MS patients with onset of MS between 7 and 30 years (n = 186) and compared our findings with a large cohort of non-inflammatory controls (n = 4100).

Data were evaluated numerically and graphically in CSF/serum quotient diagrams Reference Reiber and Peter(9)). As an extension of an earlier report Reference Reiber and Peter(9,Reference Reiber10) for the statistical purpose the intrathecal IgG and IgM synthesis was interpreted with reference to the Qmean + 2 SD as upper border of the reference range for blood derived proteins in CSF instead of the diagnostically more specific border Qlim = Q-mean + 3 SD. This improved the sensitivity for detection of an intrathecal IgM synthesis. This new CSF statistics tool which counts frequencies of increased values and also calculates mean intensities for comparison of groups and compensates for the age related difference of the barrier function in groups of different mean age was reported earlier in this journal Reference Reiber and Albaum(11)).

Our results were as follows: The increase of the mean albumin quotient QAlb (2.8-5.3 × 10-3) is age-related normal. Oligoclonal IgG was detected in all age groups with a frequency of 95-100%. The mean amount of intrathecal IgG in CSF increased with age of onset (IgGloc(mean) = 12-40 mg/L) (Reiber H, Teut M, Pohl D, Rostasy K M, Hanefeld F. Pediatric Multiple sclerosis: Age related differences and time course of the neuroimmunological response in CSF; unpublished results).

Frequency of intrathecal IgM (QIgM > Qmean (IgM) + 2 SD) was higher but intensity (mean of IgMloc (mean) was lower in early onset patients. There was no uniform tendency for increase or decrease of IgM intensity in the disease course of the single patient. The correlation ofintrathecal IgM synthesis with the clinical course of the disease showed that the presence of intrathecal IgM at time of first clinical manifestation in pediatric MS correlates with a slower progression of the disease (Stauch C, Rauchenzauner M, Pohl D, Hanefeld F, Reiber H, Rostasy KM. Intrathecal IgM synthesis in children with MS correlates with slow progression rate; unpublished results). This is in contrast to adult MS patients in whom the presence of oligoclonal IgM is associated with the onset of new relapses and an earlier conversion to secondary progression Reference Villar, Masjuan, González-Porqué, Plaza, Sádaba, Roldán, Bootello and Alvarez-Cermeño(12,Reference Villar, Masjuan, Gonzalez-Porque, Plaza, Sádaba, Roldán, Bootello and Alvarez-Cermeño13).

A certain confusion in the field comes from the interpretation of oligoclonal IgM in the CSF. In contrast to the established method of oligoclonal IgG, the existence of “oligoclonal” IgM as detected after isoelectric focusing is questioned by several groups (Reiber, personal communication). A second source of biased results comes from interpretations of intrathecal IgM by the linear IgM Index Reference Sharief and Thompson(14)). As shown recently the linear evaluation of an Index is unsuitable for statistical comparison of groups Reference Reiber and Albaum(11)).

The polyspecific, intrathecal production of antibodies against a wide range of antigens, a diagnostic hallmark in adults, was also found in children with MS. Frequencies of intrathecal measles and VZV antibody synthesis are similar in pediatric and adult MS patients, also in the disease course the intrathecal antibody synthesis does not diminish detected by serial analysis of the single patient.

Conclusions:

Although MS in childhood is characterized by important clinical differences, the findings in CSF of children with MS have all the hallmarks of a chronic-neuroinflammatory B-cell driven disease. Oligoclonal bands as detected by isoelectric focussing and the presence of measles, rubella and/or varicela antibodies are already present in children and of utmost importance do not represent a transient phenomena but a persisting immune response.

The main difference between pediatric and adult MS patients is the intensities but not the frequencies of the intrathecal IgG and IgM synthesis. Gender-related changes (pre- to post-puberty) from 1:1 to 1:2 (m:f) and median cell counts in CSF increase with age in MS. Differences between pediatric and adult MS are explained as normal age-related development but not as different neuroimmunological pathomechanism.

The neuroimmunological response in the CSF characterized the presence of oligoclonal IgG and the polyspecific response with MRZ antibodies is detected already in the earliest phase of pediatric MS and is therefore a diagnostically important difference to ADEM and other diseases.