Abstract
We investigate common pathophysiology in paediatric and adult multiple sclerosis (MS) by comparison of cerebrospinal fluid (CSF) data. We compared cerebrospinal fluid (CSF) data from eight patient groups with onset of MS at 7 to 29 years (n = 184). A new statistics program allows sensitive detection, quantifies the mean amount of intrathecal Ig synthesis in groups based on the 96% reference range of 4100 non-inflammatory controls, corrects for age-related increase of blood-derived albumin and immunoglobulins in CSF, and presents graphical data interpretation in Reibergrams. Already at onset of MS before puberty (≤10 years) the frequency of intrathecal IgG synthesis (oligoclonal IgG) was 100% like in adults with 98%, but the amount of intrathecal IgG increases twofold during puberty. Intrathecal IgM synthesis is most frequent before and during puberty (in 57—67% of patients) compared with 41% in adults. The amount of intrathecal IgM synthesis before puberty is only 30% of that in adults. IgG and IgM Index are biased evaluations not suitable for characterizing age-related dynamics. A twofold age-related increase of the albumin quotient, QAlb, as a measure of the blood—CSF barrier function, represents normal physiological growth. Cell counts in CSF are low. The pre-puberty gender ratio is about 1:1. Intrathecal antibodies against measles, rubella and/or varicella zoster virus are detected in 73% of patients before puberty compared with 89% of adults. Individual paediatric patients (n = 17), with sequential punctures over 2—5 years, show constant quantities of intrathecal IgM and specific antibodies. In conclusion, paediatric MS already at first clinical manifestation shows the complete, neuroimmunological data pattern in CSF, i.e. inflammatory signs are not gradually evolving. Paediatric and adult MS differ quantitatively but not qualitatively in neuroimmunological patterns which does not allow for discrimination between ‘early’ and ‘late’ onset MS. CSF analysis may help to discriminate between acute and mono-symptomatic chronic inflammatory disease already at earliest clinical manifestation.
Highlights
For years the rediscovery[1,2,3] of paediatric multiple sclerosis (MS) nourished the expectation of a better understanding of the pathophysiology of MS
The frequency of blood–cerebrospinal fluid (CSF) barrier dysfunction was similar in all age groups (Table 2) with a slight tendency to higher frequencies in older age
In the interpretation by quantitative intrathecal fractions (IgG-Fr(>2SD) in Table 2) the frequencies for QIgG > Qmean + 2SD (67–97%) matches this result of oligoclonal bands (OCBs) better than for the diagnostically relevant decision border QIgG > Qlim (1⁄4Qmean + 3SD) (IgG-Fr(>3SD) in Table 2): instead of a mean frequency of 72% of the adults we obtain a mean frequency of 82% and instead of the mean frequency of 69% of the total group of paediatric patients we obtain 75% (Table 4)
Summary
For years the rediscovery[1,2,3] of paediatric multiple sclerosis (MS) nourished the expectation of a better understanding of the pathophysiology of MS. The predominant IgG class reaction is detected by oligoclonal bands after isoelectric focusing[10] in 98% of the adult MS patients Owing to this high sensitivity the detection of oligoclonal IgG became an essential part of a qualified laboratory supported diagnosis of MS.[11] The less-frequent intrathecal IgM class response (20–50%) has been investigated[5] mainly with respect to its predictive value for the course of the disease.[12,13] The quantification of intrathecal IgG, IgA and IgM became possible due to the well-established and theoretically founded nonlinear reference range for blood-derived proteins in CSF14,15 avoiding incorrect interpretations due to linear IgG or IgM index with false-positive and false-negative interpretations in CSF routine diagnosis.[6] the missing compensation for the physiological age-related change of the blood– CSF barrier function, in children, led to a bias in the interpretation of earlier results. With the new statistics software[8] we correct for this physiological increase of the blood-derived albumin, IgG and IgM fractions in CSF
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