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Page 2 of 3 Müller. Neuroimmunol Neuroinflammation 2018;5:23 I http://dx.doi.org/10.20517/2347-8659.2018.27

patient often cause an insufficient appraisal of the tested compound.

Nevertheless, it is worth to mention that certain drugs, such as interferons with their flu-like side effect profile
and their more frequent application rate, support onset of certain neuropsychiatric symptoms in contrast
to glatiramer acetate or compounds with distinct less frequent intake, such as natalizumab, ocrelizumab
or cladribin. In this respect, outcomes of Table 6 are of interest in combination with the discussion on the
severity of depression in relation to the applied medications. Here the authors conclude that drug side effects
may account for the found differences between treatments. This is an important aspect, which leads the
way to select medications with a need for less frequent intake, i.e., cladribine or ocrelizumab, in the future.
Thus, this paper also emphasizes by circumstantial evidence that not only reduction of the annual relapse
rate or MRI changes are important but also the kind of MS treatment for prevention of relapses. Another
point is the individually different necessary symptomatic therapy with spasticity ameliorating compounds
or cannabis like compounds. Nearly all of them induce fatigue. Moreover, dosing depends on concomitant
factors, i.e., body weight, severity of spasticity in relation to the localisation and size of lesions. Therefore, this
trial also underlines again that (1) MS therapy is complex, (2) asks for a patient tailored regime particularly
in the more advanced stages of the disease, and (3) maintenance of MS patients often faces the additional
appearance of various kinds of non-motor symptoms, i.e., depression. There is also hysteria on safety. In
the real world, clinical researchers underline the importance of the so-called nocebo-effect. This means that
[2,3]
patient experiences a side effect once being informed on its potential occurrence . In the clinical research
scenario, the side effect profile and the tolerability of a tested immune system modulating compound appears
to have more or at least the same importance than its efficacy. In clinical practice however, the application
of a compound is often the result of a careful benefit-risk evaluation performed by the prescribing physician
and the more and more well informed, mature patient. It is more important to select a therapy for the
modulation of the immune system, which is well tolerated and accepted by the individual patients. This also
increases the adherence to compound. Particularly, compliance is an important issue in the maintenance of
MS patients. Missing adherence may also contribute or trigger the Immune-reconstitution inflammatory
syndrome. If it occurs, it will may in turn weaken the confidence of the patient and the physician in the
[4-6]
applied compound .

In contrast, the current artificial clinical study world mostly only focus on relapse prevention and MRI
findings. The fancy translational approach to test compounds, which were successful in experimental
autoimmune encephalitis models with their focus on relapse prevention by modulation of the immune
system only, looks promising, but do not reflect all the therapeutic challenges of clinical practice. The
limitation of these experimental models and thus the performed experimental investigations is the
focus on the immune system. These models often only mirror mechanisms of neuronal dying based
on immunological mechanisms modulated by B- or T-cells. Thus, experimental research neglects that
chronic neuroinflammation and associated neurodegeneration may also cause further consequences,
such as psychopathological features and personality changes. The register trials often use quality of life
scales, which disregard the individually varying, existing capacity of the human brain to compensate these
neuropsychiatric events for certain intervals before the clinical onset of initial mild and unspecific symptoms.
This so-called “neuroplasticity” phenomenon may also impact the rate of progression and thus differs in an
individual different manner. In summary, this heterogeneous and individual different disease progression in
combination with relative short trial periods may also contribute to a failure of trials on disease modification,
particularly in progressive MS. Mortality or increase of life expectance, caregiver burden or delay of
transfer to nursing homes may represent more robust clinical endpoints in terms of disease modification in
comparison to the mostly applied expanded disability status scale score or the artificial conversion endpoints
from relapse remitting to progressive MS. One must admit that the aforementioned suggested, alternative
endpoints would demand longer study durations particularly in the real world, as suggested in this paper.
However, the real world finally determines the value of treatment and the efficacy of drugs.