A prospective, multi-centre study investigating the incidence and prognosis of relapses, pseudo-relapses and other causes of (sub)acute neurological symptoms in patients with relapsing-remitting multiple sclerosis.

Relapses in patients with multiple sclerosis (MS) are common. Relapses have a
considerable impact on patients; they can lead to residual symptoms and
uncertainty and have considerable impact on daily life. It is important to
recognize relapses because the present treatment strategy aims for NEDA (No
Evidence of Disease Activity), which means no relapses, no progression of
disability and no change in MRI MS white matter lesions. A relapse indicates
activity of the disease and will lead to decision making such as start of
methylprednisolone treatment and/or change in immunomodulating therapy.
In daily practice it is however not always easy to determine whether there is a
real relapse. A possible other cause is a pseudo-relapse during a period with
infection or fever, however true relapses can also be provoked by infections.
Other possible mimics are for example other neurological conditions,
complications of treatment, heat intolerance, orthopaedic conditions, metabolic
disturbances or functional disturbances. These mimics / pseudo-relapses ask for
different care and support than relapses.
Magnetic resonance imaging (MRI) for diagnosing a relapse is not a very
sensitive test. A gadolinium-enhancing lesions which correlates with the new
clinical symptoms supports the diagnosis of a real relapse, however, new
lesions may not always be apparent on imaging and new lesions can also appear
without clinical symptoms (the clinic-radiological paradox). There are no
studies correlating the location of the lesion with the clinical localisation.
A potential biomarker to make it more easy to distinguish a relapse from a
pseudo-relapse could be serum neurofilament light protein (NFL). No research
has been done on NFL as marker to distinguish relapse from pseudo-relapse.
Hardly any literature exists on the incidence of relapses versus
pseudo-relapses in patients with (sub)acute new symptoms in MS. In this
prospective study we want to assess the cause of neurological deterioration
(relapse, pseudo-relapse, mimic) and their incidence and outcome. Also we would
like to find out if serum NFL is a good marker to distinguish relapse from
pseudo-relapse.

The primary objective of this study is to assess whether the cause of
neurological deterioration in patients with RRMS/CIS is a real relapse, a
pseudo-relapse or mimic and compare these groups on baseline characteristics.

Secondary objectives:
* To determine the duration, severity and prognosis of documented relapses
measured on the Expanded Disability Status Scale (EDSS) and patient reported
outcomes on impact on daily activities and degree of recovery and compare these
parameters between groups.
* To describe which data, derived from anamnesis, neurological examination, MRI
and laboratory tests, guide a neurologist to diagnose the cause of the
deterioration
* To determine if serum NFL differs between patients with a clear relapse, a
clear pseudo-relapse and patients in who the neurologist is in doubt between
these two causes

Tertiary (exploratory) objectives:
* To investigate the diagnostic potential of serum NFL to distinguish relapse
from pseudo-relapse
* To determine the location of the relapse (optic nerve, cerebellum, brainstem,
cerebral hemispheres or spinal cord) (in case of real relapse) and the
prognosis of a relapse in that region
* To determine if the location of the current relapse is associated with the
location of the previous relapse
* The requirement for treatment with glucocorticoids due to the relapse
* Degree of certainty about the cause of deterioration

This is a prospective, multi-centre, study. Eligible subjects with a possible
relapse with onset less than 14 days are included. The subjects will be
examined clinically at baseline, after 6 and 12 weeks. As per standard care
laboratory tests and urinary screening will be performed at baseline if
necessary. In a subgroup an extra blood sample is taken at baseline and week 12
to assess on neurofilament light chain levels (only in patients with relapse,
pseudo-relapse or when in doubt). The MRI of the brain and/or spinal cord is
performed (T1-weighted, T2-weighted, FLAIR (fluid attenuated inversion
recovery) and gadolinium enhanced) at baseline depending on the judgement of
the treating neurologist. After each visit patients will receive an e-mail with
1 or 2 questions on impact on daily activities and degree of recovery.

For each subject this study covers for a period of approximately 12 weeks.
During this period subjects will visit the hospital 3 times, which is 1 extra
visit than during regular care. During these visits a physical and neurological
examination will be performed. During the first visit a blood sample and
urinary screening will be taken (as per standard care). The visits will take
approximately 30 minutes per visit. According to standard care, in some cases a
MRI will be performed. The MRI takes about 20 minutes. At baseline and week 12
an extra blood sample will be taken in a subgroup. Risks associated with the
visits and investigations are considered minimal as these are routine
activities. After each of the 3 visits patients will receive an e-mail with 1
or 2 questions on impact on daily activities and degree of recovery.