Patient Reported Outcomes while Manipulating the Immune System in autoimmune Encephalitis

The first notion of a type of autoimmune encephalitis was in the previous
century, when *paraneoplastic neurological syndromes* were discovered. These
disorders are believed to be the result of a cytotoxic T-cell mediated
inflammatory response to intracellular antigens released through the apoptosis
of tumour cells. The activated immune cells effectuate neuronal death,
resulting in gliosis and eventually (mesiotemporal) sclerosis. These disorders
respond only limited to (immune) therapy. The long-term effects are often
substantial and lasting.

In the first decade of this century, a second group of neurological autoimmune
syndromes was discovered. These syndromes are B-cell mediated. In contrast to
the classical paraneoplastic or *onconeural* antibodies, this set of antibodies
is not always related to malignancies. The B-cells may also be activated by a
virus, i.e. after a Herpes Simplex encephalitis, or it may be idiopathic. The
activated B-cells produce antibodies directed to neuronal surface antigens.
These may be components of presynaptic ion channels involved in the release of
neurotransmitters, or postsynaptic receptors to neurotransmitters. The
antibodies in this group of neurological disorders are believed to be directly
pathogenic. They can act as an antagonist to the neurotransmitter, cause
blockage and internalisation of receptors, or act as a signalling protein to
natural killer cells, resulting in neuronal death.
Frequent clinical symptoms include cognitive and behavioural disturbances,
seizures, movement disorders, ataxia and autonomic dysregulation. The incidence
of this novel category of neurological disorders increases rapidly with the
developing knowledge and recognition of the disorders. The disorders are
potentially better treatable with immunotherapy, aimed at suppressing the
inflammatory reaction and depletion of antibodies. Nonetheless many patients
suffer from persisting neurocognitive deficits, psychiatric symptoms and
epilepsy. This is has not been studied extensively untill now.

In the literature on the prognosis of autoimmune encephalitis, outcome is
generally expressed in terms of a score on the modified Ranking Scale (MRS).
The mRS is developed for acute neurovascular events and does not incorporate
the common neurological deficits encountered by the autoimmune encephalitis
population.

1. To measure clinical outcome of patients with an autoimmune encephalitis
longitudinally.
2. To evaluate existing PROMS, developed for other (neurological) disease, for
patients with an autoimmune encephalitis.
3. To develop and validate disease-specific patient-reported outcome measures
with discriminatory value in both the acute and chronic phase of autoimmune
encephalitis.

The Centre for Neuro-inflammatory disorders at Erasmus MC is a NFU endorsed
centre of expertise. The research line on autoimmune encephalitis, mostly
conducts translational research. The PROMISE study is a partially
cross-sectional, partially prospective explorative observational cohort study,
executed in a nationwide clinical cohort of patients with an autoimmune or
paraneoplastic encephalitis.

We will start with a literature review to previously applied outcome measures
in the encephalitis literature. We will focus on autoimmune encephalitis as
well as infectious encephalitis. The previously applied outcome measures will
be divided into categories, i.e. (1) objective somatic outcomes, (2) objective
cognitive outcomes, (3) subjective (e.g. patient- and carer-reported) outcome
measures, (4) diagnostic measurements (e.g. lab, imaging and
electrophysiological measures) and (5) descriptive clinical data (e.g. number
of days in the hospital, number of days on an Intensive Care Unit, discharge
destination).

Data on somatic outcomes, diagnostic measurements and descriptive clinical data
will mostly be or have been collected as part of the standard clinical care for
this population. Additionally, we will administer cognitive tests and patient-
(and carer-)reported outcome measures, selected from the above-mentioned
literature review.

For all the previously applied cognitive tests and PROM*s, we will evaluate
what construct it aims to measure (e.g. *executive functioning*,
*functionality* or *quality of life*), the time and effort to complete it and
the content validity for the intended population. Taking these evaluations into
consideration, we will make a selection of potentially relevant measuring
instruments and individual items from these instruments, and generate an *item
pool*.

We will institute a focus group of patients representative of our intended
population to provide input on additional potentially relevant topics. We will
transcribe and code these qualitative data to be incorporated in the item pool.

After selecting and developing disease-specific test items, we will collect
data on the item pool in the cross-sectional cohort. With these data, we will
perform a quantitative analysis of the validity, reliability, redundancy and
difficulty of the items, through the application of Classical Test Theory (CTT)
as well as Item Response Theory (IRT). These statistical methods will identify
the optimal combination of items and scoring formats, to span all levels of
disease severity, and place them on a linear, interval scale to assign value to
the outcome (per construct) of individuals. This will create a psychometrically
robust disease-specific (set of) outcome measure(s).

We will inquire a subgroup of 10 to 20 patients of the cross-sectional cohort
to complete the developed instruments two times, with an interval of two weeks,
to establish test-retest reliability.

We will analyse the convergent (construct) validity of the developed measure(s)
by comparing the generated outcome values to scores on existing outcome
measures targeting the same constructs. As the item pool will comprise mainly
of items from existing outcome measures, scores can be calculated to be
compared to new PROM values without additional time burden. The new generated
PROM values will also be compared to a patient-reported VAS score for each
construct (scale of 0 to 100). To evaluate the discriminative ability of the
developed measure(s), we will compare the generated outcomes (1) between
subgroups of respondents with different levels of severity in (persisting)
neurological deficits, based on the cognitive tests and mRS scores, and (2) to
available normative reference data from literature.

The following step is to implement a structured follow-up of the prospective
cohort, provisionally terminating at two years after the diagnosis. With the
longitudinal data, we will evaluate the longitudinal responsiveness of the
measuring instrument.

Most of the contact moments, will be in line with the standard clinical care
for patients with an autoimmune encephalitis. The Patient-Reported Outcome
questionnaires and part of the cognitive tests are additional. If the patient
is not primarily treated in the Erasmus MC, we aim to travel to the treatment
clinic This way, we attempt to minimalize the effort for the patients.

There is no risks associated with participation; questions and tests may be
experienced as time-consuming or confrontational. Filling in the
Patient-Reported Outcome questionnaire will demand maximally seven times 40-80
minutes, depending on where in the disease course the patient is at inclusion.

The principal benefits of this study for the population will be (1) the
development of a means to express (expected) outcome that is more informative
for the patient and (2) an outcome more sensitive to subtle change, increasing
the power of future studies.

A potential benefit for the individual patients in the study, is that they are
closely monitored. Changes may be noticed and acted on more rapidly. However,
the tests do not replace a full neuropsychological exam administered for
diagnostic or therapeutic purposes.

As some of the syndromes (status epilepticus and seizures as part of an overt
encephalitis) consist of cognitive deficits and lower level of consciousness,
the objectives cannot be achieved without including and studying incapacitated
subjects.