Optimization of the International Paediatric Mitochondrial Disease Scale

Mitochondrial diseases are the most prevalent inherited metabolic diseases,
with an incidence of approximately 1 : 5,000 live births(Schaefer, Taylor et
al. 2004). Since mitochondria are present in almost all cells, symptoms can
arise theoretically from virtually every organ, but mostly from brain, heart,
eye and skeletal muscle(Koopman, Willems et al. 2012). There is not only large
variability in the pattern of affected organs, also the degree of disability
ranges widely. Whereas some patients remain in mainstream school and are able
to achieve e.g. swimming certificates, others die in the neonatal period or
barely interact with their environment.

Currently, there is no cure for mitochondrial diseases but there are some
promising results of pharmacological interventions in cells and animals (Koene
and Smeitink 2009; Wenz 2009; Viscomi, Bottani et al. 2011; Koopman, Willems et
al. 2012) and in some mitochondrial disorders (Hirano, Garone et al. 2012;
Koga, Povalko et al. 2012). To assess the effect of these interventions,
sensitive, reliable, valid and relevant outcome measures should be used.
Because of the heterogeneity and the multisystem nature of mitochondrial
disorders, the selection of adequate outcome measures is challenging(Koene,
Jansen et al. 2013). A combination of objective, functional, subjective and
possibly biochemical endpoints will probably be necessary to be able to compare
within the full range of the disease spectrum.

A mitochondrial disease specific follow up tool for children already exists,
namely the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS)(Phoenix,
Schaefer et al. 2006). This scale was designed to be a concise, pragmatic,
quantifiable and multidimensional tool to assess disease progression in
children with mitochondrial disorders at the outpatient clinic. The scale is
quick (25 min) to administer, reflects the multidimensional nature of the
disease and has a more or less holistic approach to disease, containing
subjective, objective and functional items. However, in our experience, some
items within the questionnaire are rather abstract and difficult to fill out in
patients with severe conditions. Therefore, we have adapted the NPMDS to a new,
more detailed and more sensitive scoring system to be used in future clinical
trials for mitochondrial disease, the International Paediatric Mitochondrial
Disease Score (IPMDS). This study has been tested by international colleagues
and The feasibility of the IPMDS was good, as indicated by a low number of
missing items (4%) and the positive evaluation of patients, parents and users.
Principal component analysis of our small sample identified three factors,
which explained 57.9% of the variance. Good construct validity was found using
hypothesis testing. The overall inter-rater reliability was good (median
ICCagreement 0.85; range 0.23 * 0.99). Please see the supplementary files for
the IPMDS, the IPMDS manual and the accepted manuscript (supplementary file 1,
2, and 3).

Several questions remain after these validation studies:
i) Which age-groups are the functional items appropriate for?
ii) What is the inter-rater realibility for assessment by research nurses,
students and physician assistants (to make implementation of the scale into
clinical practice more feasible); and
iii) What is the cause of the low reliability of some of the items within the
physical examination part (see supplementary file 4)?

Primary Objective:
To further optimize the IPMDS

Secondary Objective(s):
To determine in which age-groups the items within the IPMDS are appropriate

To determine whether the IPMDS can assessed reliably by research nurses,
students and physician assistants (to make implementation of the scale into
clinical practice more feasible)

To determine the cause of the low reliability of some of the items within the
physical examination domain (and adapt the IPMDS or the manual accordingly)*

This protocol includes three separate small observational studies.

Study i) To determine in which age-groups the items within the IPMDS are
appropriate
The IPMDS will be performed in healthy children aged 0-18 years. In the first
domain, parents and/or the child will be asked questions about e.g. chewing,
tiredness, etc (see attachment 1). In the second and third part, children will
have to participate in physical examination (neurological examination) and
functional tests. The study will take place in the child*s home environment to
make them more comfortable.

Study ii) To determine whether the IPMDS can assessed reliably by research
nurses, students and physician assistants
In ten patients with, electively admitted to the ward, the IPMDS will be
performed by three raters, of which one experienced rater, subsequently. Raters
may include: physician assistant, research nurses and medical students.
(These results will be used to facilitate implementation of the IPMDS in daily
care.)

Study iii) To determine the cause of the low reliability of some of the items
within the physical examination part
In five patients with abnormalities at neurological examination (most of the
unreliable items concern neurological examination), electively admitted to the
ward, five experienced physicians will rate the previously rated *unreliable*
items at the same time (during 1 hour in the morning). Comments on the items
and the manual with respect to this patient are noted. After the regular
examination programme for the elective admission, 2 raters rate the symptoms
again. We hypothesize that rating the patient at exactly the same time will
increase reliability, because the severity of the symptoms is likely to
fluctuate over the day.
(These results will be used to either adapt the manual or to remove the item
from the IPMDS because it is not stable.)

Since the scoring list is developed for children with a mitochondrial disease,
we cannot validate this list in adults or healthy children.

The risk associated with this study is negligible, since the study resembles a
regular outpatient clinic visit, only far longer. No intervention or invasive
procedures are involved.

The patients included in this study will be elective inpatients. The timeburden
for study ii is estimated to be three times 30 minutes, of which 5-10 minute
will be functional testing. For the convenience of the patient, we chose to
only compare three raters in the same experiment. For study iii, five children
with a mitochondrial myopathy and moderate to severe neurological disability
will be assessed at the same time by five assessors and later at the day by 2
assessors when they are already admitted to the paediatric ward.
The healthy controls and patients will not benefit from this study; though the
risks and burden are also estimated to be very low.

An advantage of the IPMDS to the patient individually might be that it is a
more structured analysis of the patient*s health state and it might give a
better overview over the patient*s problems than can be obtained in a regular
outpatient visit. Therefore, a summary letter with the findings of this study
will be sent to all physicians caring for the patient.

However, the advantages are mainly related to the group of mitochondrial
disorders. The development and the validation of the IPMDS is required to
follow-up patients in great detail. This is warranted for more detailed natural
history studies (since the disorder is genetically so heterogeneous, the
natural history of the individual biochemical and genetic defects in unknown)
and clinical trials (we are e.g. preparing a phase 1/2 trial in this
population, but lack a reliable and valid and specific outcome measure for
mitochondrial disease progression).

Healthy children: The IPMDS will be performed in a home situation, for the
convenience of the child and the parents. No physical examination or blood
samples are involved. Timeburden is estimated to be 1 hour for parents, 45
minutes for older children and about 20 minutes for children under 6 years.