A clinical rating scale for Batten disease

Reliable and relevant for clinical trials

F.J. Marshall, MD; E.A. de Blieck, MPA; J.W. Mink, MD, PhD, FAAN; L. Dure, MD; H. Adams, PhD;
S. Messing, MA, MS; P.G. Rothberg, PhD; E. Levy, BA; T. McDonough, BA; J. DeYoung, MD; M. Wang, BA;
D. Ramirez-Montealegre, MD; J.M. Kwon, MD; and D.A. Pearce, PhD

Abstract—Background: Batten disease (juvenile neuronal ceroid lipofuscinosis [JNCL]) is an autosomal recessive neuro-
degenerative disorder characterized by blindness, seizures, and relentless decline in cognitive, motor, and behavioral
function. Onset is in the early school years, with progression to death typically by late adolescence. Development of a
clinical instrument to quantify severity of illness is a prerequisite to eventual assessment of experimental therapeutic
interventions Objective: To develop a clinical rating instrument to assess motor, behavioral, and functional capability in
JNCL. Methods: A clinical rating instrument, the Unified Batten Disease Rating Scale (UBDRS), was developed by the
authors to assess motor, behavioral, and functional capability in JNCL. Children with verified JNCL were evaluated
independently by three neurologists. Intraclass correlation coefficients (ICCs) were used to estimate the interrater
reliability for total scores in each domain. Interrater reliability for scale items was assessed with weighted ␬ statistics
Results: Thirty-one children with confirmed JNCL (10 boys, 21 girls) were evaluated. The mean age at symptom onset was
6.1 ⫾ 1.6 years, and the mean duration of illness was 9.0 ⫾ 4.4 years. The ICCs for the domains were as follows: motor ⫽
0.83, behavioral ⫽ 0.68, and functional capability ⫽ 0.85. Conclusions: The Unified Batten Disease Rating Scale (UBDRS)
is a reliable instrument that effectively tests for neurologic function in blind and demented patients. In its current form,
the UBDRS is useful for monitoring the diverse clinical findings seen in Batten disease.
NEUROLOGY 2005;65:275–279

The neuronal ceroid lipofuscinoses (NCLs; Batten
disease) are a group of lysosomal diseases compris-
ing the most common neurodegenerative disorders of
childhood.1,2 Juvenile NCL (JNCL; NCL3, Batten–
Spielmeyer–Vogt disease), the most prevalent sub-
type, is characterized by progressive visual loss
between 4 and 8 years of age, seizures, psychomotor
decline, and behavioral abnormalities, with death oc-
curring in the second or third decade of life.3-5 A
number of studies have focused on specific clinical
features6-16 or correlated such features with molecu-
lar, pathologic, or imaging characteristics.17-23 Thera-
peutic studies have targeted specific symptoms
rather than overall disease progression.24-28 A scoring
system has been used to characterize a small num-
ber of patients, but no data are published regarding
its interrater reliability.29,30
We developed the Unified Batten Disease Rating
Scale (UBDRS) to quantify the physical, behavioral,
and functional aspects of JNCL. Whereas the
UBDRS is modeled after similar multimodal scales
that have proven to be extremely important in the
Additional material related to this article can be found on the Neurology
Web site. Go to www.neurology.org and scroll down the Table of Con-
tents for the July 26 issue to find the title link for this article.
evaluation of experimental therapeutics in Parkin-
son disease31 and Huntington disease,32 we thought
that it was necessary to establish the reliability and
validity of a scale uniquely targeted to the assess-
ment of JNCL because the disease 1) has distinctive
manifestations and natural history, 2) unfolds in a
developmental context, 3) results in blindness, which
itself can be expected to impact physical, behavioral,
and functional assessment, and 4) is commonly asso-
ciated with behavioral impairment that can impact
physical and cognitive assessments. We describe the
UBDRS and report on the interrater reliability of the
physical, behavioral, and functional subscales. Pre-
liminary results have been published in abstract
form.33-35
Methods. A preliminary version of the UBDRS was drafted and
circulated to acknowledged experts in the field for review and
comment. Based on this collective clinical experience and review
of the literature, we focused on three principal domains for pur-
poses of assessing interrater reliability: physical signs, behavior
and functional capability. Children were examined independently
by each of three neurologists (two pediatric neurologists and one
movement disorder neurologist specializing in neurodegenerative
disease). All children were examined sequentially by each neurol-
ogist on the same day. The parent or primary caregiver was inter-
viewed by each examining neurologist, but only the initial
examiner reviewed the seizure history and the order of symptom
onset for a given child. Cognitive and behavioral assessments by a

From the University of Rochester School of Medicine and Dentistry (Drs. Marshall, Mink, Adams, Rothberg, Ramirez-Montealegre, Kwon, and Pearce, E.A.
de Blieck, S. Messing, E. Levy, and T. McDonough), NY; Department of Pediatrics (Dr. Dure), University of Alabama–Birmingham; Dartmouth College (Dr.
DeYoung), Hanover, NH; and University of Pennsylvania (M. Wang), Philadelphia.
Funded by a grant from the Batten’s Disease Support and Research Association.
Received December 30, 2004. Accepted in final form April 11, 2005.
Address correspondence and reprint requests to Dr. F.J. Marshall, Clinical Trials Coordination Center, Department of Neurology, University of Rochester
School of Medicine and Dentistry, 1351 Mt. Hope Ave., Suite 223, Rochester, NY 14620; e-mail: fred.marshall@ctcc.rochester.edu

Copyright © 2005 by AAN Enterprises, Inc. 275

pediatric neuropsychologist were undertaken on a subset of the
children, and preliminary results of these studies have been pre-
sented elsewhere.33,34 Prior to the neurology assessments, each
parent or primary caregiver was interviewed by a study coordina-
tor for information regarding demographics, previous diagnostic
workup, and medical history. All assessments were approved by
the institutional review board at the University of Rochester, and
permission was signed on behalf of each child by the parent or
primary caregiver.
The year-1 UBDRS physical assessment included the following
items rated on a scale of 0 (normal) to 4 (severely impaired): visual
acuity, funduscopy, speech clarity, tongue protrusion, saccade ini-
tiation and velocity (horizontal and vertical), ocular pursuit (hori-
zontal and vertical), passive motion of neck and each extremity,
power in each extremity, hand tapping (bilateral), maximal dysto-
nia (bilateral), overall body bradykinesia, gait, tandem walking,
retropulsion pull-test, heel stomping (bilateral), motor tics, myoc-
lonus, rest tremor, action tremor, finger-to-nose dysmetria, and
appendicular chorea.
The year-1 behavioral assessment was based on interview with
the parent or primary caregiver. Each behavioral feature was
rated as to severity (0 ⫽ normal, 1 ⫽ mild, 2 ⫽ moderate, 3 ⫽
severe) and frequency (0 ⫽ never, 1 ⫽ sometimes, 2 ⫽ frequent,
3 ⫽ almost always). Behavioral items included sad mood, apathy,
anxiety, aggression toward others, aggression toward self, stereo-
typed/repetitive behavior, delusions, auditory hallucinations, and
obsessions. Whether or not the child required medications for
treatment of behavioral features was also recorded.
Children’s capability in each of five areas was rated based on
interview of the parent or primary caregiver: school (0 ⫽ unable to
attend special needs classroom to 3 ⫽ normal ability in main-
stream classroom), chores (0 ⫽ unable to do even simple chores to
3 ⫽ able to do all age-appropriate chores independently), play (0 ⫽
unable to play even simple games to 3 ⫽ able to play age-
appropriate games independently), activities of daily living (0 ⫽
total care to 3 ⫽ normal), overall care level (0 ⫽ full-time skilled
nursing to 2 ⫽ home). The children’s potential capability in each
of these areas was then rated again, taking into account the con-
tribution to disability due to blindness (that is, the informant was
asked to estimate hypothetical capability on the assumption that
the child’s vision was normal but that the child had the same
burden of illness in all other respects).
The average frequency of the following seizure types was rated
for each child by the initial neurology examiner based on inter-
view of the parent or primary caregiver: generalized tonic-clonic,
absence, myoclonic, complex partial without generalization, and
simple focal. The average duration of the postictal phase for gen-
eralized tonic-clonic and complex partial events was rated, as was
the duration of simple focal events. The impact of seizures was
assessed by rating the frequency of injury related to seizures, the
maximal level of care for seizure complications within the last 6
months, whether or not hospitalization was required for treat-
ment of seizures in the last 6 months, and whether anticonvulsant
therapy had been adjusted in the last month.
The first neurologic examiner estimated the month and year of
initial symptom onset based on caregiver interview. The rater
then estimated the order of major symptom emergence, including
loss of vision, motor difficulties, cognitive difficulties, behavioral
difficulties, seizures, weight loss/feeding difficulties, sleep distur-
bance, and any other specified symptoms.
The first cohort of 22 children was examined in the summer of
2002 at the annual convention of the Batten’s Disease Support
and Research Association (BDSRA) in Toronto, Ontario, Canada.
Data from the preliminary UBDRS were analyzed, and interrater
reliability for preliminary scale items was assessed with weighted
␬ statistics. Review of these data enabled us to refine our prelim-
inary version of the UBDRS by eliminating items that proved to
be homogeneously severely impaired or unaffected or that showed
extremely poor interrater reliability. In the summer of 2003, the
same neurology raters used the refined UBDRS to reassess 10
children from the 2002 cohort, along with 10 new children, all of
whom attended the annual BDSRA convention in Detroit, MI.
Owing to the large number of individual items making up each
subscale and the range of possible scores on each item, the total
scores for each subscale domain (physical, behavioral, capability)
were treated as continuous variables, and intraclass correlation
coefficients (ICCs) were used to estimate the interrater reliability
276 NEUROLOGY 65 July (2 of 2) 2005
Table 1 Order of symptom appearance (as percentage) among 31
children with juvenile neuronal ceroid lipofuscinosis, based on
parent/caregiver interview
Not
Symptom First Second Third Fourth Fifth Sixth present*
Vision 65 23 3 6 0 3 0
Seizures 3 35 23 16 6 0 16
Cognitive 6 26 35 19 3 0 10
Behavioral 13 3 19 16 23 6 19
Motor 6 10 10 26 26 0 23
Sleep 3 0 0 3 6 0 87
Feeding 3 0 0 0 3 6 87
* Not present by history at the time of the evaluation.
for total scores in each domain (Winer reliability scores).36 Interra-
ter reliability for individual scale items was again assessed using
weighted ␬ statistics, as appropriate for categorical variables.
Both ICC and weighted ␬ statistics are reported here, based on
the refined UBDRS used in the second round of evaluations.
Other elements of the UBDRS, including the seizure assessment,
the timing of symptom onset, and the order of symptom progres-
sion, were tabulated for all participants at the initial assessment.
The common deletion mutation in the CLN3 gene was ana-
lyzed using the methodology previously described.37
Results. Demographics. A total of 32 children partici-
pated. Of these, one child who was referred with a diagno-
sis of JNCL had an atypical history (global developmental
delay) and exam (prominent long-tract signs) and was
later excluded because further review of records failed to
confirm the diagnosis. There were a total of 10 boys and 21
girls, with age at onset of 6.1 ⫾ 1.6 years (mean ⫾ SD;
range 3.6 to 10.6 years). Average duration of illness at the
time of the first evaluation was 9.0 ⫾ 4.4 years (mean ⫾
SD), with a range of 2.2 to 20.1 years. Twenty-seven chil-
dren were of European origin, and four were of unspecified
heritage. Nineteen children were homozygous for the com-
mon deletion in CLN3; eight were heterozygous for this
mutation and had clinical and electron microscope studies
consistent with a diagnosis of JNCL. Four children had
JNCL by clinical and electron microscope criteria but did
not have DNA analysis for CLN3 mutations. Twenty chil-
dren had no coaffected siblings, seven had one coaffected
sibling, and four had two coaffected siblings. Two children
had lost siblings to the disease prior to the initial visit, and
another child’s sibling had died by the follow-up visit 1
year later.
Symptom progression and seizure history. Table 1
gives the order of symptom appearance by history among
the 31 children with JNCL examined at least once. Loss of
vision was the presenting or second symptom 87% of the
time, whereas seizures occurred either first or second 39%
of the time. Although sleep disturbance and feeding diffi-
culties have been reported as core clinical features of
JNCL, these symptoms were rare in our cohort and tended
to occur later in the progression of symptoms. Cognitive,
behavioral, and motor symptoms were common but typi-
cally occurred after the onset of vision loss or seizures
(figure).
Table 2 summarizes the seizure history as obtained by
the initial examining neurologist. The most common sei-
zure type was generalized (either primary or secondary),
 Table 3 Seizure impact in 31 children with juvenile neuronal
ceroid lipofuscinosis during previous 6 months (based on
caregiver interview)

Maximum level of care required for any seizure complication

Figure. Order of symptom onset by historical interview
with caregiver in 31 children with juvenile neuronal cer-
oid lipofuscinosis.
with 26 children (84%) having experienced at least one
such event. Fewer than 20% of children had myoclonic
seizures by caregiver report. For purposes of differentiat-
ing absence seizures from complex partial seizures without
secondary generalization, the rating neurologist assumed
that the latter were associated with some period of postic-
tal confusion, whereas the former were not. Because the
rater did not have access to EEG data, this assumption
may or may not be valid. Both seizure types were rela-
tively uncommon.
Table 3 summarizes the impact of seizures in JNCL
over a 6-month period based on interview of the parent or
primary caregiver. In general, seizures appeared to be rel-
atively well controlled, with a small minority of children
experiencing intractable myoclonic or absence spells.
Interrater reliability. Calculation of ICCs based on
multiple raters requires that all subjects be rated by all
raters. When there is a missing item within a subscale, a
total score for that subject on that subscale cannot be
calculated. Because of the back-to-back nature of the ex-
ams and the behavioral difficulties prominent in a number
of children, it was often the case that a given examiner for
a given child was unable to complete all assessments. Not
within last 6 mo
No specific care required ⫽ 17 (55)
First aid at home ⫽ 6 (19)
Paramedics called ⫽ 1 (3)
Emergency room visit ⫽ 5 (17)
Unknown/not applicable ⫽ 2 (6)
Frequency of injury related to seizures within last 6 mo
Never ⫽ 27 (88)
Sometimes ⫽ 2 (6)
Unknown/not applicable ⫽ 2 (6)
Hospitalization required for control of seizure in last 6 mo
None ⫽ 28 (91)
Once ⫽ 1 (3)
More than once ⫽ 0 (0)
Unknown/not applicable ⫽ 2 (6)
Anticonvulsant adjustment required in last month
No ⫽ 21 (68)
Yes ⫽ 8 (26)
Unknown/not applicable ⫽ 2 (6)
Values are no. (%).
having a particular score on one item for one examiner
necessitated eliminating the subscale score for the other
graders for this subject, even if a total score was present.
Of the 20 children evaluated by all three neurologists us-
ing the refined UBDRS, only 10 had complete data for
every item on the physical assessment subscale, 12 on the
behavioral subscale, and 12 on the capability subscale.
Table 4 provides the ICC for each of these subscales, and
figure E-1 on the Neurology Web site (go to www.neurology.
org) presents the data graphically.
Based on our experience examining children in the first
cohort, we eliminated a number of preliminary UBDRS
items: funduscopy, saccade initiation (horizontal and verti-
cal), saccade velocity (horizontal and vertical), ocular pur-
suit (horizontal and vertical), tandem walking, delusions,

Table 2 Frequency of seizure type by parental/caregiver interview among 31 children with juvenile neuronal ceroid lipofuscinosis

Less than Every 3 to Every months More than More than More than
Seizure type Never every 6 months 6 months to 3 months once a month once a week once a day Unknown

Generalized* 5 (16) 12 (39) 10 (32) 2 (6) 2 (6) 0 0 0

Absence† 20 (65) 2 (6) 0 1 (3) 1 (3) 0 2 (6) 5 (16)
Myoclonic 22 (71) 1 (3) 0 2 (6) 1 (3) 0 2 (6) 3 (10)
Complex partial†‡ 19 (61) 1 (3) 3 (10) 1 (3) 3 (10) 0 0 4 (13)
Simple partial 26 (84) 0 0 2 (6) 0 0 0 3 (10)

Values are n (%).

* Primary or secondary.
† Absence seizures distinguished from complex partial seizures by lack of postictal confusion in the former. EEG corroboration not
available.
‡ Without secondary generalization.
July (2 of 2) 2005 NEUROLOGY 65 277
Table 4 Intraclass correlations (Winer reliability single scores)
for Unified Batten Disease Rating Scale subscale total scores by
paired examiners and for all examiners
Examiners
Subscale A&B A&C B&C A&B&C
Physical, n ⫽ 10 0.93 0.84 0.74 0.83
Behavior, n ⫽ 12 0.67 0.66 0.70 0.68
Capability, n ⫽ 12 0.94 0.80 0.84 0.85
and auditory hallucinations. Tables E-1, E-2, and E-3 on
the Neurology Web site provide the weighted ␬ values for
each individual item on the refined UBDRS by examiner
pair. Because of the small number of available subjects
and the need to limit the number of times each subject was
examined, the range of scores across individual scale items
was frequently insufficient to achieve statistically signifi-
cant results. A number of items had agreement matrices
containing a single row or column of nonzero entries, im-
plying that there was insufficient variability in the ratings
to enable meaningful calculation of a ␬ statistic. For exam-
ple, Rater A evaluated power in the left leg of 18 children
and found it to be normal in 17 and mildly weak in 1.
Rater B evaluated power in the same 18 children, finding
it to be normal in all 18. They did not agree on the assess-
ment of one child. Therefore, despite the fact that they
were in absolute agreement that 17 of 18 children had
normal power in the left leg, no meaningful ␬ statistic
could be calculated. Tables E-4, E-5, and E-6 on the Neu-
rology Web site give the distributions of the median score
across all examiners for each scale item at the time of
initial assessment.
Discussion. The UBDRS is a multimodal scale for
the assessment of children with JNCL. Our early
testing of this scale demonstrates good interrater re-
liability as assessed with Winer reliability scores.
This demonstration of reliability is an important
step toward use of the scale in clinical investigations.
We are continuing development of the scale to incor-
porate assessments of cognition and development.
We recognize the need for more global assessments
of illness severity as well as assessments of caregiver
burden, and we intend to incorporate these into the
final version of the UBDRS. Ongoing studies are
measuring the biochemical and immunologic charac-
teristics of Batten disease as a means of identifying
biomarkers for progression of disease and for identi-
fication of potential targets for intervention.
Our data indicate that cognitive, behavioral, and
motor symptoms are common, typically occurring af-
ter the onset of vision loss and seizures. The nonmo-
tor data are based on retrospective assessment by
parents or caregivers, which is a limitation. How-
ever, many of the parents have kept notes about the
progression of symptoms on their children, increas-
ing the reliability of these data. Prospective longitu-
dinal assessment of children beginning in the early
stages of the disease is ongoing. In addition, formal
assessment of subjects in presymptomatic phases of
278 NEUROLOGY 65 July (2 of 2) 2005
illness may help answer the question of whether
there are subtle changes in cognitive and behavioral
function before vision loss occurs.
Limitations to the approach we have outlined in-
clude the relatively small number of children available
to undergo multiple examinations by independent
raters on the same day. Our sample size is too small
to fully address the degree of consistency across the
disease’s severity. The small sample resulted in
weighted ␬ scores for some items of the scale being
uninterpretable because of insufficient variability
across subjects. This was due in part to a selection
bias in our sample. All subjects were recruited from
families attending the annual BDSRA meetings.
Healthier children, those with more extensive care-
giving support, and those with more motivated par-
ents were more likely to travel to these meetings. It
is also likely that the healthiest children may not
travel to the conventions (e.g., those without vision
loss), as parents do not wish to expose their children
to others in more advanced stages of illness. Never-
theless, our study sample represented as many as
5% of the estimated North American population of
children with JNCL.
The responsiveness of the individual scale items
to longitudinal change as well as the inherent vari-
ability of such assessments need to be established
through longer-term follow-up of the children pre-
sented here. We did not present longitudinal data on
the 10 children examined in consecutive years be-
cause the sample size was insufficiently large to en-
able meaningful conclusions to be drawn. With use of
the means and standard deviations of the scale sum-
mary scores based on averages across the graders, it
would require 54 subjects to enable us to detect a
20% difference in the severity of physical outcomes
with 90% power. This number of subjects would be
more than sufficient to detect such a difference in
behavioral and capability outcomes.
It is our intent to continue to refine the UBDRS
based on further use in the children already exam-
ined as well as in new children with JNCL as they
are identified and as their parents agree to partici-
pate. We welcome and encourage more widespread
use of the UBDRS by neurologists caring for children
with JNCL. Readers who wish to participate in the
development of a UBDRS database are encouraged
to contact Dr. Marshall.
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DOI 10.1212/01.wnl.0000169019.41332.8a

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