ABSTRACT: Predicting the rate of disease progression has become important
as trials of new medical treatments for amyotrophic lateral sclerosis
(ALS) are planned. Bulbar onset, early impairment of forced vital capacity,
and older age have all been associated with shorter survival. We performed
a retrospective study to compare survival factors with disease progression in
a German ALS population. We analyzed disease progression in 155 patients
at intervals of 4 months over a period of 3 years. To evaluate disease
progression, the ALS functional rating scale (ALS-FRS), forced vital capacity
(FVC%), and a Medical Research Council (MRC) compound score based on
a nine-step modified MRC scale were used. We compared age (<55 years
vs.
$55 years), different sites of disease onset (bulbar vs. limb), and gender
to the rate of disease progression and performed survival analyses. No
overall significant difference could be detected when analyzing these subgroups
with regard to disease progression. By contrast, significantly longer
survival was observed in the younger age group (56 months vs. 38 months,
P < 0.0001) and in patients with limb-onset disease (51 months vs. 37
months, P = 0.0002). Using Cox analyses values we found that the declines
of ALS-FRS, FVC%, and MRC compound score were predictive of survival
(P < 0.0001, P = 0.002, and P = 0.003, respectively). Future studies are
needed to clarify whether nonspecific factors including muscle atrophy, dysphagia,
and coexisting diseases influence prediction of survival in ALS patients.
A more precise set of predictors may help to better stratify patient
subgroups for future treatment trials.
© 2002 Wiley Periodicals, Inc. Muscle Nerve
25: 709–714, 2002
DISEASE PROGRESSION IN AMYOTROPHIC LATERAL
SCLEROSIS: PREDICTORS OF SURVIVAL
T. MAGNUS, MD, M. BECK, MD, R. GIESS, MD, I. PULS, MD, M. NAUMANN, MD,
and K.V. TOYKA, MD
Clinical Research Group for Motor Neuron Disorders, Department of Neurology,
University of Wuerzburg, Germany
Accepted 8 January 2002
A
myotrophic lateral sclerosis (ALS) is the most
common motor neuron disease (MND). It is relentlessly
progressive with a mean survival of approximately
3 years,
11,13,14,17,23,24 yet with occasional longterm
survivors.
29 Survival has been associated with a
number of different factors.
9,13,17,18,21,28 Two apparent
indicators at disease onset are the patient’s age
and the site affected. Onset before the fifth decade
appears to have a better prognosis than onset past
the age of 60 years. Clinical studies have also shown
that disease onset in the limbs rather than the bulbar
muscles is predictive of longer survival time.
We investigated disease progression and whether
it predicts survival time. Our goal was to find objective
predictors of survival and disease progression as
well as their correlation with each other.
METHODS
Patients.
We retrospectively analyzed 155 of 247
patients using our extensive computed ALS clinical
database. For these patients, follow-up data for more
than 1 year and data on their survival status were
available. The remaining 92 patients were excluded
because important data points were missing, but they
were not obviously different in their type of ALS and
age distribution. All patients met the El Escorial diagnostic
criteria for probable or definite ALS.
7 The
Abbreviations:
ALS, amyotrophic lateral sclerosis; ALS-FRS, amyotrophic
lateral sclerosis functional rating scale; FVC%, forced vital capacity
(percent); MND, motor neuron disease; MRC, Medical Research Council
Key words:
amyotrophic lateral sclerosis; ALS-FRS; motor neuron disease;
progression; survival
Correspondence to:
M. Beck, Julius-Maximilians-Universita¨ t, Josef-
Schneider-Strasse 11, D-97080 Wuerzburg, Germany; e-mail:
marcus.beck@mail.uni-wuerzburg.de
© 2002 Wiley Periodicals, Inc.
Published online 4 April 2002 in Wiley InterScience (www.interscience.
wiley.com). DOI 10.1002/mus.10090
Disease Progression in ALS MUSCLE & NERVE May 2002
709
data were collected over a time period of 5
1⁄2 years.
Duration of the disease was calculated from first
symptom until the end of the observation period or
death. First symptoms included weakness of either
limb or bulbar muscles, muscle atrophy, and symptoms
due to spasticity. Symptoms were confirmed by
the family or other observers, whenever possible. Patients
were evaluated sequentially in our motor neuron
disorder outpatient clinic. All 155 patients were
treated with riluzole and antioxidants. Some patients
(
N = 33) had participated in the oral Xaliproden-
Sanofi trial EFC1923 and had received (in addition
to riluzole) either 1 mg or 2 mg of the study drug or
placebo. Among the 11 placebo-treated patients, 4
were older and 7 were younger than 55 years at disease
onset; in the treatment groups (
N = 22), 16 were
older than 55 years. In the placebo group 3 and in
the treatment group 4 patients had a bulbar onset.
Analysis of Disease Progression.
We used the ALS
functional rating scale (ALS-FRS), forced vital capacity
(FVC%), and a modified Medical Research Council
(MRC) scale to test our patients at intervals of 4
months on a total of 762 occasions. The ALS-FRS,
which has been published previously,
30 consists of
ten items, each with an ordinal rating scale (ratings
0–4) that refers to limb, bulbar, or respiratory
muscle status. This method has been proven reliable
in test–retest analyses
10 and was recommended for
clinical trials.
5
To assess pulmonary function, forced vital capacity
(FVC), was performed as recommended for ALS
clinical trials.
15 The percent-predicted forced vital
capacity (FVC%) has previously been used as a prognostic
factor for survival in the randomized clinical
trial of riluzole in ALS.
4
In addition to the commonly used six-step MRC
scale (0–5), we included three further steps (4+, 4−,
5−) to describe weakness between grades 4 and 5
more accurately.
1,6 We manually tested six muscle
groups of each upper extremity and six muscle
groups of each lower extremity. We then added the
scores and divided the sum by the number of muscle
groups tested. This score provides an easy estimate of
the overall limb muscle strength, and we will refer to
this score as the MRC compound score.
As follow-up data were available on each patient
for at least 1 year, we calculated an individual progression
rate over a time span of 1 year. Data at 1
year after the first visit were subtracted from the initial
values. We will refer to these values as
DALS-FRS,
D
FVC%, or DMRC compound score. If we had not
been otherwise notified, data on survival status were
obtained by telephone contact.
Data Analysis.
According to our ALS assessment
protocols, all data were first entered into a computer-
based database during clinic visits. Descriptive
statistics as well as significance testing and survival
modeling were performed on this set of data. The
Pearson correlation was calculated comparing single
values from each patient of the three different methods
(ALS-FRS, FVC%, MRC compound score).
Student’s
t-test was used for significance testing
after checking for variances and data distribution.
Mean values from each examination timepoint
were compared by subgroups. Univariate survival
modeling was performed using the Kaplan–Meier
analysis. Survival data also were analyzed using
the Cox proportional hazards model, a multivariate
regression method examining the effect of presumed
prognostic factors on survival time. Survival
beyond a specified time is expressed in terms of
a hazard function. The hazard function is, in turn,
a function of presumed prognostic factors and
their respective regression coefficients. Statistical
analyses were done using the SPSS program (SPSS,
Chicago, IL).
RESULTS
Demographic Analysis.
Our 155 ALS patients were
seen on an average of 4.9 visits (SD ± 2.1). The maleto-
female gender distribution was 1.8:1, and limb
onset vs. bulbar onset was 3.2:1. The age at
disease onset averaged 54.2 years (SD ± 12 years).
The delay from first symptoms to establishment
of the diagnosis averaged 10.2 months (SD ± 7.6
months).
Disease Progression.
All tests showed a significant
correlation with each other (ALS-FRS to FVC%,
r =
0.66,
P < 0.01; ALS-FRS to MRC compound score, r =
0.67,
P < 0.01; and FVC% to MRC compound score,
r
= 0.44, P < 0.01).
The data from each visit were related to the time
of disease onset. Time zero was set as the timepoint
of disease manifestation as reported by the patient or
treating physician. The timepoints entered into our
database were calculated by subtracting the reported
disease onset from the day of the respective visit.
Through this method, test scores could be related to
the duration into the disease.
ALS-FRS, FVC%, and MRC compound score declined
almost linearly during the observation period.
Within the 36 months of observation, the average
ALS-FRS declined from 35.6 to 23.6, and FVC% and
MRC compound score decreased from 98% to 57%
710
Disease Progression in ALS MUSCLE & NERVE May 2002
and 4.4 to 2.9, respectively, in the entire cohort
(
P < 0.001; Fig. 1).
Subgroup Analyses.
When patients were divided
into subgroups by age at disease onset (<55 years and
$
55 years) or site of onset (limb and bulbar), a very
similar decline of ALS-FRS, FVC%, and MRC compound
score was observed (Fig. 2). For further evaluation,
we calculated an annual individual progression
rate (
DALS-FRS, DFVC%, or DMRC compound
score).
The decline in
DALS-FRS, DFVC%, or DMRC
compound score according to age group (<55 years
and
$55 years) was 3.5, 10.6, and 0.39, respectively,
vs. 4.1, 11.5, and 0.43, respectively (
P = 0.2, P = 0.65,
and
P = 0.64). Patients with limb onset of the disease
had an annual decline in ALS-FRS, FVC%, and MRC
compound score of 3.8, 10.8, and 0.43, respectively,
in contrast to patients with bulbar onset who declined
by 3.4, 12.5, and 0.33, respectively (
P = 0.36,
P
= 0.45, and P = 0.4). This finding indicates that the
decline tended to be slightly faster for respiratory
functions but slower for overall weakness in the
bulbar-onset groups.
For exact statistical analysis, we compared values
at single timepoints from the subgroups. No significant
overall difference was detected, with one exception.
The MRC compound score in general exhibited
significant disparity in favor of the bulbar rather
than limb subgroup throughout the observation period
(
P = 0.001), perhaps because this score only
represents limb weakness.
Survival Analyses.
The average survival time of the
155 patients was 47 months (95% confidence interval
41–53). During the observation period 123 patients
died. Patients younger than 55 years or those
with limb-onset disease survived substantially longer
(56 months vs. 38 months,
P < 0.0001; 51 months vs.
37 months,
P = 0.0002, respectively; Fig. 3). Gender
was not related to survival.
To find predictors of survival, we used Cox proportional
hazard models. Both age and site of onset
had a significant predictive value for survival (
P <
0.0001 and
P < 0.0001, respectively).
Furthermore, using the rate of decline that had
been measured in all patients over a period of 1 year
in a Cox regression analysis we observed shorter survival
in patients with faster progression (
DALS-FRS,
P
< 0.0001; DFVC%, P = 0.002; and DMRC compound
score,
P = 0.003, respectively).
Survival analyses from the time of enrollment revealed
that survival was still longer in the younger
age group (
P < 0.0001), but for patients with limb-
FIGURE 1.
Disease progression measured by ALS functional
rating scale (ALS-FRS)
(A), forced vital capacity (FVC%) (B), and
MRC compound score (MRC compound score
(C). A significant,
basically linear decline of score values and measured data over
the period of 36 months is demonstrated in all three tests (P <
0.001). Mean and standard deviation shown.
Disease Progression in ALS MUSCLE & NERVE May 2002
711
FIGURE 2.
Disease progression measured by ALS-FRS, FVC%, and MRC compound score in patients <55 years (solid line) and $55
years (dashed line). No significant difference in the rate of disease progression can be detected by the three scores in
(A)–(C). In (D)–(F),
values for the identical tests are given for bulbar (solid line) and limb (dashed line) onset of the disease. Mean and standard deviation
shown.
712
Disease Progression in ALS MUSCLE & NERVE May 2002
onset disease only a trend toward longer survival was
found (
P = 0.1). There was no difference in the rate
of decline within these subgroups.
Again, the rate of decline measured by
DALSFRS,
D
FVC%, or DMRC compound score was predictive
of survival (
P = 0.0001, P = 0.01, and P = 0.01,
respectively).
DISCUSSION
We were able to confirm that survival is closely correlated
to age and site of disease onset
13,14,21 and
found that rate of disease progression is an independent
predictor of survival, regardless of whether disease
onset or time of enrollment into the study were
used for calculating progression. In contrast to our
expectation, the slope of the progression curve with
steady deterioration of functional scores was similar
in the clinical subgroups. Gender was not a predictor
for survival (data not shown). The methods used to
assess functional disability are thought to reflect disease
progression reliably, and have been used extensively
in large clinical ALS trials.
Our patient groups had similar age and gender
distribution as well as a similar survival time
compared with large demographic studies of
ALS,
13,14,21,24 suggesting that our observations can
be extrapolated to ALS in general. Previous studies
have observed a similar relationship of disease progression
to site of onset and age.
19,22,24 A potential
drawback of our study design is that not all patients
were followed individually over the entire period of
36 months. For all, at least 12 successive months were
available with extrapolation to time of onset. Analyses
of linear progression for the 12-month period did
not differ from the total analysis and we therefore
consider the estimates of progression reasonably
valid.
The positive influence of younger age on survival
may be explained by a better compensation
of declining motor function in younger
people,
2,12,15,16,25,27,31–33 in particular for the respiratory
system in which structural changes are common
at older age.
8,20,26
A recent well-designed study by Armon et al.
3
demonstrated the relationship between rate of estimated
linear disease progression and survival. When
their patients were divided into groups with faster or
slower progression, a significant difference in survival
was observed. Over a period of 12 months, we
also found significant predictive values for survival
with regard to faster declining ALS-FRS, FVC%, and
MRC compound score.
A potential limitation of our study is the inclusion
of patients who had participated in a treatment
FIGURE 3.
Kaplan–Meier curves representing the overall cumulative
survival
(A). After splitting the patients into subgroups, a
markedly longer survival for younger patients
(B) (thin shaded
line) compared with patients
$55 years (thick black line) (B) and
limb onset (thin black line)
(C) as compared with bulbar onset
(thick shaded line)
(C) is demonstrated.
Disease Progression in ALS MUSCLE & NERVE May 2002
713
trial (Sanofi trial EFC1923). As no beneficial effect
was demonstrated for the study drug when given in
addition to riluzole, we believe that any possible bias
is negligible. In addition, access to optimal medical
treatment and to medical specialists may also correlate
with survival. As access is easy and free of charge
in Germany, the data should not be biased in this
direction.
When using survival rates as a primary endpoint
in clinical trials, it seems necessary to have patients
matched for age and site of onset. Otherwise, slight
differences in these factors may influence the outcome
of studies due to selection bias. Based on our
observations, stratifying subgroups for treatment trials
may now be easier and discovering treatment effects
may be more likely.
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