Open label study of riluzole for the treatment of amyotrophic
Dr. N. Arriada-Mendicoa (*), Dr. E. Otero-Siliceo (**),
Dr. G. Burbano (**), Dra. T. Corona-Vásquez (***)
División of Neurosurgery (*), Division of Neurology (**), and Teaching Direction
National Institute of Neurology of Neurosurgery Manuel Velasco Suárez, México City,
RESUMEN: La esclerosis lateral amiotrófica (ELA), tiene una mortalidad de 80% a
5 años de iniciada. Se han utilizado múltiples tratamientos para tratar de detener su
progresión. El objetivo del presente estudio es evaluar los efectos del riluzole en la
progresión de la ELA mediante el uso de la escala de Jablecki. Se seleccionaron 50 casos
de ELA definitiva en base a los criterios de El Escorial, realizando valoraciones con la
escala al inicio y al final del estudio, que se llevó a cabo durante un año con dosis de
100 mg/día. De los pacientes iniciales, 31 (62%) completaron el estudio. La progresión
inicial fue de 0.6895 puntos/mes y la final de 0.5682 (p<0.05). En 14 casos de ELA de
inicio bulbar, la velocidad inicial fue de 0.7133 y la final de 0.5551 puntos/mes
(p<0.05) y en 17 pacientes con inicio espinal, se tuvo una velocidad inicial de 0.6702
y una final de 0.5789 puntos/mes (p<0.05). No se presentaron efectos adversos
relevantes durante el tratamiento. El uso del medicamento disminuyo la progresión de la
enfermedad, sin producir regresión de la misma, por lo que es importante a pacientes y
familiares las características no curativas del fármaco, debiendo valorarse en cada caso
la relación costo-beneficio.
ABSTRACT: Amyotrophic lateral sclerosis (ALS) has a 5-years mortality of 80%.
Several treatment modalities have been used to delay disease progression. The aim of the
currrent study was to evaluate of riluzole on clinical progression as assessed by
jableckis scale in Mexican patients with ALS. Fifty patients with a definitive
diagnosis of ALS according to El Escorial criteria were selected. To measure the
usefulness of riluzole therapy, disease progression was measured before and after
treatment with jableckis scale. Patients received a daily oral dose of 100 mg of
riluzole throughout the one-year study period. For the 50 patients initially enrolled, 31
(62%) completed the study. After the one-year, monthly progression decreased to 0.5682
points per month (p<0.05). In the 14 bulbar-onset patients with spinal-onset, initial
progression was 0.6702 points per month, which decreased to 0.5551 (p<0.05). In 17
patients with spinal-onset, initial progression was 0.6702 points per month, which
decreased to 0.5789 (p<0.05). There were no severe side effects related to therapy.
Riluzole can delay disease progression and its use should be considered in ALS patients,
after making it clear to them and their families that they will not be cured, and after
taking into account cost-benefit issues.
The term motor neuron disease is used to designate a variety of neurologic conditions
characterized by a variable dysfunction of superior and inferior motor neurons. One of
these disease is amyotrophic latera sclerosis (ALS). The sporadic form of ALS is the most
common one, accounting for more than 90% of the cases worldwide. It is more prevalent in
men, with a peak incidense in the fifth and sixth decades of life. It has a 5-year
mortality of 80%, and survival is inversely related to age at diagnosis. Multiple
mechanisms have been implicated in its pathogenesis, but is has not been possible to
define the precise events leading to disease. The main hypothesis include glutamate
excitotoxicity, formation of antibodies against calcium channels and decreased neural
Several treatment modalities have been used to stop or delay disease progression,
including steroids, thyroid hormones and neural growth factors. The only one that as
demonstrated beneficial affects is riluzole (2-amino-6-trifluorometoxibenzotiazol), which
interferes with glutamic acid effects on the CNS (excitatory amino acid). Double-blind,
placebo-controlled trials have showed and increase in tracheostomy-free time in patients
treated with riluzole. The are few side effects related to riluzole administration, these
include elevated liver enzymes and leukopenia, which usually have been reported in the
first 3 month of treatment. For this reason therapy should be monitored with serum
chemistries and blood counts frequently. The aim of the current study was to evaluate the
effect of riluzole on clinical progression as assessed by Jableckis scale in Mexican
patients with ALS. This scale had not been used in previous studies.
PATIENTS AND METHODS
Fifty patients with a definitive diagnosis of ALS according to El Escorial criteria
were selected to participate in the current study (January 1996 to January 1998).
Diagnosis was established by at least two staff neurologist National Institute of
Neurology and Neurosurgery, Mexico City. Every patients underwent complete clinical and
laboratory evaluation, including thyroid hormones, liver chemistry, electrophysiologic
testing (electromyography, motor and sensitive conduction velocities), MRI, and pulmonary
function test. Inclusion criteria were: definitive diagnosis of ALS, sporadic case, age
less than 65 years old, vital capacity greater than 60% normal liver chemistries and
signed informed consent. Exclusion criteria were, vital capacity less than 60% elevated
enzymes of participation in other experimental treatment studies for ALS. In every patient
blood was drawn for lives functional test, blood chemistry and complete blood counts at
entry and at 1,2,3,6,9, and 12 month after starting treatment. Patients were followed with
clinical and laboratory evaluations for one year by at least two of the study
We decided to use the Jablecki scale for clinical evaluation, which enabled us to
obtain objective clinical criteria to gauge the progression of ALS. Previous studies have
demonstrated the usefulness of this scale to predict disease progression, and also its
easy of application.
Jableckis scale is based on the score of 6 clinical parameters: language (4
points), swallowing (2 points), muscle strength and muscular status in each of the 4 limbs
(16 points for muscle strength and 8 points for muscle status), which comprise the most
affected in ALS. The maximum score possible is 40 points, which would reflect the degree
of disease progression in a single patient. After clinical evaluation, Jableckis
score was divided by the time since disease onset in month, so as to assess the degree of
ALS progression was measured before and after treatment as previously described.
The study was designed with a one-year follow-up so as to determine safety of riluzole
treatment and short-term effects on ALS progression. The patients and families were
informed of the risks of riluzole therapy and were asked to give written informed consent
before entry to the study. It was also made clear to them that treatment was intended to
modify disease progression and not to cure ALS. Patients received a daily oral dose of 100
mg of riluzole throughout the one-year study period.
One-year treatment ended January 1998 for the 50 patients initially enrolled, of which
31 (62%) completed the study. Of those did not complete treatment protocol, 14 (28%) were
because of non-compliance with study visits our voluntary drop-out, mainly in the first
two month of treatment with riluzole; 4 patients (8%) died of respiratory failure (none of
them presented treatment related side-effects), within a mean of 5 month after riluzole
was started; one patient (2%) has to continue drug therapy because of skin rash which
disappeared after stopping riluzole.
Thirty-one patients (11 women, 35% and 20 men, 65%), with a men age of 47.67 (SD 10.35)
years (49.16 years for women and 44.63 years for men) completed the one-year treatment.
Mean clinical evolution of ALS was 25.83 (SD 13.43) months (29.66 months in women and
23.73 months in men). None of the patients had a greater then two-fold increase in
aminotransferase . Mean values for alanine aminotransferase and aspartate aminotransferase
were 27.78 U/L at study entry, and 27.58 U/L and 26.76 U/L at the end of one-year therapy,
respectively. Complete blood counts were not significantly different before and after
Degree of disease progression as assessed by Jablecki´s scale was 0.6895 points per
month, with a mean of 17.8 points at the beginning of the study. After the one-year
treatment with riluzole, monthly progression decreased to 0.5682 points with a final
progression of 6.81 points at the end of the treatment period. Figure 1 compares disease
progression before and after treatment with riluzole in the 31 patients who completed
study protocol. Rate of progression was significantly decreased with riluzole therapy
(p<0.001 using Students test). Patients response to therapy was analyzed
according to initial clinical presentation of ALS. There were 14 patients with
bulbar-onset and 17 with spinal-onset ALS. In the bulbar-onset patients, initial disease
progression was 0.713 points per month, which decreased to 0.5551 points per month at the
end of study, difference that statisfically significant (p=0.0223). Figure 2 depicts
disease progression in the 14 subjects with bulbar-onset ALS before and after riluzole
therapy. In those patients who presented with spinal-onset ALS, disease progression before
treatment was 0.6702 points per month, which decreased to 0.5789 per month at the study
period, attaining statistical significance (p<0.05). This difference is represented
graphically in figure 3. None of the study patients required gastrostomy or tracheostomy.
None of the patients complained of ashtenia or sedation, in spite of prior studies
reporting this type of side-effects with riluzole.
Figuras 1 y 2
ALS has classically been considered a rapidly progressive and fatal disease, without
curative options. Treatment modalities are for the main part palliative, with early
physical therapy, gastrostomy and tracheostomy playing an import roll in increasing
survival and improving quality of life.
Recent advances in the phatogenesis of ALS, specially the recording of the importance
that glutamate and neural growth factors have in this disease, have triggered
investigation on novel therapeutic approaches. Previous studies have compared riluzole
versus placebo, but outcomes have been based on mortality, muscular status or the need for
tracheostomy. The use of a simple clinical scale such as the one proposed by Jablecki,
offers the advantage of objectively comparing disease in a same patient in a short period
of time, and can thus be usefuld to identify therapeutic effect of a certain drug. It also
facilitates clinical management and follow-up patient.
In concordance with previous studies, our group of patients had a greater benefit in
muscular status and strength, with improvement on language and swallowing problems. These
result support the proposed protective effect of riluzole in bulbar areas, as previously
described in the literature. There were few riluzole-related side effects, and most of the
patients who did not finish the study did so because they could comply with follow-up
visits. There were no severe side effects related to riluzole administration, one patient
had to discontinue treatment because of skin rash. In none of the patients were important
increases of live enzymes or abnormal blood counts detected during riluzole therapy.
Management of patients with ALS can not be solely based on standard medical treatment, it
should also include family and social support, prevention of depression and malnutrition,
and the use of novel disease-specific therapies such as insulin-like growth factor and
brain-derived neurotrophic factor, with the intent to delay disease progression and
improve quality of life. Rulizole can delay disease progression and its use should be
considered in ALS patients, after marking it clear to them and there families that they
will not be cured, and after taking into account cost-benefit-issues.
Caroscio J, Mulvihil M, Sterling R, Abrams B. Amyotrophic lateral sclerosis. Its
natural history. Neurologic Clin 1987;5:1-8.
Mitsumoto H, Hanson MR, Chad DA. Amyotrophic lateral sclerosis: recent advances in
pathogenesis and therapeutic trials. Arch Neurol 1988;45:189-199.
Norris F, Shepherd R, Denys E, et al. Onset, natural history and outcome in idiopathic
adult motor neuron disease. J Neurol Sci 1993;118:48-55.
Donnenfeld H, Grundman M, Ollar H, Masdeu JC. Severity at presentation and age of onset
predicts survival in amyotrophic lateral sclerosis. Ann Neurol 1989;26:140.
Eisen A. Amyotrophic lateral sclerosis is age dependent. Muscle Nerve 1993;15:41-48.
Eisen A. Amyotrophic lateral sclerosis is a multifactorial disease. Muscle Nerve
DiStefato PS. Neurotrophic factors in the treatment of motor neuron disease and trauma.
Exp Neurol 1993;124:56-59.
Longo FM. Will ciliary neurotrophic factor slow progression of motor neuron disease? Ann
Bensimon G, Lacomblez L, Maininger V, ALS/Riluzole study group. A Controlled trial in
amyotrophic lateral sclerosis. N Engl J Med 1994;330:585-591.
Lacomblez L, Bensimon G, Nigel Leigh P, Guillet P, meininger V, ALS/Riluzole study group
II. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet
Jablecki CK, Berry C, Leach J. Survival prediction in amyotrophic lateral sclerosis.
Muscle Nerve 1989;12:833-841.
Brooks BR. El Escorial World Federation of Neurology criteria for the diagnosis of
amyotrophic lateral sclerosis. J Neurol Sci 1994;124(suppl):96-107.
McDonald ER, Wiedenfeld, Hillel A, Carpenter CL, Walter RA. Survival in amyotrophic
lateral sclerosis: The role of psychological factors. Arch Neurol 1994;51:17-23.
Lange DJ, Felice KJ, Festoff BW, et al. Recombinant human insulin like growth factor in
ALS: description of a double blind placebo-controlled study. Neurology 1996;47(suppl
BDNF Study Group. Subcutaneous administration of recombinant human
methionyl-brain-derived neurotrophic factor (r-meth-huBDNF) in amyotrophic lateral
sclerosis (abstract). Ann Neurol 1995;38:971.