An
Antispasticity Effect of Threonine in Multiple Sclerosis Stephen
\s=b\ To
Doolittle, PA-C, MHP; Maria Lopez-Bresnahan, MD; Bhagwan Shahani, MD; David Schoenfeld, PhD; Vivian E. Shih, MD; John Growdon, MD; James R. Lehrich, MD
L. Hauser, MD; Teresa H.
determine whether the naturally occurring amino acid
threonine, a potential precursor for glycine biosynthesis in the spinal cord, has an effect on spasticity in multiple sclerosis, 26 ambulatory patients were entered into a random-
ized crossover trial. Threonine administered at a total daily dose of 7.5 g reduced signs of spasticity on clinical examination, although no symptomatic improvement could be detected by the examining physician or the patient. In contrast to the side effects of sedation and increased motor weakness associated with antispasticity drugs commonly used for the treatment of multiple sclerosis, no side effects or toxic effects of threonine were identified. Levels of threonine were elevated in serum and cerebrospinal fluid during treatment, but glycine levels did not change. Enhancement by threonine of glycinergic postsynaptic inhibition of the motor reflex arc in the spinal cord may represent a nonsedating, nontoxic approach to the management of spasticity in multiple sclerosis. (Arch Neurol. 1992;49:923-926) has been defined characterized by Spasticity velocity-dependent stretch reflexes (muscle tone) with as a
a
tonic don jerks,
motor
disorder increase in
neuron
Accepted
From the Boston.
PATIENTS AND METHODS
Patient
for publication January 27, 1992. Department of Neurology, Massachusetts General Hospital,
Reprint requests to the Neuroimmunology Unit, Warren 324, Massachusetts General Hospital, Boston, MA 02114 (Dr Hauser).
Population
Twenty-six patients with clinically definite MS13 were enrolled in the study. Patients were drawn from the MS population followed at Massachusetts General Hospital (MGH), Boston, and from referrals by local neurologists. Ambulatory patients with inactive or very slowly progressive MS were eligible. Inactive
disease was defined as relapsing-remitting MS that has been clin¬ ically stable (ie, nonexacerbating) for more than 2 years. Very slowly progressive disease was defined as chronic MS without change for at least 1 year, as judged by Ambulation Index and Expanded Disability Status Scales (EDSS).1415 Inclusion and exclusion criteria are summarized in Table 1.
exaggerated ten¬
from hyperexcitability of the stretch reflex.1 This restricted physiologic definition does not in¬ clude other features of the upper motor neuron syndrome, eg, the "negative" symptoms of weakness and loss of dex¬ terity and the "positive" symptom of flexor spasms.2"6 In patients with the demyelinating disease multiple sclerosis (MS), spasticity that interferes with ambulation and dex¬ terity is commonly present.7 Patients with severe paraparesis may depend on spasticity to aid in ambulation, but flexor spasms and clonus may prevent effective use of re¬ sidual strength. Spasticity may also be accompanied by pain or may result in bladder and bowel dysfunction, leading to urgency, frequency, and incontinence. Threonine, a naturally occurring amino acid, has been proposed as a candidate therapy for spasticity, based on observations that its administration increases levels of glycine in the spinal cords of rats.8 The motor reflex arc is postsynaptically inhibited by glycine that is normally re-
resulting
leased from interneurons located in the gray matter of the spinal cord and from Renshaw cells.910 Threonine might reduce spasticity by increasing glycinergic inhibition. Two uncontrolled studies have indicated a potential antispas¬ ticity effect in humans.1112 Herein, we report the findings of a double-blind crossover trial of oral administration of threonine in a population of patients with MS selected for the presence of symptomatic spasticity, relatively pre¬ served motor function, and stable disease course.
Study Design Threonine
was
supplied as a purified amino acid (Ajinomoto
Ine, Tokyo, Japan) and was incorporated into 500-mg capsules by
the research pharmacy at MGH. Placebo capsules contained lac¬ tose NF. Intact threonine and placebo capsules were identical in appearance and taste. Treatment group assignment was per¬ formed by the dispensing pharmacist according to a prescheduled randomized computer-generated order of administration. Neither examiners nor patients were aware of the order in which the treatments were given. The protocol consisted of two 8-week treatment periods sepa¬ rated by a 2-week washout period. During each treatment period, patients were asked to self-administer five capsules three times daily, for a total daily dose of 7.5 g. Compliance was assessed by frequent patient contact, by return of empty capsule bottles, and by measurement of serum threonine levels. Response to treatment was judged by physician and patient assessments, research neu¬ rologic measurements of spasticity and function, neurophysiologic quantitation of spasticity, and measurement of changes in glycine and other amino acids in cerebrospinal fluid (CSF) and blood. For each patient, neurologic assessment was performed by the same examiner before therapy, at the end of each 8-week treatment course, and again following a 2-week washout period. Assessment was performed with the EDSS,15 the Ambulation In¬ dex,14 the Ashworth Scale,16 and a Clinician Spasticity Scale that
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 06/13/2015
Table
1.—Study
Inclusion and Exclusion Criteria
Table
Inclusion criteria Men and women
aged 18 to 55 y Clinically definite multiple sclerosis,
Variable inactive
or
slowly
progressive form The presence, for at least 3 mo, of spasticity or spontaneous flexor spasms sufficient in degree to interfere with functional activities Ambulatory, with Disability Status Score s6 and Ambulation Index £5 Reasonable functional use of arms, eg, Upper-Extremity Index of 0 or 1 Good general health Ability to understand the purpose of the study and
willingness to participate,
as
demonstrated by signed
form Exclusion criteria Cancer or serious underlying medical illness (eg, serious cardiac disease, renal failure, uncontrolled diabetes mellitus, infections, peripheral vascular disease) Advanced arthritis, contractures, or other conditions that hinder evaluation of joint movement Required use of psychoactive drugs, including sedatives, consent
hypnotics, antidepressants, or neuroleptics Antispasticity treatment within 1 mo, including diazepam, baclofen, dantrolene sodium, and corticosteroids Chemotherapeutic agents, such as cyclophosphamide or azathioprine, within the past 6 mo
was
developed in an earlier pilot study. The Clinician Spasticity
Scale is
a
Characteristics 2.—Population of the Study Group*
summary of the assessments of four
measures:
upper-
extremity muscle tone, lower-extremity muscle tone, reflexes, and
spontaneous flexor spasms. For each measure, results were recorded as improved (I, +1), unchanged (U, 0), or worse (W, -1) compared with entry status. The sum of the individual spasticity assessment scores thus had a theoretical range between -4 and +4. Values less than 0 were considered "worse"; values greater than 0, "improved"; and values equal to 0, "unchanged." In addition, a Patient Spasticity Scale was developed for each patient that included the three most bothersome symptoms asso¬ ciated with spasticity (eg, painful spasms, nocturnal spasms, stiffness, and bladder symptoms). Patient Spasticity Scale scores were determined in an identical fashion as described above for the Clinician Spasticity Scale. At each follow-up session, response to treatment was recorded for each symptom as improved (I, +1), unchanged (U, 0), or worse (W, -I) compared with entry status, and a composite score was generated. Video recordings of gait and of other selected features of the examination were also obtained at each session. In addition, the examiner recorded a Global Assessment of the patient's condition (ie, improved, unchanged, or worse), and patients reported their own Global Assessment of treatment effects by completing a pa¬ tient questionnaire. For Spasticity Scores and Global Assess¬ ments, signed-rank tests were used to compare the outcome of threonine vs placebo treatments. Patients were asked to keep a diary form on which to record the occurrence of spasms and other symptoms of spasticity, as well as any adverse side effects or illnesses they experienced. Video recordings were reviewed in a blinded fashion by two of us (J.R.L. and S.L.H.) at the conclusion of the study. Before beginning each treatment course, a research dietitian instructed each patient to consume a standard 75-g protein diet, to be continued until completion of the study. Blood was drawn for standard laboratory tests, and an electrocardiogram and a chest roentgenogram were obtained. At the end of each treatment period, patients were admitted to the MGH Clinical Research Center. Electrophysiologic studies included -reflex (H max/M max ratio), F response (F mean/M max ratio), and vibratory inhibition of the -reflex determina¬ tions, the H max/M max ratio is determined by comparison of the
Age,
Value 41 ±6.5
y
Sex, F/M Disease duration, EDSS
1
5/11
12±7.4
y
4.7+1.5
score
3.0±0.9
Al
presented as mean±SEM unless otherwise indicated. EDSS indicates Expanded Disability Status Scales; Al, Ambulation Index. *Data
are
maximum amplitude of an H reflex to the maximum amplitude of the compound muscle action potential in the same muscle. Single electrical stimuli were delivered to the popliteal nerve in the popliteal fossa and the H reflex and compound muscle action po¬ tential was recorded with surface electrodes placed over the soleus muscle. The H max/M max ratio reflects the percentage of motoneurons in the motoneuron pool that can be activated by the H reflex. When the excitability of the motoneuron pool is increased, such as in spasticity, a greater number of motoneurons are excited and therefore the amplitude of H reflex is increased. The F re¬ sponse is measured after delivery of a minimum of 10 supramax¬ imal electrical stimuli. A mean amplitude of measurable F re¬ sponses (>20 µ ) is calculated in relation to the maximum am¬ plitude of the compound muscle action potential recorded from the same muscle (F mean/M max ratio). Vibratory inhibition of the reflex was recorded by applying vibration to the tendon during elicitation of the reflex from the soleus muscle. The index of max (vibrated)/H vibratory inhibition was measured as maxXlOO. Vibratory inhibition of the reflex is used to evaluate the role of presynaptic inhibition at the level of the spinal cord. In addition, measurements of the duration of electromyographic bursts recorded with surface electrodes placed over tibialis ante¬ rior muscles during foot tapping were also calculated. Simulta¬ neous fasting blood and CSF amino acid levels were measured at 9 AM following a 10-hour period of complete bed rest. Samples were analyzed for threonine and glycine with a Beckman 6300 au¬ tomated amino acid analyzer (Beckman Instruments Ine, Fullerton, Calif). The treatment code was broken after all clinical and laboratory data had been entered into the database.
RESULTS Of the 26 patients who entered the study, 24 completed both treat¬ at least one treatment period and 21 ment periods. Two patients dropped out during the first treatment period, one for nonmedicai reasons and another in whom additional antispasticity therapy was instituted. Two patients dropped out during the second treatment period, one because of an MS exacerbation and the other because of development of pneumonia (in both cases, the first treatment was placebo). Two patients believed that the second treatment was not working and stopped therapy early (in both cases, the first treatment was threonine); one of these patients was convinced to complete the entire evaluation and the other returned for clinical examination only. The characteristics of the patient population are shown in Table 2.
completed
Clinical Response The Figure diagrams the clinicians' and patients' assess¬ ments of treatment outcomes for the 21 patients who com¬ pleted both treatment periods. For all comparisons, I indi¬ cates improved; S, same; and W, worse. Response to threonine appears on the horizontal axis and response to placebo on the vertical axis. For example, reading down from the upper left-hand corner of the Figure correspond-
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 06/13/2015
Table 3.—Plasma and Cerebrospinal Fluid (CSF) Amino Acid Levels During Threonine and Placebo Treatments*
Threonine S
Clinician
W
Placebo
Spasticity Scale o
-Q V
S
P=.036 W
Variable
Threonine Treatment
Plasma threonine Plasma glycine
662.0±262.3
141.1 ±38.9
245.5±68.6
252.6±54.8
CSF threonine
118.8±57.8
33.3±12.4
6.0±3.9
6.8±3.5
CSF
glycine are expressed
•Results
Threonine I
S
W
Patient Spasticity Scale
Duncan's
either
a
tion.
as
Treatment
mean±SEM.
Multiple Range test). There was no evidence of or of a period-treatment interac¬
carryover effect
I
Laboratory Evaluations determinations (mean ± SEM) of amino acid Laboratory levels are shown in Table 4. While plasma and CSF thre¬ onine levels increased fourfold, plasma and CSF glycine levels did not differ between treatments. No differences in
o Lì
J
P=.185
W
electrophysiologic
Threonine S
W
Clinician Global Assessment
measures
(H max/M
max
ratio, F
response, vibratory inhibition of the -reflex, or duration of electromyographic bursts) were associated with threo¬ nine treatment compared with placebo treatment (data not
shown).
COMMENT ja CD
C
P=.47
W
Threonine I
S
I
1
w
Patient Global Assessment
cu
Antispasticity Effect of Threonine in Multiple Sclerosis Stephen
\s=b\ To
Doolittle, PA-C, MHP; Maria Lopez-Bresnahan, MD; Bhagwan Shahani, MD; David Schoenfeld, PhD; Vivian E. Shih, MD; John Growdon, MD; James R. Lehrich, MD
L. Hauser, MD; Teresa H.
determine whether the naturally occurring amino acid
threonine, a potential precursor for glycine biosynthesis in the spinal cord, has an effect on spasticity in multiple sclerosis, 26 ambulatory patients were entered into a random-
ized crossover trial. Threonine administered at a total daily dose of 7.5 g reduced signs of spasticity on clinical examination, although no symptomatic improvement could be detected by the examining physician or the patient. In contrast to the side effects of sedation and increased motor weakness associated with antispasticity drugs commonly used for the treatment of multiple sclerosis, no side effects or toxic effects of threonine were identified. Levels of threonine were elevated in serum and cerebrospinal fluid during treatment, but glycine levels did not change. Enhancement by threonine of glycinergic postsynaptic inhibition of the motor reflex arc in the spinal cord may represent a nonsedating, nontoxic approach to the management of spasticity in multiple sclerosis. (Arch Neurol. 1992;49:923-926) has been defined characterized by Spasticity velocity-dependent stretch reflexes (muscle tone) with as a
a
tonic don jerks,
motor
disorder increase in
neuron
Accepted
From the Boston.
PATIENTS AND METHODS
Patient
for publication January 27, 1992. Department of Neurology, Massachusetts General Hospital,
Reprint requests to the Neuroimmunology Unit, Warren 324, Massachusetts General Hospital, Boston, MA 02114 (Dr Hauser).
Population
Twenty-six patients with clinically definite MS13 were enrolled in the study. Patients were drawn from the MS population followed at Massachusetts General Hospital (MGH), Boston, and from referrals by local neurologists. Ambulatory patients with inactive or very slowly progressive MS were eligible. Inactive
disease was defined as relapsing-remitting MS that has been clin¬ ically stable (ie, nonexacerbating) for more than 2 years. Very slowly progressive disease was defined as chronic MS without change for at least 1 year, as judged by Ambulation Index and Expanded Disability Status Scales (EDSS).1415 Inclusion and exclusion criteria are summarized in Table 1.
exaggerated ten¬
from hyperexcitability of the stretch reflex.1 This restricted physiologic definition does not in¬ clude other features of the upper motor neuron syndrome, eg, the "negative" symptoms of weakness and loss of dex¬ terity and the "positive" symptom of flexor spasms.2"6 In patients with the demyelinating disease multiple sclerosis (MS), spasticity that interferes with ambulation and dex¬ terity is commonly present.7 Patients with severe paraparesis may depend on spasticity to aid in ambulation, but flexor spasms and clonus may prevent effective use of re¬ sidual strength. Spasticity may also be accompanied by pain or may result in bladder and bowel dysfunction, leading to urgency, frequency, and incontinence. Threonine, a naturally occurring amino acid, has been proposed as a candidate therapy for spasticity, based on observations that its administration increases levels of glycine in the spinal cords of rats.8 The motor reflex arc is postsynaptically inhibited by glycine that is normally re-
resulting
leased from interneurons located in the gray matter of the spinal cord and from Renshaw cells.910 Threonine might reduce spasticity by increasing glycinergic inhibition. Two uncontrolled studies have indicated a potential antispas¬ ticity effect in humans.1112 Herein, we report the findings of a double-blind crossover trial of oral administration of threonine in a population of patients with MS selected for the presence of symptomatic spasticity, relatively pre¬ served motor function, and stable disease course.
Study Design Threonine
was
supplied as a purified amino acid (Ajinomoto
Ine, Tokyo, Japan) and was incorporated into 500-mg capsules by
the research pharmacy at MGH. Placebo capsules contained lac¬ tose NF. Intact threonine and placebo capsules were identical in appearance and taste. Treatment group assignment was per¬ formed by the dispensing pharmacist according to a prescheduled randomized computer-generated order of administration. Neither examiners nor patients were aware of the order in which the treatments were given. The protocol consisted of two 8-week treatment periods sepa¬ rated by a 2-week washout period. During each treatment period, patients were asked to self-administer five capsules three times daily, for a total daily dose of 7.5 g. Compliance was assessed by frequent patient contact, by return of empty capsule bottles, and by measurement of serum threonine levels. Response to treatment was judged by physician and patient assessments, research neu¬ rologic measurements of spasticity and function, neurophysiologic quantitation of spasticity, and measurement of changes in glycine and other amino acids in cerebrospinal fluid (CSF) and blood. For each patient, neurologic assessment was performed by the same examiner before therapy, at the end of each 8-week treatment course, and again following a 2-week washout period. Assessment was performed with the EDSS,15 the Ambulation In¬ dex,14 the Ashworth Scale,16 and a Clinician Spasticity Scale that
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 06/13/2015
Table
1.—Study
Inclusion and Exclusion Criteria
Table
Inclusion criteria Men and women
aged 18 to 55 y Clinically definite multiple sclerosis,
Variable inactive
or
slowly
progressive form The presence, for at least 3 mo, of spasticity or spontaneous flexor spasms sufficient in degree to interfere with functional activities Ambulatory, with Disability Status Score s6 and Ambulation Index £5 Reasonable functional use of arms, eg, Upper-Extremity Index of 0 or 1 Good general health Ability to understand the purpose of the study and
willingness to participate,
as
demonstrated by signed
form Exclusion criteria Cancer or serious underlying medical illness (eg, serious cardiac disease, renal failure, uncontrolled diabetes mellitus, infections, peripheral vascular disease) Advanced arthritis, contractures, or other conditions that hinder evaluation of joint movement Required use of psychoactive drugs, including sedatives, consent
hypnotics, antidepressants, or neuroleptics Antispasticity treatment within 1 mo, including diazepam, baclofen, dantrolene sodium, and corticosteroids Chemotherapeutic agents, such as cyclophosphamide or azathioprine, within the past 6 mo
was
developed in an earlier pilot study. The Clinician Spasticity
Scale is
a
Characteristics 2.—Population of the Study Group*
summary of the assessments of four
measures:
upper-
extremity muscle tone, lower-extremity muscle tone, reflexes, and
spontaneous flexor spasms. For each measure, results were recorded as improved (I, +1), unchanged (U, 0), or worse (W, -1) compared with entry status. The sum of the individual spasticity assessment scores thus had a theoretical range between -4 and +4. Values less than 0 were considered "worse"; values greater than 0, "improved"; and values equal to 0, "unchanged." In addition, a Patient Spasticity Scale was developed for each patient that included the three most bothersome symptoms asso¬ ciated with spasticity (eg, painful spasms, nocturnal spasms, stiffness, and bladder symptoms). Patient Spasticity Scale scores were determined in an identical fashion as described above for the Clinician Spasticity Scale. At each follow-up session, response to treatment was recorded for each symptom as improved (I, +1), unchanged (U, 0), or worse (W, -I) compared with entry status, and a composite score was generated. Video recordings of gait and of other selected features of the examination were also obtained at each session. In addition, the examiner recorded a Global Assessment of the patient's condition (ie, improved, unchanged, or worse), and patients reported their own Global Assessment of treatment effects by completing a pa¬ tient questionnaire. For Spasticity Scores and Global Assess¬ ments, signed-rank tests were used to compare the outcome of threonine vs placebo treatments. Patients were asked to keep a diary form on which to record the occurrence of spasms and other symptoms of spasticity, as well as any adverse side effects or illnesses they experienced. Video recordings were reviewed in a blinded fashion by two of us (J.R.L. and S.L.H.) at the conclusion of the study. Before beginning each treatment course, a research dietitian instructed each patient to consume a standard 75-g protein diet, to be continued until completion of the study. Blood was drawn for standard laboratory tests, and an electrocardiogram and a chest roentgenogram were obtained. At the end of each treatment period, patients were admitted to the MGH Clinical Research Center. Electrophysiologic studies included -reflex (H max/M max ratio), F response (F mean/M max ratio), and vibratory inhibition of the -reflex determina¬ tions, the H max/M max ratio is determined by comparison of the
Age,
Value 41 ±6.5
y
Sex, F/M Disease duration, EDSS
1
5/11
12±7.4
y
4.7+1.5
score
3.0±0.9
Al
presented as mean±SEM unless otherwise indicated. EDSS indicates Expanded Disability Status Scales; Al, Ambulation Index. *Data
are
maximum amplitude of an H reflex to the maximum amplitude of the compound muscle action potential in the same muscle. Single electrical stimuli were delivered to the popliteal nerve in the popliteal fossa and the H reflex and compound muscle action po¬ tential was recorded with surface electrodes placed over the soleus muscle. The H max/M max ratio reflects the percentage of motoneurons in the motoneuron pool that can be activated by the H reflex. When the excitability of the motoneuron pool is increased, such as in spasticity, a greater number of motoneurons are excited and therefore the amplitude of H reflex is increased. The F re¬ sponse is measured after delivery of a minimum of 10 supramax¬ imal electrical stimuli. A mean amplitude of measurable F re¬ sponses (>20 µ ) is calculated in relation to the maximum am¬ plitude of the compound muscle action potential recorded from the same muscle (F mean/M max ratio). Vibratory inhibition of the reflex was recorded by applying vibration to the tendon during elicitation of the reflex from the soleus muscle. The index of max (vibrated)/H vibratory inhibition was measured as maxXlOO. Vibratory inhibition of the reflex is used to evaluate the role of presynaptic inhibition at the level of the spinal cord. In addition, measurements of the duration of electromyographic bursts recorded with surface electrodes placed over tibialis ante¬ rior muscles during foot tapping were also calculated. Simulta¬ neous fasting blood and CSF amino acid levels were measured at 9 AM following a 10-hour period of complete bed rest. Samples were analyzed for threonine and glycine with a Beckman 6300 au¬ tomated amino acid analyzer (Beckman Instruments Ine, Fullerton, Calif). The treatment code was broken after all clinical and laboratory data had been entered into the database.
RESULTS Of the 26 patients who entered the study, 24 completed both treat¬ at least one treatment period and 21 ment periods. Two patients dropped out during the first treatment period, one for nonmedicai reasons and another in whom additional antispasticity therapy was instituted. Two patients dropped out during the second treatment period, one because of an MS exacerbation and the other because of development of pneumonia (in both cases, the first treatment was placebo). Two patients believed that the second treatment was not working and stopped therapy early (in both cases, the first treatment was threonine); one of these patients was convinced to complete the entire evaluation and the other returned for clinical examination only. The characteristics of the patient population are shown in Table 2.
completed
Clinical Response The Figure diagrams the clinicians' and patients' assess¬ ments of treatment outcomes for the 21 patients who com¬ pleted both treatment periods. For all comparisons, I indi¬ cates improved; S, same; and W, worse. Response to threonine appears on the horizontal axis and response to placebo on the vertical axis. For example, reading down from the upper left-hand corner of the Figure correspond-
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 06/13/2015
Table 3.—Plasma and Cerebrospinal Fluid (CSF) Amino Acid Levels During Threonine and Placebo Treatments*
Threonine S
Clinician
W
Placebo
Spasticity Scale o
-Q V
S
P=.036 W
Variable
Threonine Treatment
Plasma threonine Plasma glycine
662.0±262.3
141.1 ±38.9
245.5±68.6
252.6±54.8
CSF threonine
118.8±57.8
33.3±12.4
6.0±3.9
6.8±3.5
CSF
glycine are expressed
•Results
Threonine I
S
W
Patient Spasticity Scale
Duncan's
either
a
tion.
as
Treatment
mean±SEM.
Multiple Range test). There was no evidence of or of a period-treatment interac¬
carryover effect
I
Laboratory Evaluations determinations (mean ± SEM) of amino acid Laboratory levels are shown in Table 4. While plasma and CSF thre¬ onine levels increased fourfold, plasma and CSF glycine levels did not differ between treatments. No differences in
o Lì
J
P=.185
W
electrophysiologic
Threonine S
W
Clinician Global Assessment
measures
(H max/M
max
ratio, F
response, vibratory inhibition of the -reflex, or duration of electromyographic bursts) were associated with threo¬ nine treatment compared with placebo treatment (data not
shown).
COMMENT ja CD
C
P=.47
W
Threonine I
S
I
1
w
Patient Global Assessment
cu
