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The Effect of Ginkgo Biloba on Functional Measures in Multiple Sclerosis: A Pilot Randomized Controlled Trial
ORIGINAL RESEARCH
THE EFFECT OF GINKGO BILOBA ON FUNCTIONAL MEASURES IN MULTIPLE SCLEROSIS: A PILOT RANDOMIZED CONTROLLED TRIAL Susan K. Johnson, PhD,1 Bruce J. Diamond, PhD,2,3# Sara Rausch, MS,4 Michael Kaufman, MD,5 Samuel C. Shiflett, PhD,6 and Linda Graves, MD7
Background: Multiple sclerosis (MS) is a chronic demyelinating neurological disease afflicting young and middle-aged adults, resulting in problems with coordination, strength, cognition, affect, and sensation. Objective: The objective of this study was to determine whether a ginkgo extract (EGb 761) improved functional performance in individuals with MS. Design: This study used a double-blind, placebo-controlled, parallel group design. The end point was change between baseline (ie, preintervention) and follow-up evaluation following a regimen of four tablets per day at 60 mg per tablet for four weeks. Setting: The study was conducted in academic and clinicalbased settings. Patients/Participants: Twenty-two individuals with MS were randomly assigned to either the treatment or control condition. Groups did not differ with respect to age, IQ, and education.
Main Outcome Measure: The main outcome measures assessed depression (Center for Epidemiologic Studies of Depression Scale [CES-D]), anxiety (State-Trait Anxiety Inventory [STAI]), fatigue (Modified Fatigue Impact Scale [MFIS]); symptom severity (Symptom Inventory [SI]) and functional performance (Functional Assessment of Multiple Sclerosis [FAMS]). Results: The ginkgo group had significantly more individuals showing improvement on four or more measures with improvements associated with significantly larger effect sizes on measures of fatigue, symptom severity, and functionality. The ginkgo group also exhibited less fatigue at follow-up compared with the placebo group. Conclusions: This exploratory pilot study showed that no adverse events or side effects were reported and that ginkgo exerted modest beneficial effects on select functional measures (eg, fatigue) among some individuals with MS.
Intervention: Half of the subjects received 240 mg per day of ginkgo special extract (EGb 761), and the other half received placebo.
Key words: fatigue, depression, symptom, EGb 761
INTRODUCTION Multiple sclerosis (MS) is a chronic demyelinating neurological disease afflicting young and middle aged adults.1 MS affects spinal and cerebral myelin, resulting in problems with coordination, strength, cognition, affect, and sensation and can range from mild to severe.2 Rate of progression varies widely, and patients face uncertainty regarding future levels of disability. The chronic nature of MS, limited help from conventional medicine, possible adverse effects of allopathic medicine, and
the unpredictability and uncontrollability of exacerbations could make complementary and alternative medicine (CAM) approaches appealing to MS patients.3 In fact, one survey found that one third of a sample of 569 MS patients reported visiting at least one alternative therapy practitioner in the previous six months, primarily for massage therapy, chiropractic, and nutritional guidance,4 and another survey of 109 MS patients found that 36% used CAM.5 Few scientific investigations have directly assessed the efficacy of CAM treatments in MS.6 Chronically ill individuals are particularly likely to use CAM, and a nationwide telephone survey found that 12% of Americans used herbal medicine in 1997.7 Because it is likely that MS (and other chronically ill) patients will seek out herbal treatments because they are accessible and are perceived as having fewer adverse effects, it would be helpful to conduct controlled investigations of the effectiveness and safety of such treatments. Ginkgo biloba is the leading over-the-counter herbal preparation in Germany8 and one of the most commonly used in the United States.9 EGb 761, the ginkgo extract used in this study, is standardized to 24% ginkgo-flavone glycosides and 6% terpenoids, and the major constituents (ie, ⬎0.1%) are flavonol monoglycosides (eg, quercetin-3-0- glucoside, quercetin-3-0rhamnoside, and 3’-0-methylmyricetin-3-0-glucoside), flavonol
1 University of North Carolina-Charlotte, Charlotte, NC 2 William Paterson University 3 Department of PM&R, UMDNJ-Newark, NJ Medical School 4 Virginia Commonwealth University 5 Carolinas HealthCare System MS Center 6 Continuum Center for Health and Healing, Beth Israel Medical Center 7 Comprehensive Rehabilitation Services, NJ EGb 761 was provided by Dr. Willmar Schwabe Company, Germany. No other support either material or financial was provided. # Corresponding author. Address: Box 43592 Upper Montclair, NJ 07043 e-mail: [email protected]
© 2006 by Elsevier Inc. Printed in the United States. All Rights Reserved ISSN 1550-8307/06/$32.00
(Explore 2006; 2:19-24. © Elsevier Inc. 2006)
EXPLORE January 2006, Vol. 2, No. 1 doi:10.1016/j.explore.2005.10.007
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diglycosides, flavonol triglycosides, coumaric esters of flavonol diglycosides, flavonoidic compound, terpenes (eg, bilobalide, ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J), organic acids, and steroids.9 In regard to biological mechanisms of activity, ginkgo has been reported to exhibit peripheral and central effects in the form of antioxidant and antiplatelet-activating factor properties, vascular-modulating properties (ie, enhancing blood flow), neurotransmitter-potentiating activity, and modulating effects on cerebrovascular tone and glucose metabolism. Ginkgo whole extract or its constituents have exhibited half lives ranging from two to four hours and activity levels that peak at 1.5 to three hours in animal and human models.9 While exhibiting a long history of safe use, it should be noted that because ginkgo exhibits monoamine oxidase (MAO)-inhibitor properties, it could exert a synergistic effect when combined with MAO-inhibitor drugs. Because ginkgo also acts as an antiplatelet-activating factor, caution should be exercised when it is administered with anticoagulants. Good tolerability using measures of renal function and blood crasis have been reported. However, in rare cases, patients have shown skin reactions, headache, and mild gastrointestinal upset.9 Ginkgo has been used to treat a variety of neurologic disorders. The German commission E (analogous to the US Food and Drug Administration [FDA] for botanicals) has approved ginkgo for symptomatic treatment of deficits in memory, concentration, and depression from organic brain disease.10 Ginkgo has a long history of safe use in treating cognitive and mood disturbances.9,11 In Germany, “cerebral insufficiency” is a frequently cited clinical indication for ginkgo. This overly inclusive diagnostic category is characterized by 12 primary symptoms: confusion, memory impairments, absentmindedness, dizziness, tinnitus, headache, low-energy levels, depressed mood, poor concentration, fatigue, anxiety, and decreased physical activity.12 Studies examining the effects of a standardized extract of the ginkgo leaf, known as EGb 761 (Wilmar Schwabe Company, Germany), on functional measures in cerebral-insufficiency patients have generally reported statistically and clinically significant improvements on measures of memory, depression, anxiety, concentration, fatigue, and dizziness.13–15 Because these symptoms are commonly observed in MS, and, given ginkgo’s purported ability to improve circulation and oxygenation in the brain, ginkgo may provide some benefit to MS patients and play a role as an adjunctive treatment in MS. Further support for using ginkgo with individuals with MS is based on a pilot study that examined the effects of three months of ginkgo on cognitive and functional measures in MS.16 The authors of this study reported that ginkgo-treated (240 mg/day) patients improved on the Paced Auditory Serial Addition Test (PASAT) and on a Perceived Deficits scale of a Quality of Life Index compared with placebo-treated patients. In addition, there was a deterioration on category fluency in the placebo group that was not observed in the ginkgo-treated group. If ginkgo can enhance the functional status of individuals with MS, it could provide a relatively safe complementary intervention for treating some of the symptoms of MS. Given the lack of research in this area, the goal of the current pilot study was to examine the effects of ginkgo on quality of life, fatigue, depres-
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sion, and symptom severity measures in MS and to identify conceptual and methodological issues that need to be addressed in designing future studies.
METHODS Participants Participants were recruited from the registry of a medically based MS center in North Carolina and from a MS Society chapter in northern New Jersey. This work was done in accordance with the appropriate institutional review body and carried out with the ethical standards set forth in the Helsinki Declaration of 1975.
Inclusion criteria. Participants had to be diagnosed with clinically definite MS as defined by Poser criteria17 by a board-certified neurologist. Clinically definite MS by Poser criteria is defined as (1) two clinical attacks and evidence of two areas of nervous system involvement by examination or (2) two clinical attacks, evidence of one area of nervous system involvement by examination, and paraclinical evidence of MS (almost always a positive magnetic resonance imaging [MRI] scan). Poser criteria can be graded as clinically definite, laboratory-supported definite, clinically probable, and laboratory-supported probable MS, but we accepted only clinical definite. The physician was the adjudicator in all cases. All Kurtzke Expanded Disability Status Score (EDSS)18 levels and types of MS were eligible for participation in the study. Exclusion criteria. Participants were not able to participate in the study for the following reasons: (1) had an exacerbation within four weeks of participating in the study; (2) had been diagnosed with neurological or psychiatric disorders unrelated to MS; (3) were taking beta blockers, calcium channel, angiotensin converting enzyme (ACE) inhibitors, or anticoagulants; (4) were currently participating in other CAM therapies. At both test sites, patients who fit the above criteria were telephoned and invited to participate in the study. Participants were told that they would have to volunteer approximately two hours of their time at both the baseline and follow-up assessments. Procedure A total of 23 participants were entered into the study and completed the baseline measures. Two participants were dropped, one because she experienced an exacerbation and one who was unable to schedule the follow-up appointment. Both of the dropped subjects were in the placebo group and did not appear to differ significantly from the mean patient profile. The final analyses were performed with 12 subjects in the ginkgo intentto-treat group and nine subjects in the placebo group. Based on prior work10 using EGb 761 (with stroke and brain injury), it was hypothesized that clinically meaningful changes (CMC) on the order of 1/3 to 1/2 standard deviations (SD) would be attained using an n of 12 subjects per group and a power of 75%.19 Although generally showing a good safety profile over a very long period of time, the literature does report that, in a small percentage of patients, skin irritation, stomach upset, and head-
Ginkgo and Functional Measures in MS
Table 1. Demographic Information Ginkgo Group Years of Age Years of Education Intelligence (NAART) Sex (M/F) Ethnicity White African American Marital Status Single Married Divorced
Placebo Group
Mean
SD
Mean
SD
48.7 15.2 43.7 1/11
11.0 2.0 8.5
52.8 16.0 42.9 3/8
9.5 1.9 10.1
11 0
8 2
1 8 2
1 7 2
ache have been observed.15 Adverse events and side effects were monitored in two ways: physical examinations postintervention and debriefings and patient log and encouraging patients to contact study personnel during the course of the study with any concerns or signs of illness.19 All participants provided informed consent; had an EDSS assessment; and had an interview with a nurse, physician, or neuropsychologist to collect demographic and medical history information. Demographic information for the subject sample is presented in Table 1. There were no significant differences in age, education, intelligence, ethnic, or gender distribution between the ginkgo and placebo groups. Case matching was not performed. Illness variables are presented in Table 2. Study Design This study used a randomized, placebo-controlled, doubleblind, parallel group design. After participants provided informed consent, they were randomly assigned to either the treatment (ginkgo) or placebo group. The random assignment was achieved by providing each participant with a subject ID number that was matched with a container labeled with a number corresponding to a random number table. The randomization procedure was implemented by an administrative assistant not associated with the experiment. The study was triple blinded because the individual performing the data analysis was blinded with respect to an individual’s group membership. One of the purposes of the study was to find out whether ginkgo extract modifies MS illness, but the study was exploratory, and a corollary objective was to assess the responsiveness of various outcome measures. The placebo was an inert tablet that contained lactose monohydrate, microcrystalline cellulose, corn starch, polyvidon, colloidal, silicon dioxide, caramel, talc, and magnesium stearate, and the film coating contained hypromellose, macrogol, titanium dioxide, and ferric oxide. The tablet was indistinguishable with respect to sight, smell, and touch. The blinding procedure was evaluated by questioning a group of 12 individuals who did not participate in the study to judge whether a tablet was ginkgo
Ginkgo and Functional Measures in MS
or placebo. The group’s accuracy was no better than chance. Furthermore, a subset of eight study participants following the study were asked whether they believed a tablet was ginkgo or placebo, and they too achieved accuracy levels that were no better than would be expected by chance alone. Ginkgo special extract (EGb 761) and placebo tablets are manufactured under pharmaceutical standards and have been used in numerous published studies, including a prior study conducted by the current author with similar findings with respect to the distinguishability of ginkgo and placebo. The end point was defined as the change between baseline (ie, preintervention) and follow-up evaluation following a regimen of four 60 mg tablets of EGb 761 (a standardized ginkgo extract manufactured to pharmaceutical standards by Dr. Wilmar P. Schwabe Company, Gmb, Germany) per day (ie, 240 mg per day) taken for 4 weeks. The dosage and duration of the EGb 761 was based on previous work cited in the literature and a prior FDA-approved clinical trial.10,19 Assessments The following measures were collected only at baseline: (1) Neurological status as determined by a physician using the EDSS.18 (2) Premorbid intelligence assessed by the North American Adult Reading Test (NAART).20 This test of verbal IQ is a modified version of the National Adult Reading Test (NART), which has been adapted for North American subjects. The NAART list comprises 50 phonetically irregular words, and participants are instructed to pronounce the words. The following measures were collected at baseline and postintervention: 1. Functional Assessment of Multiple Sclerosis (FAMS).21 The FAMS is a 59 item quality of life scale that captures the multidimensional impact of MS on physical functioning, social functioning, and emotional well-being. The participant rates each item by reporting how true each statement has been for them during the past week, ranging from (0) “not at all” to (4) “very much.” Total scores can range from zero to 236, with higher scores indicating better adjustment to MS and a better overall quality of life in patients. Internal consistency (␣ ⫽ .93) and test-retest reliability coefficients
Table 2. Illness Variables Ginkgo Group Medications EDSS (range 1-7) Duration of MS (years) Disease Classification Relapsing-remitting Secondary-progressive Progressive relapsing Primary-progressive Chronic progressive
Placebo Group
Mean
SD
Mean
SD
3.7 3.8 9.3
3.2 2.1 7.1
2.9 3.9 11.6
1.7 2,6 5.4
6 2 0 1 2
4 3 1 1 0
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2.
3.
4.
5.
(.90) for the scored items are consistently high. The subscales are psychometrically and conceptually distinct, reflecting the multidimensionality of the quality-of-life concept.21 Symptom inventory. This scale was developed specifically for MS and has documented test-retest reliability (␣ ⫽ .91), criterion validity (correlation with the EDSS was .55), and discriminant validity.22 The Symptom inventory (short form) is a 23-item Likert scale, which asks the patient to endorse how severe a given symptom has been within the past month, ranging from (0) “Not at all” to (4) “A great deal.” There are six subscales assessing neurological symptoms that are affected by MS: visual, left hemisphere, right hemisphere, brain stem/cerebellar, spinal cord, and nonlocalizing symptoms. Scores can range from zero to 92, with higher scores indicating greater symptom severity. Center for Epidemiologic Studies of Depression Scale (CES-D) The CES-D is a 20-item, reliable self-report measure of current depressive symptomatology that was constructed and validated for use in the general population.23 The items on this measure include depressed mood, feelings of guilt and worthlessness, feelings of helplessness and hopelessness, psychomotor retardation, loss of appetite, and sleep disturbance. This scale minimizes reliance on physical symptoms to assess depressive symptoms, thus there are fewer items that overlap with MS symptomatology. Responses are based on a four-point Likert-type scale (zero ⫽ rarely or none of the time and three ⫽ most or all of the time). The inventory is scored from zero to 60, with higher scores indicating greater depressive symptoms. This measure has been used in previous studies to assess MS patients with depressive symptomatology.24,25 State-Trait Anxiety Inventory (STAI). The STAI26 is a 40item questionnaire that measures levels of anxiety in general (trait) and anxiety at the present moment (state). Higher scores are associated with higher levels of anxiety. Modified Fatigue Impact Scale (MFIS). Fatigue was assessed using the MFIS as recommended by the MS Council for Clinical Practice Guidelines.27 This modified 21-item scale was designed for use with MS patients and assesses the patients’ perceived impact of fatigue on physical, cognitive, and psychosocial functioning.27 The total MFIS score can range from zero to 84, with higher scores indicating greater impact of fatigue on the individuals’ activities.
Data Analysis On the basis of an exploratory data analysis, it was determined that the raw data did not satisfy the assumptions underlying parametric statistics and that by using a parametric-based approach on the raw data, treatment effects might be masked. Instead, a combination of parametric and nonparametric analyses using transformed scores (eg, effect size and improvement on multiple measures) were performed using t tests, 2 test, and analysis of variance (ANOVA). A mixed multivariate analysis of variance (MANOVA) with repeated measures was used to evaluate targeted outcome measures at follow-up. The t test was used to evaluate treatment effect size, and a 2 test as well as an ANOVA were used to evaluate differences between and within groups with respect to change scores. Demographic data were
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analyzed using one-way ANOVAs or 2 analysis for categorical variables.
RESULTS Importantly, no side effects or adverse events were reported or observed throughout the course of this exploratory study. Outcome Measures Showing Improvement An analysis was done whereby each participant’s score on the postintervention outcome measures was assigned a “0” if the score was worse than the preintervention level and a “1” if it showed improvement. The ginkgo group improved on an average of 3.0 ⫾ 1.9 measures, and the placebo group improved on 2.2 ⫾ 1.1 measures. This difference was not significant (F [1,20] ⫽ 1.6, P ⫽ .23). On reviewing the data, it was noted that some individuals improved on three to four measures Improvement on Multiple Measures Based on the previous analysis and research suggesting that there may be individuals who are “positive” and “negative” responders,28 a 2 analysis of participants who showed improvement on four or more measures compared with baseline or preintervention levels was performed. It showed a significant advantage for the ginkgo versus the placebo group (2 ⫽ 5.0, df ⫽ 1, 2crit ⫽ 3.8, ␣ ⫽ .05). Effect Size Analysis A weakness in the previous analyses is the fact that the magnitude of improvement was not quantified. To remedy this, an effect size (ES) analysis was computed that reflected the magnitude of change from preintervention baseline levels. There were no significant differences in mean effect size between the ginkgo and the placebo groups on the STAI measure (see Table 3). However, an analysis of the mean change scores on the FAM, SI, and MFIS measures showed a significant effect size advantage for the ginkgo (Mean ⫽ .89, SD ⫽ .34) versus the placebo (Mean ⫽ .58, SD ⫽ .37) group [t(29) ⫽ 2.39, P ⫽ .02] (see Table 3). Although the placebo group showed a medium effect size (ie, ⬎.50), the ginkgo group showed a significantly larger effect size (ie, ⬃.90) (⬎.80 is generally considered a large effect29). Effect sizes of .33 (ie, 1/3 SD) have been described as corresponding to an “adequate approximation” of a minimally important difference because it falls between a small (.20) and medium effect size (.50).30 A retrospective power analysis shows that power was computed at 62.6% but that the effect size was sufficiently large to allow a modestly powered test to detect differences between the groups. Ginkgo Versus Placebo: Comparisons at Follow-up A mixed MANOVA with repeated measures was computed using between subjects factors (group: ginkgo and placebo) and within subjects factors (pre- and postintervention) (using a correction for multiple comparisons) and showed that there was a significant between group effect with respect to the MFIS (F ⫽ 6.05, P ⫽ .024) and a trend for the SI measure (F ⫽ 3.92, P ⫽ .06).
Ginkgo and Functional Measures in MS
Table 3. Significant Effect Size Changes
MFISⴱ Baseline Postintervention SI totalⴱ Baseline Postintervention FAMS totalⴱ Baseline Postintervention CES-D† Baseline Post intervention STAI‡ Baseline Postintervention
Ginkgo Mean ⫾ SD
Placebo Mean ⫾ SD
37.8 ⫾ 14.7 35.5 ⫾ 13.9
39.8 ⫾ 15.1 42.4 ⫾ 15.6
7.9 ⫾ 4.4 11.5 ⫾ 12.6
7.8 ⫾ 4.2 8.8 ⫾ 4.0
169 ⫾ 32 173 ⫾ 25
158 ⫾ 29 160 ⫾ 30
12.1 ⫾ 10.2 12.2 ⫾ 10.1
14.5 ⫾ 8.3 10.1 ⫾ 4.9
32.4 ⫾ 11.3 33.7 ⫾ 15.3
30.8 ⫾ 10.6 30.4 ⫾ 7.9
MFIS, Modified Fatigue Impact Scale; SI, Symptom Inventory; FAMS, Functional Assessment of Multiple Sclerosis; Depression Center for Epidemiologic Studies of Depression Scale (CESD) and STAI (State-Trait Anxiety Inventory) scores at baseline and after 4 weeks of treatment with ginkgo or placebo. ⴱSignificant mean effect size difference across the MFIS, SI and FAMS †Significant difference from baseline to postintervention, which was accounted for by a reduction in depression in the placebo group. ‡No change.
DISCUSSION In this exploratory randomized, placebo-controlled trial, individuals who showed improvement on multiple measures irrespective of the magnitude of the treatment effect were exclusively from the ginkgo group. Although this analysis did not take into account the magnitude of change, a subsequent effect size analysis did show that individuals in the ginkgo versus placebo group exhibited a significantly greater change (improvement) from preintervention levels on the SI, FAMS, and MFIS as reflected by mean effect size. Although the power of this test was modest (⬃63%), the effect size was relatively large (ie, nearly .90), suggesting that at least some individuals derived greater therapeutic benefits in the treatment versus the placebo group. An additional analysis that (corrected for multiple comparisons) examined group differences at follow-up showed a significant between group effect with respect to the MFIS measure (and a trend for the SI measure), showing lower levels of fatigue in the ginkgo group. The issue of heterogeneity of response to ginkgo appears to be an important factor. For example, in a double-blind, placebocontrolled pilot study, there was evidence suggesting the existence of responders (positive) and nonresponders (negative) to acute ginkgo treatment (ie, 120-mg doses of GK501) among healthy participants.28 This finding suggests considerable individual variation in response to ginkgo. The implication is that analyses that combine positive and negative responders may mask or obscure some of the beneficial effects of ginkgo. The current finding that improvement on four or more measures was only found in the ginkgo group provides additional support for
Ginkgo and Functional Measures in MS
the idea that analyses need to take into account response heterogeneity. Although placebo effects can sometimes be robust, the significantly larger mean effect size in the ginkgo group on the SI, FAMS, and MFIS provides support for the idea of response heterogeneity and the need to use measures (ie, effect size) that can help identify individuals who are “responders” versus “nonresponders.” Although ginkgo appeared to exert therapeutic effects in some individuals, it is possible that treatment duration in the current study was too brief. However, the beneficial effects of ginkgo are believed to be caused by acute changes in blood flow to the brain, elevated glucose utilization, and increased acetylcholine production,31 with studies showing treatment effects in four weeks.10,19 Clearly, the current findings are suggestive rather than definitive. However, this pilot study does raise some important methodological issues that should to be examined in future research: Future work can be enhanced by recognizing and responding to the issue of response heterogeneity (ie, the apparent existence of subgroups of responders and the commensurate need for larger sample sizes); the apparent existence of “positive responders” and “negative responders”; the sensitivity of outcome measures (ie, some measures may reflect functional domains that are more responsive to treatment effects); and the sensitivity of analysis procedures in detecting changes in populations with considerable response heterogeneity and symptom fluctuation. Future studies should examine the mechanisms that mediate why some and not other individuals benefit from ginkgo so that treatments could be more beneficially and economically targeted to specific individuals. Overall, this pilot study showed that ginkgo exerted very modest beneficial effects among some individuals with MS: Some ginkgo-treated individuals improved on select functional measures, and the effect size of those improvements tended to be larger in the ginkgo versus the placebo group. Given the heterogeneity of the MS population both with respect to treatment response and to clinical course, larger sample sizes should be used to allow for this heterogeneity so that more powerful statistical procedures can be implemented. While identifying some functional outcome measures on which a subset of individuals with MS may derive modest benefits from taking ginkgo (EGb 761), this pilot study has also helped identify some methodological issues that, if addressed, can enhance the validity and generalizability of future work.
REFERENCES 1. Poser CM. The epidemiology of multiple sclerosis. Ann Neurol. 1994;36:S180-S193. 2. Noseworthy JH, Lucchinettie C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343:938-952. 3. Johnson SK, Frederick J, Kaufman M, Mountjoy B. A controlled investigation of bodywork in multiple sclerosis. J Altern Complement Med. 1999;5:237-243. 4. Schwartz CE, Laitin E, Brotman S, LaRocca N. Utilization of unconventional treatments by persons with mutiple sclerosis: is it alternative or complementary? Neurology. 1999;52:626-629. 5. Pucci E, Cartechini E, Taus C, Giuliani G. Why physicians need to look more closely at the use of complementary and alternative medicine by multiple sclerosis patients. Eur J Neurol. 2004;11:263-267.
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6. Bowling AC, Stewart TM. Current complementary and alternative therapies for multiple sclerosis. Curr Treat Options Neurol. 2003;5:5568. 7. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997: results from a follow-up national survey. JAMA. 1998;280:1569-1575. 8. Kleijnen J, Knipschild P. Gingko biloba for cerebral insufficiency. Br J Clin Pharmacol. 1992;34:352-358. 9. Diamond B, Shiflett S, Feiwel N, et al. Ginkgo biloba extract: Mechanisms and clinical indications. Arch Physical Med Rehabil. 2000;58: 1-11. 10. Diamond BJ, Shiflett SC, Lothian A, et al. EGb 761 (Ginkgo biloba): efficacy in treating stroke and TBI. Arch Physical Med Rehabil. 2000; 80:978. 11. Curtis-Prior P, Vere D, Fray P. Therapeutic value of Ginkgo biloba in reducing symptoms of decline in mental function. J Pharm Pharmacol. 1999;51:535-541. 12. Wesnes KA, Ward T, McGinty A, Petrini O. The memory enhancing effects of a gingko biloba/panax combination in healthy middle aged volunteers. Psychopharmacology. 2000;152:353-361. 13. Vorberg G. Ginkgo biloba extract (GBE): a long-term study of chronic cerebral insufficiency in geriatric patients. Clin Trials J 1985; 22:149-157. 14. Mancini M, Agozzino B, Bompani R. Clinical and therapeutic effects of Ginkgo biloba extract (GBE) versus placebo in the treatment of psychorganic senile demential or arteriosclerotic origin. Gazzetta Medica Italiana-Archivio Per Le Scienze Mediche. 1993;152:69-80. 15. Diamond BJ, Johnson SK, Torsney K, Morodan J, Kramer P. Complementary and alternative medicines in the treatment of dementia: an evidenced based review. Drugs Aging 2003;20:981-998. 16. Kenney C, Norman M, Jacobson M, Lampinen S, Nguyen DP, Corey-Bloom J. A double-blind, placebo-controlled, modified cross-over pilot study of the effects of gingko biloba on cognitive and functional abilities in multiple sclerosis (Abstract). Neurology. April 2002. 17. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1988;13:227-231.
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18. Kurtzke JF. Rating neurological impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology. 1983;33:295-301. 19. Diamond BJ, Shiflett SC, Richards JA, Noskin O, Lothian A, Feiwel N. Ginkgo biloba extract. Mechanisms and clinical indications: commentary. Ginkgo biloba extract mechanisms, indications and preliminary data. Neurol Rep. 2001;25:70-75. 20. Blair J R, Spreen O. Predicting premorbid IQ: a revision of the National Adult Reading Test. Clin Neuropsychol. 1989;3:129-136. 21. Cella DF, Dineen K, Arnason B, et al. Validation of the Functional Assessment of Multiple Sclerosis quality of life instrument. Neurology. 1996;47:129-139. 22. Schwartz CE, Vollmer T, Lee H. Reliability and validity of two self-report measures of impairment and disability for MS. Neurology. 1999;52:63-70. 23. Radloff L. The CES-D scale: a new self-report depression scale for research in the general population. Appl Psychol Measurement. 1977; 1:385-401. 24. Krupp LB, Sliwinski M, Masur DM, Friedberg F, Coyle PK. Cognitive functioning and depression in patients with chronic fatigue syndrome and multiple sclerosis. Arch Neurol. 1994;51:705-710. 25. Shnek Z, Foley F, LaRocca N, et al. Helplessness, self-efficacy, cognitive distortions and depression in multiple sclerosis and spinal cord injury. Ann Behav Med. 1997;19:287-294. 26. Speilberger CD. Manual of the State-Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychology Press; 1983. 27. Fisk JD, Pontefract A, Ritvo PG, Archibald CJ, Murray TJ. The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci. 1994;21:9-14. 28. Canter PH, Ernst E. Multiple n ⫽ 1 trials in the identification of responders and non-responders to the cognitive effects of Gingko biloba. Int J Clin Pharmacol Ther. 2003;41:354-357. 29. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates; 1988. 30. Yost KJ, Eton DT. Combining distribution and anchor-based approaches to determining minimally important differences: the FACIT experience. Evaluation Health Professions. 2003;26:1-20. 31. Gold PE, Cahill L, Wenk GL. Gingko biloba: a cognitive enhancer? Psychol Sci Public Interest. 2002;3:2-11.
Ginkgo and Functional Measures in MS
THE EFFECT OF GINKGO BILOBA ON FUNCTIONAL MEASURES IN MULTIPLE SCLEROSIS: A PILOT RANDOMIZED CONTROLLED TRIAL Susan K. Johnson, PhD,1 Bruce J. Diamond, PhD,2,3# Sara Rausch, MS,4 Michael Kaufman, MD,5 Samuel C. Shiflett, PhD,6 and Linda Graves, MD7
Background: Multiple sclerosis (MS) is a chronic demyelinating neurological disease afflicting young and middle-aged adults, resulting in problems with coordination, strength, cognition, affect, and sensation. Objective: The objective of this study was to determine whether a ginkgo extract (EGb 761) improved functional performance in individuals with MS. Design: This study used a double-blind, placebo-controlled, parallel group design. The end point was change between baseline (ie, preintervention) and follow-up evaluation following a regimen of four tablets per day at 60 mg per tablet for four weeks. Setting: The study was conducted in academic and clinicalbased settings. Patients/Participants: Twenty-two individuals with MS were randomly assigned to either the treatment or control condition. Groups did not differ with respect to age, IQ, and education.
Main Outcome Measure: The main outcome measures assessed depression (Center for Epidemiologic Studies of Depression Scale [CES-D]), anxiety (State-Trait Anxiety Inventory [STAI]), fatigue (Modified Fatigue Impact Scale [MFIS]); symptom severity (Symptom Inventory [SI]) and functional performance (Functional Assessment of Multiple Sclerosis [FAMS]). Results: The ginkgo group had significantly more individuals showing improvement on four or more measures with improvements associated with significantly larger effect sizes on measures of fatigue, symptom severity, and functionality. The ginkgo group also exhibited less fatigue at follow-up compared with the placebo group. Conclusions: This exploratory pilot study showed that no adverse events or side effects were reported and that ginkgo exerted modest beneficial effects on select functional measures (eg, fatigue) among some individuals with MS.
Intervention: Half of the subjects received 240 mg per day of ginkgo special extract (EGb 761), and the other half received placebo.
Key words: fatigue, depression, symptom, EGb 761
INTRODUCTION Multiple sclerosis (MS) is a chronic demyelinating neurological disease afflicting young and middle aged adults.1 MS affects spinal and cerebral myelin, resulting in problems with coordination, strength, cognition, affect, and sensation and can range from mild to severe.2 Rate of progression varies widely, and patients face uncertainty regarding future levels of disability. The chronic nature of MS, limited help from conventional medicine, possible adverse effects of allopathic medicine, and
the unpredictability and uncontrollability of exacerbations could make complementary and alternative medicine (CAM) approaches appealing to MS patients.3 In fact, one survey found that one third of a sample of 569 MS patients reported visiting at least one alternative therapy practitioner in the previous six months, primarily for massage therapy, chiropractic, and nutritional guidance,4 and another survey of 109 MS patients found that 36% used CAM.5 Few scientific investigations have directly assessed the efficacy of CAM treatments in MS.6 Chronically ill individuals are particularly likely to use CAM, and a nationwide telephone survey found that 12% of Americans used herbal medicine in 1997.7 Because it is likely that MS (and other chronically ill) patients will seek out herbal treatments because they are accessible and are perceived as having fewer adverse effects, it would be helpful to conduct controlled investigations of the effectiveness and safety of such treatments. Ginkgo biloba is the leading over-the-counter herbal preparation in Germany8 and one of the most commonly used in the United States.9 EGb 761, the ginkgo extract used in this study, is standardized to 24% ginkgo-flavone glycosides and 6% terpenoids, and the major constituents (ie, ⬎0.1%) are flavonol monoglycosides (eg, quercetin-3-0- glucoside, quercetin-3-0rhamnoside, and 3’-0-methylmyricetin-3-0-glucoside), flavonol
1 University of North Carolina-Charlotte, Charlotte, NC 2 William Paterson University 3 Department of PM&R, UMDNJ-Newark, NJ Medical School 4 Virginia Commonwealth University 5 Carolinas HealthCare System MS Center 6 Continuum Center for Health and Healing, Beth Israel Medical Center 7 Comprehensive Rehabilitation Services, NJ EGb 761 was provided by Dr. Willmar Schwabe Company, Germany. No other support either material or financial was provided. # Corresponding author. Address: Box 43592 Upper Montclair, NJ 07043 e-mail: [email protected]
© 2006 by Elsevier Inc. Printed in the United States. All Rights Reserved ISSN 1550-8307/06/$32.00
(Explore 2006; 2:19-24. © Elsevier Inc. 2006)
EXPLORE January 2006, Vol. 2, No. 1 doi:10.1016/j.explore.2005.10.007
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diglycosides, flavonol triglycosides, coumaric esters of flavonol diglycosides, flavonoidic compound, terpenes (eg, bilobalide, ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J), organic acids, and steroids.9 In regard to biological mechanisms of activity, ginkgo has been reported to exhibit peripheral and central effects in the form of antioxidant and antiplatelet-activating factor properties, vascular-modulating properties (ie, enhancing blood flow), neurotransmitter-potentiating activity, and modulating effects on cerebrovascular tone and glucose metabolism. Ginkgo whole extract or its constituents have exhibited half lives ranging from two to four hours and activity levels that peak at 1.5 to three hours in animal and human models.9 While exhibiting a long history of safe use, it should be noted that because ginkgo exhibits monoamine oxidase (MAO)-inhibitor properties, it could exert a synergistic effect when combined with MAO-inhibitor drugs. Because ginkgo also acts as an antiplatelet-activating factor, caution should be exercised when it is administered with anticoagulants. Good tolerability using measures of renal function and blood crasis have been reported. However, in rare cases, patients have shown skin reactions, headache, and mild gastrointestinal upset.9 Ginkgo has been used to treat a variety of neurologic disorders. The German commission E (analogous to the US Food and Drug Administration [FDA] for botanicals) has approved ginkgo for symptomatic treatment of deficits in memory, concentration, and depression from organic brain disease.10 Ginkgo has a long history of safe use in treating cognitive and mood disturbances.9,11 In Germany, “cerebral insufficiency” is a frequently cited clinical indication for ginkgo. This overly inclusive diagnostic category is characterized by 12 primary symptoms: confusion, memory impairments, absentmindedness, dizziness, tinnitus, headache, low-energy levels, depressed mood, poor concentration, fatigue, anxiety, and decreased physical activity.12 Studies examining the effects of a standardized extract of the ginkgo leaf, known as EGb 761 (Wilmar Schwabe Company, Germany), on functional measures in cerebral-insufficiency patients have generally reported statistically and clinically significant improvements on measures of memory, depression, anxiety, concentration, fatigue, and dizziness.13–15 Because these symptoms are commonly observed in MS, and, given ginkgo’s purported ability to improve circulation and oxygenation in the brain, ginkgo may provide some benefit to MS patients and play a role as an adjunctive treatment in MS. Further support for using ginkgo with individuals with MS is based on a pilot study that examined the effects of three months of ginkgo on cognitive and functional measures in MS.16 The authors of this study reported that ginkgo-treated (240 mg/day) patients improved on the Paced Auditory Serial Addition Test (PASAT) and on a Perceived Deficits scale of a Quality of Life Index compared with placebo-treated patients. In addition, there was a deterioration on category fluency in the placebo group that was not observed in the ginkgo-treated group. If ginkgo can enhance the functional status of individuals with MS, it could provide a relatively safe complementary intervention for treating some of the symptoms of MS. Given the lack of research in this area, the goal of the current pilot study was to examine the effects of ginkgo on quality of life, fatigue, depres-
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sion, and symptom severity measures in MS and to identify conceptual and methodological issues that need to be addressed in designing future studies.
METHODS Participants Participants were recruited from the registry of a medically based MS center in North Carolina and from a MS Society chapter in northern New Jersey. This work was done in accordance with the appropriate institutional review body and carried out with the ethical standards set forth in the Helsinki Declaration of 1975.
Inclusion criteria. Participants had to be diagnosed with clinically definite MS as defined by Poser criteria17 by a board-certified neurologist. Clinically definite MS by Poser criteria is defined as (1) two clinical attacks and evidence of two areas of nervous system involvement by examination or (2) two clinical attacks, evidence of one area of nervous system involvement by examination, and paraclinical evidence of MS (almost always a positive magnetic resonance imaging [MRI] scan). Poser criteria can be graded as clinically definite, laboratory-supported definite, clinically probable, and laboratory-supported probable MS, but we accepted only clinical definite. The physician was the adjudicator in all cases. All Kurtzke Expanded Disability Status Score (EDSS)18 levels and types of MS were eligible for participation in the study. Exclusion criteria. Participants were not able to participate in the study for the following reasons: (1) had an exacerbation within four weeks of participating in the study; (2) had been diagnosed with neurological or psychiatric disorders unrelated to MS; (3) were taking beta blockers, calcium channel, angiotensin converting enzyme (ACE) inhibitors, or anticoagulants; (4) were currently participating in other CAM therapies. At both test sites, patients who fit the above criteria were telephoned and invited to participate in the study. Participants were told that they would have to volunteer approximately two hours of their time at both the baseline and follow-up assessments. Procedure A total of 23 participants were entered into the study and completed the baseline measures. Two participants were dropped, one because she experienced an exacerbation and one who was unable to schedule the follow-up appointment. Both of the dropped subjects were in the placebo group and did not appear to differ significantly from the mean patient profile. The final analyses were performed with 12 subjects in the ginkgo intentto-treat group and nine subjects in the placebo group. Based on prior work10 using EGb 761 (with stroke and brain injury), it was hypothesized that clinically meaningful changes (CMC) on the order of 1/3 to 1/2 standard deviations (SD) would be attained using an n of 12 subjects per group and a power of 75%.19 Although generally showing a good safety profile over a very long period of time, the literature does report that, in a small percentage of patients, skin irritation, stomach upset, and head-
Ginkgo and Functional Measures in MS
Table 1. Demographic Information Ginkgo Group Years of Age Years of Education Intelligence (NAART) Sex (M/F) Ethnicity White African American Marital Status Single Married Divorced
Placebo Group
Mean
SD
Mean
SD
48.7 15.2 43.7 1/11
11.0 2.0 8.5
52.8 16.0 42.9 3/8
9.5 1.9 10.1
11 0
8 2
1 8 2
1 7 2
ache have been observed.15 Adverse events and side effects were monitored in two ways: physical examinations postintervention and debriefings and patient log and encouraging patients to contact study personnel during the course of the study with any concerns or signs of illness.19 All participants provided informed consent; had an EDSS assessment; and had an interview with a nurse, physician, or neuropsychologist to collect demographic and medical history information. Demographic information for the subject sample is presented in Table 1. There were no significant differences in age, education, intelligence, ethnic, or gender distribution between the ginkgo and placebo groups. Case matching was not performed. Illness variables are presented in Table 2. Study Design This study used a randomized, placebo-controlled, doubleblind, parallel group design. After participants provided informed consent, they were randomly assigned to either the treatment (ginkgo) or placebo group. The random assignment was achieved by providing each participant with a subject ID number that was matched with a container labeled with a number corresponding to a random number table. The randomization procedure was implemented by an administrative assistant not associated with the experiment. The study was triple blinded because the individual performing the data analysis was blinded with respect to an individual’s group membership. One of the purposes of the study was to find out whether ginkgo extract modifies MS illness, but the study was exploratory, and a corollary objective was to assess the responsiveness of various outcome measures. The placebo was an inert tablet that contained lactose monohydrate, microcrystalline cellulose, corn starch, polyvidon, colloidal, silicon dioxide, caramel, talc, and magnesium stearate, and the film coating contained hypromellose, macrogol, titanium dioxide, and ferric oxide. The tablet was indistinguishable with respect to sight, smell, and touch. The blinding procedure was evaluated by questioning a group of 12 individuals who did not participate in the study to judge whether a tablet was ginkgo
Ginkgo and Functional Measures in MS
or placebo. The group’s accuracy was no better than chance. Furthermore, a subset of eight study participants following the study were asked whether they believed a tablet was ginkgo or placebo, and they too achieved accuracy levels that were no better than would be expected by chance alone. Ginkgo special extract (EGb 761) and placebo tablets are manufactured under pharmaceutical standards and have been used in numerous published studies, including a prior study conducted by the current author with similar findings with respect to the distinguishability of ginkgo and placebo. The end point was defined as the change between baseline (ie, preintervention) and follow-up evaluation following a regimen of four 60 mg tablets of EGb 761 (a standardized ginkgo extract manufactured to pharmaceutical standards by Dr. Wilmar P. Schwabe Company, Gmb, Germany) per day (ie, 240 mg per day) taken for 4 weeks. The dosage and duration of the EGb 761 was based on previous work cited in the literature and a prior FDA-approved clinical trial.10,19 Assessments The following measures were collected only at baseline: (1) Neurological status as determined by a physician using the EDSS.18 (2) Premorbid intelligence assessed by the North American Adult Reading Test (NAART).20 This test of verbal IQ is a modified version of the National Adult Reading Test (NART), which has been adapted for North American subjects. The NAART list comprises 50 phonetically irregular words, and participants are instructed to pronounce the words. The following measures were collected at baseline and postintervention: 1. Functional Assessment of Multiple Sclerosis (FAMS).21 The FAMS is a 59 item quality of life scale that captures the multidimensional impact of MS on physical functioning, social functioning, and emotional well-being. The participant rates each item by reporting how true each statement has been for them during the past week, ranging from (0) “not at all” to (4) “very much.” Total scores can range from zero to 236, with higher scores indicating better adjustment to MS and a better overall quality of life in patients. Internal consistency (␣ ⫽ .93) and test-retest reliability coefficients
Table 2. Illness Variables Ginkgo Group Medications EDSS (range 1-7) Duration of MS (years) Disease Classification Relapsing-remitting Secondary-progressive Progressive relapsing Primary-progressive Chronic progressive
Placebo Group
Mean
SD
Mean
SD
3.7 3.8 9.3
3.2 2.1 7.1
2.9 3.9 11.6
1.7 2,6 5.4
6 2 0 1 2
4 3 1 1 0
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2.
3.
4.
5.
(.90) for the scored items are consistently high. The subscales are psychometrically and conceptually distinct, reflecting the multidimensionality of the quality-of-life concept.21 Symptom inventory. This scale was developed specifically for MS and has documented test-retest reliability (␣ ⫽ .91), criterion validity (correlation with the EDSS was .55), and discriminant validity.22 The Symptom inventory (short form) is a 23-item Likert scale, which asks the patient to endorse how severe a given symptom has been within the past month, ranging from (0) “Not at all” to (4) “A great deal.” There are six subscales assessing neurological symptoms that are affected by MS: visual, left hemisphere, right hemisphere, brain stem/cerebellar, spinal cord, and nonlocalizing symptoms. Scores can range from zero to 92, with higher scores indicating greater symptom severity. Center for Epidemiologic Studies of Depression Scale (CES-D) The CES-D is a 20-item, reliable self-report measure of current depressive symptomatology that was constructed and validated for use in the general population.23 The items on this measure include depressed mood, feelings of guilt and worthlessness, feelings of helplessness and hopelessness, psychomotor retardation, loss of appetite, and sleep disturbance. This scale minimizes reliance on physical symptoms to assess depressive symptoms, thus there are fewer items that overlap with MS symptomatology. Responses are based on a four-point Likert-type scale (zero ⫽ rarely or none of the time and three ⫽ most or all of the time). The inventory is scored from zero to 60, with higher scores indicating greater depressive symptoms. This measure has been used in previous studies to assess MS patients with depressive symptomatology.24,25 State-Trait Anxiety Inventory (STAI). The STAI26 is a 40item questionnaire that measures levels of anxiety in general (trait) and anxiety at the present moment (state). Higher scores are associated with higher levels of anxiety. Modified Fatigue Impact Scale (MFIS). Fatigue was assessed using the MFIS as recommended by the MS Council for Clinical Practice Guidelines.27 This modified 21-item scale was designed for use with MS patients and assesses the patients’ perceived impact of fatigue on physical, cognitive, and psychosocial functioning.27 The total MFIS score can range from zero to 84, with higher scores indicating greater impact of fatigue on the individuals’ activities.
Data Analysis On the basis of an exploratory data analysis, it was determined that the raw data did not satisfy the assumptions underlying parametric statistics and that by using a parametric-based approach on the raw data, treatment effects might be masked. Instead, a combination of parametric and nonparametric analyses using transformed scores (eg, effect size and improvement on multiple measures) were performed using t tests, 2 test, and analysis of variance (ANOVA). A mixed multivariate analysis of variance (MANOVA) with repeated measures was used to evaluate targeted outcome measures at follow-up. The t test was used to evaluate treatment effect size, and a 2 test as well as an ANOVA were used to evaluate differences between and within groups with respect to change scores. Demographic data were
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analyzed using one-way ANOVAs or 2 analysis for categorical variables.
RESULTS Importantly, no side effects or adverse events were reported or observed throughout the course of this exploratory study. Outcome Measures Showing Improvement An analysis was done whereby each participant’s score on the postintervention outcome measures was assigned a “0” if the score was worse than the preintervention level and a “1” if it showed improvement. The ginkgo group improved on an average of 3.0 ⫾ 1.9 measures, and the placebo group improved on 2.2 ⫾ 1.1 measures. This difference was not significant (F [1,20] ⫽ 1.6, P ⫽ .23). On reviewing the data, it was noted that some individuals improved on three to four measures Improvement on Multiple Measures Based on the previous analysis and research suggesting that there may be individuals who are “positive” and “negative” responders,28 a 2 analysis of participants who showed improvement on four or more measures compared with baseline or preintervention levels was performed. It showed a significant advantage for the ginkgo versus the placebo group (2 ⫽ 5.0, df ⫽ 1, 2crit ⫽ 3.8, ␣ ⫽ .05). Effect Size Analysis A weakness in the previous analyses is the fact that the magnitude of improvement was not quantified. To remedy this, an effect size (ES) analysis was computed that reflected the magnitude of change from preintervention baseline levels. There were no significant differences in mean effect size between the ginkgo and the placebo groups on the STAI measure (see Table 3). However, an analysis of the mean change scores on the FAM, SI, and MFIS measures showed a significant effect size advantage for the ginkgo (Mean ⫽ .89, SD ⫽ .34) versus the placebo (Mean ⫽ .58, SD ⫽ .37) group [t(29) ⫽ 2.39, P ⫽ .02] (see Table 3). Although the placebo group showed a medium effect size (ie, ⬎.50), the ginkgo group showed a significantly larger effect size (ie, ⬃.90) (⬎.80 is generally considered a large effect29). Effect sizes of .33 (ie, 1/3 SD) have been described as corresponding to an “adequate approximation” of a minimally important difference because it falls between a small (.20) and medium effect size (.50).30 A retrospective power analysis shows that power was computed at 62.6% but that the effect size was sufficiently large to allow a modestly powered test to detect differences between the groups. Ginkgo Versus Placebo: Comparisons at Follow-up A mixed MANOVA with repeated measures was computed using between subjects factors (group: ginkgo and placebo) and within subjects factors (pre- and postintervention) (using a correction for multiple comparisons) and showed that there was a significant between group effect with respect to the MFIS (F ⫽ 6.05, P ⫽ .024) and a trend for the SI measure (F ⫽ 3.92, P ⫽ .06).
Ginkgo and Functional Measures in MS
Table 3. Significant Effect Size Changes
MFISⴱ Baseline Postintervention SI totalⴱ Baseline Postintervention FAMS totalⴱ Baseline Postintervention CES-D† Baseline Post intervention STAI‡ Baseline Postintervention
Ginkgo Mean ⫾ SD
Placebo Mean ⫾ SD
37.8 ⫾ 14.7 35.5 ⫾ 13.9
39.8 ⫾ 15.1 42.4 ⫾ 15.6
7.9 ⫾ 4.4 11.5 ⫾ 12.6
7.8 ⫾ 4.2 8.8 ⫾ 4.0
169 ⫾ 32 173 ⫾ 25
158 ⫾ 29 160 ⫾ 30
12.1 ⫾ 10.2 12.2 ⫾ 10.1
14.5 ⫾ 8.3 10.1 ⫾ 4.9
32.4 ⫾ 11.3 33.7 ⫾ 15.3
30.8 ⫾ 10.6 30.4 ⫾ 7.9
MFIS, Modified Fatigue Impact Scale; SI, Symptom Inventory; FAMS, Functional Assessment of Multiple Sclerosis; Depression Center for Epidemiologic Studies of Depression Scale (CESD) and STAI (State-Trait Anxiety Inventory) scores at baseline and after 4 weeks of treatment with ginkgo or placebo. ⴱSignificant mean effect size difference across the MFIS, SI and FAMS †Significant difference from baseline to postintervention, which was accounted for by a reduction in depression in the placebo group. ‡No change.
DISCUSSION In this exploratory randomized, placebo-controlled trial, individuals who showed improvement on multiple measures irrespective of the magnitude of the treatment effect were exclusively from the ginkgo group. Although this analysis did not take into account the magnitude of change, a subsequent effect size analysis did show that individuals in the ginkgo versus placebo group exhibited a significantly greater change (improvement) from preintervention levels on the SI, FAMS, and MFIS as reflected by mean effect size. Although the power of this test was modest (⬃63%), the effect size was relatively large (ie, nearly .90), suggesting that at least some individuals derived greater therapeutic benefits in the treatment versus the placebo group. An additional analysis that (corrected for multiple comparisons) examined group differences at follow-up showed a significant between group effect with respect to the MFIS measure (and a trend for the SI measure), showing lower levels of fatigue in the ginkgo group. The issue of heterogeneity of response to ginkgo appears to be an important factor. For example, in a double-blind, placebocontrolled pilot study, there was evidence suggesting the existence of responders (positive) and nonresponders (negative) to acute ginkgo treatment (ie, 120-mg doses of GK501) among healthy participants.28 This finding suggests considerable individual variation in response to ginkgo. The implication is that analyses that combine positive and negative responders may mask or obscure some of the beneficial effects of ginkgo. The current finding that improvement on four or more measures was only found in the ginkgo group provides additional support for
Ginkgo and Functional Measures in MS
the idea that analyses need to take into account response heterogeneity. Although placebo effects can sometimes be robust, the significantly larger mean effect size in the ginkgo group on the SI, FAMS, and MFIS provides support for the idea of response heterogeneity and the need to use measures (ie, effect size) that can help identify individuals who are “responders” versus “nonresponders.” Although ginkgo appeared to exert therapeutic effects in some individuals, it is possible that treatment duration in the current study was too brief. However, the beneficial effects of ginkgo are believed to be caused by acute changes in blood flow to the brain, elevated glucose utilization, and increased acetylcholine production,31 with studies showing treatment effects in four weeks.10,19 Clearly, the current findings are suggestive rather than definitive. However, this pilot study does raise some important methodological issues that should to be examined in future research: Future work can be enhanced by recognizing and responding to the issue of response heterogeneity (ie, the apparent existence of subgroups of responders and the commensurate need for larger sample sizes); the apparent existence of “positive responders” and “negative responders”; the sensitivity of outcome measures (ie, some measures may reflect functional domains that are more responsive to treatment effects); and the sensitivity of analysis procedures in detecting changes in populations with considerable response heterogeneity and symptom fluctuation. Future studies should examine the mechanisms that mediate why some and not other individuals benefit from ginkgo so that treatments could be more beneficially and economically targeted to specific individuals. Overall, this pilot study showed that ginkgo exerted very modest beneficial effects among some individuals with MS: Some ginkgo-treated individuals improved on select functional measures, and the effect size of those improvements tended to be larger in the ginkgo versus the placebo group. Given the heterogeneity of the MS population both with respect to treatment response and to clinical course, larger sample sizes should be used to allow for this heterogeneity so that more powerful statistical procedures can be implemented. While identifying some functional outcome measures on which a subset of individuals with MS may derive modest benefits from taking ginkgo (EGb 761), this pilot study has also helped identify some methodological issues that, if addressed, can enhance the validity and generalizability of future work.
REFERENCES 1. Poser CM. The epidemiology of multiple sclerosis. Ann Neurol. 1994;36:S180-S193. 2. Noseworthy JH, Lucchinettie C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343:938-952. 3. Johnson SK, Frederick J, Kaufman M, Mountjoy B. A controlled investigation of bodywork in multiple sclerosis. J Altern Complement Med. 1999;5:237-243. 4. Schwartz CE, Laitin E, Brotman S, LaRocca N. Utilization of unconventional treatments by persons with mutiple sclerosis: is it alternative or complementary? Neurology. 1999;52:626-629. 5. Pucci E, Cartechini E, Taus C, Giuliani G. Why physicians need to look more closely at the use of complementary and alternative medicine by multiple sclerosis patients. Eur J Neurol. 2004;11:263-267.
EXPLORE January 2006, Vol. 2, No. 1
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6. Bowling AC, Stewart TM. Current complementary and alternative therapies for multiple sclerosis. Curr Treat Options Neurol. 2003;5:5568. 7. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997: results from a follow-up national survey. JAMA. 1998;280:1569-1575. 8. Kleijnen J, Knipschild P. Gingko biloba for cerebral insufficiency. Br J Clin Pharmacol. 1992;34:352-358. 9. Diamond B, Shiflett S, Feiwel N, et al. Ginkgo biloba extract: Mechanisms and clinical indications. Arch Physical Med Rehabil. 2000;58: 1-11. 10. Diamond BJ, Shiflett SC, Lothian A, et al. EGb 761 (Ginkgo biloba): efficacy in treating stroke and TBI. Arch Physical Med Rehabil. 2000; 80:978. 11. Curtis-Prior P, Vere D, Fray P. Therapeutic value of Ginkgo biloba in reducing symptoms of decline in mental function. J Pharm Pharmacol. 1999;51:535-541. 12. Wesnes KA, Ward T, McGinty A, Petrini O. The memory enhancing effects of a gingko biloba/panax combination in healthy middle aged volunteers. Psychopharmacology. 2000;152:353-361. 13. Vorberg G. Ginkgo biloba extract (GBE): a long-term study of chronic cerebral insufficiency in geriatric patients. Clin Trials J 1985; 22:149-157. 14. Mancini M, Agozzino B, Bompani R. Clinical and therapeutic effects of Ginkgo biloba extract (GBE) versus placebo in the treatment of psychorganic senile demential or arteriosclerotic origin. Gazzetta Medica Italiana-Archivio Per Le Scienze Mediche. 1993;152:69-80. 15. Diamond BJ, Johnson SK, Torsney K, Morodan J, Kramer P. Complementary and alternative medicines in the treatment of dementia: an evidenced based review. Drugs Aging 2003;20:981-998. 16. Kenney C, Norman M, Jacobson M, Lampinen S, Nguyen DP, Corey-Bloom J. A double-blind, placebo-controlled, modified cross-over pilot study of the effects of gingko biloba on cognitive and functional abilities in multiple sclerosis (Abstract). Neurology. April 2002. 17. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1988;13:227-231.
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18. Kurtzke JF. Rating neurological impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology. 1983;33:295-301. 19. Diamond BJ, Shiflett SC, Richards JA, Noskin O, Lothian A, Feiwel N. Ginkgo biloba extract. Mechanisms and clinical indications: commentary. Ginkgo biloba extract mechanisms, indications and preliminary data. Neurol Rep. 2001;25:70-75. 20. Blair J R, Spreen O. Predicting premorbid IQ: a revision of the National Adult Reading Test. Clin Neuropsychol. 1989;3:129-136. 21. Cella DF, Dineen K, Arnason B, et al. Validation of the Functional Assessment of Multiple Sclerosis quality of life instrument. Neurology. 1996;47:129-139. 22. Schwartz CE, Vollmer T, Lee H. Reliability and validity of two self-report measures of impairment and disability for MS. Neurology. 1999;52:63-70. 23. Radloff L. The CES-D scale: a new self-report depression scale for research in the general population. Appl Psychol Measurement. 1977; 1:385-401. 24. Krupp LB, Sliwinski M, Masur DM, Friedberg F, Coyle PK. Cognitive functioning and depression in patients with chronic fatigue syndrome and multiple sclerosis. Arch Neurol. 1994;51:705-710. 25. Shnek Z, Foley F, LaRocca N, et al. Helplessness, self-efficacy, cognitive distortions and depression in multiple sclerosis and spinal cord injury. Ann Behav Med. 1997;19:287-294. 26. Speilberger CD. Manual of the State-Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychology Press; 1983. 27. Fisk JD, Pontefract A, Ritvo PG, Archibald CJ, Murray TJ. The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci. 1994;21:9-14. 28. Canter PH, Ernst E. Multiple n ⫽ 1 trials in the identification of responders and non-responders to the cognitive effects of Gingko biloba. Int J Clin Pharmacol Ther. 2003;41:354-357. 29. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates; 1988. 30. Yost KJ, Eton DT. Combining distribution and anchor-based approaches to determining minimally important differences: the FACIT experience. Evaluation Health Professions. 2003;26:1-20. 31. Gold PE, Cahill L, Wenk GL. Gingko biloba: a cognitive enhancer? Psychol Sci Public Interest. 2002;3:2-11.
Ginkgo and Functional Measures in MS