Ginkgo biloba extract EGb 761® alleviates neurosensory symptoms in patients with dementia: a meta-analysis of treatment effects on tinnitus and dizziness in randomized, placebo-controlled trials
Clinical Interventions in Aging
® Ginkgo biloba extract eGb 761 alleviates neurosensory symptoms in patients with dementia: a meta-analysis of treatment effects on tinnitus and dizziness in randomized, placebo-controlled trials
Rainer Spiegel 2
Roger Kalla 1
Raphael Maire 5
Heiko Mueller 4
Robert Hoerr 4
Ralf Ihl 3
Georgios Mantokoudis 0
0 Department of Otorhinolaryngology, Head and Neck Surgery, Inselspital, Bern University Hospital , Bern , Switzerland
1 Department of Neurology, Inselspital, Bern University Hospital , Bern , Switzerland
2 Division of Internal Medicine, Basel University Hospital, University of Basel , Basel , Switzerland
3 Department of Psychiatry, University of Duesseldorf, Alexian Research Center Krefeld , Krefeld , Germany
4 Clinical Research Department, Dr willmar Schwabe GmbH & Co. KG , Karlsruhe , Germany
5 Lausanne University Hospital , Lausanne , Switzerland
from roF PowerdbyTCPDF(ww.tcpdf.org) Background: Tinnitus and dizziness are frequent in old age and often seen as concomitant symptoms in patients with dementia. In earlier clinical trials, Ginkgo biloba extract EGb 761® was found to alleviate tinnitus and dizziness in elderly patients. Consequently, a meta-analysis was conducted to evaluate the effects of EGb 761® at a daily dose of 240 mg on tinnitus and dizziness associated with dementia. Methods: Randomized, placebo-controlled clinical trials of G. biloba extract EGb 761® identified by a systematic database search were included in a meta-analysis if they met all of the following selection criteria: 1) diagnosis of dementia according to generally accepted criteria, 2) treatment period of at least 20 weeks, 3) outcome measures covering at least two of the three conventional domains of assessment, 4) presence and severity of dizziness and tinnitus were assessed, and 5) assessment was done before and after randomized treatment. Results: Five trials that met the inclusion criteria were included in the meta-analysis. The risk of bias was judged as low, with Jadad scores of 3 and 5. In all trials, 11-point box scales were used to assess the severity of tinnitus and dizziness. Overall, EGb 761® was superior to placebo, with weighted mean differences for change from baseline, calculated in meta-analyses using random effects models, of -1.06 (95% CI: -1.77, -0.36) for tinnitus ( p = 0.003) and -0.77 (95% CI: -1.44, -0.09) for dizziness ( p = 0.03). Conclusion: Our findings support the notion that EGb 761® is also effective in alleviating concomitant neurosensory symptoms in patients with dementia.
neurodegenerative disorders; gait; unsteadiness; inner ear; hearing; review
open access to scientific and medical research
Neurosensory symptoms, such as tinnitus and dizziness, are frequently observed in
elderly people and even more so in patients with dementia. Five-year and 10-year
incidence rates of 18.0% and 12.7% were reported for tinnitus from the Blue
Mountains Hearing Study and the Beaver Dam Epidemiology of Hearing Loss Study,
respectively.1,2 Epidemiological studies have found an increase in the prevalence of
tinnitus as a function of age.3 Jahn et al reported 1-year prevalence rates for significant
dizziness of 20% in persons older than 60 years, 30% in those older than 70 years,
and 50% in those older than 80 years.4 In elderly patients with dementia, we found
prevalence rates between 13% and 52% for tinnitus and between 14.2% and 77.5% for
dizziness in five clinical trials.5–9 Age-related hearing loss is likely to account for higher
rates of tinnitus in the elderly and may even contribute to cognitive decline and the
development of Alzheimer’s disease (AD) and other dementias.10–13 In a case-control
Clinical Interventions in Aging 2018:13 1121–1127 1121
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study of elderly patients with neurological disorders, those
with dementia had a particularly high rate of falls (60% in 1
year), which may indicate a higher prevalence of dizziness
and impaired equilibrium control.14
Given the high comorbidity of tinnitus and dizziness in
dementia and the findings from earlier studies in which Ginkgo
biloba extract EGb 761® (Dr Willmar Schwabe GmbH & Co.
KG, Karlsruhe, Germany) alleviated tinnitus and dizziness or
vertigo,15,16 measures of tinnitus and dizziness were included in
recent clinical trials of EGb 761® in patients with dementia.
When considering why G. biloba extract EGb 761® may
alleviate tinnitus, dizziness, or vertigo in patients with
dementia, the pathomechanisms underlying these symptoms should
be taken into account. Neurons of the central vestibular and
auditory systems, cochlear hair cells, and vestibular sensory
cells have a high energy demand in order to maintain and
continuously restore their transmembrane electrical potential.
Impaired mitochondrial function and impaired perfusion are
.rvdoepww ll.syeuon ttihoonuagnhdt tsoencsoonrtyricbeultledteogbeontehractoiocnh.l1e7aErGanbd7v6e1s®tiibmuplarorvdeyssfiunnnec-r
/w an ear and cerebral blood flow by decreasing blood viscosity; it
tthp rspe also improves mitochondrial function and energy metabolism,
from roF which altogether may play a role in improving inner ear and
ed brain function in elderly people with dementia who often
loda have vascular disorders and compromised mitochondrial
onw function.18–20 The antiapoptotic and neuroprotective
propergdn ties of EGb 761® may inhibit aging-related loss of cochlear
igA and vestibular sensory cells,21–24 which may play a role in
isn tinnitus and vertigo.25,26 Coping with the distress of tinnitus
itnno as well as compensating for vestibular dysfunction involves
manpdronveeusrolepalarnstiincgit,ya.nEdGabc7c6el1e®raetnehsavnecsetsibnueluariilcnaC canoxmiepteyn,swathioilne.d18i,z27z,2i8neTsisnonfittuens cisauliskeesluyntsotecaaduinseesdsiasntrdesfesaarnodf
falling. Due to anxiolytic effects and by attenuating the
activation of the stress axis, EGb 761® may decrease the distress in
both conditions.18,29,30 By improving the speed of information
processing, it may improve gait and reduce unsteadiness.18
Here, we present a meta-analysis of the trials that used
rating scales for the assessment of presence and severity of tinnitus
and dizziness. The question addressed by this meta-analysis was
whether, taking into account all available evidence, EGb 761®
treatment was superior to placebo in alleviating tinnitus or
dizziness or both in patients with dementia who had one or both of
these neurosensory symptoms at pre-treatment examination.
Materials and methods
In 2014, Gauthier and Schlaefke published a systematic
review and meta-analysis of randomized, placebo-controlled,
double-blind clinical trials of G. biloba extract EGb 761®
in patients with mild to moderate dementia (AD, vascular
dementia [VaD], mixed dementia, ie, AD with
cerebrovascular disease [CVD]).31 The search strategy is described in
detail in their original paper.31 Our aim was to provide an
update on studies until October 2017. We did not identify
any further relevant studies. Briefly, PubMed, including
and excluding MedLine (from beginning to October 2017),
EMBASE (from January 2006 to October 2017), and
PASCAL (from beginning to end of 2015, no further update of
PASCAL existed beyond this date) were searched using
the following search terms (with * characterizing a
wildcard, and the items AND and OR being used as Boolean
functions): (ginkg* OR gingk*) AND clinical trial[pt] for
PubMed including MedLine, ((ginkg* OR gingk*) NOT
medline[sb]) AND (clinical* OR trial OR randomized) for
PubMed excluding Medline, (GINKGO OR GINGKO)
AND (HUMAN/CT OR HOMME/CTFR) for PASCAL,
and (ginkgo or gingko) AND CT=(CLINICAL TRIAL;
CLINICAL STUDY; DOUBLE BLIND PROCEDURE)
AND py.2005 for EMBASE. The papers retrieved were
assessed for eligibility by two scientists independently and
trials were selected for the review, if 1) the diagnoses were
established in accordance with generally accepted diagnostic
criteria, 2) the treatment periods were at least 20 weeks, and
3) outcome measures covered at least two of the three
conventional domains (cognition, global judgment, activities of
daily living). For the current meta-analysis, we applied two
additional inclusion criteria, requiring that 4) the presence
and severity of tinnitus or dizziness or both were assessed
and 5) assessment was done before the start and after the end
of randomized treatment. Five of the seven trials included
in the meta-analysis by Gauthier and Schlaefke met these
additional criteria.5–9 All trials were sponsored by Dr Willmar
Schwabe GmbH & Co. KG, Karlsruhe, Germany. The risk
of bias was low for all five trials, with Jadad scores of 3 and
5 (Table 1).32
In all five trials, 11-point box scales were used to assess
the presence and severity of tinnitus and dizziness. The
11-point box scale is a type of visual analog scale (VAS)
consisting of 11 adjacent boxes which contain ascending
numbers from 0 to 10 and descriptors for the extremes only,
thus providing a distinct number of possible responses in a
single dimension. Such types of 11-point VASs are often used
as measures for pain,33,34 and have also been found useful for
the assessment of other unpleasant and distressing symptoms,
such as dizziness35 or tinnitus.33,36,37 In the studies reviewed
here, 11-point box scales for tinnitus and dizziness were
administered with the extreme ends indicating “no tinnitus
at all” (0) and “extremely severe tinnitus” (
) or “no
dizziness at all” (0) and “extremely severe dizziness” (
One study enrolled patients exclusively with AD,5 while
all other studies also accepted patients with VaD or AD
with CVD.6–9 In one study, two different doses of EGb 761®
(240 mg or 120 mg) and placebo were compared;5 however,
the patients treated with 120 mg of EGb 761® were excluded
from the present meta-analysis. In all other studies, patients
received either 240 mg of EGb 761® or placebo.
For each study, EGb 761® and placebo treatment were
compared with regard to mean differences between baseline
and end of treatment on both 11-point box scales for tinnitus
and dizziness. These calculations, conducted with SAS
version 9.3, were based on individual patient data, which
were provided by Dr Willmar Schwabe GmbH & Co. KG.
Based on the study-specific mean differences, weighted mean
differences (and corresponding forest plots) were calculated
using meta-analytical models to compare EGb 761® and
placebo treatments by Review Manager (version 5). Due to
the somewhat different inclusion criteria and design of the
trial conducted by Schneider et al5 compared to the other
four trials, which were similarly designed, a random effects
model was chosen for the analysis and a fixed effects model
as a sensitivity analysis. Only data from patients who had
tinnitus or dizziness at baseline (baseline scores .0 on the
respective 11-point box scale) were included in the
respective meta-analyses. Missing data were replaced by the
In the five studies, a total of 1,972 patients, aged 50–98 years,
were randomly assigned to receive EGb 761® at a daily
dose of 240 mg or placebo. The treatment periods were
22–26 weeks. The full analysis comprised a total of 1,942
patients, of whom 904 were diagnosed with probable AD,
374 had probable VaD, and 664 had mixed dementia. Study
characteristics and demographics are provided in Table 1.
Dementia-related baseline scores and outcomes are provided
in detail by Gauthier and Schlaefke.31
Altogether, 773 patients had tinnitus at baseline (EGb
761®, 372; placebo, 401). In the individual studies,
prevalence of tinnitus ranged between 13% and 52%; the average
severity ratings varied between ~2.7 and 4.0. The baseline
scores for the 11-point box scale related to tinnitus are
provided in Table 2.
A total of 1,040 patients reported dizziness at baseline
(EGb 761®, 528; placebo, 512). Prevalence in the individual
studies ranged from 13% to 77%; the average severity ratings
varied between 2.5 and 4.3. The baseline scores for the
11-point box scale related to dizziness are shown in Table 3.
A mean reduction in tinnitus severity for the EGb
761®treated patients compared to placebo was observed in all five
trials. The difference in favor of EGb 761® was statistically
meaningful in four trials. Overall, there was a weighted mean
difference of -1.06 (95% CI: -1.77, -0.36) favoring EGb
761® at p = 0.003 (Figure 1). This was similar to the result
of the sensitivity analysis by the fixed effects model: -0.97
(95% CI: -1.16, -0.78; p , 0.001). Considering that the
average severity of tinnitus was between 2.7 and 4.0 at
baseline,5,6 the weighted mean difference corresponds to an
improvement over placebo effects by 27%–40% of baseline
severity in the single studies.
A greater reduction in dizziness was observed for the EGb
761®-treated patients in four of the five trials comprising 96% of
all patients included in the meta-analysis. The differences in
favor of EGb 761® were statistically meaningful in three trials
comprising 80% of all patients. Overall, there was a weighted
mean difference of -0.77 (95% CI: -1.44, -0.09) favoring EGb
761® at p = 0.03 (Figure 2) and similar to the fixed effects model
calculated as a sensitivity analysis: -0.98 (95% CI: -1.15, –0.81;
p , 0.001). The average severity of dizziness at baseline was
between 2.5 and 4.3.5,6 Therefore, the weighted mean difference
corresponds to an improvement over placebo effects of between
18% and 31% of baseline severity in the four larger trials.
tthp rspe Discussion
from roF In our meta-analysis, we included five randomized,
placeboded controlled clinical trials of G. biloba extract EGb 761® in
lnao patients with mild to moderate dementia. Using 11-point
dow box scales to assess the presence and severity of tinnitus
igng and dizziness, we found that a considerable proportion of
inA the patients enrolled for their diagnoses of dementia, and not
sno for tinnitus or dizziness, had such neurosensory symptoms.
itne On average, these symptoms were mild to moderate at
basetrven line. Overall, we found EGb 761® to be clearly superior to
lIca placebo in alleviating both tinnitus and dizziness. This is
iiln in line with the results of earlier trials in patients with
tinC nitus or vertigo,15,16 in whom these neurosensory symptoms
were the main complaints. It is also in line with conclusions
from systematic reviews that found EGb 761®, but not other
G. biloba extracts, to be effective in the treatment of tinnitus
and vertigo.15,16 EGb 761® is a defined extract of G. biloba
leaves that is obtained by a proprietary multi-step extraction
procedure during which pharmacodynamically active
molecules are enriched and harmful compounds are removed.
EGb 761® is adjusted to 22.0%–27.0% ginkgo flavonoids
calculated as ginkgo flavone glycosides and 2.0%–7.0%
terpene lactones consisting of 2.8%–3.4% ginkgolides A, B, C
and 2.6%–3.2% bilobalide and contains less than 5 ppm
ginkgolic acids. High batch-to-batch consistency, which
is a prerequisite for the generalization of study results to
daily clinical practice, has been demonstrated. Extracts that
result from different productive processes are inherently
different in composition, and in pharmacodynamic and
clinical activity.18 Our literature search did not identify any
randomized, placebo-controlled clinical trials of any other
Ginkgo extract in patients with dementia in which effects on
tinnitus or dizziness were evaluated.
The clinical relevance of the effects is difficult to assess.
Reductions in tinnitus severity by 27%–40% over and above
the placebo effect may represent clinically relevant effect
sizes. The effects on dizziness are less pronounced, but may
still be clinically relevant in the given population of elderly
people with ischemic and neurodegenerative CNS changes,
who are particularly prone to falling. When evaluating
clinical relevance in this context, the fact that the patients
had mild to moderate dementia has to be kept in mind.
Tinnitus may contribute to cognitive decline in dementia.12,13
Both tinnitus and dizziness cause anxiety, fear (fear of
enduring annoyance and fear of falling, respectively), and
distress.1,4,38,39 Tinnitus often leads to sleep disturbances,1,39
thus adding to the burden of night-time disturbances
frequently experienced by patients with dementia.40
Stressinduced activation of the hypothalamic–pituitary–adrenal
axis (the so-called stress axis) tends to further compromise
cognitive functioning in patients with cognitive impairment.41
Focusing on and being distracted by tinnitus may
additionally impair attention and processing speed, ie, the cognitive
abilities already compromised in patients with dementia.39
Dizziness and fear of falling often lead to reduced physical
activity, decreased participation in social life, disability, and
frailty.42 Physical activity is not only necessary to maintain
muscle mass and postural control,43,44 it is also closely
correlated with cognitive performance in elderly people with
and without cognitive impairment.45–47 Moreover, dizziness
is not only associated with fear of falling, it also increases
the risk of falling and the incidence of falling-related injuries,
such as hip fractures.4 However, hospitalization and major
surgery increase the risk of confusion and delirium and may
accelerate cognitive decline in patients with dementia.48
Our meta-analysis has some limitations related to the
studies included. First, the symptom ratings were done by
patients with dementia, which may cast doubts on their
reliability. However, patients with mild to moderate dementia are
still able to understand questions about ringing in the ears and
dizziness, when asked in simple language. They may have
problems remembering the intensity of tinnitus or dizziness at
an earlier point in time, but the 11-point box scales ask about
the current severity, and not about changes. Rating errors due
to cognitive problems may possibly increase scatter, but does
not build a consistent pattern of treatment benefits across the
studies as found in the present meta-analysis.
Second, no examinations of auditory or vestibular
functions were performed, and disabilities related to tinnitus
and dizziness were not assessed within the studies. As a
consequence, it is not known to what extent alleviation
of tinnitus and/or dizziness may have contributed to the
improvement in everyday functioning and quality of life.
After all the examinations required by current guidelines for
clinical trials in dementia have been performed, the patients
are usually too exhausted to undergo further examinations
during the same visit. Investigators were free to perform all
examinations required for medical reasons, but any findings
not related to the studies were not documented in the case
record forms. As a result, to what extent dizziness was related
to vestibular vertigo or to non-vestibular disorders remains
unknown. Yet, the dizziness-related problems in patients with
dementia are largely the same. It is possible, however, that
different proportions of patients with vestibular vertigo and
non-vestibular dizziness contributed to the heterogeneity of
the outcomes related to dizziness.
Third, average baseline scores for tinnitus and dizziness
were around 3, ie, about one-third of the range of the scales,
in most trials. As a consequence, the relative effect sizes may
lead to an overestimation of their clinical relevance. On the
other hand, floor effects cannot be excluded, so that the real
therapeutic potential of the drug could be underestimated.
In general, patients complaining of tinnitus or dizziness
should be examined for causes and contributors that are
amenable to specific treatments, irrespective of whether or
not they have dementia. Assessment of auditory or vestibular
function might provide additional information about the
underlying causes. However, in many patients the causes of
neurosensory symptoms remain unclear, and even if known,
there are often no causal or cause-specific treatments. As
outlined earlier, EGb 761® interferes with a number of
mechanisms that seem to contribute to dysfunction and degenerative
processes in the inner ear and cerebral structures.
G. biloba extract EGb 761®, at daily doses of 240 mg,
alleviated both tinnitus and dizziness in patients with dementia,
ie, in patients who are particularly vulnerable to such
disturbances. This should be taken into account when choosing
an appropriate treatment for patients with dementia and
H Mueller and R Hoerr made their contribution during
working hours paid by Dr Willmar Schwabe GmbH & Co.
KG. There was no other funding for this work. Rainer Spiegel
and Roger Kalla share first authorship.
R Spiegel and R Kalla contributed equally to the manuscript.
All authors contributed to the interpretation of the data and
the intellectual content of the manuscript and approved
the final version to be published. H Mueller performed the
R Maire received a speaker honorarium from Schwabe
Pharma AG, Kuessnacht, Switzerland; R Kalla and
G Mantokoudis were supported by the Swiss National
Science Foundation (Grant #320030-173081); R Ihl received
speaker honoraria from Dr Willmar Schwabe GmbH & Co.
KG, Karlsruhe, Germany; H Mueller and R Hoerr are
fulltime employees of Dr Willmar Schwabe GmbH & Co. KG
receiving fixed salaries. R Spiegel reports no conflicts of
interest in this work.
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