Original Paper

38

The Role of Piracetam in the Treatment

of Acute and Chronic Aphasia
W. Huber

Piracetam has been shown to improve speech in aphasic

patients. This paper reviews the evidence for this benefit in
aphasic patients with acute stroke and, in conjunction with language treatment, in post-acute and chronic aphasia. Early double-blind. placebo-controlled trials in acute stroke showed irnprovernent in several neurologic parameters including aphasia.
Subsequently two randomized double-blind placebo-controlled
studies were performed which utilised the Aachen Aphasia Test
(AAT), a validated and standardized procedure, to assess language function. Patients received placebo or piracetam 4.8g
daily for 12 weeks in one study and for 6 weeks in the other. In
both studies patients received concomitant intensive speech
therapy; one included patients 6-9 weeks after stroke while in
the other the duration of aphasia varied between 4 weeks and
3 years. compared with placebo there was improvement in
both studies on piracetam in all 5 subtests of the AAT and significant overall improvement in aphasia. This indicated that, given in conjunction with language therapy, piracetam improved
speech in patients with post-acute and chronic aphasia. In the
Piracetam in Acute Stroke Study (PASS). of 927 patients treated
within 12 hours of the onset of acute ischemic stroke, 373 were
aphasic. Treatment consisted of placebo or an intravenous bolus of 129 piracetam. 129 piracetam daily for 4 weeks and
4.8g daily for a further 8 weeks. After 12 weeks significantly
more patients (approximately lo%, P = 0.04) had recovered
from aphasia on piracetam than placebo while in 197 patients
treated within 7 hours of stroke onset, the difference in favor of
piracetam was 16%( P = 0.02). These studies indicate that piracetam improves aphasia in acute stroke and, as an adjuvant to
language therapy, in post-acute and chronic aphasia.

Introduction

Estimates suggest that more than 20 percent of patients suffering a strolte develop aphasia and that between 10 and 18 percent of survivors are left with a persisting speech deficit (Wade
et a]., 1986). The frequency of such long-term disability emphasizes the need to complement existing language therapy
programs with effective medical treatment.

Pharmacopsychiat. 1999: 32 (Supplement):38-43

8 Ceorg Thieme Verlag Stuttgart . New York

lSSN 0176-3679

The value of drug therapy for aphasia is largely unltnown for

several reasons. Demonstration of benefit in aphasic patients
is difficult (Wertz, 1993) because it must take into account
spontaneous recovery and selection of appropriate measures
for assessing change in speech (Poeck et al.. 1989; MethC et
al., 1993). Additionally, although most evidence indicates that
speech therapy is effective (Poeck et al.. 1989; Basso, 1992;
Springer and Willmes. 1993; Robey, 1994.1998). debate continues about optimal type, duration and timing (Basso et al.,
1979; Basso, 1992).These factors increase the difficulty of evaluating drug therapy, particularly in patients receiving language treatment. Few agents with therapeutic promise have
been studied in trials of adequate design (Bachman and Albert.
1990; Small, 1994).
Piracetam (NootropilaD)is a nootropic agent with neuroprotective properties that improves cognitive functions such as
learning and memory (Giurgea, 1976). Piracetam acts at the
level of the cell membrane (Woellc 1979; Muller et al., 1994,
1997) to which it binds (Peuvot et al., 1995). Piracetam has
been shown to restore towards normal the diminished membrane fluidity found in the brains of elderly mice, rats and humans and these changes are closely correlated with increases
in muscarinic (cholinergic) and NMDA (excitatory arnine) receptor populations (Muller et al., 1994; 1997), findings consistent with the postulate that piracetam improves cognitive
functions by facilitating cholinergic and excitatory amine neurotransmission (Giurgea, 1976). Restoration of decreased neuronal membrane fluidity may explain the improvement in various membrane-bound functions, e.g. neurotransmission (Pedata et al., 1984; Bering and Miiller. 1985; Copani et al., 1992;
Cohen and Miiller. 1993, Milller et al., 1994) and other mechanisms involved in neuroprotection. Piracetam has also been
shown to protect the nerve cell against hypoxia (Giurgea et
al., 1970: Gobert. 1972; Giurgea and Mouravieff-Lesuisse.
1978). Piracetam exerts its effects not only at a neuronal level
but also on the microcirculation by normalizing platelet aggregation (Bick et al., 1981; Grotemeyer et al.. 1986; Moriau et al.,
1993) and increasing red cell deformability (Henry et al.. 1981;
Fleischman, 1982). These properties lead to decreased plasma
and whole blood viscosity (Morjau et al.. 1993). Piracetam has
also been shown to possess in vivo antithrombotic activity
(Stocltmans et al., 1998).

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Department of Neurology and School of Logopedics,Rheinisch-Westfalische Hochschuie (RWTH), Aachen, Germany

The Role of Piracetam in the Treatment of Acute and Chronic Aphasia

Neuroprotection. together with hemorrheologic and antithrombotic properties, provided a rationale for the evaluation
of piraceram in acute stroke. In addition. various worlcers have
shown that piracetam improves the microcirculation at the
periphery of acute cerebral infarctions by increasing
compromized regional blood flow (Herrschaft. 1978; Heiss et
al.. 1983; Depresseux et a]., 1986; Platt et al., 1992). Piracetam
also improves impaired glucose metabolism (Depresseux et
al., 1986) and oxygen consumption (Heiss et al., 1983) in these
areas.
initial clinical trials
The first evidence suggesting clinical improvement after piracetam in aphasic patients came from a small double-blind, placebo-controlled trial in acute stroke (Herrschaft. 1988). A similar finding was reported by Platt e t al. (1992). Although these

trials utilised different methods of assessment. in both of them

significant improvement occurred in piracetam-treated patients compared to placebo in various neurological parameters
including improved speech in aphasic patients (Table 1).
Tn'als in aphasia (Table 2)
Consequently. 2 randomized double-blind. placebo-controlled
trials were performed in an attempt to confirm this effect on
aphasia by determining whether piracetam. in conjunction
with intensive language therapy. improved aphasia more than
language therapy alone (Poeck et dl.. 1993: Enderby et al.,
1994; Huber et al.. 1997).
Both studies used the Aachen Aphasia Test (AAT) (Huber et al..
1983; Huber et al., 1984) to assess the severity of aphasia. This
is a standardized procedure for evaluating aphasia developed
and validated in the German language and subsequently validated and standardized in Dutch, English and Italian. The AAT

Table 1 Initial double-blind placebo-controlled studies in acute stroke

Study

No of
patients

Number
aphasic

Time to
Treatment

Concurrent
treatment

Dosage of
Piracetam

Outcome

Herrschaft (1 988)

44

77

< 5 days

10%dextran

Platt et al. (1992)

56

56

< 3 days

Hemodilution

12
2 weeks
4.8 g/day
2 weeks
12 g/day
2 weeks
4.8 g/day
2 weeks

Recovered or improved
- Piracetam 100%
- Placebo 50%
- (P < 0.05)
Improved
- Piracetarn 74%
- Placebo 21%
(P< 0.001)

Table 2

Double-blind placebo-controlled trials with piracetam in aphasic patients

Study

NOof aphasic
patients

Duration of
aphasia

Concurrent
treatment

Dosage of
piracetam

Outcome

4 weeks to
3 years

intensive language
therapy

4.8 g/day
6 weeks

AAT" subtests
- improvement in all 5 subtests
- overall improvement 6 wks
(profile level P<0.05)
- written language P<0.05
- tokenTestP<O.l

6-9 weeks

intensive language
therapy

4.8 g/day
12 weeks

- improvement in all 5 subtests

- overall improvement 12 wks
(multivariate analysis P= 0.02)
- written language P = 0.08
- repetition P = 0.06

A. Post-acute and chronic asphasia

Poeck et al. (1 993)

Huber et al. (1997)

66

Enderby et al. (1994)

B. Aphasia in acute stroke

De Deyn e t al. (1997)

373

2 97
(< 7 hrs
after onset)
A4T =Aachen Aphasia Test

acute stroke

'"331"

12 g iv bolus
Absence of aphasia
Piracetam 33% P=0.04
12 g/day 4 wks
4.8 g/day 8 wks
Placebo 23%
< 12 hrs after stroke
Piracetam 37% P = 0.02
Placebo 21%

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Acute Stroke

Pharmacopsychiat. 1999; 32 (Supplement)

40 Pharrnacopsychiat. 1999; 32 (Supplement)

W. Huber

Methods of statistical analysis were similar in both studies. Response to the combined effect of language and drug treatment
was calculated by comparing AAT scores. and the differences in
scores from baseline, before and after treatment. The 5 AAT
subtest scores were analysed by multivariate analysis of variance (MANOVA) as well as by univariate analysis for each subtest.

consists of 6 rating scales for spontaneous speech (communicative verbal behavior, articulation and prosody, automatized
language, semantic structure, phonemic structure, syntactic
structure) and 5 subtests for the assessment of specific language impairment (subtests: Repetition, Written Language,
Naming on Confrontation. Comprehension. Token Test). The
subtest Token Test reflects the overall severity of the language
disorder. Scores for all 5 subtests in percentiles express proficiency. A reliability-weighted sum of the 5 subtest scores was
used in one study to determine the profile level, an overall and
clinically relevant measure of aphasia (Huber et al.. 1997).

Results

The effect of piracetam. 4.8 g daily for 6 weeks, as an adjuvant

to intensive language therapy and as compared with placebo,
was studied in 66 patients in whom aphasia had been present
for between 4 weeks and 3 years. Many patients thus had longstanding chronic aphasia. (Poeck et al.. 1993; Huber et al.,
1997).

In the study by Poeck et al. (1993) and Huber et al. (1997)there

was improvement in the mean scores of all AATsubtests compared with placebo. The difference between groups was significant for "written language" ( P < 0.05) and approached significance for the Tolten Test ( P < 0.1). an indicator of the overall severity of aphasia (Fig.1). The score for the profile level, the
weighted average of all subtests which also reflects the overall
severity of aphasia, was also significantly better on piracetam
than on placebo ( P < 0.05).

Enderby et al.. (1994) also reported the effect of placebo or piracetam 4.8 g daily for 12 weeks on recovely and rehabilitation
in 137 patients who had sustained a strolte 6 - 9 weelts previously. Of these. 67 were aphasic and all were receiving speech
therapy. Patients receiving piracetanl or placebo were well
matched at baseline in relevant parameters including type
and severity of aphasia and prognostic factors.

,..,

Fig. 1 Differences in percentile scores on

each of the AAT subtests (Huber et al 1997).

Profile level : p = 0.04

Difference in percentiles
16

Enderby et al. (1994) showed by MANOVA a significant overall

difference relative to baseline in favor of piracetam in AAT subtest scores, consistent with the greater average improvement

rlracetam
Placebo

12

Token
test

Repetition

Difference in percentiles

Written
language

Confrontation
naming

Comprehension

Multivariate profile analysis : p = 0.02

12

. .... C7...a'
0

......"0

....

P iracetam
Placebo

NS

p =0.06

p =0.08

NS

Token
test

Repetition

Written
language

Confrontation
naming

-.

NS

Comprehension

Fig. 2 Differences in percentile scores on

each of the AATsubtests (Enderby et al 1994).

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In both studies improvement occurred in aphasia in piracetam-treated patients compared with those given placebo.

The Role of Piracetam in the Treatment of Acute and Chronic Aph asia

Pharmacopsychiat.
1999; 32 (Supplement) 41
-

in scores observed in each of the 5 subtests (Fig.2). Mean

percentile changes relative to baseline on univariate analysis
also indicated differences in all subtests in favor of piracetam
which approached significance for "repetition" (P 0.06) and
"written language" (P = 0.08) (Fig.1).

There were no statistically significant differences in either

study between piracetam and placebo in any of the 6 scales of
spontaneous speech although Huber et al. (1997) observed improvement in some scales and a greater overall number of improvements on piracetam.
Conclusions

The Piracetam in Acute Stroke Study (PASS)

PASS was a multicenter, randomized, double-blind. placebocontrolled study in 927 patients with acute supratentorial
ischemic stroke, the aim of which was to determine whether
piracetam improved outcome when given within 12 hours of
stroke onset (De Deyn et al.. 1997). Patients received an initial
intravenous bolus injection of placebo or 12 g piracetam, 12 g
piracetam daily for 4 weeks and 4.8g piracetam daily for a further 8 weeks. The primary outcome measure was neurologic
status at 4 weelts; secondary outcomes were functional capacity and, in affected patients, aphasia at 12 weeks. The presence of aphasia was determined using the Frenchay Aphasia
Screening Test (Enderby et al.. 1987), a validated and sensitive
test which, unlike the AAT, is suitable for use by a non-specialist in acutely ill patients and can quickly differentiate aphasic
from non-aphasic patients. FAST was performed within 12
hours of the initial bolus injection. Patients whose FAST scores
were s 13 for the sum of the subscales Comprehension and Expression were considered aphasic. Patients with very mild
aphasia were thus excluded. Aphasia was present in 373 patients.
After treatment for 12 weelts. there was a significant difference
in favor of piracetam relative to placebo in the number of patients who had recovered from aphasia (piracetam 59/180.
33%: placebo 45/193, 23%; P = 0.04) (Fig. 3). In an early treatment subgroup of patients treated within 7 hours of the onset
of stroke the proportion of patients in whom aphasia had recovered was higher (piracetam 35/96. 37%; placebo 21/101.
21 %: P = 0.02).
Piracetam was well tolerated in all studies and adverse effects
were few, and rarely required withdrawal from treatment.
Discussion

Considered together, these three controlled double-blind trials

provide sound evidence that piracetam enhances recovery
from aphasia and consequently have important practical implications.

placebo Ipimacetam

Percentage of aphasic patients in total population (n=373) with

complete recovery after 12 weeks (PASS).
Fig. 3

Firstly, improvement in aphasia occurred when piracetarn was

given as an adjunct to language therapy during rehabilitation
after stroke. This was observed with aphasia of both short
(4 - 9 weeks) and long (up to 3 years) duration. Secondly, when
given in high dosage to treat acute ischemic stroke, piracetarn.
compared with placebo, significantly increased the number of
patients recovering from aphasia - by approximately 10%when
given within 12 hours of the onset of stroke and by about 15%
when given within 7 hours of onset.
The AAT was chosen ro assess post-acute and chronic aphasia
in patients undergoing language therapy because it is a reliable, psychometrically validated assessment. Additionally, it
was developed using specific linguistic principles allowing
the detail of language breakdown to be assessed. In this way
it provides a sensitive recording of the changing nature of language breakdown with repeared use. e.g. as during speech
therapy and/or drug therapy.
Its use allowed clear demonstration of differences between the
effects of piracetam and placebo. That the pattern of AAT subtest responses favoring piracetam was closely similar in both
studies reflects the sensitivity of the AAT and consequently
strengthens the evidence that the results were valid.

In the PASS study, for every 100 patients with acute stroke
treated, an additional 10- 16 recovered completely from aphasia after piracetam as compared to placebo. This finding is of
obvious practical significance. This figure also probably underestimates the extent of the benefit from piracetam because the
assessment took account only of presence or absence of aphasia and could not consider partial improvement. The full benefit from piracetam in aphasic patients with acute stroke has
therefore still to be determined. It also seems that its effect on
recovery and improvement is greatest in acute stroke.
How does piracetam act to improve aphasia? Its neuroprotective properties probably account for its effect in acute stroke
by enhancing temporarily impaired language functions in
ischemic zones, including the ischemic penumbra, through enhanced cell metabolism and neurotransmission in the presence of hypoxia (Gobert. 1972: Muller. 1992). In post-acute
and chronic aphasia, piracetam might facilitate relearning of

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The close similarity of the results of these two trials - a comparable pattern of improvement in AAT subtests together with
improvement in "written language" approaching significance
- is evidence that the findings are valid and probably clinically
relevant. Improvement occurred regardless of the duration of
aphasia which varied between 4 weeks and 3 years.

Pharmacoosvchiat. 1999: 32 (Suoolement)

degraded linguistic knowledge (Huber, 1992; Huber et a]..
1993) and learning of compensatory mechanisms might be facilitated by the known effects of piracetam on learning and
memory (Giurgea, 1976) and by facilitating transcallosal transfer of information to the opposite cerebral hemisphere (Giurgea and Moyersoons, 1979: Dirnond. 1979).
The implications of these studies in aphasic patients are substantial. The results provide clinical support for the use of piracetam in aphasic patients with acute stroke and for its use, in
conjunction with language therapy, in patients with postacute and chronic aphasia.
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Corresponding Author
Professor W. Huber
RWTH NeurologischeKlinik
MedizinischeFakultdt
Pauwelstrasse 30
D-52057 Aachen
Germany

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'r

Pharmaco~svchiat.1999: 32 ( S u ~ ~ l e m e n t l