Article
Reference
Crossover trial of subacute computerized aphasia therapy for anomia with the addition of either levodopa or placebo
LEEMANN, Béatrice, et al.
Abstract
The effect of levodopa on recovery from aphasia is controversial.
LEEMANN, Béatrice, et al . Crossover trial of subacute computerized aphasia therapy for anomia with the addition of either levodopa or placebo. Neurorehabilitation and Neural Repair , 2011, vol. 25, no. 1, p. 43-47
DOI : 10.1177/1545968310376938 PMID : 20834044
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Research Articles
Crossover Trial of Subacute
Computerized Aphasia Therapy for Anomia With the Addition of Either Levodopa or Placebo
Neurorehabilitation and Neural Repair 25(1) 43-47
©The Author(s) 201 1
Reprints and permission: http://www.
sagepub.com/journalsPermissions.nav DOl: 10.1177/1545968310376938 http://nnr.sagepub.com
(l)SAGE
Béatrice Leemann, MOl, Marina Laganaro, Ph0
2,Daphné Chetelat- Mabillard, MScl, and Armin Schnider, MOl
Abstract
Background. The effect of levodopa on recovery from aphasia is controversial, Objective. To determine whether levodopa enhances the effect of intensive computer-assisted therapy (CAT) of anomia in the postacute stage of aphasia. Methods.
Double-blind multiple case study with intrasubject crossover design comparing the effect of levodopa (100 mg) versus placebo. each given for 2 weeks. Subjects.Twelve patients with onset of aphasia from 2 to 9 weeks after stroke or traumatic brain injury were compared on naming performance on items trained and not trained with CAT. Subjects were randomized to either levodopa or placebo first,separated bya I-week washout, and then switched to the other drug intervention for the second 2-week CAT intervention. The subjects also received routine aphasia therapies during these periods. Results. Ali patients improved their naming performance for items trained by CAT in both periods (P
=
.001). No significant difference was found between the placebo and levodopa phases. Conclusion. Administration of levodopa for 2 weeks during the postacute stage of aphasia did not augment the positive effects of subacute intensive language treatment with CAT for a spoken naming task.Keywords
aphasia,levodopa, stroke, traumatic brain injury, rehabilitation
Introduction
Demonstration of benefit of aphasia treatment in the acute and postacute stages isdifficult to separate from spontane- ousrecovery; in addition, it depends on the selection ofthe outcome measure. Speech therapy is a generally accepted treatment modaliry.v' Treatment intensity seems to be an important predictor of outcome.' One way of increasing treatment intensity is computer-assisted therapy (CAT) of aphasia. CAT allows increasing the number of treated items andrepetitions per item. CAT has proven its efficacy as a complement to traditional treatments of aphasia.Y
Pharmacological treatment can improve recovery after a cerebral lesion. Studies have assessed substances such as amphetamine'v' ordrugs acting on thedopaminergic system (such as levodopa" and bromocriptine'" "), piracetam, 13,14
andsubstances influencing GABAergic, serotoninergic, and cholinergie systems.P:" Levodopa is given orally and then metabolized in the brain to dopamine (95%) and norepi- nephrine (5%).8 Decarboxylase inhibitor, which does not cross the blood-brain barrier, blocks periphery metabolism and avoids systemic effects.
Synapses aremodifiable, and changes in synaptic strength (long-term potentiation and long-term depression) areaputa- tive mechanism underlying plasticity." Synaptic strength is modulated by dopaminergic input,18an observation that may explain why the dopamine system is important for motor learning. Levodopa shortened the training time required to form motor memory in young healthy volunteers and restored the ability to form amotor memory inelderly sub- jects to alevelsimilar tothatobserved inyounger subjects.'?
Compared withplacebo, levodopa also significantly improved procedural motor learning inpatients with chronic stroke.ê?
Levodopa 100mg once a day for 3 weeks associated with physiotherapy was significantly better than placebo in reduc- ingmotor deficit in stroke patients."
'University Hospital of Geneva, Geneva, Switzerland 2University ofNeuchâtel, Neuchâtel, Switzerland Corresponding Author:
Béatrice Leemann, Service deNeurorééducation, Hôpitaux Universitaires de Genève, 121 1Genève 14,Switzerland Email:beatrice.leemann@hcuge.ch
44
Neurorehabilitation and Neural Repair 25(1)Table 1.Subjeets' Demographie and Clinieal Data
WeeksAfter
Subjeets Age (Years) Onset Gender AphasiaType Etiology Lesion
PI 76 9 Male Wernieke Ischemie stroke Temporoparietal
P2 75 2 Female Anomie Ischemie stroke Frontal
P3 67 5 Female Anomie Ischemie stroke Temporooeeipital and thalamie
P4 60 3 Female Wernieke Ischemie stroke Temporoparietal
P5 59 4 Male Anomie Cerebral venous Temporoparietal
thrombosis
P6 71 6 Male Anomie Traumatie brain injury Temporal
P7 63 7 Female Broca Ischemie stroke Frontal
P8 62 9 Male Conduetion Ischemie stroke Frontoparietal
P9 69 5 Male Anomie Traumatie brain injury Temporal
Pla 42 8 Male Broca Ischemie stroke Frontal operculum, insu la.
temporal. and internai capsule
Pli 41 5 Male Wernieke Traumatie brain injury Temporal
PI2 63 2 Male Anomie Ischemie stroke Temporal
lnhealthy subjects, levodopa 100 mg for 5days accelerated word learning.F Case reports suggested that dopaminergic drugs may also have positive effects on recovery from aphasia.? ln group studies, positive effects ofbromocriptine were reported in nonfluent chronic aphasie patients with significant improvement on word retrieval,'? in the lexical index, verbal fluency, and pause reduction+' or in verbal latency and reading comprehension, IlLevodopa 100 mg from Monday to Friday for 3 weeks, 30 minutes before speech therapy, improved language abilities inpatients with motor aphasia in a subset of language tasks (verbal fluency and repetition) assessed on an aphasia screening battery.f Other studies found no effect of adopamine receptor agonist bro- mocriptine started at 5 mg and increased to 15 mgdaily for a period of 8 weeks!? or started at3.75 mgand increased to 60 mg daily" for a period of 7 weeks in patients who had nonfluent aphasia.
The goal ofthe present study was to evaluate the effects oflevodopa on recovery from anomia in patients withapha- sia from stroke or traumatic brain injury, within 2to 9 weeks after onset, who were receiving CATinaddition toindividual traditional therapy sessions. To avoid the bias of intersub- ject variability, we use intrasubject comparison across 2 treatment phases. Patients underwent 2 periods of anomia therapy with CAT, each performed with a different word list. Each period was associated with the administration of either levodopa 100 mg or placebo.
Methods
General Procedures
We performed a multiple case study with double-blind placebo-levodopa intrasubject crossover design. Evaluations
atbaseline andafter each treatment period were performed with a naming battery already used in previous studies.' The order of administration of levodopa and placebo was randomized across subjects.
Subjeets
Patients hospitalized in the Division of Neurorehabilitation of the University Hospital of Geneva, who suffered from aphasia after stroke or traumatic brain injury, were selected.
Inclusion criteria were presence of anomia with normal to mildly impaired comprehension. Exclusion criteria were executive or apraxic dysfunctions that might interfere with the handling of keyboard or mouse, stereotypies or perse- verations dominating the aphasie symptoms, or Parkinson's syndrome requiring dopaminergic treatment. Patients were infonned about the study procedure and gave written con- sent. The study was approved by thelocal ethics committee and the Swiss agency for therapeutic products.
Seventeen subjects met the inclusion criteria and were recruited to participate in the study. Five subjects did not complete the study or were discharged for protocol devia- tion (inadequate CAT or pharmacological treatment) or insufficient level of French. Demographie data and aphasia subtype for the 12 patients included in the study are given in Table 1.
Specifte Procedures
Patients received the standard clinical treatment (4-5 hours of speech therapy per week) and additional daily CAT ses- sions (Monday to Friday) during the study period. As far as possible in the weekly planning, the patients underwent the CAT sessions in the moming and the traditional therapy
Leemann etal 45
session in theafternoon. The traditional therapy avoided tar- geting anomia and especiaIly theitems used inCAT.
CAT and assessment material consisted of 2 sets of 72 words (frequent items for severe anomia) or 2 sets of 50 words (overaIl less frequent words for milder anomia) and their associated black-and-white line drawings. The items inthe 2 sets were matched on name agreement, lexical frequency, age at which each word was acquired, length, and syllabic structure. Healthy subjects performed above 95% correct on alliists.
During CAT periods, the patient had to write (by using the keyboard) the word corresponding to a picture that appeared on the screen. Two help buttons were available:
one provided thepronounced word and the other provided help on each letter of the word.' Oral naming of aIlstimu- lus items was scored at baseline and at posttreatment assessments. Only first attempt correct response in adelay of 4 seconds was scored as correct. For each patient, the study procedure was as follows:
tl: Baseline assessment
t2: Treatment phase 1: 2 weeks of CAT on one list
+
levodopa or placebot3: Posttreatrnent assessment 1
t3': 1 week washout period (only standard clinical therapy butno CAT, no levodopa, noplacebo) t4: Treatment phase 2: 2 weeks of CAT ona second
list
+
levodopa orplacebo t5:Posttreatment assessment 2The order of the 2lists was counterbalanced, and the order of pharmacotherapy or placebo was randomized across patients. Pharmacotherapy consisted of levodopa 100mg with decarboxylase inhibitor benserazide 25 mg admin- istered in the morning 1 hour after breakfast, taken 5 of 7 days, for 2 weeks corresponding to 1 ofthe 2 CAT treat- ment periods. During the other period, placebo was admin- istered following the same procedure. Neither the study participants nor the researchers were aware about which substance (levodopa withbenserazide or placebo) was admin- istrated in the 2 treatment phases. Randomization, produc- tion ofthe placebo, labels, and lot numbers were managed by the hospital's pharmacy. Placebo and levodopa pills had the same external appearance,
Results
At baseline, naming accuracy was equivalent across the 2 lists (mean accuracy, respectively, 41% and 43%; paired t test: t(11)
=
l.38, P=
.19). Changes (delta ordifferences) in naming accuracy on each list between 2 consecutive assess- ment periods are shown in Figure 1. At the end of the CAT treatment period there was a significant increase inA.Madopar phase 1
• List trealed with CAT phase 1
1
Listtreated with CATphase 2 35%t5 (aftertreatment phase 2) 30%
25%
20%
.S 15%
!Il tn 10%
5%
0%
-5%
t3 (aftertreatment phase 1) -10%
B. Madopar phase 2
35% • List trealed w~h CAT phase 1
1Listtreatedwith CAT phase 2 30%
25%
20%
.S 15%
!Il tn 10%
5%
0%
-5%
t3 (after treatment phase 1) t5 (after treatment phase2) -10%
Figure 1.(A) Percentage of increase of correctly named items (gain) on list treated with computer-assisted therapy (CAT) in phase 1 (black bars) and on list treated with CAT in phase 2 (gray bars) when levodopa and benserazide is given in phase 1.
(B) Percentage of increase of correctly named items (gain) on list treated with CAT in phase 1 (black bars) and on list treated with CAT in phase 2 (gray bars) when levodopa and benserazide is given in phase 2. t3, Posttreatment phase 1 assessment; tS, Posttreatment phase 2 assessment
performance (F(l, Il) = 48.98, P<.0001) but nointeraction with the pharmacotherapy condition (F(l, Il) <1). Repeated- measures analysis of variance carried out ongains (difference on performance) on each list after each treatrnent phase con- finned aneffect ofCAT for treated items (interaction between listandphase:F( l, 10) = 9.6,P <.02)butno interaction with the pharmacological phase (F < 1). There was a trend for higher gains during the fust treatrnent phase in aIl patients (simple effect ofphase: F(l, 10) = 4.02, P= .07).
Individual results are shown in Table 2. McNemar's X2
were calculated on thenaming scores on each list for com- parisons across 2 consecutive assessment sessions. Ali but l patient displayed significant improvement on the treated list after the first CAT treatment phase regardless of thepharma- cological treatrnent phase. Five of 6 patients who did not receive levodopa during the second CAT treatment phase
46 " Neurorehabilitation and Neural Repair 25(1)
Table 2. Correct Naming (Percentage) at Baseline and After Each Therapy Phase on Each List and for the 12 Patients
Posttest 1 Posttest 2
Baseline Treated List Untreated List Untreated List Treated List
listA List B Levodopa Phase 1 Placebo Phase 2
PI 56% 64% 66% 50% 72% 76%'
P6 60% 52% 78%' 42% 80% 84%b
P7 52% 56% 84%b 48% 68% 76%b
PlO 8% 15% 33%b 26% 31% 38%
Pli 36% 36% 97%b 53%' 71% 85%b
PI2 38% 40% 80%b 58% 78% 88%b
Placebo Phase 1 Levodopa Phase 1
P2 70% 74% 92%b 78% 90% 96%'
P3 10% 11% 22%' 15% 15% 28%
P4 40% 42% 74%b 58% 70% 84%b
P5 32% 40% 63%b 50% 72% 76%b
P8 30% 42% 62%' 56% 50% 68%
P9 50% 47% 81%b 93%b 81% 93%
'5ignificant change relative to the previous assessment period atP<.05.
b5ignificantatP<.01.
alsoimproved significantly after this phase,andonly 3 patients with pharmacotherapy in phase 2 displayed significant improvements during this phase. Interestingly, these 3 patients (P2, P4, and P5) entered the study at very early postonset (during the first month postonset). However, noconclusion can be drawn on timepostonset effects, since patients Pl, P6, and P7, who also improved during the second levodopa therapy phase, entered the study in a later postonset stage.
ln sum, the individual results replicate the pattern observed inthe group analysis, with mostpatients displaying a CAT treatment effect regardless ofthepharmaco-therapy period.
Discussion
Our main finding isthat although all patients significantly improved their naming performance for items treated with the CAT, administration of levodopa did not modulate the amount of improvement. These results converge withprevious studies failing to show an effect of dopaminergic phar- macotherapy onrecovery from aphasia10,24 and contradict studies showing positive effects ofpharmacotherapy added to language treatment.8,11,12,23Several factors may account for these differences across studies.
First, the type of aphasia differed across studies. The case report byAlbert et al?and 3 studies with positive outcome- included onlypatients with nonfluent aphasia.11,12,23Seni6w etal8included patients irrespective of type of aphasia, but a significant effect of levodopa was observed only inpatients
with alesioninfrontal language areas. lnthe present study, only 4 patients had lesions involving the frontal lobe and only 2 of them had acircumscribed frontal lesion. Second, CATsessions assure homogeneous treatrnent across patients and phases whereas in previous studies intensity and con- tent of speech therapy was often underspecified and hardly comparable and could have introduced a bias. Third, the lack of an effect of levodopa in the present study might beduealso to a ceiling effect caused bythe fact that patients receiving intensive speech treatment might already have reached their maximal recovery potential. Fourth, the out- come measure in the present study was limited to spoken naming. Effects of phannacotherapy were reported onword retrieval.P but not all language tasks and modalities have been modulated bypharmacotherapy inthe same way.8,11,23 Finally, the timing of CAT inrelation to pharmacotherapy might be critical. Although the same doses were admin- istered as those in the study by Seni6w et al,8(l00 mg), patients received the treatment after breakfast; given that themaximal blood level is achieved in60minutes and that the half-life is 1.5 hours, it is possible that its effect was lost in some cases, especially when CAT therapy was done in the afternoon. ln the present study, 70% of the CATtreat- ments were carried out in the morning (30-180 minutes after levodopa/placebo) and 30% in the afternoon. It is therefore possible that the effect of levodopa has probably been poor or lost in 30% of the treatment sessions andthis might be a confounding bias inour study.
lnsummary, the present studypoints to the complexity of dopaminergic treatrnent for aphasia inthe postacute stage.
Leemonn et 01 47
ln O)IT results, levodopa does not modulate recovery when coupled with intensive treatment for anomia in the postacute phase. However, these results do not rule out that dopaminer- gic treatment, given 30 to 90 minutes prior to therapy, may be effective in chronic aphasie patients with an anterior les ion or that another substance might be more effective to enhance recovery from aphasia.":" The type of substance, dose, time since brain injury, and the type and intensity of therapy and timing between drug administration and therapy are impor- tant factors that need more systematic exploration.
Declaration of Conflicting Interests
The author( s) declared no potential conflicts of interest with respect to the authorship and/or publication ofthis article.
Funding
The author(s) received no financial support for the research and/or authorship of this article.
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