Notice 'management' is the main word in the abstract. The tyranny of low expectations is complete, NOT RECOVERY OR RESULTS!
Treatment of post-stroke aphasia: A narrative review for stroke neurologists
International Journal of StrokeOnlineFirst
© 2021 World Stroke Organization
, Article Reuse Guidelines
https://doi.org/10.1177/17474930211017807
© 2021 World Stroke Organization
, Article Reuse Guidelines
https://doi.org/10.1177/17474930211017807
Emilia Vitti and Argye E Hillishttps://orcid.org/0000-0002-5192-1171
Keywords
Ischaemic stroke, neurology, rehabilitation, stroke, therapy, treatment
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, USA
Corresponding author(s):
Argye E Hillis, Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Phipps 446, Baltimore, MD 21287, USA. Email: argye@jhmi.edu
Introduction
Every stroke neurologist is familiar with aphasia. It occurs in about one-third of stroke patients, most often in those with left cortical stroke1 and can be devastating. There have been many recent reviews of its treatment,2 but this one is aimed at providing helpful information to stroke clinicians, particularly neurologists. We will not provide details regarding interventions(So you survivors needing this will need to look elsewhere, but since nothing exists for100% recovery you're screwed.), as these are typically determined by a speech-language pathologist, on the basis of the individual’s needs, goals, and profile of performance on language tests. Rather, here we provide a review of evidence regarding: (1) when and for whom language therapy is most effective, (2) the variety of approaches that can be effective for different individuals, and (3) the extent to which behavioral therapy might be augmented by non-invasive brain stimulation and/or medications. We begin by discussing approaches to behavioral therapy, because medications and non-invasive brain stimulation have been used to boost the effects of behavioral interventions, rather than used independently. Our aim is to provide a practical overview that will guide physicians in deciding who, when, and where to refer people with aphasia. It addresses common problems faced by physicians when caring for patients with post-stroke aphasia.
There have also been recent reviews of the mechanisms underlying interventions to improve language after stroke,3 which have been revealed by changes in activation or functional or structural connectivity in language networks in functional imaging of language before and after treatment. Here, we focus on empirical evidence of treatment effects and refer the interested reader those reviews of mechanisms.
Behavioral interventions: Speech and language therapy
Two main, complementary approaches to intervention are impairment-based approaches and functional communication approaches. These types of treatments can appropriately be undertaken simultaneously or at different time periods for the same patient, or used at the same time post-stroke with patients with different profiles of impairment. Impairment-based approaches aim to improve specific language processes, such as lexical-semantics, phonology, or syntax,4 or performance on specific language tasks, such as naming, reading, spelling, or word and sentence comprehension.5 Functional communication approaches emphasize helping the individual communicate in every day circumstances, by eliminating communication barriers in the environment, improving success of communication by any modality (gestures, drawing, pointing, etc.) and caregiver training to enhance communication (see Martin et al.6 for illustrations of the two approaches to the same problem). Impairment-based approaches are likely effective by inducing reorganization of structure–function relationships in the brain, i.e. by inducing unimpaired brain regions to assume the function of the damaged regions.7 Functional communication approaches are compensatory, i.e. aimed to allow the individual to compensate for deficits to reduce language disability.
Efficacy of speech and language therapy
Numerous single-subject studies with multiple baseline or cross-over design and small group studies (e.g. Hillis8) demonstrate the effectiveness of a particular therapy for one or more individuals with a particular deficit. These studies are essential because language is complex, and no one therapy is useful for all deficits. Meta-analyses of these small studies generally show a statistically significant positive effect.9 The very few studies comparing the effectiveness of different types of therapy for the same individuals have been very small, although a relatively large (n = 100) cross-over trial with randomized order of a semantic versus phonological treatments has recently been completed and results are forthcoming.10 Importantly, a recent large Phase III randomized controlled trial (RCT) showed that a structured speech and language therapy (SLT) improves speech production and communication quality of life in chronic aphasia.11
Timing of speech and language therapy
No study has directly compared the effects of a specific language therapy provided at the acute or subacute stage versus the chronic stage after stroke. Animal models of stroke indicate impairment-based therapy should take advantage of the neuroplasticity that is highest early after stroke.12 Indeed, SLT is most commonly provided in the acute or subacute time period, and seems to be effective.13 However, as most patients improve in the first three months after stroke irrespective of intervention, it is very difficult to show a significant effect over and above the spontaneous recovery.14 However, carefully controlled studies of interventions more targeted to the individual’s particular deficits in the early stages after stroke clearly demonstrate positive effects. Nevertheless, the strongest evidence for treatment efficacy is in chronic aphasia.15 Reduction in language impairment with structured SLT in chronic aphasia has been demonstrated through Phase III randomized clinical trials.11 In fact, more SLT sessions in the chronic phase, even many years after stroke, is associated with greater recovery.16 About 50% of chronic stroke patients continue to improve in language even decades after stroke, even though motor recovery may have plateaued earlier,17 and additional SLT facilitates recovery.
Amount of speech and language therapy
Although there is insufficient evidence to recommend an optimal dose of SLT,18 the therapist ideally determines the optimal number and duration of treatment sessions for each individual. Unfortunately, the number of sessions received may be limited by third-party payers or other practicalities (e.g. transportation). Studies show that more SLT leads to more gains,19 but most patients receive only about 15 sessions.20 Aphasia Centers,21 telerehabilitation,22 self-administered computerized SLT23,24 can increase the amount and efficacy of therapy.
Type of therapy
Physicians do not typically order a specific type of SLT. Nevertheless, it is important to know a wide range of SLT approaches are provided, so that lack of success with one approach may not indicate that the patient has “plateaued” in language recovery. For example, for patients with apraxia of speech, a number of structured treatments have been shown to be effective, including Speech Entrainment, in which the clinician and patient read aloud a passage simultaneously, with both visual and auditory mirroring.25 Other effective approaches to treatment of apraxia of speech and/or language deficits include Oral Reading for Language in Aphasia, Melodic Intonation Therapy, Speech Production Treatment, Phonomotor Treatment, Response and Elaboration Treatment (see, Pulvermüller et al.30 for a comprehensive review). For patients with lexical-semantic deficits that underlie impaired naming and/or comprehension, both Semantic Feature Analysis26 and a computerized treatment of word–picture verification have been shown to be effective.27 Also, several studies have demonstrated gains in in grammatical processing, in both speech production and comprehension, using a structured therapy targeted to grammatical processing, in patients with Broca’s aphasia.28 A very different approach, designed for people with aphasia with a wider range of language deficits, is constraint-induced aphasia therapy (CIAT).29 Patients are encouraged to communicate only with speech, and discouraged from using other modalities, such as pointing, drawing, gestures, or writing, to communicate. Several trials have shown that this approach can improve speech production,30 although no more than usual care SLT provided at similar intensity levels.31,32 An older, but widely used and effective treatment that encourages the use of both speech and other forms of communication (gestures, drawing, pointing) to communicate a concept is Promoting Aphasic’s Communicative Effectiveness (PACE, Davis33). In PACE, the patient is asked to communicate information depicted in a picture that is not seen by the clinician. In alternate trials, the clinician communicates information in picture not seen by the patient, modelling various methods to communicate. Life Participation Approaches to Aphasia (LPAA), like PACE, takes almost the opposite approach to CIAT. LPAA focuses on encouraging people with aphasia to use residual personal strengths to communicate in any modality that is effective, and will ultimately allow the person to reintegration into the community.26 Often individualized strategies for effective communication are identified and then practiced by aphasic patient and their communication partners.34 Another advancement in aphasia treatment has been the development of: (1) Aphasia Groups,35 which may be in-person or remote using telecommunication and include social communication activities such as book clubs, (2) Intensive Comprehensive Aphasia Program (Cherney and Carpenter26) that provide intensive, daily treatment sessions using a variety of behavioral approaches tailored to a small group of patients over 2–4 weeks in a camp-like setting, and (3) Aphasia Centers36 that provide the individual with a variety of experiences in communication over a longer period, which have psycho-social benefits as well as gains in communication and various aspects of language.37 Because several large RCTs provide evidence that patients with chronic, severe aphasia are unlikely to respond to impairment-based therapy,11,14,38 these patients are likely to benefit most from compensatory approaches, including training communication partners,39 alternative communication modalities,40 or use of augmentative communication devices.42
In acute ischemic stroke, the primary mechanism of recovery is restoration of blood flow to the penumbral tissue surrounding the core infarct. Numerous large RCTs have shown overall benefit in outcome with intravenous thrombolysis42 or endovascular therapy.43 While these trials have not been designed to evaluate the effects on language, a secondary analysis of a large RCT of endovascular therapy (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; MR CLEAN) showed greater gains in the language score (0–2 points) on the NIH Stroke Scale in the intervention group compared to the control group.44 Furthermore, case series have shown that such interventions can result in improvement of language functions.45 One small RCT also showed that temporary elevation of blood flow to improve perfusion early after left hemisphere stroke due to large vessel occlusion or stenosis was associated with language improvement.46
Chronic interventions
In chronic post-stroke aphasia, no RCT has yet provided evidence that pharmaceutical intervention, in the absence of SLT, results in significant improvement in language.47 However, several trials have shown that some medications may augment the effects of SLT. A plausible mechanism of the augmentation effects of medications that modulate neurotransmitters is that language recovery often depends on neuroplasticity. That is, neural networks supporting language can be modified by: (1) incorporating new nodes into the network or (2) changing connectivity between undamaged nodes of the residual language network. Alternatively, other networks might be engaged to assume the functions of the damaged networks.48 Evidence from both humans and animals indicate that behavioral interventions such as mass practice can lead to this type of reorganization, through short- or long-term neural plasticity, facilitated by the availability of neurotransmitters such as acetylcholine, norepinephrine, serotonin, and dopamine.49 Therefore, medications that enhance the availability of these neurotransmitters could increase neuroplasticity.50 Most trials of medications to augment recovery have studied motor recovery, but several RCTs have evaluated their effects on post-stroke language recovery.
Early RCTs evaluated the effects of sympathomimetics, which elevate brain catecholamines. A few small nonrandomized trials (see Llano and Small51) and one larger RCT52 demonstrated small, but statistically significant effects of dextroamphetamine in augmenting language therapy to improve language test scores. However, results were not adjusted for differences in language therapy duration and have not been subsequently replicated. One RCT that combined levodopa with language therapy showed statistically significant effects of levodopa on a subset of language tasks,53 but other small RCTs have been negative.54
Cholinesterase inhibitors have been evaluated in small, uncontrolled studies and two RCTs for aphasia recovery. An RCT of 26 patients with chronic post-stroke aphasia showed greater improvement in aphasia severity at the end of 16 weeks of therapy with donepezil (10 mg/day) relative to placebo (p = 0.037).55 However, group differences did not persist after the four-week wash-out period. A larger RCT of 60 patients with post-stroke aphasia showed higher language scores with donepezil versus placebo, and the difference persisted after the four-week wash out (p < 0.01), but the effect size was very small.56
Memantine, a noncompetitive antagonist of the N-methyl-D-aspartate receptor, with effects on serotonin and dopamine receptors and potential reduced excitotoxicity,57 has shown similar small positive effects, possibly due to positive effects on more general cognitive functions such as attention or memory. An RCT of memantine plus SLT showed significantly greater improvements with both interventions compared to placebo or memantine alone after 16 weeks of therapy (gains of 8.5 ± 0.9 versus 3.5 ± 0.8 on a 100-point score; p = 0.00001), which declined but remained significant after a four-week wash-out period (6.0 ± 0.8 versus 3.9 ± 0.8 on a 100-point score; p = 0.041).58 However, the small group differences might not have functional significance, and the trial was not blinded. A more recent study showed that both memantine and SLT were associated with changes in cortical activity (measured with event-related potentia) that correlated with language gains.59
Selective serotonin reuptake inhibitors, which have been shown to have a positive effect on post-stroke motor recovery measured with the Fugl Meyer scale60 and greater improvements on a cognitive battery,61 but no effect on the less sensitive modified Rankin Scale,62 have not been studied in RCT for aphasia recovery. However, an RCT of escitalopram plus language therapy versus placebo plus language therapy in subacute post-stroke aphasia is underway (NCT03843463).
Non-invasive brain stimulation
Non-invasive brain stimulation, such as repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS), is a promising alternative approach to enhancing neuroplasticity to augment language recovery. rTMS, which modulates neural activity by reducing (inhibitory, low-rate rTMS) or increasing (excitatory or high-rate rTMS) synaptic firing can be used with or without SLT. In contrast, tDCS only changes the threshold of activation of neurons in the network activated by the concurrent behavioral task, such as SLT. The current is not strong enough to generate action potentials alone, so it is only effective for language improvement when used concurrently with SLT.63 Anodal (excitatory) tDCS reduces the threshold of activation of the network stimulated by the ongoing task, while cathodal tDCS has mixed effects,63 but mostly inhibitory, by increasing the threshold of activiation.64 Both animal and human studies have yielded evidence that the effects of tDCS depend on a Brain-Derived Neurotrophic Factor (BDNF)-dependent mechanism.65 Although tDCS has fairly widespread effects on neural activity, one functional magnetic resonance imaging (MRI) study showed that the effects are specific to the entire network activated by the concurrent behavioral task, as long as tDCS is applied to any part of the network.66
Trials of tDCS
One advantage of tDCS over TMS is that an excellent sham control is possible; participants are unable to distinguish the sham from real tDCS. In the sham condition, 1–4 mA stimulation is applied for 30 s, but then faded gradually to 0 mA, which mimics the sensation of continuous (e.g. 20 min) 1–4 mA stimulation, in which stimulation is generally perceived for only the first 20–30 s.63 Most recent RCTs have evaluated the effects of 1–2 mA of anodal or cathodal tDCS, applied for 15–20 min. This “dose” is based on studies by Fritsch et al.65 showing that 15 min of continuous tDCS significantly increases BDNF levels for more than 1 h. More than 35 RCTs of post-stroke aphasia, using anodal (usually applied to left hemisphere) or cathodal tDCS (usually applied to right hemisphere), or both have been published (see a systematic review67). Most of these trials in chronic post-stroke aphasia, including the largest (N = 74) double-blind RCT of tDCS,68 have reported significantly greater improvement in the primary outcome measure (generally a language task) relative to the sham group or condition.69 Most of the negative trials have studied tDCS in few (five or fewer) therapy sessions.70 Only a couple of studies have been conducted in subacute stroke, but those that included greater than five therapy sessions have been positive, and others are ongoing (e.g. NCT02674490).
Trials of rTMS
Although most RCTs include a sham group or condition, the conditions are generally distinguishable when participants receive both conditions. Thus, randomized parallel group, rather than cross-over trials are preferred (but see Rubi-Fessen et al.71). Most trials of low-frequency or high-frequency rTMS in subacute stroke have reported significantly greater language improvement in the rTMS than in the sham group or condition,72 sometimes lasting for at least three months.73 Similar positive effects of rTMS have been reported in chronic post-stroke aphasia (see meta-analysis74). Supplemental Table summarizes the results of recent trials of SLT and non-invasive brain stimulation with more than 20 participants.
Conclusions
Behavioral SLT remains the standard of care post-stroke aphasia, although different approaches to SLT may be more appropriate at different times after stroke, or for patients with different levels of severity. Most studies indicate that more time in therapy is more effective, and time in therapy may be enhanced by telerehabilitation, self-administered therapy (e.g. through language therapy apps), or participation in aphasia groups, intensive comprehensive aphasia programs, or Aphasia Centers. Alternatively or additionally, relatively small trials suggest that the efficiency and effectiveness of aphasia therapy might be enhanced by medications or non-invasive brain stimulation in addition to SLT. It is important for referring physicians to be aware that SLT can be effective regardless of the time post-stroke, and to refer patients or families to databases of ongoing clinical trials, such as ClinicalTrials.gov. Participation in clinical trials can benefit not only the scientific community (by evaluating the effects of interventions) but also the participants, who are likely to receive some sort of SLT without monetary cost. Because aphasia is associated with poor quality of life, even worse, on average, than conditions such as dementia or cancer,75 patients with post-stroke aphasia deserve an opportunity for rehabilitation regardless of the time post-stroke or severity.
Abstract
This review is intended to help physicians guide patients to optimal management of post-stroke aphasia. We review literature on post-stroke aphasia treatment, focusing on: (1) when and for whom language therapy is most effective, (2) the variety of approaches that can be effective for different individuals, and (3) the extent to which behavioral therapy might be augmented by non-invasive brain stimulation and/or medications.Keywords
Ischaemic stroke, neurology, rehabilitation, stroke, therapy, treatment
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, USA
Corresponding author(s):
Argye E Hillis, Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Phipps 446, Baltimore, MD 21287, USA. Email: argye@jhmi.edu
Introduction
Every stroke neurologist is familiar with aphasia. It occurs in about one-third of stroke patients, most often in those with left cortical stroke1 and can be devastating. There have been many recent reviews of its treatment,2 but this one is aimed at providing helpful information to stroke clinicians, particularly neurologists. We will not provide details regarding interventions(So you survivors needing this will need to look elsewhere, but since nothing exists for100% recovery you're screwed.), as these are typically determined by a speech-language pathologist, on the basis of the individual’s needs, goals, and profile of performance on language tests. Rather, here we provide a review of evidence regarding: (1) when and for whom language therapy is most effective, (2) the variety of approaches that can be effective for different individuals, and (3) the extent to which behavioral therapy might be augmented by non-invasive brain stimulation and/or medications. We begin by discussing approaches to behavioral therapy, because medications and non-invasive brain stimulation have been used to boost the effects of behavioral interventions, rather than used independently. Our aim is to provide a practical overview that will guide physicians in deciding who, when, and where to refer people with aphasia. It addresses common problems faced by physicians when caring for patients with post-stroke aphasia.
There have also been recent reviews of the mechanisms underlying interventions to improve language after stroke,3 which have been revealed by changes in activation or functional or structural connectivity in language networks in functional imaging of language before and after treatment. Here, we focus on empirical evidence of treatment effects and refer the interested reader those reviews of mechanisms.
Behavioral interventions: Speech and language therapy
Two main, complementary approaches to intervention are impairment-based approaches and functional communication approaches. These types of treatments can appropriately be undertaken simultaneously or at different time periods for the same patient, or used at the same time post-stroke with patients with different profiles of impairment. Impairment-based approaches aim to improve specific language processes, such as lexical-semantics, phonology, or syntax,4 or performance on specific language tasks, such as naming, reading, spelling, or word and sentence comprehension.5 Functional communication approaches emphasize helping the individual communicate in every day circumstances, by eliminating communication barriers in the environment, improving success of communication by any modality (gestures, drawing, pointing, etc.) and caregiver training to enhance communication (see Martin et al.6 for illustrations of the two approaches to the same problem). Impairment-based approaches are likely effective by inducing reorganization of structure–function relationships in the brain, i.e. by inducing unimpaired brain regions to assume the function of the damaged regions.7 Functional communication approaches are compensatory, i.e. aimed to allow the individual to compensate for deficits to reduce language disability.
Efficacy of speech and language therapy
Numerous single-subject studies with multiple baseline or cross-over design and small group studies (e.g. Hillis8) demonstrate the effectiveness of a particular therapy for one or more individuals with a particular deficit. These studies are essential because language is complex, and no one therapy is useful for all deficits. Meta-analyses of these small studies generally show a statistically significant positive effect.9 The very few studies comparing the effectiveness of different types of therapy for the same individuals have been very small, although a relatively large (n = 100) cross-over trial with randomized order of a semantic versus phonological treatments has recently been completed and results are forthcoming.10 Importantly, a recent large Phase III randomized controlled trial (RCT) showed that a structured speech and language therapy (SLT) improves speech production and communication quality of life in chronic aphasia.11
Timing of speech and language therapy
No study has directly compared the effects of a specific language therapy provided at the acute or subacute stage versus the chronic stage after stroke. Animal models of stroke indicate impairment-based therapy should take advantage of the neuroplasticity that is highest early after stroke.12 Indeed, SLT is most commonly provided in the acute or subacute time period, and seems to be effective.13 However, as most patients improve in the first three months after stroke irrespective of intervention, it is very difficult to show a significant effect over and above the spontaneous recovery.14 However, carefully controlled studies of interventions more targeted to the individual’s particular deficits in the early stages after stroke clearly demonstrate positive effects. Nevertheless, the strongest evidence for treatment efficacy is in chronic aphasia.15 Reduction in language impairment with structured SLT in chronic aphasia has been demonstrated through Phase III randomized clinical trials.11 In fact, more SLT sessions in the chronic phase, even many years after stroke, is associated with greater recovery.16 About 50% of chronic stroke patients continue to improve in language even decades after stroke, even though motor recovery may have plateaued earlier,17 and additional SLT facilitates recovery.
Amount of speech and language therapy
Although there is insufficient evidence to recommend an optimal dose of SLT,18 the therapist ideally determines the optimal number and duration of treatment sessions for each individual. Unfortunately, the number of sessions received may be limited by third-party payers or other practicalities (e.g. transportation). Studies show that more SLT leads to more gains,19 but most patients receive only about 15 sessions.20 Aphasia Centers,21 telerehabilitation,22 self-administered computerized SLT23,24 can increase the amount and efficacy of therapy.
Type of therapy
Physicians do not typically order a specific type of SLT. Nevertheless, it is important to know a wide range of SLT approaches are provided, so that lack of success with one approach may not indicate that the patient has “plateaued” in language recovery. For example, for patients with apraxia of speech, a number of structured treatments have been shown to be effective, including Speech Entrainment, in which the clinician and patient read aloud a passage simultaneously, with both visual and auditory mirroring.25 Other effective approaches to treatment of apraxia of speech and/or language deficits include Oral Reading for Language in Aphasia, Melodic Intonation Therapy, Speech Production Treatment, Phonomotor Treatment, Response and Elaboration Treatment (see, Pulvermüller et al.30 for a comprehensive review). For patients with lexical-semantic deficits that underlie impaired naming and/or comprehension, both Semantic Feature Analysis26 and a computerized treatment of word–picture verification have been shown to be effective.27 Also, several studies have demonstrated gains in in grammatical processing, in both speech production and comprehension, using a structured therapy targeted to grammatical processing, in patients with Broca’s aphasia.28 A very different approach, designed for people with aphasia with a wider range of language deficits, is constraint-induced aphasia therapy (CIAT).29 Patients are encouraged to communicate only with speech, and discouraged from using other modalities, such as pointing, drawing, gestures, or writing, to communicate. Several trials have shown that this approach can improve speech production,30 although no more than usual care SLT provided at similar intensity levels.31,32 An older, but widely used and effective treatment that encourages the use of both speech and other forms of communication (gestures, drawing, pointing) to communicate a concept is Promoting Aphasic’s Communicative Effectiveness (PACE, Davis33). In PACE, the patient is asked to communicate information depicted in a picture that is not seen by the clinician. In alternate trials, the clinician communicates information in picture not seen by the patient, modelling various methods to communicate. Life Participation Approaches to Aphasia (LPAA), like PACE, takes almost the opposite approach to CIAT. LPAA focuses on encouraging people with aphasia to use residual personal strengths to communicate in any modality that is effective, and will ultimately allow the person to reintegration into the community.26 Often individualized strategies for effective communication are identified and then practiced by aphasic patient and their communication partners.34 Another advancement in aphasia treatment has been the development of: (1) Aphasia Groups,35 which may be in-person or remote using telecommunication and include social communication activities such as book clubs, (2) Intensive Comprehensive Aphasia Program (Cherney and Carpenter26) that provide intensive, daily treatment sessions using a variety of behavioral approaches tailored to a small group of patients over 2–4 weeks in a camp-like setting, and (3) Aphasia Centers36 that provide the individual with a variety of experiences in communication over a longer period, which have psycho-social benefits as well as gains in communication and various aspects of language.37 Because several large RCTs provide evidence that patients with chronic, severe aphasia are unlikely to respond to impairment-based therapy,11,14,38 these patients are likely to benefit most from compensatory approaches, including training communication partners,39 alternative communication modalities,40 or use of augmentative communication devices.42
Pharmaceutical interventions
Acute interventionsIn acute ischemic stroke, the primary mechanism of recovery is restoration of blood flow to the penumbral tissue surrounding the core infarct. Numerous large RCTs have shown overall benefit in outcome with intravenous thrombolysis42 or endovascular therapy.43 While these trials have not been designed to evaluate the effects on language, a secondary analysis of a large RCT of endovascular therapy (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; MR CLEAN) showed greater gains in the language score (0–2 points) on the NIH Stroke Scale in the intervention group compared to the control group.44 Furthermore, case series have shown that such interventions can result in improvement of language functions.45 One small RCT also showed that temporary elevation of blood flow to improve perfusion early after left hemisphere stroke due to large vessel occlusion or stenosis was associated with language improvement.46
Chronic interventions
In chronic post-stroke aphasia, no RCT has yet provided evidence that pharmaceutical intervention, in the absence of SLT, results in significant improvement in language.47 However, several trials have shown that some medications may augment the effects of SLT. A plausible mechanism of the augmentation effects of medications that modulate neurotransmitters is that language recovery often depends on neuroplasticity. That is, neural networks supporting language can be modified by: (1) incorporating new nodes into the network or (2) changing connectivity between undamaged nodes of the residual language network. Alternatively, other networks might be engaged to assume the functions of the damaged networks.48 Evidence from both humans and animals indicate that behavioral interventions such as mass practice can lead to this type of reorganization, through short- or long-term neural plasticity, facilitated by the availability of neurotransmitters such as acetylcholine, norepinephrine, serotonin, and dopamine.49 Therefore, medications that enhance the availability of these neurotransmitters could increase neuroplasticity.50 Most trials of medications to augment recovery have studied motor recovery, but several RCTs have evaluated their effects on post-stroke language recovery.
Early RCTs evaluated the effects of sympathomimetics, which elevate brain catecholamines. A few small nonrandomized trials (see Llano and Small51) and one larger RCT52 demonstrated small, but statistically significant effects of dextroamphetamine in augmenting language therapy to improve language test scores. However, results were not adjusted for differences in language therapy duration and have not been subsequently replicated. One RCT that combined levodopa with language therapy showed statistically significant effects of levodopa on a subset of language tasks,53 but other small RCTs have been negative.54
Cholinesterase inhibitors have been evaluated in small, uncontrolled studies and two RCTs for aphasia recovery. An RCT of 26 patients with chronic post-stroke aphasia showed greater improvement in aphasia severity at the end of 16 weeks of therapy with donepezil (10 mg/day) relative to placebo (p = 0.037).55 However, group differences did not persist after the four-week wash-out period. A larger RCT of 60 patients with post-stroke aphasia showed higher language scores with donepezil versus placebo, and the difference persisted after the four-week wash out (p < 0.01), but the effect size was very small.56
Memantine, a noncompetitive antagonist of the N-methyl-D-aspartate receptor, with effects on serotonin and dopamine receptors and potential reduced excitotoxicity,57 has shown similar small positive effects, possibly due to positive effects on more general cognitive functions such as attention or memory. An RCT of memantine plus SLT showed significantly greater improvements with both interventions compared to placebo or memantine alone after 16 weeks of therapy (gains of 8.5 ± 0.9 versus 3.5 ± 0.8 on a 100-point score; p = 0.00001), which declined but remained significant after a four-week wash-out period (6.0 ± 0.8 versus 3.9 ± 0.8 on a 100-point score; p = 0.041).58 However, the small group differences might not have functional significance, and the trial was not blinded. A more recent study showed that both memantine and SLT were associated with changes in cortical activity (measured with event-related potentia) that correlated with language gains.59
Selective serotonin reuptake inhibitors, which have been shown to have a positive effect on post-stroke motor recovery measured with the Fugl Meyer scale60 and greater improvements on a cognitive battery,61 but no effect on the less sensitive modified Rankin Scale,62 have not been studied in RCT for aphasia recovery. However, an RCT of escitalopram plus language therapy versus placebo plus language therapy in subacute post-stroke aphasia is underway (NCT03843463).
Non-invasive brain stimulation
Non-invasive brain stimulation, such as repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS), is a promising alternative approach to enhancing neuroplasticity to augment language recovery. rTMS, which modulates neural activity by reducing (inhibitory, low-rate rTMS) or increasing (excitatory or high-rate rTMS) synaptic firing can be used with or without SLT. In contrast, tDCS only changes the threshold of activation of neurons in the network activated by the concurrent behavioral task, such as SLT. The current is not strong enough to generate action potentials alone, so it is only effective for language improvement when used concurrently with SLT.63 Anodal (excitatory) tDCS reduces the threshold of activation of the network stimulated by the ongoing task, while cathodal tDCS has mixed effects,63 but mostly inhibitory, by increasing the threshold of activiation.64 Both animal and human studies have yielded evidence that the effects of tDCS depend on a Brain-Derived Neurotrophic Factor (BDNF)-dependent mechanism.65 Although tDCS has fairly widespread effects on neural activity, one functional magnetic resonance imaging (MRI) study showed that the effects are specific to the entire network activated by the concurrent behavioral task, as long as tDCS is applied to any part of the network.66
Trials of tDCS
One advantage of tDCS over TMS is that an excellent sham control is possible; participants are unable to distinguish the sham from real tDCS. In the sham condition, 1–4 mA stimulation is applied for 30 s, but then faded gradually to 0 mA, which mimics the sensation of continuous (e.g. 20 min) 1–4 mA stimulation, in which stimulation is generally perceived for only the first 20–30 s.63 Most recent RCTs have evaluated the effects of 1–2 mA of anodal or cathodal tDCS, applied for 15–20 min. This “dose” is based on studies by Fritsch et al.65 showing that 15 min of continuous tDCS significantly increases BDNF levels for more than 1 h. More than 35 RCTs of post-stroke aphasia, using anodal (usually applied to left hemisphere) or cathodal tDCS (usually applied to right hemisphere), or both have been published (see a systematic review67). Most of these trials in chronic post-stroke aphasia, including the largest (N = 74) double-blind RCT of tDCS,68 have reported significantly greater improvement in the primary outcome measure (generally a language task) relative to the sham group or condition.69 Most of the negative trials have studied tDCS in few (five or fewer) therapy sessions.70 Only a couple of studies have been conducted in subacute stroke, but those that included greater than five therapy sessions have been positive, and others are ongoing (e.g. NCT02674490).
Trials of rTMS
Although most RCTs include a sham group or condition, the conditions are generally distinguishable when participants receive both conditions. Thus, randomized parallel group, rather than cross-over trials are preferred (but see Rubi-Fessen et al.71). Most trials of low-frequency or high-frequency rTMS in subacute stroke have reported significantly greater language improvement in the rTMS than in the sham group or condition,72 sometimes lasting for at least three months.73 Similar positive effects of rTMS have been reported in chronic post-stroke aphasia (see meta-analysis74). Supplemental Table summarizes the results of recent trials of SLT and non-invasive brain stimulation with more than 20 participants.
Conclusions
Behavioral SLT remains the standard of care post-stroke aphasia, although different approaches to SLT may be more appropriate at different times after stroke, or for patients with different levels of severity. Most studies indicate that more time in therapy is more effective, and time in therapy may be enhanced by telerehabilitation, self-administered therapy (e.g. through language therapy apps), or participation in aphasia groups, intensive comprehensive aphasia programs, or Aphasia Centers. Alternatively or additionally, relatively small trials suggest that the efficiency and effectiveness of aphasia therapy might be enhanced by medications or non-invasive brain stimulation in addition to SLT. It is important for referring physicians to be aware that SLT can be effective regardless of the time post-stroke, and to refer patients or families to databases of ongoing clinical trials, such as ClinicalTrials.gov. Participation in clinical trials can benefit not only the scientific community (by evaluating the effects of interventions) but also the participants, who are likely to receive some sort of SLT without monetary cost. Because aphasia is associated with poor quality of life, even worse, on average, than conditions such as dementia or cancer,75 patients with post-stroke aphasia deserve an opportunity for rehabilitation regardless of the time post-stroke or severity.
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