Are pharmacotherapeutics effective for treating aphasia?

INTRODUCTION: Aphasia is a communication disorder resulting from stroke and/or neurodegenerative conditions which involve the left cerebral hemisphere. It is a debilitating disorder affecting a person's ability to speak, understand, read, and write. Its impact on daily life necessitates therapeutic strategies to aid patients with aphasia. AREAS COVERED: In this special report, the authors speculate whether current pharmacotherapeutic strategies are effective in treating aphasia. The authors look at aphasia caused by different conditions and how this could impact therapy before providing the reader with their expert perspectives. The aim of this paper is for the reader to gain a clearer understanding of the efficacy of the current pharmacotherapeutic treatment paradigms as well as potential future developments. EXPERT OPINION: The exploration of pharmacotherapy for aphasia in vascular brain disorders and neurodegenerative diseases has received much attention in recent years with various therapeutic strategies having been put forward. In terms of whether pharmacotherapy is effective for the treatment of aphasia, there is still no clear-cut answer. Further research is needed with more studies requiring a greater emphasis on language and communication deficits. Biomarkers may also help clinicians provide their patients with a more personalized treatment plan.

Supporting Post-Stroke Language and Cognition with Pharmacotherapy: Tools for Each Phase of Care.

PURPOSE OF REVIEW: There is enormous enthusiasm for the possibility of pharmacotherapies to treat language deficits that can arise after stroke. Speech language therapy remains the most frequently utilized and most strongly evidenced treatment, but the numerous barriers to patients receiving the therapy necessary to recover have motivated the creation of a relatively modest, yet highly cited, body of evidence to support the use of pharmacotherapy to treat post-stroke aphasia directly or to augment traditional post-stroke aphasia treatment. In this review, we survey the use of pharmacotherapy to preserve and support language and cognition in the context of stroke across phases of care, discuss key ongoing clinical trials, and identify targets that may become emerging interventions in the future. RECENT FINDINGS: Recent trials have shifted focus from short periods of drug therapy supporting therapy in the chronic phase to longer terms approaching pharmacological maintenance beginning more acutely. Recent innovations in hyperacute stroke care, such as tenecteplase, and acute initiation of neuroprotective agents and serotonin reuptake inhibitors are important areas of ongoing research that complement the ongoing search for effective adjuvants to later therapy. Currently there are no drugs approved in the United States for the treatment of aphasia. Nevertheless, pharmacological intervention may provide a benefit to all phases of stroke care.

Pharmacotherapy for post-stroke aphasia: what are the options?

INTRODUCTION: Aphasia is a common, long-lasting aftermath of stroke lesions. There is an increased integration of pharmacotherapy as an adjunctive strategy to speech and language therapy (SLT) for post-stroke aphasia (PSA). Nevertheless, more research in pharmacotherapy for acute and chronic PSA is necessary, including the election of drugs that target different neurotransmitter systems and deficits in specific language domains. AREAS COVERED: This article updates the role of pharmacotherapy for PSA, focusing the spotlight on some already investigated drugs and candidate agents deserving of future research. Refining the precision of drug election would require using multimodal biomarkers to develop personalized treatment approaches. There is a solid need to devise feasible randomized controlled trials adapted to the particularities of the PSA population. The emergent role of multimodal interventions combining one or two drugs with noninvasive brain stimulation to augment SLT is emphasized. EXPERT OPINION: Pharmacotherapy can improve language deficits not fully alleviated by SLT. In addition, the 'drug-only' approach can also be adopted when administering SLT is not possible. The primary goal of pharmacotherapy is reducing the overall aphasia severity, although targeting language-specific deficits (i.e. naming, spoken output) also contributes to improving functional communication. Unfortunately, there is still little information for recommending a drug for specific language deficits.

Turning the Spotlight to Cholinergic Pharmacotherapy of the Human Language System.

Even though language is essential in human communication, research on pharmacological therapies for language deficits in highly prevalent neurodegenerative and vascular brain diseases has received little attention. Emerging scientific evidence suggests that disruption of the cholinergic system may play an essential role in language deficits associated with Alzheimer's disease and vascular cognitive impairment, including post-stroke aphasia. Therefore, current models of cognitive processing are beginning to appraise the implications of the brain modulator acetylcholine in human language functions. Future work should be directed further to analyze the interplay between the cholinergic system and language, focusing on identifying brain regions receiving cholinergic innervation susceptible to modulation with pharmacotherapy to improve affected language domains. The evaluation of language deficits in pharmacological cholinergic trials for Alzheimer's disease and vascular cognitive impairment has thus far been limited to coarse-grained methods. More precise, fine-grained language testing is needed to refine patient selection for pharmacotherapy to detect subtle deficits in the initial phases of cognitive decline. Additionally, noninvasive biomarkers can help identify cholinergic depletion. However, despite the investigation of cholinergic treatment for language deficits in Alzheimer's disease and vascular cognitive impairment, data on its effectiveness are insufficient and controversial. In the case of post-stroke aphasia, cholinergic agents are showing promise, particularly when combined with speech-language therapy to promote trained-dependent neural plasticity. Future research should explore the potential benefits of cholinergic pharmacotherapy in language deficits and investigate optimal strategies for combining these agents with other therapeutic approaches.

Case Report: Possible Serotonin Syndrome in a Patient Taking Kratom and Multiple Serotonergic Agents.

INTRODUCTION: Kratom, an unregulated herbal supplement, has emerged as self-treatment for anxiety/depression. Kratom exhibits inhibition at multiple cytochrome P450 isozymes involved in metabolism of prescription medications, including serotonergic agents. We report a case of possible serotonin syndrome induced by kratom use in combination with prescription psychotropic medications. CASE: A 63-year-old male presented with diaphoresis, flushing, aphasia, confusion, dysarthria, right facial droop, and oral temperature of 39.6oC (103.2oF), lactate 2.7 mmol/L, and creatine phosphokinase of 1507 IU/L. Initial differential diagnoses included acute ischemic stroke and bacterial meningitis. Despite partial treatment with alteplase and broad-spectrum antibiotics, symptoms persisted, and subsequent physical exam noted hyperreflexia, clonus, tremors, and temperature of 41.1oC (106oF). Home medications included a chronic regimen for anxiety/depression with bupropion, buspirone, desvenlafaxine, trazodone, and ziprasidone, in addition to kratom. Clinical suspicion for serotonin syndrome led to initiation of cyproheptadine, lorazepam, and cooling blankets. Aphasia, facial droop, and confusion improved after administration of cyproheptadine. Bupropion was restarted during hospitalization; remaining medications restarted at the discretion of the primary care provider. DISCUSSION: Risk of serotonin syndrome with multiple serotonergic agents is well-known. Kratom is metabolized by cytochrome P40 isozymes 3A4, 2C9, and 2D6, and exhibits inhibition at those enzymes, in addition to 1A2. Pharmacokinetic interactions of kratom with prescription serotonergic agents metabolized through these isozymes has the potential to increase systemic exposure of serotonin, potentially leading to serotonin syndrome. CONCLUSION: Because substances contained in kratom can inhibit metabolism of prescription serotonergic medications, clinicians must be aware of potential development of serotonin syndrome.

Donepezil alone and combined with intensive language-action therapy on depression and apathy in chronic post-stroke aphasia: A feasibility study.

This study explored the feasibility and effectiveness of a short-term (10-week) intervention trial using Donepezil administered alone and combined with intensive language action therapy (ILAT) for the treatment of apathy and depression in ten people with chronic post-stroke aphasia. Outcome measures were the Western Aphasia Battery and the Stroke Aphasia Depression Questionnaire-21. Structural magnetic resonance imaging and 18fluorodeoxyglucose positron emission tomography were acquired at baseline and after two endpoints (Donepezil alone and Donepezil-ILAT). The intervention was found to be feasible to implement. Large treatment effects were found. Donepezil alone and combined with ILAT reduced aphasia severity, while apathy and depression only improved with Donepezil-ILAT. Structural and functional neuroimaging data did not show conclusive results but provide hints for future research. Given these overall positive findings on feasibility, language and behavioral benefits, further studies in larger sample sizes and including a placebo-control group are indicated.

New-onset non-lesional aphasic status epilepticus. Clinical description, diagnostic clues, and treatment algorithm.

OBJECTIVES: De novo aphasic status epilepticus (ASE) in patients without a previous history of epilepsy and without cerebral lesions (aphasic NOSE) is rare. The aim of the study is to describe its clinical characteristics, etiologies, and outcome. MATERIALS & METHODS: Single-center study including consecutive patients presenting to the emergency department between 2011 and 2019 with acute aphasia, which was finally diagnosed as aphasic NOSE. Subsequent episodes of aphasia (>5 min) were recorded and divided into confirmed ASE and postictal aphasic episodes (non-ASE). Clinical characteristics of the two types of episodes were compared. RESULTS: Nineteen patients were included, suffering fifty episodes of epileptic aphasia, episodes per patient 2.6 (range 1-7). Fifteen patients (71.4%) were women, mean age at ASE onset was 66.05 years old (SD 6.3). Nine (47%) patients died, 6 of them (66.7%) during the aphasic episode. Ictal EEG was available in 37 episodes, confirming the diagnosis of ASE in 12 episodes; in 8 episodes, the EEG fulfilled the criteria of possible ASE. The most frequent etiologies were inflammatory and vascular. Comparing ASE with non-ASE episodes, ASE was longer than non-ASE (225 vs 65 h, p .024) and was treated more frequently with BZD (76 vs 24%, p .001) but with a longer delay (22.2 vs 1.5 h, p .06). CONCLUSIONS: ASE is a treatable, highly relapsing emergency, with the subsequent relapses ASE or postictal aphasia. EEG is diagnostic in half of the patients, while in others imaging techniques are also useful. Benzodiazepines should be administered. Persistent aphasia, of more than 65 hours' duration, is highly suggestive of ASE.

Effectiveness of Atomoxetine (Strattera) for the Treatment of Poststroke Aphasia Combined With Cognitive Impairment.

OBJECTIVE: In this study, we aimed for the first time to evaluate the effectiveness of atomoxetine (Strattera) in the treatment of cognitive impairment and aphasia after stroke in a large sample. METHODS: We reviewed the data of 106 patients with poststroke aphasia and cognitive impairment (atomoxetine treatment group = 55 patients vs control group = 51 patients), including scores of the Korean version of the Mini-Mental State Examination (K-MMSE) and the Korean version of the Western Aphasia Battery. Wilcoxon signed-rank tests were used to compare the initial and follow-up K-MMSE and Korean version of the Western Aphasia Battery scores. Mann-Whitney U tests were used to compare the degree of improvement in K-MMSE and Aphasia Quotient (AQ) scores between the atomoxetine and control groups. RESULTS: Baseline characteristics including age, years of education, and scores of the initial Functional Independence Measure, Korean version of the Modified Barthel Index, Hamilton Depression Rating Scale, K-MMSE, and AQ did not differ significantly between the 2 groups. Follow-up K-MMSE and AQ scores were significantly better than the initial scores in both the treatment and control groups. However, improvements in K-MMSE scores were significantly greater in the treatment group than in the control group. In addition, the atomoxetine group had significantly higher AQ scores than the control group, especially for auditory verbal comprehension and naming. CONCLUSIONS: Atomoxetine has been shown to significantly improve cognitive function and language in patients with poststroke aphasia. It is also the first study to report improvement in auditory comprehension and naming by administration of atomoxetine.

Better language through chemistry: Augmenting speech-language therapy with pharmacotherapy in the treatment of aphasia.

Speech and language therapy is the standard treatment of aphasia. However, many individuals have barriers in seeking this measure of extensive rehabilitation treatment. Investigating ways to augment therapy is key to improving poststroke language outcomes for all patients with aphasia, and pharmacotherapies provide one such potential solution. Although no medications are currently approved for the treatment of aphasia by the United States Food and Drug Administration, numerous candidate mechanisms for pharmaceutical manipulation continue to be identified based on our evolving understanding of the neurometabolic experience of stroke recovery across molecular, cellular, and functional levels of inquiry. This chapter will review evidence for catecholaminergic, glutamatergic, cholinergic, and serotonergic drug therapies and discuss future directions for both candidate drug selection and pharmacotherapy practice in people with aphasia.

Protocol for Escitalopram and Language Intervention for Subacute Aphasia (ELISA): A randomized, double blind, placebo-controlled trial.

In this forthcoming multicenter, prospective, randomized, double-blind placebo-controlled trial, we will investigate the augmentative effects of a selective serotonin reuptake inhibitor, escitalopram, on language therapy in individuals with post-stroke aphasia. We hypothesize that, when combined with language therapy, daily escitalopram will result in greater improvement than placebo in an untrained picture naming task (Philadelphia Naming Test short form) administered one week after the end of language therapy. We also will examine whether escitalopram's effect on language is independent of its effect on depression, varies with lesion location, or is associated with increased functional connectivity within the left hemisphere. Finally, we will examine whether individuals with BDNF met alleles show reduced response to treatment and reduced changes in connectivity. We expect to enroll 88 participants over four years. Participants are given escitalopram or placebo within one week of their stroke for 90 days and receive fifteen 45-minute computer-delivered sessions of language treatment beginning 60 days from the start of drug therapy. Patients then complete a comprehensive assessment of language at one, five, and twenty weeks after the last language therapy session. ELISA is the first randomized, controlled trial evaluating the effect of a selective serotonin reuptake inhibitor on the improvement of language in people with aphasia undergoing language treatment during the acute to subacute post-stroke period. Trial registration: The trial is registered with ClinicalTrials.gov NCT03843463.

Tratamientos para la depresión para personas con afasia post-ictus / Depression treatments for people with post-stroke aphasia

No hay una clara epidemiología sobre la depresión en la afasia post-ictus, pero se estima que se da en uno o dos tercios de los casos. No solo afecta al estado emocional, también limita la recuperación ante la rehabilitación. El tratamiento de la depresión post-ictus es un reto a causa de los efectos adversos, interacción de la farmacoterapia y las dificultades para evaluar los resultados clínicos. El objetivo era conocer los tratamientos no farmacológicos disponibles para estos pacientes. Para ello, se realizó una busca sistemática por palabras clave en bases de datos especializadas online seleccionando materiales de hasta 5 años atrás, dónde 10 estudios cumplieron los criterios de inclusión y exclusión. Las intervenciones halladas muestran la importancia de la intervención multidisciplinar dado que la mayoría de estudios trabajan de manera síncrona lenguaje y depresión. Los estudios tienen grandes limitaciones metodológicas y hacen presente la necesidad de futuras investigaciones de calidad.(AU)

A case of reversible aphasia-type speech disorders after treatment with quetiapine. / Odwracalna afazja po leczeniu kwetiapina ­ opis przypadku.

The study presents a case of a 64-year-old patient with diagnosed Parkinson's disease and coexisting REM sleep disorders (RBD) confirmed in a polysomnographic examination. In this patient, the use of supplementary therapy - quetiapine (50mg/daily) - due to psychotic disorders, resulted in speech disorders with sensory-motor mixed aphasia type. Aphasia occurred on the fourth day after beginning the treatment with atypical neuroleptic. In MRI examination of the head, no "fresh" cerebral ischemia was found. No focal status epilepticus was reported in the video EEG trial. Results. Complete cure occurred after discontinuation of quetiapine administration. Conclusions. Due to the above, the side-effects of quetiapine treatment were assumed as the cause of focal neurological disorders.

[Developmental dysphasia in children: a comparison of the effectiveness of two modes of peptidergic nootropic therapy]. / Disfaziya razvitiya u detei: sravnenie effektivnosti dvukh rezhimov peptidergicheskoi nootropnoi terapii.

OBJECTIVE: To study the therapeutic efficacy of two treatment modes of peptidergic nootropic medication cortexin in children with developmental dysphasia aged 3-4 years. MATERIAL AND METHODS: Ninety-four children with developmental dysphasia were divided into three groups. In group 1 (27 patients), cortexin was administered once a day intramuscularly for 10 days. After this course, the children were not prescribed drug therapy, a second examination was carried out 2 months after the start of treatment. In group 2 (40 patients), two courses of cortexin were administered at 1-month intervals, and the children were also followed up for two months. Control group 3 (27 patients) did not receive medication, but was also followed up for two months. All the parents were provided with recommendations for the stimulation of speech development in children. Before the study and two months later, speech development was assessed with special scales and questionnaires for parents. RESULTS: The increase ratio of the active vocabulary volume by 2 times or more was observed in group 2 (two courses of cortexin treatment) in 80.0% of patients (significant differences with groups 1 and 3, p<0.001), in 44.4% of group 1 (one course of cortexin), in 22.2% of the control group. Over a two-month period, the increase ratio in the active vocabulary and the number of uttered phrases in group 2 was 2.8 and 4.2 times, in group 1 2.3 and 3.6 times, respectively, in the control group it was only 1.4 and 1.5 times. Furthermore, the volume of active vocabulary in group 2 (42.4±3.6) became significantly larger (p=0.01) than in group 1 (31.7±5.6), although its initial values in group 1 (13.7±1.8) and group 2 (14.9±1.7) were similar. CONCLUSION: The results of the study confirm the higher effectiveness of two courses of the peptidergic nootropic medication cortexin in the pharmacotherapy of developmental dysphasia in children, aged 3-4 years, conducted over two months, compared with the indication of one treatment course.

Aphasia and confusion - influenza encephalopathy: atypical presentation of influenza.

Influenza encephalopathy, a rare manifestation of influenza infection in the adult population which is not widely recognised, can present with confusion and focal neurological symptoms, including aphasia. The aim of this report is to illustrate the unique presentation of influenza encephalopathy and discuss the need for close attention to and monitoring of this rare but highly fatal disease.A 28-year-old woman was admitted with acute-onset confusion and incoherent speech. CT of the head was unremarkable. Cerebrospinal fluid analysis showed elevation of protein, but was otherwise unremarkable. A detailed history revealed recent upper respiratory symptoms which prompted a rapid influenza test which was positive and oseltamivir was started. The patient's confusion and aphasia gradually improved and her speech was back to her baseline by the next day.

[Potential of peptidergic nootropic therapy in developmental dysphasia in children]. / Vozmozhnosti peptidergicheskoi nootropnoi terapii pri disfazii razvitiia u detei.

AIM: To study the therapeutic efficacy of peptidergic nootropic medication Cortexin during two-month follow-up in children with developmental dysphasia aged 3-4 years. MATERIAL AND METHODS: Fifty-four children with developmental dysphasia were randomized into two equal groups. The cortexin group received the drug once daily intramuscularly during 10 days. After this course, children did not receive any pharmacotherapy and were examined two months after the beginning of treatment. The control group did not receive pharmacotherapy and was examined twice in two months interval. All the parents were provided with recommendations for the stimulation of speech development in dysphasic children. Before treatment and two months later, speech development was assessed by special scales and questionnaires for parents. RESULTS AND CONCLUSION: After treatment with Cortexin, a significant improvement was achieved not only on the 'expressive language' scale but also on the 'attention to speech' and 'impressive language' scales. The volume of active vocabulary was increased by 2.3 times, the number of articulated phrases by 3.6 times. The evaluation of parents' questionnaires demonstrated the decrease of cerebrasthenic, psychosomatic problems, motor clumsiness, hyperactivity, attention deficit and problems with emotional control in children. The therapy contributed to the reduction of difficulties in communication and social adaptation. The positive effect of Cortexin was observed after the completion of treatment (the protracted effect).

The Efficacy and Safety of Pharmacological Treatments for Post-stroke Aphasia.

BACKGROUND: Aphasia is a common complication after stroke, and traditional speech and language therapy (SLT) has a limited effect on post-stroke aphasia (PSA). While there has been an increasing number of controlled clinical trials on the efficacy of drugs in the treatment of PSA, there have been very few systematic reviews on the efficacy and safety of pharmacological treatments in people with PSA. OBJECTIVE: To evaluate the efficacy and safety of pharmacological interventions for PSA. METHODS: The Cochrane Central Register of Controlled Trials (CENTRA), PubMed, Embase, Chinese Journal Full-text Database (CJFD), China Biology Medicine disc (CBMdisc), Wanfang Data and VIP Information System were searched for randomized controlled trials about pharmacological treatments for PSA. Literature screening using the inclusion and exclusion criteria, data extraction and methodological quality assessment of the included studies were completed by two independent reviewers. Methodological quality was considered high for modified Jadad quality scale scores of 4 to 7. RevMan 5.3 software was used to conduct a meta-analysis of high-quality studies. RESULTS: Fifteen studies (578 participants) satisfied the eligibility criteria for this systematic review. Five trials (277 participants) assessed donepezil, four studies (124 participants) assessed memantine, three studies (72 participants) assessed bromocriptine, one trial (45 patients) evaluated galantamine, one study (21 patients) evaluated amphetamine, and one trial (39 patients) evaluated levodopa. The systematic review showed that donepezil achieved remarkable results in terms of the aphasia quotient (AQ) (SMD 0.82, 95% CI 0.48-1.17, P < 0.00001), repetition ability (SMD 0. 81, 95% CI 0.57-1.06, P < 0.00001), naming ability (SMD 0.56, 95% CI 0.29-0. 84, P < 0.00001), auditory comprehension (SMD 0.85, 95% CI 0.58-1. 13, P< 0.00001) and oral expression (SMD 0.90, 95% CI 0.54-1.26, P < 0.00001). Memantine showed no pronounced improvement in auditory comprehension (SMD 0.35, 95% CI -0.05-0.74, P = 0.09) but did improve the AQ (SMD 0.57, 95% CI 0.09-1.06, P = 0. 02), naming ability (SMD 0.81, 95% CI 0.38-1.25, P = 0.0002), spontaneous speech (SMD 0.76, 95% CI 0. 39- 1.13, P < 0.0001), and repetition ability (SMD 0.37, 95% CI 0.01-0.73, P = 0.04). Bromocriptine showed pronounced improvement in naming ability (SMD -0.20, 95% CI- 0.67-0.26, P = 0.39), verbal fluency (SMD 0.02, 95% CI 0.53-0.56, P = 0.95), and repetition ability (SMD 0.29, 95% CI -0.23-0. 81, P = 0.28). There is limited and inconclusive evidence for galantamine, amphetamine and levodopa. CONCLUSION: Current evidence suggests that drugs, such as donepezil and memantine, can improve the prognosis of PSA. Donepezil has a significant effect in improving the ability of auditory comprehension, naming, repetition and oral expression. Memantine has a significant effect in improving the ability of naming, spontaneous speech and repetition. Bromocriptine showed no significant improvements in the treatment of aphasia after stroke. Data regarding galantamine, amphetamine and levodopa in the treatment of aphasia after stroke are limited and inconclusive.