Pharmacology in aphasia

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Pharmacology in Aphasia Treatment andRecovery

May 2014

Sharon Rennhack, Newsletter Editor and Practice

Coach

William Connors, MACCC-SLP , Owner

The Aphasia Center of Innovative Treatmentwww.aphasiatoolbox.com

Phone:724-494-2534

Email:[email protected]

Please note that this report contains no medical or health careadvice. See disclaimer below.


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1. Introduction:

In their recovery process, most people with aphasia (PWA) undergo speech and

language therapy. A few may also supplement their communication experiences usingAugmentative and Alternative Communication (AAC). Sadly, recovery of language

skills may well be a slow, tedious and most-often-times frustrating process.Moreover, the percentage of PWA who successfully and comfortably use AAC foreveryday communication is very, very low. So caregivers and PWA rightfullyinvestigate all alternatives (outside of traditional treatment) to supplement therecovery process.

If only there was a pill to take!

In this article and the related drug profiles, we review some of the evidence fromclinical trials concerning aphasia treatment and therapy. Certain drugs have beentrialed, including dopaminergic, cholinergic, and stimulant drugs, without clear

benefits shown. Both small- and large-scale clinical trials of treatments for aphasiahave been reported. Some of the small scale trials suggest benefit.

Some of the studies are testing how drugs can be used in combination with speechtherapy to improve recovery of various language functions. The concern here is thatit appears to be impossible to separate the positive effects on recovery thatmedication from that of treatment/practice. Additionally, some researchers have beenlooking at how treatment of other cognitive deficits such as attention, memory,cognitive flexibility and executive functions can improve communication abilities.

A very recent study on pharmacology in aphasia treatment and recovery (Aphasiology,2014) offers some hope, but seems to indicate that all the studies to date still

leave important questions unanswered. Response to medication seems to be quitedependent on the individual, and seems to work best when combined with speech-language treatment that exploits neuroplasticity effectively. Results are oftenequivocal, vague and/or confusing.


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2. Sharons Research on Pharmacology in Aphasia Treatment and

Recovery

This section reviews some of the drugs used in clinical trials.

Included are:

a. Piracetam

b. Bromocriptine

c. Donepezil

d. Amphetamines - Dextroamphetamine and Methylphenidate

e. Memantine

f. Perispinal Etanercept


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a. Piracetam

Piracetam is a gaba-aminobutyrate derivative, meaning that it is related to GABA, a

neurotransmitter that blocks impulses between nerve cells in the brain. The drug isprescribed by doctors for some conditions, mainly myoclonus, a involuntary jerking of

a muscle or group of muscles., but is used off-label for a much wider range ofapplications.

Piracetam is thought to improve learning and memory by facilitating release ofacetylcholine and excitatory amino acids, with increases in blood flow and energymetabolism.

The drug stimulates, increases, and improves the functions in acetylcholine receptors.

Concerning its application to aphasia, in a Cochrane review of 52 studies, onlyPiracetam had some beneficial effects on language abilities when given to people with

aphasia following stroke . The authors identified 10 studies that were suitable forreview. Drugs that were used in the selected trials were piracetam, bifemalane,piribedil, bromocriptine, idebenone and Dextran-40. However, it should be noted thatthe only pharmacological treatment for aphasia available in Canada is bromocriptine.

The authors found that in most trials, the methodological quality was not measurablewith only one study providing adequate data for review and analyses.

Sources:

1. Pharmacological treatment for aphasia following stroke. Cochrane Database ofSystematic Reviews 2001, Issue 4.

http://summaries.cochrane.org/CD000424/pharmacological-treatment-for-aphasia-

following-stroke

2. Piracetam Improves Activated Blood Flow and Facilitates Rehabilitation of Poststroke Aphasic Patients, Stroke, 2000; 31: 2112-2116

http://stroke.ahajournals.org/content/31/9/2112.abstract


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b. Bromocriptine

Bromocriptine is a dopamine agonist, meaning that it increases dopamine-relatedactivity in the brain, by activating dopamine receptors in the absence of dopamine.Unlike levodopa, a dopamine agonist is not changed (converted) into dopamine when

it enters the body, but it behaves like dopamine.

The drug is used in the treatment of pituitary tumors, Parkinson's disease (PD),hyperprolactinaemia, neuroleptic malignant syndrome, and type 2 diabetes.

There has been strong evidence that Bromocriptine does not improve aphasiarecovery post-stroke. However, Galling et al 2014 suggested in a single case study thebenefits of Bromochriptine for treating a non fluent patient mentioning it may also behelpful for transcortical motor or initiation problems.

In this single case study, the combined use of speech and language therapy with

Bromocriptine provided clear improvements in the participant's overall behaviors andspecifically in her verbal output.

A Berthier study in 2005 also mentioned Bromochriptine being effective for non fluentPWA who have trouble initiating. In previous studies, though, Bromocriptine was usedto treat people with non-fluent aphasia with varying levels of success.

Another recent study looked at the use of dopaminergic therapy with ParkinsonsDisease patients.

Sanchez found that Parkinsons Disease patients produced discourse that was moreefficient and coherent when the patients were on dopaminergic therapy. Studies have

demonstrated that dopaminergic medication can improve working memory andexecutive processes and therefore discourse which depends upon cognitive processes.

Sources:

1. Galling et al, A clinical study of the combined use of bromocriptine and speechand language therapy in the treatment of a person with aphasia, ,Aphasiology, Volume 28, Issue 2, 2014, pages 171-187,http://www.tandfonline.com/doi/full/10.1080/02687038.2013.838616#.U3_TXfldXj

2. Berthier ML., Drugs Aging. 2005;22(2):163-82, Poststroke aphasia:epidemiology, pathophysiology and treatment,http://www.ncbi.nlm.nih.gov/pubmed/15733022

3. Sanchez, J. et al, Preliminary evidence of discourse improvement withdopaminergic medication, Advances in Parkinsons Disease,Vol.2, No.2, 37-42 (2013)


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c.Donepezil

Donepezil is an oral medication used to treat Alzheimer's disease. It belongs to a classof drugs called cholinesterase inhibitors that also includes tacrine (Cognex).

Scientists believe that Alzheimer's disease may result from a deficiency in chemicals(neurotransmitters) used by nerves in the brain to communicate with one another.Donepezil inhibits acetylcholinesterase, an enzyme responsible for the destruction ofone neurotransmitter, acetylcholine. This leads to increased concentrations ofacetylcholine in the brain, and the increased concentrations are believed to beresponsible for the improvement seen during treatment with donepezil. The FDAapproved Donepezil for AD in 1996.

A Berthier 2005 study indicated that Donipezil might possibly have positive effectswhen used in post-stroke aphasia. A small, randomized trial suggested that Donepezil

might aid recovery by "promoting both a reorganization of cortical networks and abetter control of regional cerebral blood flow regulation.

Berthier and colleagues randomly assigned 26 patients with post-stroke aphasia thathad lasted for at least 1 year to receive either placebo or Donepezil at 5 mg/day for 4weeks and then 10 mg/day for 12 weeks, followed by a 4-week washout period.

During the study, all patients undertook standard speech-language therapy for 2hours per week. Severity of aphasia, measured at week 16 using the AphasiaQuotient of the Western Aphasia Battery, improved significantly more in patientstreated with Donepezil than in those who received placebo, at 6.4 versus 3.5 points.

In addition, the scores in the picture naming subset of the PsycholinguisticAssessment of Language Processing in Aphasia improved by 4.6 points in thedonepezil-treated group, but deteriorated by 1 point in placebo-treated patients.

The researchers report: "Between-group differences were no longer significant atweek 20 for most outcome measures, thus suggesting that Donepezil enhanceslanguage and communication performance only when it is being taken."

Source:

Berthier ML, , Poststroke aphasia : epidemiology, pathophysiology and treatment,Drugs Aging. 2005;22(2):163-82


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d.Amphetamines - Dextroamphetamine and Methylphenidate

Amphetamines belong to the general group of sympathomimetic amines, a group of

stimulants that stimulate the sympathetic nervous system, increasing mentalalertness, and increasing blood flow to muscles. These drugs used in aphasia therapy

include Dextroamphetamine and Methylphenidate.

Dextroamphetamine is used for the treatment of ADHD and narcolepsy.Dextroamphetamine may be used under circumstances other than (indicated) for off-label use in the following conditions:

Depression Autism Fragile X syndrome Developmental disabilities Stroke recovery

There is moderate evidence that dextroamphetamine improves aphasia recovery whencombined with language therapy. Administration of dextroamphetamine paired with10 1-hour sessions of speech/language therapy facilitated recovery from aphasia in asmall group of patients in the subacute period after stroke.

Methylphenidate, an amphetamine, blocks the reuptake of serotonin andnorepinephrine, and has dopaminergic activity as well. The drug is a psychostimulantdrug and substituted phenethylamine approved for treatment of attention-deficithyperactivity disorder (ADHD), postural orthostatic tachycardia syndrome andnarcolepsy. ADHD and other similar conditions are believed to be linked to sub-performance of the dopamine and norepinephrine functions in the brain, primarily in

the prefrontal cortex, responsible for self-regulation functions of inhibition, motivation,memory, and the concentration/executive functions of reasoning, organizing, solving,and planning.

Methylphenidate has been used to treat aphasia; however, this has not been provenbeneficial for all aphasia patients. Only a portion of the studies conducted have hadpositive reports on its benefits for this condition.

Sources:

1. Walker-Batson, D. et al, A Double-Blind, Placebo-Controlled Study of the Use ofAmphetamine in the Treatment of Aphasia, Stroke, 2001; 32: 2093-2098

2. Grade C. et al, Methylphenidate in Early Poststroke Recovery: A Double-Blind,Placebo-Controlled Study, Arch Phys Med Rehabil 1998;79: 1047-50


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e. Memantine

Memantine is used to treat the symptoms of Alzheimer's disease (AD; a brain diseasethat slowly destroys the memory and the ability to think, learn, communicate and

handle daily activities). Memantine is in a class of medications called NMDA receptorantagonists. It works by decreasing abnormal activity in the brain. Memantine mayimprove the ability to think and remember or may slow the loss of these abilities inpeople who have AD. However, Memantine will not cure AD or prevent the loss ofthese abilities at some time in the future.

Memantine has shown promising results on several measures of language andcommunication in clinical trials.

In a Berthier 2009 study, both Memantine and constraint-induced aphasia therapyalone improved aphasia severity, but best outcomes were achieved combining

Memantine with CIAT. Beneficial effects of Memantine and CIAT persisted on long-term follow-up.

Source:

1. Berthier ML et al, Memantine and constraint-induced aphasia therapy in chronicpoststroke aphasia, Ann Neurol. 2009 May;65(5):577-85


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f. Perispinal Etanercept

The drug Etanercept, known by its brand name Enbrel, has been proven effective inneutralizing Tumor Necrosis Factor or TNF; this is the chemical process that causesthe inflammatory response in the body. The drug has Food and Drug Administrationapproval for treating rheumatoid arthritis and psoriasis; However, the drug's use by

injection for stroke and aphasia is considered to be off-label and is not FDA-approved.

Dr. Edward Tobinick, the man behind the use of Perispinal Etanercept, is the founderand director of the Institute for Neurological Research, a private medical group. In histreatment, Tobinick injects the medicine at the back of the neck, then dips the patientbackward at a 45-degree angle. In about five minutes, the drug enters the brain andspinal area through the cerebrospinal venous system and the cerebrospinal fluid;reportedly according to Dr. Tobinicks work, the injection instantly fights the residualinflammation.

A peer-reviewed study published in December 2012 said:

Tobinick's Institute of Neurological Recovery gave Etanercept injections fromNovember 2010 to July 2012 to 617 stroke patients and 12 patients who hadsuffered a traumatic brain injury. Of the total studied, more than 80 percentsaw improvements in their ability to walk; more than 80 percent had lessspasticity; and more than 85 percent exhibited improved motor function.Improvements also were recorded in many patients' range of motion, pain andcognition, as well as their ability to speak, see, swallow, concentrate andmaintain bowel control."

According to Tobinick, some people are satisfied after a single dose. He recommends asecond injection after one month if patients want additional improvement; about a

quarter of his patients choose the second shot. Reportedly, the first patients treatedin November 2010 continue to enjoy improved mobility and cognition.

We need to carefully watch the research concerning the use of Perispinal Etanercept,since the research to date comes from one source - Dr. Edward Tobinick.

Sources:1.Ignatowski T. et al, Perispinal Etanercept for Post-Stroke Neurological and CognitiveDysfunction: Scientific Rationale and Current Evidence, CNS Drugs. 2014 May 27.http://www.ncbi.nlm.nih.gov/pubmed/24861337

2.Tobinick E. et al, Selective TNF inhibition for chronic stroke and traumatic brain injury:an observational study involving 629 consecutive patients treated with perispinaletanercept., CNS Drugs. 2012 Dec;26(12):1051-70. doi: 10.1007/s40263-012-0013-2.http://www.ncbi.nlm.nih.gov/pubmed/23100196


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3. BillsSummary Thoughts and Recommendations

1. First do no harm of course.Do any of your medical / physical conditions contraindicate the use of medications

mentioned in this document? Be sure that all of your physicians and health careproviders are aware of all of your medications. Make sure that everyone is aware ofany possible troublesome drug interactions.

2. If all is ok, it may be worth a try. As noted in all the studies, it is very difficult ifnot impossible to separate the effects of medication from treatment fromphysical/neuroplastic recovery over time. Be sure to note some baseline observationsin order to judge any effectiveness.

3. Some studies saw possible progress in anterior or frontal lesions.

4. Reviews seemed to question the methodology of all the studies.

5. My personal anecdotal experience with using pharmacology with peoplewith aphasia (PWA) has been inconsistent. Some clients/caregivers thoughtthat the meds helped, others could not tell. Most gave up the efforts after awhile. Of2 clients who received Perispinal Etanercept injections, one thought there wasimprovement in initiation of actions and speech, while the other thought there wasimprovement in balance and smell.


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4. Bills Research Notes on the six drugs in question:

A very recent study on pharmacology in aphasia treatment and recovery(Aphasiology, 2014) Fig 1 offers some ..hope.. but seems to indicate that all the

studies to date still leave important questions unanswered. Response to medicationseems to be quite dependent on the individual, and seems to work best whencombined with speech-language treatment that exploits neuroplasticity effectively.Results are often equivocal, vague and/or confusing. Fig 1

Concerning Piracetam, the results have been equivocal. A study by Huber from1999 did show some positive benefits. The PWA ranged from the acute 23 yearspost-onset. Fig. 2

This was supported by a 2000 study in STROKE by Kessler et al Fig 3

A later study by Berthier 2005 suggested that Piracetammay have value early onbut its efficacy vanishes in patients with chronic aphasia. Fig. 4

The Berthier 2005 study also mentioned Bromochriptineperhaps being effective butfor non fluent PWA who have trouble initating. Dexanfetamineand Donipezilwerealso mentioned as having possible positive effects. The operative word it POSSIBLE.

Galling et al 2014 suggested in a single case study the benefits of bromochriptinefor treating a non fluent patient mentioning it may also be helpful for transcorticalmotor or initiation problems. Fig 5

A Chochrane review study in 2001 questioned the research methodology of the

studies done to that date raising questions as to sorting the difference betweentreatment and medicine Fig 6

A review study by Tocco et al in 2014 suggested that Mematrinemay have postitiveeffects for PWA with chronic aphasia (including clients with Alzheimers disease andother neurological conditions). Fig 7

Dr. Martin Albert from Boston 2014 suggested that perhaps pharmacology can redusethe stress of linguistic anxiety PWA may experience Fig8

Fig 9 represents a recent study using Piracetamthat was discontinued. I could not

find out why it was discontinued.

A Brain and Languge study found that none of the studies were indubitable forpositive results. : - ) What language jargonish language. So they found no solidevidence that medicine helps but perhaps might in combination with SLP treatment.Fig 10

The use of dompaminergic drugs in treatment of PWA has shown mixed resultsaccording to a 2014 study. Fig 11


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Seniow et al combined SLP treatment with levodopa (used a contol group who tookplacebo) and reported some positive results especially with PWA who had moreanterior / frontal lesions. Fig 12

Gungor et al in 2011 in a German study seemed to find only improvement in auditory

comprehension using Piracetam Fig 13

A report in Drugs and Aging 2005 suggested donepezilmay have positive effects andthat Piracetemlost its positive effect with chronic aphasia. Fig 14

Aphasiatoolbox believes that customers need to carefully watch the researchconcerning the use of Perispinal Etanercept; the research to date comes from onesource - Dr. Edward Tobinick. Fig 15, Fig 16

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5. Conclusion

This report provides a review of the literature and clinical trials covering theuse of pharmacology in aphasia treatment covering 6 drugs..

We have found that results of these studies are often equivocal, vague or ambiguous.

If you have questions about our report - "Pharmacology in Aphasia Treatment &Recovery", please contact us at:

[email protected] call us at 724-494-2534.


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Addendum:Clinical Trials and Studies

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Fig 9

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Fig 11

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Fig 13

Fig 14 Drugs and Aging 2005


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Fig 15

Fig 16.


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Addendum: OtherResearch and Sources

1 . Pharmacology and Aphasia, [Hardcover], Marcelo L. Berthier (Editor), Guadalupe

Davila (Editor), To be published: 1 0 November 2014ISBN-1 0:1 1 387 99882 | ISBN-1 3: 97 8-1 1 387 99882|

This book provides clinicians and researchers with the current state-of-the-art on thepharmacological treatment of aphasia. This book was originally published as a specialissue of Aphasiology .

2. Engelter S. T, European Journal of Physical Rehabilitation Medicine, 2013 49:261 -7 , Safety in Pharmacological Enhancement in Stroke Rehabilitation

3. Teasell R. et al, Evidence-Based Review Of Stroke Rehabilitation, Chapter14_Aphasia, (13th Edition) Sept 2013 http://ebrsr.com/evidence-review/14-aphasia


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Pharmacology in aphasia