Cognitive Assessment in Amyotrophic Lateral Sclerosis Patients

8/12/2019 Cognitive Assessment in Amyotrophic Lateral Sclerosis Patients

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Cognitive Assessment in Amyotrophic Lateral Sclerosis Patients

Daniel Howard

University of Wisconsin-Madison118 Buck Cole, 625 Elm Drive

Madison, WI [email protected]

Abstract

Cognitive and behavioral impairment has been frequentlyobserved in cases of Amyotrophic Lateral Sclerosis (ALSor Lou Gehrigs Disease). However, standard neuropsycho-logical assessments are not designed to accommodate pa-tients with paralysis and difculty with speech production inlate-stage ALS. Without standardized assessment protocols,many research studies must implement their own assessmenttechniques that often introduce forms of testing bias. Eye-tracking (ET) and brain computer interface (BCI) technolo-gies have been suggested as viable solutions. This paper in-vestigates various cognitive and behavioral assessments thatcould incorporate these new technologies and minimize test-ing bias. In conclusion, assessment tasks should be designedto eliminate activities involving free recall, scoring factorsbased on time, and dexterity dependent tasks.

IntroductionAmyotrophic Lateral Sclerosis (ALS) is a progressive neu-rodegenerative disease involving motor neurons in the cere-bral cortex, corticospinal tracts, brainstem, and spinal cord

(Cipresso et al. 2011). As the disease progresses, vari-ous motor functions begin to weaken, leading to paralysis.A common, but not always consistent, progression of mo-tor function loss is hand dexterity, bipedal movement, facialexpressions, difculty swallowing (dysphagia), and speechproduction (dysarthria). The disease is called bulbar-onsetALS if speech production is affected rst. Eventually, thedisease is fatal due to respiratory failure. At this time, thereis no denitive cause of ALS but some studies attributehigher risk factors to genetics and familial inheritance, lead-ing to what is known as familial ALS or FALS. Otherwise,if there is no familial history, then then it is sporadic ALS orSALS (Talbot 2011).

In most cases, patients and their family members or ac-

quaintances only associate a loss of motor control with ALS.Essentially, even though the patient will no longer be able tomove and communicate, it is often believed that the entiretyof the person, personality and thought processes, are still thesame prior to the onset of the disease. Once all motor con-trol is lost, the individual is said to have locked-in syndromeor LIS (Laureys et al. 2005).

In memory of my father and musician, Terald W. HowardCopyright c 2013, All rights reserved.

However, recent evidence have shown that ALS is as-sociated with certain degrees of cognitive impairment andbehavioral changes (Phukan, Pender, and Hardiman 2007).Still, is this correlation a direct result of the progression of the ALS disease or is it the result of other outside factors?One alternative explanation could result from the locked-incondition. For example, a patients regularly normal cog-nitive functions and activities would atrophy due to disuse,i.e. verbal skills would diminish because an ALS patienthas fewer opportunities or isnt even able to engage in con-versations. Another possibility is a shift in behavior due toan apathetic state. Pointedly, depression could manifest andintensify over the course of a fatal diagnosis such as ALS.

One nal possibility, which will be the focus of this paper,is the suitability of the cognitive assessments chosen and ad-ministered to ALS patients. This point is particularly impor-tant because the symptoms of ALS already result in slower,more difcult motor control which impacts many well es-tablished cognitive assessment tests (Cipresso et al. 2011).

As a solution, there do exist a few alternative means toperform these tests, such as with the use of eye-tracking (ET)

technology and brain computer interfaces (BCIs). But, doesthe implementation of these technologies interfere with andaccount for how muscle control, and thus reaction time, isslowed in ALS patients compared to control group test subjects? This paper will analyze many various cognitive func-tion tests and their methods with the purpose to identify thesuitability in their use for testing ALS patients.

Note: Due to the availability and longitudinal nature of scientic studies involving persons diagnosed with ALS, aswell as the time frame for research allotted to this project, Iwill approach this problem primarily as a literature review.

BackgroundThe eld of assessing intelligence and cognitive function hasa long and established history. The rst known and recordedattempt at dening standardized tests such as an IQ test wasdone by Sir Francis Galton in 1882 (Gillham 2001). Besidesassessing intelligence, different tests have also been devel-oped to evaluate normal cognitive functions such as memoryretention and recall, verbal uency, attention, abstract rea-soning, behavior, and personality. These tests can be useful


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tools for many health practitioners such as when diagnosingAlzheimers Disease.

Another avenue being explored with cognitive assessmentinvolves patients with neurodegenerative diseases such asALS. This research is important since links have been hy-pothesized and in some cases validated regarding cogni-tive impairment and survivability of ALS patients (Hu etal. 2013; Olney et al. 2005). Since the specic causes of

ALS are still largely unknown, gaining further understand-ing in the diseases symptoms may shed some new light onthe problem. This may allow health professionals to betterdiagnose and eventually treat or even prevent the disease alltogether.

Additionally, the implications for patients who are cog-nitively impaired introduce greater concern when healthcaredecisions need to be made. If a patient has deteriorating cog-nition or executive function, decision making abilities couldbe compromised in regards to healthcare choices, nancialobligations, and end-of-life decisions. Besides the quality of life for the patients themselves, patients who exhibit formsof dementia place a higher burden on caretakers who mustwork daily with ALS patients (Phukan, Pender, and Hardi-

man 2007).Unfortunately, many established tests for cognitive func-tion were developed with the expectation that patients havecontrol over motor functions and a ability to speak (Cipressoet al. 2011). During the progression of ALS, many patientsdevelop paralysis and lose motor control, including speech.In this way, many ALS patients eventually become locked-in, wherein the patient is locked into their own mind, withlittle ability to communicate with the outside world. Some-times, the only form of communication ALS patients willhave is a blink or movement of the eye. A common solutionto restore communication in this instance is to have a care-taker read through the alphabet by order of letter frequency,where the LIS patient will blink at the appropriate letter.

However, since many neuropsychological tests require morecomplex forms of motor response, locked-in patients mayperform poorly on these exams, even after corrections andadjustments for communication factors and motor speed aremade.

However, other methods of interaction have been devel-oped and appear promising for communicating with locked-in patients. Some options feature eye tracking (ET) technol-ogy that use a camera pointed at a patients eye and mapswhere a person is looking on a computer screen. Still, mov-ing and situating an ALS patient into position with an ETmachine then calibrating it to their eye can be a tedious andtime consuming process. In normal healthcare, the use of an external device is only a last resort if all other means of

determining what a patient needs has been exhausted.Another option is brain computer interfaces (BCIs). Uti-

lizing trained personnel, BCIs can be calibrated to eachindividuals response patterns. Patients can learn to self-regulate their slow cortical potentials (SCPs) and/or senso-rimotor rhythms (SMRs) with combination of the often uti-lized evoked P300 potential in reaction to rare stimuli. Allthese signals are a member of the family of event-relatedbrain potentials (ERPs) found in an electroencephalogram

(EEG). It has been shown that apart from individuals in acomplete locked-in state (CLIS), i.e. a vegetative or co-matose state with persisting conscious cognitive function,patients can be successfully trained in operating a BCI de-vice (Kbler and Birbaumer 2008).

However, cases have shown that approximately ten per-cent of healthy individuals do not produce a robust P300signal. Plus, some studies show that ALS patients feature

less typical ERPs. Particularly, bulbar-onset ALS patientsalso showcase longer P3 latency and lower ERP amplitude.These setbacks could be signicant road blocks when imple-menting a BCI with an ALS patient (Cipresso et al. 2011).

Besides the above issues, BCIs can minimally be pro-grammed to allow basic communication in the form of yesor no responses. However, the problem is to advance beyondthis binary output since even locked-in patients can ordinar-ily manage yes/no responses without the aid of a machine,i.e. one blink no, two blinks yes. In essence, it becomes thepractitioners responsibility to design and implement com-munication channels with greater versatility than a simpleafrmative and negative response. In this way, extra caremust be taken when performing cognitive assessments on

patients who are in the locked-in state or will be in the nearfuture. By ensuring this, cognitive assessments can be ad-ministered without bias and a control mechanism can be es-tablished for the duration of a study.

Being able to open these communication channels forLIS patients can prove especially important. If near nor-mal communication can be restored, then previously testedand established cognitive assessments may be used. Thus,practitioners would be better able to diagnose, for ex-ample, frontotemporal dementia (FTD), a commonly ob-served symptom associated with ALS over the course of the diseases progression (Ringholz et al. 2005). Beingable to accurately diagnose FTD could lead to a more in-formed prognosis since some cases have shown that ALS

patients with FTD have diminished survivability rates, es-pecially those of the bulbar-onset type (Hu et al. 2013;Olney et al. 2005).

Still, since most psychological assessments for LIS indi-viduals are unveried and lack validation, there is some dif-culty in arriving at a specic diagnosis for ALS patientsregarding cognitive and behavioral changes. To note, theterms ALSci (ALS with cognitive impairment) and ALSbi(ALS with behavioral impairment) have been dened forthis purpose (Cipresso et al. 2011). In order to accuratelydiagnose conditions such as ALSci and ALSbi, it is neces-sary to compare and contrast the neuropsychological testscurrently in use. By doing so, these tests may be improvedupon and made more suitable for ALS and LIS patients.

ApproachIn this section, the various types of cognitive and behavioraltests areevaluated for their suitability and accuracy in testingALS individuals for cognitive decline.

Cognitive TestsThe process of identifying ALS patients with features of cognitive impairment continues to be questioned due to


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lack of extensive studies involving LIS patients in standardpsychological assessments (Phukan, Pender, and Hardiman2007; Cipresso et al. 2011; Hu et al. 2013). In order to mea-sure and diagnose the many possible neurological and psy-chological conditions that may be associated with the pro-gression of ALS, a litany of tests can be employed. Still,these tests may need to be retooled for LIS patients.

In regards to cognition and detecting dementia, assess-

ments similar to those for Alzheimers disease are of-ten used. The Alzheimers Association cites the tests in-cluding the General Practitioner Assessment of Cognition(GPCOG), the Mini-Cog, and the Memory ImpairmentScreen (MIS) as the most well-established and recommendtheir usage for cases involving dementia, especially giventhat the tests feature little to no education bias (Cordell et al.2013). Additionally, the previously referenced article alsothrough a much greater detailed comparison of many otherstandard assessments for Alzheimers Disease.

Studies specically involving ALS feature other com-mon assessments as well. Common areas to assess cogni-tive function in ALS fall under executive functions. Exec-utive functions are higher-level mental processes that con-

trol and organize other cognitive processes (Phukan, Pender,and Hardiman 2007) and include working memory, reason-ing, planning, and problem solving. Others cognitive pro-cesses that are analyzed are general memory, language, andvisuoperceptual functions. Tests frequently encountered inliterature are included below: Verbal Fluency - Controlled Oral Word Association

(COWA) Attention - Reverse Digit Span, Letter Span, Verbal Series

Attention Test (VSAT), and Paced Auditory Serial Addi-tion Task (PASAT)

Recall Memory - Kendrick Object Learning Task (KOLT)and California Verbal Learning Test (CVLT)

Logical Memory - Verbal Recall Episodic Memory - Verbal Pair Associate Learning

(VPAL) Confrontation Naming - Boston Naming Test (BNT) Set Shifting - Wisconsin Card Sorting Task (WCST) Planning and Working Memory - Tower of Hanoi, One-

touch Stockings of Cambridge, or Tower of London Task Cognitive Inhibition - Stroop Test Visuoperception - Judgment of Line Orientation (JLO),

Benton Facial Recognition Test

(Phukan, Pender, and Hardiman; Olney et al.; Ringholzet al.; Meier, Charleston, and Tippett; Hu et al.)

Many of the tests above may be unsuitable for or biasedagainst ALS and LIS individuals given normal implementa-tion techniques. For example, any test that suggests writtenor oral responses and features a timed component would notfavor well for ALS patients as hindered motor control willslow the response rate in an exam, even if the individual isperforming cognitively at a sufcient speed.

Some studies have suggested methods to counteract this.Specically, the COWA test pertains to accessibility of memory and requires executive control over cognitive pro-cesses. In the case of a timed verbal or category uencytask, where a patient is asked to identify words beginningwith a particular letter or members of a particular category,i.e. animals, in sixty seconds, a uency index ( f i ) algorithmis dened.

Using the new denition, patients are given the normalgeneration period of sixty seconds. Following completionof the generation period, a sufcient break is provided whereafterwards the patient completes a control period and copiesagain what they generated, being allowed to reference thelist they made. Both of these periods are timed. From thetiming parameters, the uency index is dened below:

f i =time for generation time for control

number items generated

(Abrahams et al. 2000)Assuming biases towards education levels are minimal-

ized, the solution redening the uency quantier may bevalid in the short term. However, even when including the

correction in f i , the exam will continue to depend on thetime taken for responses. Additionally, this method will con-tinue to eliminate any ALS patient who can no longer speak or write, failing in a longitudinal study as the disease pro-gresses. Overall, this test is not suitable due to the timednature, required motor function, and the free recall compo-nent.

For all the other memory based tests, a component of freerecall is not in place. Instead, components of learning andrecognition are utilized. For example, in the CVLT, subjectsare asked to recall items from a provided shopping list aftera brief delay. In the BNT, subjects must verbally identifypresented objects such as a toothbrush. In essence, Patientsare introduced specic concepts, items, or ideas and asked

to reproduce them after a delay.The only issue in these cases is whether the participantis able to physically communicate back the concepts pre-sented. As long as the method to communicate is stable anddoes not take a prolonged period of time, then these mem-ory based tests would be suitable. If communication is atime consuming task, then tests evaluating short term mem-ory may need to be discarded since too much time may passbetween the time presented a concept and the time of recall.

For the remaining tests, such as the BNT, WCST, Towerof Hanoi, Stroop Test, JLO, and the Benton Facial Recog-nition Test, the implementations can and likely already havecomputer based interfaces. By this means, ET or BCI tech-nology could be readily used for these examinations. By

requiring all participants to follow the same interface meth-ods that do not necessitate speech or dexterity based tasks,bias towards ALS patients will be largely eliminated. How-ever, it should be repeated that late-stage ALS patients mayfeature diminished ocular muscle control.

Behavioral TestsOn the other hand, behavioral tests are more often per-formed in correspondence with a caretaker or family mem-


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ber. Some standard tests include the Frontal BehavioralInventory (FBI), the Frontal Systems Behavior Inventory,and the Neuropsychiatric Inventory (Hu et al. 2013; Meier,Charleston, and Tippett 2010; Phukan, Pender, and Hardi-man 2007).

One study in particular did utilize other behavioral basedassessments, in addition to the standard NeuropsychiatricInventory, and took responses directly from ALS patients

(Meier, Charleston, and Tippett 2010). The tests focused ondecision making as well as Theory of Mind and included theFaux Pas Test, Probabilistic Reversal Learning Test, Hol-iday Apartment Task, and the Aprosodia Battery. Resultsfrom these tests impact social cognition and can inuenceresulting behavioral changes.

All of these tests were untimed, so little to no pressure wasplaced on a patient to perform expediently despite physicaldisabilities. Still, test administrators should be mindful of the additional time a patient with ALS may require in orderto complete these exams. It is possible for an individualto become fatigued over time or become apathetic towardscompletion of the tasks.

In most cases, no signicant correlations was found be-

tween behavioral changes and cognitive impairment. Still,a common nding in behavior changes range from and in-clude, in order of frequency, apathy, difculties in social judgment, irritability, agitation, stereotypy, delusions, rest-lessness, disinhibition, and depression (Meier, Charleston,and Tippett 2010; Phukan, Pender, and Hardiman 2007).To clarify, apathy is a relatively common nding, which isvastly different from depression that is usually linked to spe-cic stressors. In general, depression is not signicantly as-sociated with ALS patients when using the Geriatric Depres-sion Scale (Ringholz et al. 2005).

In general, because responses for most behavioral assess-ments are taken indirectly from a patient with ALS, there islittle that can be addressed regarding their suitability in sucha setting. In most cases, these assessments can be consid-ered largely accurate as long as procedure is followed ac-cording to the tests specications since each rating scalesystem has been heavily reviewed and veried (Malloy andGrace 2005).

As a single degree of caution, caregivers or family mem-bers providing responses to the exams should be careful toeliminate personal biases according to how an individualsbehavior may appear to change due to diminished physicalcapabilities. For example, apathy may appear to manifestsolely because an individual with ALS is no longer capa-ble of reacting to stimuli. Thus, correspondents should bestrongly encouraged to only consider personality changesseparate from physical changes.

ResultsTo review, among the cognitive assessments discussed, it isdesirable to eliminate scoring factors that rely on timed com-ponents. Additionally, free recall should be avoided wherein its stead should be recognition. As can be seen by thelatter portion of cognitive tests analyzed, such as the Wis-consin Card Sorting Task and Tower of Hanoi, these tests

can be easily programmed into a computer interface, allow-ing ET technology to be utilized in the case of full motorparalysis. Still, a degree of caution should be noted in thecase of late-stage ALS where eye movement is affected.

In regards to the behavioral assessments of ALS patients,questionnaires are primarily given to caretakers and fam-ily members and not necessarily the ALS patient beingtested. Therefore, the issue of an ALS patient with LIS does

not contribute directly to the results of these assessments.Among these results, the general consensus follows that theclinical presentation of behavioral abnormalities in ALS donot meet the Neary Criteria for FTD (Phukan, Pender, andHardiman 2007), which include:(a) Insidious onset and gradual progression

(b) Early decline in social interpersonal conduct(c) Early impairment in regulation of personal conduct

(d) Early emotional blunting(e) Early loss of insight

(Snowden, Neary, and Mann 2002)Still, it may be signicant to maintain a distinction be-

tween cognitive impairments and behavioral impairments.Maintaining the boundary could reveal different routes of disease progression and clinical courses.

ConclusionWhen considering patients living with LIS due to a brain-stem injury, as in not ALS, cognitive function appears tobe intact when measured one year or more after the brain-stem injury (Laureys et al. 2005). Yet, according to many of the aforementioned studies involving ALS and ALS patientsexhibiting LIS, there is at least some form of cognitive im-pairment. However, due to the lack of consensus on suitabletesting mechanisms for cognition and behavior on individu-als with LIS, it is difcult to pinpoint exactly and denitively

which functions of the brain are affected by the progressionof ALS.

Of the impairments most commonly cited, executive sys-tems such as attention and verbal uency are most likelyaffected while memory and language remains intact. Achange is sometimes noted in behavioral aspects as wellsuch as personality changes and poor insight (Cipresso etal. 2011). However, some studies disagree on whether cog-nitive dysfunction in ALS forms a continuum, i.e. mildto moderate to FTD (Phukan, Pender, and Hardiman 2007;Cipresso et al. 2011).

In order to validate these ndings involving potential di-agnoses of ALSci or ALSbi, various measures must be takenin order to ensure the accuracy and validity of neurologi-

cal assessments. After analyzing many different standardassessments available to practitioners today, certain choicesand modications are recommended. As an example, the re-cently published study on An Eye-Tracking Version of theTrail-Making Test analyzes many of the details surround-ing implementing ET technology for the trail-making test(Hicks et al. 2013).

To summarize, the cognitive and behavioral assessmentsavailable to practitioners today appear to reveal a degree of


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cognitive and behavioral impairment in ALS patients. How-ever, since modications must be made to the inherent de-signs of many standardized cognitive assessments, it is dif-cult to assuredly claim exact degrees of cognitive decline.

In the future, studies involving cognitive impairment inALS or LIS patients should place a greater emphasis on thedesign and methodology of the implementation of cognitiveassessments in regards to patients with limited motor con-

trol. As suggested previously, cognitive assessments used insettings involving ALS patients should avoid rating scaleswith timed factors and include response mechanisms with-out requiring speech or written feedback. Tests asking forrecognition rather than free recall should be preferred. If necessary, adjustments should be made to control groups forslower motor speed in ALS patients. Ideally, a BCI interfaceshould be implemented or if motor control of the eye mus-cles are intact and the patient is not in late-stage ALS whereeye movement may be altered, then ET technology can stillbe employed.

As a nal goal, new and improved testing mechanismsshould be developed for paralyzed patients. These testscould then be scrutinized and validated by the scientic

community, eventually being standardized as an effectivetool for neuropsychological evaluation of ALS patients.

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Cognitive Assessment in Amyotrophic Lateral Sclerosis Patients

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