Cognition, Cognitive Dysfunction,

and Cognitive Rehabilitation in

Multiple Sclero sis
Mary Pepping, PhD, ABPP-CNa,*, Julie Brunings, MS-CCC, BC-ANCDS
b
,
Myron Goldberg, PhD, ABPP-CNa

KEYWORDS
 Cognition  Cognitive rehabilitation  Cognitive retraining  Multiple sclerosis
 Cognitive dysfunction

KEY POINTS
 Nature of cognitive dysfunction in MS: complex attention, memory acquisition and
retrieval, speed of information processing, and both the neurocognitive and neurobeha-
vioral features of executive functions can all be disrupted in the context of often well-
preserved basic intelligence.
 Importance of comprehensive evaluation: this should include at a minimum a thorough
neuropsychological evaluation and clinical observations of the treating cognitive rehabil-
itation specialist.
 Pathophysiology of MS: implications for neurocognitive and neurobehavioral changes:
subcortical lesions exert a clear adverse effect on complex attention, memory retrieval,
and frontal-subcortical executive functions, with inflammatory and degenerative pro-
cesses each playing a unique role in the background strengths and weaknesses of the in-
dividual with particular forms of MS.
 Cognitive rehabilitation: sophisticated cognitive rehabilitation approaches combine clini-
cians understanding of each persons particular neurocognitive and neurobehavioral
strengths and difficulties, along with training of specific strategies designed to reduce
the negative functional effects of the problem areas.

INTRODUCTION

Cognitive functioning problems are common in multiple sclerosis (MS), occurring in at

least half of all persons with the disorder.1,2 Although the patterns of neuropsycholog-
ical disruption in people with MS are well known (ie, attention, memory acquisition and

a
Department of Rehabilitation Medicine, University of Washington School of Medicine,
Box 356490, 1959 Northeast Pacific Street, Seattle, WA 98195, USA; b Rehabilitation Therapy
Department, University of Washington Medical Center, Box 356154, 1959 Northeast Pacific
Street, Seattle, WA 98195, USA
* Corresponding author.
E-mail address: mpepping@u.washington.edu

Phys Med Rehabil Clin N Am 24 (2013) 663672

http://dx.doi.org/10.1016/j.pmr.2013.06.009 pmr.theclinics.com
1047-9651/13/$ see front matter 2013 Elsevier Inc. All rights reserved.
664 Pepping et al

retrieval, speed of information processing, and features of executive functions can be

adversely affected18), much variability exists. A comprehensive neuropsychological
evaluation is critical to effectively identify the set of neurologic and reactive disruptions
for each person with MS.9 The expert cognitive rehabilitation specialist also gathers
pertinent formal test data and important interview information at the start of therapy
to guide the plan of treatment. Observations by the treating clinician of the persons
cognitive retraining needs as well as clinical data regarding effectiveness of selected
strategies and approaches are key components of on-going evaluation for maximal
treatment effectiveness. All of these strategies also allow the clinician to provide feed-
back to the person with MS about their residual strengths and the various practical ap-
plications of those strengths to support improved function and hope.
The literature on typically preserved versus disrupted neuropsychological functions
in people with MS has been well established over the last 25 years or more of
study.1,2,6 The time of onset, range of affected features, and degree of severity may
vary with each persons disease presentation and subtype (relapsing remitting MS,
primary progressive MS, secondary progressive MS, and clinical isolated syn-
drome10,11) in the particular context of their long-standing premorbid skills and diffi-
culties. However, for most people with MS,1,2,4,7,8,12 the subcortical changes
associated with white matter disease produce predictable problems in thinking.
Lesion extension into cortical gray matter can occur,13 as can some degree of atrophy
over lengthy disease course,14 in some individuals with MS.
As we learn more about the underlying neurophysiology of MS (eg, lesion load, gray
matter involvement, atrophy, and brain regions particularly vulnerable to disruption),
we are in a better position to anticipate, understand, and treat residual neurocognitive
and neurobehavioral difficulties. Given what is known about the initial primarily
subcortical nature of disruptions and relative sparing in most instances of cortical
functions, likely strengths can also be anticipated. This knowledge of residual
strengths and difficulties can give clinicians and the patient a template to develop
pertinent strategies and procedures to support current function and help establish
effective overlearned systems for maximal future function to the fullest extent
possible.
Clinicians appreciate that these changes induced by MS do not occur in the ab-
stract. They occur each time in a specific person who is trying to find the best way
to live fully and with meaning despite the challenging constellation of symptoms
caused by MS. It is the thesis of this article that the cognitive problems that result
from MS can be anticipated, understood via appropriate examination, and then
treated to support improved performance. We would also like the reader to expand
their notion of cognitive changes to include both the neurocognitive (eg, memory
retrieval problems) and neurobehavioral (eg, reduced awareness, impulsivity
adversely affecting problem solving) dysfunction, which is important to address
when designing treatment interventions. It is also important to appreciate premorbid
personality strengths and vulnerabilities as well as reactive emotional concerns and
physical symptoms that can adversely affect thinking performance. First, an overview
is presented of the neuroanatomy, neuropathology, and neurophysiology relevant to
MS and the particular brain structures and processes that underlie areas of disrupted
versus preserved cognitive function.

PATHOPHYSIOLOGY OF MS

MS is considered to be an autoimmune-related disorder of the central nervous sys-

tem, affecting initially the myelin sheath of axons. The cause of this autoimmune
 Cognitive Rehabilitation in MS 665

variant is unknown but is believed to involve an interaction of genetic and environ-

mental factors. Brain and spinal cord regions are vulnerable. An inflammatory process
at the myelin sheath site is considered to be a hallmark initial change in MS. As this
process evolves, axonal damage and scarring have been shown.15,16 Axonal damage
has been associated with loss of axonal integrity and degeneration, which can give
rise to cerebral atrophy.17 MS-related disability is considered to stem from 2 pro-
cesses: acute inflammatory demyelination and axonal degeneration.18
Although MS is often considered a disorder affecting only subcortical white matter,
there is considerable evidence that cortical demyelination can also occur, even at the
early stages of the disease.13 That both subcortical and cortical brain regions can be
affected in MS indicates the diffuse nature of the disease and, in turn, the risk for a
widespread set of cognitive functioning problems. However, despite the potential
for diffuse brain involvement, MS lesions do tend to locate in the periventricular white
matter, cerebellum, and brainstem.19,20
Through structural neuroimaging, several MS-related pathophysiologic changes
have been examined in the literature as risks for cognitive functioning difficulties.21
Among these visualized changes, lesion load (also referred to as lesion burden), lesion
location, and global or regional atrophy have received the most attention. Lesion load
refers to the number of lesions identified on brain imaging within a given area and has
been shown in numerous studies to be correlated positively with greater cognitive
impairment.22,23 For example, Moriarty and colleagues24 reported a positive correla-
tion between juxtacortical lesion load and memory dysfunction in persons with MS.
Bermel and colleagues25 noted the role of frontal lobe disease in executive dysfunc-
tion in MS.
Global atrophy and regional brain atrophy have also been found to be especially
associated with cognitive dysfunction.14,25 Neocortical volume loss has been shown
to differentiate cognitively impaired and cognitively intact individuals with MS.26 More-
over, in 2 studies by Benedict and colleagues,26,27 the relative contribution of brain at-
rophy to cognitive impairment was greater than lesion burden, whereas width of the
third ventricle was more highly associated with cognitive dysfunction than was whole
brain atrophy.
More specifically, in some studies,28 cognitive impairment and thalamic atrophy
were linked in people with MS, particularly men.29 The reason for the sex difference
is not clear, but the central role of the thalamus as a relay station for transmission of
information among and between frontal cortex, basal ganglia, and other cortical re-
gions could explain why atrophy there would have such an important deleterious ef-
fect on key frontal-subcortical functions.

COMPREHENSIVE ASSESSMENT

In the neurorehabilitation setting, effectively evaluating and treating patients with ac-
quired brain dysfunction requires a thorough understanding of the persons abilities,
difficulties, reactions, and preferences. This understanding is essential to designing
and delivering effective treatment. Although there is a role for briefer examinations
in some circumstances to identify and document possible cognitive changes in
MS,30 a brief examination alone is not typically sufficient to fully elucidate the nature
of the persons skills and deficits for optimal treatment planning purposes. It also
does not obtain much information about personality style or features, which can
augment or impede ability to participate and benefit from treatment, as natural pre-
morbid factors or personality changes that may be developing with cortical atrophy.31
Hence, we typically use comprehensive standardized evaluations at the start of care.
666 Pepping et al

These evaluations include at a minimum in-depth neuropsychological evaluation and

may include formal speech and language evaluation and occupational therapy evalu-
ation of higher-level activities of daily living.
We would like to broaden readers view of cognitive evaluation in MS to include the
kind of on-going evaluative observation that is an integral part of the treating clinicians
role as they actively modify or refine treatment strategies and advice to fit the prob-
lems observed in the persons performance. This performance can include the quality
of the persons in-session work, completed homework assignments, or other func-
tional behavior (eg, observations of relevant behavior in the waiting room). For
example, is the person rifling through a large messy backpack full of papers trying
to find a homework assignment despite all attempts to impose some organizational
structure? Perhaps it is time to rethink the strategies or approaches being used.
A clinic-based therapist can also make note of the persons ability to keep appoint-
ments, to show up on time for those appointments, to bring with them requested ma-
terials, and to complete other scheduled activities for the week. It is easy to check if
the person has important items with them every session (eg, wallet or purse, keys,
phone, schedule, note-taking device or materials). Feedback in the form of test or
course grades for those in college or work performance evaluations for employed peo-
ple also provides objective information regarding improvements in function. Including
the persons family member periodically allows the clinician to obtain observer up-
dates on accomplishments in the home and community setting (eg, taking medica-
tions independently, better follow-through with completion of chores, improved
efficiency of verbal communication, jotting down notes to aid memory performance).

COGNITIVE REHABILITATION (COGNITIVE RETRAINING)

Cognitive rehabilitation is indebted to the early pioneers of these techniques32 in the

traumatic brain injury (TBI) population and evidence-based reviews of cognitive reha-
bilitation efficacy33 for people with TBI and other acquired neurologic dysfunction.
Cognitive retraining focuses on reducing cognitive impairment, developing
compensatory strategies to minimize the impact of the deficits, and increasing aware-
ness of impact of those deficits in daily activities. Impaired learning and memory (ie,
efficient acquisition and retrieval) as well as slowed information processing and
impaired working memory, which can adversely affect complex attention and other
cognitive abilities (eg, verbal fluency, executive functions), have all been identified
as primary cognitive difficulties associated with MS.34,35
In addition to the known disruptions that can occur in attention, memory and new
learning, speed of information processing, and features of executive function,36 peo-
ple with MS have unique additional vulnerabilities. These vulnerabilities can include
variability in day-to-day performance secondary to waxing and waning of MS symp-
toms as well as additional problems with fatigue, paresthesia, or heat sensitivity.
This variability must be taken into account when designing and delivering strategies
for effective cognitive retraining. Periodic review and updated modification of cogni-
tive rehabilitation needs and strategies over time is also recommended for people
with MS and their families to help maximize maintenance of adaptive functions.
Even although research evaluating cognitive retraining for MS is in its infancy, it
points toward neurorehabilitation being beneficial for people with various types of
cognitive problems caused by MS.37 Research specifically related to MS supports
cognitive rehabilitation of impairments in the area of executive functioning,37 as do
expert opinion articles.38 The TBI literature shows evidence to support a practice stan-
dard of metacognitive approaches for treating deficits in planning and problem
 Cognitive Rehabilitation in MS 667

solving.39 Both the MS and TBI literature identify training in the use of compensatory
techniques for memory as a practice guideline.37,4042
The TBI literature has long supported the use of cognitive rehabilitation for improved
attention.33,43 Although additional evidence is still being gathered for specific MS pop-
ulations,37 it is reasonable to consider that people with MS, for whom the ability to sus-
tain attention on relevant targets or topics and to filter competing stimuli is a main
concern of treatment, can benefit from established approaches. As further research
is conducted, many of the treatment approaches in use based on clinical usefulness
and observed improvements in function for people with MS seem likely to achieve
practice standard or practice guideline status.

Treatment Planning Interview with Patient and Family

Developing a treatment plan for cognitive retraining must begin, as noted earlier, with
effective evaluation. One of the most critical yet sometimes neglected elements of
evaluation for treatment planning is a systematic interview with the patient and family
member or significant other by the treating clinician at the outset of treatment. It is
important to understand the functional impact of impairment in order to tailor the treat-
ment plan and compensatory strategies to meet an individuals needs. Interview ques-
tions can probe for specific examples of how deficits affect daily life. The answers to
these questions are used in conjunction with test results to develop compensatory
strategies for these situations as well as strategies that can be generalized to all as-
pects of daily life. The treatment plan includes education of the patient and family
about the nature of the deficits and why it adversely affects them and development
of compensatory strategies and therapeutic activities to target specific difficulties.

Memory and New Learning

Memory and new learning are especially problematic when it is difficult to quickly
determine main ideas and filter distracting versus relevant details. As a result, memory
acquisition, storage, and retrieval become inefficient. Treatment targets memory def-
icits via extensive practice in synthesizing main elements and filtering out extraneous
details with increasingly complex material. This skill is also effective for learning to take
effective notes. The persons ability and willingness to take structured and consistent
notes during treatment and at home have been observed in clinical practice as one of
the best strategies for improved spontaneous recall and follow-through. It is vital to
develop a consistent system that uses a single location for notes and includes
prompts to write and review the notes. A commercial day planner is a simple, inexpen-
sive, and effective strategy for this system. It is also important to break new informa-
tion into smaller units to be rehearsed and practiced, then summarized and noted. This
strategy maximizes the chance that it will be stored and ready for later retrieval, before
moving on to new material.

Speed of Information Processing

Reduced speed of information processing can also adversely affect daily activities on
many levels, including in conversation, when following directions, and mentally
juggling ideas. Strategies are taught to slow the speed of incoming information by tak-
ing notes and asking clarifying questions in conversations or lectures. Receiving the
same information in multiple complementary modalities (visual, auditory, written)
seems to be beneficial to maximizing accuracy of input and retention. For example,
a person may request an e-mail follow-up of quickly presented verbal auditory instruc-
tions to reinforce memory and understanding and maximize the chances for success-
ful follow-through. It is also not an incidental factor for the person facing new
668 Pepping et al

information to enter the situation prepared (eg, to heighten their awareness of the
techniques that they need to succeed and when to use them, to put extra effort into
focused attention, to try to make use of settings that minimize distractions and tools
that maximize understanding).

Attention
The ability to shift attention without succumbing to internal or external distractions is a
significant challenge. Many people with MS describe this phenomenon as going
down the rabbit hole and then losing track of what was important. The first line of de-
fense is to assess the environment to see what kinds of distractions are present so that
those can then be minimized. Distractions can be visual, auditory, or internal. Simple
strategies include wearing headphones or earplugs to decrease nonrelevant auditory
distractions. For visual distractions, an environment can be created with limited clutter
and fewer people present. To manage internal distractions, a person can quickly jot
down intrusive ideas as they come to mind if these are items that should not be
forgotten, rather than shifting attention to the new thought. It is also helpful to have
a written plan for the day to focus on completing a particular set of tasks, few in num-
ber and manageable in size. Cognitive rehabilitation treatment also helps the person
identify those tasks that are performed routinely, either at home or at work, and to
develop a plan that helps decrease the number of times when shifts in attention are
required. An example of this strategy is to check e-mail only at scheduled times and
only for a certain period, rather than having alerts sound throughout the day that
require the person to shift attention at every announcement.

Executive Functions: Use of Structure and Routines

Structure is a critical component to successfully maintaining attention and completing
tasks in a day. Often, the person with MS is completely overwhelmed by the number
and complexity of the tasks that they must complete. They may also believe they have
no control over their schedule. However, by creating some structure, it is easier to stay
on task. Because it is difficult for someone with MS to predict how their symptoms will
affect them each day, the schedule has to have some flexibility. Helping the person
develop daily and weekly anchors (eg, routine scheduled tasks such as the morning
get-ready process or a regular exercise time with activities that can be modified if
needed) and a time to plan each day is more effective than a rigid weekly schedule
that was developed a priori to complete tasks. It is also helpful to schedule blocks
of time to work without interruption. Using consistent routines facilitates increased
attention and follow-through of tasks as well as providing effective structure to the
day/week. These routines are more successful if they are sequence based rather
than time based, because of the variability of physical symptoms (eg, fatigue).

Executive Functions: Techniques for Project Completion

People with MS are frequently unable to complete projects because they do not know
how best to start or become distracted in carrying out the project. In treatment, the
clinician helps develop a system to plan the steps in the projects, put those steps in
order, and then schedule a time to complete each of the steps. Additional strategies
to prompt the person to initiate the task or to pause and assess how they are progress-
ing may also need to be taught. Use of timers or posting and checking the plan are
suggestions for additional prompts. Another component of difficulty with project
completion is time management. People with MS sometimes report a diminished or
absent sense of elapsed time, or that tasks take longer as a result of fatigue. Further,
they may be calculating their estimates of how long a project will take based on
 Cognitive Rehabilitation in MS 669

premorbid experience and speed of performance, without taking into consideration

the effects of MS. In addition, physical limitations, heightened distractibility, and mem-
ory retrieval disruptions can all contribute to more time needed. We encourage pa-
tients to double or triple the amount of estimated time needed to complete each
step in the project. If they finish more quickly than estimated, that is bonus time, rather
than having the stress of approaching deadlines that are impossible to meet given
inaccurate planning.

Education and Awareness

The importance of the persons awareness of deficits (as well as of residual strengths)
was alluded to earlier. An important aspect of overall neurorehabilitation (of which
cognitive retraining/cognitive rehabilitation is a fundamental component) revolves
around on-going education. By helping the person understand the relationship be-
tween specific kinds of cognitive impairments and their functional difficulties, they
are better able to implement appropriate strategies. This kind of education can also
facilitate ability to generalize strategies to additional tasks. By understanding the
cause of the problem, (ie, why the difficulty manifests in the ways that it does), the per-
son is less likely to be overwhelmed by it and more likely to be empowered to take
control of the problem and its negative repercussions.

Unique Challenges for Cognitive Function in MS

There are particular challenges to providing treatment to people with MS, which are
not typical of other forms of acquired brain injury. One of the most pressing issues
for people with MS is the variability in functional deficits that they may experience
day to day related to fatigue, pain, or other sensory, motor, and physical symptoms.
The combination, intensity, and unpredictability of symptoms can also be demoraliz-
ing from a psychological stand-point, leading to reactive emotional distress, which can
aggravate the negative impact of residual neurologic difficulties. As a function of these
problems in day-to-day variability, people with MS need some degree of flexibility in
their schedules as well as time for scheduled rest breaks to pace energy expenditure.

Generalization and Follow-Through with Strategies at Home

Another challenge for people with compromise in executive functions is to achieve a
level of basic organization in ones home or work life to make most effective use of all
strategies. Working together to identify a family member, friend, or professional orga-
nizer who can assist in creating a work or home environment where visual and auditory
distractions are minimized and a truly sustainable functional organizational system is
in place may be necessary for application and maintenance of strategies. Individuals
with MS, especially given the progressive nature of the illness, also benefit from a re-
turn to treatment periodically to review relevant strategies, modify them further for cur-
rent needs, and identify new compensatory techniques as appropriate.

SUMMARY

It is our observation over a combined 70 years or more of experience in neurorehabi-

litation that the cognitive rehabilitation specialist is the instrument of change for
improved function in people with cognitive deficits caused by neurologic injury or
illness. Although computer-based tasks can be fun, or allow practice with word games
or other academic skills, unless they translate into practical applications for improved
day-to-day function, they are not the best use of the persons time and resource to
achieve specific real-world improvements in cognitive performance.
670 Pepping et al

REFERENCES

1. Rao SM, Leo GJ, Bernardin L, et al. Cognitive dysfunction in multiple sclerosis. I.
Frequency, patterns, and prediction. Neurology 1991;41(5):68591.
2. Rao SM, Leo GJ, Ellington L, et al. Cognitive dysfunction in multiple sclerosis. II.
Impact on employment and social functioning. Neurology 1991;41(5):6926.
3. Arnett PA, Rao SM, Grafman J, et al. Executive functions in multiple sclerosis: an
analysis of temporal ordering, semantic encoding, and planning abilities. Neuro-
psychology 1997;11(4):53544.
4. Fischer JS. Cognitive impairment in multiple sclerosis. In: Cook SD, editor. Hand-
book of multiple sclerosis. 3rd edition. New York: Marcel Dekker; 2001. p. 23355.
5. DEsposito M, Ohishi K, Thompson H, et al. Working memory impairments in mul-
tiple sclerosis: evidence from a dual task paradigm. Neuropsychology 1996;10:
516.
6. Beatty WW, Goodkin DE, Monson N, et al. Cognitive disturbances in patients with
relapsing remitting multiple sclerosis. Arch Neurol 1989;46:11139.
7. Beatty WW. Multiple sclerosis. In: Adams RL, Parsons OA, Gulbertson JL, et al,
editors. Neuropsychology for clinical practice: etiology, assessment, and treat-
ment of common neurological disorders. Washington, DC: American Psycholog-
ical Association; 1996. p. 22542.
8. DeLuca J, Gaudino EA, Diamond BJ, et al. Acquisition and storage deficits in
multiple sclerosis. J Clin Exp Neuropsychol 1998;20:37690.
9. Pepping M, Ehde D. Neuropsychological evaluation and treatment of multiple
sclerosis: the importance of a neuro-rehabilitation focus. Phys Med Rehabil Clin
N Am 2005;16(2):41136.
10. Huijbregts SC, Kalkers NF, de Sonneville LM, et al. Cognitive impairment and
decline in different MS subtypes. J Neurol Sci 2006;245:18794.
11. Potogas C, Giogkaraki E, Koutsis G, et al. Cognitive impairment in different MS
subtypes and clinically isolated syndromes. J Neurol Sci 2008;267(12):1006.
12. DeLuca J, Chelune GJ, Tulsky DS, et al. Is speed of processing or working mem-
ory the primary information-processing deficit in multiple sclerosis? J Clin Exp
Neuropsychol 2004;26(4):55062.
13. Trapp B, Nave KA. Multiple sclerosis: an immune or neurodegenerative disorder.
Annu Rev Neurosci 2008;31:24769.
14. Hohol MJ, Guttmann CR, Oray J, et al. Serial neuropsychological assessment
and magnetic resonance imaging analysis in multiple sclerosis. Arch Neurol
1997;54:101825.
15. OConnor P. Key issues in the diagnosis and treatment of multiple sclerosis: an
overview. Neurology 2002;59(Suppl 3):S13.
16. Vigeveno RM, Wiebenga OT, Wattjes MP, et al. Shifting imaging targets in multiple
sclerosis: from inflammation to neurodegeneration. J Magn Reson Imaging 2012;
36:119.
17. Rudick R, Fisher E, Lee JC, et al. Use of the brain parenchymal fraction to mea-
sure whole brain atrophy in relapsing remitting MS. Neurology 1999;53:1698704.
18. Chelune GJ, Stott H, Pinkston JB. Multiple sclerosis. In: Morgan J, Ricker J, ed-
itors. Textbook of clinical neuropsychology. New York: Taylor & Francis; 2008.
p. 599615.
19. Fazekas F, Barkhof F, Filippi M, et al. The contribution of magnetic resonance im-
aging to the diagnosis of multiple sclerosis. Neurology 1999;53:44856.
20. Foong J, Rozewicz L, Quaghebeur G, et al. Executive function in multiple scle-
rosis: the role of frontal lobe pathology. Brain 1997;120(Pt 1):1526.
 Cognitive Rehabilitation in MS 671

21. Wallin MT, Wilken JA, Kane R. Cognitive dysfunction in multiple sclerosis: assess-
ment, imaging and risk factors. J Rehabil Res Dev 2006;43(1):6372.
22. Rao SM, Leo GJ, Haughton VM, et al. Correlation of magnetic resonance imaging
with neuropsychological testing in multiple sclerosis. Neurology 1989;39:1616.
23. Rovaris M, Filippi M, Minicucci L, et al. Cortical/subcortical disease burden and
cognitive impairment in patients with multiple sclerosis. AJNR Am J Neuroradiol
2000;21:4028.
24. Moriarty DM, Blackshaw AJ, Talbot PR, et al. Memory dysfunction in multiple scle-
rosis corresponds to juxtacortical lesion load on fast fluid-attenuated inversion-re-
covery MR images. AJNR Am J Neuroradiol 1999;20(10):195662.
25. Bermel RA, Bakshi R, Tjoa C, et al. Bicaudate ratio as a magnetic resonance
imaging marker of brain atrophy in multiple sclerosis. Arch Neurol 2002;59:
27580.
26. Benedict RH, Bruce JM, Dwyer MG, et al. Neocortical atrophy, third ventricular
width, and cognitive dysfunction in multiple sclerosis. Arch Neurol 2006;63:
13016.
27. Benedict RH, Weinstock-Guttman B, Fishman I, et al. Prediction of neuropsycho-
logical impairment in multiple sclerosis: comparison of conventional magnetic
resonance imaging measures of atrophy and lesion burden. Arch Neurol 2004;
61:22630.
28. Fischer E, Benedict RH. Correlation of cognitive impairment and thalamic atrophy
in MS: for men only? Neurology 2012;79:17489.
29. Schoonheim MM, Popescu V, Rueda Lopes FC, et al. Subcortical atrophy and
cognition: sex effects in multiple sclerosis. Neurology 2012;79:175461.
30. Benedict RH, Fischer JS, Archibald CJ, et al. Minimal neuropsychological
assessment of MS patients: a consensus approach. Clin Neuropsychol 2002;
16(3):38197.
31. Benedict RH, Hussein S, Englert J, et al. Cortical atrophy and personality in mul-
tiple sclerosis. Neuropsychology 2008;22(4):43241.
32. Ben-Yishay Y, Diller L. Cognitive remediation in traumatic brain injury: update and
issues. Arch Phys Med Rehabil 1993;74:20413.
33. Cicerone KD, Dahlberg C, Malec JF, et al. Evidence-based cognitive rehabilita-
tion: updated review of the literature from 1998 through 2002. Arch Phys Med Re-
habil 2005;86(8):168192.
34. Mattioli FF, Stampatori CC, Bellomi FF, et al. Neuropsychological rehabilitation in
adult multiple sclerosis. Neurol Sci 2010;31:2714.
35. Rosti-Otajarvi EM, Hamalainen PI. Neuropsychological rehabilitation for multiple
sclerosis. Cochrane Database Syst Rev 2011;(11):CD009131. http://dx.doi.org/
10.1002/14651858.CD009131.pub2.
36. Flavia M, Stampatori C, Zanotti D, et al. Efficacy and specificity of intensive cogni-
tive rehabilitation of attention and executive functions in multiple sclerosis.
J Neurol Sci 2010;288(12):1015.
37. OBrien AR, Chiaravalloti N, Goverover Y, et al. Evidenced-based cognitive reha-
bilitation for persons with multiple sclerosis: a review of the literature. Arch Phys
Med Rehabil 2008;89(4):7619.
38. National Multiple Sclerosis Society. Expert opinion paper: assessment and man-
agement of cognitive impairment in multiple sclerosis. New York: The Multiple
Sclerosis Society; 2006.
39. Kennedy MR, Coelho C, Turkstra L, et al. Intervention for executive functions after
traumatic brain injury: a systematic review, meta-analysis and clinical recommen-
dations. Neuropsychol Rehabil 2008;18(3):25799.
672 Pepping et al

40. Ehlardt L, Sohlberg MM, Kennedy MR, et al. Evidence-based practice guidelines
for instructing individuals with acquired memory impairments: what have we
learned in the past 20 years? Neuropsychol Rehabil 2008;18(3):30042.
41. Sohlberg MM, Kennedy MR, Avery J, et al. Evidence based practice for the use
of external aids as a memory rehabilitation technique. J Med Speech Lang Pathol
2007;15(1):xvli.
42. Dahlberg CA, Cusick CP, Hawley LA, et al. Treatment efficacy of social commu-
nication skills training after traumatic brain injury: a randomized treatment and
deferred treatment controlled trial. Arch Phys Med Rehabil 2007;88(12):156173.
43. Cicerone K, Dahlberg C, Kalmar K, et al. Evidence-based cognitive rehabilitation:
recommendations for clinical practice. Arch Phys Med Rehabil 2000;81:
1596615.