Advances in Stroke

Advances in Brain Recovery and Rehabilitation 2010

Richard Zorowitz, MD; Michael Brainin, MD, FESO, FAHA

AbstractDiscoveries in the past year have impacted the understanding of brain recovery and there is more of a need than
ever for a foothold in recovery and rehabilitation This review reports on translational efforts, new (and old) potential
drugs, various approaches to neurorehabilitation, and brain imaging that demonstrate reorganization in the human brain
during stroke rehabilitation. (Stroke. 2011;42:294-297.)
Key Words: brain recovery imaging outcomes quality of life rehabilitation stem cells stroke recovery

O ver the past 15 years, the focus of stroke medical

advances and healthcare resources has been on acute
and subacute recovery phases, which has resulted in substan-
tial health disparities in later phases of stroke care. More
recently, the field of brain recovery has seen a plethora of
basic, translational, and applied experiments that deserve to
be discussed, reviewed, and evaluated for further research.
Unfortunately, this report can highlight only examples from
the last year that appear most relevant to the authors and hold
promise for clinical relevance. Translational research allows
basic scientists to provide clinicians with new tools for use in
patients and for assessment of their impact at the same time
as clinical researchers make novel observations about the
nature and progression of disease that often stimulate basic
investigations.1 Pharmacotherapy allows researchers to use
already available drugs and develop new medications that can
protect the brain from damage and facilitate and enhance
recovery. Approaches to rehabilitation allow researchers to
develop new methods of facilitating recovery, enhancing
compensatory strategies, and comparing techniques in the
quest to determine the most effective and efficient means of
rehabilitation. Finally, to better understand the mechanisms
of neuroplasticity, research is using imaging and neurophys-
iological techniques to document the reorganization of the
brain that accompanies functional improvement. The pur-
pose of this review is to describe some of the additions to the
literature that contributed to the ever growing knowledge
base of neurorehabilitation of stroke.
Translational Research: Bench to Bedside
and Back
Because inflammation plays a vital role in the pathogenesis of
ischemic stroke, researchers felt that brain-derived neurotro-
phic factor (BDNF) may protect brain tissues from ischemic
injury. In 1 study, intranasal BDNF was given to rats to
protect the brain from ischemic insult.2 Rats given intranasal
BDNF after temporary occlusion of the right middle cerebral
artery did not reduce infarct volume significantly, but in-
creased the number of activated and phagocytotic microglia,
suppressed tumor necrosis factor- and mRNA expression,
increased interleukin-10 and mRNA expression, and in-
creased DNA-binding activity of nuclear factor- B. Overall,
intranasal BDNF might protect the brain against ischemic
insult by modulating local inflammation through regulation
of the levels of cellular, cytokine, and transcription factor in
experimental stroke.
To deliver BDNF to the brain, Lee and associates devel-
oped genetically modified human neural stem cells that
overexpress in a mouse stroke model.3 After inducing intra-
cerebral hemorrhage in adult rats, a human neural stem cell
line that produces 6-fold higher amounts of BDNF was
transplanted into the brains. The stem cells differentiated and
renewed angiogenesis of host brain and functional recovery
in the animals, thereby suggesting that these cell lines could
be of great value as a cellular source for experimental studies
involving cellular therapy for human neurological disorders.
The Search for Potential New (and Not so
New) Drugs
Drugs also have been shown to facilitate brain recovery in
animal models. Ding and associates4 used T2-, diffusion-
weighted, and susceptibility-weighted MRI imaging to ex-
plore whether erythropoietin (EPO) initiated at 24 hours and
administered daily for 7 days after an embolic stroke assists
in repairing ischemic cerebral tissue. In a randomized trial of
22 adult Wistar rats given either treatment or control after
occlusion of the middle cerebral artery occlusion, they found
that expansion of the ipsilateral ventricle was significantly
reduced in the EPO-treated rats. The volume ratio of ipsilat-
eral parenchymal tissue relative to the contralateral hemi-
sphere was significantly increased after EPO treatment com-
pared with control animals, indicating that EPO significantly

Received December 3, 2010; accepted December 7, 2010.

From the Department of Physical Medicine and Rehabilitation (R.Z.), The Johns Hopkins University School of Medicine, and the Department of
Physical Medicine and Rehabilitation, Johns Hopkins Bayview Medical Center, Baltimore, MD; and the Department of Clinical Medicine and Prevention
(M.B.), Danube University, Krems, Austria.
Correspondence to Michael Brainin, MD, FESO, FAHA, Danube University and Danube Clinic, Department Chairman and Director, Department of
Neurology, Karl Dorrekstrasse 30, Krems, Austria 3500. E-mail michael.brainin@donau-uni.ac.at
2011 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.110.605063

294
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 Zorowitz and Brainin
reduces atrophy of the ipsilateral hemisphere. Angiogenesis
and white matter remodeling were significantly increased and
occurred earlier in EPO-treated animals than in the controls
as noted on T2- and diffusion-weighted images, respectively.
In a Phase IIa study, Cramer and associates5 gave 15 patients
24 to 48 hours postischemic infarct with National Institutes of
Health Stroke Scale scores from 6 to 24 after a 9-day course
of -human chorionic gonadotropin on Days 1, 3, and 5
followed by EPO on Days 7, 8, and 9. No safety concerns
were noted among clinical or laboratory measures, including
screening for deep vein thrombosis and serial measures of
serum hemoglobin.
As we have seen over many years, other medications have
not been effective. OCollins and colleagues6 chose magne-
sium sulfate, melatonin, and minocycline from a library of
neuroprotective agents, and these were tested in a more
realistic model favored by the Stroke Therapy Academic
Industry Roundtable. Despite the animal model, this combi-
nation of medications was not an effective neuroprotectant
when infarct volume, neurological score, and 2 newly devel-
oped scales measuring general health and physiological
homeostasis were measured.
Brain Imaging and Neuroplasticity: Just
Picture This
New imaging techniques continue to be developed and
applied to the detection and staging of white matter reorga-
nization after brain injury with and without neurorestorative
treatment. Jiang and colleagues7 demonstrated how variations
of diffusion tensor MRI methodology could detect white
matter remodeling after brain injury. In addition, Q-space
diffusion tensor MRI, an emerging diffusion-weighted imag-
ing technique that identifies the molecular diffusion proba-
bility density function without the need to assume a Gaussian
distribution, can detect early-stage axonal remodeling involv-
ing randomly oriented crossing axons.
Imaging also continues to be used in conjunction with
rehabilitation interventions to demonstrate the efficacy of the
activity. Enzinger and colleagues8 used functional MRI lon-
gitudinally to relate brain activity changes with performance
gains of the lower limb after 4 weeks of treadmill training
with partial body weight support. Their study in 18 chronic
patients (mean age, 59.913.5 years) demonstrated not only
that walking endurance improved after training, but also
greater walking endurance was correlated with increased
brain activity in the bilateral primary sensorimotor cortices,
the cingulate motor areas, and the caudate nuclei bilaterally
and in the thalamus of the affected hemisphere.
New and Expanding Therapeutic Approaches
In the past year, researchers continued to explore previously
untested stroke rehabilitation interventions as well as better
define those that have an evidence base. Wolf and associates9
compared functional improvements between stroke survivors
randomized to receive constrain-induced movement therapy
within 3 to 9 months (early group) with those randomized to
15 to 21 months after stroke (delayed group). Although both
groups improved functionally 12 months after treatment,
stroke survivors receiving constrain-induced movement ther-
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Advances in Brain Recovery and Rehabilitation 295
apy earlier demonstrated significant improvement than those
in the delayed constrain-induced movement therapy group.
However, 24 months after enrollment, there were no statisti-
cally significant differences between groups.
More research was completed to determine the efficacy of
treadmill training with body weight support. The MOBILISE
trial10 randomized 126 stroke survivors who were unable to
walk into an experimental group who received up to 30
minutes per day of treadmill walking with body weight
support and a control group who received up to 30 minutes of
overground walking. Six months after the training, more of
the experimental group was independent in ambulation and
was discharged home after rehabilitation. However, the re-
sults were not statistically significant (P0.13).
The role of electric stimulation also continued to be
pursued. Hsu and associates11 studied 66 stroke survivors
with severe motor deficit randomized to receive 0, 30, or 60
minutes of upper extremity neuromuscular electric stimula-
tion daily for 4 weeks. In this case, both groups receiving
neuromuscular electric stimulation demonstrated similar im-
provements as measured by the Fugl-Meyer Motor Assess-
ment and Action Research Arm Test scales.
The role of transcranial magnetic stimulation also received
attention in 2010. Lindenberg and colleagues12 randomized
20 stroke survivors to receive 5 consecutive sessions of
experimental or sham bihemispheric transcranial direct cur-
rent stimulation with simultaneous physical/occupational
therapy. Motor function was significantly greater in the
experimental group and outlasted the stimulation by at least 1
week. The improvement was correlated with stronger activa-
tion of intact ipsilesional motor regions during paced move-
ments of the affected limb.
Another study of M1 theta burst stimulation (TBS) was
completed by Ackerley and colleagues.13 Ten patients with
chronic subcortical stroke involving the upper limb received
intermittent TBS of the ipsilesional M1, continuous TBS of
the contralesional M1, and sham TBS in separate sessions in
conjunction with standardized training of a precision grip
task. Training with real TBS improved paretic-hand griplift
kinetics, whereas training with sham TBS resulted in deteri-
oration of griplift. Ipsilesional M1 excitability increased
after intermittent TBS of the ipsilesional M1 but decreased
after continuous TBS of the contralesional M1, resulting in
deterioration of the Action Research Arm Test. They con-
cluded the contralesional hemisphere may play a pivotal role
in recovery after stroke.
Robotics continues to be an area of focus in stroke
rehabilitation. In a randomized study evaluating stroke sur-
vivors with long-term upper-limb impairments, Lo and asso-
ciates14 compared outcomes in 127 subjects at 12 weeks when
given robot-assisted therapy, intensive comparison therapy,
or usual care. Although no adverse events were reported in
any subject, robot-assisted therapy did not significantly im-
prove motor function at 12 weeks as compared with usual
care or intensive therapy. However, in a secondary analysis,
robot-assisted therapy improved outcomes over 36 weeks as
compared with usual care but not with intensive therapy.
Even virtual reality and gaming are becoming pervasive in
stroke rehabilitation. Saposnik and colleagues15 devised a
296 Stroke February 2011
randomized, single-blinded clinical trial to compare the
feasibility, safety, and efficacy of virtual reality using the
Nintendo Wii gaming system versus recreational therapy
(playing cards, bingo, or Jenga). In the 17 subjects of their
pilot project, the 9 subjects using virtual reality using the
Nintendo Wii significantly improved in mean motor function
of 7.4 seconds on the Wolf Motor Function Test after
adjustment for age, baseline functional status, and stroke
severity. They concluded that virtual reality using the Nin-
tendo Wii is a potentially effective alternative to facilitate
rehabilitation therapy and promote motor recovery after
stroke.
Finally, 2 studies in Chinese alternative medicine should be
noted. First, a meta-analysis by Wu and colleagues16 con-
cluded that acupuncture may be effective in the treatment of
poststroke rehabilitation, [but] poor study quality and the
possibility of publication bias hinder the strength of this
recommendation. Second, Lee and associates17 completed a
systematic review on moxibustion, a traditional Chinese
method that uses the heat generated by burning herbal
preparations containing Artemisia vulgaris to stimulate acu-
puncture points. Although moxibustion is popular in east
Asian countries, their meta-analysis of 9 randomized clinical
trials found only limited effectiveness of moxibustion in
stroke rehabilitation.
Spasticity and Disability
In the year that the US Food and Drug Administration finally
approved the use of onabotulinumtoxin (Botox) for upper
limb spasticity, it is appropriate to include some research that
showed that severe poststroke spasticity is rare but when
present contributes to disability and high costs. First, Urban
and colleagues18 found that spasticity developed in 42.6% of
211 subjects 6 months poststroke, but severe spasticity was
relatively rare. Predictors for the development of spasticity
included a severe degree of paresis and hemihypesthesia at
stroke onset. Second, Lundstrom and associates19 estimated
that the mean direct costs (ie, acute and rehabilitation hospi-
talization, primary health care, medication, and costs for
municipality services) for a stroke survivor with spasticity
was $84 195 (median, $72 816; interquartile range, $53 707)
compared with $21 842 ($12 385; $17 484) for stroke survi-
vors without spasticity. Costs for hospital care, primary care,
and home or residential care also were significantly higher if
the stroke survivor had spasticity. Thus, spasticity has to be
viewed as 1 of several possible factors impeding motor
function and treatment of spasticity-related disability should
be seen as 1 of several options in chronic stroke management.
Outcomes Research
The Year 2010 also saw more studies that attempted to
delineate good and poor outcomes after stroke. As part of the
Northern Manhattan Stroke Study, Willey and associates20
reported that stroke survivors who stated that they felt
depressed 7 to 10 days poststroke were at odds of severe
disability compared with no disability at 1 (OR, 2.91; 95%
CI, 1.07 to 7.91) and 2 years (OR, 3.72; 95% CI, 1.29 to
10.71) after stroke. However, depressed mood was not
associated with overall mortality or vascular death. Rist and
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colleagues21 observed that among the 21 860 men enrolled in
the Physicians Health Study, men who consumed 1 drink
per week had a modest beneficial association with functional
outcome after stroke, but otherwise there was no strong
association between increased alcohol consumption and func-
tional outcome.
Meta-Analysis and Scientific Statements: Putting
It All Together
Over the last year, there has been an effort to educate nursing
and other members of the interdisciplinary team about the
potential for recovery in the later or more chronic phases of
stroke care. The American Stroke Association commissioned
a scientific statement that summarizes the best available
evidence and recommendations for interdisciplinary manage-
ment of the needs of stroke survivors and their families
during inpatient and outpatient rehabilitation and in chronic
care and end-of-life settings.22 The statement makes use of
the International Classification of Functioning, Disability,
and Health of the World Health Organization23 as a founda-
tion for the interdisciplinary team approach to rehabilitation
and the different care settings in which stroke survivors may
receive services.
Batchelor and colleagues24 reviewed evidence relating to
interventions that reduce falls after stroke. In the 13 studies
that met their criteria, variability of falls reported was
observed across the studies. Pooling of results was possible
for only 2 types of interventions: exercise versus usual care
(fall rate, fallers) and bisphosphonate medication versus
placebo (fallers). The only intervention shown to be effective
in reducing falls was vitamin D for female stroke survivors in
an institutional setting, but other interventions were no more
effective than usual care. Like in many other rehabilitation
studies, they conclude that further research evaluating a
range of single and multifactorial interventions for fall
prevention in the stroke population is required.
Conclusion: Still a Long Road Ahead
Much progress has been made in stroke rehabilitation over
the past months and years. The physiology of recovery is
being studied intensively. Animal models of recovery are
aimed at establishing the means by which pharmacological
and hormonal treatments to facilitate recovery can be tested
in humans. Clinical interventions that engage the stroke
survivor and stimulate the brain continue to be developed at
an increasing pace. Imaging techniques are assisting in
confirming neuroplastic changes that intensive rehabilitation
causes.
However, much still needs to be done. We still do not
know the types, doses, and combinations of physical and
pharmacological modalities that will help specific stroke
survivors. We still do not know how to initiate movement or
speech when the stroke survivor has none. We still do not
know how to effectively prevent cerebral damage using
neuroprotective agents. We still do not know how to use
cellular therapies to make the right connections that allow
regeneration of the neural system. Over the next period,
researchers must set the agenda in stroke rehabilitation so that
we can further decrease the mortality and morbidity that the
 Zorowitz and Brainin
American Stroke Association accomplished before its 2010
goal. With strong commitments from government and private
funding sources alike, the worlds stroke rehabilitation can
take strides to decrease impairments and improve activity and
participation. That is something that will never be lost in
translation.
Disclosures
None.
References
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 Advances in Brain Recovery and Rehabilitation 2010
Richard Zorowitz and Michael Brainin

Stroke. 2011;42:294-297; originally published online January 13, 2011;

doi: 10.1161/STROKEAHA.110.605063
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2011 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

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 Avances en recuperacin cerebral y rehabilitacin 2010
Richard Zorowitz, MD; Michael Brainin, MD, FESO, FAHA

ResumenLos descubrimientos realizados en el pasado ao han influido de manera importante en el conocimiento de la

recuperacin cerebral y hay ahora mayor necesidad que nunca de un punto de apoyo para la recuperacin y rehabilita-
cin. Esta revisin presenta los esfuerzos traslacionales realizados, los nuevos (y antiguos) posibles frmacos, diversos
enfoques para la neurorrehabilitacin y las tcnicas de imagen cerebral que muestran la reorganizacin del cerebro
humano durante la rehabilitacin del ictus. (Traducido del ingls: Advances in Brain Recovery and Rehabilitation
2010. Stroke. 2011;42:294-297.)

Palabras clave: brain recovery n imaging n outcomes n quality of life n rhabilitation n stem cellsn n stroke recovery

A lo largo de los ltimos 15 aos, el centro de inters en

cuanto a los avances mdicos y los recursos de asisten-
cia para el ictus ha estado en las fases de recuperacin aguda
y subaguda, y ello ha comportado disparidades sustanciales
en las fases posteriores de la asistencia del ictus. Ms recien-
temente, el campo de la recuperacin cerebral ha asistido a
una gran cantidad de experimentos bsicos, traslacionales y
aplicados que merecen un comentario, revisin y evaluacin
de cara a la investigacin futura. Lamentablemente, en este
trabajo solamente podemos resaltar algunos ejemplos del pa-
sado ao que en opinin de los autores son de la mayor rele-
vancia y parecen prometedores en cuanto a su trascendencia
clnica. La investigacin traslacional permite a los especia-
listas en ciencias bsicas proporcionar a los clnicos nuevos
instrumentos que puedan usarse en los pacientes y para eva-
luar al mismo tiempo su impacto, cuando los investigadores
clnicos hacen nuevas observaciones acerca de la naturaleza
y la progresin de la enfermedad que a menudo estimulan
las investigaciones bsicas1. La farmacoterapia permite a los
investigadores utilizar los frmacos ya disponibles y desa-
rrollar nuevas medicaciones que puedan proteger al cerebro
frente a los daos y facilitar y potenciar la recuperacin. Los
enfoques de rehabilitacin permiten a los investigadores de-
sarrollar nuevos mtodos para facilitar la recuperacin, po-
tenciar estrategias de compensacin y comparar tcnicas, en
su intento de determinar los medios de rehabilitacin ms
efectivos y eficientes. Finalmente, para comprender mejor
los mecanismos de neuroplasticidad, la investigacin utili-
za tcnicas de imagen y tcnicas neurofisiolgicas para do-
cumentar la reorganizacin del cerebro que acompaa a la
mejora funcional. El objetivo de esta revisin es describir
algunas de las nuevas aportaciones de la literatura que han
contribuido a aumentar la base de conocimientos cada vez
ms amplia de la neurorrehabilitacin del ictus.
Investigacin traslacional: del laboratorio a la
cabecera del paciente y de nuevo al laboratorio
Dado que la inflamacin desempea un papel crucial en la
patogenia del ictus isqumico, los investigadores conside-
raron que el factor neurotrfico de origen cerebral (BDNF)
poda proteger a los tejidos cerebrales frente a la lesin
isqumica. En un estudio, se administr BDNF intranasal
a ratas para proteger al cerebro frente a la agresin isqu-
mica2. En las ratas tratadas con BDNF intranasal tras una
oclusin transitoria de la arteria cerebral media derecha
no hubo una reduccin significativa del volumen de infar-
to, pero s se observ un aumento del nmero de clulas
de microgla activadas y fagocitarias, una supresin del
factor de necrosis tumoral- y la expresin de su mRNA,
un aumento de la interleuquina-10 y la expresin de su
mRNA, y un aumento de la actividad de unin al ADN
del factor nuclear-B. Globalmente, el BDNF intranasal
podra proteger al cerebro frente a la agresin isqumica al
modular la inflamacin local mediante la regulacin a los
niveles celular, de citoquinas y de factores de transcrip-
cin en el ictus experimental.
Para administrar BDNF en el cerebro, Lee y colaborado-
res desarrollaron clulas madre neurales humanas modifi-
cadas genticamente que se sobreexpresan en un modelo
de ictus en el ratn3. Tras inducir una hemorragia intra-
cerebral en ratas adultas, se trasplant a los cerebros una
lnea de clulas madre neurales humanas que produce un
cantidad 6 veces superior de BDNF. Las clulas madre se
diferenciaron y produjeron una angiognesis renovada en
el cerebro husped y una recuperacin de los animales,
lo cual sugera que estas lneas celulares podran ser de
gran valor como fuente de clulas para los estudios expe-
rimentales relativos al tratamiento celular de los trastornos
neurolgicos humanos.

Recibido el 3 de diciembre de 2010; aceptado el 7 de diciembre de 2010.

Department of Physical Medicine and Rehabilitation (R.Z.), The Johns Hopkins University School of Medicine, and the Department of Physical Me-
dicine and Rehabilitation, Johns Hopkins Bayview Medical Center, Baltimore, MD; y Department of Clinical Medicine and Prevention (M.B.), Danube
University, Krems, Austria.
Remitir la correspondencia a Michael Brainin, MD, FESO, FAHA, Danube University and Danube Clinic, Department Chairman and Director, De-
partment of Neurology, Karl Dorrekstrasse 30, Krems, Austria 3500. Correo electrnico michael.brainin@donau-uni.ac.at
2011 American Heart Association, Inc.

Stroke est disponible en http://www.stroke.ahajournals.org DOI: 10.1161/STROKEAHA.110.605063

93
94 Stroke Julio 2011
La bsqueda de posibles frmacos nuevos
(y no tan nuevos)
Se ha demostrado tambin que los frmacos facilitan la re-
cuperacin cerebral en modelos animales. Ding y colabora-
dores4 utilizaron imgenes de RM con ponderacin T2, con
ponderacin de difusin y con ponderacin de susceptibili-
dad, para explorar si la eritropoyetina (EPO) iniciada a las 24
horas y administrada diariamente durante 7 das tras un ictus
emblico facilitaba la reparacin del tejido cerebral isqumi-
co. En un ensayo aleatorizado realizado en 22 ratas Wistar
adultas a las que se administr el tratamiento o un control tras
la oclusin de la arteria cerebral media, se observ que la ex-
pansin del ventrculo (homolateral) se reduca significativa-
mente en las ratas tratadas con EPO. El cociente de volumen
del tejido del parnquima homolateral respecto al hemisferio
contralateral aument significativamente tras el tratamiento
con EPO en comparacin con los animales de control, lo cual
indicaba que la EPO reduce significativamente la atrofia del
hemisferio homolateral. La angiognesis y el remodelado de
la sustancia blanca aumentaron significativamente y se pro-
dujeron de forma ms temprana en los animales tratados con
EPO, en comparacin con los controles, segn lo indicado
por las imgenes con ponderacin T2 y con ponderacin de
difusin, respectivamente. En un ensayo de Fase IIa, Cramer
y colaboradores5 estudiaron a 15 pacientes a las 24 a 48 horas
de sufrir un infarto isqumico, con unas puntuaciones de la
National Institutes of Health Stroke Scale de 6 a 24 tras una
tanda de 9 das de administracin de -gonadotropina cori-
nica humana los das 1, 3 y 5, seguido de EPO los das 7, 8
y 9. No surgi ninguna alarma de seguridad en cuanto a los
parmetros clnicos y de laboratorio, incluido el examen de
deteccin de la trombosis venosa profunda y las determina-
ciones seriadas de la hemoglobina srica.
A lo largo de muchos aos hemos visto cmo otras medi-
caciones no eran eficaces. OCollins y colaboradores6 eligie-
ron de una biblioteca de agentes neuroprotectores el sulfato
magnsico, la melatonina y la minociclina, y los estudiaron
en un modelo ms realista recomendado por la Stroke The-
rapy Academic Industry Roundtable. A pesar del modelo ani-
mal, esta combinacin de medicaciones no fue eficaz para la
neuroproteccin cuando se utiliz el volumen de infarto, la
puntuacin neurolgica y 2 escalas recientemente desarrolla-
das que miden la salud general y la homeostasis fisiolgica.
Tcnicas de imagen cerebral y neuroplasticidad:
simplemente visualizarlo
Se continan desarrollando tcnicas de imagen que se aplican
a la deteccin y la determinacin del estadio de la reorgani-
zacin de la sustancia blanca tras la lesin cerebral con o sin
un tratamiento de neurorreparacin. Jiang y colaboradores7
observaron que las variaciones en la metodologa de RM de
tensor de difusin podan detectar el remodelado de la sus-
tancia blanca tras la lesin cerebral. Adems, la RM de tensor
de difusin de espacio Q, una nueva tcnica de imagen con
ponderacin de difusin que identifica la funcin de densidad
de probabilidad de difusin molecular sin necesidad de asu-
mir una distribucin de Gauss, puede detectar el remodelado
axnico en una fase inicial, en la que hay axones con cruces
de orientacin aleatoria.
Las tcnicas de imagen se continan utilizando tambin
en combinacin con intervenciones rehabilitadoras para de-
mostrar la eficacia de la actividad. Enzinger y colaboradores8
utilizaron la RM funcional longitudinalmente para relacio-
nar los cambios de la actividad cerebral con la ganancia de
funcin de la extremidad inferior tras 4 semanas de entrena-
miento en cinta sin fin con apoyo parcial del peso corporal.
Su estudio llevado a cabo en 18 pacientes crnicos (media
de edad, 59,913,5 aos) demostr no slo que el ejercicio
de resistencia de caminar mejora tras el entrenamiento, sino
tambin que una mayor capacidad de caminar estaba corre-
lacionada con un aumento de la actividad cerebral en la cor-
teza sensitivomotora primaria bilateral, las reas motoras del
cngulo y los ncleos caudados bilaterales, as como en el
tlamo del hemisferio afectado.
Enfoques teraputicos nuevos y en expansin
Durante el pasado ao, los investigadores han continuado ex-
plorando intervenciones de rehabilitacin del ictus no evalua-
das anteriormente, as como definiendo mejor aquellas que
disponen de unas base de evidencia. Wolf y colaboradores9
compararon las mejoras funcionales de pacientes que haban
sobrevivido a un ictus y a los que se asign aleatoriamente
el empleo de una terapia de movimiento inducido por cons-
triccin en los primeros 3 a 9 meses (grupo de tratamiento
temprano) con las de los pacientes asignados a una terapia
a los 15 a 21 meses del ictus (grupo de tratamiento tardo).
Aunque ambos grupos presentaron una mejora funcional 12
meses despus del tratamiento, los que recibieron la terapia
de movimiento inducida por constriccin de forma ms tem-
prana presentaron una mejora significativa en comparacin
con los tratados de forma tarda. Sin embargo, 24 meses des-
pus de la inclusin, no hubo diferencias estadsticamente
significativas entre los grupos.
Se han realizado nuevas investigaciones para determinar la
eficacia del entrenamiento en cinta sin fin con apoyo del peso
corporal. En el ensayo MOBILISE10 se estudi a 126 pacien-
tes que haban sobrevivido a un ictus y no podan caminar,
y se les asign aleatoriamente a un grupo experimental tra-
tado con ejercicio en cinta sin fin con apoyo de peso corpo-
ral durante hasta 30 minutos al da o a un grupo control con
ejercicio de caminar en el suelo durante hasta 30 minutos.
Seis meses despus del entrenamiento, hubo ms pacientes
del grupo experimental que mostraron una independencia en
la deambulacin y fueron dados de alta para regresar a su do-
micilio tras la rehabilitacin. Sin embargo, los resultados no
fueron estadsticamente significativos (p = 0,13).
Se contina investigando tambin el papel de la estimula-
cin elctrica. Hsu y colaboradores11 estudiaron a 66 pacien-
tes que haban sobrevivido a un ictus con un dficit motor
grave y les asignaron aleatoriamente la aplicacin de 0, 30
60 minutos de estimulacin elctrica neuromuscular en la
extremidad superior diariamente durante 4 semanas. En es-
te caso, los dos grupos tratados con estimulacin elctrica
neuromuscular presentaron mejoras similares segn las de-
terminaciones realizadas con las escalas Fugl-Meyer Motor
Assessment y Action Research Arm Test.
En 2010 se ha prestado atencin tambin a la estimulacin
magntica transcraneal. Lindenberg y colaboradores12 estu-
diaron a 20 pacientes que haban sobrevivido a un ictus y les
 Zorowitz y Brainin Avances en recuperacin cerebral y rehabilitacin 2010 95
asignaron aleatoriamente 5 sesiones consecutivas de estimu-
lacin con corriente continua transcraneal bihemisfrica o
un tratamiento simulado, junto con una terapia fsica/ocupa-
cional simultnea. La funcin motora fue significativamen-
te mayor en el grupo experimental, y persisti despus de la
simulacin, al menos durante 1 semana. La mejora estuvo
correlacionada con la activacin ms potente de las regiones
motoras homolaterales intactas durante los movimientos esti-
mulados de la extremidad afectada.
Ackerley y colaboradores13 realizaron otro estudio con la
estimulacin con salvas theta de M1 (TBS). Diez pacientes
con ictus subcorticales crnicos que afectaban a la extremi-
dad superior fueron tratados con TBS intermitente de la M1
homolateral a la lesin, TBS continua de la M1 contralateral
respecto a la lesin o una TBS simulada en sesiones sepa-
radas, junto con un entrenamiento estandarizado de la tarea
de aprensin de precisin. El entrenamiento con TBS real
mejor la cintica de prensin-elevacin de la mano parti- numtoxina (Botox) para la espasticidad de la extremidad su-
ca, mientras que la TBS simulada produjo un deterioro de la
prensin-elevacin. La excitabilidad de la M1 homolateral a
la lesin aument tras la TBS intermitente de la M1 homola-
teral pero se redujo tras la TBS continua de la M1 contrala-
teral, causando un deterioro en la Action Research Arm Test.
Los autores llegaron a la conclusin de que el hemisferio
contralateral a la lesin puede desempear un papel clave en
la recuperacin tras el ictus.
La robtica contina siendo un campo de inters en la re-
habilitacin del ictus. En un estudio aleatorizado en el que se
evalu a pacientes que haban sobrevivido a un ictus y pre-
sentaban un deterioro de la funcin de la extremidad superior
a largo plazo, Lo y colaboradores14 compararon los resulta-
dos obtenidos en 127 pacientes a las 12 semanas al utilizar
un tratamiento robotizado, un tratamiento de comparacin
intensivo o la asistencia habitual. Aunque no se registraron
acontecimientos adversos en ningn paciente, el tratamiento
robotizado no mejor de forma significativa la funcin moto-
ra a las 12 semanas en comparacin con la asistencia habitual
o la terapia intensiva. Sin embargo, en un anlisis secundario,
el tratamiento robotizado mejor los resultados a lo largo de
36 semanas, en comparacin con la asistencia habitual pero
no en comparacin con el tratamiento intensivo.
Incluso la realidad virtual y los juegos se estn introdu-
ciendo de manera generalizada en la rehabilitacin del ictus.
Saposnik y colaboradores15 disearon un ensayo clnico alea-
torizado y ciego simple para comparar la viabilidad, seguri-
dad y eficacia de la realidad virtual utilizando el sistema de
juego de Nintendo Wii en comparacin con el tratamiento
recreativo (jugar a cartas, bingo o jenga). En los 17 pa-
cientes de su proyecto piloto, los 9 que utilizaron la realidad
virtual con la Nintendo Wii mejoraron significativamente en
la funcin motora media de 7,4 segundos en la Wolf Motor
Function Test tras introducir un ajuste para la edad, el estado
funcional basal y la gravedad del ictus. Los autores llegaron
a la conclusin de que la realidad virtual con el empleo de la
Nintendo Wii puede ser una alternativa efectiva para facilitar
el tratamiento de rehabilitacin y fomentar la recuperacin
motora tras el ictus.
Por ltimo, deben sealarse 2 estudios de medicina alter-
nativa china. El primero de ellos, un metanlisis de Wu y
colaboradores16 lleg a la conclusin de que la acupuntura
puede ser eficaz en el tratamiento de la rehabilitacin tras el
ictus, [pero] la mala calidad de los estudios y la posibilidad
de un sesgo de publicacin limitan la fuerza de esta recomen-
dacin. En segundo lugar, Lee y colaboradores17 llevaron a
cabo una revisin sistemtica de la moxibustin, un mtodo
tradicional chino que utiliza el calor generado por la quema
de preparados de plantas medicinales que contienen Artemi-
sia vulgaris para estimular los puntos de acupuntura. Aunque
la moxibustin es popular en los pases del oriente asitico,
el metanlisis de 9 ensayos clnicos aleatorizados solamente
encontr una efectividad limitada de la moxibustin en la re-
habilitacin del ictus.
Espasticidad y discapacidad
En el ao en el que la Food and Drug Administration de
EEUU ha autorizado finalmente el uso de la onabotuli-
perior, es apropiado mencionar algunas investigaciones que
han mostrado que la espasticidad grave tras el ictus es muy
poco frecuente pero, cuando se da, contribuye a causar la dis-
capacidad y unos costes elevados. En primer lugar, Urban y
colaboradores18 observaron que se produjo una espasticidad
en el 42,6% de 211 pacientes 6 meses despus del ictus, pe-
ro la espasticidad grave fue relativamente infrecuente. Los
factores que predecan la aparicin de espasticidad eran un
grado elevado de paresia y hemihipoestesia al inicio del ic-
tus. En segundo lugar, Lundstrm y colaboradores19 calcula-
ron que los costes directos medios (es decir, hospitalizacin
aguda y de rehabilitacin, asistencia sanitaria primaria, me-
dicacin y costes de los servicios sociales) para un paciente
que sobreviva a un ictus con espasticidad eran de $84.195
(mediana, $72.816; rango intercuartiles, $53.707) en com-
paracin con $21.842 ($12.385; $17.484) para los supervi-
vientes a un ictus sin espasticidad. Los costes de asistencia
hospitalaria, atencin primaria y cuidados domiciliarios o
en residencia fueron tambin significativamente mayores si
el superviviente del ictus presentaba espasticidad. As pues,
la espasticidad debe considerarse uno de los varios factores
posibles que impiden la funcin motora y el tratamiento de
la discapacidad asociada a la espasticidad debe considerarse
una de las varias opciones existentes para el tratamiento cr-
nico del ictus.
Investigacin sobre parmetros de valoracin
En el ao 2010 hemos asistido tambin a nuevos estudios que
han intentado delimitar el buen o mal resultado despus de
un ictus. Como parte del estudio Northern Manhattan Stroke
Study, Willey y colaboradores20 indicaron que los pacien-
tes que sobrevivan a un ictus e indicaban que estaban de-
primidos 7 a 10 das despus del episodio tenan una mayor
probabilidad de presentar una discapacidad grave que de no
presentar discapacidad al cabo de 1 ao (OR, 2,91; IC del
95%, 1,07 a 7,91) y de 2 aos (OR, 3,72; IC del 95%, 1,29
a 10,71) despus del ictus. Sin embargo, el estado de nimo
deprimido no se asoci a la mortalidad global ni a la muerte
de causa vascular. Rist y colaboradores21 observaron que, en
los 21.860 varones incluidos en el estudio Physicians Health
Study, que consuman < 1 bebida por semana hubo una aso-
ciacin favorable modesta con los resultados funcionales tras
96 Stroke Julio 2011
el ictus, pero por lo dems no se observ ninguna asociacin
intensa entre el aumento del consumo de alcohol y el resulta-
do funcional.
Metanlisis y declaraciones cientficas: combinarlo
todo
En el pasado ao se ha realizado un gran esfuerzo por for-
mar al personal de enfermera y otros miembros del equipo
interdisciplinario acerca del potencial de recuperacin en las
fases posteriores o ms crnicas de la asistencia del ictus. La
American Stroke Association encarg la elaboracin de una
declaracin cientfica que resumiera la mejor evidencia dis-
ponible y las recomendaciones para el manejo interdiscipli-
nario de las necesidades de los pacientes que han sobrevivido
a un ictus y sus familias durante la rehabilitacin del paciente
hospitalizado o ambulatorio y en los contextos de asistencia
crnica y terminal22. Esa clasificacin utiliza la clasificacin
International Classification of Functioning, Disability, and
Health de la Organizacin Mundial de la Salud23 como base
para el abordaje con un equipo interdisciplinario de la reha-
bilitacin y los diferentes contextos en los que se presta asis-
tencia a los pacientes que han sobrevivido a un ictus.
Batchelor y colaboradores24 revisaron la evidencia relativa
a las intervenciones que reducen las cadas tras el ictus. En
los 13 estudios que cumplan sus criterios, se observ la va-
riabilidad de las cadas descritas en los estudios. Solamente
fue posible combinar los resultados para 2 tipos de interven-
ciones: ejercicio frente a asistencia habitual (frecuencia de
cadas, pacientes que sufrieron alguna cada) y medicacin
de bisfosfonato en comparacin con placebo (pacientes que
sufrieron alguna cada). La nica intervencin para la que se
demostr una eficacia en la reduccin de las cadas fue la
vitamina D en las mujeres que haban sobrevivido a un ictus
y estaban internadas, pero las dems intervenciones no fue-
ron ms eficaces que la asistencia habitual. Como en muchos
otros estudios de rehabilitacin, los autores concluyen que
sern necesarias nuevas investigaciones para evaluar toda
una gama de intervenciones individuales o multifactoriales
para la prevencin de las cadas en la poblacin con ictus.
Conclusin: queda un largo camino
por recorrer
En los ltimos meses y aos se han realizado grandes avan-
ces en la rehabilitacin del ictus. Se est estudiando intensa-
mente la fisiologa de la recuperacin. Los modelos animales
de la recuperacin tienen como objetivo establecer los me-
dios con los que poner a prueba los tratamientos farmaco-
lgicos y hormonales para facilitar la recuperacin en el ser
humano. Se continan desarrollando a un ritmo creciente in-
tervenciones clnicas que involucran a los pacientes que han
sobrevivido a un ictus y estimulan el cerebro. Las tcnicas
de imagen estn facilitando la confirmacin de los cambios
neuroplsticos que causa la rehabilitacin intensiva.
Sin embargo, queda mucho por hacer. Todava no co-
nocemos los tipos, dosis y combinaciones de modalidades
de terapia fsica y de tratamiento farmacolgico que sern
tiles para pacientes especficos que han sobrevivido a un
ictus. Todava no conocemos cmo iniciar el movimiento
o el habla cuando el paciente que ha sobrevivido a un ic-
tus no los tiene. Todava no conocemos cmo prevenir de
manera efectiva el dao cerebral con el empleo de agentes
neuroprotectores. Todava no conocemos cmo utilizar las
terapias celulares para establecer las conexiones correc-
tas que permitan la regeneracin del sistema neural. En el
prximo periodo, los investigadores debern establecer los
puntos a considerar en la rehabilitacin del ictus, de mane-
ra que podamos reducir en mayor medida la mortalidad y
la morbilidad que la American Stroke Association ha esta-
blecido antes de su objetivo de 2010. Con un compromiso
claro por parte de la administracin y de las fuentes de fi-
nanciacin privadas, la rehabilitacin del ictus en el mun-
do puede tener resultados en la reduccin del deterioro y la
mejora de la actividad y la participacin. Esto es algo que
no se puede olvidar.
Declaraciones de conflictos de intereses
Ninguna.
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 4 Stroke Vol. 6, No. 2

Advances in Stroke 2010 Stroke Vol. 42; 294-297

2010
Advances in Brain Recovery and Rehabilitation 2010
Richard Zorowitz, MD; Michael Brainin, MD, FESO, FAHA

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