Brain tumor rehabilitation

Authors:
Mary Vargo, MD

Affiliations:
From the Department of Physical
Medicine and Rehabilitation,
MetroHealth Rehabilitation
Institute of Ohio, Case Western INVITED REVIEW
Reserve University, Cleveland.

Correspondence:
All correspondence and requests for
reprints should be addressed to:
Brain Tumor Rehabilitation
Mary Vargo, MD, Case Western Reserve
University, Department of Physical
Medicine and Rehabilitation, ABSTRACT
MetroHealth Medical Center, 2500
MetroHealth Drive, 1st Floor Hamann Vargo M: Brain tumor rehabilitation. Am J Phys Med Rehabil 2011;
Building, Cleveland, OH 44109. 90(suppl):S50YS62.

Disclosures: Brain and other central nervous system tumors have a very high likelihood of
Financial disclosure statements have producing long-term disabling effects owing to the tumor itself and the effects of
been obtained, and no conflicts of treatment, including surgical complications, neurotoxic effects of radiation, and
interest have been reported by the debility caused by chemotherapy. Even benign or low-grade brain tumors can
authors or by any individuals in control
of the content of this article. cause significant disability. Brain tumors occur over the life span, showing pro-
gressively higher incidence with advancing age. The common types of primary
0894-9115/11/9005(Suppl)-0S50/0
brain tumor differ between pediatric and adult age groups. Evidence for effec-
American Journal of Physical
Medicine & Rehabilitation tiveness of rehabilitation is favorable. Brain tumor patients treated in acute reha-
Copyright * 2011 by Lippincott bilitation settings improve comparably with individuals with stroke or traumatic
Williams & Wilkins brain injury. Although patients with primary brain tumors have been better studied
than those with metastatic disease, significant gains with inpatient rehabilitation
DOI: 10.1097/PHM.0b013e31820be31f
have been reported in the latter group also. Outpatient programs to address
cognitive deficits in brain tumor survivors, including cognitive therapy and pharma-
cologic strategies, have found benefit. While the patient is receiving rehabilitation
care, physiatrists, in interdisciplinary collaboration with the pertinent oncology-
related services, assist with managing symptoms including fatigue, headache,
and sleep disturbance and medical complications including depression, seizures,
and thromboembolic disease. Better methods are needed to identify patients
for rehabilitation services when appropriate over the course of the disease
process.
Key Words: Cancer Rehabilitation, Brain Tumors, Central Nervous System Tumors,
Treatment, Cognitive Therapy, Collaboration

A lthough comprising just 1.4% of all malignancies, brain and other nervous
system tumors are of core importance in cancer rehabilitation because of their
extremely high rate of disabling sequelae.1 Nervous system neoplasms are
histologically diverse and include both malignant and benign diagnoses.
Malignant brain lesions may be primary or metastatic. Survivorship varies
among brain neoplasm subtypes. In general, for malignant brain tumor,
although 5-yr survivorship has improved, it remains modest (33.9% for all
ages and 71.4% for children, 1988Y2005).2 For benign brain tumor, survivor-
ship is much better. However, some benign etiologies may be difficult to fully
resect (e.g., craniopharyngiomas), are prone to recur (e.g., nerve sheath tumors),
or may develop anaplastic features (e.g., a small percentage of meningiomas or

S50 Am. J. Phys. Med. Rehabil. & Vol. 90, No. 5 (Suppl), May 2011

Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

ependymomas). Therefore, even for an individ- nant brain tumor (29.5/100,000) and 267,000 had
ual with a benign etiology of tumor, the disease a history of benign brain tumor (97.5/100,000);
trajectory can have a protracted and challenging the remaining individuals had tumors of uncertain
course. behavior.3
Among PBT diagnoses, the type of tumor pres-
ent varies with age. Embryonal/neuroectodermal
BRAIN TUMOR INCIDENCE tumors and pilocytic astrocytomas are most com-
AND PREVALENCE mon in childhood, and meningioma and malignant
In 2008, there were an estimated 52,236 gliomas are the most common etiologies among
new primary brain tumor (PBT) diagnoses in the adults (Table 1).7,8 Among PBT cases, meningiomas
United States, with 22,000 being malignant (rate, comprise 32% of cases; and malignant gliomas, 39%
6/100,000 for malignant tumor and 9/100,000 for of cases. Eighty-one percent of all malignant PBTs
benign tumor). Overall incidence is slightly greater are malignant gliomas.
in women than in men (17.2 vs. 15.8/100,000); Children are more likely to have posterior fossa
however, malignant PBT occurs more often in men tumors than adults are, with the cerebellum being
than in women (7.6 vs. 5.4/100,000).3 The inci- the most common location in children younger
dence of malignant PBT increases with age, and than 10 yrs and brainstem nearly as common as
in adults, survival decreases with more advanced cerebral location.5 In adults, frontal (25%), tem-
age at diagnosis.3 Median age at diagnosis of PBT poral (20.1%), parietal (14.6%), and overlapping
is 56 yrs.3 However, it should also be noted that regions (19.8%) are the most common locations.4
brain tumor is the second most common childhood In terms of impact of brain tumor on rehabil-
malignancy and the most common childhood solid itation systems, relative to other brain rehabilita-
tumor,4 with 3,750 cases (includes malignant and tion diagnoses, such as traumatic brain injury
benign)5 among individuals younger than 20 yrs (TBI) or stroke, little published data are avail-
in the United States. Thirteen percent of all pri- able. It has been estimated that on a yearly basis,
mary brain cancers present in individuals younger 80,000Y90,000 of an estimated 1.4 million survi-
than 20 yrs.3 The incidence of PBT is highest in vors of TBI will incur signiﬁcant disability or re-
whites, followed by Hispanics and African Americans quire increased medical care.9,10 Regarding stroke,
(16.8, 15.4, and 13/100,000, respectively). The in- in 2005, there were an estimated 892,300 acute
cidence of metastatic brain tumor is less clear, with hospitalizations for cerebrovascular disease and,
estimates ranging up to ten times greater than among Medicare recipients, 85,516 inpatient reha-
that of PBT.6 bilitation admissions.11 Although incidence data
Regarding prevalence, in 2000, there were an are available, the likelihood of brain tumor patients
estimated 359,000 people (131/100,000) living with needing and receiving rehabilitation services, as
a history of brain tumor, including at least 26,000 compared with patients with brain injury or stroke,
children. Of those, 81,000 had a history of malig- is not known. However, some data are available

TABLE 1 Brain tumor incidence in various age groups
Most Common Brain Tumor Second Most Common Brain Tumor
Age, yrs (Incidence per 100,000) (Incidence per 100,000)
0Y4 Embryonal/PNET/medulloblastoma (1.06) Pilocytic astrocytoma (0.99)
5Y9 Pilocytic astrocytoma (1.01) Embryonal/PNET/medulloblastoma (0.73)
10Y14 Pilocytic astrocytoma (0.83) Malignant glioma (0.44)
15Y19 Pilocytic astrocytoma (0.63) Pituitary adenoma (0.6)
20Y34 Pituitary adenoma (1.16) Meningioma (0.91)
35Y44 Meningioma (3.32) Pituitary adenoma(1.56)
45Y54 Meningioma (6.87) Glioblastoma (3.70)
Q85 Meningioma (29.53) Glioblastoma (7.63)
Data from American Brain Tumor Association Facts and Figures 2009 (www.abta.org).
PNET indicates primitive neuroectodermal tumor.

www.ajpmr.com Brain Tumor Rehabilitation S51


on the benefit from rehabilitation, relative to other growth retardation in children. Extreme obesity
diagnoses, particularly stroke (see ‘‘Inpatient Brain may occur because of hypothalamic involvement.14
Tumor Rehabilitation’’). They are difficult to fully resect, so although long-
term survival is good, recurrences commonly oc-
cur. Cognitive deficits, most notable in memory and
BRAIN TUMOR SUBTYPES processing speed, have been described.15
Although survival information for malignant tu- Primary central nervous system lymphomas
mor types is included as a general reference, there is comprise 3% of PBTs. Risk is highest in those
variation, with younger age and higher performance with immune compromise, including patients with
status at presentation being favorable indicators. Re- human immunodeficiency virus or history of organ
cent reviews that describe current and developing transplant. Median survival (24Y40 mos) is best
oncologic evaluation and treatment methods for brain with chemotherapy, with or without radiation
tumor are available, which are beyond the scope of therapy, as opposed to resection. However, under-
this article.7,12 lying immune compromise can be a barrier to
Gliomas include astrocytomas, oligodendrogli- chemotherapy. Because of treatment with whole
omas, and ependymomas. Astrocytomas with good brain radiation, risk of later onset toxicity is rela-
cure potential upon resection include pilocytic as- tively high.7
trocytoma, pleomorphic xanthoastrocytoma, and sub- Medulloblastoma and other primitive neu-
ependymal giant cell astrocytoma.7 roectodermal tumors such as pineoblastoma and
Higher grade astrocytomas include grade II neuroblastoma are most common in children.
astrocytomas (median survival, 5 yrs), grade III an- Histologically, they are identical, but medulloblas-
aplastic astrocytomas (median survival, 2Y3 yrs), tomas, which arise in the cerebellum, have the best
and grade IV glioblastoma multiforme (GBM; me- prognosis.12 Long-term survival is about 80% with
dian survival, 12Y14 mos). GBM is the most com- medulloblastoma and about 50% with other types.7
mon, comprising 20% of all PBTs.7 Temozolomide, Medulloblastoma comprises about 2% of PBTs
an alkylating agent, has synergistic efficacy when overall and produces long-term sequelae including
given during radiation therapy for GBM. Afterward, neurocognitive deficits (100%; including learning
it is given as maintenance, raising median survival and memory deficits in 88% and high incidence in
for GBM from 12 to 14 mos.12 Oligodendrogliomas multiple other spheres), other neurologic sequelae
comprise 3.7% of all PBTs and may be low grade (72%; most commonly ataxia in 50% and facial
or anaplastic.7 Survival averages 10 yrs for low- weakness in 22%), and endocrine abnormalities
grade tumor, 8 yrs for those with mixed features, (61%). Seventy-two percent exhibit altered school
and 3Y5 yrs for anaplastic variants. Ependymomas performance. In one study, social function was the
(about 2% of PBTs) are low grade, but may be ana- quality-of-life dimension most affected.16
plastic, and are more common in the spinal cord or Brain metastases occur most frequently with
posterior fossa than in the supratentorial region. lung, breast, colorectal, melanoma, and genitouri-
Meningiomas are usually benign and originate nary cancers, especially lung and breast because
in the dura. Surgical resection is usually feasible, they are more common overall. Eighty percent of
and stereotactic radiotherapy has been used for brain metastases affect the cerebral hemispheres,
some sites such as sphenoid, parasagittal, orbital, most commonly at the gray-white junction, where
tentorial, or clivus locations.7 In rare cases, ana- blood vessel caliber changes are found and tumor
plastic changes may be present. emboli become trapped.7 Most other brain metas-
Pituitary adenomas comprise 6%Y8% of PBTs, tases are in the cerebellum. In about half of cases,
and issues may include encroachment on optic the brain metastasis is solitary and may be amenable
pathways and endocrine disturbance.7 to focal therapies, including resection.12 Life ex-
Nerve sheath tumors (8% of PBTs) are located pectancy is less than 6 mos for most patients with
in the posterior fossa, producing cranial nerve brain metastasis, but most who undergo resection
findings including hearing loss, vertigo, facial palsy, die of systemic, not intracranial, involvement.12
dysphagia, facial numbness, and hydrocephalus. Leptomeningeal spread may also occur, especially
Craniopharyngiomas (0.7% of PBTs) are em- from hematologic malignancies, lung, breast, mel-
bryonic malformations of the sellar area, may affect anoma, and gastric carcinoma, producing cranial
hypothalamic and pituitary structures, and produce nerve or spinal nerve root findings.7 Median sur-
hydrocephalus.13 Craniopharyngiomas can affect vival is 4Y6 wks without treatment, although it may
vision and hormonal status and may produce be prolonged by 3Y6 mos by antitumor therapies.

S52 Vargo Am. J. Phys. Med. Rehabil. & Vol. 90, No. 5 (Suppl), May 2011


TREATMENT COMPLICATIONS ataxia, dementia, and incontinence, requiring sup-
Surgical Complications portive treatment.18
Separate from the previously mentioned pro-
The postsurgical period is often the pivotal
cesses, chronic diminished cognitive function has
point around which rehabilitation services are
also been reported after whole brain radiation.
organized for brain tumor patients. It is at this time
Individuals receiving radiation therapy before age
that the impact on overall function of the both the
7 yrs or after age 60 yrs are thought to be most
tumor (usually newly diagnosed or progressed/
vulnerable to this process.18 Among children re-
recurrent) and of the craniotomy itself becomes
ceiving whole brain radiation, attention, proces-
most acutely obvious. In addition to rehabilita-
sing speed, visual motor/visual spatial function, and
tion therapies, there is also a heightened need for
working memory are most commonly affected.19
pain management, for other supportive medical
Endocrine disturbance can occur, leading to growth
management (such as treatment of infection, bowel
disturbance, the most common manifestation of
and bladder complications, management of nutri-
hypothalamic radiation exposure.18 Cerebral vas-
tion, and other medical comorbidities), and for
culopathy, including accelerated atherosclerosis,
consideration of thromboembolic and antiepileptic
after radiation therapy has been described both
precautions.
in children and adults.18 Those with prolonged
survival may be at risk of a second malignancy as
Radiation Therapy Complications a late effect of radiation.
Radiation encephalopathy can be divided into
acute (within 2 wks of treatment), early delayed Chemotherapy Complications
(1Y4 mos after completion of therapy), or late Although temozolomide, noted previously as
delayed (4 mos to Q4 yrs) forms. There is less risk of modestly improving survival in GBM, is relatively
acute radiation encephalopathy with modern pro- well tolerated, adverse effects can include fatigue,
tocols. However, to avoid precipitating cerebral alopecia, constipation, and headache. Studies of an-
edema, corticosteroids should be maintained over tiangiogenic agents such as bevacizumab, a mono-
the radiation course, including avoidance of too clonal antibody that neutralizes vascular endothelial
rapid of a taper to a lower dose. Acute radiation growth factor, which is highly expressed in GBM, are
encephalopathy is the most likely form to be seen showing promise. More antiangiogenic agents are
in inpatient rehabilitation settings. The patient ex- undergoing trials, including aflibercept, which has
hibits headaches, nausea, decreased alertness, wors- 100 times the affinity for vascular endothelial growth
ening of existing focal symptoms, and possibly factor as bevacizumab.20
seizures. Individuals with metastatic brain tumor may be
Patients with early delayed encephalopathy, on a variety of chemotherapeutic agents, the dis-
thought to be caused by demyelination and often cussion of which is beyond the scope of this article.
termed a somnolence syndrome, can exhibit leth- However, concerns of particular importance to re-
argy and cognitive-behavioral changes.17 The en- habilitation would include fatigue (which occurs
cephalopathy often resolves over the course of because of numerous agents), peripheral poly-
several months, more rapidly with corticosteroids. neuropathy (also related to numerous agents but
It is necessary to distinguish the encephalopathy most notably vincristine and taxanes), and cardiac
from tumor recurrence or infection. effects (most notably related to anthracyclines).
Posterior fossa radiation can produce a delayed
syndrome of ataxia, diplopia, dysarthria, and nys- REHABILITATION NEEDS AMONG
tagmus, with most patients recovering over 6 to BRAIN TUMOR SURVIVORS
8 wks but rarely progressing to coma and even A seminal study found that more than 80% of
death.17 Among cranial nerves, the optic nerve is central nervous system tumor patients exhibit re-
most vulnerable to radiation toxicity.17 habilitation needs, the greatest proportion of any
Late delayed encephalopathy, including radia- tumor type.1 The most common neurologic com-
tion necrosis, can be difficult to distinguish from plications among brain tumor patients undergoing
recurrence. Prognosis is variable, and treatment for acute rehabilitation were described by Mukand and
necrosis includes resection.17 Late delayed en- include cognitive deficits (80%), weakness (78%),
cephalopathy may also present as an atrophy syn- and visual-perceptual deficits (53%). Three or more
drome after doses of greater than 3000 cGy whole deficits were seen in 75% of patients; and five or
brain irradiation. Symptoms consist of late-onset more deficits, in 39%.21 Hemispheric side of tumor



is of unclear significance. In one study of 68 patients databases, such as the Functional Independence
receiving neuropsychologic testing, Hahn et al.22 Measure,31 that exist for inpatient rehabilitation. In
found that individuals with left hemisphere tumors one study, the Barthel Index was a useful measure
have more memory problems, depressive symp- of functional status among outpatients undergoing
toms, distractability, impaired verbal fluency, and radiation therapy, correlating with the Karnofsky
verbal learning compared with those with right performance score and showing prognostic value in
brain lesions. However, another rehabilitation study terms of survival.32
reported better functional outcomes in those with As with cancer patients in general, there is a
left brain lesions compared with those with right need for improved methods to identify outpatient
brain lesions.23 In the study of Hahn et al., GBM brain tumor patients who may benefit from reha-
patients exhibited poorer psychomotor speed and bilitation. This is especially relevant for the subset
visual tracking than did individuals with other who have not undergone inpatient rehabilitation
etiologies of brain tumor. and may have milder, but still significant, deficits.
The Functional Assessment of Cancer Therapy33 has
Inpatient Brain Tumor Rehabilitation a brain subscale and a symptom index, which are of
Various studies have shown that brain tumor potential utility in identifying rehabilitation needs.
patients in acute rehabilitation settings make Although exercise has been one of the more
comparable functional gains as do patients under- robust areas of cancer rehabilitation research,34
going rehabilitation for stroke.23Y26 They have evidence is just beginning to emerge among brain
comparable or shorter length of stay and compa- tumor survivors and, in this group of patients,
rable rate of discharge with those of the community. might prove to be particularly efficacious. In addi-
There are conflicting data on whether radiation tion to the potentially debilitating effects of surgi-
concurrent with the rehabilitation stay is associated cal resection and adjuvant therapy, brain tumor
with better27 or worse23 outcomes. Better progress patients commonly receive heavy long-term doses
is likely to be made with the initial presentation of glucocorticoid therapy, which can produce severe
to inpatient rehabilitation, as opposed to a repeat muscle wasting and weakness.35Y37 Studies have
admission. Rehabilitation outcomes have not been suggested that resistance and endurance exercise
found to be significantly different in those with training can significantly reverse muscle atrophy
malignant vs. those with benign brain tumor, nor and weakness in noncancer clinical populations
among those with primary vs. those with metastatic treated with glucocorticoids.35,38,39 For those with
brain tumor.28 Reasons for the relatively favorable brain tumor, the best mode and vehicle for pro-
outcomes have been speculated to include generally moting exercise rehabilitation have yet to be de-
strong social supports, lack of associated injuries, termined. We may start to understand how best to
aggressive discharge planning because of prognosis, provide these services by first investigating patient
and possibly less behavioral sequelae than other preferences unique to this population.
brain rehabilitation populations, such as TBI.29 In one study investigating exercise preferences,40
Brain tumor patients, and cancer rehabilita- 75% of subjects had grade III or IV disease, pre-
tion patients in general, do seem to have a higher dominantly anaplastic astrocytoma and GBM. Only
incidence of interrupted rehabilitation stay,27,30 in 47% perceived themselves as able to exercise during
some studies ranging from 25% to 35%. Among treatment, whereas 84% did after treatment. Only
cancer patients in general, one retrospective study 45% wanted information about exercise during
found infection to be the major cause of interrupted treatment, whereas 70% did afterward. During
stay.30 Malignant vs. benign disease status has not treatment, the preferred form of exercise was
been found to affect incidence of interrupted stays,30 walking (51%), which did not change after treat-
perhaps because in the acute rehabilitation set- ment (53%). Home was the preferred site for exer-
ting, factors related to recent craniotomy and over- cise; only about 5% preferred to exercise at a
all severity of neurologic impairments predominate, hospital-based center. Individuals were more likely
rather than sequelae of other oncologic treatments to consider a local fitness center after, rather than
or long-term prognosis. during, treatment (22.6% vs. 9.4%). These data
suggest that although most studies of exercise in
Outpatient Brain Tumor Rehabilitation cancer survivors have been performed in either in-
Outcomes among outpatients with brain tumor patient hospital or supervised outpatient settings,
have not been as systematically described, in part at least some of the focus during treatment should
because of the lack of standardized metrics and be on developing a home program. Measuring



compliance with, and results of, the home program those encountered in other brain rehabilitation
compared with more directly supervised settings is populations. Although comprehensive coverage
also important.40 of such management is beyond the scope of this
Family and caregiver needs must also be ad- review, the following discussion highlights some
dressed, with concerns including dealing with family issues pertinent to brain tumor patients. Among
issues (changing roles and relationships, financial oncology patients, the concept of the ‘‘symptom
concerns, and patient need for assistance), managing cluster’’ has been described and often relates to
challenging behaviors, dealing with personal feelings, tumor biology, for example, fatigue and proinflam-
and navigating through the medical system (com- matory cytokine production.46 Regarding symptom
municating with the physician and understanding clusters, the brain tumor population has received
the system of care).41 Organizations that provide limited attention to date, although intracranial
patient support include the National Brain Tumor pressure and location-dependent factors are felt to
Foundation (http://www.braintumor.org), the Amer- be relevant.46 One survey of high-grade glioma
ican Brain Tumor Association (http://www.abta.org), patients found that the symptom cluster of depres-
the Brain Tumor Society (http://www.tbts.org), sion, fatigue, sleep disturbance, cognitive impair-
and the Children’s Brain Tumor Foundation ment, and pain were significantly correlated with
(http://www.childrensneuronet.org).42 each other and explained 62% of the variance in
functional status.47
Vocational Outcomes
Compared with other cancer survivor popula- Fatigue
tions, survivors of brain tumor and other neurologic Fatigue is commonly considered to have a
system malignancies are less likely to be working, multifactorial basis, including deconditioning,
which is related to their diagnosis (odds ratio [OR], endocrine-metabolic abnormalities, infection, ane-
2.2 for unemployment).43 Other diagnoses highly mia, depression, sleep disturbance, nutritional fac-
likely to affect long-term employment status include tors, and treatment adverse effects, including
head and neck cancers (OR, 1.7) and blood cancers chemotherapy, radiation, and antiepileptic drug ad-
(OR, 3.03). A report from the Finnish Cancer regis- verse effects.48 There is much overlap between mea-
try of 12,542 cancer survivors found that 45% of sures to treat fatigue and those to promote optimal
individuals with central nervous system malignan- cognitive function, especially attention. Fatigue may
cies were working 2Y3 yrs after diagnosis, com- be more pronounced in individuals with deep/central
pared with 69% of age- and sex-matched controls.44 compared with laterally situated brain tumors and
Data from the Childhood Cancer Survivor Study, in those with greater neurologic impairment.42 One
a very large registry with sibling controls, found study found fatigue (and also mood) to be worse
31.7% of survivors of pediatric central nervous sys- in individuals with low-grade brain tumor than
tem cancers reporting functional impairments into in a control group with hematologic malignancy.49
adulthood, with an OR of 18 compared with sib- For malignant brain tumor in particular, treatment
lings. (Functional impairments included need for may be protracted, with radiation therapy produc-
help with personal care needs, instrumental activi- ing fatigue and temozolomide, given cyclically over
ties of daily living, or impairments interfering with many months, with further potential for fatigue,
holding a job or attending school.) This was by far leading to progressive debility. The patient should
the highest percentage seen in survivors of any type be counseled about potential fatigue with treatment
of malignancy, followed by bone tumor survivors to maximize reconditioning efforts when the clinical
at 16.2%. However, the bone tumor survivors were status permits.
more likely to report activity limitations, which Nonpharmacologic treatments are similar to
focused on specific physical tasks such as climbing those advised for other types of cancer and include
stairs or walking one block (26.8% vs. 17.8%).45 exercise, behavioral and coping strategies, high-
protein diet, adequate hydration, and management
MANAGEMENT OF SPECIFIC of anemia. Pharmacologic treatments can include
COMPLICATIONS AND SYMPTOMS medications to optimize sleep, mood, and pain con-
DURING BRAIN TUMOR trol. Medications that may be aggravating fatigue
REHABILITATION should be changed or discontinued. Concern of an
Physical and cognitive impairments, common endocrine etiology of fatigue is particularly high in
symptoms, and medical complications in patients tumors involving the hypothalamic-pituitary axis,
with brain tumor are presumed to be similar to such as pituitary adenoma and craniopharyngioma.



Stimulants including methylphenidate and modafinil Cognitive therapy has also received attention.
may be effective in reducing fatigue.42 One study of glioma patients found improved sub-
jective, but not objective, cognitive functioning
Sleep Disturbance at the end of therapy. But at 6 mos, the cognitive
Sleep disturbance may occur in patients with rehabilitation group had improved attention and
brain tumor, just as in other etiologies of brain verbal memory and less report of mental fatigue
injury. As noted in ‘‘Fatigue,’’ related factors such as compared with randomized controls.55 Another
pain and depressed mood should be treated, if ap- study of brain tumor patients and their caregivers
propriate, as well as situational factors, such as reported good tolerance of a cognitive rehabilita-
nighttime noise and interruptions, and symptoms tion program, consisting of six 50-min sessions over
such as night sweats, hot flashes, and need for 2 wks, with 88% of participants reporting that
nighttime urination. Sleep agents should be pro- they used strategies consisting of a calendar and
vided if necessary. Hiccups may occur in the setting specific problem-solving skills. Although satisfac-
of brain tumor, especially medullary lesions, and tion was high, outcome data were limited because
may interfere with sleep if severe50; treatment is of limited follow-up. Quality-of-life scores (per
with chlorpromazine or numerous other agents. Functional Assessment of Cancer Therapy-Brain)
did not differ between subjects and controls.56 An-
Cognition other study of cognitive therapy in childhood can-
Cognitive dysfunction and attentional deficits cer survivors (twenty 2-hr sessions) found improved
are both very common and highly disrupting to academic performance in language and mathe-
many individuals with brain tumor. Among the matics and improved parent report of attention in
pharmacologic options used for cognitive dysfunc- daily activities but little impact on neurocognitive
tion in this setting, methylphenidate has been best variables, compared with controls. A higher level
studied. One study of 30 malignant glioma patients of ‘‘metacognitive strategies’’ (survivors attending
on varying doses of methylphenidate found effec- to and managing their own resources) was also
tiveness of dosing as low as 10 mg twice daily. Im- observed.19 A study using 12 cognitive subtests
provements were seen in various cognitive testing of the Repeatable Battery for the Assessment of
parameters pertaining to memory, reasoning, and Neuropsychological Status in glioma patients found
verbal fluency, as well as subjective benefits in that four subtests (Figure Copy, Coding, List
gait, stamina, and motivation.51 A controlled study Recognition, and Story Recall) captured 90% of
among pediatric cancer survivors, most of whom had the impaired subgroup.57
brain tumor diagnoses, found that most showed In children, younger age at treatment may be a
improved sustained attention, as well as caregiver risk factor for lower IQ,58 which is probably related
report of increased attentional ability.52 Another to impaired learning over a longer period subsequent
pediatric survivorship study of brain tumor and to treatment. However, in a study of 22 patients
leukemia patients, using a double-blind crossover after cerebellar tumor resection, age at onset did
design, found improved attention and parent and not influence long-term performance in cognitive
teacher report of attentional function, social func- function or postural responses.59 One study com-
tioning, and ‘‘academic competence.’’ Significant paring pediatric TBI and brain tumor survivors
adverse effects were also noted, with some subjects found more psychologic and social adjustment
discontinuing the drug.53 problems in the TBI group. TBI survivors were more
Other agents that have been studied include likely to externalize problems, and brain tumor
donepezil (after brain irradiation), ginkgo biloba, patients were more likely to internalize them.60
hyperbaric oxygen, bevacizumab (also in brain radi- Because of the prolonged treatment often re-
ation therapy patients), indomethacin (because of quired for childhood malignancies and the fact
preclinical research findings of restored neurogene- that pediatric neurologic malignancy patients are
sis from inflammatory blockade after cranial irradia- significantly less likely to finish high school than
tion), and combined treatment with levothyroxine peers,19 there has also been advocacy for improved
and liothyronine (in the setting of hypothyroidism).54 hospital-based education programs.
Most studies to date lack control groups, a concern
with designs involving precognitive and postcogni- Mood
tive testing, particularly because there may be a Low mood may be addressed with adjustment
significant learning effect from the repeated testing counseling and exercise, as well as with managing
itself. sleep, fatigue, and pain. Medication will also be



indicated in some cases and is generally selected phenobarbital.63 Conversely, chemotherapy drugs
based on tolerance and managing adverse effect have also been implicated in reducing anticonvul-
profiles. Bupropion should be avoided because of sant concentration and effectiveness, for example,
its effect of lowering the seizure threshold. effects of cisplatin and carmustine on phenytoin
and of adriamycin and cisplatin on carbamazepine
Weakness and valproate.63 Increased toxicity of antiepileptics
Weakness may be of central origin related to or chemotherapy agents has also been reported.
tumor location or may be caused by debility or Newer drugs including levetiracetam, gabapentin,
myopathy. Myopathy has been reported in 10% of lamotrigine, and topiramate are also being used
brain tumor patients receiving dexamethasone for successfully, with the advantage of fewer cognitive
more than 2 wks, with two-thirds of patients having adverse effects65 and lack of hepatic microsomal
onset between weeks 9 and 12.61 However, extended system induction. Studies of levetiracetam as an
duration of treatment is often needed to prevent add-on or monotherapy have found 50% reduction
radiation encephalopathy. Risk may be lower in in seizures in a majority (60%Y65%) of patients,
patients on phenytoin, probably because of induc- with few adverse effects.63,66 A recent consensus
tion of hepatic metabolism of the corticosteroid.61 A statement recommends levetiracetam (except in
nonfluorinated corticosteroid formulation, such as the presence of renal dysfunction) or lamotrigine
prednisone or hydrocortisone, may be preferable.61 (except in the presence of liver dysfunction) as first-
Physical training has been shown to improve line agents.67 Others point to valproate being better
muscle strength and size in individuals taking low tolerated than other first-line agents, with use of
to moderate doses of prednisone.62 Because onset this agent as first line and using newer agents as
of myopathic weakness may not occur for several add-ons.63 Gabapentin has been well tolerated, but
weeks, it is important to address physical activity efficacy may be somewhat less. Another reported
beyond the inpatient phase. adverse effect of anticonvulsants (especially phe-
nytoin, also phenobarbital and carbamazepine)
Seizures has been synergistic effect in risk for cutaneous
Seizures are a common presenting symptom reactions, including Stevens-Johnson syndrome,
of brain tumors, occurring in about 20%Y40% of in patients receiving cranial radiation therapy.
high-grade glioma patients and at least 50%Y85% Although the pathogenic mechanism is not well
of individuals with low-grade tumors. They are understood, it has been recommended that patients
the presenting symptom in 15%Y20% of patients undergoing radiation therapy receive agents with
with brain metastasis.12,63 Tumors involving cortical a low potential for allergic cutaneous reactions,
structures are more likely to be associated with sei- such as valproate, levetiracetam, or gabapentin.66
zure, especially those involving the temporal cortex, Prospective studies68,69 and a meta-analysis70
primary sensorimotor cortex, or supplemental areas, of brain tumor patients without previous seizure
and in younger individuals, especially children and have not found efficacy of prophylaxis. Limited
adolescents.63 Epilepsy may be refractory to treat- data exist for agents other than phenytoin, pheno-
ment in 12%Y50% of cases.63 Anticonvulsant agents barbital, and valproic acid. It is not known whether
are useful for treating a variety of other problems, electroencephalographic data have any role in
including depression, anxiety, behavioral issues, decision making.66 If a seizure has already occurred,
and pain.64 anticonvulsant treatment should be maintained,66
For seizure treatment, traditional first-line but guidelines on how long to keep patients on
agents such as phenytoin, carbamazepine, and val- anticonvulsant treatment after a seizure has oc-
proic acid are equally efficacious. A common adverse curred are lacking. For those with brain tumor,
effect is cytochrome P450 enzyme induction, seen incidence is related to tumor type, with low-
with phenobarbital, phenytoin, and carbamazepine grade gliomas presenting more frequently with
(and, to a lesser extent, lamotrigine and topiramate). seizures, compared with high-grade PBTs or me-
Cytochrome P450 induction is a concern because tastases.63,71Y74 Seizures are more likely in cortical
numerous chemotherapy agents are also metabo- tumors than in infratentorial, deep gray, or white
lized by this system, and use of antiseizure agents matter lesions.73
can result in accelerated metabolism, reducing the In rehabilitation, care is often rendered in
effects of such agents as taxanes, vinca alkaloids, and the postoperative period, raising the question of
methotrexate.63 The efficacy of corticosteroids may whether the context of the recent craniotomy makes
also be reduced by phenytoin, carbamazepine, and advisable a period of anticonvulsant management.



A consensus statement recommends (as a guide- heparin (LMWH), although it is increasingly being
line but not a standard) that anticonvulsants be used. When given for extended periods up to 6 mos,
tapered and discontinued after 1 wk in patients the incidence of recurrent thromboembolic disease
with no previous seizures.75 However, if the patient has been reported as 50% less with LMWH than
is to receive radiation, maintaining an anticon- with warfarin in patients with cancer (not limited
vulsant agent, preferably not one associated with to brain tumor).79 The shorter half-life of unfrac-
adverse cutaneous reactions (see above), is a con- tionated heparin is considered an advantage in
sideration.66 Results of studies after craniotomy dealing with the patient at risk of intracranial
(not limited to brain tumor patients) have been bleeding, but there is also a risk of transient over-
variable, ranging from lack of benefit for phenytoin anticoagulation with the heparin bolus. Sometimes,
or valproate76 to an older study favoring prophylaxis this concern is addressed by foregoing the bolus
because of higher-than-baseline risk for the first in lower risk thrombotic patients or using a mini
ten postoperative weeks.77 Therefore, for an individ- (half-dose) bolus.78
ual patient, discussion with other managing phys- Contraindications to anticoagulation include
icians, especially the neurosurgeon in the case of recent spontaneous bleeding (as opposed to blood in
postcraniotomy patients, remains prudent. the surgical cavity, which might not preclude
anticoagulation),78 severe thrombocytopenia,79 and
Thromboembolic Disease recent thrombolytic therapy.78 Relative contra-
Symptomatic venous thromboembolic disease indications include recent systemic bleeding and
has been described in 19%Y29% of patients with severe hypertension.78 High rates of spontaneous
gliomas and up to 60% if asymptomatic disease is hemorrhage are seen in the setting of thyroid
considered. Incidence in metastatic brain tumor cancer, melanoma, renal cell carcinoma, and cho-
patients is about 20%.78 Although a majority of cases riocarcinoma, and thus, anticoagulation is often
have been described postoperatively, thrombotic avoided in these tumor types. Conventionally,
events at other times throughout the clinical course full-dose anticoagulation is typically avoided for
can occur. Risk factors include larger tumors, lo- 10Y14 days after neurosurgery, but some studies
cation (supratentorial 9 infratentorial), presence of have found that it can be given safely as early as
intraluminal thrombosis in the tumor pathologic day 3.78 In the rehabilitation setting, the neu-
specimen (OR, 17.8),79 age older than 60 yrs, pres- rosurgeon should be involved in discussion and
ence of hemiparesis, use of chemotherapy, and decision making regarding the initiation of anti-
variable report of operative time greater than coagulation. Duration of treatment has been de-
4 hrs.78,79 Although malignancy itself is a risk factor scribed as extending up to 6Y12 mos in those
for thromboembolic disease, among postoperative with cured brain tumors and indefinitely in those
brain tumor patients, one series reported higher with ongoing malignancy.78
incidence in meningioma (up to 72%) than in ma- For prophylaxis, although mechanical mea-
lignant glioma or metastatic disease.80 sures are partially effective, especially pneumatic
The physiologic basis of thromboembolic risk compression, low-dose unfractionated heparin or
includes altered coagulation factors and weakness LMWH conveys additional benefit, with 38% risk
and immobility. In addition, corticosteroids may reduction compared with mechanical measures
increase risk of thromboembolic disease, based on alone in neurosurgical patients. The optimal pro-
increased levels of factors VII, VIII, and XI and of phylactic regimen has not been established. One
fibrinogen.78 In glioma patients, individuals with study found similar efficacy (nonsymptomatic throm-
blood type A or AB have a higher risk than do those boembolic disease) and bleeding rates (very low)
with blood type O, probably related to differences in between unfractionated heparin and LMWH, when
level of von Willebrand factor and factor VIII.81 combined with stockings and pneumatic compres-
In the setting of thromboembolic disease, in- sion.83 Aspirin 325 mg has also been suggested to
ferior vena cava filters have often been used because provide partial prophylaxis in high-risk patients,
of concern about risk of intracerebral hemorrhage although there is limited, but favorable, data.84 In
with systemic anticoagulation. However, compli- a recent meta-analysis of neurosurgical patients,
cation rates of inferior vena cava filters are high including but not limited to cancer patients, lower
in this population, described in up to 62% of rates of deep vein thrombosis were seen with ei-
patients.82 Bleeding with unfractionated heparin ther heparin modality than with stockings or pla-
treatment has been described in 0%Y4% of patients. cebo, but no statistically significant difference
Data are more limited with low-molecular-weight was found between the heparin modalities and



pneumatic compression. Incidence of intracranial cally significant functional gains in swallowing, with
bleeding was 1.52/1000 in the LMWH group and 50% of patients consuming a regular diet by time of
0.35/1000 with unfractionated heparin and, in the discharge home.89 Dysphagia has been described in
case of unfractionated heparin, did not differ from 85% of brain tumor patients at end of life.90
patients not receiving chemoprophylaxis. However,
the analysis was limited by the relatively small Communication and End-of-Life Issues
numbers of neoplasm and elderly patients.85 A re-
Patients and families often have questions about
cent trial (PRODIGE study) attempted to ran-
their primary oncology care and prognosis while in
domize patients who have malignant gliomas to
rehabilitation settings. Communication with the on-
treatment with dalteparin or placebo to determine
cology care services must be maintained to optimally
the benefits of primary prophylaxis.86 However, the
address such questions, and palliative care team ex-
study had to be terminated prematurely, and, al-
pertise should be sought when appropriate and
though patients receiving dalteparin had a lower
available. A change in status may result in a need for
rate of VTE, the difference did not reach statistical revised goal setting, for example, a switch from
significance.
strengthening and reconditioning to comfort and
safety.
Headache
Headaches have been reported in 53%Y77% of
brain tumor patients.42 More than three-quarters CONCLUSION
of patients exhibit the Btension[ type, but up to 5% Individuals with brain tumor have a high inci-
of patients will have migraine-like headaches. dence of neurologic impairments, resulting in func-
Although headaches are often generalized, supra- tional deficits for which rehabilitation services are
tentorial tumors tend to produce discomfort anterior necessary, and which evidence to date supports as
to a line drawn between the ears, and infratentorial beneficial. The overall care needs are similar to those
tumors refer to pain behind this line.50 Headaches are seen in individuals with other etiologies of brain
more common with infratentorial (64%Y84%) com- disorder, such as stroke or brain trauma. In the in-
pared with supratentorial (34%Y60%) lesions and patient rehabilitation setting, patients with brain
with midline (95%) tumors.50 Compared with other tumor have comparable functional outcomes as
headaches, those associated with increased intracra- other brain rehabilitation groups. Specific clinical
nial pressure are more likely to be severe, continuous, management concerns that pertain to the brain tu-
associated with nausea and vomiting, and refractory mor population, as discussed in this review, should
to analgesics. The headaches are thought to be caused be incorporated into patient care.
by local traction on pain-sensitive structures, such as
arteries, veins, venous sinuses, cranial nerves, and
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