Brain tumor rehabilitation


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O artigo fala sobre a reabilitação em pacientes com tumores cerebrais sob uma visão multidisciplinar, visando a funcionalidade e tratamento das sequelas.

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Brain tumor rehabilitation

  1. 1. Authors:Mary Vargo, MDAffiliations:From the Department of PhysicalMedicine and Rehabilitation,MetroHealth RehabilitationInstitute of Ohio, Case Western INVITED REVIEWReserve University, Cleveland.Correspondence:All correspondence and requests forreprints should be addressed to: Brain Tumor RehabilitationMary Vargo, MD, Case Western ReserveUniversity, Department of PhysicalMedicine and Rehabilitation, ABSTRACTMetroHealth Medical Center, 2500MetroHealth 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 ofFinancial disclosure statements have producing long-term disabling effects owing to the tumor itself and the effects ofbeen obtained, and no conflicts of treatment, including surgical complications, neurotoxic effects of radiation, andinterest have been reported by the debility caused by chemotherapy. Even benign or low-grade brain tumors canauthors or by any individuals in controlof 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 primary0894-9115/11/9005(Suppl)-0S50/0 brain tumor differ between pediatric and adult age groups. Evidence for effec-American Journal of PhysicalMedicine & 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 traumaticWilliams & Wilkins brain injury. Although patients with primary brain tumors have been better studied than those with metastatic disease, significant gains with inpatient rehabilitationDOI: 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 orS50 Am. J. Phys. Med. Rehabil. & Vol. 90, No. 5 (Suppl), May 2011 Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
  2. 2. ependymomas). Therefore, even for an individ- nant brain tumor (29.5/100,000) and 267,000 hadual 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 uncertaincourse. behavior.3 Among PBT diagnoses, the type of tumor pres- ent varies with age. Embryonal/neuroectodermalBRAIN 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 amongnew primary brain tumor (PBT) diagnoses in the adults (Table 1).7,8 Among PBT cases, meningiomasUnited 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 PBTsbenign tumor). Overall incidence is slightly greater are malignant women than in men (17.2 vs. 15.8/100,000); Children are more likely to have posterior fossahowever, malignant PBT occurs more often in men tumors than adults are, with the cerebellum beingthan in women (7.6 vs. 5.4/100,000).3 The inci- the most common location in children youngerdence of malignant PBT increases with age, and than 10 yrs and brainstem nearly as common asin 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 overlappingis 56 yrs.3 However, it should also be noted that regions (19.8%) are the most common locations.4brain 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 injurybenign)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 acutecidence 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 patientsestimated 359,000 people (131/100,000) living with needing and receiving rehabilitation services, asa 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) 55Y64 Meningioma (10.91) Glioblastoma (8.09) 65Y74 Meningioma (17.61) Glioblastoma (12.47) 75Y84 Meningioma (24.42) Glioblastoma (14.13) Q85 Meningioma (29.53) Glioblastoma (7.63) Data from American Brain Tumor Association Facts and Figures 2009 ( PNET indicates primitive neuroectodermal Brain Tumor Rehabilitation S51 Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
  3. 3. 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 Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
  4. 4. 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 haspoint 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 agethat the impact on overall function of the both the 7 yrs or after age 60 yrs are thought to be mosttumor (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, andtion therapies, there is also a heightened need for working memory are most commonly affected.19pain management, for other supportive medical Endocrine disturbance can occur, leading to growthmanagement (such as treatment of infection, bowel disturbance, the most common manifestation ofand 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 bothprecautions. in children and adults.18 Those with prolonged survival may be at risk of a second malignancy asRadiation Therapy Complications a late effect of radiation. Radiation encephalopathy can be divided intoacute (within 2 wks of treatment), early delayed Chemotherapy Complications(1Y4 mos after completion of therapy), or late Although temozolomide, noted previously asdelayed (4 mos to Q4 yrs) forms. There is less risk of modestly improving survival in GBM, is relativelyacute 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 endothelialrapid of a taper to a lower dose. Acute radiation growth factor, which is highly expressed in GBM, areencephalopathy is the most likely form to be seen showing promise. More antiangiogenic agents arein inpatient rehabilitation settings. The patient ex- undergoing trials, including aflibercept, which hashibits headaches, nausea, decreased alertness, wors- 100 times the affinity for vascular endothelial growthening of existing focal symptoms, and possibly factor as bevacizumab.20seizures. 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 occurscephalopathy often resolves over the course of because of numerous agents), peripheral poly-several months, more rapidly with corticosteroids. neuropathy (also related to numerous agents butIt is necessary to distinguish the encephalopathy most notably vincristine and taxanes), and cardiacfrom tumor recurrence or infection. effects (most notably related to anthracyclines). Posterior fossa radiation can produce a delayedsyndrome of ataxia, diplopia, dysarthria, and nys- REHABILITATION NEEDS AMONGtagmus, with most patients recovering over 6 to BRAIN TUMOR SURVIVORS8 wks but rarely progressing to coma and even A seminal study found that more than 80% ofdeath.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 undergoingrecurrence. Prognosis is variable, and treatment for acute rehabilitation were described by Mukand andnecrosis 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 moredrome after doses of greater than 3000 cGy whole deficits were seen in 75% of patients; and five orbrain irradiation. Symptoms consist of late-onset more deficits, in 39%.21 Hemispheric side of Brain Tumor Rehabilitation S53 Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
  5. 5. 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. MeasuringS54 Vargo Am. J. Phys. Med. Rehabil. & Vol. 90, No. 5 (Suppl), May 2011 Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
  6. 6. compliance with, and results of, the home program those encountered in other brain rehabilitationcompared with more directly supervised settings is populations. Although comprehensive coveragealso important.40 of such management is beyond the scope of this Family and caregiver needs must also be ad- review, the following discussion highlights somedressed, with concerns including dealing with family issues pertinent to brain tumor patients. Amongissues (changing roles and relationships, financial oncology patients, the concept of the ‘‘symptomconcerns, and patient need for assistance), managing cluster’’ has been described and often relates tochallenging behaviors, dealing with personal feelings, tumor biology, for example, fatigue and proinflam-and navigating through the medical system (com- matory cytokine production.46 Regarding symptommunicating with the physician and understanding clusters, the brain tumor population has receivedthe system of care).41 Organizations that provide limited attention to date, although intracranialpatient support include the National Brain Tumor pressure and location-dependent factors are felt toFoundation (, the Amer- be relevant.46 One survey of high-grade gliomaican Brain Tumor Association (, patients found that the symptom cluster of depres-the Brain Tumor Society (, sion, fatigue, sleep disturbance, cognitive impair-and the Children’s Brain Tumor Foundation ment, and pain were significantly correlated with( each other and explained 62% of the variance in functional status.47Vocational Outcomes Compared with other cancer survivor popula- Fatiguetions, survivors of brain tumor and other neurologic Fatigue is commonly considered to have asystem 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, includinghead 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 optimalindividuals with central nervous system malignan- cognitive function, especially attention. Fatigue maycies were working 2Y3 yrs after diagnosis, com- be more pronounced in individuals with deep/centralpared with 69% of age- and sex-matched controls.44 compared with laterally situated brain tumors andData from the Childhood Cancer Survivor Study, in those with greater neurologic impairment.42 Onea very large registry with sibling controls, found study found fatigue (and also mood) to be worse31.7% of survivors of pediatric central nervous sys- in individuals with low-grade brain tumor thantem cancers reporting functional impairments into in a control group with hematologic malignancy.49adulthood, with an OR of 18 compared with sib- For malignant brain tumor in particular, treatmentlings. (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 overties 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 shouldthe highest percentage seen in survivors of any type be counseled about potential fatigue with treatmentof malignancy, followed by bone tumor survivors to maximize reconditioning efforts when the clinicalat 16.2%. However, the bone tumor survivors were status permits.more likely to report activity limitations, which Nonpharmacologic treatments are similar tofocused on specific physical tasks such as climbing those advised for other types of cancer and includestairs or walking one block (26.8% vs. 17.8%).45 exercise, behavioral and coping strategies, high- protein diet, adequate hydration, and managementMANAGEMENT OF SPECIFIC of anemia. Pharmacologic treatments can includeCOMPLICATIONS AND SYMPTOMS medications to optimize sleep, mood, and pain con-DURING BRAIN TUMOR trol. Medications that may be aggravating fatigueREHABILITATION should be changed or discontinued. Concern of an Physical and cognitive impairments, common endocrine etiology of fatigue is particularly high insymptoms, 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 Brain Tumor Rehabilitation S55 Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
  7. 7. 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 beS56 Vargo Am. J. Phys. Med. Rehabil. & Vol. 90, No. 5 (Suppl), May 2011 Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
  8. 8. indicated in some cases and is generally selected phenobarbital.63 Conversely, chemotherapy drugsbased 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 carbamazepineWeakness 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 usedbrain tumor patients receiving dexamethasone for successfully, with the advantage of fewer cognitivemore than 2 wks, with two-thirds of patients having adverse effects65 and lack of hepatic microsomalonset between weeks 9 and 12.61 However, extended system induction. Studies of levetiracetam as anduration of treatment is often needed to prevent add-on or monotherapy have found 50% reductionradiation 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 consensustion of hepatic metabolism of the corticosteroid.61 A statement recommends levetiracetam (except innonfluorinated corticosteroid formulation, such as the presence of renal dysfunction) or lamotrigineprednisone 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 bettermuscle strength and size in individuals taking low tolerated than other first-line agents, with use ofto moderate doses of prednisone.62 Because onset this agent as first line and using newer agents asof myopathic weakness may not occur for several add-ons.63 Gabapentin has been well tolerated, butweeks, it is important to address physical activity efficacy may be somewhat less. Another reportedbeyond 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 wellof individuals with low-grade tumors. They are understood, it has been recommended that patientsthe presenting symptom in 15%Y20% of patients undergoing radiation therapy receive agents withwith 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.66zure, especially those involving the temporal cortex, Prospective studies68,69 and a meta-analysis70primary sensorimotor cortex, or supplemental areas, of brain tumor patients without previous seizureand in younger individuals, especially children and have not found efficacy of prophylaxis. Limitedadolescents.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 whetherare useful for treating a variety of other problems, electroencephalographic data have any role inincluding 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 onagents 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 corticalnumerous chemotherapy agents are also metabo- tumors than in infratentorial, deep gray, or whitelized by this system, and use of antiseizure agents matter lesions.73can result in accelerated metabolism, reducing the In rehabilitation, care is often rendered ineffects of such agents as taxanes, vinca alkaloids, and the postoperative period, raising the question ofmethotrexate.63 The efficacy of corticosteroids may whether the context of the recent craniotomy makesalso be reduced by phenytoin, carbamazepine, and advisable a period of anticonvulsant Brain Tumor Rehabilitation S57 Copyright © 2011 Lippincott Williams & Wilkins. 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  9. 9. 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 andS58 Vargo Am. J. Phys. Med. Rehabil. & Vol. 90, No. 5 (Suppl), May 2011 Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
  10. 10. pneumatic compression. Incidence of intracranial cally significant functional gains in swallowing, withbleeding was 1.52/1000 in the LMWH group and 50% of patients consuming a regular diet by time of0.35/1000 with unfractionated heparin and, in the discharge home.89 Dysphagia has been described incase of unfractionated heparin, did not differ from 85% of brain tumor patients at end of life.90patients not receiving chemoprophylaxis. However,the analysis was limited by the relatively small Communication and End-of-Life Issuesnumbers of neoplasm and elderly patients.85 A re- Patients and families often have questions aboutcent trial (PRODIGE study) attempted to ran- their primary oncology care and prognosis while indomize 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 optimallythe 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 andthough patients receiving dalteparin had a lower available. A change in status may result in a need forrate of VTE, the difference did not reach statistical revised goal setting, for example, a switch fromsignificance. strengthening and reconditioning to comfort and safety.Headache Headaches have been reported in 53%Y77% ofbrain tumor patients.42 More than three-quarters CONCLUSIONof 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 aretentorial tumors tend to produce discomfort anterior necessary, and which evidence to date supports asto a line drawn between the ears, and infratentorial beneficial. The overall care needs are similar to thosetumors refer to pain behind this line.50 Headaches are seen in individuals with other etiologies of brainmore 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 brainwith midline (95%) tumors.50 Compared with other tumor have comparable functional outcomes asheadaches, those associated with increased intracra- other brain rehabilitation groups. Specific clinicalnial 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, shouldto analgesics. The headaches are thought to be caused be incorporated into patient local traction on pain-sensitive structures, such asarteries, veins, venous sinuses, cranial nerves, andportions of the dura. REFERENCES Management of headache includes corticoste- 1. Lehmann J, DeLisa JA, Warren CG, et al: Cancer re-roids, especially in the setting of increased intracra- habilitation assessment of need development and education of a model of care. Arch Phys Med Rehabilnial pressure and, sometimes, surgery or radiation 1978;59:410Y9therapy. Analgesics will usually be required after 2. American Cancer Society. Cancer facts and figurescraniotomy. If headache recurs, there should be 2009. Atlanta, GA: American Cancer Society, 2009.suspicion of recurrent tumor. If oncologic worsening Available at: Accessed onhas been ruled out as producing the headache, in January 19, 2010most cases, management can proceed empirically 3. Horner MJ, Ries LAG, Krapcho M, et al, eds. SEERaccording to treatment for the symptom pattern (i.e., Cancer Statistics Review, 1975Y2006. Bethesda, MD:tension, migraine, neuralgic, cervicogenic, local tis- National Cancer Institute. Available at: http://seer.sue, or scar pain) seen in other conditions, such as headaches.87,88 4. Barnholtz-Sloan JS, Sloan AE, Schwartz AG: Chapter 25. Cancer of the brain and other central nervousDysphagia system. SEER Survival Monograph. Available at: A retrospective study found that 63% of brain 5. Gurney JG, Smith MA, Bunin GR: CNS and mis-tumor patients and 73% of stroke patients admitted cellaneous intracranial and intraspinal acute rehabilitation were identified as having SEER Pediatric Monograph. Bethesda, National Cancerdysphagia. When stroke and brain tumor dysphagia Institute, were matched, both had similar statisti- Brain Tumor Rehabilitation S59 Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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