Year : 2019 | Volume
: 6 | Issue : 2 | Page : 42--49
Neuropsychiatric sequelae in childhood brain tumor survivors
Mohammad Abu-Hegazy1, Hend Ahmed El-Hadaad2, Abdulkhaleq Saeed Alghamdi3,
1 Department of Neurology, Mansoura University, Mansoura, Egypt
2 Department of Clinical Oncology and Nuclear Medicine, Mansoura University, Mansoura, Egypt
3 Department of Emergency, Taif Mental Hospital, Taif, Saudia Arabia
Prof. Mohammad Abu-Hegazy
Deapartment of Neurology, Mansoura University, Mansoura
Childhood brain tumor (BT) survivors have increased. Physical, cognitive, social functions, and overall quality of life (QOL), may be diminished in response to tumors or their treatments in children. The tumor itself, surgery, chemotherapy, and radiotherapy can contribute to neurocognitive sequelae to debilitating levels. Short-term memory, attention, processing speed, visual-motor processing, and spatial relations deficits may occur months to years after treatment. BT survivors may develop motor, intellectual, visual, and psychoemotional dysfunctions, with moderate-to-severe disabilities. Among survivors of the central nervous system tumors, ocular deficits are common. Platinum-based chemotherapy and posterior and middle cranial fossa radiotherapy have contributed to ototoxicity. Survivors of treated temporal lobe cyst suffered from incapacitating depression and psychosis in one study; however, it is not clear if psychiatric and somatic symptoms are caused by BTs or as a response to psychological stresses after diagnosis or treatment. Childhood (BT) survivors experienced significant lower Health-Related QOL scores than in the normal population. It is a major challenge, for the medical team to prevent these late effects. The article will address the following items: neurological; including cognitive impairment and psychiatric sequelae; QOL in childhood (BT) survivors and how to minimize, prevent, and treat them. The neurological, cognitive, psychiatric, and social problems that develop early in childhood BT survivors may extend into adulthood. Life-long support and follow-up care are recommended for childhood BT survivors. Treatment protocols should be placed considering the reduction of neurocognitive and late neurological deficits.
|How to cite this article:|
Abu-Hegazy M, El-Hadaad HA, Alghamdi AS. Neuropsychiatric sequelae in childhood brain tumor survivors.J Health Res Rev 2019;6:42-49
|How to cite this URL:|
Abu-Hegazy M, El-Hadaad HA, Alghamdi AS. Neuropsychiatric sequelae in childhood brain tumor survivors. J Health Res Rev [serial online] 2019 [cited 2020 Jul 3 ];6:42-49
Available from: http://www.jhrr.org/text.asp?2019/6/2/42/263245
Childhood brain tumor (BT) survivors have increased recently. Physical, cognitive, social functions, and overall quality of life (QOL) may be diminished, as an impact to neurocognitive, neurological, and psychiatric deficits, in response to tumors or their treatments in children.
The tumor itself, surgery, chemotherapy, and particularly radiotherapy can all contribute to neurocognitive sequelae. Severe cognitive decline in children may result from cranial radiotherapy. Cognitive dysfunction, with prominent short-term memory affection, is perhaps the most common sequelae of BT therapy.
Patients experience progressive attention, memory function, quantitative skills, processing speed, visual-motor processing, and spatial relations deficits months to years after treatment.
In a study conducted on 56 childhood BT survivors with different tumors, Lannering et al. found, motor dysfunction in 25%, intellectual dysfunction in 38%, visual dysfunction in 20%, and psychoemotional dysfunction in 14%, and moderate or severe disability in 34%.
Childhood (BT) survivors experienced significant lower Health-Related QOL (HRQOL) scores than the normal population, for most aspects, as measured by the Medical Outcomes Short Form-36. Reports assessing QOL in pediatric patients have demonstrated lower overall QOL in children with central nervous system (CNS) tumors compared to their healthy counterparts. Tumor recurrence, location, and postoperative radiotherapy have an impact on QOL subscales.
Neurological Sequelae in Childhood Brain Tumors Survivors
Seventy percent of childhood BT survivors may suffer some abnormality in their neurological status as a late sequela; however, no significant differences between sex and treatment modalities were observed. Seizures have been developed in 21%–25% and nearly 50% have shown some motor/coordination impairment at least 5 years after diagnosis of BT in other studies. Sensorimotor deficits have been documented in more than 50% of posterior fossa BT survivors in literature.
Motor deficits in treated BT in the pediatric age group are multifactorial. They may be due to damage to the central areas that control movement and from peripheral nerve damage as well. Neurological symptoms may also be produced by compression upon adjacent structures and increased intracranial pressure. Resection of a tumor, in some instances, may worsen neurological problems existing or lead to new deficits.
Neurological deficits following radiotherapy are attributed to radiation field infarction or parenchymal necrosis. Vincristine chemotherapy is usually associated with peripheral motor neuropathy.
Ataxia, inability to coordinate movements voluntarily, results in children with lesions involving the cerebellum and can manifest as, dysarthria, tremors, dysmetria, dysphagia, gait changes, and low muscle tone. It is common with posterior fossa tumors. 26% and 49% of childhood BT survivors developed motor and coordination problems, respectively, in one study. Children receiving cancer therapy may also experience cranial nerve palsies, limb paresis, or hemiparesis/plegia.
Activities of daily living and individual's abilities at home, school, and work are always influenced by neurological motor deficits that impair physical function. One study reported that 155 BT survivors had lower grip strength and knee extension strength than healthy controls; lower exercise tolerance was also noted. Moreover, survivors with physical performance defects were more likely to reside as dependents and not to attend college than did controls.
Among survivors of CNS tumors, ocular deficits are also common. Cataracts, blindness, dry eyes, and double vision are not uncommon following radiotherapy involving the eye. Cataracts may also be produced after treatment with prednisone in childhood BT survivors, whereas treatment with chemotherapeutic agents such as vincristine, cytarabine, or doxorubicin, is associated with an increased risk of optic neuropathy, keratoconjunctivitis, and conjunctivitis. Significant impairment in performance limitations, and disability as well as physical functioning, will result from visual impairments.
Impaired balance in CNS tumors compared with normal controls, occurring because of tumor infiltration and removal, additionally after exposure to cranial irradiation. Although among survivors of childhood cancer, studies which have evaluated the effects of balance deficits on function, indicate that functional performance can be affected adversely by balance deficits.
Both platinum-based chemotherapy and posterior and middle cranial fossa radiotherapy have contributed to sensorineural ototoxicity and hearing loss. In a large study of 5-year survivors of various pediatric BTs, 20% was the prevalence of self-reported deafness or hearing loss.
Vinca alkaloids commonly used to treat BTs, most prominently vincristine and to a lesser extent, vinblastine and vinorelbine frequently cause peripheral neuropathy. Vincristine causes an axonal neuropathy affecting both sensory and motor fibers, particularly small sensory fibers through disruption of axonal microtubules in almost all patients. Fingertip and foot paresthesias, muscle cramps, foot and wrist drop, and sensory loss of varying degrees are the presenting clinical manifestations. Vincristine commonly causes an autonomic neuropathy, in addition, the sensory and motor neuropathies. Focal neuropathies and cranial neuropathies are also possible.
Of the late effects experienced by childhood BT survivors, neurocognitive impairment is the most prominent. Children's brains are vulnerable to effects of tumor-directed treatments as they are in a constant state of development. In addition to the tumor itself, treatment modalities can affect this development and alter neurocognitive outcomes.
Attention-deficit disorders, deficient mental processing speed, working memory impairment, and executive function loss combine together, resulting in academically and intellectually disadvantaged survivors. Intelligent quotient drops by about 3–4 points annually in some children. Brain changes as calcifications, leucoencephalopathy, and white matter volume decrease correlate with these neurocognitive functioning drops.
Childhood CNS malignancy survivors are at higher risk for impairment in neurocognitive functioning in adulthood, specifically, if they got a ventriculoperitoneal shunt placed, received cranial radiation, suffered a cerebrovascular stroke, or left with hearing or motor impairments. Neurocognitive impairment affects adversely important adult outcomes.
Short-term memory dysfunction is the most common neurocognitive sequela of BT therapy. Neurocognitive sequelae can be attributed to the tumor itself, neurosurgery, chemotherapy, and particularly radiotherapy. Cranial radiotherapy causes severe and incapacitating cognitive impairment in survived children.
In survivors with neuropsychological sequelae, hippocampal dysfunction is a prominent feature. Disruption of limbic and frontal networks implies for cognitive impairment.
Surgery and/or radiation to the brain, high systemic doses of methotrexate, and intrathecal methotrexate therapy can result in neurocognitive complications. Progressing neurocognitive deficits in children treated with cranial radiation, become apparent within 1–2 years following completion of therapy. Affected children may experience academic difficulties due to information-processing deficits, and are prone to problems in receptive attention span, visual perceptual motor skills, and expressive language. The reduction of cranial radiation dose for children and combined dose/field modification for children with BTs has resulted in a decrease in prevalence and severity of neurocognitive complications. Chemotherapy alone may lead to neurocognitive complications primarily restricted to attention, complex fine-motor functioning, and executive function; however, the evidence is less established.
Poorer neurocognitive outcomes are attributed to a number of well-known risk factors.
After treatment of CNS cancers, young age survivors have poor neurocognitive outcomes. This is due to the ongoing development of the nervous system particularly cortical and subcortical white matter. To lessen the neurocognitive defect without compromising the medical outcome in infantile BTs, delaying the use of cranial radiation therapy is advisable.
Perioperative neurological severity
Late neurocognitive effects in children operated for BTs are directly related to neurological severity in the perioperative period. Perioperative factors, such as seizures, hydrocephalic changes and disease comorbidities (e.g., Down Syndrome), and postoperative factors, such as ataxia and the total neurological severity score had been examined as predictors of neurocognitive outcome and founded significantly correlated with visuospatial skills, memory, attention, and performance intelligence quotient (IQ).
Radiotherapy was the most important predictor of cognitive adverse outcome.
Cranial irradiation using the biologically effective dose (BED) has previously shown to be significantly associated with endocrine outcome. There is a significant negative correlation between BED to the tumor site and verbal IQ.
Children with BTs under 3 years of age, treated without cranial radiation therapy had average range scores of intellectual functioning and academic achievement, in contrary to those who were treated with cranial radiotherapy who had significant deficits.
Copeland et al. characterized the neurocognitive functioning change, using growth curve analyses, to 27 children diagnosed as posterior fossa tumors during infancy and concluded that better neurocognitive outcomes were found in children with cerebellar tumors and absence of cranial radiotherapy. Other studies concluded that IQ decreases two or more points annually in those treated with radiotherapy.
Neurocognitive disability is closely related to needing-shunt hydrocephalus and is considered a significant risk factor. It is documented that patients who require shunting may have extensive brain tissue damage preoperatively and postoperatively as a complication of shunting, and this will result in a decrease in cognitive performance. Shunting for hydrocephalus before the age of 2 years even in patients without BTs has been associated with reduced IQ.
Hemispheric tumors have resulted in greater IQ impairment than in other areas.
Psychiatric Sequelae in Childhood Brain Tumors Survivors
Some survivors may experience anxiety, others depression, and many may develop somatic symptoms. It is unclear whether they are caused by psychological stress after the diagnosis and treatment or by the tumor itself.
Apathy and Depression
In a study conducted on children with posterior fossa tumors, the rate of apathy was significantly higher in survivors compared with the comparison group, even after group differences in age and sex were taken into account. Apathy was present in similar proportions in survivors of the two most common classes of posterior fossa tumors: medulloblastomas and astrocytomas. Depression and attention-deficit hyperactivity disorders were found in children with suprasellar and pineal region germ cell tumor survivors. Depressive symptoms refractory to antidepressant treatment was found following of left frontal neurocytoma surgical resection. Kugaya et al. reported depressed mood, agitation, depersonalization, ideas of reference, and suicidal ideation associated with ependymal cyst, while Burkle and Lipowski reported depression, hypersomnia, anhedonia, and low energy in patients with third and lateral ventricle colloid cyst, also poor concentration, memory lapses, and delusions are associated.
Excessive talking, elated mood, visual hallucinations, and grandiosity were present in children with third ventricle neuroepithelial cyst survivors even with no development of neurologic symptoms. Survivors with pontine cavernous angiomas may suffer enhanced talkativeness, personality changes, psychomotor agitation, decreased need for sleep, and sex drive.
Survivors after treatment of left temporal lobe intracerebral cyst were suffering from refractory depression and psychosis in a study conducted by Bunevicius et al. Treated bilateral basal ganglia germinoma survived children experienced psychosis and obsessive-compulsive disorders. Left hemiparesis, diabetes insipidus, and academic performance defects also resulted.
Ventricular cyst associated with personality changes, aggressive behavior, emotional lability and hypersexual behavior that showed some improvement with surgery.
Survivors with right sylvian valley cavernous hemangioma in the frontal side experienced anorexia nervosa that showed partial improvement with surgery. Anorexia nervosa, delusions, and catatonia are findings in survivors with right parietal lobe arachnoid cyst, hypothalamus teratomas, and third ventricle teratoma.
Quality of Life in Childhood Brain Tumors Survivors
QOL has been studied in survivors. Most of the studies have shown a significantly decreased QOL in comparison to the general population or to other childhood cancer survivors. Physical, psychological, social, and cognitive dimensions have been affected.
Poor HRQOL is reported in childhood BT survivors. Of psychosocial functioning, education, employment, marital status, ability to drive, and living independently are the main domains usually impaired. Childhood BTs survivors may also exhibit depression. In addition, they suffer from a spectrum of neuropsychiatric sequelae such as sensory impairment, seizures, apathy, inattention or processing speed impairment, sleep dysregulation, cognitive deficits, emotional deficits, and executive dysfunction. These sequelae result in disabilities that affect the survivors' daily lives with poor educational attainment, unemployment/underemployment, depression or anxiety, and physical performance limitations resulting in restricted environmental access. By the time, these deficits interfere with successful integration into society and accordingly affect life satisfaction.
In a study conducted on 49 Taiwanese childhood BT survivors, positive correlations were found between the type of cancer, protective factors, measures of resilience, measured by the Minneapolis-Manchester QOL Tool, while negative correlations were found between individual risks, illness-related risks, and HRQL. Others have found that personality traits such as imagination, in children surviving cancer significantly predict HRQL.
In one study that used the KINDL questionnaire, 49 survivors of mixed BTs rated their total HRQL higher than their peers, but their parents did not rate their children's HRQL as higher than their peers.
Cranial radiation treatment was identified as a risk factor for poor HRQL in three studies. The larger the volume of brain irradiated and radiation of children before the age of five was identified as negatively affecting HRQL.
One study reported mean total fatigue scores for 86 BT survivors as nearly two standard deviations lower than normative data. Children who had not received treatment in >1 year had a lower QOL score than children who had more recently completed treatment. In another study, HRQL scores were lower for patients with BTs reporting fatigue, including those who had not received treatment for years.
Prevention and Treatment of Neuropsychiatric Sequelae in Childhood Brain Tumors Survivors
It is a major challenge, for the medical team, psychologists and rehabilitation specialists, to prevent these late effects. Advances in neurosurgery, chemotherapy, and radiotherapy techniques help largely, but sometimes, it is not very successful in preventing these late complications. Prevention depends in part on the ability to predict those at greatest risk.
Preventing Neurocognitive Late Effects
Delivering a fractionated greater number of small doses of cranial radiation, effectively reduce toxicity to the surrounding normal tissue. Advanced radiotherapy techniques as stereotactic radiosurgery precisely target a tumor; the radiation converges on the tumor while sparing surrounding tissues. Conformal radiotherapy is also effective in minimizing neurocognitive late effects while successfully treating patients. Anxiety about the treatment, especially the need for immobilization with a mask, can be treatment-limiting. Adverse effects from treatment, including cognitive impairment and endocrinopathies, can result in psychiatric symptoms.
Intensity-modulated radiation therapy has been suggested as a way to spare neural stem cells when treating BTs.
Preliminary evidence suggests potential sparing of cognitive and academic functions with focal proton beam radiotherapy.
Prevention can be performed by applying advanced chemotherapy regimens such as regimens aimed to reduce therapies and/or dose to an acceptable toxicity level while maintaining therapeutic efficacy as well as others that aim to increase the dose than the toxic level by the addition of cytoenhancers and chemoprotectants to the regimens.
Butler and others conducted studies on childhood cancer survivors using three disciplines of training techniques: special education/educational psychology, brain injury rehabilitation, and clinical psychology and reported favorable results. In addition, cognitive rehabilitation programs aimed at improvement of memory, attention, and executive function, as well as comprehensive programs, which combine pharmacological and neuropsychological treatment modalities, may also be effective in preventing the neurocognitive decline in childhood BT survivors. The long-term functional outcome for children treated for low-grade astrocytoma is favorable; however, some patients report neurological complications and learning difficulties, which are unmet in school. Therefore, there is a need to identify those who need more thorough medical and cognitive follow-up programs including interventions in school.
Preventing and Treating Psychiatric Late effects
After treatment of tumors, neuropsychiatric and behavioral disorders can persist or worsen. psycho/as well as pharmaco/therapy can be used to improve the overall functions and QOL. Persistent psychiatric disorders' therapy is also complicated by the risk for development of delirium and seizures as possible side effects. Psychotic and depressive disorders may result from steroid use. Treatment using the multidisciplinary team approach it is of utmost value.
Psychiatric or behavioral symptoms may be completely cured after surgical excision, while debulking or preventing tumor growth may partially reduce these symptoms. Acute mass effects treatment, such as intracranial hypertension or hydrocephalus may control behavioral symptoms and improve cognitive functioning. The long-term functional outcome for children treated for low-grade astrocytoma is favorable. However, some patients report neurological complications and learning difficulties, which are unmet in school. Therefore, there is a need to identify those who need more thorough medical and cognitive follow-up programs including interventions in school.
Selective serotonin reuptake inhibitors have a favorable side effect profile and less potential to cause delirium. Methylphenidate is effective in patients with secondary depression. Mood stabilizers best treat manic symptoms. Possible neuroprotective effects of lithium in patients with BTs who treated with radiation have been explored. Electroconvulsive therapy is the modality of choice to treat refractory depression in BTs without edema or intracranial hypertension.
Psychotic syndromes with disturbances in thought content and processes, delusions, and hallucinations can be treated with antipsychotics. Most authors prefer the second-generation antipsychotics as they possess a lower incidence of adverse events compared to the first-generation antipsychotics. Some case reports noted the effectiveness of these agents; however, higher risk for seizures and delirium was noted with clozapine and olanzapine. Other treatment modalities such as psychotherapy are also important and helpful. It serves to improve the emotional and cognitive status, interpersonal and psychosocial impacts, and overall functional status. Development of effective but less toxic treatment protocols like targeted delivery modalities is crucial to preserve cognitive function in survivors of childhood BTs. Schools educational support is considered standard of care, also there is a significant opportunity to improve educational programming and to optimize academic outcomes. Intervention paradigms have shown some promise in recent years including direct training of neurocognitive functions affected by treatment for PBT.
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Conflicts of interest
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|1||Peris-Bonet R, Martínez-García C, Lacour B, Petrovich S, Giner-Ripoll B, Navajas A, et al. Childhood central nervous system tumours – Incidence and survival in Europe (1978-1997): Report from automated childhood cancer information system project. Eur J Cancer 2006;42:2064-80.|
|2||Lannering B, Marky I, Lundberg A, Olsson E. Long-term sequelae after pediatric brain tumors: Their effect on disability and quality of life. Med Pediatr Oncol 1990;18:304-10.|
|3||Anderson VA, Godber T, Smibert E, Weiskop S, Ekert H. Cognitive and academic outcome following cranial irradiation and chemotherapy in children: A longitudinal study. Br J Cancer 2000;82:255-62.|
|4||Strother D. Tumors of the central nervous system. In: Pizzo PA, editor. Principles and Practice of Pediatric Oncology. Philadelphia: Lippincott, Williams and Wilkins; 2002. p. 751-824.|
|5||Zeltzer LK, Lu Q, Leisenring W, Tsao JC, Recklitis C, Armstrong G, et al. Psychosocial outcomes and health-related quality of life in adult childhood cancer survivors: A report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev 2008;17:435-46.|
|6||Bhat SR, Goodwin TL, Burwinkle TM, Lansdale MF, Dahl GV, Huhn SL, et al. Profile of daily life in children with brain tumors: An assessment of health-related quality of life. J Clin Oncol 2005;23:5493-500.|
|7||Pietilä S, Korpela R, Lenko HL, Haapasalo H, Alalantela R, Nieminen P, et al. Neurological outcome of childhood brain tumor survivors. J Neurooncol 2012;108:153-61.|
|8||Macedoni-Luksic M, Jereb B, Todorovski L. Long-term sequelae in children treated for brain tumors: Impairments, disability, and handicap. Pediatr Hematol Oncol 2003;20:89-101.|
|9||Johnson DL, McCabe MA, Nicholson HS, Joseph AL, Getson PR, Byrne J, et al. Quality of long-term survival in young children with medulloblastoma. J Neurosurg 1994;80:1004-10.|
|10||Merchant TE, Pollack IF, Loeffler JS. Brain tumors across the age spectrum: Biology, therapy, and late effects. Semin Radiat Oncol 2010;20:58-66.|
|11||Cochrane DD, Gustavsson B, Poskitt KP, Steinbok P, Kestle JR. The surgical and natural morbidity of aggressive resection for posterior fossa tumors in childhood. Pediatr Neurosurg 1994;20:19-29.|
|12||Zorzi AP, Grant R, Gupta AA, Hodgson DC, Nathan PC. Cranial nerve palsies in childhood parameningeal rhabdomyosarcoma. Pediatr Blood Cancer 2012;59:1211-4.|
|13||Duffner PK, Horowitz ME, Krischer JP, Friedman HS, Burger PC, Cohen ME, et al. Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 1993;328:1725-31.|
|14||Ness KK, Morris EB, Nolan VG, Howell CR, Gilchrist LS, Stovall M, et al. Physical performance limitations among adult survivors of childhood brain tumors. Cancer 2010;116:3034-44.|
|15||Gunn ME, Lähdesmäki T, Malila N, Arola M, Grönroos M, Matomäki J, et al. Late morbidity in long-term survivors of childhood brain tumors: A nationwide registry-based study in Finland. Neuro Oncol 2015;17:747-56.|
|16||Kadan-Lottick NS, Dinu I, Wasilewski-Masker K, Kaste S, Meacham LR, Mahajan A, et al. Osteonecrosis in adult survivors of childhood cancer: A report from the childhood cancer survivor study. J Clin Oncol 2008;26:3038-45.|
|17||Whelan KF, Stratton K, Kawashima T, Waterbor JW, Castleberry RP, Stovall M, et al. Ocular late effects in childhood and adolescent cancer survivors: A report from the childhood cancer survivor study. Pediatr Blood Cancer 2010;54:103-9.|
|18||Schoch B, Hogan A, Gizewski ER, Timmann D, Konczak J. Balance control in sitting and standing in children and young adults with benign cerebellar tumors. Cerebellum 2010;9:324-35.|
|19||Brown CJ, Flood KL. Mobility limitation in the older patient: A clinical review. JAMA 2013;310:1168-77.|
|20||Armstrong GT, Liu Q, Yasui Y, Huang S, Ness KK, Leisenring W, et al. Long-term outcomes among adult survivors of childhood central nervous system malignancies in the childhood cancer survivor study. J Natl Cancer Inst 2009;101:946-58.|
|21||Graf WD, Chance PF, Lensch MW, Eng LJ, Lipe HP, Bird TD. Severe vincristine neuropathy in Charcot-Marie-tooth disease type 1A. Cancer 1996;77:1356-62.|
|22||Ris MD, Noll RB. Long-term neurobehavioral outcome in pediatric brain-tumor patients: Review and methodological critique. J Clin Exp Neuropsychol 1994;16:21-42.|
|23||Askins MA, Moore BD 3rd. Preventing neurocognitive late effects in childhood cancer survivors. J Child Neurol 2008;23:1160-71.|
|24||Ellenberg L, Liu Q, Gioia G, Yasui Y, Packer RJ, Mertens A, et al. Neurocognitive status in long-term survivors of childhood CNS malignancies: A report from the childhood cancer survivor study. Neuropsychology 2009;23:705-17.|
|25||Abayomi OK. Pathogenesis of cognitive decline following therapeutic irradiation for head and neck tumors. Acta Oncol 2002;41:346-51.|
|26||Reimers TS, Ehrenfels S, Mortensen EL, Schmiegelow M, Sønderkaer S, Carstensen H, et al. Cognitive deficits in long-term survivors of childhood brain tumors: Identification of predictive factors. Med Pediatr Oncol 2003;40:26-34.|
|27||Wahba HA, Abu-Hegazy M, Wasel Y, Ismail EI, Zidan AS. Adjuvant chemotherapy after reduced craniospinal irradiation dose in children with average-risk medulloblastoma: A 5-year follow-up study. J BUON 2013;18:425-9.|
|28||Kadan-Lottick NS, Brouwers P, Breiger D, Kaleita T, Dziura J, Liu H, et al. A comparison of neurocognitive functioning in children previously randomized to dexamethasone or prednisone in the treatment of childhood acute lymphoblastic leukemia. Blood 2009;114:1746-52.|
|29||Ater JL, van Eys J, Woo SY, Moore B 3rd, Copeland DR, Bruner J. MOPP chemotherapy without irradiation as primary postsurgical therapy for brain tumors in infants and young children. J Neurooncol 1997;32:243-52.|
|30||Ater JL, Moore BD 3rd, Francis DJ, Castillo R, Slopis J, Copeland DR. Correlation of medical and neurosurgical events with neuropsychological status in children at diagnosis of astrocytoma: Utilization of a neurological severity score. J Child Neurol 1996;11:462-9.|
|31||Taylor RE, Bailey CC, Robinson K, Weston CL, Ellison D, Ironside J, et al. Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom children's cancer study group PNET-3 study. J Clin Oncol 2003;21:1581-91.|
|32||Cichowski K, Shih TS, Schmitt E, Santiago S, Reilly K, McLaughlin ME, et al. Mouse models of tumor development in neurofibromatosis type 1. Science 1999;286:2172-6.|
|33||Copeland DR, deMoor C, Moore BD 3rd, Ater JL. Neurocognitive development of children after a cerebellar tumor in infancy: A longitudinal study. J Clin Oncol 1999;17:3476-86.|
|34||Spiegler BJ, Bouffet E, Greenberg ML, Rutka JT, Mabbott DJ. Change in neurocognitive functioning after treatment with cranial radiation in childhood. J Clin Oncol 2004;22:706-13.|
|35||Hoppe-Hirsch E, Laroussinie F, Brunet L, Sainte-Rose C, Renier D, Cinalli G, et al. Late outcome of the surgical treatment of hydrocephalus. Childs Nerv Syst 1998;14:97-9.|
|36||Madhusoodanan S, Ting MB, Farah T, Ugur U. Psychiatric aspects of brain tumors: A review. World J Psychiatry 2015;5:273-85.|
|37||Carroll C, Watson P, Spoudeas HA, Hawkins MM, Walker DA, Clare IC, et al. Prevalence, associations, and predictors of apathy in adult survivors of infantile (<5 years of age) posterior fossa brain tumors. Neuro Oncol 2013;15:497-505.|
|38||Oreskovic NM, Strother CG, Zibners LM. An unusual case of a central nervous system tumor presenting as a chief complaint of depression. Pediatr Emerg Care 2007;23:486-8.|
|39||Kohler CG, Burock M. ECT for psychotic depression associated with a brain tumor. Am J Psychiatry 2001;158:2089.|
|40||Kugaya A, Fujikawa T, Yoshimura Y, Uchitomi Y, Yamawaki S, Hirohata T. Ependymal cyst and psychiatric symptoms. J Neurol Neurosurg Psychiatry 1996;60:461-2.|
|41||Burkle FM Jr., Lipowski ZJ. Colloid cyst of the third ventricle presenting as psychiatric disorder. Am J Psychiatry 1978;135:373-4.|
|42||Bhatia MS, Srivastava S, Jhanjee A, Oberoi A. Colloid cyst presenting as recurrent mania. J Neuropsychiatry Clin Neurosci 2013;25:E01-2.|
|43||Yetimalar Y, Iyidogan E, Basoglu M. Secondary mania after pontin cavernous angioma. J Neuropsychiatry Clin Neurosci 2007;19:344-5.|
|44||Bunevicius A, Deltuva VP, Deltuviene D, Tamasauskas A, Bunevicius R. Brain lesions manifesting as psychiatric disorders: Eight cases. CNS Spectr 2008;13:950-8.|
|45||Mordecai D, Shaw RJ, Fisher PG, Mittelstadt PA, Guterman T, Donaldson SS. Case study: Suprasellar germinoma presenting with psychotic and obsessive-compulsive symptoms. J Am Acad Child Adolesc Psychiatry 2000;39:116-9.|
|46||Jones AM. Psychiatric presentation of a third ventricular colloid cyst in a mentally handicapped woman. Br J Psychiatry 1993;163:677-8.|
|47||Houy E, Debono B, Dechelotte P, Thibaut F. Anorexia nervosa associated with right frontal brain lesion. Int J Eat Disord 2007;40:758-61.|
|48||Wolańczyk T, Komender J, Brzozowska A. Catatonic syndrome preceded by symptoms of anorexia nervosa in a 14-year-old boy with arachnoid cyst. Eur Child Adolesc Psychiatry 1997;6:166-9.|
|49||Chipkevitch E, Fernandes AC. Hypothalamic tumor associated with atypical forms of anorexia nervosa and diencephalic syndrome. Arq Neuropsiquiatr 1993;51:270-4.|
|50||Berek K, Aichner F, Schmutzhard E, Kofler M, Langmayr J, Gerstenbrand F. Intracranial germ cell tumor mimicking anorexia nervosa. Klin Wochenschr 1991;69:440-2.|
|51||Brinkman TM, Li Z, Neglia JP, Gajjar A, Klosky JL, Allgood R, et al. Restricted access to the environment and quality of life in adult survivors of childhood brain tumors. J Neurooncol 2013;111:195-203.|
|52||Zeltzer LK, Recklitis C, Buchbinder D, Zebrack B, Casillas J, Tsao JC, et al. Psychological status in childhood cancer survivors: A report from the childhood cancer survivor study. J Clin Oncol 2009;27:2396-404.|
|53||Mostow EN, Byrne J, Connelly RR, Mulvihill JJ. Quality of life in long-term survivors of CNS tumors of childhood and adolescence. J Clin Oncol 1991;9:592-9.|
|54||Zebrack BJ, Gurney JG, Oeffinger K, Whitton J, Packer RJ, Mertens A, et al. Psychological outcomes in long-term survivors of childhood brain cancer: A report from the childhood cancer survivor study. J Clin Oncol 2004;22:999-1006.|
|55||Nolan VG, Gapstur R, Gross CR, Desain LA, Neglia JP, Gajjar A, et al. Sleep disturbances in adult survivors of childhood brain tumors. Qual Life Res 2013;22:781-9.|
|56||Kirchhoff AC, Krull KR, Ness KK, Park ER, Oeffinger KC, Hudson MM, et al. Occupational outcomes of adult childhood cancer survivors: A report from the childhood cancer survivor study. Cancer 2011;117:3033-44.|
|57||Brinkman TM, Zhu L, Zeltzer LK, Recklitis CJ, Kimberg C, Zhang N, et al. Longitudinal patterns of psychological distress in adult survivors of childhood cancer. Br J Cancer 2013;109:1373-81.|
|58||Chou LN, Hunter A. Factors affecting quality of life in Taiwanese survivors of childhood cancer. J Adv Nurs 2009;65:2131-41.|
|59||De Clercq B, De Fruyt F, Koot HM, Benoit Y. Quality of life in children surviving cancer: A personality and multi-informant perspective. J Pediatr Psychol 2004;29:579-90.|
|60||Musial-Bright L, Panteli L, Hernáiz Driever P. Pediatric low-grade glioma survivors experience high quality of life. Childs Nerv Syst 2011;27:1895-902.|
|61||Aarsen FK, Paquier PF, Arts WF, Van Veelen ML, Michiels E, Lequin M, et al. Cognitive deficits and predictors 3 years after diagnosis of a pilocytic astrocytoma in childhood. J Clin Oncol 2009;27:3526-32.|
|62||Barr RD, Simpson T, Whitton A, Rush B, Furlong W, Feeny DH, et al. Health-related quality of life in survivors of tumours of the central nervous system in childhood – A preference-based approach to measurement in a cross-sectional study. Eur J Cancer 1999;35:248-55.|
|63||Meeske K, Katz ER, Palmer SN, Burwinkle T, Varni JW. Parent proxy-reported health-related quality of life and fatigue in pediatric patients diagnosed with brain tumors and acute lymphoblastic leukemia. Cancer 2004;101:2116-25.|
|64||Meeske KA, Patel SK, Palmer SN, Nelson MB, Parow AM. Factors associated with health-related quality of life in pediatric cancer survivors. Pediatr Blood Cancer 2007;49:298-305.|
|65||Abu-Hegazy M, El-Hadaad HA. Neurocognitive Effects of Primary Brain Tumors. IN: Agrawal A, editor. Neurooncology-Newer Developments, IntechOpen, London, 2016. p. 241. DOI: 10.5772/62924. Available from: https://www.intechopen.com/books/neurooncology-newer-developments/neurocognitive-effects-of-primary-brain-tumors. [Last accessed 2019 Jun 03].|
|66||Holmes EG, Holmes JA, Park EM. Psychiatric care of the radiation oncology patient. Psychosomatics 2017;58:457-65.|
|67||Jaganathan A, Tiwari M, Phansekar R, Panta R, Huilgol N. Intensity-modulated radiation to spare neural stem cells in brain tumors: A computational platform for evaluation of physical and biological dose metrics. J Cancer Res Ther 2011;7:58-63.|
|68||Warren E, Child A, Cirino P, Grosshans D, Mahajan A, Paulino A, et al. QOL-24. Better social, cognitive and academic outcomes among pediatric brain tumor survivors treated with proton versus photon radiation therapy. Neuro Oncol 2018;20:166.|
|69||Doolittle ND, Anderson CP, Bleyer WA, Cairncross JG, Cloughesy T, Eck SL, et al. Importance of dose intensity in neuro-oncology clinical trials: Summary report of the sixth annual meeting of the blood-brain barrier disruption consortium. Neuro Oncol 2001;3:46-54.|
|70||Butler RW. Attentional processes and their remediation in childhood cancer. Med Pediatr Oncol 1998;Suppl 1:75-8.|
|71||Copeland DR, Askins MA. Behavioral medicine in cancer care. In: Chan K, Raney RB. editors. Pediatric Oncology. New York, NY: Springer Science and Business Media, Inc.; 2005. p. 244-255|
|72||Gehring K, Sitskoorn MM, Aaronson NK, Taphoorn MJ. Interventions for cognitive deficits in adults with brain tumours. Lancet Neurol 2008;7:548-60.|
|73||Price TR, Goetz KL, Lovell MR. Neuropsychiatric aspects of brain tumors. In: Yudofsky SC, Hales RE, editors. The American Psychiatric Publishing Textbook of Neuropsychiatry and Behavioral Neurosciences. 5th ed. Arlington, VA: American Psychiatric Publishing, 2007. p. 735-64.|
|74||Kristiansen I, Strinnholm M, Strömberg B, Frisk P. Clinical characteristics, long-term complications and health-related quality of life (HRQoL) in children and young adults treated for low-grade astrocytoma in the posterior fossa in childhood. J Neurooncol 2019;142:203-10.|
|75||Dubovsky SL. Psychopharmacological treatment in neuropsychiatry. In: Yudofsky SC, Hales RE, editors. The American Psychiatric Press Textbook of Neuropsychiatry. Washington, DC: American Psychiatric Press, 1992. p. 663-701.|
|76||Meyers CA, Weitzner MA, Valentine AD, Levin VA. Methylphenidate therapy improves cognition, mood, and function of brain tumor patients. J Clin Oncol 1998;16:2522-7.|
|77||Khasraw M, Ashley D, Wheeler G, Berk M. Using lithium as a neuroprotective agent in patients with cancer. BMC Med 2012;10:131.|
|78||Krayem BH, Dunn NR, Swift RG. Psychosis after right temporal lobe tumor resection and recurrence. J Neuropsychiatry Clin Neurosci 2014;26:E47.|
|79||Stoudemire A, Fogel BS, Gulley LR, Moran MG. Psychopharmacology in the medical patient. In: Stoudemire A, Fogel BS, editors. Psychiatric Care of the Medical Patient. New York: Oxford University Press; 1993. p. 155-206.|
|80||Alias H, Lau SC, Schuitema I, de Sonneville LM. Neuropsychological consequences for survivors of childhood brain tumor in Malaysia. Front Psychol 2018;9:703.|
|81||Stavinoha PL, Askins MA, Powell SK, Pillay Smiley N, Robert RS. Neurocognitive and psychosocial outcomes in pediatric brain tumor survivors. Bioengineering (Basel) 2018;5. pii: E73.|