|Year : 2019 | Volume
| 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
|Date of Submission||29-Mar-2019|
|Date of Acceptance||22-May-2019|
|Date of Web Publication||23-Jul-2019|
Prof. Mohammad Abu-Hegazy
Deapartment of Neurology, Mansoura University, Mansoura
Source of Support: None, Conflict of Interest: None
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.
Keywords: Cancer survivors, Childhood, Neurological, Psychiatric, Sequelae
|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;6:42-9
|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 Feb 25];6:42-9. Available from: http://www.jhrr.org/text.asp?2019/6/2/42/263245
| Introduction|| |
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
There are no conflicts of interest.
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