Clinical manifestations

Presentation and course

The effects of treatment of CNS tumors are highly variable and secondary to the location of the tumor, underlying tumor pathology, age of the patient, and ultimate treatment modalities required. The presentation and course of neurologic sequelae varies wildly based on the underlying symptom or sign, and common complications in pediatric brain tumor survivors are described.

Headaches. Headache is a common presentation of pediatric CNS tumors due to the location and increased intracranial pressure from both communicating and noncommunicating hydrocephalus. In a large meta-analysis of presenting symptoms, the most frequent cited complaint was headache in all groups (33%), with the highest incidence in posterior fossa tumors (67%) (34). Location of the tumor and age of the patient affected the rate of headache among pediatric patients across studies. Several studies correlated the location of tumor with infratentorial and midline location with increased headache prevalence at presentation compared to supratentorial tumors. Younger age (younger than 3 or 4 years) showed lower rates of headache at presentation, ranging from 10% to 30%, with nausea/vomiting and hydrocephalus being more prevalent (34).

Headaches are not only a presenting sign; several studies have reported a higher incidence of headaches in survivors and headache-related disability compared to sibling and community controls. There are similar trends in cancer survivors and the general population; females are more likely than males to develop post-therapy headaches, and headaches are the most common pain syndrome reported. In association with the CCSS self-reported questionnaires of survivors of pediatric cancer, Wells and colleagues showed that the cumulative incidence of headaches increased from 38% at 5 years post-diagnosis to 53% at 30 years from diagnosis, with a significant risk in survivors as compared to siblings (33).

Seizures. Seizures secondary to tumor location or hydrocephalus and neurosurgical intervention are common in pediatric brain tumor patients, as well as ongoing seizures in long-term survivors. About 1% to 3% of pediatric patients who present with new-onset seizures are diagnosed with brain tumors, whereas 12% to 30% of patients with brain tumors present with new-onset seizures. Location and histology are risk factors for seizures. Supratentorial location is a risk factor for seizures at presentation compared to infratentorial and midline location. Low-grade glial tumors are frequently associated with seizures and intractable epilepsy, particularly dysembryonal neuroepithelial tumors and ganglioglioma (32).

In survivors of pediatric brain tumors, seizures remain a significant symptom and cause an increased burden on quality of life. In the childhood cancer study of cancer survivors, seizures increased from 27% at 5 years post-diagnosis to 41% at 30 years, with 12 times higher risk in survivors compared to sibling controls. Subtotal resection, cortical location, frontal and temporal lobe radiation, history of stroke, and history of recurrence was associated with an increased risk of seizures (32; 33). Studies have shown that CNS tumor survivors with seizures have poorer executive function and processing speed, and resolution of seizures is associated with improved attention and memory (27).

Posterior fossa syndrome. Infratentorial tumors are the most common in the pediatric population and almost always necessitate surgical resection due to obstructive hydrocephalus and improved prognosis. Posterior fossa syndrome (also known as cerebellar mutism) is a unique complication following surgery in the pediatric population that was first described by Wisoff and Epstein in 1984. Since that time, the syndrome has been refined with attempts to clinically define the characteristics, risk factors, and long-term outcomes. It is typically characterized by the development of absence or reduction in speech within 1 week of surgery and is often accompanied by ataxia, tremor, hemiparesis, and emotional lability. Incidence after posterior fossa tumor surgery is reported in a wide range of 8% to 30% (04; 29; 15; 02). Tumor location and histology have been associated with increased risk, including higher rates in medulloblastoma compared to low-grade or pilocytic tumors. Midline/vermis location and invasion into the brainstem and cerebellar peduncles also confers higher risk (15; 02). The role of specific surgical techniques has been controversial, with some retrospective studies showing a difference in rates of posterior fossa syndrome and others showing no difference (04; 29). Additionally, younger age has been associated with increased risk (15).

Leukoencephalopathy. Survivorship of childhood cancer, and brain tumors in particular, has increased over the past 20 years with intensification of treatment, including radiation and chemotherapy. However, the long-term effects on the developing brain, cognition, and ability to continue to learn have been shown to be significantly affected in these patients. Chronic leukoencephalopathy and white matter changes have been associated with both radiation and chemotherapy. Clinically, patients who receive radiation have been shown to have significant neurocognitive impairment with declining IQ scores that continues for years after therapy. Neuropsychological testing has shown that while white matter changes can be delayed, neurocognitive impairment can begin shortly after the completion of therapy (26).

In addition to neurocognitive decline and inability to learn at the same rate as age-matched peers, leukoencephalopathy secondary to treatment can result in neurologic deficits depending on the areas involved. Motor involvement ranging from difficulties with fine motor skills and handwriting to more severe weakness and spasticity have been seen in conjunction with white matter changes; however, it is often difficult to correlate to white matter changes in combination with other treatments received (26). Although often transient, neurologic deficits can be more permanent and create lifelong deficits.

Imaging shows white matter changes, which can be either diffuse or focal symmetric or asymmetric T2 hyperintensities, often in the periventricular white matter, centrum semiovale, and corona radiata with or without cerebral volume loss (26). Several studies have shown that the degree of white matter loss is associated with poorer cognitive outcomes, including executive function, verbal learning, and parental reports of cognitive concerns (17; 16).

Risk factors for leukoencephalopathy and cognitive decline increase therapy at a younger ages as well as at higher radiation doses. Additionally, female sex has been associated with an increased risk of leukoencephalopathy. Those receiving a combination of radiation and chemotherapy, particularly high-dose and intrathecal methotrexate, also have an increased risk (26).

Neuropathy. Peripheral neuropathy is the most common neurologic complication of cancer treatment and has been described as present in up to 78% of pediatric cancer survivors (09). Certain chemotherapies, including the vinka alkaloid vincristine and platin-based therapies, are most implicated in peripheral neuropathy and are common treatments in pediatric CNS tumors (30). Vinka alkaloids commonly cause a lower limb, length-dependent predominant sensory axonal neuropathy that frequently resolves with cessation of the chemotherapy (14). However, increased cumulative doses have been associated with motor abnormalities, including foot drop and cranial nerve involvement, and autonomic dysfunction associated with constipation and ileus (30). Platin-based chemotherapy is also shown to cause peripheral neuropathy. Although most commonly seen with oxplatin (used mostly in adult malignancies), cisplatin has also been implicated in the development of neuropathy in pediatric patients and may have a more protracted course than that seen in vincristine (14). Studies evaluating the risk factors for developing peripheral neuropathy are mixed, but younger age at treatment possibly increases risk, as does cumulative dose, particularly of cisplatin. Additionally, genetic studies have evaluated and found that ethnicity and particular single nucleotide polymorphisms may increase risk (30). Despite the expected improvement with stopping chemotherapy, long-term survivors continue to have high reported incidences of peripheral neuropathies, and neuromuscular dysfunction in long-term survivors is associated with obesity, anxiety and depression, and decreased employment (09).

Vasculopathy. Cranial radiation therapy has been an integral part of improving survival in pediatric brain tumors over the past 40 years but has led to accelerated cranial radiation therapy vasculopathies. In a review of all cancer survivors, risk of late occurring strokes had a RR of 7.8 compared to that of sibling controls. Forty-three percent of the CNS survivor cohort reported strokes compared to 13% of non-CNS cancer survivors (22). Vasculopathy was detected in 9.9% of a large cohort of brain tumor survivors, with 6.2% designated as severe vasculopathy, most commonly seen in suprasellar/optic chiasmatic tumors. A higher dose of radiation is associated with a higher risk of vasculopathy as well as younger age at the time of radiation (01).

Radiation-induced moya-moya syndrome is a progressive, occlusive severe vasculopathy that develops after radiation with involvement of the distal carotid arteries and its proximal branches and can be seen after cranial radiation therapy. The highest incidence of moya-moya syndrome in pediatric CNS survivors are those with radiation to the optic chiasm/suprasellar region, commonly low-grade gliomas and craniopharyngiomas with its proximity to the Circle of Willis. Younger age at radiation and higher dose of radiation are risk factors for moya-moya syndrome development. Patients with underlying genetic factors, including neurofibromatosis type 1, are at higher risk at baseline, and radiation increases this risk (05).

A rare entity that is poorly understood in survivors of pediatric brain tumors after radiation therapy is SMART syndrome (stroke-like migraine attacks after radiation therapy), which is characterized by migraine-like headaches and focal neurologic deficits or seizures and is thought to be associated with vascular disease and ongoing reactivity.

Radiation necrosis. Radiation necrosis is a well-known complication of radiation therapy for CNS tumors and has been documented in the pediatric population (13). Oftentimes, radiation necrosis is asymptomatic and diagnosed on surveillance imaging, but when symptomatic, symptoms are related to the location of the necrosis and edema and can be similar to symptoms from tumor presentation. Cerebral cortex involvement can be associated with hemiparesis, numbness, seizures, or headaches. Brainstem involvement is associated with cranial nerve abnormalities, respiratory distress, and ataxia. Imaging characteristics of radiation necrosis can include ring enhancement with mass effect, which is difficult to distinguish from recurrent tumor. In pediatrics, radiation necrosis incidence has been reported in 3% to 26% of patients and is dependent on whether all cases are reported or only symptomatic cases (08; 07). In reports including both symptomatic and asymptomatic cases, the rates of symptomatic cases account for 10% to 30% of all cases and required treatment. Median time from radiation varies among reports, but it is most often seen 4 to 8 months post radiation. However, cases have been reported at as early as 1 month and as delayed as over 1 year. Although rates vary, there is particular interest in photon versus proton, especially in posterior fossa and brainstem fields, with concerns that proton therapy increases the risk of brainstem radiation necrosis. Reviews have shown that photon therapy causes brainstem necrosis at rates of 2% to 8%, whereas proton therapy shows rates of 9% to 16% (08).

Risk factors have been explored with attempted mitigation. A higher dose of radiation is associated with higher rates of radiation necrosis. Studies of proton therapy have shown that limiting doses to less than 55 Gy reduces the rates of radiation necrosis to those previously seen in photon therapy (08). In addition to dose, tumor pathology and location likely play a role. Although the majority of studies report outcomes in high-grade tumors, progressive low-grade tumors treated with radiation are also at risk for radiation necrosis. Similar to other studies, median time to show radiation changes was 6 months, with the majority showing changes within the first year. However, patients with low-grade gliomas showed that radiation changes continued and lasted a median of 2 years post-radiation, pointing to a more protracted course than that seen in high-grade tumors (07).

Sleep. Sleep is an integral part to cognitive function and wakefulness during the day and is often disrupted for patients undergoing cancer therapy. Brain tumor survivors are at increased risk of long-term sleep disorders due to the nature of the tumor itself disrupting sleep architecture as well as the treatment. A systematic review looking at sleep in brain tumor survivors found that survivors commonly reported excessive daytime sleepiness, fatigue, irregular breathing, and snoring. On polysomnography, sleep-related breathing disorders/apnea were present in 64% of survivors and secondary narcolepsy/hypersomnia was diagnosed in 41% of patients. Untreated sleep disorders are associated with decreased quality of life, worse social functioning, and worse school performance. Although tumor location was not statistically significant, suprasellar tumors, particularly craniopharyngiomas, are the most commonly reported location leading to sleep disorders and are likely related to hypothalamic involvement in critical sleep pathways (10; 23).

Secondary malignancies. An unfortunate complication of CNS cancer treatment is the risk for secondary malignancies. Evaluations of multi-institutional and population-based studies of long-term survivors have been studied to understand the incidence and risk factors of secondary malignancies (31; 33). A 20-year cumulative incidence of secondary malignancies of childhood cancer survivors has ranged from 3% to 6% across cohorts and increases to a 30-year cumulative incidence of up to 8% of all cancer survivors, a 4- to 6-fold increase from the general population (03; 31; 33). Radiation, in particular, poses an increased risk of secondary CNS malignancies in pediatric brain tumor survivors. CNS tumor survivors receiving cranial radiation therapy have been shown to have a significant increase in intracranial malignancies, with meningiomas and high-grade gliomas being most common. Meningiomas occur at the highest rate, although they were often noted to be omitted in studies due to their benign nature (03). Meningiomas are important to note in survivors, however, because in addition to the need for further surgery or treatment, having a secondary meningioma was shown to correlate with increased risk of other neurologic sequalae, including seizures, coordination issues, and decreased vision (33).

Risk factors associated with the development of secondary neoplasms include younger age, larger radiation volume, and higher radiation dose. Two large population-based cohort studies found a dose-dependent increase in rates of meningioma and glioma with higher radiation doses (31). The timing of development of secondary malignancies varies greatly and depends on the primary cancer, genetic predisposition syndromes, and dose of radiation received (03). Radiation-induced high-grade gliomas most commonly develop in the first decade after radiation. Meningiomas occur much later, with a median latency of around 20 years following radiation with some variability in a dose-dependent fashion (03; 31; 33).

Immunotherapy. Although not a specific symptom, immunotherapy has become an increasingly used modality in the treatment of pediatric CNS tumors and has its own unique associated neurologic complications of therapy. The landscape of immunotherapy is broad and includes immune checkpoint inhibitors (ICI), tumor-specific monoclonal antibodies, chimeric antigen receptor (CAR) T-cell therapy, vaccines, and oncolytic viral therapy. ICIs have the most data on neurologic toxicities and are seen in 4% to 6% of the ICI trials, including meningitis, encephalitis, peripheral neuropathy, and myasthenia gravis type presentations. These mostly occur in the acute period shortly after administration. Similarly, CAR T-cells are currently in phase I trials in pediatric brain tumors and being administered both intravenously and intrathecally. This leads to both direct and indirect immune responses; inflammation can lead to headaches, seizures, aphasia, and cerebral edema. These side effects can be serious in up to a third of patients and require close monitoring. Similar to ICI therapy, the neurologic side effects are mostly seen in the acute period of administration (12). The long-term neurologic effects of immunotherapy in brain tumor survivors is unknown but will need to continue to be monitored as immunotherapy becomes more prevalent in the treatment of these patients.

Prognosis and complications

Prognosis is variable and dependent on many factors, including treatment type, dose, and age of the patient. The neurocognitive deficits that follow radiotherapy are generally progressive, whereas the deficits caused by a tumor itself or by surgical resection tend to be fixed and may improve slightly. Chemotherapy-related neurologic dysfunction can be transient, static, or progressive depending on the agent, its use in concert with other anti-cancer modalities, and its dose and time course in a particular patient.

Seizures. The outcome of seizure control varies depending on the timing of onset of seizures, tumor location, tumor histology, and cancer-directed treatment received. Gross total resection, particularly in low-grade gliomas, is predictive of seizure freedom in up to 95% of patients, but in those with subtotal resection or recurrent tumor, seizures can be difficult to control. A large study showed that 13% of patients required two or more antiseizure medications in long-term follow-up (32).

Posterior fossa syndrome. The majority of reports on posterior fossa syndrome are retrospective in nature, with a wide range of tumor types, histology, and treatment types as well as difficulty classifying due to no standardized criteria for diagnosis and severity. One large medulloblastoma study prospectively evaluated all patients up to 5 years post-diagnosis and noted that all patients showed some neurologic recovery, but of those diagnosed with posterior fossa syndrome, none demonstrated a normal neurologic exam at 23 months post-diagnosis. Older age at diagnosis of posterior fossa syndrome and high ataxia score at baseline were associated with longer time to return of ambulation. Younger aged patients, while more likely to develop posterior fossa syndrome, tended to have faster and more complete recovery (15).

Neurocognitive outcomes and leukoencephalopathy. Neurocognitive decline and neurologic deficits from leukoencephalopathy and cancer therapy in patients with brain tumors (in addition to the tumor itself) varies wildly among patients and tumor types. Baseline delays prior to diagnosis as well as the development of hydrocephalus and seizures at presentation have been associated with worse prognosis. Ongoing educational and neurocognitive support can help create an individualized plan to help survivors reach their full potential.

Vasculopathy. The risk of vasculopathy and subsequent stroke risk is higher in cancer survivors as compared to the general population, and the risk continues to increase the further the survivor is from treatment in a dose-dependent fashion. Those receiving less than 50 Gy of cranial radiation therapy were shown to have a 12-fold increase 30 years after treatment (22). As patients age, the risk for stroke increases with associated comorbid conditions, including hypertension and diabetes, with atherosclerotic risk factors playing a more prevalent role at a younger age than the general population. Mitigating known controllable risk factors in patients with an increased risk of stroke secondary to vasculopathy can improve the prognosis and decrease stroke risk in this patient population.

Radiation necrosis. Prognosis of radiation necrosis in pediatrics is favorable, and the majority of patients remain asymptomatic and are followed with serial imaging showing resolution over time. However, a small percentage require acute treatment due to worsening neurologic function in the short term. Location of the tumor and subsequent radiation contribute to prognosis. Those developing radiation necrosis of the brainstem often have more severe symptoms and rarely require long-term supportive care due to the eloquent areas involved (06).

Sleep. Although sleep-related disorders are common and long-term ongoing issues for brain tumor survivors, treatment of the underlying sleep disorder portrays a good prognosis and reversal of the secondary consequences. Adequate recognition, diagnosis, and treatment can reverse the effects on quality of life and school performance for most patients.

Secondary malignancies. Prognosis for secondary malignancies is variable and depends on the specific underlying malignancy. Radiation-induced malignant gliomas have a dismal prognosis with no standard of care therapy, with 5-year survival of less than 20%. Secondary meningiomas showed a 5-year survival ranging from 70% to 100%, although they may often show progression over time and need multiple surgeries or repeat radiation (03).

Biological basis

Etiology and pathogenesis

Many nervous system cell types continue to divide and regenerate throughout life. Astrocytes and oligodendroglial populations replenish themselves continually, as do the endothelial cells that comprise the neurovasculature. These support cells are necessary for normal neuronal physiology and normal function of the peripheral nerves. These dynamic cell populations are vulnerable to the cytostatic and mutagenic actions of cancer therapies. In addition to supportive glial cells and their microenvironments, it is now better understood that neurogenesis continues postnatally, with hippocampal stem and progenitor cells contributing to new neuronal production, and appears to be critical to performance in memory tasks. The disruption of neurogenesis and proinflammatory environment induced by chemotherapy and radiation therapies can explain the cognitive and memory deficits often seen in cancer survivors despite normal conventional brain imaging (20). Mindfulness of these physiological processes may elucidate further targets for the prevention of cognitive decline in CNS tumor survivors.

Posterior fossa syndrome. Better understanding of clinical features, risk factors, and improvement in imaging techniques have dominated the literature in an attempt to understand the pathophysiology of posterior fossa syndrome. Diffusion-weighted imaging has shown that disruption of the dentate-thalamo-cortical pathway, as well as postoperative changes in the superior cerebellar peduncle and mesencephalic tegmentum, are implicated in the development of posterior fossa syndrome. In a retrospective study, damage to the left or bilateral dentate nucleus was found in 100% of those who developed posterior fossa syndrome and only 30% of those who did not. Additionally, involvement of the superior cerebellar peduncle was significantly associated with posterior fossa syndrome development (02). Other studies found that longer surgery and prolonged retraction were associated with the development of posterior fossa syndrome (04). A single center study in which surgical practices were adjusted, including telovelar approach and minimization of heavy retraction, showed a reduction in posterior fossa syndrome from 39% to 11% (04). Additionally, a prospective study showed that there was a significantly lower incidence of posterior fossa syndrome in high-volume pediatric centers as compared to low-volume centers (15).

Leukoencephalopathy and cognition. The pathogenesis of leukoencephalopathy is likely multifactorial and has been proposed to be related to ongoing inflammation, demyelination, and capillary loss. Autopsy reports of patients who received radiation identified ongoing inflammation and microglia with the cessation of neurogenesis, which could explain the inability to learn at similar rates and the higher risk seen in younger patients at critical times in neurodevelopment (21). With a wide range of clinical presentations, even with similar treatment regimens, a study looked to identify genetic markers that portrayed increased risk of development of leukoencephalopathy. No candidate gene predicted neurocognitive outcomes, but APOEe4 carriers showed worsening neurocognitive performance over time (16).

Neuropathy. The pathophysiology of chemotherapy-induced peripheral neuropathy is thought to be related to the disruption of microtubule formation, particularly the vinka alkaloids, which are mitotic inhibitors and causes apoptosis. Platinums similarly bind DNA strands, leading to cell arrest and each resulting in disruption and axonal damage (30).

Vasculopathy. The development of vasculopathy after radiation is a complex and multifactorial phenomenon.

Radiation can affect the vasculature via two broad mechanisms, leading to an increased risk of stroke. Cranial radiation therapy leads to early development of nonatherosclerotic arteriopathy (moya-moya in the most severe cases) through intimal thickening and medial necrosis as well as accelerated intracranial atherosclerosis, which leads to increased rates of atherosclerosis-related strokes in younger aged survivors compared to controls (05; 22).

Radiation necrosis. The exact mechanism of cerebral radiation necrosis is unknown, but two models have been proposed and have led to targeted therapy. Radiation causes disruption of the blood-brain barrier, vascular injury, and endothelial damage, leading to upregulation of cytokine production, VEGF over-expression, and intercellular adhesion molecules causing an inflammatory response and apoptosis. This ongoing endothelial damage and inflammatory response leads to increased blood-brain barrier permeability and vasogenic edema, which contributes to further cell necrosis. Additionally, radiation causes direct damage to glial cells that can lead to vasogenic edema and hypoxia that further upregulates VEGF. Oligodendrocyte damage can specifically lead to myelin loss and demyelination and further inflammation (28).

Sleep. The pathogenesis of sleep-related disorders in brain tumor survivors is likely multifactorial. Adenotonsillar hypertrophy and obesity contribute to obstructive sleep apnea, similar to the general population, and tumors in the hypothalamic region often lead to hypothalamic obesity and increase the risk of obstructive sleep apnea. Additionally, tumor location in the hypothalamus, brainstem, or posterior fossa are more likely to disrupt the sleep/wakefulness neural pathways as well as disrupt the balance of hypocretin and orexin produced by neurons in the hypothalamus that are critical to sleep architecture and modulating wakefulness (10).

Epidemiology

The incidence of neurosequelae of CNS tumors varies and depends on the age and gender of the patient, the location of the tumor, and the therapy modalities required. Although the majority of neurologic side effects occur during the first several months of treatment and are reversible, neurologic long-term effects remain one of the most common among pediatric cancer survivors. Studies of long-term survivors across all cancer types have shown the prevalence of neurologic symptoms range from 30% to 80%. Brain tumor survivors are unique in that in addition to chemotherapy-related effects, they show evidence of tumor and surgical-related complications as well as long-term effects of radiotherapy directed to the central nervous system with the highest risk of profound late effects (25).

Prevention

With an increase in recognition of long-term neurologic effects and the goal of understanding risk factors, prevention and early recognition have become an important focus in ongoing clinical trials. Screening guidelines and risk-reducing behaviors for common complications, including vascular imaging, surveillance for secondary malignancies, and abnormal endocrinopathies, have been developed by consensus groups to identify and treat complications early (25). Additionally, studies are looking at de-escalation of treatment strategies, such as reduced radiation doses or fields and early neurocognitive interventions that might limit radiation-induced neurologic long-term effects without affecting survival (NCT02724579, NCT01878617, NCT04065776). Additionally, a large phase III trial is looking at the role of memantine for neurocognitive protection in pediatric patients receiving cranial radiation therapy (NCT 04939597).

The Children’s Oncology Group has published well-defined long-term follow-up guidelines for childhood cancer survivors that are grouped based on the treatment received and include important neurologic testing and screening to improve recognition, diagnosis, and ultimately treat neurologic complications of cancer for survivors (11).

Differential diagnosis

Confusing conditions

Neurocognitive and other CNS symptoms in a patient with a known CNS malignancy should prompt evaluation for tumor recurrence, underlying toxic/metabolic process, and seizure activity. Peripheral nervous system symptoms may require EMG/NCV, metabolic evaluation, and lumbar puncture or imaging studies to look for extracranial metastases if the symptoms are not usually associated with the chemotherapeutic agents used.

Diagnostic workup

New nervous symptoms in a patient with a history of CNS malignancy should prompt evaluation for tumor recurrence, underlying toxic/metabolic process, and seizure activity, with consideration of brain/spine MRI, metabolic evaluation, lumbar puncture, or EMG/NCV depending on presenting symptoms.

Management

Posterior fossa syndrome. Although there has been increased knowledge in our understanding of the prevalence and pathogenesis of posterior fossa syndrome, no specific treatment is available. Reducing risk factors as well as intensive and prolonged therapies are the mainstay of treatment for these patients. Ongoing studies are needed to continue to develop risk mitigation as well as evaluate whether any particular treatments are more beneficial.

Leukoencephalopathy and cognitive. There is no known treatment or reversal for leukoencephalopathy or cognitive changes secondary to therapy. Intensive neurocognitive intervention and supportive care can help with educational intervention at an early stage and identify those that will need increased support in school to help achieve maximal potential. Ongoing studies of the medulloblastoma are looking at the ability to reduce radiation dose to decrease the long-term neurocognitive effects without affecting survival. Additionally, there is work looking into the use of memantine during and after radiation to evaluate the protective effect from neurocognitive decline secondary to radiation.

Neuropathy. Although multiple medications are often utilized in peripheral neuropathy, few have been shown to be efficacious in clinical trials. A review found evidence that supported the use of duloxetine and acupuncture as the only treatments to significantly reduce pain and improve quality of life. Topical formulations, including lidocaine, were not significantly helpful. Nonpharmacological interventions, such as exercise and physical therapy, as well as cognitive behavioral therapy did show significant improvement in pain and functional outcomes in cancer survivors (18).

Vasculopathy. There is no standard of treatment for patients with radiation vasculopathy, and treatment involves an individual approach for each patient. Primary preventative measures implemented in the general population, including control of comorbid conditions (hypertension, diabetes, atrial fibrillation, and tobacco use) and antiplatelet and anti-lipid medications, are recommended (11). In patients with severe vasculopathy or moya-moya syndrome and symptomatic stroke, surgical intervention for revascularization can be considered on an individual patient basis.

Radiation necrosis. For symptomatic radiation necrosis, dexamethasone is the standard of care to improve symptoms. However, given the side effects, newer treatments have been evaluated in pediatric patients, although prospective data are limited. Given the proposed pathogenesis and involvement of VEGF, bevacizumab, a VEGF monoclonal antibody, is being increasingly used for radiation necrosis. Small pediatric case series of bevacizumab have shown tolerable toxicities, with up to 90% showing both clinical and radiographic improvement, whereas standardized dosing and duration have not been established. Hyperbaric oxygen therapy is also a treatment option for symptomatic radiation necrosis and is thought to improve tissue oxygenation, leading to neovascularization and reduction of inflammation. Small case reports and series have shown that it is well-tolerated with limited side effects, and more than 50% show improvement clinically, radiographically, or both (06).

Sleep. Treatment is aimed at the specific sleep-related disorder and often requires a multimodal approach. Cognitive behavioral therapy for sleep-related disorders is often the first approach and remains an important tool. Melatonin can help regulate the sleep-wake cycle in pediatric patients. Sleep-related breathing disorders respond well to adenotonsillectomy as well as ventilatory treatment that can improve attention, social interaction, and school performance. Secondary narcolepsy is less studied, but evidence of stimulants or modafinil can be used and help with daytime fatigue and improve alertness during the day (19).

Secondary malignancies. Early recognition on screening is important in the outcomes and intervention, particularly in secondary meningiomas given their good survival. Screening guidelines for patients who received craniospinal radiation vary, although continued surveillance is important to recognize secondary malignancies. Treatment is focused on the underlying tumor type, although no standard of care therapy exists for radiation-induced gliomas, which are often resistant to repeat radiation and known chemotherapy. Further analysis on the risk factors, screening, and treatment for radiation-induced secondary malignancies is needed to better understand their biology and treatment.

Outcomes

Prognosis is variable and dependent on the specific neurologic symptom in question, underlying malignancy, treatment modalities, and age of the patient as well as any underlying comorbidities that can exacerbate neurologic complications. Goals of management include supportive care and limiting the effects on daily functioning through a mixture of nonpharmaceutical and pharmaceutical interventions.