General Child Neurology
Perinatal hypoxic-ischemic encephalopathy
May. 30, 2022
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Short- and long-term complications of antineoplastic treatment of brain tumors contribute greatly to the morbidity of these neoplasms. In this updated article, the author discusses the complications and long-term sequelae of treatment for brain tumors. Surgery, radiation therapy, chemotherapy, and immunotherapy are considered; treatment of complications and comorbidities of brain tumors (eg, antiseizure medications for symptomatic seizure prevention) are considered elsewhere in MedLink Neurology.
• Although survival from childhood brain tumors has improved greatly, sequelae of their treatment remain problematic.
• Enhanced targeting of brain tumor treatment based on molecular characteristics of the individual tumor holds the promise of avoiding some sequelae of treatment.
• Sequelae of brain tumor treatment during childhood are related to the predominant locations of these tumors, insufficient targeting of treatments to the neoplastic cells, and the potential of de novo oncogenesis and secondary tumors to result from DNA- and replication-targeted therapies.
The impact of tumors of the CNS on patients results not only from their high morbidity and mortality rates, but also from the sequelae of the tumors themselves and the treatment thereof. Neurocognitive sequelae are perhaps the most problematic of the effects of the treatment of CNS tumors; they can occur in both children and adults. Symptomatic epilepsy, motor and sensory dysfunction, and vascular changes also occur as early or remote effects of treatment.
Determinants of incidence and nature of sequelae of treatment of CNS tumors. Whether and in what form sequelae occur after treatment of CNS tumors depends on a variety of factors (115). The location of the tumor is critical, particularly in patients for whom surgery or local implantation of a radiation source is part of the treatment (26). For example, in children with craniopharyngiomas, endocrine sequelae are common because of the proximity of the pituitary to the tumor and treatment site (58; 49). Regardless of treatment modality, obesity is a common sequela of tumors and therapies that alter endocrine and metabolic function; fatigue is, in turn, a common comorbidity of obesity in these children (52). In two reported patients, apparent cognitive and behavioral sequelae were found to be related to the sleep disturbance thought to be caused by tumor- and treatment-related hypothalamic dysfunction (17). The age of the patient is also an important determinant, as delivery of radiation therapy to a developing brain has more potent and longer-lasting effects than when radiation is delivered to a mature brain (115). The nature, route of delivery, and dose of the therapy are important as well, and efforts continue to minimize the delivery of toxic therapies to normal brain. In this regard, surgical approaches include stereotactic localization of interventions; radiation therapy approaches include brachytherapy, proton beam radiation, and hyperfractionated delivery of the radiation dose; chemotherapy approaches include intra-arterial delivery of chemotherapeutic agents. More recent attention has focused on the potential of nanoparticle-guided delivery of immunologic, molecular, and conventional chemotherapeutic agents (69) and immunotherapy, including CAR-T cell therapy aimed at tumor-specific or -selective antigens (79) and checkpoint inhibitor therapies (96) in the treatment of CNS tumors in children and adults.
Surgery. A study of adults with a variety of brain tumor types indicates that mortality in the perioperative period is lower in high-volume centers than in low- or medium-volume centers (62). That said, complication rates and types in survivors of surgery for brain tumors do not vary with procedure volume.
A syndrome of postoperative mutism in children who undergo surgery for posterior fossa tumors has long been known. A review of the literature from 1982–2017 on children with this syndrome characterized postoperative mutism as also including dysarthria, ataxia, hypotonia, and behavioral and affective symptoms (57).
Transnasal endoscopic surgery for skull base tumors can result in permanent hyposmia or anosmia, and acutely, CSF leak, meningitis, and nasal dysfunction have been reported (24). Surgical treatment of pineal region tumors can result in transient cerebellar or eye movement dysfunction (77). Not surprisingly, resection of pituitary neoplasms can result in hypopituitarism (33). Obesity and disruption of puberty and linear growth are particularly problematic in children with craniopharyngiomas, but it is difficult to parse out how much of this is due to surgery, radiation therapy, and the tumor itself (51).
Radiation therapy. Radiation therapy is perhaps the most thoroughly studied factor contributing to neurologic sequelae of brain tumor treatment. Classically, the complications of radiotherapy are categorized in terms of acute, subacute or early delayed, and late forms (68). Radiation toxicity occurs in all parts of the nervous system: brain, spinal cord, and peripheral nerve. For the purpose of this review, the brain will be the focus. Standard of care for childhood brain tumors remains photon irradiation in most centers. Cognitive impairment, vasculopathy and stroke, and secondary neoplasms are among its long-term sequelae, and a report underscores the potential for coexistence of multiple consequences of craniospinal irradiation in childhood (43; 109). Proton beam radiation therapy holds the hope of lower dose and more targeted delivery of radiation; in one study, fatigue (91.7%), radiation dermatitis (75%), focal alopecia (100%), nausea (41.7%), cephalgia (58.3%), and transient cerebral edema (16.7%) were the most common acute toxicities (02). Early longitudinal data in children treated with proton beam therapy for medulloblastoma indicate lower risk of secondary neoplasia and vasculopathy than children treated with photon irradiation. Dosimetric comparison and calculation of lifetime risk of secondary neoplasia in these two groups suggests a five to 10 times greater risk with photon than proton beam therapy (55; 60).
In children with metastatic tumors of the brain without leptomeningeal spread, tumor-related outcomes of focal radiation therapy appear comparable to those with whole brain radiation therapy, providing the potential to limit the effects of radiation therapy to the normal brain (47).
(1) Acute complications
Encephalopathy. Early in brain tumor therapy, acute encephalopathy may occur but is decreasingly common with improvements in radiotherapy techniques. Symptoms include nausea/vomiting, drowsiness, headache, dysarthria, or possibly worsening of preexisting neurologic deficits. This syndrome may be associated with fever. The risk of acute encephalopathy increases with radiation fraction size exceeding 2 Gy. The etiology appears to be disruption of the blood-brain barrier (18; 100; 68), with resultant vasogenic edema and subsequently increased intracranial pressure. A transient increase in white matter edema may be seen on neuroimaging. The prognosis is generally excellent; however, herniation and death are possible if the intracranial pressure is already increased, as may be the case with posterior fossa or intraventricular tumors. Acute radiation-induced encephalopathy usually responds to corticosteroid therapy. Patients with large tumors and mass effect should receive corticosteroids prior to beginning radiotherapy to prevent acute encephalopathy.
Fatigue. Many adult patients undergoing cranial irradiation experience severe and progressive fatigue. This occurs part way through the course of radiotherapy, typically between weeks three and six of radiotherapy for primary brain tumors and near the end of radiotherapy to one to two weeks after the completion of radiotherapy for metastatic disease (99; 67). In one study of 104 patients with metastatic disease to brain, the incidence of excessive fatigue was reported to be 85% in patients who underwent whole brain radiotherapy plus radiosurgery, as compared to 28% in patients undergoing radiosurgery alone (54). The efficacy of methylphenidate and modafinil in reducing the severity of fatigue has been questioned (122; 11; 21). It has been suggested that proton beam therapy in pediatric patients suffering from CNS tumors is well-tolerated with regard to acute toxicity (22; 110). Similarly, craniospinal irradiation utilizing proton beam also appears to be well-tolerated in adults in the acute setting (09; 06). Long-term studies are needed to evaluate whether the proton beam modality results in improved long-term toxicity, particularly for pediatric patients.
(2) Subacute complications
Somnolence syndrome. The somnolence syndrome consists of drowsiness, lethargy, excessive sleep, headache, nausea, and anorexia. It occurs several weeks after cranial irradiation, and the course is typically biphasic, with initial occurrence in the second week following therapy, subsidence for several weeks, recurrence in week 5, and resolution within 5 days. The reported incidence varies greatly, depending on factors such as radiation dose, fractionation, tumor type, and diagnostic criteria. EEG findings reveal diffuse slowing during the symptomatic period, with normalization of the EEG after symptoms resolve (91). Sleep latency studies of adults with postradiation somnolence syndrome demonstrate a shift of predominant sleep pattern from NREM 1 to NREM 2 at 6 weeks after radiation (44). It has been proposed that inflammation plays a role in this syndrome, suggesting potential approaches to prophylaxis and therapy (05); however, the syndrome is self-limiting and patients generally return to normal in several weeks after onset (91; 44).
Transient cognitive impairment. A transient decline in cognition, distinct from the late-onset progressive cognitive syndrome, may be a subacute complication of cranial irradiation. This type of cognitive dysfunction, predominantly characterized by verbal memory dysfunction, carries a good prognosis and does not appear to predict development of the late-delayed cognitive syndrome (39).
(3) Chronic complications
Radionecrosis. Radiation necrosis of the CNS has been reported in the treatment of both intracranial and extracranial tumors, such as nasopharyngeal carcinoma. Radiation necrosis typically occurs one to two years after radiation, but latency as short as three months and as long as 30 years have been reported (38; 89). Radiographically, it can be difficult to distinguish from recurrent tumor.
Recognition of the risk factors for radiation necrosis and novel methods for radiotherapy delivery have resulted in a decrease in its incidence. Radiation total dose and fraction size are important risk factors, and a total external beam dose of 55 to 60 Gy delivered in 1.8 to 2.0 Gy fraction constitute the upper limits of a “safe” dose. Other risk factors include lesion volume and location, old age, associated chemotherapy, and vascular risk factors such as diabetes. Volumetric modulated arc therapy allows more targeted delivery of conventional radiation therapy to the tumor, with avoidance of normal tissue and reduces the incidence of subsequent radiation necrosis. Proton beam radiation therapy methods, including pencil beam scanning, passively scattered, and intensity modulated proton therapy result in further lowering of the incidence of radiation necrosis (30; 118).
Radiation necrosis can result in devastating clinical consequences. Patients present with focal neurologic symptoms, often recapitulating the presenting symptoms of the patient’s initial disease in the case of primary brain tumors, severe cognitive deficits, signs and symptoms of increased intracranial pressure, or seizures. Approximately one half of patients present with seizure as the first sign. Imaging characteristics of radiation necrosis are very similar to recurrent tumor. CT reveals hypodensity and variable contrast enhancement. MRI shows T1 hypointensity and T2 hyperintensity predominantly involving white matter. Conventional MRI is unable to differentiate radiation necrosis from recurrent high-grade tumor. Lesions frequently enhance with gadolinium and mass effect may be present. Dynamic susceptibility contrast MRI is a perfusion MRI method that affords determination of blood volume in the region of the abnormality; recurrent tumor exhibits higher perfusion than areas of radiation necrosis and reliably allows differentiation of the two from one another (106; 124). Early studies suggest that PET, PET/CT, and PET/MRI hold promise for improved diagnostic sensitivity in this regard (20).
Histopathologically, the lesions of radiation necrosis predominantly affect white matter. Vascular changes include vessel wall hyalinization, thickening and fibrinoid necrosis, fibrinous exudates, vascular hemorrhage, and thrombosis. These changes affect the small arteries and arterioles. Demyelination is also evident.
Treatment of radiation necrosis involves surgical excision and steroid therapy. Additional therapies have been proposed, including anticoagulants, hyperbaric oxygen, and alpha-tocopherol (80), but their clinical utility has yet to be proven. Bevacizumab, an antibody against vascular endothelial growth factor, has been proposed and studied as a therapy for radiation necrosis (32; 97; 102; 80).
Most of the studies of radiation necrosis of the CNS have involved adult patients. However, one meta-analysis of radiation necrosis of the CNS in children suggests an incidence of 4.6% in children who received cranial irradiation treatment with or without concomitant chemotherapy (25). The most frequently noted symptoms and signs were ataxia (43.8%), cranial nerve palsies (39.6%), weakness (37.5%), headache (18.8%), and vision changes (6.3%). Therapeutic interventions tried did not differ from those used in adults. Response to therapy was generally favorable; 52.1% (n=25) of patients demonstrated symptomatic improvement, or imaging improvement, or both; and 27.1% (n=13) demonstrated stabilization.
Leukoencephalopathy. Diffuse white matter changes may occur as a late-delayed effect of radiation alone, a combination of radiotherapy and chemotherapy, or, more rarely, after chemotherapy alone. Clearly, radiation and chemotherapy have a synergistic effect. In addition to concomitant chemotherapy such as methotrexate, risk factors for radiation-induced leukoencephalopathy include higher radiation dose and age greater than 60 years (46; 75). This diffuse white matter injury is an entity distinct from radiation necrosis. As patients are surviving longer after cancer therapies, radiation-induced leukoencephalopathy is an increasingly important complication of treatment. Histopathology reveals rarefaction of white matter, reactive astrogliosis, and foci of necrosis (75). In the most severe form, disseminated necrotizing leukoencephalopathy, necrotic foci become confluent and a prominent axonopathy is noted ultrastructurally (88). Neuroimaging reveals hypodensity on CT scans and increased T2/FLAIR signal in the white matter. Diffuse atrophy is often seen. MR spectroscopy reveals loss of NAA, Cho, and Cr, implying axonal and membrane damage in the abnormal-appearing white matter (117). Diffusion-tensor imaging in patients subjected to brain radiation and temozolomide reveals early demyelination and axonal injury in otherwise normal-appearing white matter (81).
Stroke. Ischemic stroke, transient ischemic attacks, and intracranial hemorrhage have been attributed to remote cranial or neck radiation therapy for cancer (90; 12). A study of 1360 survivors of childhood cancer who received cranial radiation therapy only, supra-diaphragmatic radiation therapy only, both cranial and supradiaphragmatic radiation therapy, or neither cranial nor supradiaphragmatic radiation therapy demonstrated a stroke incidence at 45 years of age of 10%, 5.4%, 12.5%, and 0.1%, respectively (114). Postirradiation stroke or intracranial or intraparenchymal bleeding can result from small or medium and large vessel vasculopathy (107; 71; 95). Reversible stroke-like migraine attacks with hemispheric hypoperfusion have also been described in both children and adults (01; 04; 36; 120).
A small study in children with a variety of CNS cancers suggests that the incidence of large vessel vasculopathy and stroke is lower after proton beam therapy than after photon beam (ie, conventional) radiation therapy. Time to occurrence averaged 1.5 years after completion of therapy with proton beam irradiation, a considerably shorter latency than the five years reported for photon irradiation. The incidence of large vessel vasculopathy in a single institution study of children undergoing proton beam craniospinal irradiation was between 6% and 7%, 80% of whom presented with stroke, although historically 19% was reported for children who underwent photon beam irradiation (55).
Dementia. Associated with diffuse leukoencephalopathy, with or without radionecrosis, is a devastating dementia syndrome (75). The dementia is typically a subcortical dementia characterized by deficits in memory, attention, and intellectual function. Gait disturbance, urinary incontinence, and personality changes may occur. Cortical functions such as praxis and language are relatively spared. Typical onset is within two years of radiation exposure, and the course is usually progressive. A large meta-analysis of the literature found an incidence of post-radiation dementia to be 12% (19). Risk factors are the same as for leukoencephalopathy, including radiation dose, fractions size, volume of brain irradiated, older age, and concomitant chemotherapy. Methylphenidate and anticholinesterases such as donepezil are sometimes used for symptomatic relief (104). As the survival of patients with brain tumors improves, an increasing number develop impairment of normal cerebrospinal fluid reabsorption through arachnoid granulations. This leads to a communicating hydrocephalus with cognitive impairment, gait unsteadiness, and urinary symptoms. Some of these patients may benefit from placement of a ventriculoperitoneal shunt (111).
Mild to moderate cognitive impairment. Cognitive dysfunction, characterized by prominent dysfunction of short-term memory, is perhaps the most common sequelae of radiotherapy. Cranial radiotherapy, even with newer methods, can cause a debilitating cognitive decline in both children (116; 41; 112; 123) and adults (42; 70). Months to years after cranial radiation exposure, patients exhibit progressive deficits in short-term memory, spatial relations, visual motor processing, quantitative skills, and attention. Hippocampal dysfunction is a prominent feature of these neuropsychological sequelae. In fact, the severity of the cognitive deterioration was found in one study to depend on the radiation dosage delivered to the left hippocampus, thalamus, and frontal lobes (42). According to Day and colleagues, there is some evidence that memantine may help prevent cognitive deficits for adults with brain metastases receiving cranial irradiation, and there is evidence that donepezil may have a role in treating cognitive deficits in adults with primary or metastatic brain tumors who have been treated with cranial irradiation (21). Patient withdrawal affected the statistical power of both studies. It has more recently been suggested that demyelination plays a role in the evolution of late cognitive sequelae and dementia associated with radiation therapy for brain tumors, and that “remyelinative therapies,” such as those used in multiple sclerosis, may be helpful (46).
Incidence of cognitive sequelae. Induced impairment in cognition has been very well described in children. It is estimated that when irradiated at less than seven years of age, nearly 100% of children require special education; after seven years of age approximately 50% of children require special education. Some degree of memory dysfunction is thought to occur in the majority of children. The incidence of memory dysfunction in adult patients has been difficult to quantify, largely due to a lack of uniformity in neuropsychometric testing in the literature. However, as adults are surviving longer after treatment and the long-term consequences of radiation are becoming more important for this population, an extremely high rate of cognitive dysfunction of varying degrees has been recognized, such as in long-term survivors of childhood Hodgkin lymphoma (56).
Mild to moderate cognitive dysfunction is inconsistently associated with radiological findings on conventional MRI and frequently occurs in patients with normal-appearing conventional neuroimaging. Use of 7T susceptibility weighted imaging, however, suggests that the prevalence of cerebral microbleeds correlates with cognitive dysfunction in children, adolescents, and young adults who have undergone cranial radiation for brain tumors (76). Clinically significant memory deficit in the absence of radiological findings implicates damage to a subtle process with robust physiological consequences. Although cognitive impairment may be a subtle complication, it can have a profound effect on overall quality of life (112).
Radiotherapy-induced tumors. Criteria for definition as a radiation-induced tumor include a long latency (years to decades) to occurrence of the second tumor and location of the tumor within the radiation portal. Although uncommon and apparently decreasing in incidence as radiation therapy techniques improve, secondary tumors do occur following cranial irradiation. Among such secondary tumors, meningiomas, gliomas, and sarcomas constitute roughly 70%, 20%, and 10%, respectively. In an Israeli study of 10,834 patients exposed in childhood to an average dose of only 1.5 Gy for tinea capitis, the relative risk of developing a neural tumor was found to be 6.9. In patients receiving 2.5 Gy, the relative risk was 20 (98). After cranial irradiation for childhood leukemia, one series found a relative risk of 22 for secondary tumor (82). A series of 379 patients (mostly children) treated with radiotherapy and chemotherapy for non-disseminated medulloblastoma demonstrated a 10-year cumulative risk of secondary malignancy of 4.2%; these malignancies consisted of both CNS and non-CNS neoplasms (85). A retrospective study of 221 children treated with scanning proton therapy for CNS malignancies revealed secondary malignancies in 1.4% after a mean follow-up time of 4 years (range, 0.3-18 years) (113).
More than 300 cases of radiation-induced meningiomas have been reported (03). Authors frequently differentiate between low-dose (less than 10 Gy) irradiation and high-dose (greater than 20 Gy) irradiation-induced meningiomas. The latency from time of treatment to meningioma development ranges from one to three decades (84; 108). There is an increased incidence of cellular atypia and aggressive subtypes following irradiation (108; 94). A cytogenetic study of radiation-induced meningiomas revealed consistent abnormalities involving chromosome 1p (125).
More than 100 cases of secondary gliomas have been reported; of these, approximately 40% are glioblastoma (07). Gliomas arise after a mean latency of 9.6 years (103). To date, four cases of gliomas at sites of previous radiosurgery have also been reported (103; 66). Prognosis is often poor in secondary gliomas relative to spontaneous forms, due either to a more aggressive behavior or because treatment options are limited by previous exposures.
Rarely, sarcomas involving the skull base, calvaria, or dura may occur. Osteosarcoma, fibrosarcoma, and chondrosarcoma have been reported.
Early longitudinal studies and extrapolation from dosimetric data suggest that the lifetime risk of second neoplasms after proton beam irradiation for childhood CNS cancer is five to 10 times lower than after conventional photon radiation therapy (60).
Chemotherapy. Chemotherapy-induced cognitive impairment is common in patients with systemic cancer. It has been termed “chemofog” or “chemobrain” and is characterized by deficits in memory function and concentration (08; 50; 65). Cognitive impairment is common, as well, in patients with CNS malignancy treated with chemotherapy. Like CNS toxicity of cranial or neck radiation therapy, CNS toxicity of chemotherapy can develop acutely, after a brief latency, or after a long latency. It can include dysfunctional information processing, executive function, psychomotor speed, and attention (31; 78). It is often difficult to ascribe neurotoxicity to a particular chemotherapeutic agent or even to chemotherapy in general, as patients with brain tumors most often undergo co-temporal multimodal therapies.
Methotrexate, especially when administered both intravenously and intrathecally, or in combination with cranial radiotherapy, can result in leukoencephalopathy that is similar to the leukoencephalopathy that occurs with radiotherapy alone. Nonenhancing periventricular white matter lesions, ventriculomegaly, and cortical atrophy characterize this syndrome. Clinically, it is frequently associated with progressive cognitive deficits that range from mild memory dysfunction to frank dementia. However, the white matter disease observed on neuroimaging is not necessarily correlated with cognitive deficits (28; 83).
Temozolomide is used in the treatment of high-grade gliomas. Although there is evidence that temozolomide monotherapy does not result in cognitive impairment, it is not yet clear whether temozolomide, like other chemotherapeutic agents, synergizes with radiation therapy in this regard (107; 105).
Bevacizumab has been hypothesized to be responsible for the unexpected emergence of late-onset radiation-induced posterior optic neuropathy in three patients with glioblastoma (53).
The combination of cisplatin and etoposide has been used in children with progressive low-grade glioma of varied histological type. Sensorineural hearing loss was the most common neurologic side effect and drug dose reduction was found to decrease its incidence and severity without compromising patient survival (64). Sensorineural hearing loss has been ascribed to cisplatin in adults with high-grade astrocytomas (59).
Vincristine is well known to cause peripheral neuropathy, and its use in patients with CNS tumors is no exception (59; Moore and Pinkerton 2009; 23). Transient dysarthria has been reported with irinotecan, an agent used for high-grade glioma (16; 61), in a patient with colon cancer (93).
Approximately 20% of children who underwent high-dose chemotherapy followed by autologous stem cell transplant for recurrent brain tumors developed grade 3 or 4 neurotoxicity (34). High-dose thiotepa treatment is, in particular, associated with a 26% incidence of serious neurologic adverse events, including headaches, tremors, confusion, seizures, cerebellar syndrome, and coma. Children being treated for brain tumors are at higher risk for neurologic adverse events than those with other cancers, and treatment with the opioid tramadol for pain also increased risk (63).
CAR-T cells. CAR-T cells link the antigen-binding aspects of an antibody to the cytolytic capabilities of a T cell, thereby targeting antigenically “different” cancer cells for destruction (87). CAR-T cell therapies aimed at CNS tumor-specific or selective antigens are in clinical use for leukemias and lymphomas but are early in their experimental use for CNS malignancy. A phase I study in adults with glioblastoma used systemic administration of EGFRvIII-targeted CAR-T cells and effected clearance of the antigen from the CNS, but with subsequent reemergence of EGFRvIII-negative tumor (15).
Studies of neurotoxicity of CAR-T cell therapies for leukemia and lymphoma revealed a cytokine release syndrome that resulted in fever, hypotension, and, in severe cases, multiorgan failure. Neurotoxicity can be associated with cytokine release syndrome, but has also been reported in its absence. Mild to moderate neurotoxicity presents with headache, tremor, aphasia, movement disorders, and encephalopathy. Symptom severity can fluctuate over the course of the illness. A common manifestation of toxic encephalopathy preserves alertness but involves inattention, disorientation, confusion, or language disturbances. In severe cases, generalized seizures, coma, intracranial hemorrhage, and a fatal rapid onset diffuse cerebral edema can result (45).
Studies of GD2-CAR-T cells in animal models of diffuse pontine glioma did not reveal cytokine release syndrome, even with systemic administration (79), suggesting that this effect depends on the neoplastic immune cells and their secretion or release on lysis of cytokines. However, mice bearing intracranial human glioma xenografts and treated with systemic GD2-CAR-T cells developed brainstem inflammatory changes, including T-cell infiltration, which resulted in hydrocephalus. Three clinical trials of HER-2-, EGFR-, or IL13R-directed CAR-T cells, respectively, in patients with brain tumors have been recruiting subjects (29).
Preclinical xenograft studies of CAR-T cell therapy in medulloblastoma and ependymoma that leverage the implications of tumor subtype for tumor antigen expression have shown some promise (87).
Other immunotherapies in various stages of investigation for children and adults with brain tumors include tumor antigen-directed vaccines and oncolytic viruses or lymphocytes (29).
Systemic toxicities of CAR-T cells include fevers, hypotension, hypoxia, end organ dysfunction, cytopenias, coagulopathy, and hemophagocytic lymphohistiocytosis. Neurologic toxicities include encephalopathy, cognitive dysfunction, dysphasias, seizures, and cerebral edema (10).
Checkpoint inhibitors. Checkpoint inhibitors block the activity of immunosuppressive checkpoint molecules that negatively regulate immune cell function. As such, they prevent evasion of the immune system by cancer cells. Checkpoint inhibitors in clinical trials that include or are designed for children with intracranial malignancies are aimed at the immunoregulatory proteins CTLA-4, PD-1, or IDO, respectively. These ongoing trials include the checkpoint inhibitors pembrolizumab, nivolumab, and indoximab (10; 29). Choi and colleagues have noted the ability of CAR-T cells to secrete checkpoint inhibitors (15).
Systemic toxicities of checkpoint inhibitors include fatigue, fever, rash, neutropenia, and infection. Neurologic toxicities of checkpoint inhibitors include encephalopathy, myelopathy, myasthenia gravis, myopathy, and myositis (27; 101).
Glucocorticoids. Corticosteroids such as prednisone and dexamethasone are used for a number of reasons in management of CNS malignancies, including reduction of peritumoral edema, as well as antineoplastic effect in patients with primary CNS lymphoma. Corticosteroids have a number of systemic and neurologic side effects. Common neurologic side effects include steroid myopathy and alterations in mood. Steroid psychosis, steroid-induced dementia, and cortical atrophy also occur. Corticosteroids may play an important role in cognitive dysfunction during and after cancer therapy. In animal models, corticosteroids are known to impair physiology, including hippocampal neurogenesis. In humans, prednisone therapy has been demonstrated to impair verbal memory function (40) and children treated for acute lymphoblastic leukemia exhibited more severe long-term cognitive dysfunction if their regimen included dexamethasone (119).
Prognosis is variable. 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.
A 49-year-old, right-handed man presented to a neurology clinic for evaluation of memory difficulties. Four years prior to presentation he was treated for a squamous cell carcinoma of the paranasal sinuses with docetaxel, cisplatin, and 5-FU, followed by radiotherapy. He first noted difficulty with memory function approximately two years after therapy, and memory deficits progressively worsened. He gave examples such as walking into the kitchen for a glass of water, and by the time he reached it he forgot why he went there, or putting laundry in the washer and forgetting he had done so. He reported that he could no longer drive because he got lost so easily. Examination revealed he was alert and oriented, but somewhat inattentive, with zero to three item recall at five minutes. MRI revealed bilateral medial temporal lobe necrosis. The patient was started on daily 5 mg oral Aricept. This resulted in some improvement of his memory function; subsequent memory testing revealed two of three item recall at five minutes.
Although the majority of the nervous system is formed during development, many cell types continue to divide and regenerate throughout life. Astro- 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. Newborn neurons, particularly the dentate granule cell neurons of the hippocampus, are constantly generated throughout life. This process of adult hippocampal neurogenesis is thought to be crucial to proper memory function. These dynamic cell populations are vulnerable to the cytostatic and mutagenic actions of cancer therapies. Mindfulness of these physiological processes may elucidate many incompletely understood mechanisms of neurotoxicity from cancer therapies.
Mild to moderate cognitive impairment after radiotherapy. Hippocampal neurogenesis is a subtle physiological process susceptible to radiation injury. Studies in animal models have demonstrated that therapeutic doses of cranial irradiation virtually ablates neurogenesis (86; 72; 74), and that this inhibition of neurogenesis correlates with impaired performance on hippocampal-dependent memory tests (92). Surprisingly, irradiation does not simply deplete the stem cell population, but rather disrupts the microenvironment that normally supports hippocampal neurogenesis (72). This microenvironmental perturbation is due largely to irradiation-induced microglial inflammation, and anti-inflammatory therapy with the nonsteroidal anti-inflammatory agent indomethacin partially restores hippocampal neurogenesis and function (74). Human trials have been underway to evaluate the clinical utility of anti-inflammatory therapy during cranial radiotherapy.
Additional possible mechanisms underlying mild to moderate cognitive dysfunction include subtle white matter dysfunction and altered regional blood flow due to microvascular disease.
Radionecrosis. The etiology of radiation necrosis is not yet clear. Histopathology reveals vascular damage and demyelination, implicating the vascular cells or oligodendrocytes or both, as the targets of radiation injury. Classically, radiation injury has been attributed to either the vascular hypothesis or the glial hypothesis. The vascular hypothesis states that radiation-induced vasculopathy and the resultant ischemic necrosis account for radiation injury. The glial hypothesis proposes that radiation-induced damage to oligodendrocytes and their precursors is the underlying cause of radiation injury. However, the lesions of radiation necrosis are not typical of either pure vascular or demyelinating disease, and neither hypothesis seems sufficient alone to account for radiation necrosis (73).
Chemotherapeutic neuropathy. The mechanism of chemotherapeutic neuropathy is perhaps best understood for agents that affect microtubule assembly, function, or stability. Impairment of axonal transport is central to this effect. Axonal transport seems to be most affected distally, and those neurons that depend most critically on distal axonal growth (eg, sensory neurons) are most impaired by use of these agents (37).
The incidence of neurocognitive sequelae of CNS tumors varies and depends on the age and gender of the patient, the location of the tumor, and the nature of the therapy required (eg, surgery alone versus surgery plus radiotherapy and chemotherapy). Stroke incidence is related to radiation dose and time from completion of radiation therapy. Other neurologic sequelae of cancer treatment occur primarily with chemotherapy and are specific to the particular agents used. There is some evidence that the incidence of remote stroke and other ischemic sequelae after radiation therapy is influenced by the use of chemotherapeutic drugs.
Current and future studies are attempting to reduce the incidence of neurocognitive sequelae by further reducing and conforming the dose of radiation to tumor in addition to using novel neuroprotective (for the nontumor brain cells) or radiosensitizing (for the cancerous cell) agents. In a randomized trial, Chang and colleagues showed that stereotactic radiosurgery alone produced fewer neurocognitive deficits compared to the combination of stereotactic radiosurgery and whole brain radiotherapy (14). Additionally, anti-inflammatory agents may help to protect sensitive stem cell compartments in the brain from radiation-induced damage (74). There is emerging evidence that the use of superoxide dismutase mimics and glutathione synthesis enhancers prevents chemotherapeutic agent-induced neuropathy by a mechanism involving scavenging of reactive oxygen species (35; 48). Duloxetine has also been said to be useful in this regard (121).
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 should include appropriate neuroimaging (usually MRI with and without gadolinium), EEG if seizure is suspected, and evaluation of any toxic/metabolic process suspected. A careful mental status examination and possibly formal neuropsychological evaluation are appropriate. EMG/NCV may also be warranted in peripheral neuropathies.
Methylphenidate and modafinil may reduce the severity of fatigue (122).
Anti-inflammatory therapy is a potential, but as of yet unproven, therapy for mild-to-moderate memory dysfunction following radiotherapy (74). For radionecrosis, therapy with anticoagulants, antiplatelet agents, hyperbaric oxygen, and alpha tocopherol have all been proposed (80). For radiation-induced dementia, methylphenidate and anticholinesterases such as donepezil are sometimes used for symptomatic relief (104). The results of a pilot study of donepezil for improving cognitive dysfunction in survivors of pediatric brain tumors favors further investigation of this approach (13).
Antioxidants, anti-inflammatory agents, and antidepressants are suggested as preventive and symptomatic therapeutic agents for chemotherapeutic-induced peripheral neuropathy (48).
Prognosis is variable. 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. Peripheral neuropathy is often permanent but improves in severity over time.
Nina Schor MD PhD
Dr. Schor of the National Institutes of Health and Deputy Director of the National Institute of Neurological Disorders and Stroke has no relevant financial relationships to disclose.See Profile
Roger J Packer MD
Dr. Packer of Children’s National Hospital and George Washington University has no relevant financial relationships to disclose.See Profile
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