Presentation and course
Radiation-related nervous system side effects can affect every level of the nervous system and can be classified either anatomically or temporally (Tables 1 and 2).
Table 1. Anatomic Classification of Radiation-Related Nervous System Side Effects
• Acute encephalopathy • Subacute (“early delayed”) encephalopathy • Delayed cerebral radiation necrosis • Progressive space occupying radiation necrosis • Diffuse late brain injury (atrophy and dementia) • Radiation-induced brain tumors
• Hypothalamic, pituitary, and thyroid hypofunction
Cranial neuropathies (including optic neuropathy)
• Subacute (transient) myelopathy • Chronic progressive (necrotic) myelopathy • Motor neuronopathy and radiculopathy
Brachial and lumbosacral plexuses
• Transient brachial plexopathy • Chronic brachial and lumbosacral plexopathy
• Perineural fibrosis • Malignant peripheral nerve sheath tumors
Cerebral vascular disease
• Intracranial arterial occlusive disease • Internal carotid artery thrombosis • Accelerated atherosclerosis • Carotid artery rupture • Aneurysmal hemorrhage • Cryptic vascular malformations • Cavernous angiomas • Cardioembolic TIA or stroke • Lacunar infarct
Table 2. Temporal Classification of Radiation-Related Nervous System Side Effects
• Acute encephalopathy
• Subacute (“early delayed”) encephalopathy • Subacute (transient) myelopathy • Transient brachial plexopathy
• Delayed cerebral radiation necrosis • Diffuse late brain injury (atrophy and dementia) • Neuroendocrine dysfunction • Optic neuropathy • Cranial neuropathy • Chronic progressive (necrotic) myelopathy • Motor neuronopathy • Chronic brachial and lumbosacral plexopathy • Peripheral neuropathy • Cerebral vasculopathy • Radiation-induced tumors
Accurate diagnosis based on clinical manifestations is critical in order to exclude other potentially treatable disorders, to prevent unnecessary diagnostic procedures and inappropriate antineoplastic therapy, and to allow for meaningful intervention.
Acute complications. Common acute side effects of radiation therapy include fatigue, headache, loss of appetite, nausea, and vomiting, and re-emergence or worsening of preexisting neurologic symptoms.
In the setting of therapeutic radiation therapy, acute radiation encephalopathy is a rare occurrence. It is characterized by lethargy, possibly accompanied by new or progressive focal deficits, headache, nausea, vomiting, fever, and seizures. Onset is within the first two weeks of treatment (may be as early as within 24 hours).
Subacute complications. Lethargy, impaired memory retrieval, and cognitive and behavioral changes may develop within one month from initiation of radiation therapy and extending to within 4 months following radiation therapy completion (“early delayed encephalopathy”). Ataxia, nystagmus, nausea, vomiting, and dysarthria may be present when the brainstem has been irradiated. Patients may experience transient hearing loss from soft tissue swelling and/or inflammatory otitis media.
Subacute myelopathy may occur following radiation therapy to the cervical (less often thoracic or thoracolumbar) spinal cord. Lhermitte sign, transient electric shock sensation with next flexion, may be the sole symptom. The neurologic exam is normal. Symptom onset peaks at 4 to 6 months (range 1 to 30 months) after radiation exposure.
Late (chronic) complications. Late complications of CNS radiation therapy include radiation necrosis, cognitive deficits, endocrinopathies, cranial neuropathies, myelopathy, cerebrovascular disease, and secondary tumors.
Patients with delayed cerebral radiation necrosis may present with headache, personality change, focal deficits, and seizures. These symptoms typically develop insidiously 4 months to 4 years or more (median 14 months) after treatment. Occasionally, gait impairment, incontinence, and dysarthria can occur. Rarely, the presentation is fulminant, and even less commonly, established radiation necrosis may be complicated by acute hemorrhage (10).
A more diffuse late brain injury manifests clinically in progressive cognitive impairment, characterized by deficits in memory, attention, and executive function, fatigue, and even personality change and dementia. Age at irradiation is one primary determinant of this sequelae. The negative impact on neurocognition is more pronounced in children and older adults, particularly over the age of 70. In children, even low doses of cranial irradiation can be associated with declines in IQ and academic achievement. Children may also exhibit memory deficits, fine motor and visual-spatial dysfunction, and psychological disturbances (49; 45).
Radiation to the sellar, parasellar, or hypothalamic regions can result in endocrine dysfunction. Among adults, endocrine dysfunction can occur insidiously, developing over months to years and often undiagnosed. Children who receive brain radiation are even more vulnerable. Patients should undergo regular endocrine evaluation if their treatment was to this region, and they should receive prompt treatment for pituitary deficiencies. The most common radiation-induced endocrinopathies are hypothyroidism and growth hormone deficiency.
Radiation induced optic neuropathy can occur after irradiation of the optic apparatus, including the retina, optic nerve, chiasm and pituitary region, or optic radiation. Painless, progressive, monocular visual loss, or constriction of visual fields is the typical presentation. Altitudinal field cuts are common; “dimming” of vision or “spotty” visual loss are typical patient descriptions. The presence of pain or homonymous field defects weigh strongly against the diagnosis. Onset ranges from three months to several years (median 11 months).
Although the optic nerves are the most sensitive of the cranial nerves to radiation therapy, other cranial neuropathies can develop following exposure to therapeutic radiation (05). Radiation-induced cranial neuropathy occurs 1 to 37 years (mean 5.5 years) following radiation therapy (generally for head and neck or orbital tumors). In order of frequency, cranial nerves XII, XI, X, V, and VI are affected.
Chronic progressive myelopathy is the delayed spinal cord syndrome corresponding to cerebral radiation necrosis (19; 62). It most commonly occurs following radiation therapy of tumors in the chest, mediastinum, cervical region, or head and neck. The syndrome frequently presents with ascending paresthesias, dysesthesias, or sensory loss in one or both lower extremities, followed by weakness and signs of myelopathy. A partial transverse myelitis or Brown-Sequard syndrome is common, as is disturbance of sphincter function. Symptoms begin 3 to 30 months or more (median 20 months) after treatment, and progression is usually gradual over weeks to months.
The cerebral vasculature can be damaged by radiation. Depending on the portion of the vascular tree affected and the type of vascular lesion, transient ischemia, strokes, or hemorrhage can occur and typically in 10 or more years following radiation exposure, necessitating long-term surveillance (60). Children are more vulnerable than adults in their risk of developing radiation-induced vasculopathy. Radiation-induced cerebral microbleeds and large vessel cerebral vasculopathy have been reported in pediatric patients undergoing radiation therapy for brain tumors (50; 29). Radiation-induced cavernous malformations are another manifestation of radiation-related cerebrovascular disease, associated with brain doses in the range of 45 to 60 Gy (52). Moyamoya syndrome is a rare complication of cranial irradiation, particularly in children who received higher doses to the circle of Willis (68). Radiation that is administered to the neck can result in delayed carotid atherosclerosis. Tumor embolization to the brain is a rare cause of stroke.
Radiation-induced CNS tumors constitute a small but serious risk for patients undergoing radiotherapy for the management of cerebral neoplasms. Studies of pediatric survivors who developed second brain tumors have found that meningiomas are the most common. The average latency period for the appearance of the second tumor was eight years, but meningiomas had a longer latency period, ranging from 16 to 30 years in one study. Other common second cancer histologies include peripheral nerve sheath tumors and gliomas. The symptoms of radiation-induced intracranial tumors are indistinguishable from those of their nonradiation-induced counterparts, but radiation-induced intracranial tumors are typically more aggressive pathologically and clinically. Radiation-induced meningiomas, for example, are higher grade with high labeling indices, may appear with multiple synchronous tumors, and tend to recur more frequently and earlier after gross total resection (54; 66). NF2 gene rearrangements, which appear to be specific to radiation-induced meningiomas, have been described in approximately half of patients with such tumors (02).
In addition to CNS-specific side effects, a constellation of acute or late nonneurologic symptoms are common after cranial irradiation (Table 3).
Table 3. Nonneurologic Side Effects of Cranial Irradiation
• Hair loss • Dermatitis • Parotitis • Growth inhibition in children • Facial dysmorphism in children
The most common and often most debilitating effect of cranial radiation therapy is progressive fatigue (usually between weeks 3 and 5 in fractionated radiotherapy), which may often persist for several weeks after the completion of therapy.
Prognosis and complications
Except in some patients with acute encephalopathy, the acute and subacute complications of radiation are generally mild, transient, or treatable with corticosteroids. The symptoms of early delayed encephalopathy begin to resolve within 2 to 4.5 months of onset (04), whereas those of subacute myelopathy disappear within four months of onset. Recognition of these acute and subacute syndromes permits early intervention or reassurance and may obviate the need for invasive or expensive diagnostic interventions and therapy directed at presumed tumor recurrence.
In contrast, the late complications of radiation are generally progressive and severe. They typically result in significant disability and are of particular concern in patients with potentially curable disease (eg, childhood acute leukemias, intracranial germ cell tumors, pituitary tumors, and meningiomas), or tumors compatible with long survival (eg, oligodendrogliomas and limited brain metastases with well-controlled systemic disease).