Radiation Injury



Radiation Injury


Christopher Zammit

Edward (Mel) J. Otten



INTRODUCTION

The first known description of nervous system injury by radiation was in 1930 by Fischer and Holfelder. Contemporary medicine’s use of radiotherapy to treat malignancies has brought radiation injury into daily clinical discussion. The expansion of nuclear energy programs during the 1970s increased the risk for widespread radiation injury in the event of nuclear plant failure. The Three Mile Island accident in 1979 and disasters at the Chernobyl Nuclear Power Station in 1986 and the Fukushima Nuclear Power Plant following a tsunami in 2011 have provided real reminders of the ongoing risk.

Radiation injury is the result of exposure to ionizing radiation. Nonionizing radiation does not cause neurologic injury; its biologic injury is limited to thermal surface injury. Nervous system injury results from x-rays or gamma rays; alpha and beta particles also produce ionizing radiation, but they do not penetrate tissue by more than 8 mm and therefore do not reach the central or peripheral nervous system. Internal injury can result when alpha or beta particles are ingested, but even in such cases, their proximity to central neurologic structures limits their ability to produce significant neurologic injury.

The amount of radiation absorbed is described in terms of gray (Gy), where one Gy is equal to one joule of radiation absorbed per kilogram of tissue. A radiation-absorbed dose (rad) is equal to 100th of a Gy (i.e., 100 rad = 1 Gy). One rad is also equal to one roentgen equivalent man (rem), that is, 1 rad = 1 rem. In contrast, the dose of radiation delivered is described in sieverts (Sv), where 1 Sv is equal to 100 rem. To provide context, we are exposed to approximately 3 millisieverts (mSv) per year from natural radioactive material and cosmic radiation. Furthermore, one head computed tomography (CT) delivers 2 mSv of radiation.

Radiation effects on the nervous system and other organ systems (Table 129.1) can be difficult to predict, as the amount of radiation delivered is not necessarily equal to the amount absorbed, particularly when considering occupational or environmental exposures. The clinical effects of radiation are related to the individual susceptibility, dose rate, dose absorbed, and distribution of the dose.








TABLE 129.1 Radiation Effects

























  • Acute cerebral edema




  • Early-delayed leukoencephalopathy or demyelination




  • Late-delayed radiation necrosis




  • Myelopathy




  • Vasculopathy




  • Plexopathy




  • Neuropathy (including cranial and optic neuropathy)




  • Neuroendocrine disorders




  • Radiation-induced tumors




  • Neuropsychiatric, behavioral, and cognitive disturbances



EPIDEMIOLOGY

As mentioned earlier, the incidence of radiation injury is related to individual patient characteristics, the dose amount, dose rate, and distribution of the exposure. Hypertension and diabetes mellitus increase the risk of radiation injury. Radiation injury may occur after scalp radiation for tinea capitis, radiotherapy to the head or neck for malignancy, whole-brain radiation for acute lymphoblastic leukemia (ALL) or small cell carcinoma, brachytherapy, or radiotherapy for intracranial malignancies.

Acute cerebral edema may occur days to weeks after radiation. It rarely occurs at doses below 2 Gy and is seen in about half of the time after doses over 7.5 Gy. Delayed leukoencephalopathy and/or demyelination typically occur between 1 and 6 months after exposure. Radiation necrosis is seen between 6 months and 7.5 years after radiotherapy, with a median onset of 14 months, and 75% of patients experience symptoms within 3 years. The cumulative dosing threshold for necrosis is reported as being 50 to 60 Gy, with a 5% incidence in those receiving a total of 50 Gy in daily doses of 2 Gy.

Myelopathy occurs 1 to 3 years after radiation, with peaks in incidence at 12 to 14 months and 24 to 28 months. Similar to radiation necrosis, 5% of patients receiving total doses of approximately 60 Gy to the spinal cord have been reported to develop myelopathy, but this is not consistent.

Intracranial and extracranial vasculopathy have been seen over 20 years after radiation exposure. Stroke-like migraine attacks after radiation therapy (SMART) syndrome has been reported many years after whole-brain radiation. It is rare with an incidence and risk factors that are not well described.

Plexopathy and neuropathy (including cranial and optic neuropathy) are typically seen after radiation directed at the affected region. Brachial plexopathy after radiation for breast cancer has a median onset of 4.5 months. Transient symptoms are seen in 1% to 2% of those receiving doses of 50 Gy. Lumbosacral plexopathy is rarely seen, even at doses of up to 70 to 80 Gy. Neuropathy is rarely seen at doses under 60 Gy. Optic neuropathy is seen within 3 years of exposure when it occurs.

The radiation dose threshold associated with neuroendocrine disorders in children is less than that for the previously mentioned injuries. Growth hormone (GH) deficiency is seen in fractionated doses of less than 20 Gy. Sixty-five percent of children undergoing prophylactic cranial radiation for ALL in a total dose of 20 to 30 Gy are observed to have a GH deficit. Other neuroendocrine disorders occur at total doses over 40 to 50 Gy, including gonadotropin deficiency, thyrotropin deficiency, adrenocorticotropic hormone deficiency, and hyperprolactinemia.


Cognitive and neuropsychiatric disturbances are all too common in children receiving radiation for malignancies, with some series reporting rates of 100%. Radiotherapy that traverses the hippocampus or frontostriatal brain circuitry is felt to increase the risk of occurrence.

Radiation-induced tumors include meningiomas, sarcomas, gliomas, and peripheral nerve tumors. Meningiomas have a latency of up to 37 years at doses of 8.5 Gy and as short as 18 months after 20 Gy. Sarcomas are seen about 10 years after doses of 50 Gy with an unclear frequency. The relationship between glioma occurrence and radiation therapy is not agreed upon. However, high-volume cell phone use has been associated with the occurrence of gliomas (and meningiomas) and the risk appears to be related to the “dose” of cell phone use. Peripheral nerve tumors are seen in about 10% of patients receiving radiation therapy directed through a peripheral nerve.


PATHOBIOLOGY

Ionizing radiation causes biologic injury by damaging the most basic elements that make up cellular structures and conduct cellular processes. The x-rays and/or gamma rays collide with electrons, causing elements to become ionized that were not otherwise, altering their ability to conduct cellular functions. This will damage DNA, leading to mutations that contribute to the increased malignancy risk. Cells that have high rates of turnover are the most vulnerable to this damage (e.g., hematopoietic, mucosal, endothelial, and gastrointestinal cells).

The early cerebral edema is suspected to be secondary to vascular endothelial dysfunction, causing vasogenic edema (hence its clinical response to corticosteroids). The latently observed leukoencephalopathy is thought to be the result of a transient demyelination due to oligodendrocyte dysfunction, as the time frame corresponds with expected myelin turnover.

Radiation necrosis is predominately a white matter process that may occur by one or more of the following mechanisms: glial dysfunction, vasculopathy, or immunologic. Glial dysfunction is supported by histologic changes including white matter necrosis, cystic cavitation with gliosis, and patchy demyelination suspected to be the result of oligodendrocytes injury. Alternatively, vascular injury has been observed histologically as perivascular lymphocytic infiltration, endothelial proliferation, fibrinoid degeneration, capillary occlusion, and intraluminal thrombosis of medium- and smallsized arteries. Endothelial cell injury then causes vasogenic edema. A mineralizing microangiopathy is seen in nearly 20% of patients at autopsy and can be appreciated clinically as calcifications at the gray-white junction on head CT. Lastly, an immunologic mechanism is suspected to occur when irradiated glial cells release antigens that induce an autoimmune reaction.








TABLE 129.2 Acute Radiation Syndrome Prognosis Based on Acute Symptoms and 48-Hour Absolute Lymphocyte Count









































Radiation Dose (Gy)


Acute Symptoms


24-hour CNS Symptoms


48-hour Absolute Lymphocyte Count


Prognosis/Mortality


0-0.4


None to very mild, onset ˜6 h


None to very mild headache


1,400-3,000 (normal)


Excellent, <5%


0.5-2


None to mild, onset 2-6 h


None to headache


1,000-1,399


Good, <5%


2-4


Mild to moderate, onset 1-2 h


Brief cognitive impairments


500-999


Fair, 5-50%


4-8


Moderate to severe, onset 10-60 min


Drowsy to confused


100-499


Poor, 50-100%


>8


Severe, onset within 10 min


Immediate lethargy, coma, seizures


100


Dismal, 100%


CNS, central nervous system.


In myelopathy, white matter necrosis is seen after higher radiation doses, whereas lower doses are observed to cause vascular damage, with a more delayed presentation. Asymptomatic animals are found to have a spongy vacuolation of the spinal cord white matter. In contrast, the animals with paralysis were found to have tissue destruction and vascular changes, predominately in the posterior and lateral columns.

Plexopathies and neuropathies can be the result of an occlusion of an artery (e.g., subclavian artery stenosis causing a brachial plexopathy) or radiation fibrosis, producing external compression around the nerve. Peripheral nerve ischemia due to radiation injury to the vasa nervorum is also suspected. Autopsies of those with radiation vasculopathy reveal myointimal proliferation, hyalinization, and occlusion.


CLINICAL FEATURES

Acutely radiated victims of an occupational or environmental event or accident typically do not know the dose of radiation they were exposed to. Symptoms of acute radiation sickness (ARS) on presentation include nausea, vomiting, diarrhea, or headache. The onset, persistence, and severity of symptoms are used to gage the dose and therefore prognosis of the victim. If neurologic symptoms are present acutely and are not the result of an injury sustained from a blast or other traumatic force, such as a decreased level of consciousness, ataxia, and seizures, the estimated radiation exposure is greater than 10 Gy and mortality is 100%. Those with a moderate radiation dose (2 to 6 Gy) may develop some mild transient cognitive impairment. Those with a higher dose (˜6 to 10 Gy) will have more significant disturbances in cognition and consciousness that persist beyond 24 hours and have an expected survival of less than 5%. If the radiation dose remains uncertain due to confounders or an ambivalent presentation, the absolute lymphocyte count at 48 hours can provide further insight into the estimated radiation dose absorbed (Table 129.2).

Symptoms of cerebral edema from radiation injury following therapeutic radiotherapy with high daily dose fractions appear within a few days to weeks and include headache, nausea, and vomiting. Alopecia and scalp erythema may also be seen. Injury to
the pharyngeal mucosa may cause pharyngitis and eustachian tube dysfunction leading to otitis media. A delayed leukoencephalopathy can present 4 to 10 weeks after radiation with somnolence and headache. A posterior fossa syndrome of ataxia, dysarthria, and nystagmus may follow radiation to the middle ear area for glomus jugulare tumors.

Radiation necrosis is a delayed-late consequence of radiation that presents between 6 months and 7.5 years after radiotherapy with clinical manifestations that may mimic the original tumor. Other presentations may include seizures, headaches, or increased intracranial pressure (ICP). Focal or lateralizing neurologic deficits can be neuroanatomically linked to the site of the treated malignancy or distant from it.

Early-delayed radiation myelopathy is transient and presents within 6 months of radiotherapy. Lhermitte sign (i.e., flexion of the neck causes an electric shock sensation down the spine) is reported in up to 15% of those receiving radiation for Hodgkin lymphoma. Delayed radiation myelopathy presents 1 to 3 years following radiotherapy and presents with painless numbness and paresthesias, which then progress to include a spastic gait, sphincter symptoms, and limb weakness. Less commonly, acute paraplegia occurs acutely over a few hours and in this instance is thought to be the result of vascular injury causing infarction. Also worth mentioning is a syndrome that simulates motor neuron disease, which progress over 1 to 2 years and then plateaus.

Radiation-induced vasculopathy typically presents as a transient ischemic attack and/or ischemic stroke. Cerebrovascular malformations have been reported in the field of irradiated tissue as well. This time course to onset can be short or several decades after radiotherapy. SMART syndrome presents many years after wholebrain radiation and presents with seizures, headaches, and strokelike symptoms.

Radiation plexopathy is observed in three distinct clinical syndromes. A transient plexus injury presents 3 to 6 months following radiotherapy with paresthesias, pain, or weakness. Acute ischemic brachial neuropathy has an acute presentation that does not progress and is painless. Radiation fibrosis presents with painless paresthesias involving the upper (brachial) plexus +/- swelling of the arm about 4 years after radiotherapy. Tumor recurrence can also present in a delayed fashion with paresthesias, but there is typically no swelling, it is painful, and it affects the lower plexus.

Optic neuropathy presents with painless visual loss, decreased visual acuity, and/or abnormal visual fields within 3 years of radiotherapy. Exam demonstrates papilledema followed by optic atrophy and hemorrhagic exudates.

Endocrine dysfunction presents with growth arrest in children, a decrease in muscle mass, and an increase in adipose tissue in adults. Gonadotropin deficiency manifests as a failure to enter puberty in children and with amenorrhea, infertility, sexual dysfunction, and decreased libido in adults. Thyrotropin deficiency presentations may include weight gain and lethargy. Adrenocorticotropic hormone deficiency is uncommon and presents with lethargy, fatigue, fasting hypoglycemia, and hyponatremia. Hyperprolactinemia is featured by delayed puberty, galactorrhea, and amenorrhea in women and decreased libido and impotence in men.

Neuropsychological sequela of radiation is most conspicuous when it manifests with a delayed IQ decline, learning disability, or academic failure. Detailed neuropsychiatric testing can reveal deficits in memory, executive function, processing speed, and verbal selective reminding. A syndrome of ataxia, cognitive disturbance, and urinary incontinence has been described that resolves with ventriculoperitoneal shunting.


Jul 27, 2016 | Posted by in NEUROLOGY | Comments Off on Radiation Injury

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