Neurologic complications of radiation therapy

Epidemiology 

The incidence of radiation-induced nervous system complications varies with the radiation dose, field size, and fractionation scheme; degree of edema; patient age; underlying diseases (malignant and nonmalignant); concomitant treatments; and length of survival after completion of radiation (Table 1). As a rule, incidence increases and latency decreases with higher total doses, higher fraction size, and larger volumes of treated nervous system [2].

Table 1. Factors predisposing to radiation-induced nervous system injury

	Treatment factors	High total dose (>5000 cGy)
		Increased fraction size (>200 cGy)
		Large treatment volume (eg, whole brain)
		Novel radiation delivery technique (stereotactic radiosurgery; brachytherapy; accelerated, hyperfractionated radiation)
		Concurrent chemotherapy (particularly with known radiosensitizing agents)
	Disease factors	Close proximity of target tumor to nervous system structures
		Increased tumor-associated edema
		Tumors compatible with long survival
	Patient factors	Young age (<12 years, especially <5 years)
		Old age (>60 years)
		Vascular risk factors (hypertension, diabetes, hyperlipidemia)
		Intrinsic radiation sensitivity of the involved nervous system structures (eg, hypothalamus and retina>optic nerves, cortex, pituitary>brainstem, other cranial nerves, peripheral nerves)
		Genetic instability syndromes (eg, ataxia telangiectasia, vonRecklinghausen disease)

Among the acute complications, acute radiation encephalopathy is now uncommon because of careful radiation treatment planning and the judicious use of corticosteroids. In contrast, fatigue and other nonspecific side effects associated with conventional and stereotactic cranial irradiation (Box 1) occur in the majority of patients. Except for subacute myelopathy, which is seen in up to 15% of patients treated with mantle irradiation for Hodgkin disease, the subacute complications of nervous system irradiation are also uncommon.

In contrast to the acute and subacute complications of radiation, late radiation effects are relatively common. Delayed cerebral radionecrosis occurs in approximately 5% of patients receiving more than 5000 cGy of cranial irradiation, although the actual incidence is dose and fraction size dependent (Fig. 1A, B; Fig. 2A, B). Hypertension, diabetes, concomitant chemotherapy (particularly with known radiosensitizing agents) [3], [4], [5], [6], [7], accelerated hyperfractionated radiation [8], stereotactic radiosurgery, and interstitial brachytherapy increase the frequency and accelerate the time course of this form of late-radiation-related injury. Up to 20% of patients receiving stereotactic radiosurgery [9] and as many as 80% of patients undergoing interstitial brachytherapy develop symptomatic radionecrosis, usually 3 to 12 months after treatment [10].

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Fig. 1. (A) Hematoxylin and eosin-stained light micrograph (40× magnification) of a brain biopsy from a 37-year-old man with a progressive right hemiparesis and new enhancing left frontal mass at the site of a previously resected and radiated (60 Gy in 30 fractions, 16 months earlier) anaplastic astrocytoma. The micrograph demonstrates large areas of coagulative white matter necrosis; multiple telangiectasias; multinucleated astrocytes; and abnormal small arteries showing fibrinoid necrosis, endothelial proliferation, vessel wall thickening and hyalinization, and thrombosis, all characteristic of brain of radionecrosis. (B) H&E-stained (20× magnification) brain biopsy from the same patient with radiation-induced necrosis. (C) Myelin-stained whole mount of the pons (at autopsy) from a 24-year-old woman with a medulloblastoma who received craniospinal irradiation (24 Gy in 16 fractions) and high-dose BCNU with bone marrow transplant 8 months earlier. The specimen shows multifocal demyelination throughout the pons, consistent with treatment-related injury.

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Fig. 2. (A) Axial, enhanced, T1-weighted brain MRI demonstrating a bifrontal enhancing mass straddling the falx in a 63-year-old woman with metastatic breast cancer. A left frontal metastasis at the site of left frontal enhancement on the current MRI scan was irradiated 10 months earlier (36 Gy, 12 fractions). (B) Axial FDG PET scan of the brain corresponding to the MRI in (A), demonstrating a hypometabolic right frontal mass consistent with radiation necrosis, and a hypermetabolic left frontal mass suggestive of tumor. Subsequent craniotomy and resection confirmed both diagnoses.

Radiation-related white matter changes are extremely common on CT and MRI scans [11], [12], and as many as 20% of patients with these radiographic correlates of diffuse late brain injury develop frank radiation-induced dementia [13] (Fig. 3A–D). The incidence is greatest in patients receiving whole-brain radiation therapy with fractions greater than 200 cGy and in patients surviving more than 1 year. Concurrent methotrexate or nitrosourea chemotherapy may increase the risk. Subtle, nonprogressive personality and cognitive changes are even more frequent and are more pronounced in children and in those over 60 years of age.

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Fig. 3. (A, B) Axial, unenhanced, T2-weighted brain MRIs from a 63-year-old man with a right frontal glioblastoma multiforme with a progressive dementia and no evidence of tumor recurrence, previously treated with resection, wide-field cranial irradiation (60 Gy, 30 fractions), and concurrent paclitaxel chemotherapy 14 months earlier. The MRIs show a diffuse increase in T2-signal throughout the white matter of both hemispheres and generalized atrophy. (C, D) Axial and coronal, unenhanced, T1-weighted brain MRIs from a 21-year-old woman treated with craniospinal irradiation (30 Gy in 20 fractions, with a boost to the posterior fossa) for a medulloblastoma 14 years earlier. The MRIs show significant cortical and cerebellar atrophy. The neurologic examination showed mild-to-moderate cognitive deficits and a wide-based gait.

The manifestations of radiation-induced endocrine dysfunction are often subtle and difficult to distinguish from other treatment- and tumor-related symptoms. As a consequence, this type of radiation-related disorder is underdiagnosed, and incidence estimates are unreliable. At least one biochemical endocrine abnormality has been detected in two thirds to three quarters of children and adults at some point after radiotherapy [14], [15]. In a recent case-control study, 26% of patients had chemical evidence of hypothalamic hypothyroidism, 32% showed evidence of hypothalamic hypogonadism, and 29% had hyperprolactinemia [14]. Children are more susceptible to radiation-related endocrine dysfunction than adults, and increased activity of the hypothalamic or pituitary axis (eg, during puberty), concurrent cisplatin or nitrosourea chemotherapy, and higher radiation therapy doses (especially >1800 cGy) also predispose to this complication.

Pre-existing neuropathy (secondary to diabetes), ischemia (secondary to surgery), or chemotherapy with cisplatin, vincristine, bleomycin, or doxorubicin may predispose to radiation-induced cranial neuropathy, although the overall incidence is low. Compromise of the local vascular supply (eg, by pituitary region tumors) or concurrent vincristine, methotrexate, or 5-fluorouracil chemotherapy may increase the incidence of postradiation optic neuropathy, but this complication remains relatively rare.

Incidence estimates for chronic progressive myelopathy range from 0.2% to 5% for spinal cord doses of 45 Gy in 180-cGy to 200-cGy fractions [16]. Proposed ED5 and ED50 values for this type of radiation-induced complication are 57 to 61 Gy and 68 to 73 Gy, respectively. Young age; accelerated hyperfractionated radiation schedules; large volumes of irradiated cord; and concurrent methotrexate, cytarabine, mitotane, and probably other radiosensitizing chemotherapies increase the frequency of chronic progressive myelopathy (Fig. 4).

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Fig. 4. Sagittal, enhanced, T1-weighted MRI of the lower thoracic spine in a 71-year-old man with metastatic adenocarcinoma of the colon who received concurrent spine irradiation (30 Gy in 10 fractions for an epidural metastasis) and 5-fluorouracil chemotherapy 16 months earlier. The patient presented with back pain, progressive, bilateral leg weakness, and urinary urgency and incontinence. Subsequent spinal cord biopsy was consistent with a treatment-induced necrotic myelopathy.

Radiation-induced brachial or lumbar plexopathy occurs in 1% to 9% of conventionally treated patients and is severe in approximately 5%. Young age, concurrent chemotherapy, and large fraction size may increase the frequency of radiation plexopathy to as high as 19%. Pre-existing vascular disease (including hypertension [17], hyperlipidemia, and diabetes), young age, von Recklinghausen disease, and concurrent chemotherapy may predispose to radiation syndromes affecting the cerebral vasculature. In patients surviving 5 years or more after cervical irradiation, hemodynamically significant carotid disease (17% of patients by ultrasound), symptomatic carotid disease (12%), and stroke (6.9%) are common [18] (Fig. 5A–C).

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Fig. 5. (A) Right carotid angiogram in a 72-year-old man who received bilateral neck and supraclavicular radiation (4320 cGy in 24 fractions) for a diffuse large B-cell lymphoma 8 years before presenting with left eye amaurosis fugax. The angiogram, obtained shortly after his neurologic presentation, demonstrates greater than 90% stenosis of the right internal carotid artery (and slightly less severe stenosis of the external carotid artery). Characteristic of radiation-induced carotid artery disease, the stenoses are sharply demarcated and occur within the radiation ports. (B) Left carotid angiogram of the same patient. Again, dramatic stenosis of the left internal carotid artery and less severe stenosis of the external carotid artery, both sharply demarcated and restricted to the field of the previous radiation, are seen. (C) Left carotid angiogram after stenting of the left internal carotid artery in the same patient. No further episodes of transient neurologic dysfunction have occurred in the 2 years since bilateral stenting was performed.

The incidence of radiation-induced second primary tumors is directly proportional to the radiation dose and inversely proportional to the age at which the radiation is received. In children who received a mean dose of 150 cGy for tinea capitis, a relative risk (RR) of 8.4 (95% confidence interval [CI], 4.8 to 14.8) for the development of neural tumors of the head and neck was seen in a large population-based case-control study [19]. This increased risk included gliomas (RR 2.6), meningiomas (RR 9.5) and peripheral nerve sheath tumors (RR 18.8). Even in children with skin hemangiomas who received small radiation doses (mean 7 cGy), a significantly increased risk of intracranial tumors (standardized incidence ratio 1.42, 95% CI 1.13 to 1.75) was found [20]. For patients receiving higher radiation doses for treatment of pituitary adenomas (42.5 Gy to 50 Gy), a RR for malignant brain tumors of 16 (95% CI 4.4 to 41) was seen, with an actuarial risk of secondary gliomas of 1.7% at 10 years and 2.7% at 15 years [21]. In one large institutional series, 3.7% of 272 patients with meningiomas treated over a 10-year period had received previous full-dose cranial irradiation for a different primary brain tumor [22]. A 20-year cumulative incidence of subsequent brain tumors in children treated for acute lymphoblastic leukemia of 1.39% (95% CI 0.63% to 2.15%) has been reported [23], [24]. Genetic susceptibility [25], [26], in the form of von Recklinghausen disease or ataxia-telangiectasia (even the heterozygous carrier state), is an important predisposing factor to radiation-related second primary tumors.

Clinical characteristics 

Radiation-related nervous system injury can affect every level of the nervous system and can occur acutely during the course of treatment or months or years after treatment has been completed. Different syndromes of nervous system injury have been characterized and can be classified anatomically or temporally (Table 2, Table 3). Because the same nervous system structures are susceptible to different radiation-related syndromes occurring at differing times after radiation therapy, a temporally based classification scheme dividing complications into acute, subacute, and late onset is particularly useful clinically.

Table 2. Anatomic classification of radiation-related nervous system injury

	Brain	Acute encephalopathy
		Subacute (“early delayed”) encephalopathy
		Delayed cerebral radionecrosis
		Diffuse late brain injury (atrophy and dementia)
		Radiation-induced brain tumors
	Neuroendocrine	Hypothalamic, pituitary, and thyroid hypofunction
	Cranial neuropathies (including optic neuropathy)
	Spinal cord	Subacute (transient) myelopathy
		Chronic progressive (necrotic) myelopathy
		Motor neuronopathy
	Brachial and lumbosacral plexuses	Transient brachial plexopathy
		Chronic brachial and lumbosacral plexopathy
	Peripheral nerves	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 transient ischemic attack (TIA) or stroke
		Lacunar infarct

Table 3. Temporal classification of radiation-related nervous system injury

	Time course	Onset	Syndromes
	Acute (early)	During the course of radiation	Acute encephalopathy
	Subacute	1 to 6 months after radiation	Subacute (“early delayed”) encephalopathy
			Subacute (transient) myelopathy
			Transient brachial plexopathy
	Late (chronic)	>6 months after radiation	Delayed cerebral radionecrosis
			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

Late (chronic) complications 

Delayed cerebral radionecrosis is the best described late complication of cranial radiation. It occurs after intentional irradiation of the intracranial contents or after inadvertent exposure of the brain to radiation (eg, the temporal lobes in patients with head and neck cancer) [8], [30], [34], [37]. Headache, personality change, focal deficits, and seizures typically develop insidiously 4 months to 4 years or more (median 14 months) after treatment. Papilledema and other signs of increased intracranial pressure may be present. Rarely, the presentation is fulminant, and even less commonly, established radiation necrosis may be complicated by acute hemorrhage [38].

A second, more diffuse late brain injury is manifest clinically by gradual intellectual decline, short-term memory loss, fatigue, and personality change, culminating (after 6 months to several years) in full-blown radiation-related dementia [27], [33], [39], [40]. Cases occurring even decades after cranial irradiation have been reported. Occasionally, gait impairment, incontinence, and dysarthria occur. Even with the relatively low doses of cranial irradiation (eg, 2400 cGy) given prophylactically to children with acute lymphoblastic leukemia or to adults with small-cell lung cancer (SCLC), or in patients receiving pituitary irradiation [41], significant declines in IQ and academic achievement are common, as are memory deficits, fine motor and visual-spatial dysfunction, and psychological disturbances [42], [43]. Symptoms are more pronounced with decreasing age at the time of radiation therapy (especially in children under 7 years). Patients over 60 years are also particularly susceptible to this type of late radiation toxicity [44].

The same types of radiation therapy that predispose to cerebral injury can result in radiation-induced endocrine dysfunction, usually on a hypothalamic rather than a pituitary basis [14], [15], [45]. Growth hormone is most frequently affected, followed by gonadotrophins, thyrotropin, and corticotropin. Hyperprolactinemia is also common and may resolve spontaneously. Diabetes insipidus is rare. Disturbances of sleep, libido, personality, appetite, thirst, and cognitive function occasionally result directly from hypothalamic dysfunction. Primary hypothyroidism may complicate this picture when treatment includes neck, cervical spine, or craniospinal irradiation. In a case-control study, even overt symptoms such as weight gain (48% of patients), cold intolerance (35%), fatigue (70%), erectile dysfunction (48%), and dysmenorrhea (75%) were often overlooked or attributed to other causes, in some cases for many years, until a formal endocrine evaluation was performed as part of a research protocol [14]. Post-radiation optic neuropathy can complicate conventional or stereotactic radiation therapy involving the optic apparatus (eg, for tumors involving the retina, optic nerve, chiasm, or pituitary region) and can occur after radiation therapy to intracranial tumors not directly contiguous with the visual system [46]. Painless, progressive, monocular vision loss or constriction of visual fields is the typical presentation. Altitudinal field cuts are common; “dimming” of vision or “spotty” vision loss are typical patient descriptions. The presence of pain or homonymous field defects weighs strongly against the diagnosis. Retinal arteriolar narrowing, disc edema, and peripapillary hemorrhages are the early funduscopic correlates. Onset ranges from 3 months to 3 years (median 11 months).

Although the optic nerves are the most sensitive of the cranial nerves to radiation injury, other cranial neuropathies occasionally develop after exposure to therapeutic radiation [47]. Radiation-induced cranial neuropathy occurs 1 to 37 years (mean 5.5 years) after radiation therapy (generally for head and neck or orbital tumors). In order of frequency, cranial nerves XII, XI, X, V, and VI are most commonly affected. The recurrent laryngeal nerve can be injured after radiation therapy for breast or lung cancer or after I-131 treatment of thyroid cancer. Prominent fibrosis of the soft tissues of the neck precedes cranial nerve involvement by months or years. Chronic progressive myelopathy is a delayed spinal cord syndrome corresponding to cerebral radionecrosis [16], [35] (Fig. 4). It most commonly occurs after 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.

Rarely, a gradually progressive syndrome of muscle wasting, fasciculations, weakness, and areflexia is seen after spinal cord irradiation [48]. This post-radiation motor neuronopathy most frequently involves the lumbar and sacral spinal cord levels. Sensation and sphincter function may be mildly affected, but pain is unusual. Symptoms typically develop 2 to 8 months after radiation therapy.

The brachial and lumbar plexuses may also be damaged by radiation, usually after treatment of head and neck, breast, lung, thyroid, testicular, gynecologic, prostate, or colorectal cancers or Hodgkin and non-Hodgkin lymphomas [49], [50], [51]. Most series have described a 5-year median latency of symptom onset, but one large series found no latency, with all cases occurring within 5 months after the completion of radiation therapy [50]. Paresthesias or dysesthesias of the affected limb and gradually progressive weakness are characteristic (Table 4). Pain is unusual, in contrast to cases of malignant plexopathy. In cases of radiation-induced brachial plexopathy, ipsilateral lymphedema is common. The upper plexus is almost always involved (in at least 75% of cases), whereas lower plexus involvement is more common with malignant plexopathy. In radiation-induced lumbosacral plexopathy, bilateral (though often asymmetric) plexus involvement is the rule. Pain, sphincter dysfunction, unilateral or isolated upper (L2 to L4) plexus symptoms, bony erosion, and hydronephrosis suggest a malignant etiology. The electromyographic finding of myokymic discharges is very suggestive of a radiation-related plexopathy. Myokymia is present in at least one affected muscle in 50% to 70% of patients with radiation-induced brachial plexopathy but is rare in malignant plexopathy.

Table 4. Features distinguishing radiation from neoplastic plexopathy

		Radiation-induced	Neoplastic
	Brachial plexopathy
	Latency (median)	5 years	<1 year
	Presenting symptom
	Pain	20%	80%
	Weakness	13%	5%
	Numbness	73%	19%
	Anatomic distribution
	Upper plexus	42%	11%
	Lower plexus	24%	62%
	Entire plexus	30%	26%
	Horner syndrome	8%	47%
	Bowel or bladder symptoms	NA	NA
	Bilateral symptoms	0%	0%
	CT scan
	Mass lesion	0%	92%
	Tissue plane loss	62%	12%
	Myelogram positive	0%	35%
	Myokymia on EMG	63%	4%
	Usual outcome	Disability	Death
	Median survival	>10 years	18 months
	Lumbosacral plexopathy
	Latency (median)	5 years	<1 year
	Presenting symptom
	Pain	7%	91%
	Weakness	58%	4%
	Numbness	36%	4%
	Anatomic distribution
	Upper plexus	17%	30%
	Lower plexus	46%	49%
	Entire plexus	38%	23%
	Horner syndrome	NA	NA
	Bowel or bladder symptoms	0%	12%
	Bilateral symptoms	79%	23%
	CT scan
	Mass lesion	0%	91%
	Tissue plane loss	?	?
	Myelogram positive	0%	21%
	Myokymia on EMG	64%	0%
	Usual outcome	Disability	Death
	Median survival	>10 years	18 months

Abbreviation: NA, not applicable.

The cerebral vasculature may be damaged by radiation to the brain, sellar region, head and neck, or chest. Depending on the portion of the vascular tree exposed to radiation and the type of vascular lesion produced, transient ischemia, strokes, or hemorrhage may occur (Table 5) [17], [52], [53], [54], [55], [56]. Transient ischemic attacks, stroke, and myocardial infarction [57], [58] can occur after irradiation of the ascending aorta, proximal common carotid arteries, and heart (eg, for head and neck cancer, lymphoma, or breast cancer). A syndrome consisting of multiple transient ischemic attacks months to years (median 2 years) after mantle irradiation for Hodgkin disease has been described [59]. Radiation-induced tumors may arise within the brain (meningiomas, gliomas, and lymphomas), dura (fibrosarcoma and malignant fibrous histiocytoma), cranial bones (osteosarcoma), or spinal and peripheral nerves (malignant peripheral nerve sheath tumor, malignant schwannomas, and neurofibrosarcoma) after therapeutic, prophylactic, or diagnostic irradiation [19], [21], [60], [61], [62]. Latencies are long: 5 months to 26 years (mean 14 years) for gliomas, 5 to 40 years (mean 21 years) for meningiomas, and 3 to 41 years (mean 15.4 years) for peripheral nerve sheath tumors. Most cases have occurred after full-dose radiotherapy for pituitary adenomas or other potentially curable primary brain tumors (eg, medulloblastomas, germinomas, and meningiomas) or after prophylactic cranial irradiation (usually 24 cGy) in children with acute lymphoblastic leukemia [23], [24] or in adults with SCLC, but even very low-dose radiation (eg, as used for acne, tinea capitis, or dental diagnosis) has been associated with an increased incidence of tumors at an even longer latency (mean of 37 years for meningiomas). The symptoms of radiation-induced intracranial tumors are identical to those of their nonradiation-induced counterparts, but radiation-induced intracranial tumors are typically aggressive microscopically and clinically. Radiation-induced meningiomas, for example, are generally histologically malignant or contain atypical features; they are multiple; they have high labeling indices; and they tend to recur early and with high frequency after gross total resection. Radiation-induced peripheral nerve sheath tumors present as painful, enlarging masses within the field of previous radiation; they produce progressive neurologic dysfunction and are histologically malignant.

Table 5. Radiation-induced cerebral vasculopathies

	Syndrome	Characteristics
	Intracranial arterial occlusive disease
		Age: Child
		Affected vessels: ICA, MCA, PCA; moyamoya pattern on angiography
		Latency after radiation: 9 months to 15.5 years (5.2 years)
		Frequency, dose (cGy): rare, >4500
		Associated conditions: Usually after radiation therapy of optic glioma or parasellar region tumors; von Recklinghausen disease and young age are predisposing factors.
	Thrombotic occlusion
		Age: Adult
		Affected vessels: Internal carotid
		Latency after radiation: 3 months to 27 years (>3 years)
		Frequency, dose (cGy): Rare, >6500
		Associated conditions: After neck irradiation; lymphoma; head and neck tumors
	Accelerated atherosclerosis
		Age: Adult
		Affected vessels: EC or IC vessels within radiation therapy ports
		Latency after radiation: 1 to 30+ years (10 years)
		Frequency, dose (cGy): >10%, >5000
		Associated conditions: Hypertension, hyperlipidemia, and pre-existing vascular disease are predisposing factors.
	Lacunar infarction
		Age: Child, young adult
		Affected vessels: Small penetrating arteries
		Latency after radiation: 2.01 (0.26 to 5.7) years
		Frequency, dose (cGy): 5-year cumulative incidence 4% to 12%, 4800 to 7020
		Associated conditions: Age >5 years at the time of radiation therapy
	Carotid artery rupture
		Age: Adult
		Affected vessels: Common carotid
		Latency after radiation: 4 to 52 weeks
		Frequency, dose (cGy): Rare, >5500
		Associated conditions: Preceded by radical neck dissection and wound infection
	Cerebral aneurysms∗
		Age: Child
		Affected vessels: ICA, PCA, basilar artery
		Latency after radiation: 9 to 19 years
		Frequency, dose (cGy): Rare, >4000
		Associated conditions: Intrathecal 198Au; alpha-1-antitrypsin deficiency; Ehlers Danlos syndrome
	Cryptic vascular malformations†
		Age: Child
		Affected vessels: Intracranial arterioles, venules
		Latency after radiation: 5 to 72 months (32.5 months)
		Frequency, dose (cGy): Uncommon, >4500
		Associated conditions: Young age
	Cavernous angiomas†
		Age: Child
		Affected vessels: Intracranial capillaries
		Latency after radiation: 3 to 10 years (8.1 years)
		Frequency, dose (cGy): Uncommon, 1800–6000
		Associated conditions: Young age

∗ 198Au was administered intrathecally, three times at 6-month intervals, in patients with medulloblastomas (radiation dose 10 to 15 mCi per injection). † Pathologic data are scant; these entities may ultimately be reclassified as a single lesion type.

Differential diagnosis and approach to the patient 

In general, the most frequent and most pressing diagnosis competing with radiation-related nervous system injury is recurrent tumor. For specific syndromes, however, other neurologic and non-neurologic conditions may complicate the differential (Table 6).

Table 6. Cancer-related disorders mimicking the symptoms of radiation toxicity

	Radiation-related syndrome	Alternative etiologies
	Acute and subacute encephalopathy and myelopathy	Metabolic encephalopathy Drug toxicity
		Partial seizures
		Hydrocephalus
		Tumor progression or hemorrhage
		Increased edema
		Leptomeningeal carcinomatosis
		Epidural metastases
	Delayed radionecrosis	Tumor recurrence
		Metastatic or second primary tumor
		Leptomeningeal carcinomatosis
		Hydrocephalus
		Abscess
	Diffuse late brain injury	Tumor recurrence
		Leptomeningeal carcinomatosis
		Medication effect
		Psychiatric disorders
		Partial seizures
		Alzheimer type dementia
		Encephalitis (infectious or paraneoplastic)
	Endocrine dysfunction	Psychiatric disorders
		Corticosteroids
		Nutritional deficiencies
		Effects of chemotherapy
		Vertebral body irradiation
	Optic neuropathy	Drug effect
		Paraneoplastic disorder
		Stroke
		Multiple sclerosis
		Optic nerve tumors
		Metastases to the orbit, optic nerve, pituitary, chiasm, or skull base
		Leptomeningeal carcinomatosis
		Increased intracranial pressure
	Cranial neuropathy	Tumor recurrence
		Metastases to the skull base
		Basilar meningitis
		Chemotherapy
		Radiation effect on afferent receptors
	Chronic progressive myelopathy	Epidural or intramedullary metastasis
		Leptomeningeal carcinomatosis
		Chemotherapy side effects
		Paraneoplastic necrotizing myelopathy
	Motor neuronopathy	Effects of chemotherapy
		Nutritional deficiency
		Paraneoplastic motor neuronopathy (lymphomas)
		Leptomeningeal carcinomatosis
		Malignant or radiation plexopathy
	Plexopathy	Metastatic tumor
		Leptomeningeal carcinomatosis
		Chemotherapy side effects
		Ischemic, compression, para-infectious neuropathies
		Rheumatologic disease or osteoarthritis
	Cerebrovascular disease	Nonbacterial thrombotic endocarditis
		Disseminated intravascular coagulation
		Tumor emboli
		Partial seizures
		Vasculitis

When new symptoms develop over days or weeks, are mild, or improve over the weekend break from radiation therapy, a presumptive diagnosis of acute radiation encephalopathy and an empirical increase of steroid dose are reasonable. Marked or abrupt deterioration or fluctuating symptoms raises the possibilities of tumor progression, tumor-associated hemorrhage or increased edema, obstructive hydrocephalus, unrecognized seizures, or infection within or outside of the central nervous system, and an urgent CT or MRI scan is appropriate. In patients with early delayed encephalopathy, the MRI often shows increased edema, patchy or confluent areas of increased signal on T2-weighted and FLAIR sequences, and, occasionally, focal areas of enhancement [11]. Neurosurgical intervention is resorted to only if the appearance of the scan suggests the possibility of treatment failure and the severity of symptoms makes the need for alternative therapy an urgent consideration. In the absence of a confounding neurologic disease such as multiple sclerosis or concern about tumor recurrence or new spinal metastases, additional diagnostic investigations are unnecessary in cases of subacute myelopathy. Symptoms mimicking subacute myelopathy have also been reported after high-dose chemotherapy with autologous bone marrow transplant and with conventional doses of cisplatin chemotherapy [63].

In the context of radiation-related nervous system injury, a common diagnostic quandary arises when a patient presents with a recurrent mass in the same location as the original tumor. When the new lesion develops within 8 months of the completion of standard radiation therapy, the presumption of recurrent tumor can be made with fair certainty, but the possibility of delayed radiation necrosis must still be considered. PET, SPECT, or MRI scanning with MR spectroscopy frequently helps to resolve this dilemma (Fig. 2). Radionecrotic lesions are typically hypometabolic on [18F]fluorodeoxy-glucose or [11C]methionine PET scanning, “cold” on 201Thallium or 99mTechnetium HmPAO scans, and show markedly decreased perfusion and high diffusion (perfusion-diffusion mismatch) on diffusion- and perfusion-weighted MRI scans [64], [65], [66], [67]. MR spectroscopy reveals markedly reduced N-acetyl-aspartate and myoinositol levels, abnormal lipid and lactate peaks, and a normal choline-to-creatine ratio [68], [69]. Because false negative, false positive, and nondiagnostic studies occur [69], a stereotactic biopsy or second resection may be appropriate if aggressive therapy is being considered. Similarly, a functional imaging study and a stereotactic biopsy are usually indicated in cases where the “recurrence” develops late (particularly after 2 years); the original tumor was low grade; PET, SPECT, or functional MRI scanning is suggestive of radionecrosis; or unconventional radiation protocols or concurrent chemotherapy were used in the initial treatment. Although tumor and radionecrosis are the leading diagnostic possibilities, abscess, stroke, and demyelinating lesions can occasionally be misleading.

Diffuse late brain injury can also present a clinical and radiographic diagnostic dilemma. Clinically, leptomeningeal disease, encephalitis (infectious or paraneoplastic), concurrently administered drugs (anticonvulsants, antibiotics—quinolones and cephalosporins in particular [70], steroids, and analgesics), metabolic abnormalities, systemic infection, endocrine hypofunction, and depression enter into the differential diagnosis. Chemotherapy alone, including conventional and high-dose regimens, can produce cognitive, neurophysiologic, and radiographic changes that mimic the effects of radiation [71], [72], [73], [74]. Because the radiographic correlates of delayed radiation encephalopathy include diffuse cerebral atrophy, ventricular enlargement, and white matter abnormalities, confusion with periventricular small vessel disease, Alzheimer or other dementias, multiple sclerosis, progressive multifocal leukoencephalopathy, or transependymal CSF resorption in the setting of hydrocephalus can occur, and a diagnosis should not be made on radiographic grounds alone. A careful search for infection, review of concurrent medications, measurement of liver enzymes, serum electrolytes, thyroid and adrenal function, and a lumbar puncture (for pressure, cytology, and cultures) are generally indicated. When seizures are suspected, an EEG may be helpful. A trial of antidepressant or stimulant therapy may also be warranted.

The symptoms of radiation-induced endocrinopathy may be subtle. The effects of steroids, chemotherapy, other medications, surgery, vertebral body irradiation, psychological disturbances, nutritional deficiencies, and the tumor itself may mask or be mistaken for endocrinopathy, and compensated or minimally symptomatic endocrine abnormalities may precede overt disease by years. In patients who have received pituitary, neck, or craniospinal irradiation, pituitary failure or primary hypothyroidism may occur, complicating the diagnostic picture further. Rarely, corticotropin deficiency may complicate the tapering of corticosteroids. Practically, baseline screening of free T4, TSH, FSH, LH, prolactin, testosterone, and (in children) GH before radiation, every 6 months thereafter and when suggestive symptoms develop, is appropriate. Because hypothalamic dysfunction is a frequent cause of radiation-induced endocrinopathy, conventional screening often fails to detect clinically significant disease, and more sophisticated laboratory testing is often necessary [45]. In cases where clinical evidence of hypothyroidism exists in the absence of diagnostic laboratory abnormalities, a therapeutic trial of thyroid replacement may confirm the diagnosis and produce a gratifying clinical response. Such an approach is taken with testosterone in male patients but is not appropriate in growth-delayed children with normal biochemical GH studies.

Disturbances of taste and gag reflex and salivation commonly develop during the course of radiation therapy and are the result of damage to afferent receptors rather than to the cranial nerves. Decreased hearing secondary to cochlear (rather than VIIIth nerve) injury or to serous otitis media is frequent, but vestibular dysfunction does not occur. The most common diagnosis competing with radiation-induced cranial neuropathy is malignant base-of-skull disease. A shorter latency for recurrent tumor after radiation therapy (2 to 27 months) and a different frequency of cranial nerve involvement (V and VI are most common, followed by IX, X, and XII) aid in clinical differentiation of the two etiologies.

CT or MRI scanning with special attention to the skull base may demonstrate recurrent tumor, but serial scanning over time may be required. Because the presentations of leptomeningeal cancer, basilar meningitis, Lyme disease, sarcoidosis, and paraneoplastic encephalomyelitis can include cranial neuropathies, a lumbar puncture, brain MRI, and, in selected cases, paraneoplastic autoantibody testing are also necessary.

Primary optic nerve tumors (including radiation-induced tumors); metastases to the orbit (breast cancer accounts for half of these), optic nerves or chiasm, pituitary, skull base, or leptomeninges; increased intracranial pressure; cerebrovascular disease; chemotherapy effects (most importantly, tamoxifen, cis-platinum, and intra-arterial BCNU); venous sinus thrombosis; and paraneoplastic disease (retinopathy, optic neuritis, and encephalomyelitis) can simulate radiation-induced optic neuropathy. Funduscopic and MRI findings (optic nerve enlargement and focal areas of enhancement) characteristic of the radiation-related disorder may provide clues to the correct diagnosis [75], [76], [77].

Epidural metastases, intramedullary tumor or hemorrhage, leptomeningeal disease, toxicity from chemotherapy (particularly intrathecal methotrexate or cytarabine), and paraneoplastic subacute necrotizing myelopathy are competing diagnostic possibilities for chronic progressive radiation myelopathy. Radiation-induced myelopathy is characteristically painless, whereas pain is usually prominent with epidural and intramedullary tumor. Furthermore, radiation myelopathy is a slowly progressive disorder, whereas abrupt worsening often occurs in malignant cord syndromes, and paraneoplastic myelopathy is a fulminant disease leading to death within weeks to a few months. Enhanced MRI scanning and malignant cells on a cytologic preparation of the CSF are helpful in distinguishing these diagnostic alternatives.

Post-radiation motor neuronopathy [48] resembles the paraneoplastic motor neuronopathy seen rarely in patients with lymphoma and can be confused with leptomeningeal carcinomatosis, malignant or radiation-related plexopathy, the effects of nutritional deficiency, and toxicity from chemotherapy, such as vincristine. Electromyelography reveals denervation with preserved conduction velocities. Metastases to the brachial or lumbar plexuses, epidural space, or leptomeninges, ischemic plexitis, brachial or lumbosacral neuritis, cervical arthritis, joint bursitis, myofascial pain, misdirected intragluteal injections, and diabetic-, compression-, and chemotherapy-induced neuropathies may complicate the differential diagnosis between malignant and radiation plexopathy (Table 4). Enhanced MRI scanning of the appropriate plexus and spinal cord levels and cytologic examination of the CSF are required. Myokymic discharges on an electromyographic study may also be helpful. In patients with no identifiable tumor, with prolonged disease-free intervals, or with medically intractable pain, surgical exploration may be required for diagnosis and therapy [78].

In addition to conventional causes of cerebrovascular disease, chemotherapy-induced and paraneoplastic vasculopathy, compression of cerebral vessels by tumor, and parainfectious vasculitis (eg, secondary to varicella zoster after ophthalmic shingles) must be considered in the differential of radiation-induced vascular disease. MRI scanning and MR angiography help to select among potential etiologies. Carotid stenoses in segments of the vessel included within the radiation ports but uncommonly involved by typical atherosclerotic disease (eg, the proximal common carotid artery, internal carotid artery distal to the bifurcation, small and medium-sized intracranial arteries) implicate radiation as the cause. Occlusion of one or more arteries of the Circle of Willis and a moyamoya pattern of collateral vessels are characteristic in patients with intracranial vascular occlusive disease.

Recurrent cancer is the most pressing differential diagnostic consideration when considering radiation-related second primary tumors. The signs, symptoms, and radiographic appearance of intracranial second primary tumors are indistinguishable from their spontaneously arising analogues. Scarring, atrophy, hair loss, and keratoses in the overlying skin are clinical clues to the etiology, even when the previous radiation has been forgotten.

Treatment and prevention 

No specific intervention for radiation-related fatigue beyond adequate rest and prudent scheduling of activities is generally necessary. When recent or rapid tapering of corticosteroids has taken place, a return to higher doses may be beneficial. Occasionally, stimulant medication (methylphenidate or modafinil) may be considered. Increasing doses of corticosteroids generally ameliorates the symptoms of acute radiation encephalopathy and may hasten improvement in some patients with early delayed encephalopathy. No treatment is necessary for subacute myelopathy or transient brachial plexopathy, both of which are self-limited.

Treatment for most forms of delayed radiation injury to the nervous system is unsatisfactory, and symptoms are rarely self-limited. Corticosteroids are sometimes helpful in reducing the mass effect and associated deficits caused by cerebral radiation necrosis, but they are not usually beneficial in radiation myelopathy [30], [37]. Resection (to remove the radionecrotic mass) or neurolysis (in the case of radiation plexopathy) may improve or stabilize these syndromes, but these procedures are not consistently rewarding [79]. Shunting has been helpful in some patients with diffuse radiation brain injury and dementia, at least transiently [40]. Successful treatment with hyperbaric oxygen has been reported in children with delayed cerebral radionecrosis [80] and in adults and children with radiation-related optic neuropathy and radiation myelopathy, but the treatment has been more consistently rewarding in the latter group. Anticoagulation (generally with heparin followed by Coumadin) has produced remarkable recovery of function in many patients with delayed cerebral radionecrosis, chronic radiation myelopathy, and radiation plexopathy for whom very high doses of corticosteroids have not been beneficial [81]. Improvement with anticoagulation has been noted even years after the onset of symptoms. Although side effects from both of these approaches have been minimal, neither has been studied in a randomized, controlled trial, and the mechanism of action remains conjectural. Case reports have also described improvement in radiation-related optic neuropathy with anticoagulation [82] and cerebral radionecrosis with pentoxifylline [83].

Most radiation-related tumors are histologically and clinically aggressive. Treatment options are identical as for the analogous nonradiation-induced tumors but are rarely as successful.

Because of the increasing frequency of delayed radiation-related nervous system injury and the paucity of successful interventions, attention has increasingly focused on prevention. Reductions in overall radiation dose, fraction size, and treatment volume; aggressive control of increased intracranial pressure; modifications in radiation dose when concurrent chemotherapy is being used; and exploration of alternatives to irradiation in the very young and very old have been effective in reducing the frequency of radiation injury but are often not possible. Recent studies suggest that variations in lymphocyte or skin fibroblast radiosensitivity may predict the occurrence of radiation-related nervous system toxicity [84]. Although current assays are too imprecise and correlations with outcome are too inconsistent, individual tailoring of radiation dose based on laboratory assays of normal tissue radiosensitivity, cytokine production, or molecular or cytogenetic probes are plausible [85], [86]. Prophylactic antiplatelet therapy, cholesterol-lowering agents, and yearly carotid ultrasound screening are appropriate for patients at risk for accelerated carotid atherosclerosis. Preventative interventions using hormone suppressive therapy (in children at risk for radiation-induced endocrinopathy), cytokine-active agents (like the TNF-alpha inhibitors pentoxifylline, etanercept, and infliximab), and antiplatelet drugs (in adults undergoing cranial irradiation) have been proposed, but results from prospective trials are not available. Tentative evidence suggests that treatment with pro- and anti-inflammatory, anti-thrombotic, and anti-angiogenesis agents, disruption of cell adhesion molecule function, and manipulation of gene products regulating apoptosis in response to radiation injury may allow selective enhancement of radiation injury in tumor cells and avoidance of injury in surrounding normal tissue [87], [88]. Specific inhibitors of free radical generation (tetracyclines), excitotoxic amino acids (ceftriaxone), polyamine synthesis (difluoromethylornithine), neuronal activity (pentobarbital and lidocaine), and macrophage chemotaxis in response to radiation-induced cellular injury have shown some protective benefit in animal models [89], [90], [91], [92]. The benefit of these interventions in clinical practice and their potential effects on tumor control remain to be elucidated.

Summary 

Injury to the central and peripheral nervous systems is an increasingly frequent consequence of standard radiation treatment protocols for tumors involving or adjacent to nervous system structures. Characteristic temporal, clinical, radiographic, and laboratory features distinguish a number of specific radiation injury syndromes, but meticulous and repeated evaluations over time are often required to establish a diagnosis. These syndromes vary with regard to prognosis and therapeutic options, and competing diagnoses with very different natural histories and therapies often mask or mimic the signs and symptoms of radiation-related nervous system injury. The ability to efficiently negotiate this complicated differential diagnostic landscape allows for early diagnosis of tumor recurrence or an alternative etiology, prompt institution of appropriate therapy, avoidance of unnecessary diagnostic studies, and confident prognostication for patients and families. Even after the diagnosis of a radiation-related complication is made, continued vigilance for additional sites or manifestations of radiation injury is mandatory. Meanwhile, further research into treatment, prevention, and the causes of individual susceptibility to radiation injury are essential.