NEUROLOGY and GENERAL MEDICINE
Michael J. Aminoff
25 Neurological Complications of Chemotherapy and Radiation Therapy
Lisa M. DeAngeli · Jean-Yves Delattre · Jerome B. Posner

RADIATION THERAPY

    Therapeutic ionizing irradiation may affect the nervous system in one of two settings: First, damage to neural structures may occur when structures are included in the radiation portal. This damage can occur whether the cancer undergoing radiation therapy is within or outside the nervous system. Second, nervous system dysfunction can also occur secondarily when therapeutic irradiation damages blood vessels supplying the brain or endocrine organs necessary for appropriate nervous system function (usually the thyroid gland) or when the irradiation causes tumors that compress or destroy nervous system structures. Nervous system dysfunction caused by radiation therapy can occur acutely or may be delayed by weeks, months, or even years following the successful completion of treatment. The likelihood that radiation therapy will damage the nervous system depends on many factors, including the total dose delivered to the nervous system, the dose delivered with each treatment or the dose per fraction, the total volume of nervous system irradiated, the time after completion of radiation therapy, the presence of other systemic diseases that enhance the side effects of irradiation (e.g., diabetes, hypertension), and other unidentifiable host factors. The side effects of radiation therapy are detailed later. More extensive reviews can be found elsewhere.

Primary Neurological Damage

    BRAIN

    Encephalopathy caused by radiation therapy occurs in three forms: acute, early delayed (2 weeks to 4 months), and late delayed (4 months to 24 years)

Table 25-10.  RADIATION-INDUCED INJURY: DIRECT DAMAGE TO THE CNS
Time After Radiation
Clinical Findings
Possible Mechanisms
Brain      
 Acute (minutes to days)
 Early delayed (weeks)
Increased intracranial pressure
Diffuse: somnolence syndrome
Focal: simulates recurrent tumor
Acute vasogenic edema
Demyelination
 Delayed (months to years)      
  Necrosis Diffuse: dementia (rare)
Focal: simulates recurrent tumor
Glial and vascular destruction
  Leukoencephalopathy Asymptomatic or dementia Unknown
Atrophy
Spongiosis of white matter
Normal-pressure hydrocephalus
Spinal Cord      
 Early delayed (weeks) Lhermitte's sign Demyelination
 Delayed (months to years)      
  Spinal cord necrosis Transverse myelopathy Glial and vascular destruction
  Motor neuron disease Flaccid paraparesis, amyotrophy Unknown
  Arachnoiditis Often asymptomatic Radiation-induced damage to the leptomeninges
 Hemorrhage Acute myelopathy Vascular lesions

    Acute Encephalopathy

    Acute encephalopathy usually follows large radiation therapy fractions given to patients with increased intracranial pressure from primary or metastatic brain tumor, particularly in the absence of corticosteroid coverage. Immediately following treatment, susceptible patients develop headache, nausea, vomiting, somnolence, fever, and worsening of neurological symptoms, rarely severe enough to culminate in cerebral herniation and death. Acute encephalopathy usually follows the first radiation fraction and becomes progressively less severe with each ensuing fraction. Usually, the disorder is mild, with the patient developing headache and nausea in the evening following irradiation.

    The pathogenesis of the disorder is not certain. Some observers believe it is secondary to a rise in intracranial pressure, with cerebral edema following breakdown of the blood-brain barrier by ionizing irradiation. Experimental evidence indicates that a single dose of 300 cGy delivered experimentally to an animal causes substantial breakdown of the blood-brain barrier, which is still evident 2 hours after radiation; after 24 hours, the barrier has reconstituted itself. Corticosteroids substantially prevent this breakdown of the blood-brain barrier. A few observers have noted an increase in intracranial pressure following a single dose of radiation therapy, but others have failed to document such an increase either in humans or in animals even if clinical symptoms develop.

    For the clinician, there are two implications. First, patients harboring large brain tumors, particularly with signs of increased intracranial pressure, should probably not be treated with large doses per fraction. Doses of 200 cGy per fraction or less appear to be acceptable in such patients. Second, all patients undergoing brain irradiation should be protected with corticosteroids (8 to 16 mg of dexamethasone daily or more if increased intracranial pressure is symptomatic), preferably for at least 24 hours before the start of radiation therapy. Both clinical and experimental evidence indicates that corticosteroids ameliorate the acute complications of irradiation.

    Early Delayed Encephalopathy

    Early delayed encephalopathy usually begins in the second or third month after irradiation but can begin anywhere from 2 weeks to 4 months after treatment. If the patient has a brain tumor, the symptoms of early delayed encephalopathy often simulate tumor progression. For example, the patient may develop recurrence of headache, lethargy, and worsening of lateralizing signs. Changes on CT scan or MRI may include an increase in the size of the lesion and sometimes the occurrence of contrast enhancement not previously present. These changes resolve spontaneously if the disorder is due to radiation encephalopathy rather than tumor recurrence, and this resolution can be hastened by the use of corticosteroids. The patient and the scan remain improved after corticosteroids are discontinued, indicating that the disorder was early delayed encephalopathy rather than tumor recurrence.

    Early delayed encephalopathy also occurs in patients without brain tumors. Early delayed encephalopathy after prophylactic irradiation of the brain of children with leukemia has been called the “radiation somnolence syndrome.”This disorder is characterized by somnolence often associated with headache, nausea, vomiting, and, sometimes, fever. The EEG may be slow, but there are no focal neurological signs. The syndrome is ameliorated by corticosteroids but will also resolve spontaneously. The disorder is sometimes seen in adults following prophylactic radiation therapy for small cell lung cancer.

    A rare and serious neurological syndrome is brainstem encephalopathy following irradiation of posterior fossa tumors, or when the brainstem has been included in the irradiated field for head and neck cancer.The most frequent symptoms are ataxia, diplopia, dysarthria, and nystagmus. Most patients recover spontaneously within 6 to 8 weeks. Rarely, the symptoms progress to stupor, coma, and death.

    The pathogenesis of early delayed encephalopathy is believed to be demyelination, resulting from damage to oligodendroglia and subsequent breakdown of myelin sheaths. The best evidence supporting that hypothesis consists of pathological studies in patients with early delayed brainstem encephalopathy in which confluent areas of demyelination with varying degrees of axonal loss are found in areas that were irradiated.There is an associated loss of oligodendrocytes and abnormal and often multinucleated giant astrocytes. Furthermore, the latency in the onset and timing of resolution correspond to the cycle of myelin turnover.

    Late Delayed Radiation Necrosis

    Late delayed radiation necrosis usually begins a year or two after the completion of radiation therapy. The symptoms depend on the nature of the primary disease. In patients who are treated for primary or metastatic brain tumors, symptoms generally recapitulate those of the brain tumor, leading the physician to suspect tumor recurrence. In addition, the MRI or CT scan mimics recurrence, with the appearance of a contrast-enhancing lesion that is indistinguishable from tumor. Occasionally, a lesion suggesting a tumor appears at a distant site. Positron emission tomography with glucose can help distinguish radiation necrosis from recurrent tumor, the former showing decreased glucose uptake (cold area), the latter an increased glucose uptake (hot area).

    A second clinical picture has occurred when the patient's brain was included in the radiation portal, but there was no underlying brain tumor. Examples include irradiation of head and neck tumors, including pituitary tumors, and prophylactic irradiation of the brain. Because only a portion of the brain has usually been irradiated and there was no previous brain damage, new focal neurological signs are the rule. For example, bilateral medial temporal destruction sometimes follows irradiation for nasopharyngeal or pituitary tumors, and frontal or temporal lobe destruction follows treatment for ocular or maxillary sinus tumors. The clinical features are similar to those of a brain tumor, with signs of increased intracranial pressure and focal signs, depending on the site of brain damage. The MRI usually reveals a mass, occasionally with contrast enhancement. An arteriogram may show vascular beading that suggests a vasculopathy. A definitive diagnosis can only be made pathologically.

    Histologically, the typical lesion is an area of coagulative necrosis in the white matter, with relative sparing of the overlying cortex. Microscopically, the most striking abnormalities are found in blood vessels, with hyalinized thickening and fibrinoid necrosis of the walls, often associated with vascular thrombosis, vascular hemorrhages, and accumulation of perivascular fibrinoid material.

    Radiation necrosis is often treated best with resection. Most patients respond only transiently to corticosteroids, although there are occasional reports of prolonged responses after corticosteroid therapy without surgery.Other suggested treatments, such as aspirin and anticoagulation, that are based on the rationale that the disorder is primarily vascular, have not proved useful.

    There are three hypotheses concerning the pathogenesis of this disorder. The first is that the vascular changes lead to infarction and necrosis. The second is that radiation therapy directly damages glial cells, both astrocytes and oligodendrocytes, leading to destruction of tissue. The third is that the radiation causes release of brain antigens with subsequent antibody formation and immune destruction of the brain. None of these potential mechanisms are mutually exclusive and all may contribute to the damage.

    Cerebral Atrophy

    Cerebral atrophy often follows whole-brain irradiation. The atrophy may occur in patients who are irradiated prophylactically or in patients harboring brain tumors in whom irradiation has eradicated the tumor. It usually begins 6 to 12 months after radiation therapy. The patient may be asymptomatic but, more commonly, suffers memory loss and, in some instances, severe cognitive dysfunction. Some patients have gait abnormalities and urgency incontinence, suggesting normal-pressure hydrocephalus. MRI of virtually all patients receiving whole-brain irradiation in excess of 3,000 cGy shows cerebral atrophy with enlarged sulci and ventricles; there may also be symmetric periventricular white matter hyperintense signals on T2-weighted or FLAIR (fluid-attenuated inversion recovery) images. Symptomatic patients appear to have greater degrees of cerebral atrophy and ventricular dilatation than asymptomatic patients. In some instances, the ventricular dilatation is out of proportion to the sulcal atrophy; when such patients are symptomatic with dementia, gait apraxia, and incontinence, they may respond to ventriculoperitoneal shunt. Cerebral atrophy also occurs in children receiving prophylactic brain irradiation for acute leukemia. The atrophy is associated with learning disability.

    The pathogenesis of the cerebral atrophy is not clear. In some instances, true communicating hydrocephalus, perhaps from radiation-induced arachnoiditis or obliteration of pacchionian granulations, appears to be causal. In other instances, there is simply loss of cerebral substance. Pathology reveals spongiosis of the white matter, but no vascular changes such as those seen with radiation necrosis. Except in patients who respond to shunting, there is no treatment for the cerebral atrophy.

    SPINAL CORD

    There are no acute effects of radiation on the spinal cord. In the past, it was believed that, as with the brain, high doses of radiation delivered to the spinal cord for the treatment of epidural spinal cord compression might worsen neurological symptoms. Both clinical and experimental evidence have refuted this belief. Therefore, clinical deterioration of patients with metastatic spinal cord compression during radiotherapy is usually due to tumor progression.

    Early Delayed Radiation Myelopathy

    Early delayed radiation myelopathy is common after irradiation of the neck  Several weeks after irradiation, the patient develops a Lhermitte's sign that persists for weeks or months and then spontaneously disappears. Some investigators have reported delayed sensory evoked potentials,but others have not.Symptoms are believed to result from demyelination of the posterior columns of the spinal cord. Their presence does not predict the development of late delayed radiation spinal cord injury.

    Late Delayed Radiation Myelopathy

    Late delayed radiation myelopathy appears in two forms. The first and most common is characterized by progressive myelopathy, often beginning as a Brown-Séquard syndrome and progressing over weeks or months to cause paraparesis or quadriparesis.Usually the symptoms progress subacutely, but in some instances they progress over several years and, at times, may stabilize, leaving the patient with only mild or moderate paraparesis. The disorder probably never resolves spontaneously. Myelogram and MRI are usually normal, though rarely, in the acute stages, spinal cord swelling may be identified, and the area of damage may enhance with contrast material.Spinal cord atrophy develops at a later stage  Pathologically, the lesions are characterized by confluent areas of necrosis with a predilection for the white matter, particularly the deeper parts of the posterior columns and superficial areas of the posterolateral tracts. Vascular changes are similar to those of radiation necrosis in the brain but are usually less striking. There is no effective treatment, although corticosteroids sometimes delay progression of the lesion.

    A few patients have been described with hemorrhage in the spinal cord developing many years after irradiation. Characteristically, 8 to 30 years after radiation therapy to the spinal cord, a patient without prior neurological symptoms suddenly develops back pain and leg weakness. MRI suggests acute or subacute hemorrhage in the spinal cord. The cord may be slightly atrophic, but no other lesions are found. After several days, the patient typically begins to improve, and the neurological symptoms may resolve entirely. A few patients have had recurrent episodes of spinal cord hemorrhage. The pathogenesis is probably related to telangiectatic vascular changes caused by the radiation therapy. A biopsy sample of the spinal cord from one patient was said to show an arteriovenous malformation.

    A second form of late delayed radiation myelopathy is a motor neuron syndrome that characteristically follows pelvic irradiation for testicular tumors but has occurred after lumbosacral irradiation for other tumors or after craniospinal irradiation for medulloblastoma. This disorder occurs 3 months to 23 years following irradiation and is characterized by the subacute onset of flaccid leg weakness affecting both distal and proximal muscles accompanied by atrophy, fasciculations, and areflexia. It is usually bilateral and symmetric but may either begin in or remain restricted to one leg. Sensory changes are absent. Sphincter and sexual functions are normal. The CSF may contain an increased protein concentration. The myelogram is normal. Although electromyography (EMG) reveals varying degrees of denervation, sensory and motor nerve conduction velocities are normal. The deficit usually stabilizes after several months to a few years; often patients are still able to walk, but some may become paraplegic.

    The disorder is impossible to differentiate from a pure motor polyneuropathy or isolated motor neuron loss. It also resembles the paraneoplastic syndrome of subacute motor neuronopathy. A single report describes a motor neuron syndrome confined to the arms that developed 3 years following cervical irradiation and was associated with a cystic hypodense cavity affecting the spinal cord from C4 to C6

    The pathological report of one patient with a motor neuron syndrome in the lower extremities describes randomly distributed demyelination and axon loss in both sensory and motor roots, with areas of complete demyelination. The roots involved were primarily those of the cauda equina, with some anterior horn cells (motor neurons) in the lumbar cord exhibiting chromatolysis suggestive of secondary damage.

    CRANIAL NERVES

    The clinical features of radiation injury to the cranial and peripheral nerves and the special senses are shown in . Anosmia may follow irradiation. Taste is affected in almost every patient who undergoes cranial radiotherapy. Visual loss may follow irradiation of the eye or brain. It may be caused by radiation-induced “dry eye syndrome,” glaucoma, or cataract; more commonly, it may result from retinopathy or optic neuropathy. The optic neuropathy following irradiation begins 7 to 26 months after the irradiation and is characterized by painless monocular or bilateral blindness. Papilledema and retinal hemorrhages may be present. The likelihood of visual loss is probably increased by the use of concomitant chemotherapy, and visual loss can generally be prevented by shielding the eyes at the time of irradiation. Hearing loss also follows radiation therapy to the brain or ear. Radiation-induced otitis media causes a conductive hearing loss that may require myringotomy for relief. This disorder usually appears during or shortly following radiation therapy. It is different from the sensorineural hearing loss that is a late delayed effect of radiation therapy and has been attributed to an endarteritis producing vascular damage of the cochlear or acoustic nerve.The lower cranial nerves, particularly the hypoglossal nerve, are often involved as a late delayed effect of radiation therapy delivered to the neck. The pathogenesis appears to be radiation fibrosis. Recurrent laryngeal, vagal, and sympathetic fibers (Horner's syndrome) may be involved as well.

Table 25-11.  RADIATION-INDUCED INJURY: DAMAGE TO THE CRANIAL AND PERIPHERAL NERVES AND ORGANS OF SPECIAL SENSE
Cranial Nerves
 Visual system
  Retinopathy
  Optic neuropathy
  Central retinal artery occlusion
 Taste and smell
  Acute, transient loss of taste and smell during radiation therapy
  Chronic loss of smell (rare)
 Hearing and vestibular system
  Radiation otitis
  Cochlear endarteritis
  8th-nerve neuropathy (rare)
 Involvement of the lower cranial nerves
  12th nerve most frequently affected (fibrosis)
Brachial Plexus Neuropathies
 ?Acute
 Early delayed (rare)
 Delayed brachial plexopathy (fibrosis)
Delayed Lumbosacral Plexopathy
Delayed Sciatic Neuropathy (after intraoperative irradiation)

    PERIPHERAL NERVES

    There are no acute changes in peripheral nerve function following radiation therapy, although Haymaker and Lindgren mentioned that paresthesias may occur when patients are “under the beam.”Early delayed brachial plexus dysfunction is characterized by paresthesias in the hand and forearm, sometimes associated with pain and accompanied by weakness and atrophy in a C6 to T1 distribution.Nerve conduction studies reveal segmental slowing, and the course is characterized by recovery over a few weeks or months. This disorder is particularly common in patients with breast cancer because the brachial plexus is frequently included in the radiotherapy port of the primary cancer. Late delayed radiation plexopathy has been reported after irradiation of either the brachial or lumbosacral plexus, although the former is much more common. The disorder usually occurs a year or more after radiation therapy with doses of 6,000 cGy or greater. Brachial plexopathy is characterized by paresthesias and weakness of the hand or arm. There may be sensory loss, particularly in the fingers and hand, but the numbness and weakness often progress to a panplexopathy, rendering the entire arm useless. This disorder is frequently accompanied by lymphedema and by palpable induration in the supraclavicular fossa. Myokymia on electrodiagnostic testing in the territory of affected nerves helps to differentiate radiation damage from tumor infiltration of the plexus. The radiation-induced disorder is usually painless, which distinguishes it from tumor plexopathy, which is typically painful. A CT scan or MRI usually reveals a diffuse loss of tissue planes without a mass. Occasionally, radiation damage can produce a marked fibrotic reaction, such that a mass of fibrosis is evident that cannot be distinguished from tumor recurrence. In such cases, surgical exploration of the plexus may be necessary to establish the correct diagnosis. There is no treatment for radiation plexopathy, although painful paresthesias may be relieved by amitriptyline or gabapentin.

    Lumbosacral plexopathy causes weakness of one or both legs. As with radiation brachial plexopathy, pain is usually absent and, when present, is generally mild.The disorder often affects the foot, and sensory disturbances as well as weakness are present in most cases. EMG frequently reveals myokymic discharges, which help to differentiate the process from tumor recurrence. At times, exploration is necessary to make the diagnosis. Radiation-induced lumbosacral plexopathy is often slowly progressive over many years. The pathogenesis of radiation plexopathy and peripheral nerve disease is believed to be related to fibrosis causing damage to Schwann cells, rather than stemming from direct damage to the nerves themselves.

Secondary Neurological Involvement

    RADIOGENIC TUMORS

    The manner in which the nervous system may be affected secondarily after radiation therapy is summarized :

Table 25-12.  SECONDARY INVOLVEMENT OF THE NERVOUS SYSTEM FOLLOWING RADIATION THERAPY
Radiogenic Tumors
 Meningiomas
 Sarcomas
 Gliomas
 Schwannomas
Vascular Lesions
 Stenosis/occlusion of the supraclinoid internal carotid
 Moyamoya disease
 Extracranial stenosis/occlusion
 Carotid rupture (rare)
Endocrinopathy
 Primary hypothyroidism
 Hyperparathyroidism
 Hypothalamic pituitary dysfunction
  Growth hormone deficiency (most frequent)
  Hyperprolactinemia
  Cortisol deficiency (rare)
  Gonadotropin deficiency (rare)

    Radiation-induced tumors, including meningiomas, sarcomas, and, less frequently, gliomas and malignant schwannomas, may appear years to decades after irradiation of nervous system tissue; secondary tumors may develop after even low doses of radiation therapy. An epidemiological study following a group of children who received low-dose scalp irradiation for tinea capitis demonstrated a 9.5-fold increase in the incidence of meningiomas as compared with a control group. Malignant or atypical nerve sheath tumors may follow irradiation of the brachial, cervical, or lumbar plexuses. Signs and symptoms of radiogenic tumors are no different from tumors that arise without prior radiation therapy, and their surgical treatment is similar. Some patients may be able to tolerate additional radiation therapy or chemotherapy if the tumor is malignant and cannot be totally excised surgically.

    VASCULAR ABNORMALITIES

    Lesions of large intracranial or extracranial blood vessels may follow radiation therapy by months to years. Patients may develop transient ischemic attacks or cerebral infarcts. Arteriography reveals stenosis or occlusion of the artery within the radiation portal. A particularly vulnerable area is the supraclinoid portion of the internal carotid artery in children who have received brain irradiation. This occlusion is sometimes associated with moyamoya disease. The pathology of radiation-induced vascular occlusion is similar to that of severe atherosclerosis, although there may be marked periarterial fibrosis, so that at surgery it is difficult to separate the intima from the media. This condition can be distinguished from other forms of atherosclerosis by its restriction to the segment of vessel within the radiation field without evidence of widespread atherosclerosis elsewhere, by the younger age of the patients affected, and by the atypical location of the stenotic carotid segments, which are often situated distal or proximal to the bifurcation.If appropriate, endarterectomy can be successfully performed on patients with extracranial vascular disease.

    ENDOCRINOPATHIES

    Primary hypothyroidism may appear many years after irradiation for Hodgkin's disease or head and necktumors or, less frequently, after craniospinal irradiation. The patient may not have the typical stigmata of hypothyroidism but instead presents either with central or peripheral nervous system dysfunction, including encephalopathy, ataxia, and peripheral neuropathy. If the CSF protein concentration is elevated, as it often is in hypothyroidism, the patient may undergo an extensive workup prior to recognition that the neurological disorder is caused by hypothyroidism. Thyroid function should be studied in any patient with neurological symptoms who has undergone prior irradiation to the neck or head.

    Hypercalcemic hyperparathyroidism has been reported to follow radiation therapy. Hypothalamic-pituitary dysfunction is a frequent delayed complication of irradiation for head and neck or brain tumors, especially in children. In children, the most frequent endocrinopathy is growth hormone deficiency, which is more often symptomatic in patients irradiated for primary brain tumor than after prophylactic irradiation for acute leukemia because of the higher doses used to treat most brain tumors.Growth should be carefully monitored in children irradiated for brain tumor, and treatment given if deficiency is detected. Growth hormone deficiency should be differentiated from growth failure resulting from spinal irradiation. Gonadotropin deficiency and secondary or tertiary hypothyroidism are less frequent endocrinopathies.

    In adults, hypothalamic pituitary dysfunction is a common sequela of irradiation for head and neck tumors. In a large study, it was found that 5 to 9 years after irradiation, 48 percent of patients had decreased growth hormone, 13 percent had decreased cortisol (two-thirds of them requiring cortisol replacement), 40 percent had increased prolactin, and 8 percent had decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Most studies suggest that the hypothalamus is more likely to be damaged by radiation compared with the pituitary gland itself.

    In adults, radiation-induced hypothalamic pituitary dysfunction also occurs in about one-third of long-term survivors of primary brain tumors. The most frequent abnormalities are hypothalamic hypogonadism associated with hyperprolactinemia and hypothyroidism.