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. |