Painful cranial neuralgias can arise from base of skull metastases, leptomeningeal metastases, or head and neck cancers.²¹ Several well-described pain syndromes are seen with skull base metastases²² and most often occur with primary tumors of the breast, lung, and prostate. Constant aching pain in the region of the bone destruction and progressive cranial nerve palsies are the principal manifestations.

The cavernous sinus consists of a venous plexus, the carotid artery, cranial nerves, and sympathetic axons. Cavernous sinus syndrome (CSS) is caused by multiple etiologies, and MRI is the most sensitive tool for diagnosis.²³ The syndrome is characterized by multiple cranial neuropathies. The clinical presentation includes impairment of ocular motor nerves, Horner syndrome, and sensory loss of the 1st or 2nd divisions of the trigeminal nerve in various combinations. The pupil may be involved or spared. Various degrees of pain including painful opthalmoplegia may occur dependent on the particular cranial nerve involved. Tumors are a frequent cause of CSS and include pituitary adenomas, meningiomas, nasopharyngeal carcinoma, lymphoma, and metastases. CSS typically involves cranial nerves III, IV, V (V1, V2), and VI. Patients may complain of periocular pain, paresthesia, and diplopia.

The middle cranial fossa syndrome is characterized by facial numbness, paresthesias, or dysesthetic neuropathic pain in the distribution of the second or third divisions of the trigeminal nerve, and by associated motor deficits such as weakness in the masseter or temporalis muscles or abducens palsy.

Glossopharyngeal neuralgia may be the presenting symptom of the jugular foramen syndrome.²² Pain is perceived over the ear or the mastoid region and may radiate into the neck or shoulder. Neurologic deficits can include
a Horner-syndrome as well as paresis of the palate, vocal cords, sternocleidomastoid muscle, or trapezius muscle. Syncopal attacks have also been reported.²⁴ This syndrome has also been ascribed to leptomeningeal metastases²⁵ and to local extension of head and neck malignancies.²⁶ It is sometimes associated with syncope.

Tumors in the middle or posterior fossa rarely can produce a syndrome which resembles classical trigeminal neuralgia.²⁷, ²⁸, ²⁹, ³⁰ Leptomeningeal metastases in the posterior fossa can also generate this type of pain.³¹ A small fraction (between 1% and 6%) of patients with pain in the trigeminal distribution is discovered to have tumors affecting the trigeminal nerve.²⁷, ²⁸,³⁰ The most common tumors are meningiomas, acoustic neuromas, and epidermoid tumors. Other tumors that have been reported to cause facial pain include trigeminal schwannomas, carcinomas of the cranial base, brainstem gliomas, arachnoid cysts, and lymphomas.³² Tumors affecting the trigeminal nerve root are typically associated with trigeminal neuralgia or tic douloureux, whereas tumors involving either the trigeminal ganglion or divisions are more likely to cause painful trigeminal neuropathy (atypical facial pain).²⁷ New onset of trigeminal neuralgia in a patient with cancer should lead to careful imaging of the base of skull with computed tomography (CT) or MRI.²⁸ Trigeminal neuralgia that is secondary to tumor usually presents as a constant, dull, well-localized pain related to the underlying pathology involving bone and other somatic structures, associated with paroxysmal episodes of lancinating or throbbing pain.³³

Perineural spread of head and neck tumors may also be associated with significant pain. Squamous cell carcinomas of the face commonly extend by perineural spread, and are an important cause of facial pain syndromes.³⁴ Other head and neck cancers spreading perineurally may also cause pain in a trigeminal distribution.³⁵ Perineural spread, when present, typically involves cranial nerves V and VII because of their extensive subcutaneous distributions.³⁶ Glossopharyngeal neuralgia usually is caused by local nerve infiltration in the neck or base of skull. It typically produces throat and neck pain, radiating to the ear and mastoid, and may be aggravated by swallowing. Occasionally, syncope accompanies severe pain.³⁷, ³⁸ Malignant mental neuropathy is a neurologic manifestation of cancer characterized by numbness in the region innervated by the mental nerve (skin of the chin, oral mucosa, and lower lip). Distally, mandibular bone tumors, with direct nerve infiltration, were the most frequent original neoplasm, being found in 50% of cases. Proximally, the most frequent were tumors located at the base of the skull; these lesions may cause bone destruction or infiltration of the leptomeninges close to the gasserian ganglion region.³⁹ Although the lesion can be painful, it is relatively infrequent. The syndrome may be associated with breast cancer, lymphomas, prostate cancer, and leukemia. The appearance of the syndrome may be a warning sign of a systemic cancer or of its recurrence.

Intercostal nerve injury secondary to rib metastases with local extension is the most commonly described tumorrelated painful mononeuropathy. Patients with tumor invasion of the sciatic notch may present with symptoms resembling sciatica. Other nerves may be involved as well, but this is not a common clinical issue.

Radicular pain is described as corresponding to the dermatomal territory innervated by the dorsal spinal roots. Cancer-related radiculopathy may be unilateral or bilateral, but it tends to be unilateral in the cervical and lumbosacral regions and bilateral in the thorax. Radiculopathy in cancer patients typically is caused by epidural tumor mass or leptomeningeal metastases. Coughing, sneezing, positional change, and physical strain exacerbate the pain, which often has dysesthetic qualities. Leptomeningeal metastases are also capable of generating radicular pain and are characterized by multifocal neurological signs and symptoms at a variety of levels, including cranial neuralgias. Generalized headache with radicular pain in the low back and buttocks is a common presentation of this disease.⁴⁰

Leptomeningeal metastasis has been described as the detection of tumor cells in the leptomeninges or cerebrospinal fluid (CSF) remote from the site of a primary tumor. Synonyms include carcinomatous meningitis, neoplastic meningitis, neoplastic meningosis, leukemic meningitis (for leukemia), lymphomatous meningitis (for lymphoma), and meningeal carcinomatosis (for carcinoma). Oncologists and neurologists have increasingly reported diffuse leptomeningeal metastases of extracranial malignant tumors, most commonly with adenocarcinoma of the lung and breast, lymphomas, and melanomas.⁴⁰, ⁴¹, ⁴²

Leptomeningeal spread has been reported in 5% to 8% of solid tumors, 5% to 29% of non-Hodgkin lymphomas (NHL), and 11% to 70% of leukemias.⁴³ Although the incidence of metastatic lesions in the brain is high in patients with small-cell lung carcinoma (SCLC), clinical problems from metastases to the spinal cord or leptomeninges have been rare.⁴⁴ Meningeal involvement was once a common complication of acute lymphoblastic leukemia before the advent of CNS prophylaxis, but it now occurs in fewer than 5% of patients. Leptomeningeal metastases develop in 1% to 8% of patients with systemic cancer45; median survival is 3 to 6 months.⁴⁶ Without treatment, the prognosis is dismal: survival averages 6 weeks.⁴⁷

Several mechanisms may be responsible for leptomeningeal spread, including hematogenous, direct extension, (transport through the valveless venous plexus, extension along nerves, perineural/perivascular lymphatics, escape from choroid plexus or subependymal metastases, and from surgical manipulation. Leptomeningeal tumors can encase spinal and cranial nerves or directly invade them and lead to demyelination and axon destruction. Dissemination, once tumor cells reach the leptomeninges, is by exfoliation into the CSF space. Leptomeningeal metastases can cause symptoms by direct compression of brain structures (by meningeal nodules causing focal symptoms), irritation of adjacent brain (seizures), blocking of CSF pathways (leading to
hydrocephalus and increased intracranial pressure), ischemia, or stroke (by constriction of pial arteries), cranial and peripheral nerve palsies (by direct nerve involvement), metabolic derangements (by decreasing available glucose for brain by rapidly growing tumor cells), and by causing meningeal fibrosis.

The characteristic clinical presentation of leptomeningeal metastases is the simultaneous occurrence of symptoms and signs related to more than one area of the neuraxis. The clinical presentation of leptomeningeal metastasis is pleomorphic and commonly affects the cerebral hemispheres, cranial nerves, or spinal cord and its roots. Symptoms are usually multifocal and more diffuse than one discrete lesion could present. They include headache, back and radicular pain, multiple cranial and spinal nerve involvement, and alterations in mental status. Pain is present in 30% to 76% of cases.⁴⁰,⁴⁸ Table 10.1 lists the frequency of spinal cord symptoms and signs in patients with leptomeningeal metastases. Pain is by far the most common symptom (80%); 25% of patients report diffuse headache; and pain in a spinal, radicular, or meningeal pattern is reported by 50%. Focal neurologic findings include cranial neuropathies, mononeuritis, radiculopathy, urinary incontinence, and visual disturbance.

The diagnosis is dependent upon identifying malignant cells with CSF examination or upon characteristic gadolinium-enhanced MRI findings. T1-weighted gadolinium-enhanced sequence of the entire neuraxis (brain and spine) plays an important role in supporting the diagnosis, demonstrating the involved sites and guiding treatment (Fig. 10.1). MRI images typically show enhancing nodular lesions. The combination of CSF studies and neuroimaging is the optimal diagnostic strategy. Neurologic examination will reveal multifocal involvement of the CNS, cranial nerves, and spinal roots, which are the clinical hallmark of this disease. Although CSF analysis is almost always abnormal, only a positive CSF cytology or demonstration of intrathecal synthesis of tumor markers is pathognomonic.

Pain syndromes can arise from infiltration of the cervical plexus.⁴⁹ The upper four cervical ventral rami join to form the cervical plexus, which lies adjacent to C1-C4
vertebrae. The four cutaneous branches can be found at the posterior border of the sternocleidomastoid muscle as they enter the posterior triangle of the neck. Nociceptive referral patterns from the face and neck overlap because sensory afferents from the cervical plexus terminate in the spinal tract of the trigeminal along with the sensory afferents from cranial nerves V, VII, IX, and X. Local pain accompanied by lancinating or dysesthetic components referred to the retroauricular and nuchal areas (lesser and greater auricular nerves), preauricular area (greater auricular nerve), anterior neck and shoulder (transverse cutaneous and supraclavicular nerves), and the jaw (marginomandibular nerve) characterize cervical plexopathy.21 Ipsilateral Horner syndrome or hemidiaphragmatic paralysis may also occur. CT or MRI evaluation may be necessary to determine the location of the tumor in soft tissues or within the epidural space. Local extension of a head and neck tumor or cervical lymph node metastasis is the common predisposing diagnosis. In patients with head and neck tumors who have previously had radical neck dissection and radiation therapy, new onset or worsening pain includes a differential diagnosis of post-radical neck dissection syndrome or tumor recurrence. Infections often complicate and exacerbate pain in this region.

Lung or breast cancers are the most likely to invade the brachial plexus (Fig. 10.2). The lower plexus is usually the first portion to be involved. Tumor infiltration of the brachial plexus commonly stems from lymph node metastases from breast carcinoma or lymphoma, or by direct extension from lung carcinoma (ie, Pancoast tumor). The designation of “Pancoast” tumor is described in “Neoplastic Processes and Pain, Lung Cancer.” Both compression of the plexus or invasion of the nerves of the plexus by tumor cells can lead to severe, neuropathic pain.

Brachial plexopathy commences with pain in 85% of patients. Neurologic deficits usually develop well after the pain has become an issue.⁵⁰, ⁵¹ The pain is then associated with numbness, paresthesias, allodynia, and hyperesthesias in the entire upper extremity (Fig. 10.3). Typically, the pain begins in the shoulder girdle, where it is often described as pressure or aching, and radiates to the elbow, medial forearm, and fourth and fifth fingers. This is related to the observation that initially the lower plexus is more likely to be involved than the upper portion. The triceps reflex is often absent. Eventually, the patient is likely to report a burning quality to the pain. Hyperesthesia along the ulnar aspect of the forearm and the hand is a frequent finding. Both motor and sensory changes usually imply C7, C8, and T1 involvement.⁵¹

Upper plexus (C5, C6) involvement frequently leads to pain in the shoulder girdle, with burning pain in the tips of both the index finger and thumb. Upper plexus involvement usually progresses into panplexopathy. Lung tumors can present with pain in the distribution of the intercostobrachial nerve (axilla and upper chest wall).⁵²

Horner syndrome and tumor invasion of adjacent vertebrae may accompany plexus invasion; there is a high risk of concurrent epidural extension.⁴⁸,⁵³ We advise that when a patient with tumor-based brachial plexopathy is imaged (usually with an MRI), the adjacent epidural space be included in the imaging. With this information, the
radiation oncologist can plan the treatment field so as to include the entire tumor. Clinical examination findings can also imply tumor extension into the spinal foramina. A Spurling maneuver can help to identify the spinal canal as the site of pathology.⁵⁴ The Spurling maneuver requires the examiner to produce oblique extension of the neck on the affected side with axial compression to the head. By narrowing the affected foramen, pain may be produced in the upper extremity. Any patient with paraspinal or foraminal disease should be suspected to harbor epidural extension of tumor.

Neuroradiologic evaluation for brachial plexopathy has been the CT and the MRI. Fluorodeoxyglucose (FDG)-PET scanning is a very useful tool for the assessment of patients with suspected metastatic plexopathy, particularly if other imaging studies are normal (Fig. 10.4).⁵⁵ FDG-PET can also distinguish radiation-induced from metastatic plexopathy. Another useful tool to make this distinction is electromyography (EMG) (Table 10.2). In patients with metastatic brachial plexopathy, the EMG usually shows fibrillation potentials and positive waves (evidence of denervation) in affected muscles. Radiationinduced brachial plexopathy tends to have slowed nerve conduction velocity in both motor and sensory nerves.

The lumbosacral plexus can be damaged by direct tumor infiltration from adjacent soft tissues or lymph nodes or by compression from metastases in the adjacent bony pelvis. Local extension or nodal metastases from colorectal and other pelvic tumors (cervix, uterus, bladder, prostate), sarcomas (Fig. 10.5), and lymphomas are the common causes of lumbosacral plexopathy, but rarer causative neoplasms include metastases from breast or lung cancer or melanoma⁴⁹ (Table 10.3). The most common neurologic complication in patients with advanced cervical cancer has been lumbosacral plexopathy caused by retroperitoneal lymph node metastases.⁵⁶

Carcinomatous lumbosacral plexopathy is manifested by severe, aching, pressure-like, unrelenting pain localized varyingly in the pelvis, low back, or hip, or referred into the leg in a radicular or nonradicular pattern.⁵⁷ The sites of referred pain are dependent upon the components of the plexus that are involved. The pain can be described as burning, cramping, or lancinating. Sensory symptoms of numbness and paresthesias, as well as weakness and leg edema, commonly develop weeks to months later. Lumbosacral plexopathy may lead to “hot and dry foot” syndrome that suggests sympathetic fiber dysfunction.58 Clinical signs of lumbosacral plexopathy are leg weakness (86%), sensory loss (73%), reflex loss (64%), and leg edema (47%). Associated findings commonly include positive straight-leg raising tests and sciatic notch tenderness.⁵⁹

The specific clinical syndrome produced by tumor invasion of the lumbosacral plexus depends on the levels of nerve involvement. Approximately one third of patients will present with infiltration of the upper plexus and present with pain in the back, lower abdomen, flank, iliac crest, or anterolateral thigh as well as neurological findings suggesting L1-L4 involvement. Involvement of the lower plexus occurs in approximately one half of patients and presents with pain in the buttocks and perineum with referral to the posterolateral leg and thigh. L4-S1 neurological deficits, leg edema, and bowel or bladder dysfunction (Fig. 10.6) frequently accompany the pain. Sacral plexopathy may arise directly from a bony sacral lesion or a presacral mass. Involvement of the lumbosacral trunk is characterized by numbness of the dorsal medial foot and sole with associated weakness of knee flexion, ankle dorsiflexion, and inversion. Sphincter dysfunction and perineal sensory loss are caused by coccygeal plexus invasion. One fifth of patients manifest panplexopathy; their pain may refer anywhere in the territory of the lumbosacral plexus. Associated leg edema frequently accompanies lumbosacral plexopathy.⁵⁸

Jaeckle et al.⁵⁷ reported on 85 patients with lumbosacral plexopathy and pelvic tumor documented by CT
or biopsy. They described three clinical syndromes: lower (L4-S1), 51%; upper (L1-L4), 31%; and panplexopathy (L1-S3), 18%. Three fourths of the patients reported the insidious onset of pelvic or radicular leg pain, followed by sensory symptoms and weakness that began weeks to months later. The combination of leg pain, weakness, edema, rectal mass, and hydronephrosis suggests plexopathy due to cancer. CT showed pelvic tumor in 96% of such patients. Roughly, one half of such patients will have epidural extension seen on an imaging study.

Patients who have been previously treated with radiation therapy present a difficult distinction between tumor or radiation plexopathy. MRI has been found to be more sensitive than CT for diagnosing cancer-induced lumbosacral plexopathy.⁶⁰ MRI is, therefore, the best choice for the evaluation of patients with clinical and electrophysiologic evidence of plexopathy who are suspected to have a systemic cancer. Imaging must include the L1 vertebral body through to the true pelvis. The common neurologic findings include leg weakness, sensory loss, reflex asymmetry, focal tenderness to palpation (in the lumbar region in an upper plexopathy, sciatic notch and sacrum in a lower plexopathy, and lumbosacral region in
pan-plexopathy), rectal mass, decreased sphincter tone, and positive direct and reverse straight leg raising signs.

Pain over the sacrum is usually the result of the spread of cancer of the bladder, pelvic organs, or colon. Such tumors lead to a dull, aching midline pain as well as burning or throbbing pain in the soft tissues of the rectal and/or perineal region. The pain is exacerbated by sitting or lying. With bilateral involvement, sphincter incontinence and impotence in the male are commonly seen. The sacrum and the sciatic notches may be tender to palpation. Both direct and reverse straight leg raising tests may be positive. Compromise of the S1 and S2 roots can lead to weakness of ankle plantar flexion and the absence of ankle jerk reflexes (Fig. 10.7). There is usually sensory loss in both the perianal and genital regions; pain and sensory loss as well as distortions of sensation are common.

Radicular pain is reported as radiating into a limb or around the trunk wall. The pain is sharp and lancinating in quality and travels in a restricted zone from central to peripheral. It may be described as episodic, recurrent, or paroxysmal. Although radicular pain may be described by some patients as a deep tissue pain, it almost always has a cutaneous component in proportion to the number of cutaneous afferent fibers that are ectopically activated. Nociceptive pain is induced by activity at the peripheral terminals of Aδ and C fibers, whereas radicular pain is caused by the ectopic firing of axons and does not originate in nerve terminals. Ectopic activation of axons may occur as a result of mechanical deformation of a dorsal root ganglion, mechanical stimulation of previously damaged axons in peripheral nerve or nerve roots, inflammation of a dorsal root ganglion, and possibly by ischemic damage to the dorsal root ganglia. Acute or chronic spine pain may be described as cramping or knifelike, but may also be just dull or aching. Chronic spine pain without a radicular component is generally aching, dull, or burning, or any combination of these three features. Movement or change in position often exacerbates spinal pain.

Central pain is defined as pain due to disease or dysfunction in the CNS and includes pathology in the spinal cord, brain stem, or cerebral hemispheres. Central pain mechanisms are complex. Gain in neuronal excitability, loss of
inhibition, and increased facilitation may contribute to a central sensitization and disinhibition of pain pathways.7 Central pain problems due to spinal cord injury and stroke are well described.⁶¹, ⁶² Damage to spinothalamic sensory pathways, although not the only mechanism, is thought to be important in the pathogenesis of both of these sources of neuropathic pain. In addition, damage to the pain and temperature pathways is an important contributor to the development of central pain in traumatic brain injury patients.⁶³ The occurrence of hyperexcitability and hyperreactivity within the nervous system is also an important mechanism in the pathogenesis of central pain. Clinically, this may be manifested by the presence of allodynia, hyperpathia, and exaggerated wind-up sensations. Electrophysiologic studies and brain scans confirm that deafferented neurons in the thalamus and somatosensory cortex of patients with central pain may undergo plastic changes and become hyperexcitable.⁶⁴, ⁶⁵, ⁶⁶ At a cellular level, the glia play a crucial role in the maintenance of neuronal homeostasis in the CNS.⁶⁷, ⁶⁸ Glial cells represent 70% of the cells in the CNS under normal conditions, and microglia represent 5% to 10% of glia.⁶⁹ Microglia are rapidly activated in the CNS in response to pathological events, including trauma, ischemia, inflammation, hypoxia, neurodegeneration, and viral or bacterial infection, releasing proinflammatory cytokines and causing pathological pain.⁷⁰ Microglia also repair injured cells by releasing neurotrophic factors and appear to dynamically modulate neuronal function under both normal and pathological conditions.⁶⁸ Microglial cells secrete a large variety of substances, including growth factors, cytokines, complement components, lipid mediators, extracellular matrix components, enzymes, free radicals, neurotoxins, nitric oxide, and prostaglandins.⁷¹ Microglial activation appears to have an important role in neuropathic pain.72

Central pain syndromes are not commonly ascribed to cancer. Gonzales et al.⁷³ reported on the prevalence and characteristics of central pain states in hospitalized patients with cancer. The prevalence of central pain was 4%. Primary and metastatic tumors and their treatment, including surgery, radiation, and chemotherapy, were all potential causes. Furthermore, the occurrence of central pain in patients with primary CNS tumors was higher in patients with spinal tumors compared to patients with brain tumors (P < .0001). Of the 27 patients reported with cancer or cancer treatment-related central pain, nearly all levels of the CNS were involved in central pain, except for the brainstem. Including leptomeningealrelated pain, 78% of patients had a spinal cord site of injury. Seventeen patients had thoracic spinal cord injury pain, two had cervical cord injury pain, and three parietal injury pain. The primary CNS tumor types included spinal cord ependymoma,⁴ astrocytoma,¹ melanocytoma,¹ glioblastoma,¹ neuroectodermal,¹ melanocytoma;¹ thalamic oligodendroglioma,¹ lymphoma,¹

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