Management strategies for patients with pain from intracranial pathology derive from general principles of supportive care and focus on both oncologic and analgesic interventions (Table 36.2). The use of surgery to manage symptoms from intracranial pathology is limited to highly selected patients to relieve specific syndromes that are refractory to more conservative treatment. For example, rare patients undergo resection of a large cerebellar metastasis to reduce severe headache, despite the presence of other, less symptomatic, metastatic lesions. Others are offered shunt insertion for hydrocephalus or percutaneous aspiration of a tumor cyst through an Ommaya reservoir, if relief of mass effect on initial aspiration results in a significant relief of symptoms. Radiotherapy is frequently effective relieving pain or other symptoms from metastatic disease, even if the primary tumor is relatively radiation resistant (6). If the goal of treatment is limited to symptom control alone, patients are generally candidates for radiotherapy if life expectancy is greater than 2 months and symptoms are not easily managed with more conservative means.

Chemotherapy can be palliative for metastatic intracranial disease from specific tumor primaries, including breast (7), small cell carcinoma of the lung (8), testes (9), and others. Hormonal therapy can be well tolerated and can be effective in shrinking metastatic disease in patients with breast or prostate cancer who have not been previously exposed to such treatment.

The role of corticosteroids to manage symptoms from intracranial pathology requires particular emphasis. An empiric course over a few days can be used to establish efficacy. Dexamethasone, the preferred agent, is available in oral and parenteral formulations and generally lacks mineralocorticoid (salt-retaining) effect, but has an increased risk of hyponatremia which may lead to increased edema generation. Nonfluorinated corticosteroids such as prednisone may have less risk of causing myopathy (10). The dose–effect relationship of dexamethasone is a controversial subject, and the optimum dose for tumor-related cerebral edema has not been established. Comparison of 4-, 8- and 16-mg per day dexamethasone (Decadron) therapy in 89 patients with CT-proved brain metastasis, no signs of impending herniation, and Karnofsky scores of 80 or less showed the same degree of improvement in Karnofsky score over 1 week and more frequent toxicity in the 16-mg per day group over 4 weeks (11). Another study of 12 patients with brain metastasis treated with high-dose dexamethasone for 48 hours reported complete responses in only 3 patients, partial response in 1, and no response in 8 (12). Other reports support the use of steroid doses much higher than the conventional 4 mg every 6 hours, up to 96 mg over 24 hours, suggesting that the ideal dexamethasone dose should be established for each individual patient (13). Other therapies which may contribute to reducing brain edema include prevention of overhydration, severe hypertension, and seizures; use of furosemide; and, in severe situations, use of osmotherapy with mannitol or hypertonic saline and surgery when consciousness is impaired or brain herniation is imminent (14).

In patients with brain tumor, cushingoid facies predict the presence of steroid myopathy (10). Other side effects of steroids include hyperglycemia, present in nearly 50% treated over a long period (14), cataracts, osteoporosis, and dose-dependent neuropsychiatric effects, seen in 18.5% of patients at doses greater than 12 mg per day Decadron (80 mg per day prednisone) (15). The side effects can become disabling over time. To reduce the risk of side effects, the lowest effective dose of steroid should be identified by methodical titration upward or downward.

Central pain is defined as pain associated with a lesion of the central nervous system, particularly of the spinothalamic tract or thalamus (16). Central pain must be differentiated from other types of neuropathic pain associated with lesions of the peripheral nervous system and from nociceptive pain associated with ongoing stimulation of nociceptors by a tissue-damaging lesion. Current theories of central pain postulate selective deafferentation of the spinothalamic tract over prior concepts of thalamic pain as the more likely underlying mechanism (17).

Many types of structural lesions in the brain and spinal cord can cause central pain. Although the type, duration, and size of the lesion can influence the tendency to produce central pain, similar lesions may or may not be painful or may produce different types of pain (16). Only a few patients with susceptible lesions actually develop central pain. The locations of the most painful lesions are in the spinal cord, lower brain stem, and ventral posterior part of the thalamus (16). The most common causes of these lesions are spinal cord trauma and cerebrovascular accidents. Interestingly, intracranial and spinal tumors have a low prevalence of central pain and the few described cases refer to expansive lesions in the contralateral parietal cortex, not thalamic tumors (17). Several patients have reported central pain due to meningioma. In a series of 49 patients with thalamic tumors, only one had central pain (18).

The diagnosis of central pain depends on a detailed neurologic history and examination along with laboratory investigations, including CT scans or MRI, CSF analysis, neurophysiologic testing, and other tests as appropriate. Symptoms characteristic of central pain are rarely psychogenic in origin (16).

The onset of central pain may be immediate or delayed, first appearing years after the original problem. Although the pain typically has a burning, tingling, or “pins and needles” quality, it may be superficial, deep, or both. It is not always dysesthetic and can have a variety of descriptors in the same or different regions. The sensation is often unlike any prior experience and
is typically difficult to describe (16). The pain may be triggered by physical activity, stress, loud noise, vibrations, weather changes, altered muscle or visceral function, or seizures. It is usually constant, varies in severity from mild tingling to unbearable, and may have more than one element; commonly, a severe intermittent component is superimposed on constant pain. Central pain is usually permanent, although transient pain in patients with spinal cord injury and complete cessation of pain either spontaneously or after the occurrence of new lesions have been reported (16). Although not necessary for its development, central pain is usually associated with a sensory deficit in the same area as the pain. Hypesthesia to temperature is the most common finding. Sensory deficits are consistent with the site of the known lesion; for example, ventral posterior thalamic lesions may be associated with a hemibody sensory loss, and low brainstem infarcts may produce a crossed, dissociated sensory loss.

The management of central pain is based largely on clinical experience. Treatment modalities include pharmacotherapy, sensory stimulation, neurosurgical procedures, and sympathetic blockade (19). The first-line drugs are antidepressants with noradrenergic properties, specifically amitriptyline hydrochloride, which appears to be the most effective but also has the most side effects. Other medications have been found to be effective in randomized controlled trials for central pain, including intravenous lidocaine (20), intravenous morphine (21), oral lamotrigine (19), and gabapentin (22). Carbamazepine and other membrane-stabilizing drugs may be useful as second agents for the treatment of central pain, although carbamazepine at doses up to 800 mg per day in one study did not produce significant pain relief compared with placebo (23). The best central pain response to antidepressants is seen in post-stroke patients, whereas antiepileptic drugs (AEDs) seem to be most effective for paroxysmal central pain (19). Nonsteroidal anti-inflammatory drugs and oral opioids generally have a weak or no effect. A range of other therapies are used, including γ-aminobutyric acid (A) agonists (e.g., diazepam [Valium]), intrathecal (IT) baclofen, clonidine, neuroleptics, systemically administered local anesthetics, and naloxone hydrochloride (19). Patients with brain injury should be treated for motor spasticity which can contribute to chronic pain with resultant loss of function. Stimulation techniques include low- and high-frequency transcutaneous electrical nerve stimulation, spinal cord stimulation, and deep brain stimulation. Motor-cortex stimulation, a relatively new technique, is reported to benefit certain forms of intractable pain (24). Transection of spinal nerves (e.g., dorsal root entry zone lesions) or cordotomies are offered to patients primarily with intractable cancer-related pain and have limited temporal effectiveness of about 1 year before recurrence which is more difficult to manage (25).

Cranial neuralgias are of particular significance to the patient with cancer, as they frequently lead to a diagnosis of base of skull or neck metastases. Also, the frequent response of these pain syndromes to a regimen containing selected adjuvant analgesics (e.g., anticonvulsants) highlights the value of prompt diagnosis. Trigeminal and glossopharyngeal neuralgias are characterized by paroxysmal lancinating pain in the face or throat and neck, respectively. Pain lasts from a few seconds to a minute or two, with frequent recurrence. The pain is often spontaneous at onset, but it may be initiated by sensory stimuli such as touch or tickle applied to certain trigger areas; movements such as chewing or talking can also precipitate pain. Other features, such as continuous dull aching, burning, or pressure pain, are often reported (26). The differential diagnosis includes disorders of the jaw, teeth, sinuses, base of skull, and neck. Although these neuralgias are most commonly idiopathic, the onset of cranial neuralgia in a patient with a cancer history mandates a search for metastatic disease. Numb chin syndrome, involving facial and oral numbness in the distribution of the mental nerve, has been associated with a metastatic etiology in 89% of patients (27). Radiologic studies include CT scan or MRI with views of the base of skull and sinuses. Plain radiographs or tomograms of the skull base may show abnormalities. CSF analysis may be abnormal in patients with associated leptomeningeal metastases (LM).

A seizure may be defined as an episode of uncontrolled motor, sensory, or psychological activity caused by the sudden excessive discharge of cerebral cortical neurons (28), followed by a postictal phase of metabolic cerebral depression lasting a variable period. The first appearance of any seizure during adulthood, with or without a localizing aura, is sufficiently suspicious to warrant an investigation for neoplasm.

Generalized or focal seizures occur in 20–50% of patients with brain tumors (28). The occurrence of a seizure depends on the tumor site, type, and infiltration or expansive properties. In patients with supratentorial tumors, seizures are a presenting symptom in up to half of patients (29). The highest seizure incidences occur with oligodenrogliomas (92%), astrocytomas (70%), meningiomas (67%), and glioblastomas (37%) (29). In patients with slow-growing chronic tumors, the seizure incidence is as high as 75% and may predate other symptoms for years (29). Focal seizures are associated with tumors involving the motor cortex, the sensory cortex, or the temporal lobe. Temporal lobe gliomas typically produce psychomotor seizures, with or without olfactory hallucinations (uncinate fits); abnormal visual or auditory perception; déjà vu phenomenon; or automatic behavior (28). Parietal lobe tumors may cause generalized or focal sensory seizures, and occipital lobe neoplasms have been associated with an aura of flashing lights, but not formed images. Infratentorial tumors and neoplasms involving only the white matter are not commonly associated with seizures.

In patients with intracerebral metastases, the occurrence of seizures at presentation or during the course of illness was 27% in one series of 470 patients (30). The most common primary sites were melanoma (67% incidence of seizures), lung (48%), breast (32%), and unknown primary tumor (55%). With the exception of malignant melanoma and choriocarcinoma, metastatic brain neoplasms are less likely to cause seizures than primary brain tumors. The presence of multiple metastases or combined brain and LM are the conditions most frequently associated with seizures. Seizures associated with cerebral metastases are usually of the simple or complex partial type.

Seizures can be an indication of tumor progression or recurrence. Other etiologies, such as electrolyte disturbances (e.g., hyponatremia), drug interactions, and noncompliance with anticonvulsants may predispose to late development of seizures. Status epilepticus, defined as a persistent seizure (usually considered to last longer than 5 minutes) or repeated seizures without interictal return of consciousness, is a neurologic emergency. Acute management begins with assurance of the airway, ventilation, and perfusion. Blood should be sampled for urgent electrolyte screen and other appropriate tests, and intravenous glucose should typically be given (usually 50 mL of a 50% solution) before any results are known. The typical treatment protocol involves the intravenous administration of a benzodiazepine, such as lorazepam or diazepam, followed by intravenous loading with phenytoin (PHT) or valproate sodium. Persistent seizure activity beyond 7–10 minutes is an indication for continuous electroencephalographic monitoring
and to start general anesthetic procedures, with intubation followed by a short-acting barbiturate (pentobarbital sodium), or continuous infusion of midazolam or propofol (28). The minimal dose of anesthetic agents required to stop electrographic seizures is generally recommended. Although focal continuous epilepsy (epilepsy partialis continua) is also treated promptly, this syndrome is less injurious to the patient and is usually treated without the high-dose intravenous drugs administered for generalized status (28).

The routine use of prophylactic anticonvulsants in patients with brain tumor is generally recommended only in patients who present with seizures and in those undergoing craniotomy. Even the evidence that prophylactic antiepileptics prevent postoperative seizures is not consistent (31), although the American Academy of Neurology has a practice guideline that it is appropriate to taper and discontinue prophylactic anticonvulsants after the first postoperative week in patients who have not had a seizure (32). No published data show efficacy of anticonvulsants in preventing seizures beyond the postoperative phase in patients with malignant primary or metastatic brain tumors who have never had a seizure (33). In one study, a 10% incidence of late seizures in patients with brain metastases was noted, regardless of whether prophylactic PHT was given (34); however, serum anticonvulsant levels were subtherapeutic in two thirds of the patients who developed seizures. Two randomized prospective studies with over 130 patients found no significant benefit of prophylactic anticonvulsants in preventing late seizures over placebo or no treatment in patients with brain tumor who had no prior history of seizures (35, 36). A meta-analysis of over 400 patients found no AED benefit at 1 week and at 6 months, regardless of neoplastic type (33). One study suggested that patients with cerebral metastases from melanoma should probably receive prophylactic anticonvulsants due to the higher risk of seizures (up to 50%) in this group and a high risk of seizures in those not treated with prophylaxis (37%) (37). The most commonly prescribed drug is PHT, in doses of 300–400 mg per day which, along with carbamazepine, phenobarbital, and the newer anticonvulsant oxcarbazepine, induces P450 enzymes in the liver and may lead to increased metabolism of chemotherapeutic agents with similar metabolism and conversely lower anticonvulsant levels due to their increased metabolism (31). For patients undergoing chemotherapy with a history of seizures, better choices may include valproate sodium, gabapentin, lamotrigine, topiramate, levetiracetam, and zonisamide which are not enzyme inducers (31) (see Table 36.3 for main indications and doses of AED).

Concomitant use of dexamethasone also increases the required dose of AEDs such as PHT and reduces the bioavailability of dexamethasone (38). Toxic PHT levels may occur with frequent dosage adjustments and can produce side effects of nystagmus and ataxia. More serious complications from PHT include erythema multiforme and Stevens-Johnson syndrome, which have been associated with concomitant whole brain radiation therapy (WBRT) (39); myopathy (40); immunosuppressive effects specifically targeted against cell-mediated immunity (41); hepatoxicity; hyperkinetic movement disorder; and osteomalacia (28).

Discontinuation of seizure prophylaxis in patients with a benign tumor and preoperative seizures has been recommended only for patients with complete excision of a benign tumor who remain seizure free after 12 months. The risk of relapse remains at least 35% if the patient has had previous seizures (42).

Singultus (hiccups) is a forceful involuntary inspiration caused by a spasmodic contraction of the diaphragm that terminates with the sudden closure of the glottis. The closure of the glottis results in the characteristic hiccup sound. Hiccups serve no known physiologic function (43) and are usually a transient benign disorder that resolves without medical therapy. Chronic hiccups may reflect underlying pathology, including a lesion that irritates the peripheral vagus or phrenic nerves, drug toxicity, metabolic abnormalities, infection, and intracranial disease. Rarely, chronic hiccups are psychogenic.

The mechanism of hiccup may involve dysfunction of peripheral components or central connections of the reflex arc. The afferent neural pathway is composed of sensory branches of the phrenic and vagus nerves as well as dorsal sympathetic afferents from T6 through T12. The principal efferent limb, which produces the diaphragmatic contraction, includes motor fibers of the phrenic nerve and efferent branches to the glottis and external intercostal muscles (inspiratory). There is reciprocal inhibition of the expiratory intercostal muscles. The separate innervation of right and left hemidiaphragms and the long course of the two phrenic nerves, each of which contacts various organs, account for the large variety of reported mechanisms for hiccup. Hiccups may be bilateral or unilateral; most of these occur in the left diaphragm. The central control of hiccups, although not yet fully defined, is believed to include a supraspinal center that is integrated with the respiratory center output to respiratory motor neurons in the spinal cord (44). Experimental electrical stimulation of the medulla in cats has demonstrated the generation of hiccup-like responses in the medullary reticular formation lateral to the nucleus ambiguus, just rostral to the obex (45). Cells in the nucleus raphe magnus containing the inhibitory neurotransmitter γ-aminobutyric acid may be the source of inhibitory inputs to the hiccups reflex arc. The reported rate of repetitive hiccups is between 4 and 60 per minute; the most common rate is 17–20 per minute—not surprisingly, similar to the respiratory rate (43).