14.1 Neurological problems in advanced cancer

Neurological complications are frequent in populations with advanced cancer. An adequate neurological assessment is always important in addressing pain, cognitive symptoms, and peripheral and central nervous system (CNS) complications.

Intracranial pressure (ICP) is the result of the balance between the liquid (cerebrospinal fluid (CSF), blood interstitial fluid) and solid content of the cranium. It is not constant but depends on systemic blood pressure; its changes are maintained within narrow limits. The normal brain can tolerate small variations usually without clinical consequences.

An adult’s cranium is a fixed vault so an increase in one of the three components—brain, blood, CSF—causes a reduction in one of the others.

Pathological processes, such as tumours, abscesses, or haematomas, increase intracranial contents that compress brain parenchyma. They also disrupt the blood–brain barrier, which may lead to increased intracranial blood volume. If this occurs slowly, there may be no increase in ICP, at least temporarily. This is due to compensatory mechanisms, such as enhanced CSF reabsorption, reduced intracranial blood volume, and increased drainage through the lymphatic and circulatory system. When these mechanisms are insufficient or if the process is acute, ICP rises rapidly and may cause death, with or without brain distortion or herniation (see below).

The clinical picture of increased ICP is characterized by an altered state of consciousness, headache, nausea and vomiting, papilloedema, and, at times, focal signs. An altered state of consciousness is the most frequent sign, starting with psychomotor retardation, and slowing of verbal and motor responses. This can progress to stupor and then coma.

Headache progresses and can be severe. It usually is diffuse, more intense in the supine position, and worse in the morning immediately after awakening. It can awaken the patient from sleep, and also is worsened by head movements, cough, and the Valsalva manoeuvre. Nausea and vomiting frequently accompany the headache. Vomiting may be projectile in children with posterior fossa lesions, which can directly stimulate the trigger zone in the fourth ventricle.

Papilloedema is a specific sign of increased ICP but its sensibility is low, so it often is absent, even in severe cases. Among the focal signs that occur frequently in those with increased ICP, the most frequent is diplopia due to paralysis of the abducens nerve. This nerve, with its long intracranial course, is particularly sensitive to traction or compression. Other signs may occur in either the sensory or motor systems. Seizures also may occur in the setting of increased ICP.

In children, increased ICP often is accompanied by non-specific findings or may manifest as irritability, labile mood, negativity, or aggressive or hostile behaviours. A focal sign relatively more common in children is the ‘sunset’ sign; downward ocular deviation, eyelids retraction due to compression of the quadrigeminal plate.

In the setting of intracranial hypertension, the physiological fluctuation in ICP can be interrupted suddenly by abnormal pressure waves, including waves of very high pressure, or plateau waves (Lundberg, 1960). These pressure waves, which usually last seconds to minutes, may be accompanied by acute pressure symptoms that are sudden acute neurological symptoms or worsening of general neurological conditions (Box 14.1.1).

Dural reflections of the falx cerebri and tentorium cerebelli divide the cranial box into compartments, and raised ICP can result in pressure gradients between compartments. These pressure gradients can, in turn, lead to shifts of brain parenchyma or herniations: subfalcial, tentorial, upward cerebellar, and cerebellar pressure cone. These can be merely a relief for crowding or a sign of overfilled sovratentorial and posterior fossa compartments, but when they occur rapidly, or interfere with CSF circulation and cause hydrocephalus, they can be life-threatening.

In both primary and secondary brain tumours, oedema is an important cause of increased ICP. The underlying pathogenic mechanism of oedema is the loss of osmotically active substances such as albumin from the circulatory system into the brain interstitial tissue, which is caused by disruption of the blood–brain barrier within the tumour and in the surrounding cerebral parenchyma. According to the classic classification (Klatzo, 1967), there are four broad types of brain oedema:

Tumour-induced brain oedema is sustained mainly, at least initially, by vasogenic mechanisms. Interstitial and osmotic oedema are rare and do not apply to the perturbations produced by a tumour.

Conservative management of cerebral oedema has two main goals: maintenance of cerebral perfusion pressure (CPP) and reduction of vasogenic oedema (Rosner et al 1995). CPP is defined as mean arterial pressure minus ICP. Intracranial processes can impair CPP by increasing ICP and disrupting cerebrovascular autoregolation. The consequences of reduced CPP are cerebral ischaemia, compensatory and dilatation of cerebral vessels, with further increase of ICP. Since hypovolaemia reduces arterial pressure and therefore CPP, the patient with elevated ICP does not require fluid restriction, but should be kept euvolaemic with adequate fluid intake.

Interventions that assist in maintaining CPP and reducing vasogenic oedema are varied. Consideration of these interventions depends on the goals of care. Aggressive management strategies, such as assisted ventilation to lower the partial pressure of carbon dioxide may not be considered when the goals are purely palliative.

Positioning: a neutral head position should be adopted, with the head at least 30° above the heart to facilitate venous drainage from the head.

Infusion of hypertonic solutions: rapid reduction of ICP and cerebral oedema with hypertonic solutions has been utilized since 1925 (Howe, 1925). Nowadays, used hyperosmolar solutions are mannitol, and hypertonic saline (Ropper, 2012).

Hyperosmolar solutions are only effective if the blood–brain barrier is intact; action is by removal of water from normal brain parenchyma, as ICP is lowered in proportion to the volume of undamaged brain. There is little value on oedema around a lesion where the blood–brain barrier is damaged. In addition such solutions do not have a role in asymptomatic cerebral oedema.

Mannitol is the most commonly used agent (Ropper, 2012). Its activity is based initially on an increase in blood flow, leading to improved cerebral perfusion. Only later does it create an osmolar gradient between blood and brain and extract water from the cerebral compartment. Usually more water than sodium is eliminated, resulting in hypovolaemia and hyponatraemia. There is no interaction between mannitol and glucose metabolism. There are a number of other actions associated with the therapeutic effect of mannitol, including a diuretic effect, an increase in red cell deformability, and a rapid reduction of the diameter of arterioles and small veins of the brain surface. Mannitol is not metabolized and is excreted by the kidneys; with moderate reduction of glomerular filtration, it can accumulate in the central compartment. Although it can be administered orally, bioavailability is very poor and the usual approach is intravenous (IV) infusion, aiming to achieve concentrations higher than 5 mmol/L, which are active osmotically and persist for 4–6 hours. Mannitol 18% or 20% solutions are used and the suggested dose regimen for both adults and children is 1 g/kg delivered over 15–30 minutes immediately, then 0.25 g/kg every 6 or 8 hours. The regimen can vary according to the severity of symptoms and the presence of acute and symptomatic brain herniation. Daily doses should never be higher than 150–200 g/day. Renal disease, congestive heart failure, and intracerebral haemorrhage may contraindicate the use of mannitol. Mannitol therapy should never extend for more than 3–4 days. Salt and water balance should be monitored carefully to avoid dehydration and hypotension. Hyperosmolality should also be prevented by cessation of therapy at values of 320 mOsmol/kg.

Hypertonic saline used in the past only for craniocerebral trauma is now used for increased ICP not responsive to mannitol. It is as effective in lowering ICP as mannitol. Besides osmotic action, it has a vasoregulatory immunological action. Doses: NACL 3%: 5–10 mL/kg in 5–10’; NACL 23.4%: 30 mL/dose, repeatable. When hypertonic solution is used for a longer period than a few days, a risk for rebound effect exists. This rebound effect is, in part, a consequence of the osmotic agents entering the intracranial compartment, with inversion of the osmotic gradient between blood, extracellular fluid, and brain.

Corticosteroids: corticosteroids initially gained a wide application in treating ICP (Galicich and French, 1961). The mechanism of action is based fundamentally on their ability to block the outflow of blood components from the capillary bed into the brain tissue at the site of blood–brain barrier damage. Dexamethasone does not reduce the water content of the swelling brain tissue (as mannitol does), and reduction of ICP does not occur before 48–72 hours. Nonetheless, it is common to observe a clinical improvement before this and within the first 24 hours.

Doses and administration schedules of corticosteroids have never been established by specific guidelines. It is, therefore, worthwhile considering the relative potency of the different drugs and their pharmacological characteristics (Schimmer and Parker, 2006) (Table 14.1.1).

Sodium retention activity is 1 for cortisol, 0.8 for hydrocortisone, 0.8 for prednisone and methylprednisolone, and 0 for betamethasone and dexamethasone.

Dexamethasone is found in higher concentrations within the CSF compared with other corticosteroids because it is less bound to plasma proteins. This should be taken into account when switching from one steroid to another, in addition to the data shown in Table 14.1.1. The dose of dexamethasone used in metastatic or primary brain tumours varies according to the clinical findings and degree of oedema, from 4 mg every 6 hours to 96 mg/day in patients with more severe symptoms or impending herniation. Once the patient is stabilized clinically, the total dose can be given in one or two daily doses, as suggested by the drug’s pharmacokinetic profile. In children, the suggested initial dose of dexamethasone is 1 mg/kg followed by doses of 0.4–1 mg/kg in one or more daily doses. Clinical experience suggests that higher doses can be administered safely, if needed.

Although it is common for steroids to be continued indefinitely, continuation of steroid therapy must always be under constant review. Steroids should not be continued if there is no clear medical indication for therapy, or the clinical benefit is exceeded by side effects. Steroid side effects are significant and some may add to the disability of patients (e.g. weakness due to myopathy). Box 14.1.2 lists the side effects of corticosteroids. Although not all are relevant to short-term management of symptoms in palliative care, many can seriously impact on the quality of life of patients and require careful balancing with therapeutic effects. If a steroid is no longer indicated, it should be tapered and discontinued.

A seizure is a transient occurrence of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain (Fisher et al., 2005).

Seizures are encountered not infrequently in palliative medicine. They may be caused by structural disease of the brain, non-structural causes, or both. Structural problems include metastatic cerebral lesions and infectious causes. The most common non-structural causes include metabolic derangement and drug toxicity (Delanty et al., 1998).

Seizures are classified according to their electroencephalographic (EEG) features as partial or focal, which applies to any seizure related to an initiating focus that can be identified in a specific brain area, and generalized, which refers to seizures that appear to begin bilaterally. Seizures that originate as truly generalized electrical discharges are defined as primary generalized seizures; those that begin locally and evolve into generalized tonic–clonic seizures are termed secondary generalized seizures.

Depending on the level of consciousness during attacks, partial or focal seizures are classified as follows:

Simple partial seizures are associated with a normal level of consciousness. Only a selective area of the cortex participates in the seizure activity, causing symptoms that depend on the function of that part of the cortex. Therefore, partial motor, sensory, autonomic, and affective seizures are possible. At times when symptoms of this kind precede the onset of a generalized seizure they are called an ‘aura’.

Complex partial seizures combine focal symptoms with an altered state of consciousness. These are the most common type of seizures in adults and probably the most common encountered in palliative care. The patient seems awake but is not meaningfully engaged with the environment. If there is verbal output, questions are not answered appropriately and the patient may repeat words or sentences. Eyes can be fixed or rolling purposelessly. The patient may be immobile or engaged in repetitive behaviours (motor automatisms), such as grimacing, snapping fingers, chewing, running, or undressing. If physically restrained, behaviours can become hostile or aggressive. The seizure lasts on average 3 minutes and is followed by a post-ictal phase, which can include somnolence, delirium, and headache, and can last for several hours. After complete recovery, the patient has no recall of the event, but sometimes may remember the aura. The partial complex seizure can itself be preceded by an aura, which may be equivalent to a simple partial seizure.

Generalized seizures can be non-convulsive, which also are called absence or petit mal; or convulsive, which are known as tonic–clonic or grand mal seizures.

Generalized tonic–clonic (grand mal) seizures start with a sudden loss of consciousness, at times accompanied by shouting (due to forced air expiration by sudden contraction of the diaphragm). Diffuse muscle rigidity follows, which is accompanied by cyanosis. After a short time, myoclonus and muscle fasciculations occur and the patient can bite his or her tongue. The latter clonic phase typically lasts 2 minutes or less, but more prolonged episodes can occur. At the end, post-ictal phase presents with deep sleep and slow deep breathing. Later the patient gradually awakens, often complaining of headache.

Prophylactic therapy of seizures in palliative medicine usually should not be undertaken if the patient has never had seizures. Although prophylactic anticonvulsant treatment in patients with primary brain tumours or metastases may be considered in selected cases, very few studies have addressed the efficacy of this approach and one randomized clinical trial confirmed that prophylactic treatment did not prevent seizures in patients with brain metastases who had never had seizures (Glantz et al., 1994).

The ideal anticonvulsant drug for palliative care should have no metabolic interactions, lack significant side effects, and also have parenteral formulations, so few drugs are available. General characteristics of antiepileptic drugs (AEDs) are summarized in Table 14.1.2 together with the recommended dosage. Blood levels of some anticonvulsants should be monitored because of the unpredictability of metabolic changes and drug interactions, but it must be remembered that clinical response and not blood levels should guide dosage.

Phenobarbital is available in oral and parenteral formulations. It is effective in both partial and generalized tonic–clonic seizures. It is metabolized by liver cytochrome P450 and has a very slow plasma clearance (4–5 days), which can be prolonged by liver disease. It has a wide therapeutic index but can cause drowsiness, ataxia, and severe rash (Stevens–Johnson syndrome and the more extensive toxic epidermal necrolysis, Lyell syndrome). It can interfere with the metabolism of several chemotherapy agents and in chronic use is associated with pseudo-rheumatism, which can worsen the symptoms of a concurrent steroid-induced osteoporosis.

Phenytoin is the first-line drug in simple and complex partial seizures, and in generalized tonic–clonic seizures. Dosing can vary from 4 to 8 mg/kg/day in two to three daily administrations, preferably after eating. The IV formulation of phenytoin, or fosphenytoin, can be systemically loaded and provide rapid control of seizures. The advantages of phenytoin are the relative lack of sedative effects, and good tolerability at higher than recommended doses. Side effects due to chronic use include ataxia, gastrointestinal (GI) disturbances, gingival hypertrophy, hirsutism, osteoporosis, and megaloblastic anaemia. The use of phenytoin also may be problematic due to variation in blood levels produced by the administration of many other drugs that interfere with liver metabolism, absorption, or protein binding. Interactions have been demonstrated with ciclosporin, cis-platinum, and paclitaxel. Significant pharmacokinetic interaction is found with concurrent dexamethasone, which can reduce phenytoin plasma levels by 50%. Severe allergic reactions involving rash, hypersensitivity reactions, liver toxicity, and myelosuppression have been reported, but are rare.

Sodium valproate is active in most types of generalized seizures (tonic, myoclonic, absence, tonic–clonic), including secondary generalized partial seizures. Doses start at 250–500 mg/day and are increased by 250 mg/week up to 1000–3000 mg/day. In children, the initial dose is 10–15 mg/kg/day, increased by the same incremental doses. Dose escalation can occur more quickly if needed, and an IV formulation is available in some countries, which can allow tolerable loading doses. Common side effects of sodium valproate are tremors, sedation, ataxia, GI symptoms, and thrombocytopenia. Liver enzymes and blood ammonia can be increased. Although severe liver toxicity can occur (usually in the first 6 months of therapy), all reported cases occurred in children under the age of 3 years who also were receiving other anticonvulsants.

Levetiracetam is used for partial and secondary generalized tonic–clonic seizures. The drug is well tolerated, and the most frequent side effects are somnolence, asthenia, and dizziness. The starting dose may be the same as the minimally effective dose of 750–1000 mg/daily, increasing to 40–40 mg/kg in children and 3000 mg in adults.

Lacosamide is approved as adjunctive treatment for focal seizures, with or without secondary generalization, that do not respond to other AEDs. Lacosamide does not affect the plasma concentration of carbamazepine, sodium valproate, clonazepam, and levetiracetam, but its tolerability may be adversely affected by a sodium-blocking AED such as carbamazepine, sodium valproate, lamotrigine, or topiramate. Lacosamide usually does not cause sedation, and cardiac side effects are comparable to those of other AEDs, but dizziness is frequent, especially at high doses. The drug is well absorbed after oral administration and it may be started at dose of 50 mg twice a day, increasing weekly by 100 mg up to a maintenance dose of 200–600 mg/day.

Mechanistically, status epilepticus represents the failure of the natural homeostatic seizure-suppressing mechanisms responsible for seizure termination (Engel, 2006). As defined for adults and children older than age 5, status epilepticus is a seizure that lasts 30 minutes or more, or two or more seizures that occur without complete recovery of consciousness in between. Although the definition requires a continuous seizure for 30 minutes, it should be recognized that the likelihood of spontaneous resolution of a seizure becomes small after 5 minutes. For this reason, the treatment used for status epilepticus should be considered whenever a seizure lasts 5 minutes or more.

Status epilepticus may be classified by the type of seizure (Engel, 2006). The broadest classification distinguishes non-convulsive status epilepticus from convulsive status epilepticus. Non-convulsive status epilepticus can manifest as an absence type and as a partial complex type. The most common convulsive status epilepticus in populations with advanced illness presents as continuous or repeated tonic–clonic seizures. Non-convulsive status epilepticus is characterized by EEG seizure activity without convulsive activity. It is a significant cause of impaired consciousness in patients with complex toxic–metabolic encephalopathies, occurring in 8% of comatose patients, according to recent data (Towne et al., 2000).

Partial complex non-convulsive status epilepticus may be particularly challenging to diagnose and treat. Seizure activity may fluctuate and often originates from a temporal cortical area that may not be evident on routine EEG. The syndrome may present as a confusional state with variable clinical findings. It may be continuous or frequently recurrent, or discontinuous, with recurrent partial complex seizures and recovery of consciousness between episodes. The duration of a status episode is highly variable and can be as long as weeks. In 40% of cases, the episode is shorter than 24 hours; in another 40%, the episode lasts from 1 to 10 days. The clinical manifestations may take the form of a prolonged delirium, with or without psychotic behaviours and automatisms, or have a more baffling presentation. Some patients have minimal difficulty answering questions but demonstrate affective changes, such as fear, or paranoid ideation.

Convulsive status epilepticus takes the form of continuous or frequently recurrent abnormal motor movements with alteration of consciousness. The risk of cerebral damage and serious complications, including cerebral oedema with increased ICP and acute brain herniations acidosis and rhabdomyolysis, usually demands an emergent approach to management (Chen and Wasterlain, 2006). Treatment has a high rate of success if initiated early, before neuronal injury and time-dependent pharmacoresistence develop. A suggested algorithm for the management of status epilepticus is given in Table 14.1.3.

Lorazepam (Riviello et al., 2013) is considered the drug of choice for the initial emergent management of convulsive status epilepticus. The mean time to clinical effect is 3 minutes. The half-life is 10–15 hours, but effective brain levels are maintained for 8–24 hours. It has no active metabolites. It should be infused IV not faster than 2 mg/min, to reduce the risk of respiratory depression. It is well absorbed also after intramuscular (IM) administration.

Diazepam enters the brain in a few seconds but because of its high lipid solubility, redistribution to all body tissues is rapid, with a consequent fall in brain concentration. Its anticonvulsant effect is therefore very brief and a second dose may be necessary after only 20–30 minutes. Rectal formulations are available. Recommended doses are 10 mg in adults and 5 mg (0.5 mg/kg) in children. Rectal administration at these doses does not cause respiratory depression. After IM administration, absorption is very variable and unpredictable and this route should generally be avoided.

Midazolam is water soluble, has a very short half-life, and has no active metabolites. Its onset of action is 3 minutes after IV administration, and 5 minutes and 15 minutes, respectively, after IM and oral administration. The good IM absorption is an important advantage in cases of difficult venous access or in pre-hospital setting (Silbergleit et al., 2012). In refractory status epilepticus, the initial dose is 0.2 mg/kg (concomitant use of opioids or recent use of other benzodiazepines involves lower doses, i.e. 0.05 mg/kg) followed by 0.05–0.5 mg/kg/h IV infusion. Higher dose may be used in refractory status epilepticus without significant morbidity.

Sodium valproate is available as a parenteral formulation and provides an alternative to phenytoin. Studies confirm the efficacy and safety of valproate infusion, including infusion at high doses in patients with repetitive seizures. Valproate is relatively contraindicated in cirrhosis or hepatic failure, and liver function should be monitored during therapy. However, fatalities have been reported only in children under 2 years who were concurrently treated with other anticonvulsant drugs.

Levetiracetam: IV levetiracetam seems to be effective and safe in the treatment of acute repeated seizures and status epilepticus in children (McTague et al., 2012). It can be used as first choice or add-on if sodium valproate has been already in use or fails. This drug has no interactions because it has no hepatic metabolism.

Phenytoin when given intravenously, has a relatively rapid onset of action (10–20 minutes). It has no sedative effects, does not cause respiratory depression, and has a long duration of action. It may be used to abort the seizure in benzodiazepine-refractory status epilepticus. In the latter situation, it may be given IV infusion at a rate that should not exceed 50 mg/min. After diluting phenytoin in saline, the solution should be infused within 1 hour. The loading dose usually is 20 mg/kg but could be less, and is 15 mg/kg in elderly patients. A loading dose of 15–20 mg/kg can be also administered orally but poor gastric tolerability limits the use of this route in some patients. Side effects may be related to excessively fast infusion rates, as may occur in emergency situations, and include cardiac arrhythmias, hypotension, and CNS depression. The ‘purple glove syndrome’ is due to the high pH of the drug (−13), which manifests as blue discolouration and distal oedema near the site of infusion about 2 hours after administration. After the loading dose, the duration of the therapeutic effect is about 24 hours. Blood levels can be checked 120 minutes after the end of the infusion.

IV phenobarbital is an option if benzodiazepines, valproic acid, levetiracetam, or phenytoin fail. The peak clinical effect is delayed for 20–60 minutes after administration.

Lacosamide has been used as add-on treatment in refractory status epilepticus when standard drugs failed, and it was effective and safe (Sutter et al., 2013).

Delirium has been defined as a transient organic brain syndrome characterized by the acute onset of disordered attention and cognition, accompanied by disturbances of cognition, psychomotor behaviour, and perception (Caraceni and Grassi, 2011) (see also Chapter 17.5). Delirium is considered to be a single taxonomic entity, and the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) proposes specific diagnostic criteria for its diagnosis and confirms that delirium is to be considered primarily a disturbance of consciousness (Box 14.1.3) (APA, 2000).

Delirium may be considered to be a stereotyped response of the brain to a spectrum of insults and as a distinctive state on the continuum between normal wakefulness and stupor and coma (Engel and Romano, 1959). Other terms for this condition include ‘encephalopathy’ and ‘acute confusional state’. The latter descriptions are used commonly by neurologists to describe acute changes in mental status.

The diagnosis of delirium requires that consciousness and attention are assessed together with cognitive function and performance. The Mini Mental State Examination (MMSE) is the most widely used method and can be applied to bedside patient assessment. It assesses cognitive function but is not a diagnostic tool. It screens for cognitive failure and can be abnormal in dementia as well as in delirium, or in other disorders that affect cognitive performance.

In contrast to the MMSE, the Confusion Assessment Method is a diagnostic system that can be used to apply the DSM criteria for the diagnosis of delirium. It is very sensitive and specific when applied by trained personnel (Inouye et al., 1990). More recently the Nursing Delirium Screening Scale (NUDESC) has been proposed as a useful instrument for screening delirium cases to be used by nurses; its role in palliative care still needs to be elucidated fully (Gaudreau et al., 2005).

The Delirium Rating Scale (DRS) (Trzepacz et al., 2001) and the Memorial Delirium Assessment Scale (MDAS) (Breitbart et al., 1997) are instruments specifically designed to assess delirium and its severity. These tools can be used to evaluate a range of symptoms that occur in patients with delirium.

Subtle changes frequently precede the onset of delirium. These minor symptoms and behavioural changes may go unnoticed, only to be recalled later in family or staff interviews. A patient who becomes restless, anxious, depressed, irritable, angry, or emotionally labile may be manifesting these premonitory symptoms of delirium. The differential diagnosis is complex, however, and includes adjustment disorder and any of a large number of neurological conditions, including dementia.

The first of the DSM-IV diagnostic criteria for delirium relates to disturbance of consciousness and impaired attention. This disturbance can be highly variable, characterized by increased or decreased arousal, or merely by distractibility and reduced responsiveness. Three clinical variants of delirium have been described based on the type of arousal disturbance: hypoalert–hypoactive, hyperalert–hyperactive, and mixed type (with fluctuations from hypoalert to hyperalert) (Liptzin and Levkoff, 1992; Caraceni and Grassi, 2011).

Attention is affected also by specific changes in the patient’s ability to concentrate, which can be subtle. Attention disturbances may be evidenced by an inability to maintain a conversation or to attend to its flow, language abnormalities, and difficulties in writing (Wallesch and Hundsaltz, 1994).

The second DSM criterion for delirium relates to the presence of changed cognition. This may take the form of disorientation, memory deficits, or disturbances of language, reasoning, or perception. It is important to recognize that a diagnosis of delirium may be established in the presence of any one of these cognitive abnormalities.

Language abnormalities are frequent in delirium and are often compounded by the presence of incoherent reasoning. Language may lack fluency and spontaneity, and conversation may be prolonged and interrupted by long pauses or repetitions. Writing abilities are affected early and more severely than other language-related skills (Chédru and Geschwind, 1972; Macleod and Whitehead, 1997). Delirium affects reasoning and patients frequently demonstrate irrelevant or rambling thinking, abnormal conceptualization, and altered insight.

Perceptual abnormalities (hallucinations and illusions) and delusions, but also may be typical of delirium, especially in some subtypes such as delirium tremens or other types of hyperactive delirium. These disturbances in perception are systematically assessed in the DRS and the MDAS.

Delusions may be associated with hallucinations. These delusions are frequently poorly organized and characterized by paranoid features (Wolf and Curran, 1935; Lipowski, 1990).

Delirium can interfere significantly with family and staff understanding of patient’s suffering. A small study of 14 patients with cancer pain and severe cognitive failure found that during episodes of agitated cognitive failure, pain intensity, as assessed by a nurse, was significantly higher than the patient’s assessment had been before and after the episode (Bruera et al., 1992). Upon complete recovery, none of these patients recalled having had any discomfort during the episode.

The third and fourth criteria for diagnosis of delirium relates to the time course and organic aetiology of the disturbance. For diagnosis, there must be evidence confirming that the disturbance has developed over a short period of time and tends to fluctuate during the course of the day. Fluctuation in the clinical manifestations of delirium is usually apparent in disturbance of the sleep–wake cycle. The phenomenon known as ‘sundowning’ refers to the worsening of symptoms toward evening and probably has to do with sleep–wake abnormalities that are aggravated by environmental factors. The organic aetiology will be discussed below.

In addition to mental status changes, neurological examination of the patient with delirium may identify findings associated with diffuse brain dysfunction, such as multifocal myoclonus and asterixis. Some findings may be relatively specific for one or more aetiologies. For example, tremulousness is typical of alcohol withdrawal states; miosis and mydriasis suggest opioid toxicity and anticholinergic toxicity, respectively; and tachypnoea may be a manifestation of a central process, or of sepsis or hypoxaemia.

Prevalence of delirium ranges from 20–30% of patients when admitted to palliative care services to 60–80% of those in the last days of life (Caraceni et al., 2000; Hosie et al., 2013), figures are higher than in the hospitalized elderly population (Francis et al., 1990). Altered mental state is the second most common reason for neurological consultation at a tertiary cancer centre (Clouston et al., 1992; Ljubisavljevic and Kelly, 2003).

In a study by Gagnon et al., 20% of 89 consecutively hospitalized cancer patients were delirious on admission and, among the others, 32% developed delirium subsequently (Gagnon et al., 2000). In a sample of 104 patients admitted to an acute palliative care unit, Lawlor et al. diagnosed delirium in 44 patients (42%), and of the remaining 60, delirium developed in 45% (Lawlor et al., 2000). Reversal of delirium occurred in 46 (49%) of 94 episodes in 71 patients and terminal delirium occurred in 46 (88%) of the 52 deaths (Lawlor et al., 2000). Reversibility of delirium was observed in 27% of episodes occurring during hospice admission (Leonard et al., 2008).

Disease-related and sociodemographic factors that may predispose to delirium or predict its occurrence have not been well documented in cancer patients. In one study, dyspnoea, anorexia, presence of brain metastases, performance status, and physician estimated prediction of survival were associated with the diagnosis of delirium but only univariate statistics were applied (Johnson et al., 1992).

Inouye and colleagues have proposed a multifactorial model for delirium in the hospitalized elderly (Inouye et al., 1999). The model involves the interaction between ‘baseline vulnerability’ and ‘precipitating factors. In this model, baseline vulnerability is defined by the predisposing factors at the time of admission to hospital, and the precipitating factors are the noxious events that occurred during hospitalization. The factors that Inouye et al. specifically demonstrated to be contributory to baseline vulnerability in the elderly include visual impairment, severity of illness, cognitive impairment, and an elevated serum urea nitrogen/creatinine ratio of 18 or greater (dehydration) (Inouye et al., 1999). Other studies have implicated risk factors, including, age, dementia, depression, alcohol abuse, the preoperative use of anticholinergic drugs, poor functional status, and markedly abnormal preoperative serum sodium, potassium, or glucose levels (Schor et al., 1992; Gaudreau et al., 2005). Among medications, neuroleptics, opioids, and anticholinergic drugs (Schor et al., 1992; Caraceni et al., 2000, 2011; Gaudreau et al., 2005) have also been implicated as risk factors for delirium.

In cancer patients, the potential aetiologies of delirium, as distinct from ‘risk factors’, may be divided into direct effects related to tumour involvement and indirect effects. The latter category includes drugs, electrolyte imbalance, cranial irradiation, organ failure, nutritional deficiencies, vascular complications, paraneoplastic syndromes, and many other factors (Box 14.1.4).

A survey of 140 confused cancer patients referred for a neurology consultation demonstrated a single cause of the altered mental status in 31% and multiple causes in 69%; the median number of probable contributing factors in each patient was three (Tuma and DeAngelis, 2000). Drugs, especially opioids, were associated with altered mental status in 64% of patients, metabolic abnormalities in 53%, infection in 46%, and recent surgery in 32%. A structural brain lesion was the sole cause of encephalopathy in 15% of patients. Two-thirds of the patients in this survey recovered cognitive function when the cause of the delirium was treated.

In the study by Lawlor and colleagues of 104 patients with advanced cancer admitted to a palliative care unit (Lawlor et al., 2000), the median number of precipitating factors was three, and 49% of patients had delirium that was reversible. Although the use of psychoactive medications, predominantly opioids, was the precipitating factor that was independently associated with reversibility of the delirium, the authors concluded that more than one factor (e.g. opioid medication and dehydration) usually requires attention if the delirium is to be reversed (Lawlor et al., 2000). In the study by Gaudreau et al. (2005) the use of opioids at doses of 90 mg of daily oral morphine or more was associated independently at multivariate analysis with the risk of delirium. Other studies have demonstrated that drug interactions with opioid metabolism and metabolic failure (especially renal impairment) can produce unexpected toxicities, especially in the patient with advanced disease (Fainsinger et al., 1993; Bortolussi et al., 1994; Caraceni and Grassi, 2011).

Cognitive compromise is probably one of the most common presenting symptoms or signs of brain (Posner, 1995) and leptomeningeal metastases (Weitzener et al., 1995). Non-convulsive epileptic status, which can occur in association with complex metabolic problems and also with ifosfamide encephalopathy, is a condition that also can result in altered consciousness manifesting with delirium (Towne et al., 2000).

In reviewing the causes of delirium, it is important to recognize that many are common and potentially reversible in the population with advance illness. These factors include, among others, dehydration, borderline renal function, infections, metabolic disturbances, drug withdrawal, and the use of psychoactive medications such as opioids (Tuma and DeAngelis, 2000; Gaudreau et al., 2005; Leonard et al., 2008; Caraceni et al., 2011).

Clinical assessment should include careful physical and neurological examination. Specific mental status assessment can follow the above-mentioned recommendations and can be helped by the systematic use of the NuDESC MMSE, DRS, MDAS, or CAM (Inouye et al., 1990; Breitbart et al., 1997; Trzepacz et al., 2001; Gaudreau et al., 2005). Aetiological screening should involve a rational and stepwise implementation of procedures (Table 14.1.4). The completeness of the list is not incompatible with a policy of avoiding procedures which are considered inappropriate for the individual patient.

Symptomatic management often is required both in reversible and irreversible cases, and is based on non-pharmacological and pharmacological therapies.

In a classic study by Inouye et al., systematic reorientation and a risk-modifying protocol reduced the incidence of delirium among elderly hospitalized patients (Inouye et al., 1999). A calm, quiet environment, with good light, is important to allow for potential recovery and to help the patient to reorientate to time and space. The process may be further assisted by placing a clock or calendar where the patient can see them, and by permitting the patient to see or touch a well-known object from the patient’s house. Presence in the room of family members can be advantageous.

In managing the delirious patient, a close collaboration between staff and family is fundamental. Special attention needs to be focused on communication. Family members may be particularly stressed by observing the change of the patient’s usual behaviour and by a new barrier to communication. The family must be informed about the characteristics of delirium, including fluctuation of cognitive function, its relationship with the disease conditions, potential for reversibility, role of therapies, and short-term prognosis.

Family members may require special care as they react to what they interpret as the patient’s suffering or pain. The behaviour of families, particularly those strained by the burden of caregiving, can swing from requests to withdraw medication to advocating sedation; caregiver distress may be compounded by personal problems in facing suffering and death (Buss et al., 2007; Morita et al., 2007; Caracenie and Grassi, 2011).

It is very important to clarify the potential aetiological role of existing therapies. For example, it is customary to blame opioid medications for mental changes that are actually caused by the complex interaction of several factors.

In communicating with the patient, the clinician should show empathy and to ask simple questions (‘Do you feel confused?’). The patient may be fearful and should be reassured. As needed, logic and rational communication should be supplanted by more direct non-verbal communication. The patient should be encouraged to communicate with well-known family members, and this communication should focus more on affective aspects than on discussions that could confuse or frighten the delirious patient.

Agitated delirium often requires pharmacological treatment to control behaviours that could result in harm for the patient and others, and to treat hallucinations or delusions that may be contributing to patient suffering. The treatment of hypoactive deliria is more debatable and will depend on individual clinical judgement.

The usual first-choice drug for agitated delirium is haloperidol (Canadian Coalition for Seniors’ Mental Health, 2006; Campbell et al., 2009), since it has relatively low sedating potency and fewer anticholinergic and cardiovascular effects than other neuroleptics. Table 14.1.5 gives guidelines for the use of haloperidol and alternative drugs.

Haloperidol has been used via IV infusion, although it is not licensed for this route of administration (Canadian Coalition for Seniors’ Mental Health, 2006). Very high IV doses have been safely administered. Therapeutic effects in hyperactive delirium typically are seen at doses of 6–12 mg/day; difficult cases may require higher doses or sedation with other drugs. Careful titration of the dose at the bedside is the most important recommendation to improve outcome. ECG monitoring should be considered before and during haloperidol therapy to monitor possible prolongation of the Q–T interval that can occasionally occur with most neuroleptics; torsade de pointe has been described as a rare complication of haloperidol administration via the IV and oral routes (Jackson et al., 1997).

Alternative neuroleptics can be used if greater sedation is desired or haloperidol is contraindicated. Droperidol and chlorpromazine are relatively sedating, and recently, risperidone, clozapine, quetiapine, ziprasidone, and olanzapine have been used (Caraceni and Grassi, 2011). Benzodiazepines are first-choice agents in the treatment of delirium related to alcohol or other sedative-hypnotic withdrawal. They also can be added in cases of delirium when anxiolytic and sedative effects are considered particularly desirable or in cases unresponsive to neuroleptic medications. They should be used cautiously, however, because they can worsen delirium, especially in the elderly (Campbell et al., 2009), they should not be used in hepatic encephalopathy.

In the management of delirium in the setting of advanced illness, more than one drug may be needed. In one case series of 39 patients, only 20% could be managed by haloperidol alone (Stiefel et al., 1992). When sedation is necessary to control symptoms, the combination of an opioid with a neuroleptic and an antihistamine such as promethazine can be particularly effective. Alpha 2 agonists (clonidine or dexmedetomidine) can be useful to obtain controlled sedation; they can be used in combination with neuroleptics and opioids and do not have respiratory depressant effects. Their use in palliative care is still based on personal experience (Alfonso and Reis, 2012).

Neurological complications are estimated to occur in up to 20% of patients with cancer. In a large consultation survey conducted at a comprehensive cancer centre, the most frequent complaints were pain and altered mental status (Table 14.1.6) (Ljubisavljevic and Kelly, 2003).

Intracranial metastases are found at autopsy in about 25% of patients who died of cancer (Posner, 1995). Other common intracranial lesions involve the skull and meninges. There is evidence that the incidence of brain metastases and leptomeningeal metastases is increasing, because of better control of systemic disease and longer survival, which allow ‘sanctuary’ cells in the CNS to evolve into clinically significant lesions. Lung cancer, melanoma, and breast cancer are the primary tumours most frequently associated with metastatic spread to the brain parenchyma. Tumours such as melanoma usually cause multiple lesions, while breast cancer more often causes single lesions (some 50% of breast cancer patients have a single lesion and 20% two lesions). Brain metastases can cause symptoms by compression, local destruction, irritation of brain tissue, brain oedema, and bleeding. The most common effect of a metastatic lesion is brain oedema and increased ICP. Focal symptoms can be due to oedema or bleeding. As discussed previously, typical presentations include cognitive failure, focal signs, seizures, and the syndrome of intracranial hypertension.

After clinical presentation of a brain metastasis, the median survival is about 2 months if no treatment is given, depending on tumour type (Posner, 1995). Patients who have access to brain radiotherapy and respond favourably to this modality usually die of their systemic disease. Patients who do not receive radiotherapy or do not respond often die of direct effects of the brain metastasis (Boogerd et al., 1993).

The signs and symptoms of brain metastases are highly variable. Symptoms can present progressively and deceptively, or alternatively, can be sudden, and ‘stroke-like’. It should be remembered that in many patients formal neurological tests of strength and mental function will reveal signs of changes in the CNS that are not otherwise apparent (Posner, 1995).

Headache is an important symptom of brain metastasis. The headache usually is aching in quality and moderate to severe in intensity. It is caused by compression or traction of intracranial pain-sensitive structures. With supratentorial lesions, it is often bifrontal, although it can occur on one side—always that of the tumour.

Headache occurs more frequently during the night and in early morning, and is more severe with infratentorial lesions that affect CSF circulation, causing hydrocephalus and increased ICP.

The treatment of a brain metastasis requires a careful assessment of the type of cancer and its sensitivity to radiation and chemotherapy, the neurological status of the patient, the extent of systemic disease, symptoms, and other complications and comorbidities, expectations concerning quality of life with and without treatment, and both the goals of care expressed at the time of diagnosis and the broader values of the patient. It should be understood that the provision of supportive treatment only is among the therapeutic options available.

Surgery is indicated only for single metastases with limited or no systemic disease, especially with radio-resistant tumours (Kaal et al., 2005). Whole-brain irradiation produces neurological improvement in the majority of patients but survival after treatment is only 4–6 months. Metastases from breast and lung cancers usually have a relatively good response to radiotherapy, showing both clinical and radiological improvement. Clinical improvement in the absence of radiological improvement is relatively common during treatment of metastases from melanoma, colon cancer, or renal cancer.

Newer techniques for focal radiation may be of benefit. Focal brain irradiation or ‘radiosurgery’ can have a role in treating single, or occasionally two, brain metastases, sometimes in combination with whole brain irradiation. The aim of this strategy is eradication of disease from the brain and radiosurgery is used as a substitute for surgery in this context (Kaal et al., 2005).

Treatment with steroids is recommended for all symptomatic patients with brain metastases or primary brain tumour. The main therapeutic effect is probably related to a reduction in peri-tumoral oedema from partial restoration of the blood–brain barrier. Steroids are also recommended for all patients undergoing brain irradiation. Treatment should start 48 hours before radiation. A regimen of dexamethasone 8–16 mg/day in one single administration, which is tapered beginning the 2nd week of radiation is recommended. Tapering should be gradual (2–4 mg every 5th day).

Higher steroid doses can be given acutely if symptoms recur (e.g. restarting 16 mg/day) or if there are signs of increased ICP or cerebral herniation (e.g. 16–100 mg IV once, followed again by tapering). If a steroid cannot be discontinued, the dose should be tapered to the minimum required for symptom control. Dexamethasone taper and discontinuation should always be attempted after completion of radiation treatment, since in most patients steroids are not necessary to preserve neurological function.

Most cases of epidural spinal cord compression in populations with cancer are caused by a vertebral body metastasis invading the epidural space posteriorly and compressing the spinal cord or cauda equina. Invasion of the epidural space through the intervertebral foramina by a paraspinal lesion also can occur, and is relatively more likely in lymphoma and neuroblastoma; the absence of a bony lesion on radiography in these cases can lead to misdiagnosis. Very rarely, spinal cord syndromes are due to epidural or cord metastases.

Spinal cord, including conus medullaris, and cauda equina lesions have similar aetiologies, mechanisms, and clinical implications, and are therefore usually considered together.

Epidural spinal cord compression is a frequent problem in patients with cancer, occurring in 25% of patients with lung cancer, 16% with prostate cancer and 11% of patients with myeloma. It is a neurological emergency, as functional outcome is dependent on the degree of neurological impairment at diagnosis, the promptitude of therapy and the initial response to therapy. Other factors important in prognosis are tumour histology and rate of progression of the neurological symptoms. The importance of early diagnosis cannot be overemphasized; symptoms are usually present for some weeks before the neurological emergency occurs. Pain precedes other neurological symptoms in almost every case, but diagnosis is often delayed until the onset of neurological symptoms and signs.

Pain of long duration, which suddenly changes its characteristics, should prompt re-evaluation and spinal imaging. Pain in a crescendo pattern is particularly worrying, as are pain aggravated by lying down, pain associated with the Valsalva manoeuvre, and radicular pain (pain occurring or radiating in a dermatomal distribution).

Other clinical features, are impaired deambulation for lower limb paralysis, ataxia or sensory loss, and altered function of bladder, and less frequently, bowel.

The occurrence of a Lhermitte’s sign also should raise concern about the possibility of tumour compression of the spinal cord. A Lhermitte’s sign, also described as ‘barber’s chair sign’ in the British literature, is a shock-like sensation passing down the trunk and one or more extremities when the neck is flexed. It also may occur spontaneously or be precipitated by sudden limb movements, or by coughing or sneezing. It is due to demyelination or compression of the posterior column of the spinal cord in the cervical or upper thoracic regions. Lhermitte’s sign is frequent in multiple sclerosis, but it is not uncommon in cancer-related spinal cord dysfunction. In the cancer population, the differential diagnosis ranges from relatively benign conditions such as transient radiation myelopathy and cisplatin injury, to severe complications such as cord compression and progressive radiation myelopathy (Ventafridda et al., 1991).

Neurological examination discloses signs related to the location of the compressive lesion. If the spinal cord is involved (typically with lesions at or above, the T12–L1 spinal level), signs are consistent with myelopathy and usually begin with paraesthesiae, or sensory loss in the feet, which ascends as the compression worsens. Weakness of hip flexors, and then other lower extremity muscles, also occurs. The sensory signs are helpful in defining the level of the compression (Table 14.1.7) (Hellmann et al., 2013). If the lesion is at the T12–L1 level, a conus medullaris syndrome may be the presenting phenomenology, with early loss of sphincter control and ‘saddle’ sensory symptoms or signs. A more caudal lesion causes a cauda equine syndrome, which is usually prominently asymmetric, with weakness or sensory changes affecting one leg more than another.

Emergency imaging of the spinal cord and canal should be carried out in patients with cancer and back pain who have symptoms of myelopathy (including conus medullaris) or cauda equine syndrome. Ideally, this should be done when the characteristic back pain is noted and before significant neurological signs ensue (Portenoy et al., 1989).

Figure 14.1.1 summarizes the clinical and radiological findings that should prompt either immediate treatment or spinal cord imaging with magnetic resonance imaging (MRI), the results of which will dictate the treatment modality (Hellmann et al., 2013). Although MRI is the best imaging procedure in these patients, myelography or computed tomography (CT) still has a place when MRI is unavailable. There may be multiple lesions and the whole spine should be evaluated.

If the goals of care support aggressive treatment of epidural spinal cord or cauda equine compression, corticosteroids and radiation should be offered (Ingham et al., 1993; Spinazzé et al., 2005) (see also Chapter 12.3). Steroids can reduce pain, preserve neurological function, and improve functional outcome after definitive treatment (Sorensen, et al., 1994). Dexamethasone in high doses is recommended for high-degree lesions, as shown by severe or rapidly progressing neurological abnormalities, or by MRI evidence of a severe lesion). A low-dose regimen should be used for low-degree lesions, as suggested by stable or slowly progressing neurological findings, or by MRI or myelography. One high-dose regimen included an initial IV bolus of 100 mg followed by a tapering schedule of 96 mg orally for 3 days and subsequent halving of the dose every 3rd day until the end of radiation treatment (Spinazzé et al., 1994; Posner, 1995). The use of such high doses for severe epidural spinal cord compression has been questioned (Vecht et al., 1989), and lower doses between 16 and 32 mg are often clinically used. If surgery is considered, posterior laminectomy alone is now seldom if at all indicated (Findlay, 1984). A more rational surgical approach for anteriorly compressing lesions is vertebral body resection (Harrington, 1988), but the procedure requires intact vertebral elements above and below the affected level to stabilize the spine after surgery. Surgery is the first choice where the site of the primary tumour is unknown, where there is relapse after radiation treatment, and in cases of spinal instability or vertebral displacement. It should also be considered when neurological symptoms progress during radiotherapy, in plegia of rapid onset, and when the tumour is not likely to be radiosensitive.

Some series showed impressive results with vertebral resection. In one series, 13 of 36 paraplegic patients regained ambulation (Harrington, 1988). One controlled clinical trial suggests that surgery can be the first choice for selected patients with better prognoses (Patchell et al., 2005). Careful individual indication is key, prognosis and expected quality of life should influence the decision.

Leptomeningeal metastases (also known as carcinomatous meningitis or meningeal carcinomatosis) are caused by the dissemination of cancerous cells throughout the subarachnoid space. These cells can reach the meninges through the general circulation or the perineural spaces along nerve roots, by direct invasion from epidural lesions, or by direct seeding from existing brain tumours (Chamberlain, 2006). Meningeal involvement can be multifocal or diffuse, and either visible on imaging as discrete masses or not visible on imaging because of microscopic infiltration.

Leptomeningeal metastases were once considered an unusual complication of systemic cancer (1–8% of cases at autopsy) (Posner, 1995) but these are increasingly seen nowadays, usually as a result of breast or lung cancer, lymphoma, leukaemia, or melanoma. Life expectancy is usually short, ranging from 3 to 6 months in patients who have received intensive treatment. Many patients are not offered treatment and their survival is shorter (Posner, 1995; Chamberlain, 2006).

The clinical findings associated with leptomeningeal disease may relate to CNS or peripheral nervous system dysfunction, or some combination. The clinical syndromes are highly variable. The pathophysiology includes abnormality in the flow and absorption of CSF (which can result in hydrocephalus), direct involvement of the cranial and peripheral nerve meningeal sheets, competition with brain metabolism, invasion of the brain parenchyma or nerve roots, and areas of focal ischaemia.

The most common symptoms are headache, change in mental status, and radicular-type pain (Posner, 1995; Formaglio and Caraceni, 1998; Chamberlain, 2006), but cranial nerve involvement, seizures, polyradiculopathy, and cauda equina syndrome also occur in varying combinations. Multiple symptoms, from involvement of different levels of the neuraxis, are often seen.

Diagnosis is usually confirmed from examination of the CSF (Chamberlain, 2006). While malignant cells may not be apparent in the first sample of CSF, other abnormalities are usually found, such as high opening pressure, high protein content, increased white cell count, or low glucose content. In one series, only 3% of the first samples were completely normal (Chamberlain, 2006). Other markers and immunocytochemical techniques have not been found to have clinical value (Chamberlain, 2006). Repeated lumbar punctures often are needed to establish the diagnosis. Contrast-enhanced MRI also can be useful (Formaglio and Caraceni, 1998) (Fig. 14.1.2), as the only sign of leptomeningeal metastases may be slight enhancement of the meninges due to blood–brain barrier disruption or focal enlargement of roots.

Traditionally, treatment modalities have been based on a combination of corticosteroids, radiotherapy, and intrathecal or intraventricular chemotherapy. Systemic chemotherapy may also be helpful in some cases with appropriate tumour histology. In one series, only 23% of treated patients could be regarded as long-term survivors. Intrathecal chemotherapy did not achieve better results than systemic chemotherapy (median survival 23 months) (Siegal et al., 1994; Chamberlain, 2006), and caused a treatment-related leucoencephalopathy in 58% of cases. The role of intrathecal chemotherapy is questionable particularly in solid tumours.

Lesions at the base of the skull are commonly caused by metastasis from breast, prostate, and other tumours (Greenberg et al., 1981) or from local invasion by advanced head and neck tumours (Vecht et al., 1992) (see Chapter 13.1). Symptoms secondary to bone lesions are commonly associated with alterations of cranial nerve function. Headache at the site of the lesion or referred to the vertex or to the entire affected side of the head is also frequent (Greenberg, 1981; Posner, 1995). The best imaging procedure for all these syndromes is CT scan with bone window studies. Treatment with radiation is indicated, to control pain and neurological dysfunction. Any combination of pain related to the involvement of the cranial and facial bone and of the trigeminal nerve associated with other cranial nerve dysfunction should receive careful clinical evaluation (Foley, 1979; Greenberg et al., 1981; Weinstein et al., 1986; Vecht et al., 1992).

The most common presentation is a constant dull, well-localized pain related to the underlying disease of bone and other somatic structures. This pain may be associated with paroxysmal episodes of lancinating or throbbing pain. The quality of the pain only rarely can mimic classical trigeminal neuralgia, an atypical facial pain is more common (Cheng et al., 1993). Atypical trigeminal pain and sensory abnormalities in the peripheral distribution of the V nerve, occasionally associated with incomplete lesions of the VII nerve, have been reported with different facial neoplasms (Cheng et al., 1993).

Involvement of the mental nerve does not usually produce pain but can cause the ‘numb chin syndrome’ of mental anaesthesia. This is a sign of disease of the jaw or, more frequently, of the base of the skull, leptomeninges carcinomatosis, and local perineural spread of lip carcinoma. The symptom can occur months before the discovery of a bony lesion (Burt et al., 1992).

The typical patient has throat and neck pain, which radiates to the ear and is aggravated by swallowing. Pharyngeal and other carcinomas of the neck can present with odynophagia with reflex otalgia. Severe pain may be associated with syncope (Weinstein et al., 1986). Although it has been described with leptomeningeal disease, it commonly results from local nerve infiltration in the neck or base of the skull.

Radiculopathy is usually caused by the compression of nerve roots by vertebral, paraspinal lesions, or by leptomeningeal metastases. The pain of a root lesion is usually focal and radiates in the distribution of the affected root. It is sometimes difficult to distinguish a polyradiculopathy from a plexus lesion; CT and MRI are useful for imaging non-bony paraspinal lesions. MRI is necessary for imaging the epidural space.

Herpes zoster and post-herpetic neuralgia are common in patients with cancer and should always be considered in the differential diagnosis of painful radiculopathies.

Infiltration of the cervical plexus by tumour can be a result of compression by head and neck neoplasms or metastases to cervical nodes. Symptoms usually include local lancinating or dysaesthetic pain referred to the retro-auricular and nuchal areas, the shoulder, and the jaw. Sensory abnormalities define the affected (greater auricular and greater occipital) nerves (Vecht et al., 1992). The differential diagnosis should include post-radical neck dissection syndrome. The diagnosis in patients with head and neck cancer may be difficult because of the postoperative and post-radiation changes often found in these patients. CT or MRI scan is appropriate, and imaging of the cervical spine and paraspinal structures is very important in distinguishing between bony lesions, cervical radiculopathy, and epidural spinal cord compression.

Five per cent of the neurological consultations at a comprehensive cancer centre were found to be initiated by brachial plexopathy (Burt et al., 1992). It occurs most often with breast and lung carcinoma, and with lymphoma. The plexus can be compressed or infiltrated by tumour lying in contiguous structures, such as axillary or supraclavicular nodes, or the apex of the lung. Pain is the first symptom in 85% of patients (Kori et al., 1981), preceding other neurological symptoms or signs by weeks or months.

Breast and lung malignancies typically affect the lower plexus (C7–T1) (Fig. 14.1.3) and cause pain in the shoulder, elbow, hand, and the fourth and fifth finger. Lung tumours can affect the intercostobrachial nerve, giving rise to a pain syndrome and associated sensory disturbances in the axilla (C8–T1–T2). The upper brachial plexus (C5–C6) can also be affected, especially by breast cancer, when pain is usually referred to the paraspinal region, shoulder, biceps region, elbow, and hand; burning dysaesthesia in the index finger or thumb is common. The hallmark of the syndrome is the neuropathic nature of the pain with numbness, paraesthesia, allodynia, and hyperaesthesia.

CT scan with narrow sections and contrast enhancement is effective in imaging soft tissue and bony structures in the plexus area. All patients with symptoms of brachial plexopathy should have a scan of the contiguous paravertebral region before radiation therapy, since extension of disease in this region is common (13/41 cases in one series). MRI is particularly useful in imaging the contiguous epidural space. While use of both techniques can give helpful complementary information in doubtful cases, sometimes neither is helpful even in cases of proven metastatic plexopathy (Krol, 1993). Comparative data on specificity and sensitivity of the two techniques are lacking.

Epidural invasion eventually will occur in some patients with brachial plexopathy (Fig. 14.1.4). Imaging of the epidural space is essential when patients develop Horner’s syndrome, panplexopathy, vertebral body erosion, or a paraspinal mass detected on CT scan. These are often hallmark symptoms of tumour progression into the epidural space.

Radiation fibrosis is important in the differential diagnosis of brachial plexopathy in cancer (Table 14.1.8), particularly in patients who have had radiotherapy and who present with upper plexus signs. Positron emission tomography (PET) scan can be very helpful in distinguishing fibrosis from tumour. Pain is often less prominent in patients with radiation-induced plexopathy.

Although electrodiagnostic studies and imaging may distinguish radiation-induced plexopathy from malignant invasion (Harper et al., 1989), this differential diagnosis sometimes is difficult. In these cases, PET scan can be very useful but, at times, surgical exploration of the plexus is necessary to rule out fibrosis, a new primary tumour, a radiation-induced tumour, or recurrent cancer.

Lumbosacral plexopathy is one of the most disabling complications of cancer. Although it is commonly associated with colorectal, cervical, and other pelvic malignancies (bladder, uterus, prostate, sarcoma, lymphoma), it can also be caused by breast or lung cancer, or melanoma. Retroperitoneal tumours (e.g. sarcoma, metastatic nodal tumours) may affect the lumbosacral plexus or its roots more proximally.

The presenting symptom in almost all cases (93%) (Jaeckle et al., 1985) is pain in the buttocks or the legs. Pain often precedes other symptoms by weeks or months. It is usually followed by numbness, paraesthesia, weakness, and, later, leg oedema. The pain is usually aching or pressure-like in quality, and is rarely burning or dysaesthetic. In one series (Jaeckle et al., 1985), an upper plexopathy (L1–L4) was found in about one-third of cases, a lower plexopathy (L4–S1) in one-half of cases, and panplexopathy (L1–S3) in about 20% (Table 14.1.9).

Other structures can be involved. These include nerve roots from proximal extension of the tumour, or contiguous structures, such as the sympathetic chain or the psoas muscle. Selective involvement of the L1, iliohypogastric, ilioinguinal, or genitofemoral nerves can produce pain and paraesthesia in the inguinal and scrotal region.

A sacral plexopathy, often overlapping a sacral polyradiculopathy, can be produced from direct extension of a presacral mass invading the sacrum, as sometimes occurs with rectosigmoid and bladder carcinomas. The coccygeal plexus is usually affected in patients with sphincter dysfunction and perineal ‘saddle’ sensory loss.

Tumour is often found in the lumbar vertebrae, sacrum, or pelvis of patients with lumbosacral plexopathy (45/76 patients) and epidural extension is also common, especially with retroperitoneal tumours. Hydroureter or hydronephrosis is extremely common at diagnosis (Jaeckle et al., 1985; Thomas et al., 1985).

Lumbosacral plexopathy can occur after pelvic irradiation. Thomas et al. (1985) reported that radiation-induced lumbosacral plexopathy very rarely presents with pain and has a median latency of 5 years from radiotherapy. Motor involvement is bilateral in 80% of cases and electromyography can be a useful diagnostic tool. Other differential diagnoses include leptomeningeal carcinomatosis, and cauda equina compression.

MRI and CT scanning both image the lumbosacral plexus effectively. CT gives more information on the bony structures, while MRI is more accurate for soft tissues. The assessment should extend from L1 through the true pelvis (Jaeckle et al., 1985), and should include the spine and adjacent pelvic soft tissues.

Mononeuropathy is less common than plexopathy or radicular lesions (Anoine and Camdessanche, 2007). It is caused by compression or infiltration of a nerve by bony lesions, or by soft tissue masses in the limbs. Intercostal nerve neuropathy from invasion of the chest wall is the most common of the mononeuropathies caused by cancer. Obturator, femoral, and sciatic neuropathies are seen when tumour involves the soft tissue along the nerve distribution in the pelvis and thigh. Peroneal mononeuropathy can occur with bony lesions of the head of the fibula and sarcoma of the popliteal fossa. Ulnar and radial neuropathies result from bony lesions in the elbow or humerus. These mononeuropathies must be distinguished from traumatic or compressive lesions, and from nutritional–metabolic lesions of nerves.

Management of pain is often difficult in these syndromes; opioids are indicated and adjuvants for neuropathic pain should be used for specific indications. Clinical experience suggests that dexamethasone can be particularly effective for pain due to compression and oedema of peripheral nerves.

Polyneuropathy in cancer patients can be caused by chemotherapy, metabolic disturbance or nutritional deficiency, or paraneoplastic syndromes (Box 14.1.5) (Lipton et al., 1991; Anoine and Camdessanche, 2007).

Peripheral neuropathy is characterized by a stocking-glove distribution of negative sensory and positive sensory symptoms. Loss of sensation may predominate, or there may be painless paraesthesia or distressing burning dysaesthesia, allodynia, and hyperalgesia. Early sensory loss and later motor signs (weakness) are characteristic of some drug-induced sensorimotor neuropathies (vincristine, paclitaxel). Sensory involvement can be selective in neuropathies associated with cisplatin or paraneoplastic syndromes. Often the only early sign of polyneuropathy is reduction or loss of the ankle reflex. Muscle cramps may be associated with neuropathy and can sometimes be prominent symptoms in vincristine neuropathy. Muscle cramps are relatively frequent in cancer.

Paraneoplastic sensory neuropathy and sensory neuropathy caused by vincristine or paclitaxel is often more painful than that caused by cisplatin. Cisplatin induces a sensory neuropathy mainly affecting the cells of the dorsal root ganglia. There is predominant involvement of the large fibre functions (proprioception), which causes sensory ataxia rather than pain. Vinca alkaloids and paclitaxel produce a mostly sensory axonopathy with some motor component. New antineoplastic drugs that interfere with specific metabolic pathways, such as bortezomid, also have distinct toxic effects on the peripheral nervous system (Anoine and Camdessanche, 2007).

Clinical examination is usually sufficient for diagnosis of a polyneuropathy, although nerve conduction studies and electromyography may provide additional information (Lipton et al., 1991). Treatment is palliative, with analgesics and adjuvants.

Paraneoplastic neurological syndromes (PNSs) are a group of neurological disorders that occur in patients with malignant tumour in which an immune-mediate mechanism and not a direct effect of the cancer is the cause. PNSs are rare, affecting less than 1/10 000 of patients with cancer, except Lambert–Eaton myasthenic syndromes (LEMSs) which affect about 3% of patients with small cell lung cancer, and myasthenia gravis, which affects about 15% of patients with tymoma. They can affect central or peripheral nervous systems, neuromuscular junction, or muscle (Darnell and Posner, 2003; Viaccoz and Honnorat, 2013) (Table 14.1.10)

Many PNSs are now recognized. For some of them with well-characterized onco-neuronal antibodies, the nature of the tumour is suggested by the antibody itself; for others the mechanism of the disease is less known, but all are severe and can affect patients’ quality of life, even if the underlying tumour is healed or stable. The specific antibodies and their pathogenic role need to be evaluated carefully by highly specialized professionals (Darnell and Posner, 2003; Viacozz and Honnorat, 2013).

In general, neurological symptoms and signs develop acutely and are severe. Subtle, long-lasting symptoms are not usually caused by paraneoplastic syndromes. Only examination of CSF and immunofluorescence techniques for testing circulating autoantibodies can aid diagnosis because MRI scans are often normal and only LEMSs and myasthenia gravis have neurophysiological classic features.

The clinical course is independent of that of the original tumour, which in 50% of cases is found after the onset of neurological symptoms. The associated tumour often is small and slow growing, and may have a relatively benign course. Spontaneous remissions have been seen, but the syndrome is usually irreversible.