Hypotension and Syncope

HUGH CALKINS
DOUGLAS P. ZIPES

Syncope is a sudden transient loss of consciousness and postural tone with spontaneous recovery. Loss of consciousness results from a reduction of blood flow to the reticular activating system located in the brain stem and does not require electrical or chemical therapy for reversal. The metabolism of the brain, in contrast to that of many other organs, is exquisitely dependent on perfusion. Consequently, cessation of cerebral blood flow leads to loss of consciousness within approximately 10 seconds. Syncope is an important clinical problem because it is common, is costly, is often disabling, may cause injury, and may be the only warning sign before sudden cardiac death.[1] [2] [3] [4] [14A] [21A] [21B] [28A] Patients with syncope account for 1 percent of hospital admissions and 3 percent of emergency department visits.[1] Elderly persons have a 6 percent annual incidence of syncope. Surveys of young adults have revealed that up to 50 percent report a prior episode of loss of consciousness, most of which are isolated events that never come to medical attention. The annual cost of evaluating and treating patients with syncope has been estimated to be $800 million dollars.[2] Patients who experience syncope also report a markedly reduced quality of life, similar to that experienced by patients with chronic diseases such as rheumatoid arthritis and chronic obstructive pulmonary disease.[3]
CLASSIFICATION OF THE CAUSES OF SYNCOPE
The causes of syncope can be classified into four primary groups: vascular, cardiac, neurologic/cerebrovascular, and metabolic/miscellaneous (Table 27-1) . Vascular causes of syncope can be further subdivided into anatomical, orthostatic, and reflex-mediated causes. A similar approach to subclassification of the causes of syncope can be applied to the other three diagnostic groups. The probable cause of syncope can be identified in approximately 75 percent of patients.[5] [6]
Vascular Causes of Syncope
Vascular causes of syncope, particularly reflex-mediated syncope and orthostatic hypotension, are by far the most common causes of syncope, accounting for at least one third of all syncopal episodes. In contrast, subclavian steal syndrome is an exceedingly uncommon cause of syncope, accounting for less than 0.1 percent of syncopal episodes.
Orthostatic Hypotension
When a person stands, 500 to 800 ml of blood is displaced to the abdomen and lower extremities, resulting in an abrupt drop in venous return to the heart. This leads to a decrease in cardiac output and stimulation of aortic, carotid, and cardiopulmonary baroreceptors that trigger a reflex increase in sympathetic outflow. As a result, heart rate, cardiac contractility, and vascular resistance increase to maintain a stable systemic blood pressure on standing.[7] Orthostatic hypotension, which is defined as a 20-mm Hg drop in systolic blood pressure or a 10-mm Hg drop in diastolic blood pressure within 3 minutes of standing, results from a defect in any portion of this blood pressure control system.[8] Orthostatic hypotension may be asymptomatic or may be associated with symptoms such as lightheadedness, dizziness, blurred vision, weakness, palpitations, tremulousness, and syncope. These symptoms are often worse immediately on arising in the morning and/or after meals or exercise. Syncope that occurs after meals, particularly in the elderly, may result from a redistribution of blood to the gut. A decline in systolic blood pressure of about 20 mm Hg approximately 1 hour after eating has been reported in up to one third of elderly nursing home residents.[9] Although usually asymptomatic, it may result in lightheadedness or syncope.
Drugs that either cause volume depletion or result in vasodilation are the most common cause of orthostatic hypotension (Table 27-2) . Elderly patients are particularly susceptible to the hypotensive effects of drugs because of reduced baroreceptor sensitivity, decreased cerebral blood flow, renal sodium wasting, and an impaired thirst mechanism that develops with aging.[10] Orthostatic hypotension may also result from neurogenic causes, which can be subclassified into primary and secondary autonomic failure.[8] [11] Primary causes are generally idiopathic, whereas secondary causes are associated with a known biochemical or structural anomaly or are seen as part of a particular disease or syndrome. There are three types of primary autonomic failure. Pure autonomic failure (Bradbury-Eggleston syndrome) is an idiopathic sporadic disorder characterized by orthostatic hypotension, usually in conjunction with evidence of more widespread autonomic failure such as disturbances in bowel, bladder, thermoregulatory, and sexual function. Patients with pure autonomic failure have reduced supine plasma norepinephrine levels. Multiple system atrophy (Shy-Drager syndrome) is a sporadic, progressive, adultonset disorder characterized by autonomic dysfunction, parkinsonism, and ataxia in any combination. The third type of primary autonomic failure is Parkinson's disease with autonomic failure. A small subset of patients with Parkinson's disease may also develop autonomic failure, including orthostatic hypotension. In addition to these forms of chronic autonomic failure is a rare acute panautonomic neuropathy.[12] This generally presents in young people and results in a widespread severe sympathetic and parasympathetic failure with orthostatic hypotension, loss of sweating, disruption of bladder and bowel function, fixed heart rate, and fixed dilated pupils.
Postural orthostatic tachycardia syndrome (POTS) is a milder form of chronic autonomic failure and orthostatic intolerance characterized by the presence of symptoms of orthostatic intolerance, a 28-beats/min or greater increase in heart rate, and the absence of a significant change in blood pressure within 5 minutes of standing or upright tilt.[13] [14] POTS appears to result from a failure of the peripheral vasculature to appropriately vasoconstrict under orthostatic

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ETIOLOGIES OF SYNCOPE
Vascular
Anatomical
Subclavian steal
Orthostatic
Drug-induced
Hypovolemia
Primary disorders of autonomic failure
Pure autonomic failure (Bradbury-Eggleston syndrome)
Multiple system atrophy (Shy-Drager syndrome)
Parkinson's disease with autonomic failure
Secondary neurogenic
Postprandial (in the elderly)
Postural orthostatic tachycardia syndrome (POTS)
Reflex-mediated
Neurally mediated syncope/vasovagal syncope
Carotid sinus hypersensitivity
Situational (cough, defecation, micturition, swallow)
Glossopharyngeal syncope
Trigeminal neuralgia


Cardiac
Anatomical
Aortic dissection
Aortic stenosis
Atrial myxoma
Cardiac tamponade
Hypertrophic cardiomyopathy
Mitral stenosis
Myocardial ischemia/infarction
Pulmonary embolism
Pulmonary hypertension
Arrhythmias
Bradyarrhythmias
Atrioventricular block
Pacemaker malfunction
Sinus node dysfunction/bradycardia
Tachyarrhythmias
Supraventricular tachycardia
Ventricular tachycardia
Torsades de pointes/long QT syndrome


Neurological/Cerebrovascular
Arnold Chiari malformation
Migraine
Seizures (partial complex, temporal lobe)
Transient ischemic attack/vertebrobasilar insufficiency/cerebrovascular accident


Metabolic/Miscellaneous
Metabolic
Hyperventilation (hypocapnea)
Hypoglycemia
Hypoxemia
Drugs/alcohol
Miscellaneous
Psychogenic syncope
Hysterical
Panic disorder
Anxiety disorder
Cerebral syncope
Hemorrhage
Unknown


stress. POTS may also be associated with syncope due to neurally mediated hypotension (see later). In some patients, the postural orthostatic tachycardia syndrome may result from an abnormality in the clearance of norepinephrine from the synaptic cleft.[14A] Approximately 90 percent of norepinephrine that is released into the synaptic cleft is cleared by uptake into the neuron by the norepinephrine transporter. A recent report identified a mutation in the norepinephrine transporter gene in a family with several affected family members.[14A]
REFLEX-MEDIATED SYNCOPE.
There are many reflex-mediated

AUSES OF ORTHOSTATIC HYPOTENSION
Drugs
Diuretics
Alpha-adrenergic blocking drugs
Terazosin (Hytrin), labetalol
Adrenergic neuron blocking drugs
Guanethidine
Angiotensin-converting enzyme inhibitors
Antidepressants
Monoamine oxidase inhibitors
Alcohol
Diuretics
Ganglion-blocking drugs
Hexamethonium, mecamylamine
Tranquilizers
Phenothiazines, barbiturates
Vasodilators
Prazosin, hydralazine, calcium channel blockers
Centrally acting hypotensive drugs
Methyldopa, clonidine


Primary Disorders of Autonomic Failures
Pure autonomic failure (Bradbury-Eggleston syndrome)
Multiple system atrophy (Shy-Drager syndrome)
Parkinson's disease with autonomic failure


Secondary Neurogenic
Aging
Autoimmune disease
Guillain-Barre syndrome, mixed connective tissue disease, rheumatoid arthritis
Eaton-Lambert syndrome, systemic lupus erythematosus
Carcinomatosis autonomic neuropathy
Central brain lesions
Multiple sclerosis, Wernicke's encephalopathy
Vascular lesions or tumors involving the hypothalmus and midbrain
Dopamine beta-hydroxylase deficiency
Familial hyperbradykinism
General medical disorders
Diabetes, amyloid, alcoholism, renal failure
Hereditary sensory neuropathies, dominant or recessive
Infections of the nervous system
Human immunodeficiency virus infection, Chagas' disease, botulism, syphillis, botulism
Metabolic disease
Vitamin B12 deficiency, porphyria, Fabry's disease, Tangier disease
Spinal cord lesions
Adapted from Bannister SR (ed): Autonomic Failure. 2nd ed. Oxford, Oxford University Press, 1988, p 8.


syncopal syndromes (see Table 27-1) . In each case, the reflex is composed of a trigger (the afferent limb) and a response (the efferent limb). This group of reflex-mediated syncopal syndromes has in common the response limb of the reflex, which consists of increased vagal tone and a withdrawal of peripheral sympathetic tone and leads to bradycardia, vasodilation, and, ultimately, hypotension, presyncope, or syncope. What distinguishes these causes of syncope are the specific triggers. For example, micturition syncope results from activation of mechanoreceptors in the bladder; defecation syncope results from neural inputs from gut wall tension receptors; and swallowing syncope results from afferent neural impulses arising from the upper gastrointestinal tract. The two most common types of reflex-mediated syncope, carotid sinus hypersensitivity and neurally mediated hypotension, are discussed later.
The termneurally mediated hypotension/syncope (also known as neurocardiogenic, vasodepressor, and vasovagal syncope and as "fainting") has been used to describe a common abnormality of blood pressure regulation characterized by the abrupt onset of hypotension with or without

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bradycardia. Triggers associated with the development of neurally mediated syncope are those that either reduce ventricular filling or increase catecholamine secretion. These include the sight of blood, pain, prolonged standing, a warm environment or hot shower, and stressful situations. Under these types of situations, patients with this condition develop severe lightheadedness and/or syncope. It has been proposed that these clinical phenomena result from a paradoxical reflex that is initiated when ventricular preload is reduced by venous pooling. This leads to a reduction in cardiac output and blood pressure, which is sensed by arterial baroreceptors. The resultant increased catecholamine levels, combined with reduced venous filling, leads to a vigorously contracting volume-depleted ventricle. The heart itself is involved in this reflex by virtue of the presence of mechanoreceptors, or C-fibers, consisting of nonmyelinated fibers found in the atria, ventricles, and the pulmonary artery.[15] [16] [17] [18] [19] It has been proposed that vigorous contraction of a volume-depleted ventricle leads to activation of these receptors in susceptible individuals. These afferent C-fibers project centrally to the dorsal vagal nucleus of the medulla, leading to a "paradoxic" withdrawal of peripheral sympathetic tone and an increase in vagal tone, which, in turn, causes vasodilation and bradycardia. The ultimate clinical consequences are syncope or presyncope. Not all neurally mediated syncope results from activation of mechanoreceptors. In humans, it is well known that the sight of blood or extreme emotion can trigger syncope. These observations suggest that higher neural centers can also participate in the pathophysiology of vasovagal syncope. In addition, central mechanisms can contribute to the production of neurally mediated syncope.[18] [20]
Syncope due to carotid sinus hypersensitivity results from stimulation of carotid sinus baroreceptors, which are located in the internal carotid artery above the bifurcation of the common carotid artery. This condition is diagnosed by applying gentle pressure over the carotid pulsation just below the angle of the jaw, where the carotid bifurcation is located. Pressure should be applied unilaterally for approximately 5 seconds, after first listening for a carotid bruit. It has recently been reported that the sensitivity of diagnosing carotid sinus hypersensitivity can be increased, with no change in specificity, by performing carotid sinus massage during 60- or 70-degree upright tilt.[21A] [21B] The normal response to carotid sinus massage is a transient decrease in the sinus rate and/or slowing of atrioventricular (AV) conduction. Three types of abnormal responses have been described: (1) the cardioinhibitory response, characterized by marked bradycardia (>3-second pause); (2) the vasodepressor type, characterized by a 50-mm Hg fall in the systolic blood pressure in the absence of bradycardia; and (3) the mixed response. Carotid sinus hypersensitivity is commonly detected in patients with syncope. One study reported the presence of carotid sinus hypersensitivity in 65 of 279 patients (23 percent) who presented to the emergency department with falls.[21] It is important to recognize that carotid sinus hypersensitivity is also commonly observed in asymptomatic elderly patients, with carotid sinus hypersensitivity identified in one study in more than one third of asymptomatic patients undergoing cardiac catheterization for coronary artery disease. Because of this, the diagnosis of carotid sinus hypersensitivity should be approached cautiously after excluding alternative causes of syncope.
Cardiac Causes of Syncope
Cardiac causes of syncope, particularly tachyarrhythmias and bradyarrhythmias, are the second most common causes, accounting for 10 to 20 percent of syncopal episodes. Ventricular tachycardia is the most common tachyarrhythmia that can cause syncope. Supraventricular arrhythmias can also cause syncope, although the great majority of patients with supraventricular arrhythmias present with less severe symptoms such as palpitations, dyspnea, and lightheadedness. Bradyarrhythmias that can result in syncope include sick sinus syndrome as well as AV block. Anatomical causes of syncope result from obstruction to blood flow, such as a massive pulmonary embolus, an atrial myxoma, and/or aortic stenosis.
Neurological Causes of Syncope
Neurological causes of syncope, including migraines, seizures, Arnold Chiari malformations, and transient ischemic attacks, are surprisingly uncommon causes of syncope, accounting for less than 10 percent of all cases of syncope. The majority of patients in whom a "neurological" cause of syncope is established are found in fact to have had a seizure rather than true syncope.[5]
Metabolic/Miscellaneous Causes of Syncope
Metabolic causes of syncope are rare, accounting for less than 5 percent of syncopal episodes. The most common metabolic causes of syncope are hypoglycemia, hypoxia, and hyperventilation. The establishment of hypoglycemia as the cause of syncope requires demonstration of hypoglycemia during the syncopal episode. Although the mechanism of hyperventilation-induced syncope has been generally considered to be due to a reduction in cerebral blood flow, a recent study demonstrated that hyperventilation alone was not sufficient to cause syncope. This suggests that hyperventilation-induced syncope may also have a psychological component.[22] Psychiatric disorders may also cause syncope. It has been reported that up to 25 percent of patients with syncope of unknown origin may have psychiatric disorders for which syncope is one of the presenting symptoms.[23] Cerebral syncope is a rare, recently described cause of syncope resulting from cerebral vasoconstriction induced by orthostatic stress.[24]
Relationship Between Prognoses and the Cause of Syncope
The prognosis of patients with syncope varies greatly with diagnosis. Syncope of unknown origin or syncope due to a noncardiac etiology (including reflex mediated syncope) is generally associated with a benign prognosis. In contrast, syncope due to a cardiac cause is associated with a 30 percent mortality at 1 year.
DIAGNOSTIC TESTS
Identification of the precise cause of syncope is often challenging. Because syncope usually occurs sporadically and infrequently, it is extremely difficult to either examine a patient or obtain an electrocardiogram (ECG) during an episode of syncope. For this reason, the primary goal in the evaluation of a patient with syncope is to arrive at a presumptive determination of the cause of syncope.
History and Physical Examination
The history and physical examination is the most important component of the evaluation of a patient with syncope.[5] [25] [26] [27] In one prospective series of 433 patients a diagnosis was established based on the history and physical examination in 144 patients, representing 58 percent of those patients in whom a diagnosis was established.[5] When taking a clinical history, particular attention should then be focused on (1) determining if the patient experienced true syncope as compared with a transient alteration in consciousness without loss of postural tone; (2) determining if the patient has a history of cardiac disease or if a family history of cardiac disease, syncope, or sudden death exists;

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DIFFERENTIATING SYNCOPE DUE TO NEURALLY MEDIATED HYPOTENSION, ARRHYTHMIAS, AND SEIZURES

NEURALLY MEDIATED HYPOTENSION
ARRHYTHMIAS
SEIZURE
Demographics/Clinical Setting
Female>male gender
Younger age (<55 yr)
More episodes (>2)
Standing, warm room, emotional upset
Male>female gender
Older age (>54 yr)
Fewer episodes (<3)
Any setting
Younger age (<45 yr)
Any setting


Premonitory Symptoms
Longer duration (>5 sec)
Palpitations
Blurred vision
Nausea
Warmth
Diaphoresis
Lightheadedness
Shorter duration (<6 sec)
Palpitations less common
Sudden onset or brief aura
(deja vu, olfactory, gustatory, visual)


Observations During the Event
Pallor
Diaphoretic
Dilated pupils
Slow pulse, low blood pressure
Incontinence may occur
Brief clonic movements may occur
Blue, not pale
Incontinence can occur
Brief clonic movements can occur
Blue face, no pallor
Frothing at the mouth
Prolonged syncope (duration >5 minutes)
Tongue biting
Horizontal eye deviation
Elevated pulse and blood pressure
Incontinence more likely*
Tonic clonic movements if grand mal


Residual Symptoms
Residual symptoms common
Prolonged fatigue common (>90%)
Oriented
Residual symptoms uncommon (unless prolonged unconsciousness)
Oriented
Residual symptoms common
Aching muscles
Disoriented
Fatigue
Headache
Slow recovery

pain

One learns quickly in dealing with such patients that not all pain is the consequence of serious disease. Every day, healthy persons of all ages have pains that must be taken as part of normal sensory experience. To mention a few, there are the “growing pains” of children; the momentary hard pain over an eye or in the temporal or occipital regions, which strikes with such suddenness as to raise the suspicion of a ruptured intracranial aneurysm; the more persistent ache in the fleshy part of the shoulder, hip, or extremity that subsides spontaneously or in response to a change in position; the fluctuant precordial discomfort of gastrointestinal origin, which conjures up fear of cardiac disease; the breathtaking “stitch in the side,” due to intercostal or diaphragmatic cramp. These normal pains, as they should be called, tend to be brief and to depart as obscurely as they came. Such pains come to notice only when elicited by an inquiring physician or when experienced by a patient given to worry and introspection. They must always be distinguished from the pain of disease.
Whenever pain—by its intensity, duration, and the circumstances of its occurrence—appears to be abnormal or when it constitutes the chief complaint or one of the principal symptoms, the physician must attempt to reach a tentative decision as to its mechanism and cause. This is accomplished by a thorough interrogation of the patient, with the physician carefully seeking out the main characteristics of the pain in terms of

1.
Location

2.
Mode of onset

3.
Provoking and relieving factors

4.
Quality and time-intensity attributes

5.
Duration

6.
Severity
Knowledge of these factors in every common disease is the lore of medicine. The severity of pain is often difficult to assess. Extreme degrees of pain are betrayed by the patient's demeanor, but lesser degrees can be roughly estimated by the extent to which the pain has interfered with the patient's sleep, work, and other activities or by the patient's need for bed rest. Some physicians find it helpful, particularly in gauging the effects of analgesic agents, to use a “pain scale,” i.e., to have the patient rate the intensity of his pain on a scale of zero (no pain) to ten (worst pain) or to mark it on a line. Needless to say, this general approach is put to use every day in the practice of internal medicine. Together with the physical examination, including tests designed to reproduce and relieve the pain, and ancillary diagnostic procedures, it enables the physician to identify the source of most pains and the diseases of which they are a part.
Once the pains due to the more common and readily recognized diseases of each organ system are eliminated, there remain a significant number of chronic pains that fall into one of four categories: (1) pain from an obscure medical disease, the nature of which has not yet been disclosed by diagnostic procedures; (2) pain associated with disease of the central or peripheral nervous system (i.e., neurogenic or neuropathic pain); (3) pain associated with psychiatric disease; and (4) pain of unknown cause.
Pain due to Undiagnosed Medical Disease
Here the source of the pain is usually peripheral and caused by a lesion that irritates and destroys nerve endings. Hence the term nociceptive pain is often used, but it is ambiguous. It usually means an involvement of structures bearing the termination of pain fibers. Carcinomatosis is the most frequent example. Osseous metastases, peritoneal implants, invasion of retroperitoneal tissues or the hilum of the lung, and implication of nerves of the brachial or lumbosacral plexuses can be extremely painful, and the origin of the pain may remain obscure for a long time. Sometimes it is necessary to repeat all diagnostic procedures after an interval of a few months, even though at first they were negative. From experience one learns to be cautious about reaching a diagnosis from insufficient data. Treatment is directed to the relief of pain, at the same time instilling in the patient a need to cooperate with a program of expectant observation.
Neurogenic, or Neuropathic, Pain
These terms are generally used interchangeably to designate pain that arises from direct stimulation of nervous tissue itself, central or peripheral, exclusive of pain due to stimulation of sensitized C fibers (i.e., the nociceptive pain described above). This category comprises a variety of disorders involving single and multiple nerves, notably trigeminal neuralgia and those due to herpes zoster, diabetes, and trauma (including causalgia); a number of polyneuropathies of diverse type; root irritation, e.g., from a prolapsed disc; spinal arachnoiditis and spinal cord injuries; the thalamic pain syndrome of Déjerine-Roussy; and rarely parietal lobe infarction (Schmahmann and Leifer). The clinical features that characterize central pain have been reviewed by Schott. As a rule, lesions of the cerebral cortex and white matter are associated not with pain but with hypalgesia. Particular diseases giving rise to neuropathic pain are considered in their appropriate chapters. The following remarks are of a general nature, applicable to all of the painful states that compose this group.
The features that characterize neurogenic and neuropathic pain are their persistence and generally poor response to analgesic medication; their burning, gnawing, aching, and often shooting or lancinating quality; their frequent association with hyperesthesia, hyperalgesia, allodynia, and hyperpathia (see above); the presence in many cases of a sensory deficit and some autonomic dysfunction; and the variable temporal relationship of the pain to the disease of which it is an expression.
Peripheral Nerve Pain Painful states that fall into this category are in most cases related to disease of the peripheral nerves, and it is to pain from this source that the term neuropathic is more strictly applicable. Pain states of peripheral nerve origin far outnumber those due to spinal cord, brainstem, thalamic, and cerebral disease. Although the pain is localized to a sensory territory supplied by a nerve plexus or nerve root, it often radiates to adjacent areas. Sometimes the onset of pain is immediate on receipt of injury; more often it appears at some point during the evolution or recession of the disorder. The disease of the nerve may be obvious, expressed by the usual sensory, motor, reflex, and autonomic changes, or these changes may be undetectable by standard tests. In the latter case, the term neuralgia is the preferred term.
The postulated mechanisms of peripheral nerve pain are diverse and probably differ from those of central diseases. In peripheral nerve, one mechanism is denervation hypersensitivity, first described by Walter Cannon. He noted that when a group of neurons is deprived of its natural innervation, they become hyperactive. Some neurologists point to a reduced density of certain types of fibers in nerves supplying a causalgic zone as the basis of the burning pain, but the comparison of nerves from painful and nonpainful neuropathies has not proved to be consistently different. Dyck and colleagues, in a study of painful versus nonpainful axonal neuropathies, concluded that there was no difference between them in terms of the type of fiber degeneration. The occurrence of ectopic impulse generation all along the surface of injured axons and the possibility of ephaptic activation of unsheathed axons seems applicable particularly to causalgic states in which nerve pain appears to be abolished by sympathetic denervation. Stimulation of the nervi nervorum of larger nerves by an expanding intraneural lesion or a vascular change was postulated by Asbury and Fields as the mechanism of nerve trunk pain. Regenerating axonal sprouts, as in a neuroma, are also hypersensitive to mechanical stimuli. On a molecular level, it has been shown that sodium channels accumulate at the site of a neuroma and all along the axon after nerve injury, and this gives rise to ectopic and spontaneous activity of the sensory nerve cell and nerve fiber. Such firing has been demonstrated in humans after nerve injury. This mechanism is concordant with the relief of neurogenic pain by sodium channel–blocking anticonvulsants. Spontaneous activity in nociceptive C fibers is thought to give rise to burning pain; firing of large myelinated A fibers is believed to produce dysesthetic pain induced by tactile stimuli. The abnormal response to stimulation is also influenced by sensitization of central pain pathways. Hyperalgesia is proposed to result from such a mechanism (see Woolf and Mannion). Possibly more than one of these mechanisms is operative in a given peripheral nerve disease.
Central Pain In central lesions, deafferentation of secondary neurons in the posterior horns or of sensory ganglion cells that terminate on them may cause the deafferented cells to become continuously active and, if stimulated by a microelectrode, to reproduce pain. In the patient whose spinal cord has been transected, there may be intolerable pain in regions below the level of the lesion. It may be exacerbated or provoked by movement, fatigue, or emotion and projected to areas disconnected from suprasegmental structures (akin to the phantom pain in the missing part of an amputated limb). Here, and in the rare cases of intractable pain with lateral medullary or pontine lesions, loss of the descending inhibitory systems seems a likely explanation. This may also explain the pain of the Déjerine-Roussy thalamic syndrome described on page 172. Altered sensitivity and hyperactivity of central neurons is an alternative possibility.
Further details concerning the subject of neuropathic pain can be found in the writings of Scadding and of Woolf and Mannion (see References).
Pain in Association with Psychiatric Diseases
It is not unusual for patients with endogenous depression to have pain as the predominant symptom. And most patients with chronic pain of all types are depressed. Wells and colleagues, in a survey of a large number of depressed and chronic pain patients, have convincingly corroborated this clinical impression. Fields has elaborated a theoretical explanation of the overlap of pain and depression. In such cases one is faced with an extremely difficult clinical problem—that of determining whether a depressive state is primary or secondary. In some instances the diagnostic criteria cited in Chap. 57 provide the answer, but in others it is impossible to make this distinction. Empiric treatment with antidepressant medication or, failing this, with electroconvulsive therapy is one way out of the dilemma.
Intractable pain may be the leading symptom of both hysteria and compensation neurosis. Every experienced physician is familiar with the “battle-scarred abdomen” of the woman with hysteria (so-called Briquet disease) who has demanded and yielded to one surgical procedure after another, losing appendix, ovaries, fallopian tubes, uterus, gallbladder, etc., in the process (“diagnosis by evisceration”). The recognition and management of hysteria are discussed in Chap. 56.
Compensation neurosis is often colored by persistent complaints of headaches, neck pain (whip-lash injuries), low-back pain, etc. The question of ruptured disc is often raised, and laminectomy and spinal fusion may be performed (sometimes more than once) on the basis of dubious radiologic findings. Complaints of weakness and fatigue, depression, anxiety, insomnia, nervousness, irritability, palpitations, etc., are woven into the clinical syndrome, attesting to the prominence of psychiatric disorder. Long delay in settlement of litigation, allegedly to determine the seriousness of the injury, only enhances the symptoms and prolongs the disability. The medical and legal professions have no certain approach to such problems and often work at cross-purposes. We have found that a frank, objective appraisal of the injury, an assessment of the psychiatric problem, and encouragement to settle the legal claims as quickly as possible work in the best interests of all concerned. While hypersuggestibility and relief of pain by placebos, etc., may reinforce the physician's belief that there is a prominent factor of hysteria or malingering (see Chap. 56), such data are difficult to interpret and are not acceptable in court.
Chronic Pain of Indeterminate Cause
This is the most difficult group of all—pain in the thorax, abdomen, flank, back, face, or other part that cannot be traced to any visceral abnormality. Supposedly all neurologic sources, such as a spinal cord tumor, have been excluded by repeated examinations and imaging procedures. A psychiatric disorder to which the patient's symptoms and behavior might be attributed cannot be discerned. Yet the patient complains continuously of pain, is disabled, and spends a great deal of effort and money seeking medical aid.
In such a circumstance, some physicians and surgeons, rather than concede their helplessness, may resort to extreme measures such as exploratory thoracotomy, laparotomy, or laminectomy. Or they may injudiciously attempt to alleviate the pain and avoid drug addiction by severing roots and spinal tracts, often with the result that the pain moves to an adjacent segment or to the other side of the body.
This type of patient should be seen frequently by the physician. All the medical facts should be reviewed and the clinical and laboratory examinations repeated if some time has elapsed since they were last done. Tumors in the hilum of the lung or mediastinum, in the retropharyngeal, retroperitoneal, and paravertebral spaces, or in the uterus, testicle, kidney, and prostate offer special difficulty in diagnosis, often being undetected for many months. Neurofibroma causing pain in an unusual site, such as one side of the rectum or vagina, is another type of tumor that may defy diagnosis for a long time. Neurologic pain is almost invariably accompanied by alterations in cutaneous sensation and other neurologic signs, the finding of which facilitates diagnosis; the appearance of the neurologic signs may be long delayed, however. The possibility of drug addiction as a motivation should be eliminated. It is impossible to assess pain in the addicted individual, for the patient's complaints are woven into his need for medication. Temperament and mood should be evaluated carefully from day to day; the physician must remember that the depressed patient often denies being depressed and may occasionally smile. When no medical, neurologic, or psychiatric disease can be established, one must be resigned to managing the painful state by the use of nonnarcotic medications and frequent clinical re-evaluations. Such a course, though not altogether satisfactory, is preferable to prescribing excessive opioids or subjecting the patient to ablative surgery.
Because of the complexity and difficulty in diagnosis and treatment of chronic pain, most medical centers have found it advisable to establish pain clinics. Here a staff of internists, anesthesiologists, neurologists, neurosurgeons, and psychiatrists are able to review each patient in terms of drug dependence, neurologic disease, and psychiatric problems. Success is achieved by treating each aspect of chronic pain, with emphasis on increasing the patient's tolerance of pain by means of biofeedback, meditation and related techniques, by using special invasive anesthetic special procedures (discussed later in the chapter), by establishing a regimen of pain medication, and by controlling depressive illness.
Rare and Unusual Disturbances of Pain Perception
Lesions of the parieto-occipital regions of one cerebral hemisphere sometimes have peculiar effects on the patient's capacity to feel and react to pain. Under the title of pain hemiagnosia, Hecaen and Ajuriaguerra described several cases of left-sided paralysis from a right parietal lesion which, at the same time, rendered the patient hypersensitive to noxious stimuli. When pinched on the affected side, the patient, after a delay, became agitated, moaned, and seemed distressed but made no effort to fend off the painful stimulus with the other hand or to withdraw from it. In contrast, if the good side was pinched, the patient reacted normally and moved the normal hand at once to the site of the stimulus to remove it. The motor responses seem no longer to be guided by sensory information from one side of the body.
There are also two varieties of rare individuals who from birth are totally indifferent to pain (“congenital insensitivity to pain”) or are incapable of feeling pain (“universal analgesia”). The former have an uncertain congenital deficiency of a neurotransmitter or an equally obscure peculiarity of the central receptive apparatus (see Chap. 9), and the second group suffers from either a congenital lack of pain neurons in dorsal root ganglia, a polyneuropathy, or a lack of pain receptors in the primary afferent neuron.
The phenomenon of asymbolia for pain is another rare and unusual condition, wherein the patient, although capable of distinguishing the different types of pain stimuli from one another and from touch, is said to make none of the usual emotional, motor, or verbal responses to pain. This patient seems totally unaware of the painful or hurtful nature of stimuli delivered to any part of the body, whether on one side or the other. The current interpretation of asymbolia for pain is that it represents a particular type of agnosia (analgagnosia) or apractagnosia (cf. Chap. 22), in which the organism loses its ability to adapt its emotional, motor, and verbal actions to the consciousness of a nociceptive impression. “Le sujet a perdu la compréhension de la signification de la douleur.” We have been unable to corroborate the existence of this syndrome from our own clinical experience.
Treatment of Intractable Pain
Once the nature of the patient's pain and underlying disease have been determined, therapy must include some type of pain control. Initially, of course, attention is directed to the underlying disease, with the idea of eliminating the source of the pain by appropriate medical, surgical, or radiotherapeutic measures.
If the patient is ridden with disease and will not live more than a few weeks or months, is opposed to surgery, or has widespread pain, surgical measures are out of the question. However, pain from widespread osseous metastases, even in patients with hormone-insensitive tumors, may be relieved by radiation therapy or by hypophysectomy. Pain confined to a restricted area of the jaw or face may be relieved by nerve root blocks; by radiofrequency destruction of the trigeminal nerve, roots, or ganglion; or in some cases by decompressive surgery of an aberrant vascular loop that abuts a root in the posterior fossa. Usually, nerve section is not a satisfactory way of relieving restricted pain of the trunk and limbs because the overlap of adjacent nerves prevents complete denervation. Another procedure to be considered before undertaking the section of several contiguous sensory roots is the regional delivery of narcotic analogues, such as fentanyl or ketamine, by means of an external pump and a catheter that is implanted percutaneously in the epidural space in proximity to the dorsal nerve roots in the affected region; this device can be used safely at home.
If radiation therapy and other medical and surgical measures are not feasible or fail to relieve the pain, a program utilizing analgesic medication must be undertaken. Central to such a program is the use of opioids, which to this day represent the most effective analgesic agents for the management of severe chronic pain due to medical disease.
A useful way in which to undertake the management of chronic pain that affects several parts of the body, as in the patient with metastases, is with codeine, oxycodone, or propoxyphene taken together with aspirin, acetaminophen, or another nonsteroidal anti-inflammatory agent. The analgesic effects of these two types of drugs are additive, which is not the case when narcotics are combined with diazepam or phenothiazine. Antidepressants may have a beneficial effect on pain, even in the absence of overt depression. This is true particularly in cases of neuropathic pain (painful polyneuropathy and some types of radicular pain). Sometimes these nonnarcotic agents may in themselves or in combination with other treatment modalities be sufficient to control the patient's pain, and the use of narcotics can be kept in reserve.
Use of Opioids and Opiates Should the foregoing measures prove to be ineffective, one must turn to more potent narcotic agents. Methadone and levorphanol are the most useful drugs with which to begin, because of their effectiveness by mouth and the relatively slow development of tolerance. The oral route should be utilized whenever possible, since it is more comfortable for the patient than the parenteral route. Also, the oral route is associated with less side effects, except for nausea and vomiting, which tend to be worse than with parenteral administration. Should the latter become necessary, one must be aware of the ratios of oral to parenteral dosages required to produce equivalent analgesia. These are indicated in Table 8-1.




Table 8-1 Common drugs for the management of chronic pain


If oral medication fails to control the pain, the parenteral administration of codeine or more potent opioids becomes necessary. Again, one may begin with methadone, dihydromorphone (Dilaudid), or levorphanol, given at intervals of 4 to 6 h, because of their relatively long duration of action (particularly in comparison to meperidine). Alternatively, one may first resort to the use of transdermal patches of drugs such as fentanyl, which provide relief for 24 to 72 h and which we have found particularly useful in the treatment of pain from brachial or lumbosacral plexus invasion by tumor. Long-acting morphine preparations are useful alternatives. Should long-continued injections of opiates become necessary, the optimal dose for the relief of pain should be established and the drug then given at regular intervals around the clock, rather than “as needed.” The administration of morphine (and other narcotics) in this way represents a laudable shift in attitude among physicians. For many years it was taught that the drug should be given in the smallest possible doses, spaced as far apart as possible, and repeated only when severe pain reasserted itself. It has become clear that such usage of the drug results in unnecessary discomfort and, in the end, the need to use larger doses. The fear of creating narcotic dependence and the expected phenomenon of increasing tolerance must be balanced against the overriding need to relieve pain. The most pernicious aspect of addiction, that of compulsive drug-seeking behavior and self-administration of the drug, occurs only rarely in this setting and usually in patients with a previous history of addiction or alcoholism, with depression as the primary problem, or with certain character defects that have been loosely referred to as “addiction proneness.” Even in patients with severe acute or postoperative pain, the best results are obtained by allowing the patient to determine the dose and frequency of intravenous medication, so-called patient-controlled analgesia, or PCA. Again, the danger of producing addiction is minimal.
Excellent guidelines for the use of orally and parenterally administered opioids for cancer-related pain are contained in the article of Cherny and Foley and in the publication of the U.S. Department of Health and Human Services (see References).
The regimen outlined above conforms with current information about pain-control mechanisms. Aspirin and other nonsteroidal anti-inflammatory analgesics are believed to prevent the activation of nociceptors by inhibiting the synthesis of prostaglandins in skin, joints, viscera, etc. Morphine and meperidine given orally, parenterally, or intrathecally presumably produce analgesia by acting as “false” neurotransmitters at receptor sites in the posterior horns of the spinal cord—sites that are normally activated by endogenous opioid peptides (see Fig. 8-5). The separate sites of action of nonsteroidal analgesics and opioids provide an explanation for the therapeutic usefulness of combining these drugs. Yet another mechanism, described earlier in this chapter, consists of the physiologic activation of the intrinsic analgesic system (descending pathways from brain to spinal cord) by electrical stimulation, administration of placebo, and possibly acupuncture; short bursts of transcutaneous electrical stimulation may also suppress pain in this way. Not only do opioids act directly on the central pain-conducting sensory systems but they also exert a powerful action on the affective component of pain. Serotoninergic neurons are also thought to play a role in pain modulation.
Other Supplemental Medications Tricyclic antidepressants, especially the methylated forms (imipramine, amitriptyline, and doxepin), block serotonin reuptake and thus enhance the action of this neurotransmitter at synapses and putatively facilitate the action of the intrinsic opiate analgesic system. As a general rule, relief is afforded with tricyclic antidepressants in the equivalent dose range of 75 to 125 mg daily of amitriptyline, but little benefit accrues with higher doses. The newer serotoninergic antidepressants seem not to be as effective for the treatment of chronic neuropathic pain (see review by McQuay and colleagues), but these agents have not yet been extensively investigated in this clinical condition.
Anticonvulsants have a beneficial effect on many central and peripheral neuropathic pain syndromes but are generally less effective for causalgic pain due to partial injury of a peripheral nerve. The mode of action of phenytoin, carbamazepine, neurontin, and other anticonvulsants in suppressing the lancinating pains of tic douloureux and certain polyneuropathies as well as pain after spinal cord injury and myelitis is not understood. The biphosphate compound pamidronate, known to relieve several painful bone disorders, is being adopted increasingly for the treatment of causalgic pain, but the precise indications for its use remain to be defined.
The use of analgesic (nonnarcotic and narcotic), anticonvulsant, and antidepressant drugs in the management of chronic pain are summarized in Table 8-1.
Treatment of Neuropathic Pain
The treatment of pain induced by nerve root compression or intrinsic peripheral nerve disease utilizes several special techniques, some of which fall in the province of the anesthesiologist. If the pain is regional and has a predominantly burning quality, capsaicin cream can be applied locally, care being taken to avoid contact with the eyes and mouth. The irritative effect of this chemical seems in some cases to mute the pain. Concoctions of “eutectic” mixtures of local anesthetic creams (EMLA) and the simpler lidocaine gel preparation may provide relief in postherpetic neuralgia and painful peripheral neuropathies.
Injections of epidural corticosteroids or mixtures of analgesic and steroids are helpful in selected cases of lumbar or thoracic nerve root pain and occasionally in painful peripheral neuropathy, but precise criteria for the use of this measure are not well established. Root blocks with lidocaine or with longer-acting local anesthetics are helpful at times in establishing the precise source of radicular pain. Their main therapeutic use in our experience has been for thoracic radiculitis from shingles, chest wall pain after thoracotomy, and diabetic radiculopathy. Similar local injections are used in the treatment of occipital neuralgia.
The infusion of lidocaine has a brief beneficial effect on many types of pain, including neuropathic varieties, localized headaches, and facial pain, and it is said to be useful in predicting the response to longer-acting agents such as its oral analogue, mexiletine, although this relationship has been erratic in our experience (see Table 8-1). Mexiletine is given in an initial dose of 150 mg per day and slowly increased to a maximum of 300 mg three times daily; it should be used very cautiously in patients with heart block.
Finally, reducing sympathetic activity within somatic nerves by direct injection of the sympathetic ganglia in affected regions of the body (stellate ganglion for arm pain and lumbar ganglia for leg pain) has met with mixed success in neuropathic pain, including that of causalgia and reflex sympathetic dystrophy. A variant of this technique utilizes regional intravenous infusion of a sympathetic blocking drug (bretylium, guanethidine, reserpine) into a limb that is isolated from the systemic circulation by the use of a tourniquet. It is known as a “Bier block,” after the developer of regional anesthesia for single-limb surgery. The use of these techniques, and the intravenous infusion of the adrenergic blocker phentolamine, is predicated on the concept of “sympathetically sustained pain,” meaning pain that is mediated by the interaction of sympathetic and pain nerve fibers (“false synapse” or “ephapsis”) or by the sprouting of adrenergic axons in partially damaged nerves. This form of treatment is still under study, but the most consistent responses to sympathetic blockade are obtained in cases of true causalgia that results from partial nerve injury and in reflex sympathetic dystrophy. These pain syndromes have been referred to by a number of different names, most recently as the “complex regional pain syndrome,” but all refer to the same constellation of burning and other regional pains that may or may not conform to a nerve or root distribution (see page 1438). A number of other treatments have proven successful in some patients with reflex sympathetic dystrophy, but the clinician should not be sanguine about their chances of success over the long run. Perhaps the most novel and promising of these has been the use of bisphosphonates (pamidronate, alendronate), which have been beneficial in painful disorders of bone, e.g., Paget disease and metastatic bone lesions. Another treatment of last resort is the epidural infusion of drugs such as ketamine; sometimes this has a lasting effect on causalgic pain.
The therapeutic approaches enumerated here are usually undertaken in sequence. They reflect the general ineffectiveness of currently available treatments and our uncertainty as to the mechanisms of neuropathic pain. There are occasional successes, most of them temporary. Further references can be found in the article by Katz.
Use of Ablative Surgery in the Control of Pain
It is the authors' considered opinion that a program of medical therapy should always precede ablative surgical measures. Only when a variety of analgesic medications (including opioids) combined with phenothiazines and anticonvulsants, and only when certain practical measures, such as regional analgesia or anesthesia, have completely failed should one turn to neurosurgical procedures. Also, one should be very cautious in suggesting a procedure of last resort for pain that has no established cause, as, for example, limb pain that has been incorrectly identified as causalgic because of a burning component of the pain but in which there has been no nerve injury.
The least destructive procedure consists of implantation of an electrical stimulator, usually adjacent to the posterior columns. This procedure, which enjoyed a brief period of popularity, affords only incomplete relief and is difficult to maintain in place; it is now little used. The use of nerve section and dorsal rhizotomy as definitive measures for the relief of regional pain has already been discussed, under “Treatment of Intractable Pain,” above.
Spinothalamic tractotomy, in which the anterior half of the spinal cord on one side is sectioned at an upper thoracic level, effectively relieves pain in the opposite leg and lower trunk. This may be done as an open operation or as a transcutaneous procedure in which a radiofrequency lesion is produced by an electrode. The analgesia and thermoanesthesia may last a year or longer, after which the level of analgesia tends to descend and the pain to return. Bilateral cordotomy is also feasible, but with greater risk of loss of sphincteric control and, at higher levels, of respiratory paralysis. Motor power is nearly always spared because of the position of the corticospinal tract in the posterior part of the lateral funiculus.
Pain in the arm, shoulder, and neck is more difficult to relieve surgically. High cervical transcutaneous cordotomy has been used successfully, with achievement of analgesia up to the chin. Commissural myelotomy by longitudinal incision of the anterior or posterior commissure of the spinal cord over many segments has also been performed, with variable success. Lateral medullary tractotomy is another possibility but must be carried almost to the midline to relieve cervical pain. The risks of this latter procedure and also of lateral mesencephalic tractotomy (which may actually produce pain) are so great that neurosurgeons have to all intents abandoned these operations.
Stereotactic surgery on the thalamus for one-sided chronic pain is still used in a few clinics, and the results have been instructive. Lesions placed in the ventroposterior nucleus are said to diminish pain and thermal sensation over the contralateral side of the body while leaving the patient with all the misery or affect of pain; lesions in the intralaminar or parafascicular-centromedian nuclei relieve the painful state without altering sensation (Mark). Since these procedures have not yielded predictable benefits to the patient, they are now seldom practiced. The same unpredictability pertains to cortical ablations. Patients in whom a severe depression of mood is associated with a chronic pain syndrome have been subjected to bilateral stereotactic cingulotomy or the equivalent, subcaudate tractotomy. A considerable degree of success has been claimed for these operations, but the results are difficult to evaluate. Orbitofrontal leukotomy has been virtually discarded because of the personality change that it produces (see Chap. 22).
Unconventional Methods for the Treatment of Pain
Included under this heading are certain techniques such as biofeedback, meditation, imagery, acupuncture, some forms of spinal manipulation, as well as transcutaneous electrical stimulation. Each of these may be of value in the context of a comprehensive pain management program, conducted usually in a pain clinic, as a means of providing relief from pain and suffering, reducing anxiety, and diverting the patient's attention, even if only temporarily, from the painful body part. Attempts to quantify the benefits of these techniques—judged usually by a reduction of drug dosage in response to a particular form of treatment—have given mixed results. Nevertheless, it is unwise for physicians to dismiss these methods out of hand, since well-motivated and apparently well-balanced persons have reported subjective improvement with one or another of these methods and, in the final analysis, this is what really matters. Conventional psychotherapy in combination with the use of medication and, at times, of electroconvulsive therapy can be of great benefit in the treatment of associated depressive symptoms, as discussed above

PHYSIOLOGIC ASPECTS OF PAIN

The stimuli that activate pain receptors vary from one tissue to another. As pointed out above, the adequate stimulus for skin is one that has the potential to injure tissue, i.e., pricking, cutting, crushing, burning, and freezing. These stimuli are ineffective when applied to the stomach and intestine, where pain is produced by an engorged or inflamed mucosa, distention or spasm of smooth muscle, and traction on the mesenteric attachment. In skeletal muscle, pain is caused by ischemia (the basis of intermittent claudication), necrosis, hemorrhage, and injection of irritating solutions, as well as by injuries of connective tissue sheaths. Prolonged contraction of skeletal muscle evokes an aching type of pain. Ischemia is also the most important cause of pain in cardiac muscle. Joints are insensitive to pricking, cutting, and cautery, but pain can be produced in the synovial membrane by inflammation and by exposure to hypertonic saline. The stretching and tearing of ligaments around a joint can evoke severe pain. Injuries to the periosteum give rise to pain but probably not to other sensations. Arteries are a source of pain when pierced by a needle or involved in an inflammatory process. Distention of arteries, as occurs with thrombotic or embolic occlusion, and excessive arterial pulsation, as in migraine, may be sources of pain; other mechanisms of headache relate to traction on arteries and the meningeal structures by which they are supported (see Chap. 10). Pain due to intraneural lesions probably arises from the sheaths of the nerves. Nerve root(s) and sensory ganglia, when compressed (e.g., by a ruptured disc), give rise to pain.
With damage to tissue, there is a release of proteolytic enzymes, which act locally on tissue proteins to liberate substances that excite peripheral nociceptors. These pain-producing substances—which include histamine, prostaglandins, serotonin, and similar polypeptides as well as potassium ions—elicit pain when they are injected intra-arterially or applied to the base of a blister. Other pain-producing substances such as kinins are released from sensory nerve endings or are carried there by the circulation. Also, vascular permeability may be increased by these substances.
In addition, direct stimulation of nociceptors releases polypeptide mediators that enhance pain perception. The best-studied of these is substance P, which is released from the nerve endings of C fibers in the skin during peripheral nerve stimulation. It causes erythema by dilating cutaneous vessels and edema by releasing histamine from mast cells; it also acts as a chemoattractant for leukocytes. This reaction, called neurogenic inflammation by White and Helme, is mediated by antidromic action potentials from the small nerve cells in the spinal ganglia and is the basis of the axon reflex of Lewis. This reaction is abolished in certain peripheral nerve diseases and can be studied electrophysiologically as an aid to clinical localization.
Perception of Pain
The threshold for perception of pain, i.e., the lowest intensity of a stimulus recognized as pain, is approximately the same in all persons. It is lowered by inflammation, a process that is called sensitization and is clinically important because in sensitized tissues ordinarily innocuous stimuli can produce pain. The pain threshold is, of course, raised by local anesthetics and by certain lesions of the nervous system as well as by centrally acting analgesic drugs. Mechanisms other than lowering or raising the pain threshold are important as well. Placebos reduce pain in about one-third of the groups of patients in which such effects have been recorded. Acupuncture at sites anatomically remote from painful operative fields apparently reduces the pain in some individuals. Distraction and suggestion, by turning attention away from the painful part, reduce the awareness of and response to pain. Strong emotion (fear or rage) suppresses pain, presumably by activation of the above-described descending adrenergic system. The experience of pain appears to be lessened in manic states and enhanced in depression. Neurotic patients in general have the same pain threshold as normal subjects, but their reaction may be excessive or abnormal. The pain thresholds of frontal lobotomized subjects are also unchanged, but they react to painful stimuli only briefly or casually if at all. The degrees of emotional reaction and verbalization (complaint) also vary with the personality and character of the patient.
The conscious awareness or perception of pain occurs only when pain impulses reach the thalamocortical level. The precise roles of the thalamus and cortical sensory areas in this mental process are not fully understood, however. For many years it was taught that the recognition of a noxious stimulus as such is a function of the thalamus and that the parietal cortex is necessary for appreciation of the intensity, localization, and other discriminatory aspects of sensation. This traditional separation of sensation (in this instance awareness of pain) and perception (awareness of the nature of the painful stimulus) has been abandoned in favor of the view that sensation, perception, and the various conscious and unconscious responses to a pain stimulus comprise an indivisible process. That the cerebral cortex governs the patient's reaction to pain cannot be doubted, however. It is also likely that the cortex can suppress or otherwise modify the perception of pain in the same way that corticofugal projections from the sensory cortex modify the rostral transmission of other sensory impulses from thalamic and dorsal column nuclei. It has been shown that central transmission in the spinothalamic tract can be inhibited by stimulation of the sensorimotor areas of the cerebral cortex, and, as indicated above, a number of descending fiber systems have been traced to the dorsal horn laminae from which this tract originates.
Endogenous Pain-Control Mechanisms
In recent years, the most important contribution to our understanding of pain has been the discovery of a neuronal analgesia system, which can be activated by the administration of opiates or by naturally occurring brain substances with the pharmacologic properties of opiates. This endogenous system was first demonstrated by Reynolds, who found that stimulation of the ventrolateral periaqueductal gray matter in the rat produced a profound analgesia without altering behavior or motor activity. Subsequently, stimulation of other discrete sites in the medial and caudal regions of the diencephalon and rostral bulbar nuclei (notably raphe magnus and paragigantocellularis) were shown to have the same effect. Under the influence of such electrical stimulation, the animal could be operated upon without anesthesia and move around in an undisturbed manner despite the administration of noxious stimuli. Investigation disclosed that the effect of stimulation-produced analgesia (SPA) is to inhibit the neurons of laminae I, II, and V of the dorsal horn, i.e., the neurons that are activated by noxious stimuli. In human subjects, stimulation of the midbrain periaqueductal gray matter through stereotactically implanted electrodes has also produced a state of analgesia, though not consistently. Other sites in which electrical stimulation is effective in suppressing nociceptive responses are the rostroventral medulla (nucleus raphe magnus and adjacent reticular formation) and the dorsolateral pontine tegmentum. These effects are relayed to the dorsal horn gray matter via a pathway in the dorsolateral funiculus of the spinal cord. Ascending pathways from the dorsal horn, conveying noxious somatic impulses, are also important in activating the modulatory network. These connections are illustrated in Fig. 8-5.
As indicated earlier, opiates also act pre- and postsynaptically on the neurons of laminae I and V of the dorsal horn, suppressing afferent pain impulses from both the A-d and C fibers. Furthermore, these effects can be reversed by the narcotic antagonist naloxone. Interestingly, naloxone can reduce some forms of stimulation-produced analgesia. Levine and colleagues have demonstrated that not only does naloxone enhance clinical pain but it also interferes with the pain relief produced by placebos. These observations suggest that the heretofore mysterious beneficial effects of placebos (and perhaps of acupuncture) may be due to activation of an endogenous system that shuts off pain through the release of pain-relieving endogenous opioids, or endorphins (see below). Prolonged pain and fear are the most powerful activators of this endogenous opioid-mediated modulating system. The same system is probably operative under a variety of other stressful conditions; for example, some soldiers, wounded in battle, require little or no analgesic medication (“stress-induced analgesia”). The opiates also act at several loci in the brainstem, at sites corresponding with those producing analgesia when stimulated electrically and generally conforming to areas in which neurons with endorphin receptors are localized.
Soon after the discovery of specific opiate receptors in the central nervous system (CNS), several naturally occurring peptides, which proved to have a potent analgesic effect and to bind specifically to opiate receptors, were identified (Hughes et al). These endogenous, morphine-like compounds are generically referred to as endorphins, meaning “the morphines within.” The most widely studied of these compounds are b-endorphin, a peptide sequence of the pituitary hormone b-lipotropin, and two other peptides, enkephalin and dynorphin. They are found in greatest concentration in relation to opiate receptors in the midbrain. At the level of the spinal cord, opiate receptors are essentially enkephalin receptors. A theoretical construct of the roles of enkephalin (and substance P) at the point of entry of pain fibers into the spinal cord is illustrated in Fig. 8-6. A subgroup of dorsal horn interneurons also contain enkephalin; they are in contact with spinothalamic tract neurons.




Figure 8-6 Theoretical mechanism of action of enkephalin (endorphin) and morphine on the transmission of pain impulses from the periphery to the CNS. Spinal interneurons containing enkephalin synapse with the terminals of pain fibers and inhibit the release of the presumptive transmitter, substance P. As a re-sult, the receptor neuron in the dorsal horn receives less excita-tory (pain) impulses and transmits fewer pain impulses to the brain. Morphine binds to unoccupied enkephalin receptors, mimicking the pain-suppressing effects of the endogenous opiate enkephalin.


Thus it would appear that the central effects of a painful condition are determined by many ascending and descending systems utilizing a variety of transmitters. A deficiency in a particular region would explain persistent or excessive pain. Opiate addiction might conceivably be accounted for in this way, and also the discomfort that follows withdrawal of the drug. Indeed, it is known that some of these peptides not only relieve pain but suppress withdrawal symptoms. It has been speculated that in the limbic regions, disturbances in the formation of neurotransmitters could be the basis of unpleasant and distressing emotional states (e.g., depression).
Finally it should be noted that the descending pain-control systems probably contain noradrenergic and serotoninergic as well as opiate links. A descending norepinephrine-containing pathway, as mentioned, has been traced from the dorsolateral pons to the spinal cord, and its activation blocks spinal nociceptive neurons. The rostroventral medulla contains a large number of serotoninergic neurons. Descending fibers from the latter site inhibit dorsal horn cells concerned with pain transmission, perhaps providing a rationale for the use of certain serotonin agonists in patients with chronic pain.

ANATOMY AND PHYSIOLOGY OF PAIN

Historical Perspective
For more than a century, views on the nature of pain sensation have been dominated by two major theories. One, known as the specificity theory, was from the beginning associated with the name of von Frey. He asserted that the skin consisted of a mosaic of discrete sensory spots and that each spot, when stimulated, gave rise to one sensation—either pain, pressure, warmth, or cold; in his view, each of these sensations had a distinctive end organ in the skin and each stimulus-specific end organ was connected by its own private pathway to the brain. A second theory was that of Goldscheider, who abandoned his own earlier discovery of pain spots to argue that they simply represented pressure spots, a sufficiently intense stimulation of which could produce pain. According to the latter theory, there were no distinctive pain receptors, and the sensation of pain was the result of the summation of impulses excited by pressure or thermal stimuli applied to the skin. Originally called the intensivity theory, it later became known as the pattern or summation theory.
In an effort to conciliate the pattern and specificity theories, Head and his colleagues, in 1905, formulated a novel concept of pain sensation, based on observations that followed division of the cutaneous branch of the radial nerve in Head's own forearm. The zone of impaired sensation contained an innermost area in which superficial sensation was completely abolished. This was surrounded by a narrower (“intermediate”) zone, in which pain sensation was preserved but poorly localized; extreme degrees of temperature were recognized in the intermediate zone, but perception of touch, lesser differences of temperature, and two-point discrimination were abolished. To explain these findings, Head postulated the existence of two systems of cutaneous receptors and conducting fibers: (1) an ancient protopathic system, subserving pain and extreme differences in temperature and yielding ungraded, diffuse impressions of an all-or-none type, and (2) a more recently evolved epicritic system, which mediated touch, two-point discrimination, and lesser differences in temperature as well as localized pain. The pain and hyperesthesia that follow damage to a peripheral nerve were attributed to a loss of inhibition that was normally exerted by the epicritic upon the protopathic system. This theory was used for many years to explain the sensory alterations that occur with both peripheral and central (thalamic) lesions. It lost credibility for several reasons, but mainly because Head's original observations (and deductions upon which they were based) could not be corroborated (see Trotter and Davies; also Walshe). Nevertheless, both a fast and a slow form of pain conduction were later corroborated (see below).
A much later refinement of the pattern and specificity concepts of pain was made in 1965, when Melzack and Wall propounded their “gate-control” theory. They observed, in decerebrate and spinal cats, that peripheral stimulation of large myelinated fibers produced a negative dorsal root potential and that stimulation of small C (pain) fibers caused a positive dorsal root potential. They postulated that these potentials, which were a reflection of presynaptic inhibition or excitation, modulated the activity of secondary transmitting neurons (T cells) in the dorsal horn, and that this modulation was mediated through inhibitory (I) cells. The essence of this theory is that the large-diameter fibers excite the I cells, which, in turn, cause a presynaptic inhibition of the T cells; conversely, the small pain afferents inhibit the I cells, leaving the T cells in an excitatory state. Melzack and Wall emphasized that pain impulses from the dorsal horn must also be under the control of a descending system of fibers from the brainstem, thalamus, and limbic lobes.
At first the gate-control mechanisms seemed to offer an explanation of the pain of ruptured disc and of certain chronic neuropathies (large fiber outfall), and attempts were made to relieve pain by subjecting the peripheral nerves and dorsal columns (presumably their large myelinated fibers) to sustained, transcutaneous electrical stimulation. Such selective stimulation would theoretically “close” the gate. In some clinical situations, these procedures have indeed given relief from pain, but not necessarily due to stimulation of large myelinated fibers alone (see Taub and Campbell). And in a number of other instances relating to pain in large- and small-fiber neuropathies, the clinical behavior has been quite out of keeping with what one would expect on the basis of the gate-control mechanism. As with preceding pain theories, flaws have been exposed in the physiologic observations on which the theory is based. These and other aspects of the gate-control theory of pain have been critically reviewed by P. W. Nathan.
During the last few decades there has been a significant accrual of information on cutaneous sensibility, demanding a modification of earlier anatomic-physiologic and clinical concepts. Interestingly, much of this information is still best described and rationalized in the general framework of specificity, as will be evident from the ensuing discussion on pain and that on other forms of cutaneous sensibility in the chapter that follows.
Pain Receptors and Peripheral Afferent Pathways
In terms of peripheral pain mechanisms, as already implied, there is indeed a high degree of specificity, though not an absolute specificity in the von Frey sense. It is now well established that two types of afferent fibers in the distal axons of primary sensory neurons respond maximally to nociceptive (i.e., potentially tissue-damaging) stimuli. One type is the very fine, unmyelinated, slowly conducting C fiber (0.4 to 1.1 mm in diameter), and the other is the thinly myelinated, more rapidly conducting A-delta (A-d) fiber (1.0 to 5.0 mm in diameter). The peripheral terminations of both these primary pain afferents, or receptors, are the free, profusely branched nerve endings in the skin and other organs; these are covered by Schwann cells and contain little or no myelin. There is considerable evidence, based on their response characteristics, that a degree of subspecialization exists within these freely branching, nonencapsulated endings and their small fiber afferents. Three broad categories of free endings, or receptors, are recognized: mechanoreceptors, thermoreceptors, and polymodal nociceptors. Each ending transduces stimulus energy into an action potential in nerve membranes. The first two types of receptors are activated by innocuous mechanical and thermal stimulation, respectively; the mechanoeffects are transmitted by both A-d and C fibers and the thermal effects only by C fibers. The polymodal afferents are most effectively excited by noxious or tissue-damaging stimuli, but they can respond as well to both mechanical and thermal stimuli and to chemical mediators such as those associated with inflammation. Moreover, certain A-d fibers respond to light touch, temperature, and pressure as well as to pain stimuli and are capable of discharging in proportion to the intensity of the stimulus. The stimulation of single fibers by intraneural electrodes indicates that they can also convey information concerning the nature and location of the stimulus (local sign). These observations on the polymodal functions of A-d and C fibers would explain the earlier observations of Lele and Weddell that modes of sensation other than pain can be evoked from structures such as the cornea, which is innervated solely by free nerve endings.
The peripheral afferent pain fibers of both A-d and C types have their cell bodies in the dorsal root ganglia; central extensions of these nerve cells project, via the dorsal root, to the dorsal horn of the spinal cord (or, in the case of cranial pain afferents, to the nucleus of the trigeminal nerve, the medullary analogue of the dorsal horn). The pain afferents occupy mainly the lateral part of the root entry zone. Within the spinal cord, many of the thinnest fibers (C fibers) form a discrete bundle, the tract of Lissauer (Fig. 8-1A). That Lissauer's tract is predominantly a pain pathway is shown (in animals) by the ipsilateral segmental analgesia that results from its transection, but it contains deep sensory, or propriospinal, fibers as well. Although it is customary to speak of a lateral and medial division of the posterior root (the former contains small pain fibers and the latter, large myelinated fibers), the separation into discrete functional bundles is not complete, and in humans the two groups of fibers cannot be differentially interrupted by selective rhizotomy.




Figure 8-1 A. Spinal cord in transverse section, illustrating the course of the afferent fibers and the major ascending pathways. Fast-conducting pain fibers are not confined to the spinothalamic tract but are scattered diffusely in the anterolateral funiculus. B. Transverse section through the sixth cervical segment of the spinal cord of the cat, illustrating the subdivision of the gray matter into laminae according to Rexed. LM and VM, lateromedial and ventromedial groups of motor neurons.


Dermatomic Distribution of Pain Fibers
Each sensory unit (the sensory nerve cell in the dorsal root ganglion, its central and peripheral extensions, and cutaneous and visceral endings) has a unique topography that is maintained throughout the sensory system from the periphery to the sensory cortex. The discrete segmental distribution of the sensory units permits the construction of sensory maps, so useful to clinicians. This aspect of sensory anatomy is elaborated in the next chapter, which includes maps of the sensory dermatomes and cutaneous nerves. However, as a means of quick orientation to the topography of peripheral pain pathways, it is useful to remember that the facial structures and anterior cranium lie in the fields of the trigeminal nerves; the back of the head, second cervical; the neck, third cervical; the epaulet area, fourth cervical; the deltoid area, fifth cervical; the radial forearm and thumb, sixth cervical; the index and middle fingers, seventh cervical; the little finger and ulnar border of hand and forearm, eighth cervical–first thoracic; the nipple, fifth thoracic; the umbilicus, tenth thoracic; the groin, first lumbar; the medial side of the knee, third lumbar; the great toe, fifth lumbar; the little toe, first sacral; the back of the thigh, second sacral; and the genitoanal zones, the third, fourth, and fifth sacrals. The distribution of pain fibers from deep structures, though not fully corresponding to those from the skin, also follows a segmental pattern. The first to fourth thoracic nerve roots are the important sensory pathways for the heart and lungs; the sixth to eighth thoracic, for the upper abdominal organs; and the lower thoracic and upper lumbar, for the lower abdominal viscera.
The Dorsal Horn
The afferent pain fibers, after traversing Lissauer's tract, terminate in the posterior gray matter or dorsal horn, predominantly in the marginal zone. Most of the fibers terminate within the segment of their entry into the cord; some extend ipsilaterally to one or two adjacent rostral and caudal segments; and some project, via the anterior commissure, to the contralateral dorsal horn. The cytoarchitectonic studies of Rexed in the cat (the same organization pertains in primates and probably in humans) have shown that second-order neurons, the sites of synapse of afferent sensory fibers in the dorsal horn, are arranged in a series of six layers or laminae (Fig. 8-1B). Fine, myelinated (A-d) fibers terminate principally in lamina I of Rexed (marginal cell layer of Waldeyer) and also in the outermost part of lamina II; some A-d pain fibers penetrate the dorsal gray matter and terminate in the lateral part of lamina V. Unmyelinated (C) fibers terminate in lamina II (substantia gelatinosa). Yet other cells that respond to painful cutaneous stimulation are located in ventral horn laminae VII and VIII. The latter neurons are responsive to descending impulses from brainstem nuclei as well as segmental sensory impulses. From these cells of termination, second-order axons connect with ventral and lateral horn cells in the same and adjacent spinal segments and subserve both somatic and autonomic reflexes. The main bundle of secondary neurons subserving pain sensation projects contralaterally (and to a lesser extent ipsilaterally) to higher levels.
In recent years, a number of important observations have been made concerning the mode of transmission and modulation of pain impulses in the dorsal horn and brainstem. Excitatory amino acids (glutamate, aspartate) and nucleotides such as adenosine triphosphate (ATP) are the putative transmitters at terminals of primary A-d sensory afferents. Also, A-d pain afferents, when stimulated, release several neuromodulators that play a role in the transmission of pain sensation. Slower neurotransmission by C neurons involves other substances, of which the most important is the 11–amino acid peptide known as substance P. In animals, substance P has been shown to excite nociceptive dorsal root ganglion and dorsal horn neurons; furthermore, destruction of substance P fibers produces analgesia. In patients with the rare condition of congenital neuropathy and insensitivity to pain, there is a marked depletion of dorsal horn substance P.
A large body of evidence indicates that opiates are important modulators of pain impulses that are relayed through the dorsal horn and centers in the medulla and pons. Thus, opiates have been noted to decrease substance P; at the same time, flexor spinal reflexes, which are evoked by segmental pain, are reduced. Opiate receptors of three types are found on both presynaptic primary afferent terminals and postsynaptic dendrites of small neurons in lamina II. Moreover, lamina II neurons, when activated, release enkephalins, endorphins, and dynorphins—all of which are endogenous, morphine-like peptides that bind specifically to opiate receptors and inhibit pain transmission at the dorsal horn level. The subject of pain modulation by opiates and endogenous morphine-like substances is elaborated further on.
Spinal Afferent Tracts for Pain
Lateral Spinothalamic Tract As indicated above, axons of secondary neurons that subserve pain sensation originate in laminae I, II, V, VII, and VIII of the spinal gray matter. The principal bundle of these axons decussates in the anterior spinal commissure and ascends in the anterolateral fasciculus to terminate in several brainstem and thalamic structures (Fig. 8-2). It is of clinical consequence that the axons from each dermatome decussate one to three segments above the level of root entry; in this way a discrete lesion of the lateral spinal cord creates a loss of pain and thermal sensation of the contralateral trunk, the dermatomal level of which is two to three segments below that of the spinal cord lesion. As the ascending fibers cross the cord, they are added to the inner side of the spinothalamic tract (the principal afferent pathway of the anterolateral fasciculus), so that the longest fibers from the sacral segments come to lie most superficially and fibers from successively more rostral levels occupy progressively deeper positions (Fig. 8-3). This somatotopic arrangement is of importance to the neurosurgeon insofar as the depth to which the funiculus is cut will govern the level of analgesia that is achieved; for the neurologist, it provides an explanation of the “sacral sparing” of sensation created by centrally placed lesions of the spinal cord.




Figure 8-2 The main somatosensory pathways. Offsets from the ascending anterolateral fasciculus (spinothalamic tract) to nuclei in the medulla, pons, and mesencephalon and nuclear terminations of the tract are indicated in Fig. 8-4.






Figure 8-3 Spinal cord showing the segmental arrangement of nerve fibers within major tracts. On the left side are indicated the “sensory modalities” that appear to be mediated by the two main ascending pathways. Note the broad zone close to the gray matter occupied by propriospinal fibers. C, cervical; L, lumbar; S, sacral; Th, thoracic. (Adapted by permission from Brodal A: Neurological Anatomy, 3rd ed. New York, Oxford University Press, 1981.)






Figure 8-4 The paleospinothalamic tract is illustrated on the right. This is a slow-conducting multineuron system that mediates poorly localized pain from deep somatic and visceral structures. On the left is the major descending inhibitory pathway, derived mainly from the periaqueductal gray matter and brainstem raphe nuclei. It modulates pain input at the dorsal horn level.


Other Spinocerebral Afferent Tracts In addition to the lateral spinothalamic tract—the fast-conducting pathway that projects directly to the thalamus—the anterolateral fasciculus of the cord contains several more slowly conducting, medially placed systems of fibers. One such group of fibers projects directly to the reticular core of the medulla and midbrain and then to the medial and intralaminar nuclei of the thalamus; this group of fibers is referred to as the spinoreticulothalamic or paleospinothalamic pathway (Fig. 8-4). At the level of the medulla, these fibers synapse in the nucleus gigantocellularis; more rostrally, they connect with nuclei of the parabrachial region, midbrain reticular formation, periaqueductal gray matter, and hypothalamus. A second, more medially placed pathway ascends to the brainstem reticular core via a series of short interneuronal links. It is not clear whether these spinoreticular fibers are collaterals of the spinothalamic tracts, as Cajal originally stated, or whether they represent an independent system, as more recent data seem to indicate. Probably both statements are correct. There is also a third, direct spinohypothalamic pathway. All three spinoreticular fiber systems lie in the posteromedial part of the lateral column. The conduction of diffuse, poorly localized pain arising from deep and visceral structures (gut, periosteum) has been ascribed to these pathways. Melzack and Casey have proposed that this fiber system (which they refer to as paramedian), with its diffuse projection via brainstem and thalamus to the limbic and frontal lobes, subserves the affective aspects of pain, i.e., the unpleasant feelings engendered by pain. It is evident that these spinoreticulothalamic pathways continue to evoke the psychic experience of pain even when the direct (anterolateral) spinothalamic pathways have been interrupted. However, it is the lateral pathway, which projects to the ventroposterolateral (VPL) nucleus of the thalamus and thence to discrete areas of the sensory cortex, that subserves the sensory-discriminative aspects of pain, i.e., the processes that underlie the localization, quality, and possibly the intensity of the noxious stimulus. Also, the pathways for visceral pain from the esophagus, stomach, small bowel, and proximal colon are carried largely in the vagus nerve and terminate in the nucleus of the solitary tract (NTS) before projecting to the thalamus, as described below. Other abdominal viscera still activate the NTS when the vagus is severed in animals, probably passing through the splanchnic plexus.
It should be emphasized that the foregoing data concerning the cells of termination of cutaneous nociceptive stimuli and the cells of origin of ascending spinal afferent pathways have all been obtained from studies in animals (including monkeys). In humans, the cells of origin of the long (direct) spinothalamic tract fibers have not been fully identified. Information about this pathway in humans has been derived from the study of postmortem material and from the examination of patients subjected to anterolateral cordotomy for intractable pain. As mentioned above, unilateral section of the anterolateral funiculus produces a relatively complete loss of pain and thermal sense on the opposite side of the body, extending to a level two or three segments below the lesion. After a variable period of time, pain sensation usually returns, probably being conducted by pathways that lie outside the anterolateral quadrants of the spinal cord and which gradually increase their capacity to conduct pain impulses. One of these is a longitudinal polysynaptic bundle of small myelinated fibers in the center of the dorsal horn (the dorsal intracornual tract); another consists of axons of lamina I cells that travel in the dorsal part of the lateral funiculus.
Thalamic Terminus of Pain Fibers
The direct spinothalamic fibers separate into two bundles as they approach the thalamus. The lateral division terminates in the ventrobasal and posterior groups of nuclei. The medial contingent terminates mainly in the intralaminar complex of nuclei and in the nucleus submedius. Spinoreticulothalamic (paleospinothalamic) fibers project onto the medial intralaminar (primarily parafascicular and centrolateral) thalamic nuclei; i.e., they overlap with the terminations of the medially projecting direct spinothalamic pathway. Projections from the dorsal column nuclei, which have a modulating influence on pain transmission, are mainly to the ventrobasal and ventroposterior group of nuclei. Each of the four thalamic nuclear groups that receives nociceptive projections from the spinal cord has a distinct cortical projection, and each is thought to play a different role in pain sensation (see below).
One practical conclusion to be reached from these anatomic and physiologic studies is that at thalamic levels, fibers and cell stations transmitting the nociceptive impulses are not organized into discrete loci. In general, neurophysiologic evidence indicates that as one ascends from peripheral nerve to spinal, medullary, mesencephalic, thalamic, and limbic levels, the predictability of neuron responsivity to noxious stimuli diminishes. Thus it comes as no surprise that neurosurgical procedures for interrupting afferent pathways become less and less successful at progressively higher levels of the brainstem and thalamus.
Thalamocortical Projections
The ventrobasal thalamic complex and the ventroposterior group of nuclei project to two main cortical areas: the primary sensory (postcentral) cortex (a small number terminate in the precentral cortex) and the upper bank of the sylvian fissure. These cortical areas are described more fully in Chap. 9, but it can be stated here that they are concerned mainly with the reception of tactile and proprioceptive stimuli and with all discriminative sensory functions, including pain. The extent to which either cortical area is activated by thermal and painful stimuli is uncertain. Certainly, stimulation of these (or any other) cortical areas in a normal, alert human being does not produce pain. The intralaminar nuclei, which also project to the hypothalamus, amygdaloid nuclei, and limbic cortex, probably mediate the arousal and affective aspects of pain and the autonomic responses.
Thalamic and cerebral cortical localization of visceral sensation is not well known. However, cerebral evoked potentials and increased cerebral blood flow (by PET studies) have been demonstrated in the thalamus and pre- and postcentral gyri of patients undergoing rectal balloon distention (Silverman et al; Rothstein et al).
Descending Pain-Modulating Systems
Of great importance was the discovery of a system of descending fibers and way stations that modulate activity in nociceptive pathways. The one system that has been studied most extensively emanates from the frontal cortex and hypothalamus and projects to cells in the periaqueductal region of the midbrain and then passes to the ventromedial medulla. From there it descends in the dorsal part of the lateral fasciculus of the spinal cord to the posterior horns (laminae I, II, and V; see further discussion under “Endogenous Pain-Control Mechanisms” and Fig. 8-5). Several other descending pathways, noradrenergic and serotoninergic, arise in the locus ceruleus, dorsal raphe nucleus, and nucleus reticularis gigantocellularis and are also important modifiers of the nociceptive response. The significance of these pain-modulating pathways is discussed further on.

Parkinson Disease

Maurice Victor, Allan H. Ropper, Raymond D. Adams


This common disease, known since ancient times, was first cogently described by James Parkinson in 1817. In his words, it is characterized by “involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forward, and to pass from a walking to a running pace, the senses and intellect being uninjured.” Strangely, his essay contains no reference to rigidity or to slowness of movement, and it stresses unduly the reduction in muscular power. The same criticism can be leveled against the term paralysis agitans, which appeared for the first time in 1841, in Marshall Hall's textbook Diseases and Derangements of the Nervous System.
Certain aspects of the natural history of the disease are of interest. As a rule, it begins between 40 and 70 years of age, with the peak age of onset in the sixth decade. It is infrequent before 30 years of age (only 4 of 380 cases in one series), and most series contain a somewhat larger proportion of men. Trauma, emotional upset, overwork, exposure to cold, “rigid personality,” and so on, among many other factors, have been suggested as predisposing to the disease, but there is no convincing evidence to support any such claims. The possible relationship to repeated cerebral trauma and to the “punch-drunk” syndrome (dementia pugilistica, page 944) has been particularly problematic and is unresolved despite the documentation provided by several celebrated cases (Lees). Idiopathic Parkinson disease is observed in all countries, all ethnic groups, and all socioeconomic classes, although the incidence in blacks is only one-quarter that in whites; in Asians, the incidence is one-third to one-half that in whites. A lack of concordance of Parkinson disease in twins appears to negate the role of genetic factors, but a study of dopamine metabolism utilizing PET scanning has shown that 75 percent of asymptomatic twins of Parkinson patients had evidence of striatal dysfunction and only a small portion of dizygotic twins showed these changes (Piccini et al). These data suggest a more substantial role for an inherited trait in cases of ostensibly sporadic disease. Also, Krüger and colleagues have reported a 13-fold increased susceptibility to the disease in patients who harbor a combination of a-synuclein and apolipoprotein E genotypes (see below).
While familial cases are decidedly rare, Golbe and colleagues have described two large kindreds (probably related and originating from a small town in southern Italy) in which 41 patients in four generations were affected. The illness in their cases was characteristic of Parkinson disease both clinically and pathologically, the only unusual features being a somewhat earlier onset (mean age 46 years), a relatively rapid course (10 years from onset to death), and a reported incidence of tremor in only 8 of the 41 patients. The dominantly inherited parkinsonism described by Dwork and others also differed clinically (onset in third decade, prominence of dystonia) and pathologically (absence of Lewy bodies) from classic Parkinson disease. It was in the latter kindred and in three Greek families that Polymeropoulos et al identified a locus on chromosome 4q that contained a mutation for a-synuclein, a main component of the Lewy body. Other families in which there have been mendelian patterns of inheritance are associated with gene defects at other sites (but still mostly on chromosome 4). These genetic data have been reviewed by Dunnett and Björklund.
The disease is common. In North America there are approximately 1 million patients, constituting about 1 percent of the population over the age of 65 years. The incidence in all countries where vital statistics are kept is similar. Considering its frequency, coincidence in a family on the basis of chance occurrence might be as high as 5 percent.
Clinical Features The core syndrome of expressionless face, poverty and slowness of voluntary movement, “resting” tremor, stooped posture, axial instability, rigidity, and festinating gait has been fully described in Chap. 4, and only certain diagnostic problems and variants in the clinical picture need to be considered here. The early symptoms may be difficult to perceive and are often overlooked. Advancing years have a way of rendering the spine and limbs less pliable and elastic, and in the senium the gait may become short-stepped and then reduced to a shuffle. The voice tends to become soft and monotonous. Hence it is all too easy to attribute the early symptoms of Parkinson disease to the effects of aging. For a long time the patient may not be conscious of the inroads of the disease; at first the only complaints may be of aching of the back, neck, shoulders, or hips and of vague weakness. A slight stiffness and slowness of movement or a reduction in the natural swing of one arm during walking are ignored, until one day it occurs to the physician or to a member of the family that the patient has Parkinson disease. Infrequency of blinking, as pointed out originally by Pierre Marie, is often a helpful early sign. The usual rate (12 to 20 blinks per minute) is reduced in the parkinsonian patient to 5 to 10. And with it there is a slight widening of the palpebral fissures, creating a stare (Stellwag sign). A reduction in movements of the small facial muscles imparts the characteristic expressionless (“masked”) appearance (hypomimia). When seated, the patient makes fewer small shifts and adjustments of position than the normal person (hypokinesia), and the fingers straighten and assume a flexed and adducted posture at the metacarpophalangeal joints.
The characteristic tremor, which usually involves a hand, is often listed as the initial sign; but in at least half the cases, observant family members will have remarked earlier on the patient's relative immobility and poverty of movement. Moreover, in 20 to 25 percent of cases the tremor is mild and intermittent or evident in only one finger or one hand. The tremor of the fully developed case takes several forms, as was remarked in Chap. 6. The 4-per-second “pill-rolling” tremor of the thumb and fingers is seen in only a small proportion of patients and is typically present when the hand is motionless, i.e., not used in voluntary movement (hence the term resting tremor). Complete relaxation, however, greatly reduces or abolishes the tremor, and a volitional movement usually but not always dampens it momentarily. The rhythmic beat coincides with an alternating burst of activity in agonists and antagonists in the electromyogram (EMG). The arm, jaw, tongue, eyelids, and foot are less often involved. The least degree of tremor is felt during passive movement of a rigid part (cogwheel phenomenon or Negro's sign). The tremor shows surprising fluctuations in severity and is aggravated by walking and excitement, but tremor frequency remains constant (Hunker and Abbs). One side of the body is typically involved before the other, and the tremor then remains asymmetrical as the illness advances.
Lance and associates have called attention to another common type of tremor in Parkinson disease—a fine, 7- to 8-per-second, slightly irregular action tremor of the outstretched fingers and hands. This tremor, unlike the slower one, persists throughout voluntary movement, is not evident with the limb in a resting position, and is more easily suppressed by relaxation. Electromyographically, it lacks the alternating bursts of action potentials seen in the more typical tremor. The patient may have either type of tremor or both.
We have been less impressed with rigidity and hypertonus as important early findings. They tend to appear in the more advanced stages of the disease. Once rigidity develops, it is constantly present; it can be felt by the palpating finger and seen as a salience of muscle groups even when the patient relaxes. When the examiner passively moves the limb, a mild resistance appears from the start (without the short free interval that characterizes spasticity), and it continues evenly throughout the movement, in both flexor and extensor groups, being interrupted only by the cogwheel phenomenon. Both the rigidity and its cogwheel feature can be elicited by having the patient occupy the opposite limb with a motor task requiring some degree of concentration, such as tracing circles in the air or touching each finger to the thumb. Postural hypertonus predominates in the flexor muscles of trunk and limbs and confers upon the patient the characteristic flexed posture. Particulars of the parkinsonian disorders of muscle tone, stance, and gait are discussed further in Chap. 4 and Chap. 7.
Regarding the quality of volitional and postural movements, a few additional points should be made. The patient is slow and ineffective in attempts to deliver a quick hard blow; he cannot complete a quick (ballistic) movement by a single burst of agonist-antagonist-agonist sequence of energizing activity, like the normal person; several bursts are needed (Hallett and Khoshbin). Alternating movements, at first successful, become progressively impeded and finally are blocked completely or adopt the rhythm of the patient's tremor. Also, the patient has difficulty in executing two motor acts simultaneously. Originally the impaired facility of movement was attributed to rigidity, but the observation that appropriately placed surgical lesions can abolish rigidity without affecting the disorder of movement refutes this interpretation. Thus the difficulty is not one of rigidity but one of bradykinesia (slowness in both the initiation and execution of movement), the extreme degree of which is akinesia. The latter deficits underlie the characteristic poverty of movement, shown by infrequency of swallowing, slowness of chewing, a limited capacity to make postural adjustments of the body and limbs in response to displacement of these parts, a lack of small “movements of cooperation” (as in arising from a chair without first adjusting the feet), absence of arm swing in walking, etc. Despite a perception of muscle weakness, the patient is able to generate normal or near-normal power, especially in the large muscles; however, in the small ones, strength is slightly diminished.
As the disorder of movement worsens, all customary activities show the effects. Handwriting becomes small (micrographia), tremulous, and cramped, as first noted by Charcot. The voice softens and the speech seems hurried and monotonous; the voice becomes less audible and finally the patient only whispers. Exceptionally, “mumbling” is an early complaint. Caekebeke and coworkers refer to the speech disorder as a “hypokinetic dysarthria”; they attribute it to respiratory, phonatory, and articulatory dysfunction. The consumption of a meal takes an inordinately long time. Each morsel of food must be swallowed before the next bite is taken. Walking becomes reduced to a shuffle; the patient frequently loses his balance, and in walking forward or backward must “chase the body's center of gravity” with a series of short steps in order to avoid falling (festination). Defense and righting reactions are faulty. Falls do occur, but surprisingly infrequently given the degree of postural instability. Gait is typically improved by sensory guidance, as by holding the patient at the elbow, whereas obstacles have the opposite effect, at times causing the patient to “freeze” in place. Difficulty in turning over in bed is a characteristic feature as the illness advances, but the patient rarely volunteers this information. Shaving or applying lipstick becomes difficult, as the facial muscles become more immobile and rigid.
Persistent extension or clawing of the toes, jaw clenching, and other fragments of dystonia may enter the picture but rarely are early findings.
As noted above, these various motor impediments and tremor characteristically begin in one limb (more often the left) and spread to one side and later to both sides, until the patient is quite helpless. Yet in the excitement of some unusual circumstance (a fire, for example), the patient is capable of brief but remarkably effective movement (kinesis paradoxica).
Regarding other elicitable neurologic signs, there is an inability to inhibit blinking in response to a tap over the bridge of the nose or glabella (Myerson sign), but grasp and suck reflexes are not present and buccal and jaw jerks are rarely enhanced. Commonly there is an impairment of upward gaze and convergence; if noted early in the disease, this raises the possibility of progressive supranuclear palsy. The bradykinesia may extend to eye movements, in that patients may show a delay in the initiation of gaze to one side, slowing of conjugate movements (decreased maximal saccadic velocity), hypometric saccades, and breakdown of pursuit movements into small saccades. There are no sensory changes. Drooling is troublesome; an excess flow of saliva has been assumed, but actually the problem is one of failure to swallow with normal frequency. Seborrhea and excessive sweating are probably secondary as well, the former due to failure to cleanse the face sufficiently, the latter to the effects of the constant motor activity. Postural instability can be elicited by tugging at the patient's shoulders from behind and noting the lack of a small step backward to maintain balance. The tendon reflexes vary, as they do in normal individuals, from being barely elicitable to brisk. Even when parkinsonian symptoms are confined to one side of the body, the reflexes are usually equal on the two sides, and the plantar responses are flexor. Exceptionally, the reflexes on the affected side are slightly more brisk, which raises the question of corticospinal involvement; but the plantar reflex remains flexor. In these respects, the clinical picture differs from that of corticobasal ganglionic degeneration, in which rigidity, hyperactive tendon reflexes, and Babinski signs are combined with apraxia (see further on). There is a tendency to syncope in some cases; this was found by Rajput and Rozdilsky to be related to cell loss in the sympathetic ganglia. However, syncope is never as prominent as in striatonigral degeneration.
At times, Parkinson disease is complicated by a dementia, a feature that had been commented upon by Charcot. The reported frequency of this combination varies considerably, based on the selection of patients and type of testing. An estimate of 10 to 15 percent (Mayeux et al) is generally accepted and matches our experience. The incidence increases with advancing age, approaching 65 percent in Parkinson patients above 80 years of age. In some instances of Parkinson disease with dementia, MRI reveals lesions in the cerebral white matter (in T1-weighted images) not seen in parkinsonians without dementia. The pathologic basis of the dementia in Parkinson disease is discussed below.
The overall course of the disease is quite variable. In the majority of patients, the mean period of time from inception of the disease to a chairbound state is 7.5 years (Hoehn and Yahr; Martilla and Rinne). On the other hand, as many as one-third of cases are relatively mild and remain stable for 10 years or more.
Diagnosis Early in the course of Parkinson disease, when only a slight asymmetry of stride or an ineptitude of one hand is present and tremor has yet to appear and impart the unmistakable stamp of the disease, a number of small signs already alluded to may be helpful in diagnosis. These include a reduced blink rate, the Myerson glabellar sign, a lack of arm swing, digital impedance (a tendency for rapid alternating movements to be slowed, to assume a tremor rhythm, or to be blocked altogether) and perceptible rigidity of one arm when the opposite limb is occupied in a motor task such as tracing circles in the air. Lack of a Babinski sign or of increased tendon reflexes in the affected limbs eliminates a corticospinal lesion as the cause of slowed movements, and lack of a grasp reflex helps to exclude a premotor cerebral disorder.
The main difficulty in diagnosis is to distinguish Parkinson disease from the many parkinsonian syndromes, some caused by other degenerative diseases and some by medications or toxins. Parkinson disease is far more common than any of the syndromes that resemble it. Bradykinesia and rigidity of the limbs and axial musculature are shared symptoms, but only in Parkinson disease is “resting” tremor an early sign, and it remains prominent even late in the illness.
The typical signs of Parkinson disease, when present in their entirety, impart an unmistakable clinical picture. When not all the signs are evident, there is no alternative but to re-examine the patient at several-month intervals until it is clear that Parkinson disease is present or until the signature of another degenerative process becomes evident (e.g., vertical gaze impairment in progressive supranuclear palsy; dysautonomia with fainting, bladder, or vocal cord signs in striatonigral degeneration; early and rapidly evolving dementia or psychosis in Lewy body disease, or apraxia in corticobasal ganglionic degeneration). If the patient's symptoms warrant, a beneficial response to levodopa also gives a reasonably secure although not entirely conclusive indication of the presence of Parkinson disease. The other parkinsonian syndromes are for the most part unchanged by the drug.
As pointed out on page 813, the epidemic of encephalitis lethargica (von Economo encephalitis) that spread over western Europe and the United States after the First World War left great numbers of parkinsonian cases in its wake. No definite instance of this form of encephalitis had been recorded before the period 1914–1918, and virtually none has been seen since 1930; hence postencephalitic parkinsonism is no longer a diagnostic consideration. Rarely, a Parkinson-like syndrome has been described with other forms of encephalitis (particularly with Japanese B virus and eastern equine encephalitis).
In England and Europe an “arteriopathic” or “arteriosclerotic” form of Parkinson disease was at one time much diagnosed, but we have never been convinced of its reality. Pseudobulbar palsy from a series of lacunar infarcts or from Binswanger disease (page 878) can cause a clinical picture simulating certain aspects of Parkinson disease, but unilateral and bilateral corticospinal tract signs, hyperactive facial reflexes, spasmodic crying and laughing, and other characteristic features distinguish spastic bulbar palsy from Parkinson disease. Of course, the parkinsonian patient in advancing years is not impervious to cerebrovascular disease, and the two conditions then overlap.
Normal-pressure hydrocephalus can create a syndrome that resembles Parkinson disease, particularly in regard to gait and postural instability and at times to bradykinesia; but rigid postures, slowness of alternating movements, hypokinetic ballistic movements, and resting tremor are not part of the clinical picture.
Senile (familial or essential) tremor is distinguished by its fine, quick quality, its tendency to become manifest during volitional movement and to disappear when the limb is in a position of repose, and the lack of associated slowness of movement, flexed postures, etc. The head is more often involved in senile tremor than in Parkinson disease. Some of the slower, alternating forms of essential tremor are difficult to distinguish from parkinsonian tremor, and one can only wait to see whether it is the first manifestation of Parkinson disease.
Progressive supranuclear palsy (see further on) is characterized by rigidity and dystonic postures of the neck and shoulders, a staring and immobile countenance, and a tendency to topple when walking—all of which are suggestive of Parkinson disease. Inability to produce vertical saccades and, later, paralysis of upward and downward gaze and eventually of lateral gaze with retention of reflex eye movements establish the diagnosis in most cases. Strict adherence to the diagnostic criteria for Parkinson disease also permits its differentiation from corticostriatospinal, striatonigral, and corticobasal ganglionic degeneration and Machado-Joseph disease—all of which are discussed in other parts of this chapter.
Paucity of movement, unchanging attitudes and postural sets, and a slightly stiff and unbalanced gait may be observed in patients with an anergic or hypokinetic (“retarded”) type of depression. Since as many as 25 to 30 percent of parkinsonian patients are depressed, the separation of these two conditions may then be difficult (see page 1612). The authors have seen patients who were called parkinsonian by competent neurologists but whose movements became normal when antidepressant medication or electroconvulsive therapy was given.
The rapid onset of the Parkinson syndrome, especially in conjunction with other medical diseases, should always raise the suspicion of drug effects; phenothiazines, haloperidol, and the neuroleptics pimozide and metoclopramide, used at times as antiemetics, all cause a slight masking of the face, stiffness of the trunk and limbs, lack of arm swing, fine tremor of the hands, and mumbling speech. They may also evoke an inner restlessness, a “muscular impatience,” an inability to sit still, and a compulsion to move about much like that which occurs at times in the parkinsonian patient (akathisia; page 118). Spasms of the neck, face, and jaw muscles (open mouth, protruded tongue, retrocollis or torticollis, grimacing) may also be provoked by such drugs. A mild, localized rigidity of an arm due to local tetanus was studied by R. D. Adams) in a patient who had been referred as a case of acute parkinsonism.
All in all, if one adheres to the strict definition of Parkinson disease—bradykinesia, “resting” tremor, postural changes and instability, cogwheel rigidity, and response to L-dopa—errors in diagnosis are few. Yet in a series of 100 cases, studied clinically and pathologically by Hughes and associates, the diagnosis was inaccurate in 25 percent. The reasons are that about this number of Parkinson patients do not have the characteristic tremor and about 10 percent do not respond to L-dopa. These authors noted that early dementia and autonomic disorder and the presence of ataxia and corticospinal signs were reliable exclusion criteria.
Pathology and Pathogenesis It is now accepted that a loss of pigmented cells in the substantia nigra and other pigmented nuclei (locus ceruleus, dorsal motor nucleus of the vagus) is the most constant finding in both idiopathic and postencephalitic Parkinson disease. The substantia nigra is visibly pale to the naked eye; microscopically, the pigmented nuclei show a marked depletion of cells and replacement gliosis, findings that enable one to state with confidence that the patient must have suffered from Parkinson disease. Also, many of the remaining cells of the pigmented nuclei contain eosinophilic cytoplasmic inclusions with a faint halo, called Lewy bodies. These are seen in practically all cases of idiopathic Parkinson disease. They were present in a few postencephalitic cases as well, but in the latter neurofibrillary tangles were more usual. However, both of these cellular abnormalities appear occasionally in the substantia nigra of aging, nonparkinsonian individuals. Possibly the individuals with Lewy bodies would have developed Parkinson disease if they had lived a few more years. Noteworthy is the finding by McGeer et al that nigral cells normally diminish with age, from a maximal complement of about 425,000 to 200,000 at age 80. Tyrosine-hydroxylase, the rate-limiting enzyme for dopamine, diminishes correspondingly. These authors found that in patients with Parkinson disease, the number of pigmented neurons was reduced to about 30 percent of that in age-matched controls. Using more refined counting techniques, Pakkenberg and coworkers estimated the average total number of pigmented neurons to be 550,000 and to be reduced by 66 percent in Parkinson patients. The number of nonpigmented neurons in their control subjects was 260,000 and again was reduced in patients by 24 percent. Thus, aging contributes importantly to nigral cell loss, but the cell depletion is so much more marked in Parkinson disease that some factor other than aging must also be operative.
Other depletions of cells are widespread, but they have not been quantitatively evaluated and their significance is less clear. There is neuronal loss in the mesencephalic reticular formation, near the substantia nigra. These cells project to the thalamus and limbic lobes. In the sympathetic ganglia, there is slight neuronal loss and Lewy bodies are seen; this is also true of the pigmented nuclei of the lower brainstem as well as of the putamen, caudatum, pallidum, and substantia innominata. Dopaminergic neurons that project to cortical and limbic structures, to caudate nucleus and nucleus accumbens, and to periaqueductal gray matter and spinal cord are affected little or not at all. The lack of a consistent lesion in either the striatum or the pallidum is noteworthy in view of the reciprocal connections between the striatum and the substantia nigra and the depletion of striatal dopamine that characterizes the parkinsonian state.
The statistical data relating Parkinson and Alzheimer diseases are difficult to assess because of different methods of examination from one reported series to another (Quinn et al). Nevertheless, the overlap of the two diseases is more than fortuitous, as indicated in an earlier part of this chapter. In our own pathologic material, the majority of the demented Parkinson patients showed Alzheimer-type changes, but there were several in whom few plaques or neurofibrillary changes could be found or in whom the cortical neuronal loss was accompanied by a widespread distribution of Lewy bodies (Lewy body dementia, discussed earlier, on page 1120).
Of great interest in recent years has been the observation, both in human opiate addicts and in monkeys, that a neurotoxin (known as MPTP) can produce irreversible signs of parkinsonism and selective destruction of cells in the substantia nigra (as described on page 105). The toxin, ingested by persons who self-administered an analogue of meperidine, was shown to bind with high affinity to an extraneural enzyme, monoamine oxidase, which transformed it to a toxic metabolite, pyridinium MPP+. The latter is bound by the melanin in the dopaminergic nigral neurons in sufficient concentration to destroy the cells. The precise mechanism by which MPTP produces the Parkinson syndrome is unsettled. One hypothesis is that the inner segment of the globus pallidus is rendered hyperactive because of reduction of the GABA influence of the subthalamic nucleus. The theory of an environmental toxin as a cause of Parkinson disease has been greatly stimulated by the MPTP findings. (Uhl et al; see also the review by Snyder and D'Amato). The disease is more frequent in industrialized countries and agrarian areas in which toxins are commonly used, but its universal occurrence would militate against any one toxin. To date, no chemical toxin, heavy metal, etc., has been incriminated in the causation of Parkinson disease.
Provocative recent discoveries have involved the synaptic protein alpha-synuclein, the main component of Lewy bodies in both the sporadic and inherited forms of Parkinson disease as well as in Lewy body disease. Synuclein normally exists in a soluble unfolded form, but in high concentrations it forms aggregates of neurofilaments to form the Lewy body. Immunostaining techniques have also disclosed less specific proteins, such as ubiquitin and tau, within the Lewy bodies. Furthermore, as noted earlier, in four unrelated families with the rare autosomal dominant form of Parkinson disease, a mutation on chromosome 4 has been found that codes for an aberrant form of synuclein (Polymeropoulos et al). However, no gene error relating to synuclein has been found in patients with sporadic Parkinson disease and the misfolding of synuclein as a cause of the common sporadic disease is only a speculation.
Treatment Although there is no known treatment that will halt or reverse the neuronal degeneration that presumably underlies Parkinson disease, methods are now available that afford considerable relief from symptoms. Treatment can be medical or surgical, although reliance is placed mainly on drugs, particularly on L-dopa.
At present, L-dihydroxyphenylalanine (L-dopa) is unquestionably the most effective agent for the treatment of Parkinson disease, and the therapeutic results, even in those with far-advanced disease, are much better than have been obtained with other drugs, even newer ones that act as dopamine agonists. As mentioned earlier, some degree of response is so nearly universal that many neurologists use it as a diagnostic criterion. The theoretical basis for the use of this compound rests on the observation that striatal dopamine is depleted in patients with Parkinson disease but that the remaining nigral cells are capable of producing dopamine by taking up its precursor, L-dopa. The neurons of the striatum that are targets of nigral projections are not depleted and remain receptive to any dopamine released by nigral cells. Over time, however, the number of remaining nigral neurons that convert L-dopa to dopamine becomes inadequate and the receptivity to dopamine of the striatal target neurons becomes excessive, possibly as a result of denervation hypersensitivity; this results in both a reduced response to L-dopa and to paradoxical and excessive movements (dyskinesias) with each dose.
By combining a decarboxylase inhibitor (carbidopa or benserizide), which is unable to penetrate the central nervous system (CNS), with L-dopa, the decarboxylation of L-dopa to dopamine is greatly diminished in peripheral tissues. This permits a greater proportion of L-dopa to reach nigral neurons and, at the same time, a reduction in the peripheral side effects of L-dopa and dopamine (nausea, hypotension, etc.). Combinations of levodopa-carbidopa are available in a 10:1 or 4:1 ratio and the benserizide combination in a 4:1 ratio. The initial dose of levodopa-carbidopa is typically one-half of a 100-mg/25-mg tablet given two or three times daily and increased slowly until optimum improvement is achieved, usually up to a maximum of two tablets administered four times daily, or a similar dose of the 250-mg/25-mg combination. A newer class of catechol-O-methyltransferase (COMT) inhibitors, typified by tolcapone, extends the plasma half-life and the duration of L-dopa effect by preventing its breakdown (as opposed to increasing its bioavailability as with carbidopa). But these drugs require further study, for there have been several complications and rare unexplained deaths after their use.
Long-acting preparations of levodopa-carbidopa may reduce dyskinesias in some patients (Hutton and Morris) in the advanced stages of disease, but our experience with these drugs given earlier in the course has been less impressive. In transferring a patient from conventional L-dopa/carbidopa preparations to the long-acting formulation, the frequency of administration can be roughly halved while the total amount of L-dopa initially remains unchanged. The absorption of the long-acting drug, however, is approximately 70 percent, often necessitating a slight increase in total dose. To facilitate the treatment of morning rigidity and tremor, the long-acting tablet can be broken in half to speed absorption or a small dose of conventional medication can be given at the same time. Often some degree of dyskinesia must be accepted as the price to be paid for the therapeutic effect.
Bromocriptine, pergolide, and lisuride are synthetic ergot derivatives whose action in Parkinson disease is explained by their direct stimulating effect on dopamine (D2) receptors, which are located on corticostriate neurons, thus bypassing the depleted nigral neurons. The newer nonergot dopamine agonists ropinirole and pramipexole seem to be tolerated well and have a duration of effectiveness similar to that of other D2 agonists; these agents are very helpful in supplementing L-dopa and are now increasingly popular as the sole therapeutic agent before L-dopa is instituted. Rascol and colleagues have reported that the use of ropinirole during the first 5 years of the parkinsonian illness controlled the symptoms satisfactorily and, in addition, reduced the incidence of dyskinesias, compared to treatment with L-dopa. Why dyskinesias are less frequent with ropinirole than with L-dopa is not known. Bromocriptine should be introduced cautiously, 7.5 to 10 mg daily in three to four divided doses, and the dosage increased very slowly to an optimal level of 40 to 60 mg daily; levodopa-carbidopa should be reduced concomitantly by 50 percent. A dose of 5 to 10 mg of bromocriptine has about the equivalent effect of 100/25 mg levodopa/carbidopa. It has a longer duration of action than L-dopa and causes nausea and vomiting less often, but otherwise the action and side effects of the two drugs are much the same. Even small doses of these drugs, when first introduced, may induce a prolonged episode of hypotension. Our observations are in agreement with those of Marsden, who found that of 263 patients, all but 82 had abandoned one of the ergot dopamine agonists after 6 months because of lack of effect or adverse reactions. Nevertheless, a proportion of patients continue to benefit for up to 3 years. Ropinirole and pramipexole are useful in smoothing the effects of L-dopa and allowing a reduction in its dose. As with the ergot-based dopamine agonists, they can be utilized in some patients as the sole treatment for a limited time. They may produce sudden and unpredictable sleepiness, similar to narcolepsy, and patients should be warned of this possibility in relation to driving. More data are required to judge the efficacy of initiating therapy with a dopamine agonist rather than with L-dopa combinations.
Because of the side effects of levodopa and of dopaminergic agents, particularly in older patients, some neurologists avoid all types of pharmacotherapy if the patient is in the early phase of the disease and the parkinsonian symptoms are not troublesome. When the symptoms become more annoying, initial therapy with either amantadine 100 mg bid or an anticholinergic medication may be advised. Only when the symptoms begin to interfere with work and social life or falling becomes a threat is a carbidopa/levodopa preparation introduced, and then at the lowest possible dose—10/100 mg bid or tid. This dose is slowly increased until maximal benefit is achieved.
Another approach, now controversial, has been to initiate the treatment of new cases of Parkinson disease with the monoamine oxidase inhibitor selegiline, 5 mg bid, and to continue its use until symptoms become disabling, at which point L-dopa or a dopamine agonist is introduced. Selegiline inhibits the intracerebral metabolic degradation of dopamine, and clinical trials conducted by the Parkinson Study Group have suggested that it slows progression of the disease in its early stages. Subsequent observations, however, have not confirmed the view that selegiline markedly alters the natural course of the disease, and we use it infrequently.
As already mentioned, L-dopa is not without significant side effects, so that its use is limited in some circumstances. Approximately two-thirds of patients tolerate the drug initially and experience few serious adverse effects; one-third will show dramatic improvement, especially in hypokinesia and tremor. Many patients are at first troubled by nausea, especially if the medication is not taken with meals, and a few have orthostatic hypotensive episodes. Nausea usually disappears after several weeks of continued use or can be allayed by the specific dopaminergic chemoreceptor antagonist domperidone. Coincident psychiatric symptoms may also present problems and are to be expected in 15 to 25 percent of patients, particularly in the elderly. Depression is occasionally a serious problem, even to the point of suicide; delusional thinking may occur in these circumstances. This combination of movement and psychiatric disorders is difficult to treat, and one must institute an antidepressant regimen or one of the newer class of antipsychotic medications that are associated with few extrapyramidal side effects, as described below and in Chap. 50. Trazodone has been helpful in treating depression and insomnia, which may be a major problem. The selective serotonin reuptake inhibitors are useful in apathetic depressions, but some patients report worsening of parkinsonian symptoms. Excitement and aggressiveness appear in a few. A return of libido may lead to sexual assertiveness.
Confusion and outright psychosis (hallucinations and delusions), seen in advanced cases of Parkinson disease when high doses of L-dopa are required, is first treated by attempting to reduce the dose of the drug. If this is not possible, the atypical neuroleptics olanzapine, clozapine, risperidone, or quetiapine in low doses are often successful (Friedman and Lannon). The side effects of these drugs include sleepiness, orthostatic hypotension, sialorrhea, and the most serious, agranulocytosis, requiring regular monitoring of the blood count. Clozapine has been said to provide an additional benefit of suppressing dyskinesias in advanced Parkinson disease (Bennett et al), but it requires weekly surveillance of the blood count because of the idiosyncratic occurrence of agranulocytosis in up to 2 percent of patients. Although useful in the treatment of frankly psychotic patients, these drugs tend to be far less effective once dementia has supervened. The anticonvulsant valproate is also said to be useful in this circumstance, but our experience with this drug has not been as favorable as with clozapine. Despite their lesser tendency to produce rigidity, olanzapine and probably the other similar agents in high doses eventually worsen motor disability.
The most common and troublesome effects of L-dopa, requiring individualization of therapy, are end-of-dose failure, the “on-off” phenomenon, and the induction of involuntary movements—restlessness, head wagging, grimacing, lingual-labial dyskinesia, and choreoathetosis and dystonia of the limbs, neck, and trunk. The on-off phenomenon refers to an unpredictable change in the patient, in a matter of minutes or from one hour to the next, from a state of relative mobility to one of complete or nearly complete immobility. These disorders eventually appear in about 75 percent of patients within 5 years. Above a certain daily dose, which varies from patient to patient, very few patients escape these effects, forcing a reduction in dosage.
If involuntary movements are induced by relatively small doses of L-dopa, the therapeutic effect may be enhanced to some extent by the addition of other dopaminergic agents, such as pergolide, bromocriptine, or the newer nonergot preparations, such as ropinirole and pramipexole (see below) and, to some extent, amantadine. The use of long-acting preparations of L-dopa may also be helpful in reducing dyskinesias, as mentioned above. Amantadine, an antiviral agent, is thought to act by releasing dopamine from striatal neurons; it also has an anticholinergic property. It is given in doses of 50 to 100 mg three times daily. Its benefit appears almost immediately but tends to be slight. In addition to anticholinergic symptoms (dry mouth, etc.), the side effects are similar to those of L-dopa but are much milder. Edema of the legs has been troublesome in some patients. However, amantadine is effective in combination with L-dopa and may reduce the dyskinesias and motor fluctuations associated with advanced disease (Verhagen Metman et al). Given alone or in combination with L-dopa, it offers a modest alternative treatment for patients with early Parkinson disease or those who are having untoward effects with standard doses of L-dopa.
The notion that the administration of L-dopa early in the disease might reduce the period over which it remains effective has been largely dispelled, but some experts continue to adhere to this idea. Cedarbaum et al, who reviewed the course of the illness in 307 patients over a 7-year period, found no evidence that the early initiation of L-dopa treatment predisposes to the development of motor response fluctuations, dyskinesia, and dementia. Also, the large multicenter study reported by Diamond et al indicated that patients who were given L-dopa early in the disease actually survived longer and with less disability than those who were started late.
Anticholinergic agents have long been in use and are still given occasionally, either in conjunction with L-dopa or to patients who cannot tolerate the latter drug. Several synthetic preparations are available, the most widely used being trihexyphenidyl (Artane) and benztropine mesylate (Cogentin) and amantadine (see above). When tremor is the most prominent symptom, we have had success with the related drug ethopropazine (Parsidol, Parsitan in Canada). In order to obtain maximum benefit from the use of these drugs, they should be given in gradually increasing dosage to the point where toxic effects appear: dryness of the mouth (which can be beneficial when drooling of saliva is a problem), blurring of vision from pupillary mydriasis (for which corrective glasses may be indicated), constipation, and sometimes urinary retention (especially with prostatism). Unfortunately, mental slowing, confusional states, hallucinations, and impairment of memory—especially in patients with already impaired mental function—are frequent side effects of these drugs and sharply limit their usefulness. Ethopropazine, 50 to 200 mg daily, is given in divided doses. We have effectively managed cases of isolated parkinsonian tremor in young patients using anticholinergic drugs alone. The optimum dosage level is the point at which the greatest relief from tremor is achieved within the limits of tolerable side effects. Occasionally, further benefit may accrue from the addition of one of the antihistaminic drugs, such as diphenhydramine or phenindamine. An important note of warning: anticholinergic agents or L-dopa should not be discontinued abruptly in advanced cases. If this is done, the patient may become totally immobilized by a sudden and severe increase of tremor and rigidity; rarely, a neuroleptic syndrome has been induced by such withdrawal.
Long-term treatment with L-dopa or dopamine receptor agonists has not prevented the slow advance of the disease. With progressive loss of nigral cells, there is an increasing inability to store L-dopa and periods of drug effectiveness become shorter. In some instances, the patient becomes so sensitive to L-dopa that as slight an excess as 50 to 100 mg will precipitate choreoathetosis; if the dose is lowered by the same amount, the patient may develop disabling rigidity. With the end-of-dose loss of effectiveness and on-off phenomenon, which with time become increasingly frequent and unpredictable, the patient may experience pain, respiratory distress, akathisia, depression, anxiety, and even hallucinations. Some patients function quite well in the morning and much less well in the afternoon, or vice versa. In such cases, and for end-of-dose and on-off phenomena, one must titrate the dose of L-dopa and utilize more frequent doses during the 24-h day; combining it with a dopamine agonist or use of the long-acting preparations may be helpful. Sometimes temporarily withdrawing L-dopa and at the same time substituting other medications will control the on-off phenomenon.
Based on the hypothesis that alimentary-derived amino acids antagonize the clinical effects of L-dopa, the use of a low-protein diet has been advocated as a means of controlling the motor fluctuations described above (Pincus and Barry). Symptoms can often be reduced by the simple expedient of eliminating dietary protein from breakfast and lunch. Moreover, this dietary regimen may permit the patient to reduce the total daily dose of L-dopa. Such dietary manipulation is worth trying in appropriate patients; it is not harmful, and most of our patients who have persisted with this diet have reported improvement in their symptoms or an enhanced effect of L-dopa.
Surgical Measures Until recently, success with L-dopa had practically replaced the use of ablative surgical therapy. The latter involves the stereotactic placement of lesions in either the globus pallidus, ventrolateral thalamus, or subthalamic nucleus, contralateral to the side of the body chiefly affected. The best results have been obtained in relatively young patients, in whom unilateral tremor or rigidity, rather than akinesia, are the predominant symptoms. The symptoms that have responded least well to operation (or to treatment with L-dopa) are postural imbalance and instability, paroxysmal akinesia, bladder and bowel disturbances, dystonia, and speech difficulties.
In the last decade, through the work of Laitinen and others, this mode of therapy has been revived and expanded. Under precise stereotactic control and with placement of a lesion in the posterior and ventral (medial) part of the globus pallidus, improvement of contralateral parkinsonian symptoms has been effected more reliably than in the past. Also, postoperatively, there is an enhanced responsiveness to L-dopa and a reduction of drug-induced dyskinesias, To what extent the improvement will be sustained remains to be determined, since the disease process continues to advance. In patients who have been studied for more than a few years, the beneficial effects on dyskinesias contralateral to the operation are sustained to some extent, but not in the ipsilateral limbs. The improvement in “off-state” bradykinesia is lost after 2 or so years and any betterment in axial rigidity and imbalance is lost in many patients within a year of operation, as summarized by Gregory and by Lang et al. In the only randomized trial to date that has compared pallidotomy to continued medical treatment of patients with dyskinesias, bradykinesia, or severe fluctuations in response to L-dopa, de Bie and colleagues demonstrated a clear improvement in motor function after surgery, while the group treated with medication continued to worsen. Using patient diaries, they estimated that dyskinesias were reduced 50 percent contralateral to the operated side and that parkinsonian symptoms during the “off phase” were improved by 30 to 50 percent. These improvements do not persist indefinitely and are in part due to the ability to reduce the dose of L-dopa. It should be mentioned that most groups have abandoned the pallidum as a surgical target in favor of the subthalamic nucleus.
Recently, through the use of implanted electrodes, the sites that are the targets of ablative procedures have been subjected to high-frequency stimulation—with virtually identical if not better results. In particular, high-frequency stimulation of the subthalamic nucleus has produced impressive improvement in all features of the disease (Limousin et al). Long-term studies are in progress to determine the persistence of these effects and their merits in comparison to ablative lesions.
The cerebral implantation of adrenal medullary tissue from 8- to 10-week-old human fetuses has provided a modest but undeniable improvement in motor function (Spencer et al), and some patients also appear to have benefited from the striatal implantation of human fetal and porcine nigral cells and autologous adrenal cells. These procedures are hampered by many difficulties, mainly in obtaining tissue and the failure of grafts to survive. Much of the original enthusiasm for these procedures has subsided, and it seems unlikely that they will have wide applicability in the treatment of Parkinson disease in the near future. Investigation into their possible usefulness continues.
Finally, in the management of the patient with Parkinson disease, one must not neglect the maintenance of optimum general health and neuromuscular efficiency by a planned program of exercise, activity, and rest; expert physical therapy and exercises such as those performed in yoga may be of help in achieving these ends. Sleep may be aided by the soporific antidepressants. Postural imbalance can be greatly mitigated by the use of a cane or walking frame. Hypotensive episodes respond to 0.5 mg of fludrocortisone (Florinef) each morning. In addition, the patient often needs much emotional support in dealing with the stress of the illness, in comprehending its nature, and in carrying on courageously in spite of it.