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.

CLINICAL AND PSYCHOLOGIC ASPECTS OF PAIN

Terminology Several terms related to the experience of altered sensations and pain are often used interchangeably, but each has specific meaning. Hyperesthesia is a general term for heightened cutaneous sensitivity. The term hyperalgesia refers to an increased sensitivity and a lowered threshold to painful stimuli. Inflammation and burns of the skin are common causes of hyperalgesia. The term hypalgesia, or hypoalgesia, refers to the opposite state—i.e., a decreased sensitivity and a raised threshold to painful stimuli. A demonstrable defect in pain perception (i.e., an elevated threshold) in the affected part, associated with an increased reaction to the stimulus once it is perceived, is sometimes referred to as hyperpathia (subtly different from hyperalgesia). In this circumstance there is an excessive reaction to all stimuli, even those (such as light touch) that normally do not evoke pain, a symptom termed allodynia. The elicited allodynic pain may have unusual features, being diffuse, modifiable by fatigue, emotion, etc., and often mixed with other sensations. The mechanism of these abnormalities is not clear, but both hyperpathia and allodynia are common features of neuropathic or neurogenic pain, i.e., pain generated by peripheral neuropathy. These features are exemplified by causalgia, a special type of burning pain that results from interruption of a peripheral nerve (see page 1438).
Skin Pain and Deep Sensibility As indicated earlier, the nerve endings in each tissue are activated by different mechanisms, and the pain that results is characterized by its quality, locale, and temporal attributes. Skin pain is of two types: a pricking pain, evoked immediately on penetration of the skin by a needle point, and a stinging or burning pain, which follows in a second or two. Together they constitute the “double response” of Lewis. Both types of dermal pain can be localized with precision. Ischemia of nerve by the application of a tourniquet to a limb abolishes pricking pain before burning pain. The first (fast) pain is thought to be transmitted by the larger (A-d) fibers and the second (slow) pain, which is somewhat more diffuse and longer-lasting, by the thinner, unmyelinated C fibers.
Deep pain from visceral and skeletomuscular structures is basically aching in quality; if intense, it may be sharp and penetrating (knife-like). Occasionally there is a burning type of pain, as in the “heartburn” of esophageal irritation and rarely in angina pectoris. The pain is felt as being deep to the body surface. The pain is diffuse and poorly localized, and the margins of the painful zone are not well delineated, presumably because of the relative paucity of nerve endings in viscera.
Referred Pain The localization of deep pain raises a number of problems. Although deep pain has indefinite boundaries, its location always bears a fixed relationship to the skeletal or visceral structure that is involved. It tends to be referred not to the skin overlying the viscera of origin but to other areas of skin innervated by the same spinal segment (or segments). This pain, projected to some fixed site at a distance from the source, is called referred pain. Small-caliber pain afferents from deep structures project to a wide range of lamina V neurons in the dorsal horn, as do cutaneous afferents. The convergence of deep and cutaneous afferents on the same dorsal horn cells, coupled with the fact that cutaneous afferents are far more numerous than visceral afferents and have direct connections with the thalamus, probably explains the phenomenon of referred pain.
Since the nociceptive receptors and nerves of any given visceral or skeletal structure may project upon the dorsal horns of several adjacent spinal or brainstem segments, the pain may be fairly widely distributed. For example, afferent pain fibers from cardiac structures, distributed through segments T1 to T4, may be projected superficially to the inner side of the arm and the ulnar border of the hand and arm (T1 and T2) as well as the precordium (T3 and T4). Once this pool of sensory neurons in the dorsal horns of the spinal cord is activated, additional noxious stimuli may heighten the activity in the whole sensory field ipsilaterally and, to a lesser extent, contralaterally.
Another peculiarity of localization is aberrant reference, explained by an alteration of the physiologic status of the pools of neurons in adjacent segments of the spinal cord. For example, cervical arthritis or gallbladder disease, causing low-grade discomfort by constantly activating their particular segmental neurons, may induce a shift of cardiac pain cephalad or caudad from its usual locale. Any pain, once it becomes chronic, may spread quite widely in a vertical direction on one side of the body. On the other hand, painful stimuli arising from a distant site exert an inhibitory effect upon segmental nociceptive flexion reflexes in the leg (DeBroucker et al). Yet another clinical peculiarity of segmental pain is the reduction in power of muscle contraction that it may cause (reflex paralysis, or algesic weakness).
In an injured nerve, the unmyelinated sprouts of A-d and C fibers become capable of spontaneous ectopic excitation and afterdischarge and susceptible to ephaptic activation (Rasminsky). They are also sensitive to locally applied or intravenous catecholamines because there are adrenergic receptors on the regenerating fibers. Either this mechanism or ephapsis (nerve-to-nerve cross-activation) is thought to be the basis of causalgia and other forms of reflex sympathetic dystrophy; either mechanism would explain the relief afforded by sympathetic block. This subject is discussed in greater detail in relation to peripheral nerve injuries (see page 1438).
Central sensory structures, e.g., sensory neurons in the dorsal horns of the spinal cord or thalamus, if chronically bombarded with pain impulses, may become autonomously overactive (being maintained in this state perhaps by excitatory amino acids) and may remain so after the peripheral pathways have been interrupted. Peripheral nerve lesions have been shown to induce enduring derangements of central (spinal cord) processing (Fruhstorfer and Lindblom). Avulsion of nerves or nerve roots may cause chronic pain even in analgesic zones (anesthesia dolorosa or “deafferentation pain”). In experimentally deafferented animals, neurons of lamina V begin to discharge irregularly in the absence of stimulation. Later the abnormal discharge subsides in the spinal cord but can still be recorded in the thalamus. Hence, painful states such as causalgia, spinal cord pain, and phantom pain are not abolished simply by cutting spinal nerves or spinal tracts.
Pain has several other singular attributes. It does not appear to be subject to negative adaptation—i.e., pain may persist as long as the stimulus is operative—whereas other somatic stimuli, if applied continuously, soon cease to be effective. Furthermore, prolonged stimulation of pain receptors sensitizes them, so that they become responsive to even low grades of stimulation, such as touch (allodynia). Another remarkable characteristic of pain is the strong feeling or affect with which it is endowed, nearly always unpleasant. Since pain has this affective element, psychologic conditions assume great importance in all persistent painful states. It is of interest that despite this strong affective aspect of pain, it is difficult to recall precisely, or to re-experience from memory, a previously experienced acute pain. Also, the patient's tolerance of pain and capacity to experience it without verbalization are influenced by race, culture, and religion. Some individuals—by virtue of training, habit, and phlegmatic temperament—remain stoic in the face of pain, and others react in an opposite fashion. Pain may be the presenting or predominant symptom in a depressive illness (Chap. 57).
Finally, a comment should be made about the devastating behavioral effects of chronic pain. To quote from Ambroise Paré, a sixteenth-century French surgeon, “There is nothing that abateth so much the strength as paine.” Continuous pain increases irritability and fatigue, disturbs sleep, and impairs appetite. Ordinarily strong persons can be reduced to a whimpering, pitiable state that may arouse the scorn of healthy observers. Patients in pain may seem irrational about their illness and make unreasonable demands on family and physician. Characteristic also is an unwillingness to engage in or continue any activity that might enhance their pain. They withdraw from the main current of daily affairs. Their thoughts and speech come to be dominated by the pain. Once a person is subjected to the tyranny of chronic pain, depressive symptoms are practically always added. The demand for and dependence on narcotics often complicate the clinical problem.

Posttraumatic Headache

A variety of nonspecific symptoms may follow closed head injury, regardless of whether consciousness is lost. Headache is often a conspicuous feature. Some authorities believe that psychological factors may be important because there is no correlation of severity of the injury with neurologic signs.
The headache itself usually appears within a day or so following injury, may worsen over the ensuing weeks, and then gradually subsides. It is usually a constant dull ache, with superimposed throbbing that may be localized, lateralized, or generalized. It is sometimes accompanied by nausea, vomiting, or scintillating scotomas.
Disequilibrium, sometimes with a rotatory component, may also occur and is often enhanced by postural change or head movement. Impaired memory, poor concentration, emotional instability, and increased irritability are other common complaints and occasionally are the sole manifestations of the syndrome. The duration of symptoms relates in part to the severity of the original injury, but even trivial injuries are sometimes followed by symptoms that persist for months.
Special investigations are usually not helpful. The electroencephalogram may show minor nonspecific changes, while the electronystagmogram sometimes suggests either peripheral or central vestibulopathy. CT scans or MRI of the head usually show no abnormal findings.
Treatment is difficult, but optimistic encouragement and graduated rehabilitation, depending on the occupational circumstances, are advised. Headaches often respond to simple analgesics, but severe headaches may necessitate treatment with amitriptyline, propranolol, or ergot derivatives.

Cluster Headache (Migrainous Neuralgia)

Cluster headache affects predominantly middle-aged men. Its cause is unclear but may relate to a vascular headache disorder or a disturbance of serotonergic mechanisms. Activation of cells in the ipsilateral hypothalamus has been shown to occur. There is often no family history of headache or migraine. Episodes of severe unilateral periorbital pain occur daily for several weeks and are often accompanied by one or more of the following: ipsilateral nasal congestion, rhinorrhea, lacrimation, redness of the eye, and Horner's syndrome. Episodes often occur at night, awaken the patient, and last for less than 2 hours. Spontaneous remission then occurs, and the patient remains well for weeks or months before another bout of closely spaced attacks occurs. During a bout, many patients report that alcohol triggers an attack; others report that stress, glare, or ingestion of specific foods occasionally precipitates attacks. In occasional patients, typical attacks of pain and associated symptoms recur at intervals without remission. This variant has been referred to as chronic cluster headache.
Examination reveals no abnormality apart from Horner's syndrome that either occurs transiently during an attack or, in longstanding cases, remains as a residual deficit between attacks.
Treatment of an individual attack with oral drugs is generally unsatisfactory, but subcutaneous (6 mg dose) or intranasal (20-mg/spray) sumatriptan or inhalation of 100% oxygen (7 L/min for 15 minutes) may be effective. Dihydroergotamine (1–2 mg intramuscularly or intravenously) is sometimes used. Butorphanol tartrate, a synthetic opioid agonist-antagonist administered by nasal spray, may also be helpful. The dose is 1 mg (one spray in one nostril), repeated after 60–90 minutes if necessary. Ergotamine tartrate is an effective prophylactic and can be given as rectal suppositories (0.5–1 mg at night or twice daily), by mouth (2 mg daily), or by subcutaneous injection (0.25 mg three times daily for 5 days per week). Various prophylactic agents that have been found to be effective in individual patients are valproate, cyproheptadine, lithium carbonate (monitored by plasma lithium determination), prednisone (20–40 mg daily or on alternate days for 2 weeks, followed by gradual withdrawal), and verapamil (240–480 mg daily). Topiramate (25–200 mg daily) or valproate (750–1500 mg daily) may also be useful in some instances.

HEADACHE

Headache is such a common complaint and can occur for so many different reasons that its proper evaluation may be difficult. Headaches of acute onset are discussed in Common Symptoms. Chronic headaches are commonly due to migraine, tension, or depression, but they may be related to intracranial lesions, head injury, cervical spondylosis, dental or ocular disease, temporomandibular joint dysfunction, sinusitis, hypertension, and a wide variety of general medical disorders. Although underlying structural lesions are not present in most patients presenting with headache, it is nevertheless important to bear this possibility in mind. About one-third of patients with brain tumors, for example, present with a primary complaint of headache.
The intensity, quality, and site of pain—and especially the duration of the headache and the presence of associated neurologic symptoms—may provide clues to the underlying cause. Migraine or tension headaches are often described as pulsating or throbbing; a sense of tightness or pressure is also common with tension headache. Sharp lancinating pain suggests a neuritic cause; ocular or periorbital icepick-like pains occur with migraine or cluster headache; and a dull or steady headache is typical of an intracranial mass lesion. Ocular or periocular pain suggests an ophthalmologic disorder; band-like pain is common with tension headaches; and lateralized headache is common with migraine or cluster headache. In patients with sinusitis, there may be tenderness of overlying skin and bone. With intracranial mass lesions, headache may be focal or generalized; in patients with trigeminal or glossopharyngeal neuralgia, the pain is localized to one of the divisions of the trigeminal nerve or to the pharynx and external auditory meatus, respectively.
Inquiry should be made of precipitating factors. Recent sinusitis or hay fever, dental surgery, head injury, or symptoms suggestive of a systemic viral infection may suggest the underlying cause. Migraine may be exacerbated by emotional stress, fatigue, foods containing nitrite or tyramine, or the menstrual period. Alcohol may precipitate cluster headache. Temporomandibular joint dysfunction causes headache or facial pain that comes on with chewing; trigeminal or glossopharyngeal neuralgia may also be precipitated by chewing, and masticatory claudication sometimes occurs with giant cell arteritis. Cough-induced headache occurs with structural lesions of the posterior fossa, but in many instances no specific cause can be found.
The timing of symptoms is important. Headaches are typically worse on awakening in patients with sinusitis or an intracranial mass. Cluster headaches tend to occur at the same time each day or night. Tension headaches are worse with stress or at the end of the day.
The onset of severe headache in a previously well patient is more likely than chronic headache to relate to an intracranial disorder such as subarachnoid hemorrhage or meningitis. The need for further investigation is determined by the initial clinical impression.
A progressive headache disorder, new onset of headache in middle or later life, headaches that disturb sleep or are related to exertion, and headaches that are associated with neurologic symptoms or a focal neurologic deficit usually require cranial MRI or CT scan to exclude an intracranial mass lesion. Signs of meningeal irritation and impairment of consciousness also indicate the need for further investigation (cranial CT scan or MRI and examination of the cerebrospinal fluid) to exclude subarachnoid hemorrhage or meningeal infection. The diagnosis and treatment of primary neurologic disorders associated with headache are considered separately under these disorders.
Tension Headache
Patients frequently complain of poor concentration and other vague nonspecific symptoms, in addition to constant daily headaches that are often vise-like or tight in quality and may be exacerbated by emotional stress, fatigue, noise, or glare. The headaches are usually generalized, may be most intense about the neck or back of the head, and are not associated with focal neurologic symptoms.
When treatment with simple analgesics is not effective, a trial of antimigrainous agents (see Migraine, below) is worthwhile. Techniques to induce relaxation are also useful and include massage, hot baths, and biofeedback. Exploration of underlying causes of chronic anxiety is often rewarding. Local injection of botulinum toxin type A is sometimes helpful, has few systemic adverse effects, and requires only infrequent administration.
Depression Headache
Depression headaches are frequently worse on arising in the morning and may be accompanied by other symptoms of depression. Headaches are occasionally the focus of a somatic delusional system. Antidepressant drugs are often helpful, as may be psychiatric consultation.
Migraine
Essentials of Diagnosis



Headache, usually pulsatile.



Nausea, vomiting, photophobia, and phonophobia are common accompaniments.



May be transient neurologic symptoms (commonly visual) preceding headache of classic migraine.



No preceding aura is common.
General Considerations
The pathophysiology of migraine probably relates to the neurotransmitter serotonin. Headache may result from release of neuropeptides acting as neurotransmitters at trigeminal nerve branches, leading to an inflammatory process; another possible mechanism involves activation of the dorsal raphe nucleus. Imaging studies have revealed changes in brainstem regions involved in sensory modulation, suggesting that migraine relates to a failure of normal sensory processing.
Clinical Findings
Classic migrainous headache is a lateralized throbbing headache that occurs episodically following its onset in adolescence or early adult life, although not all headaches that are throbbing in character are of migrainous origin. Moreover, in many cases the headaches do not conform to this pattern, although their associated features and response to antimigrainous preparations nevertheless suggest that they have a similar basis. In this broader sense, migrainous headaches may be lateralized or generalized, may be dull or throbbing, and are sometimes associated with anorexia, nausea, vomiting, photophobia, phonophobia, and blurring of vision. They usually build up gradually and may last for several hours or longer. They have been related to dilation and excessive pulsation of branches of the external carotid artery. Focal disturbances of neurologic function may precede or accompany the headaches and have been attributed to constriction of branches of the internal carotid artery. Visual disturbances occur quite commonly and may consist of field defects; of luminous visual hallucinations such as stars, sparks, unformed light flashes (photopsia), geometric patterns, or zigzags of light; or of some combination of field defects and luminous hallucinations (scintillating scotomas). Other focal disturbances such as aphasia or numbness, tingling, clumsiness, or weakness in a circumscribed distribution may also occur.
Patients often give a family history of migraine. Attacks may be triggered by emotional or physical stress, lack or excess of sleep, missed meals, specific foods (eg, chocolate), alcoholic beverages, menstruation, or use of oral contraceptives.
An uncommon variant is basilar artery migraine, in which blindness or visual disturbances throughout both visual fields are initially accompanied or followed by dysarthria, disequilibrium, tinnitus, and perioral and distal paresthesias and are sometimes followed by transient loss or impairment of consciousness or by a confusional state. This, in turn, is followed by a throbbing (usually occipital) headache, often with nausea and vomiting.
In ophthalmoplegic migraine, lateralized pain—often about the eye—is accompanied by nausea, vomiting, and diplopia due to transient external ophthalmoplegia. The ophthalmoplegia is due to third nerve palsy, sometimes with accompanying sixth nerve involvement, and may outlast the orbital pain by several days or even weeks. The ophthalmic division of the fifth nerve has also been affected in some patients. Ophthalmoplegic migraine is rare; more common causes of a painful ophthalmoplegia are internal carotid artery aneurysms and diabetes.
In rare instances, the neurologic or somatic disturbance accompanying typical migrainous headaches becomes the sole manifestation of an attack ("migraine equivalent"). Very rarely, the patient may be left with a permanent neurologic deficit following a migrainous attack.
Treatment
Management of migraine consists of avoidance of any precipitating factors, together with prophylactic or symptomatic pharmacologic treatment if necessary.
SYMPTOMATIC THERAPY
During acute attacks, many patients find it helpful to rest in a quiet, darkened room until symptoms subside. A simple analgesic (eg, aspirin, acetaminophen, ibuprofen, or naproxen) taken right away often provides relief, but treatment with extracranial vasoconstrictors or other drugs is sometimes necessary. Cafergot, a combination of ergotamine tartrate (1 mg) and caffeine (100 mg), is often particularly helpful; one or two tablets are taken at the onset of headache or warning symptoms, followed by one tablet every 30 minutes, if necessary, up to six tablets per attack and ten tablets per week. Because of impaired absorption or vomiting during acute attacks, oral medication sometimes fails to help. Cafergot given rectally as suppositories (one-half to one suppository containing 2 mg of ergotamine) or dihydroergotamine mesylate (0.5–1 mg intravenously or 1–2 mg subcutaneously or intramuscularly) may be useful in such cases. Alternatively, prochlorperazine administered rectally (25 mg suppository) or intravenously (10 mg) may be prescribed. Ergotamine-containing preparations may affect the gravid uterus and thus should be avoided during pregnancy.
Sumatriptan, which has a high affinity for serotonin1 receptors, is a rapidly effective agent for aborting attacks when given subcutaneously by an autoinjection device. It can also be taken in a nasal form, but absorption is limited, and an oral preparation is available. Zolmitriptan, another selective serotonin1 receptor agonist, has high bioavailability after oral administration and is also effective for the acute treatment of migraine. The optimal initial dose is 5 mg, and relief usually occurs within 1 hour. A newly developed nasal formulation has a rapid onset of action. A number of other triptans are available, including rizatriptan, naratriptan, almotriptan, frovatriptan, and eletriptan. Eletriptan (up to 80 mg over 24 hours) is useful for acute therapy and frovatriptan, which has a longer half-life, may be worthwhile for patients with prolonged attacks (up to 7.5 mg over 24 hours). Triptans may cause nausea and vomiting. They should probably be avoided in women who are pregnant and in patients with risk factors for stroke (such as hypertension, prior stroke or transient ischemic attack, diabetes mellitus, hypercholesterolemia, obesity). Triptans are contraindicated in patients with coronary or peripheral vascular disease. When used with selective serotonin reuptake inhibitors (SSRIs) or serotonin/norepinephrine reuptake inhibitors (SNRIs), triptans may precipitate the potentially fatal serotonin syndrome (agitation, confusion, fever, incoordination, vomiting, tachycardia, and alterations in blood pressure).
The neuroleptic droperidol is also helpful in aborting acute attacks. Metoclopramide given intravenously may be helpful and is being studied. Narcotic analgesics are needed in rare instances, such as meperidine (100 mg intramuscularly) or butorphanol tartrate by nasal spray (1 mg/spray in one nostril, repeated after 3 or 4 hours if necessary). Intravenous propofol in subanesthetic doses may help in intractable cases.
PROPHYLACTIC THERAPY
Prophylactic treatment may be necessary if migrainous headaches occur more frequently than two or three times a month. Some of the more common drugs used for this purpose are listed in Table 24–1. Their mode of action is unclear and may involve both an effect on extracerebral vasculature and a cerebral effect, eg, by stabilizing serotonergic neurotransmission. Several drugs may have to be tried in turn before the headaches are brought under control. Once a drug has been found to help, it should be continued for several months. If the patient remains headache-free, the dose can then be tapered and the drug eventually withdrawn. Botulinum toxin type A is also effective for migraine prevention in some patients; it has few systemic side effects and need only be given at intervals of several months. Although acupuncture has been widely used in the prophylaxis of migraine, a randomized controlled trial failed to show any difference between it and sham acupuncture.

TESTS FOR AUTOANTIBODIES ASSOCIATED WITH AUTOIMMUNE DISEASE

Agglutination Assays
Red cells are incubated with purified specific antigen (eg, thyroglobulin), which is adsorbed to the cell surface. The antigen-coated cells are suspended in the patient's serum, and antibody is detected by red cell agglutination. Antigen-coated latex particles are substituted for red cells in latex fixation tests.
Enzyme-Linked Immunosorbent Assay
Antibodies to various tissue antigens can be readily detected by these tests. Extracted and purified antigens are fixed to a plastic microtiter well or beads. The patient's serum is added, and excess proteins are removed by washing and centrifugation. Adherent immunoglobulin is then detected when a second antibody coupled to an enzyme (eg, alkaline phosphatase) is added. Finally, the enzyme's substrate is added; color forms and is measured in a spectrophotometer. This test can also be adapted for antigen detection by placing the antibody on the plastic surface. ELISA is very sensitive and less cumbersome than radioimmunoassay techniques.
Immunofluorescence Microscopy
This technique is most frequently used for detection of antinuclear antibody (ANA). Frozen sections of mouse liver or other substrates are cut and placed on glass slides or, alternatively, monolayers of cultured cell lines may be used. A patient's serum is placed over the sections and incubated. Fluorescein-conjugated rabbit anti-human immunoglobulin is then applied and washed. ANA specifically binds to the nucleus, and the fluorescein conjugate binds to the human antibody. Fluorescence of the cell nucleus on microscopy indicates a positive test.
Complement Fixation
Specific antigen, unknown serum, and complement are combined. Sheep red blood cells coated with anti-sheep cell antibody are added for 30 minutes at 37 °C. If antigen-specific antibody is present in the patient's serum, complement is bound and consumed, preventing lysis of sheep red cells.

Arbuckle MR et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003 Oct 16;349(16):1526–33. [PMID: 14561795]

Colglazier CL et al. Laboratory testing in rheumatic diseases: a practical review. South Med J. 2005 Feb;98(2):185–91. [PMID: 15759949

SELECTIVE IMMUNOGLOBULIN A DEFICIENCY

Selective IgA deficiency is the most common primary immunodeficiency disorder and is characterized by the absence of serum IgA with normal levels of IgG and IgM; its prevalence is about 1:500 individuals. Most persons are asymptomatic because of compensatory increases in secreted IgG and IgM. Some affected patients have frequent and recurrent infections such as sinusitis, otitis, and bronchitis. Some cases of IgA deficiency may spontaneously remit. When IgG2 subclass deficiency occurs in combination with IgA deficiency, affected patients are more susceptible to encapsulated bacteria and the degree of immune impairment can be more severe. Patients with a combined IgA and IgG subclass deficiency should be assessed for functional antibody responses to glycoprotein antigen immunization.
Atopic disease and autoimmune disorders can be associated with IgA deficiency. Occasionally, a sprue-like syndrome with steatorrhea has been associated with an isolated IgA deficit. Treatment with commercial immune globulin is ineffective, since IgA and IgM are present only in trace quantities in these preparations. Frequent infusions of plasma (containing IgA) or unwashed blood transfusions are hazardous, since anti-IgA antibodies may develop, resulting in systemic anaphylaxis or serum sickness.

Woof JM et al. The function of immunoglobulin A in immunity. J Pathol. 2006 Jan;208(2):270–82. [PMID: 16362985]

COMMON VARIABLE IMMUNODEFICIENCY
Essentials of Diagnosis
Defect in terminal differentiation of B cells, with absent plasma cells and deficient synthesis of secreted antibody.
Frequent sinopulmonary infections secondary to humoral immune deficiency.
Confirmation by evaluation of serum immunoglobulin levels and deficient functional antibody responses.
General Considerations
The most common cause of panhypogammaglobulinemia in adults is common variable immunodeficiency, a heterogeneous immunodeficiency disorder clinically characterized by an increased incidence of recurrent infections, autoimmune phenomena, and neoplastic diseases. The onset generally is during adolescence or early adulthood but can occur at any age. The prevalence of common variable immunodeficiency is about 1:80,000 in the United States.
Clinical Findings
SYMPTOMS AND SIGNS
The pattern of immunoglobulin isotype deficiency is variable. Most patients present with significantly depressed IgG levels, but over time all antibody classes (IgG, IgA, and IgM) may be affected. Increased susceptibility to pyogenic infections is the hallmark of the disease. Virtually all patients suffer from recurrent sinusitis, with bronchitis, otitis, pharyngitis, and pneumonia also being common infections. Infections may be prolonged or associated with unusual complications such as meningitis or sepsis.
Gastrointestinal disorders are commonly associated with common variable immunodeficiency, and a sprue-like syndrome, with diarrhea, steatorrhea, malabsorption, protein-losing enteropathy, and hepatosplenomegaly, may develop in patients. Paradoxically, there is an increased incidence of autoimmune disease (20%), although patients may not display the usual serologic markers. Autoimmune cytopenias are most common, but autoimmune endocrinopathies, seronegative rheumatic disease, and gastrointestinal disorders are also commonly seen. Lymph nodes may be enlarged in these patients, yet biopsies show marked reduction in plasma cells. Noncaseating granulomas are frequently found in the spleen, liver, lungs, or skin. There is an increased propensity for the development of B cell neoplasms (50- to 400-fold increase risk of lymphoma), gastric carcinomas, and skin cancers.
LABORATORY FINDINGS
Diagnosis is confirmed in patients with recurrent infections by demonstration of functional or quantitative defects in antibody production. Serum IgG levels are usually less than 250 mg/dL; serum IgA and IgM levels are also subnormal. Decreased to absent functional antibody responses to protein antigen immunizations establish the diagnosis.
The cause of the panhypogammaglobulinemia in the majority of common variable immunodeficiency patients is an intrinsic B cell defect preventing terminal maturation into antibody-secreting plasma cells. In a small number, excessive suppressor T cell activity that inhibits B cells—or helper T cell activity inadequate to assist B cells to make antibody—has been identified. The absolute B cell count in the peripheral blood in most patients, despite the underlying cellular defect, is normal. A subset of these patients have concomitant T cell immunodeficiency with increased numbers of activated CD8 cells, splenomegaly, and decreased delayed-type hypersensitivity.
Treatment
Patients may be treated aggressively with antibiotics at the first sign of infection. Since antibody deficiency predisposes patients to high-risk pyogenic infections, antibiotic coverage should be sure to cover encapsulated bacteria. Only after the development of bronchiectasis or after sinus surgery do patients become significantly affected by more virulent organisms such as Staphylococcus aureus or Pseudomonas aeruginosa. Maintenance intravenous immune globulin (IGIV) therapy is indicated, with infusions of 300–500 mg/kg of IGIV given at about monthly intervals. Adjustment of dosage or of the infusion interval is made on the basis of clinical responses and steady-state trough serum IgG levels. Such therapy is effective in decreasing the incidence of potentially life-threatening infections and increasing quality of life. The yearly cost of monthly infusions can be in excess of $20,000–$30,000.

Castigli E et al. Molecular basis of common variable immunodeficiency. J Allergy Clin Immunol. 2006 Apr;117(4):740–6. [PMID: 16630927]

Cunningham-Rundles C. Immune deficiency: office evaluation and treatment. Allergy Asthma Proc. 2003 Nov–Dec;24(6):409–15. [PMID: 14763242]

Weiler CR et al. Common variable immunodeficiency: test indications and interpretations. Mayo Clin Proc. 2005 Sep;80(9):1187–200. [PMID: 16178499]

NONALLERGIC RHINITIS

NONALLERGIC RHINITIS
Vasomotor Rhinitis
Vasomotor rhinitis can be the primary cause of chronic nasal congestion, rhinorrhea or, less commonly, sneezing paroxysms. About one-fifth of patients who seek medical attention at an allergy/immunology subspecialty clinic complaining of chronic rhinitis will actually have nonallergic, vasomotor rhinitis; one-third of patients in whom allergic rhinitis is diagnosed will also have a vasomotor component to the disease. Nonspecific nasal hyperreactivity leads to symptoms triggered by cold temperature, inhaled irritants, strong odors, spicy food, and other nonallergic environmental stimuli. Intranasal corticosteroids (eg, fluticasone), azelastine, and ipratropium, and oral decongestants may be effective as monotherapy or in combination.
Nasal Polyposis
Compared with the general population, nasal polyps are not found more frequently in patients with allergic rhinitis, but they are associated with aspirin sensitivity syndrome, chronic sinusitis, allergic fungal sinusitis, Churg-Strauss syndrome, and cystic fibrosis. Benign inflammatory outgrowths of nasosinus mucosa, nasal polyps (see photograph) can lead to nasal airway obstruction, hyposmia, and chronic sinusitis. Compared with placebo, topical corticosteroids have been shown to improve polyposis, but the response rate to topical agents alone is commonly inadequate and treatment with systemic corticosteroids is usually required. Since concomitant chronic sinusitis is almost always present, cotreatment with appropriate antibiotics is usually recommended. Some cases will require surgical intervention, and regardless of the treatment, recurrence is a frequent complication.

DRUG & FOOD ALLERGY

General Considerations
Some drugs are clearly more immunogenic than others, and this can be reflected in the incidence of drug hypersensitivity. A partial list of drugs frequently implicated in drug reactions includes
-lactam antibiotics, sulfonamides, phenytoin, carbamazepine, allopurinol, muscle relaxants used for general anesthesia, nonsteroidal anti-inflammatory drugs, antisera, and antiarrhythmic agents. Many drugs can be associated with recognizable known toxicities, drug interactions, or idiosyncratic reactions that are not immune-mediated. These must be distinguished from true hypersensitivity reactions because the prognosis and management differ. Some estimate that only 10% or less of adverse reactions to drugs are true hypersensitivity reactions. Patients with multidrug hypersensitivity are quite rare, and those reporting "allergies" to more than three distinct classes of drugs should be carefully evaluated since intolerance to many of these drug classes may not be immunologic.
Four foods account for 90% of food allergy in adults: peanuts, tree nuts, fish, and shellfish. Food hypersensitivity must be distinguished from food intolerance, which is more common and more variable in terms of underlying mechanism. An example of food intolerance would be lactose intolerance, which is due to an enzyme deficiency rather than an IgE-mediated hypersensitivity.
Clinical Findings
SYMPTOMS AND SIGNS
The development of symptoms and the nature of the adverse drug reaction can suggest whether an immunologic process is responsible for symptoms. Factors to consider include type of symptoms, history of previous drug exposure, time of onset after starting the drug, presence of other systemic involvement, coexisting illness, and concurrent drug use. In previously sensitized individuals, immediate hypersensitivity is manifested by rapid development of urticaria, angioedema, or anaphylaxis. Delayed onset of urticaria accompanied by fever, arthralgias, and nephritis may indicate the development of an immune complex-mediated disorder. Drug fever and Stevens-Johnson syndrome probably act by immune hypersensitivity mechanisms. In genetically slow acetylators and in AIDS patients with depleted hepatic glutathione levels, drugs such as sulfamethoxazole are not rapidly excreted during drug metabolism. This altered drug metabolism favors the generation of haptenated immunoreactive metabolites as well as drug reactions, such as delayed morbilliform eruptions. Other types of immune-mediated dermatologic drug reactions include lupus-like syndromes caused by procainamide, isoniazid, phenytoin, or hydralazine. Drugs that have been associated with the development of systemic or cutaneous vasculitis include leukotriene receptor antagonists, allopurinol, phenytoin, thiazides, nonsteroidal anti-inflammatory drugs, furosemide, cimetidine, gold, hydralazine, and many antibiotics (eg, penicillin, sulfonamides, quinolones, and tetracycline). Cutaneous vasculitides are usually associated with fixed lesions, with histologically-proven immune-complex involvement.
Food hypersensitivity is manifest by symptoms consistent with IgE-mediated immediate hypersensitivity/anaphylaxis but commonly is also accompanied by abdominal pain, nausea, vomiting, or diarrhea. More rarely, atopic dermatitis may be the sole clinical expression of food allergy. The onset of allergic food reactions is rapid, usually within minutes to a couple of hours of ingestion, and the reaction is usually quite reproducible. Oral allergy syndrome is a self-limited form of fruit and vegetable hypersensitivity, where symptoms are confined to the oropharynx. Due to cross-reactivity between certain fruit and vegetable allergens and certain seasonal pollens, ingestion of these foods causes a contact allergy with pruritus of lips, tongue, and palate typically without other symptoms or signs of systemic anaphylaxis. The most common cross-reacting foods and pollens are apples and carrots, which cross-react with birch pollen; melons and bananas, which cross-react with ragweed pollen. Many of these antigens involved in oral allergy syndrome are heat labile and denature during cooking. Immunologic cross-reactivity appears to also underlie the association of latex allergy and hypersensitivity to avocado, banana, chestnut, kiwi, and papaya. Unlike the oral allergy syndrome, however, systemic anaphylaxis upon ingestion of these foods may develop in 35–50% of patients who are allergic to latex (so called latex-fruit syndrome).
LABORATORY FINDINGS
Allergy testing
Allergy skin testing is only available for a limited number of drugs (penicillin, insulin, streptokinase, chymopapain, heterologous serum), since patients may react to the native drug as well as any metabolite that covalently binds to native protein and becomes immunoreactive. Skin testing is available for patients with suspected immediate hypersensitivity to penicillin or
-lactam antibiotics (see Infectious Diseases: Common Problems & Antimicrobial Therapy). The degree of cross-reactivity between the cephalosporin antibiotics and penicillins is uncertain. The incidence of IgE-mediated hypersensitivity appears to be less than 5%. There appears to be no allergic cross-reactivity between the monobactam antibiotics (aztreonam) and penicillin or other
-lactam antibiotics. A high degree of cross-reactivity exists between penicillin and the carbapenem, imipenem, so this drug should be given to the penicillin-allergic patient with the same degree of caution as if the patient were to receive penicillin.
If the likelihood of immunologic reaction is low—based on the history and the assessment of likely offending agents—and if no allergy testing is available, judicious test dose challenges may be considered in a monitored setting. If the likelihood of IgE-mediated reaction is significant, these challenges are risky and rapid drug desensitization is indicated.
The gold standard for allergy food testing is skin-prick testing with actual food items, but due to the inconvenience and potential risk for systemic reactions, this form of testing is usually preceded by IgE RAST testing or skin prick testing with commercially available extracts or both. Food allergy testing must be interpreted within the context of the clinical picture, since false-positive tests can occur.
Provocation tests
Occasionally, direct allergen challenge of the target organ or tissue under controlled conditions is required for definitive diagnosis. Such challenges may be bronchial, nasal, conjunctival, oral, or cutaneous. A positive test confirms that the test substance can cause the reaction, but it does not prove that an immunologic mechanism is responsible.
In most cases of suspected allergy to a food or drug, placebo-controlled oral challenge is the definitive test. To be considered a positive result, the reported clinical findings must be reproduced during provocation testing. A blinded provocation test may be preceded by an open challenge (no placebo control), which, if negative, negates the necessity for logistically difficult blinded challenge. Freeze-dried foods in large opaque capsules provide a sufficient dose of allergen for testing. This should not be done in patients with suspected food- or drug-induced anaphylaxis.
Treatment
For IgE-mediated drug hypersensitivity, acute rapid desensitization may allow administration of a drug if there is no suitable alternative treatment regimen. This procedure carries a significant risk and should be undertaken in an intensively monitored setting. This is accomplished by a course of oral or parenteral doses starting with extremely low doses (dilutions of 1 x 10–6 or 1 x 10–5 units) and increasing to the full dose over a period of hours. IgE-mediated reactivity diminishes during the course of this desensitization, creating a temporary drug-specific refractory state. During the refractory period, skin histamine responsiveness is maintained, and mast cells may be activated by other stimuli but the patient may receive the desired drug with a very low risk of anaphylaxis. Acute rapid desensitization may work through cellular mechanisms different from those involved in standard injection immunotherapy, and the refractory period is maintained only throughout the course of uninterrupted therapy.
Various slow desensitization protocols have been developed for patients suffering from late-appearing morbilliform eruptions (eg, AIDS patients with sulfamethoxazole-induced dermatitis). These eruptions are not IgE-mediated, and the slow reintroduction of drug allows for less haptenation during sulfonamide metabolism with generation of less immunoreactive drug metabolites. This form of desensitization is distinct from rapid desensitization of IgE-mediated drug allergy. Desensitization for non–IgE-mediated drug reactions has been successful for aspirin, nonsteroidal anti-inflammatory drugs, and allopurinol.
Any history or finding consistent with toxic epidermal necrolysis or Stevens-Johnson syndrome would be an absolute contraindication for drug readministration.
For any proven food hypersensitivity, strict avoidance is the only rational recommendation. Patients should also be provided with an epinephrine autoinjector (Epi-pen) if indicated.

Grammer LC et al. Drug allergy and protocols for management of drug allergies, 3rd edition. Part II. General principles of prevention of allergic drug reactions. Allergy Asthma Proc. 2004 July–August; 25(4):267–272.

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Sicherer SH et al. An expanding evidence base provides food for thought to avoid indigestion in managing difficult dilemmas in food allergy. J Clin Allergy Immunol. 2006 Jun;117(6):1419–22. [PMID: 16751007]

BIOCHEMICAL GENETICS

Biochemical genetics deals not only with enzymatic defects but also with proteins of all functions, including cytoskeletal and extracellular structure, regulation, and receptors. The principal functions of the biochemical genetics laboratory are to determine the presence or absence of proteins, to assess the qualitative characteristics of proteins, and to verify the effectiveness of proteins in vitro. The key elements from the referring clinician's perspective are: (1) to indicate what the suspected clinical diagnoses are and (2) to make certain that the proper specimen is obtained and transported to the laboratory in a timely manner.
Indications for Biochemical Investigations
Some inborn errors are relatively common in the general population, eg, hemochromatosis, defects of the low-density lipoprotein receptor, and cystic fibrosis (Table 44–3). Others, although rare across the entire population, are common in certain ethnic groups, such as Tay-Sachs disease in Ashkenazic Jews, sickle cell disease in African Americans, and thalassemias in populations from around the Mediterranean basin and Asia. Many of these disorders are autosomal recessive, and the frequency of heterozygotes is many times that of the fully expressed disease. Screening for carrier status can be effective if certain requirements are satisfied (Table 44–4). For example, all of the United States and the District of Columbia require screening of newborns for phenylketonuria and often other metabolic diseases. Such programs are cost-effective even for rare conditions such as phenylketonuria, which occurs in only one of every 11,000 births. Unfortunately, not all disorders that meet the requirements in Table 44–4 are screened for in every state. Furthermore, compliance is highly variable among programs, and follow-up diagnostic tests, management, and counseling are in some cases inadequate. Babies most likely to be missed are those born at home and those discharged before they have digested much milk or formula. In some states, parents can refuse to have their infants studied. Several commercial laboratories have marketed screening for over 35 inborn errors of metabolism to hospitals. This supplemental newborn screening involves tandem mass spectroscopic analysis of the same blood spots used in state-mandated programs.
Use of the biochemical genetics laboratory for other than screening purposes must be justified by the need for data on which to base a diagnosis of specific disorders or classes of related disorders. The possibilities are limited only by the extent of knowledge, the enthusiasm of the primary clinician or consultant, the willingness of the patient or family to pursue the diagnosis and specimens to be taken, and the availability of a laboratory to examine the specimens.
Though many inborn defects are so subtle they escape detection, there are a number of clinical situations in which an inborn error should be part of the differential diagnosis. The urgency with which the investigation is undertaken will vary depending on the severity of the disorder and the availability of treatment. Table 44–5 lists various clinical presentations.
The possibility of acute metabolic disease of the neonate is the most important indication, because prompt diagnosis and treatment may often make the difference between life and death. The clinical features are nonspecific because the newborn has a limited repertoire of responses to severe metabolic insults. The physician must be both inclusive and systematic in evaluating such ill babies.

Cleary MA et al. Developmental delay: when to suspect and how to investigate for an inborn error of metabolism. Arch Dis Child. 2005 Nov;90(11):1128–32. [PMID: 16243864]

Erbe RW et al. Neonatal screening. In: Emery and Rimoin's Principles and Practice of Medical Genetics, 5th ed. Rimoin DL et al (editors). Churchill Livingstone, 2007.

Scriver CR et al. The Metabolic and Molecular Bases of Inherited Disease, 8th ed. McGraw-Hill, 2001.

Seashore MR et al. Newborn screening and the pediatric practitioner. Semin Perinatol. 2005 Jun;29(3):182–8. [PMID: 16114581]

AUTOIMMUNITY

AUTOIMMUNITY
Autoimmune diseases cannot be explained by a solitary cause or mechanism. Small amounts of autoantibodies are normally produced and may have physiologic roles in cellular interactions. Positive serologic findings may be found years before the development of pathogenic autoimmunity or clinical illness, and in some cases, they represent normal immunity or "benign autoimmunity" without disease. The major theories regarding the development of autoimmune disease are (1) release of normally sequestered antigens; (2) escape from anergy or defective apoptosis (programmed cell death) leading to abnormal autoreactive cellular clones; (3) shared antigens between the host and microorganisms, ie, "molecular mimicry"; and (4) defects in helper or suppressor T cell function. A genetic susceptibility is also a likely determinant of autoimmune disease. In nearly all autoimmune diseases, multiple mechanisms of autoimmunity are operative.
Cell-Mediated Autoimmunity
Certain autoimmune diseases are mediated by T cells that have become specifically immunized to autologous tissues. Cytotoxic or killer T cells generated by this aberrant immune response injure specific organs in the absence of serum autoantibodies. Diminished suppressor T cell activity or loss of clonal anergy results in disordered regulation of immune function and consequent autoreactivity. The immune damage in systemic (non-organ-specific) diseases such as systemic lupus erythematosus may be due to such a mechanism.
Antibody-Mediated Autoimmunity
Several autoimmune diseases have been shown to be caused by autoantibodies in the absence of cell-mediated autoimmunity. The autoimmune hemolytic anemias, idiopathic thrombocytopenia, and Goodpasture's syndrome appear to be mediated solely by autoantibodies directed against autologous cell membrane constituents. In these diseases, antibody attaches to cell membranes and fixes complement; the ensuing inflammatory reaction injures the cells.
Anti-receptor antibodies that compete with or mimic physiologic agonists for cellular receptors cause several diseases. In Graves' disease, antibodies are present that bind to thyroid cells' thyroid-stimulating hormone and thereby stimulate thyroid hormone production. In rare instances of type 1 diabetes mellitus, anti-insulin receptor antibodies cause insulin resistance in peripheral target tissues. Antibodies to acetylcholine receptors of the myoneural junction in myasthenia gravis block neuromuscular transmission and produce muscle weakness.
Immune Complex Disease
In this group of diseases (systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, some drug-induced hemolytic anemias, and thrombocytopenias), autologous tissues are injured as "innocent bystanders." Autoantibodies are not directed against cellular components of the target organ but rather against autologous or heterologous antigens in the serum. The resultant antigen-antibody complexes bind nonspecifically to autologous membranes (eg, glomerular basement membrane) and fix complement. Fixation and subsequent activation of complement components produce a local inflammatory response resulting in tissue injury.
AUTOIMMUNE DISEASES
The diagnosis and treatment of specific autoimmune diseases are described elsewhere in this book. Autoantibodies associated with certain autoimmune diseases may not be pathogenetic but are thought to be markers or by-products of the injury (eg, autoimmune thyroiditis and antithyroglobulin antibody). See Table 19–2 for autoantibody patterns in connective tissue diseases. (See also Musculoskeletal Disorders.)
Modified, with permission, from Harvey AM et al (editors). The Principles and Practice of Medicine, 22nd ed. Appleton & Lange, 1988; White RH et al. Clinical significance and interpretation of antinuclear antibodies. West J Med. 1987 Aug;147(2):210–3; and Tan EM. Autoantibodies to nuclear antigens (ANA): their immunobiology and medicine. Adv Immunol. 1982;33:167–240.

ANAPHYLAXIS, URTICARIA, & ANGIOEDEMA

Essentials of Diagnosis
Anaphylaxis is a systemic reaction with cutaneous symptoms, associated with dyspnea, visceral edema, and hypotension.
Urticaria is characterized by large, irregularly shaped, pruritic, erythematous wheals.
Angioedema is painless, deep, subcutaneous swelling, often involving periorbital, circumoral, and facial regions.
These disorders may be diagnosed clinically, especially in the context of allergen exposure; detection of specific IgE or elevated serum tryptase can confirm the diagnosis.
General Considerations
Certain allergens—especially drugs, insect venoms, and foods—may induce an IgE antibody response, causing a generalized release of mediators from mast cells and resulting in systemic anaphylaxis. This potentially fatal condition affects both nonatopic and atopic persons. Isolated urticaria and angioedema are more common cutaneous forms of anaphylaxis with a better prognosis.
Food allergies cause an estimated 150 fatalities per year in the United States, most cases being due to ingestion of peanuts, tree nuts, shellfish, and fish. Common childhood food allergies such as milk, soy, wheat, and egg are often outgrown over time if strict avoidance is practiced.
-Lactam antibiotics may be involved in 400–800 fatalities per year, and stinging insect venom causes about 50 fatalities per year. Chronic relapsing urticaria, angioedema, and, less commonly, anaphylaxis, however, are not always due to IgE-mediated hypersensitivity. In a minority of cases—perhaps 10% or less—underlying systemic disorders such as systemic mastocytosis or subclinical infection or inflammatory disorders may be manifested by episodic urticaria or angioedema. Idiopathic causes are commonly responsible for chronic or relapsing symptoms, suggesting that some cases may be associated with autoimmune processes including the production of histamine-liberating autoantibodies directed against Fc
mast cell membrane receptors. A review of 593 patients with recurrent episodes of anaphylaxis seeking medical attention at a university medical center revealed that most (70%) anaphylactic episodes in adults were classified as idiopathic in nature. In contrast, the bulk (35–55%) of anaphylactic reactions in children are caused by food allergies. Twenty percent of the population will experience urticaria or angioedema during their lifetime, and the estimated prevalence of idiopathic anaphylaxis is 34,000 patients in the United States.
Clinical Findings
SYMPTOMS AND SIGNS
The manifestations are (1) hypotension or shock from widespread vasodilation or dysrhythmia, (2) respiratory distress from bronchospasm or laryngeal edema, (3) gastrointestinal and uterine muscle contraction, and (4) flushing, pruritus, urticaria and angioedema (see photograph).
LABORATORY FINDINGS
In vivo allergy skin testing and in vitro RAST testing can detect allergen-specific IgE for a variety of foods, hymenoptera (bee, wasp, hornet, fire ant) venom, latex, and some medicines. Skin testing for food allergy is appropriate only if the patient has symptoms consistent with IgE-mediated allergy (eg, urticaria, angioedema, or anaphylaxis) within 2 hours after eating the suspect food.
Determination of serum tryptase can be used to identify recent anaphylactic reactions or other reactions due to systemic mast cell activation. Tryptase is a mast cell-derived neutral protease with a half-life of 60–90 minutes. Elevated tryptase levels have been associated with anaphylaxis, systemic mastocytosis, and non-IgE-mediated diseases characterized by mast cell degranulation ("anaphylactoid reactions"). Histamine is released during these disorders and has a very short serum half-life but may be briefly detectable during symptomatic periods.
If IgE-mediated hypersensitivity is not found and symptoms become relapsing or chronic (over 6 weeks in duration), a screening battery of laboratory tests may be done after a thorough history and physical examination. Appropriate diagnostic testing should follow any positive findings on examination or review of systems. Patients suffering from recurrent angioedema should also be tested for C1-esterase inhibitor deficiency. Measuring a serum C4 level is an easy screening test for C1-esterase inhibitor deficiency/hereditary angioedema because it will be low in most cases.
Treatment
TREATMENT OF ANAPHYLAXIS
At the first suspicion of anaphylaxis, airway, breathing, and circulation are assessed. If systemic anaphylaxis is suspected, aqueous epinephrine 1:1000 in a dose of 0.2–0.5 mL (0.2–0.5 mg) is injected intramuscularly. Repeated injections can be given every 5–15 minutes as necessary. Between 40% and 70% of patients suffering from severe anaphylaxis will require more than one injection of epinephrine. Injection in the anterolateral thigh may lead to more predictable and rapid absorption compared with subcutaneous administration. Epinephrine can stabilize hemodynamics, cause bronchodilation, and prevent further mast cell degranulation. Rapid intravenous infusion of large volumes of fluids (saline, lactated Ringer's injection, plasma, colloid solutions, or plasma expanders) is essential to replace loss of intravascular plasma into tissues in patients with hypotension caused by marked vasodilation. Other vasopressor drugs (high-dose dopamine, norepinephrine, phenylephrine) may be necessary if the patient remains hypotensive.
Airway obstruction is caused by edema of the larynx and hypopharynx or by bronchospasm. The former is treated by maintenance of an airway with endotracheal intubation or tracheostomy. Inhalation of selective
2-adrenergic agonists such as albuterol, and intravenous administration of aminophylline (0.5 mg/kg/h IV with 6 mg/kg loading dose over 30 minutes) are effective for bronchospasm.
Antihistamines (H1- and H2-receptor antagonists) such as diphenhydramine (25–50 mg orally, intramuscularly, or intravenously every 4–6 hours) and ranitidine (150 mg orally every 12 hours or 50 mg intramuscularly or intravenously every 6–8 hours) may be useful adjuvant therapies for alleviating the cutaneous manifestations of urticaria or angioedema and pruritus and for the gastrointestinal and uterine smooth muscle spasms. Corticosteroids will not reverse respiratory obstruction or shock but may reduce prolonged reactions or relapses. Long-term combined oral antihistamine and prednisone therapy reduces the number and severity of attacks in patients with frequent life-threatening episodes of idiopathic anaphylaxis. Medical therapy does not reliably prevent true IgE-mediated hypersensitivity reactions.
There may be a clinical biphasic or late-phase response in anaphylaxis, causing a recrudescence of symptoms hours (most commonly 6–12 hours) after exposure to the allergen. The incidence of late phase reactions is estimated to be between 1% and 20%. Since this may occur after subsidence of the immediate-phase response, all patients with anaphylaxis should be monitored for up to 24 hours, discharged with injectable epinephrine, and educated about the possible recurrence of symptoms.
Anaphylaxis in a patient being treated with
-adrenergic blocker drugs is a special problem because of refractoriness to epinephrine and selective
-adrenergic agonists. Higher doses of adrenergic drugs are required for the desired effect; glucagon (0.5–1 mg intravenously, intramuscularly, or subcutaneously may be repeated 30 minutes later) in patients taking
-blockers may be beneficial. Patients being treated with angiotensin-converting enzyme inhibitors may suffer from more severe hypotension due to blockade of renin-angiotensin-dependent compensatory mechanisms.
TREATMENT OF URTICARIA AND ANGIOEDEMA
These disorders are discussed fully in Dermatology. If urticaria or angioedema is found to be secondary to underlying inflammatory or infectious processes, treatment of the primary disorder can lead to remission of cutaneous symptoms.
VENOM IMMUNOTHERAPY
Patients demonstrating immediate hypersensitivity reactions to stinging insects (honey bees, wasps, hornets, yellow jackets, and imported fire ants) with documented venom-specific IgE on allergy skin testing should receive venom immunotherapy for prevention of anaphylaxis. A 5-year course of venom-specific immunotherapy is indicated for persons suffering from generalized urticaria, angioedema, bronchospasm, or hypotension after insect venom exposure. Large isolated local reactions to insect stings are not a predisposing factor for systemic anaphylaxis. Untreated individuals have a 50–60% risk of anaphylactic response to subsequent stings. Venom immunotherapy is highly protective, affording 98% protection from life-threatening reactions on rechallenge. Rarely, anaphylaxis has been associated with other biting insects, including Triatoma and mosquito, but diagnostic reagents and therapeutic extracts are not consistently available for these other species.

Dibbern DA Jr. Urticaria: selected highlights and recent advances. Med Clin North Am. 2006 Jan;90(1):187–209. [PMID: 16310530]

Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. The diagnosis and management of anaphylaxis: an updated practice parameter. J Allergy Clin Immunol. 2005 Mar;115(3 Suppl 2):S483–523. [PMID: 15753926]

Moffitt JE et al. Stinging insect hypersensitivity: A practice parameter update. J Allergy Clin Immunol. 2004 Oct;114(4):869–86. [PMID: 15480329]

Simons FE. Anaphylaxis, killer allergy: long-term management in the community. J Allergy Clin Immunol. 2006 Feb;117(2):367–77. [PMID: 16461138]

Weiler CR et al. Genetic test indications and interpretations in patients with hereditary angioedema. Mayo Clin Proc. 2006 Jul;81(7):958–72. [PMID: 16835976]

Amyloidosis

Essentials of Diagnosis
The diagnosis is based on clinical suspicion, family history, and preexisting long-standing infection or debilitating illness.
Microscopic examination of biopsy (eg, gingival, renal, rectal) or surgical specimens is diagnostic.
Fine-needle biopsy of subcutaneous abdominal fat is a simple and reliable method for diagnosing secondary systemic amyloidosis.
General Considerations
Amyloidosis is a group of disorders manifested by impaired organ function due to infiltration with insoluble protein fibrils. Different fibrils can be correlated with the clinical syndromes. In primary amyloidosis (AL), the protein fibrils are monoclonal immunoglobulin light chains, whereas in secondary amyloidosis (AA), protein deposits are derived from acute phase reactant apolipoprotein precursors. Familial amyloidosis syndromes commonly cause infiltrative neuropathies. Other types of amyloidosis may also be hereditary. Over 20 types of fibrils have been identified in amyloid deposits. Amyloidosis due to deposition of
2-microglobulin in carpal ligaments occurs in long-term hemodialysis patients.
Clinical Findings
SYMPTOMS AND SIGNS
The symptoms and signs of primary amyloidosis are due to amyloid infiltration and subsequent malfunction of the infiltrated organ (eg, nephritic syndrome and renal failure, cardiomyopathy and cardiac conduction defects, Alzheimer's disease, intestinal malabsorption and pseudo-obstruction, carpal tunnel syndrome, macroglossia, peripheral neuropathy, end-organ insufficiency of endocrine glands, respiratory failure, capillary damage with ecchymosis). Secondary amyloidosis is more often limited to the liver, spleen, and adrenals. Familial syndromes commonly cause infiltrative neuropathies.
LABORATORY TESTS
The diagnosis of primary amyloidosis is based on clinical suspicion with corroboration provided by detection of a monoclonal gammopathy on serum protein electrophoresis and microscopic examination of abdominal fat pad aspirates; rectal or gingival biopsies reveal amyloid protein (green birefringence under polarizing microscope after Congo red staining). In systemic disease, rectal or gingival biopsies show a sensitivity of about 80%, bone-marrow biopsy about 50%, and abdominal fat aspiration between 70% and 80%. The latter is a simple and reliable method for diagnosing systemic amyloidosis.
Differential Diagnosis
When evaluating a patient with suspected primary amyloidosis, it is important to consider other causes of the presenting symptoms and signs, including multiple myeloma, hemochromatosis, sarcoidosis, Waldenström's macroglobulinemia, metastatic tumors, and other cause of nephrotic syndrome, such as lupus nephritis.
Treatment
Treatment of localized amyloid tumors is by surgical excision. There is no effective treatment of systemic amyloidosis, and death usually occurs within 1–3 years. Care is generally supportive, although hemodialysis and immunosuppressive therapy may be useful. When concomitant multiple myeloma is found, it is treated in the standard way (see Hematology). Secondary disease is usually approached by aggressively treating the predisposing disease, but remission of fibril deposition does not occur. Bone marrow transplant after chemotherapy has been used in selected patients.
Heavy Chain Disease (, , )
These are rare disorders in which the abnormal serum and urine protein is a part of a homogeneous ,
, or
heavy chain. The clinical presentation is more typical of lymphoma than multiple myeloma, and there are no destructive bone lesions.
chain disease presents as a lymphoproliferative disorder with autoimmune features.
chain disease is frequently associated with severe diarrhea and infiltration of the lamina propria of the small intestine with abnormal plasma cells.
chain disease is associated with chronic lymphocytic leukemia.

Gertz MA et al. Amyloidosis: diagnosis and management. Clin Lymphoma Myeloma. 2005 Nov;6(3):208–19. [PMID: 16354326]

Gertz MA et al. Amyloidosis. Best Pract Res Clin Haematol. 2005;18(4):709–27. [PMID: 16026746]

Merlini G et al. Molecular mechanisms of amyloidosis. N Engl J Med. 2003 Aug 7;349(6):583–96. [PMID: 12904524]

Vesole DH et al; Plasma Cell Disorders Working Committee of the Center for International Blood and Marrow Transplant Research. High-dose therapy and autologous hematopoietic stem cell transplantation for patients with primary systemic amyloidosis: a Center for International Blood and Marrow Transplant Research Study. Mayo Clin Proc. 2006 Jul;81(7):880–8. [PMID: 16835967]

Amyloidosis

Essentials of Diagnosis
The diagnosis is based on clinical suspicion, family history, and preexisting long-standing infection or debilitating illness.
Microscopic examination of biopsy (eg, gingival, renal, rectal) or surgical specimens is diagnostic.
Fine-needle biopsy of subcutaneous abdominal fat is a simple and reliable method for diagnosing secondary systemic amyloidosis.
General Considerations
Amyloidosis is a group of disorders manifested by impaired organ function due to infiltration with insoluble protein fibrils. Different fibrils can be correlated with the clinical syndromes. In primary amyloidosis (AL), the protein fibrils are monoclonal immunoglobulin light chains, whereas in secondary amyloidosis (AA), protein deposits are derived from acute phase reactant apolipoprotein precursors. Familial amyloidosis syndromes commonly cause infiltrative neuropathies. Other types of amyloidosis may also be hereditary. Over 20 types of fibrils have been identified in amyloid deposits. Amyloidosis due to deposition of
2-microglobulin in carpal ligaments occurs in long-term hemodialysis patients.
Clinical Findings
SYMPTOMS AND SIGNS
The symptoms and signs of primary amyloidosis are due to amyloid infiltration and subsequent malfunction of the infiltrated organ (eg, nephritic syndrome and renal failure, cardiomyopathy and cardiac conduction defects, Alzheimer's disease, intestinal malabsorption and pseudo-obstruction, carpal tunnel syndrome, macroglossia, peripheral neuropathy, end-organ insufficiency of endocrine glands, respiratory failure, capillary damage with ecchymosis). Secondary amyloidosis is more often limited to the liver, spleen, and adrenals. Familial syndromes commonly cause infiltrative neuropathies.
LABORATORY TESTS
The diagnosis of primary amyloidosis is based on clinical suspicion with corroboration provided by detection of a monoclonal gammopathy on serum protein electrophoresis and microscopic examination of abdominal fat pad aspirates; rectal or gingival biopsies reveal amyloid protein (green birefringence under polarizing microscope after Congo red staining). In systemic disease, rectal or gingival biopsies show a sensitivity of about 80%, bone-marrow biopsy about 50%, and abdominal fat aspiration between 70% and 80%. The latter is a simple and reliable method for diagnosing systemic amyloidosis.
Differential Diagnosis
When evaluating a patient with suspected primary amyloidosis, it is important to consider other causes of the presenting symptoms and signs, including multiple myeloma, hemochromatosis, sarcoidosis, Waldenström's macroglobulinemia, metastatic tumors, and other cause of nephrotic syndrome, such as lupus nephritis.
Treatment
Treatment of localized amyloid tumors is by surgical excision. There is no effective treatment of systemic amyloidosis, and death usually occurs within 1–3 years. Care is generally supportive, although hemodialysis and immunosuppressive therapy may be useful. When concomitant multiple myeloma is found, it is treated in the standard way (see Hematology). Secondary disease is usually approached by aggressively treating the predisposing disease, but remission of fibril deposition does not occur. Bone marrow transplant after chemotherapy has been used in selected patients.
Heavy Chain Disease (, , )
These are rare disorders in which the abnormal serum and urine protein is a part of a homogeneous ,
, or
heavy chain. The clinical presentation is more typical of lymphoma than multiple myeloma, and there are no destructive bone lesions.
chain disease presents as a lymphoproliferative disorder with autoimmune features.
chain disease is frequently associated with severe diarrhea and infiltration of the lamina propria of the small intestine with abnormal plasma cells.
chain disease is associated with chronic lymphocytic leukemia.

Gertz MA et al. Amyloidosis: diagnosis and management. Clin Lymphoma Myeloma. 2005 Nov;6(3):208–19. [PMID: 16354326]

Gertz MA et al. Amyloidosis. Best Pract Res Clin Haematol. 2005;18(4):709–27. [PMID: 16026746]

Merlini G et al. Molecular mechanisms of amyloidosis. N Engl J Med. 2003 Aug 7;349(6):583–96. [PMID: 12904524]

Vesole DH et al; Plasma Cell Disorders Working Committee of the Center for International Blood and Marrow Transplant Research. High-dose therapy and autologous hematopoietic stem cell transplantation for patients with primary systemic amyloidosis: a Center for International Blood and Marrow Transplant Research Study. Mayo Clin Proc. 2006 Jul;81(7):880–8. [PMID: 16835967]

ALLERGIC RHINITIS

Essentials of Diagnosis
Seasonal or perennial occurrence of nasal pruritus, congestion, rhinorrhea, or paroxysms of sneezing, which may be associated with lower respiratory symptoms, eye erythema, pruritus, irritation, tearing, or eczematous dermatitis.
Environmental aeroallergen exposure.
Presence of specific-IgE antibody to tested aeroallergens.
Clinical Findings
In addition to the symptoms listed above, up to 40% of patients with allergic rhinitis also manifest lower respiratory symptoms: cough, wheezing, chest tightness, or dyspnea. The physical examination may reveal edematous or inflamed nasal mucosa. In severe cases, the affected mucosa may be pale, boggy, or blue-tinged from vascular engorgement and venous congestion. Nasal symptoms can be nonspecific, however, and the differential diagnosis can include viral rhinitis, bacterial sinusitis, vasomotor rhinitis, nasal polyposis, drug-induced rhinitis, hormonal rhinitis, rhinitis medicamentosa, atrophic rhinitis, gastroesophageal reflux, and systemic disorders such as thyroid disease or Wegener's granulomatosis. Even a basic understanding of regional aeroallergen patterns and seasons can aid the clinician during the evaluation of patients presenting with acute or chronic rhinitis.
Patients with moderate to severe disease, those who are potential candidates for allergen immunotherapy, and those with strong predisposing factors for atopic diatheses (eg, a strong family history of atopy or ongoing exposure to potential sources of allergen) should undergo testing. Since the development of rhinitis precedes the presentation of asthma in over 50% of cases, early intervention may decrease the risk of more severe clinical allergic disease. Patients with comorbidities or associated complications such as allergic asthma, allergic conjunctivitis, chronic cough, sinusitis, polyposis, eczema, or otitis media may also benefit from evaluation by a subspecialist.
Treatment
The three basic principles of allergy management are avoidance of the allergen, symptomatic pharmacologic therapy, and specific allergen immunotherapy. Patients with suboptimal responses to reasonable therapeutic interventions benefit from diagnostic allergy skin testing.
AVOIDANCE THERAPY
Avoidance is the most effective treatment for any allergic condition but may be limited in its applicability. It cures the clinical manifestations but does not reduce the sensitivity to the allergen.
Pollens
Airborne allergens can travel significant distances, but concentrations are highest near their source. Pollen release occurs in the early morning, and airborne levels depend on temperature and wind velocity. Closing windows and remaining in air-conditioned environments can decrease exposure when pollen counts are high.
Animal danders
If the allergy is slight, the patient may benefit from merely keeping the animal out of the bedroom; usually, however, it is necessary to remove the animal from the home altogether. Hypersensitivity to animal dander can be exquisite, and passively transferred dander can accumulate to significant levels in "off-limits" areas. Washing or otherwise treating the fur of a live animal has not been proved to reduce allergenicity.
House dust and dust mites
The mattress and pillows should be encased in dust mite-proof material, and all other bedding should be washed weekly and dried at high temperature. The bedroom floor should be uncarpeted. The room should be dusted frequently. Electronic air purifiers are of unproved effectiveness for dust mite reduction since the primary source of exposure is the bed. Acaricides are not recommended. Dust mite reduction interventions can be successful adjunctive measures to medical therapy, can significantly reduce symptoms, and can reduce bronchial hyperreactivity and medication requirements in sensitized patients.
Mold spores
Out of doors, mold spores are unavoidable during certain seasons. Nevertheless, activities such as gardening and farming can be associated with acute high levels of exposure and should be avoided. Indoor mold contamination can be controlled by repairing leaks, by preventing mold buildup in bathrooms and around windows, and by replacement of mold-contaminated carpeting.
DRUG THERAPY
Three classes of pharmacotherapy are useful for IgE-mediated diseases, based on (1) inhibition of release of mediators from mast cells, (2) inhibition of the action of mediators on their target cells, and (3) reversal of the vascular and inflammatory responses in the target tissues (Table 19–1).
Antihistamines
Antihistamine drugs competitively inhibit the binding of histamine to H1 receptors and are useful for the treatment of IgE-mediated allergy. There are a number of such drugs, but the use of first-generation antihistamines (chlorpheniramine, brompheniramine, diphenhydramine, clemastine, hydroxyzine) are limited by sedation, neurocognitive impairment, and dry mucous membranes. Rare complications include seizures and tachyarrhythmias. Second-generation nonsedating histamine H1-receptor-blocking drugs, loratadine, fexofenadine, and desloratadine appear not to be associated with arrhythmias and, along with cetirizine, are the systemic drugs of choice. Cetirizine is mildly sedating, but the incidence of side effects is markedly lower than that of its parent compound, hydroxyzine. Azelastine is a topical antihistamine preparation that is applied intranasally to decrease its systemic side effects. Because of methodologic issues, publication bias, and inability to generalize findings, providing a rank order of potency and clinical efficacy for the available antihistamines is difficult. Clinical tolerance or tachyphylaxis does not occur at prescribed dosages but an incomplete response to antihistamine therapy often indicates the need for combined treatment with a corticosteroid nasal spray. This highlights the necessity to control both the early phase and late phase of the allergic response for optimal symptom control.
Antihistamine therapy only rarely alleviates symptoms of asthma, although it is not contraindicated when used to treat concomitant rhinitis or pruritus. The antipruritic effect of antihistamines may be a useful adjunct in treatment of eczematous diseases.
Sympathomimetic drugs
Adrenergic agonists are used for both
-adrenergic (vasoconstricting) and
-adrenergic (bronchodilating) properties.
-Adrenergic agonists can be used orally (pseudoephedrine, phenylephrine) or topically (phenylephrine, naphazoline, oxymetazoline) as nasal decongestants and topically as conjunctival vasoconstrictors. Daily use of topical preparations can lead to rapid development of rebound vasodilation (rhinitis medicamentosa). The main side effects of oral decongestants are insomnia, tremor, and tachycardia.
Corticosteroids
These drugs have a therapeutic role in virtually all types of allergic diseases because of their anti-inflammatory action rather than by their immunosuppressive effects. Systemic use for the treatment of allergic disease, however, requires close attention to toxicity. Corticosteroids are available in oral, intramuscular, intravenous, intranasal, and bronchial inhalation forms; as eye drops; and in topical formulations for dermatologic use. Short-term systemic burst therapy can be used for treatment of severe asthma, marked allergic rhinitis, allergic fungal sinusitis, and allergic bronchopulmonary aspergillosis. Because of complications, including cataracts, corneal ulceration, keratitis, and glaucoma, the prescription of corticosteroid eye drops should be reserved for ophthalmologists.
Topical corticosteroid nasal sprays are effective and appear safe for long-term use, but epistaxis can occur and nasal septum perforation is a rare complication. Although the dosages and formulations available for the treatment of asthma vary greatly in terms of dosage and clinical potency, intranasal preparations of flunisolide, fluticasone, beclomethasone, mometasone, budesonide, and triamcinolone are similarly efficacious for the treatment of allergic rhinitis. Long-term topical corticosteroid therapy for allergic rhinitis is an essential aspect of management of the inflammatory phase of the disease. It may take several days of consistent use before optimal responses are seen, but these compounds have consistently proved superior to antihistamine monotherapy for control of nasal pruritus, sneezing, and nasal congestion. Surprisingly, they may also provide some relief from concomitant eye pruritus and have shown positive effects on sleep, which can be adversely affected in patients with allergic rhinitis. Topical corticosteroids may also be effective for treatment of vasomotor rhinitis and may be used as adjunctive treatment for sinusitis in combination with antibiotic therapy.
Cromolyn sodium and sodium nedocromil
Pretreatment with these drugs prevents the response to allergen by stabilizing the mast cell, although the specific molecular mechanisms of action are unknown. Although unrelated, they have similar effects and, because of poor bioavailability, are effective only when applied directly to the involved organ. Their action is short-lived, so that they must be given three or four times a day. Cromolyn is available as a bronchial inhaler, nasal spray, and ophthalmologic preparation; nedocromil is available in metered-dose inhalers. In comparison with topical corticosteroids they appear to be much less potent, but the drugs have very few side effects and wide margins of safety.
Anticholinergic agents
Ipratropium bromide is effective as a nasal topical agent for use in rhinitis. Mucous membrane glandular secretion is under cholinergic control and can be inhibited by anticholinergic agents. First-generation antihistamines have systemic anticholinergic activity, but ipratropium is preferred as adjunctive treatment of allergic rhinitis or as primary treatment for many types of nonallergic rhinitis. Ipratropium does not alleviate sneezing, pruritus, or nasal congestion but can be useful for treatment of postnasal drip and rhinorrhea.
Leukotriene antagonists
Montelukast is an effective drug for the treatment of asthma. To a much more limited degree, leukotriene antagonists can be efficacious for the treatment of allergic rhinitis, either as monotherapy or combined with an antihistamine. By inhibiting leukotriene-mediated vasodilation vascular permeability and by potentially reducing eosinophilic inflammation, orally administered montelukast can provide symptomatic relief, especially for nasal congestion. It is less effective than intranasal corticosteroids, however.
Nasal saline irrigation
A variety of methods can be used to lavage the nasal cavity. Nasal saline irrigation can improve mucociliary clearance, as well as remove crusts, inspissated mucus, and accumulated secretions. Some studies have shown improvement in chronic rhinosinusitis with hyperosmolar lavage but isotonic normal saline (8 ounces lukewarm tap water mixed with salt (one-quarter to one-half teaspoon), and a pinch of baking soda) seems preferred by many patients. In cases where patients suffer from thick, tenacious nasal discharge, saline irrigation prior to administration of topical agents may improve drug delivery and efficacy.
IMMUNOTHERAPY
Treatment of atopy—especially allergic rhinitis—by the repeated long-term injection of allergen has been shown in many controlled clinical trials to be an effective method for reducing or eliminating symptoms and signs of the allergic disorder.
Indications
The severity and duration of a patient's symptoms should be considered when selecting candidates for allergen immunotherapy. This treatment is recommended for patients with severe allergic rhinoconjunctivitis who respond poorly to drug therapy, those seeking to lower their long-term medication requirements, and for those whose allergens are not avoidable. Immunotherapy is unequivocally effective in patients with allergic rhinitis and allergic conjunctivitis who react to pollens, mold, and house dust mites. It reduces immunologic hypersensitivity, symptoms, and medication requirements. In children with documented allergic rhinitis, immunotherapy may reduce the risk of subsequent development of asthma. The efficacy of immunotherapy in allergic asthma is still debated, but a meta-analysis of 20 randomized, controlled trials done by Abramson showed a positive benefit in patients with allergic asthma. The lower clinical response rates observed in asthma have been attributed to the multifactorial nature of the disease. Immunotherapy is of no value in atopic dermatitis.
Immunologic effects
"Allergen immunotherapy" is preferable to "desensitization" because the immunologic basis for this treatment has not been clearly elucidated. Nevertheless, certain immunologic changes can be induced by these injections. Circulating levels of IgE antibodies specific to the injected allergens increase slightly during the first few months, then decrease, eventually to substantially lower levels than before treatment. Seasonal rises in IgE antibodies to pollens are blunted or eliminated. IgG blocking antibody is produced. Changes in regulatory T cells favoring suppression of IgE antibody production and apoptosis of antigen-specific T cell clones have been noted. TH2 cytokine responses may be shifted toward TH1 responses in peripheral blood mononuclear cells. Higher thresholds for release of inflammatory mediators and decreases in late-phase allergic reactions might also be related to the reduction in biologic sensitivity of end-organ systems (eyes, nose, bronchi, and skin).
Clinical effects
Most patients with allergic rhinitis caused by aeroallergens become more tolerant to natural pollen exposure during successive seasons while receiving immunotherapy. A small minority becomes completely asymptomatic, but most patients enjoy a significant decrease in symptoms and medication usage. Only high-dose injected immunotherapy has been demonstrated to be effective. A beneficial response may persist for years after treatment is stopped. The clinical effects and immunologic responses are antigen-specific, but the treatment may also decrease the risk of developing new environmental sensitivities.
Procedure
A sterile aqueous solution of the allergen or allergens responsible for the patient's disease is administered by subcutaneous injection in increasing doses once or twice a week until a maintenance dose is reached, at which time the interval is advanced to every 4 weeks. The maintenance dose is typically one to ten thousand times the starting dose. Ascending doses are used to minimize the risk of systemic allergic reactions during initial stages of immunotherapy. Three to 5 years is a typical course of therapy. Oral immunotherapy remains experimental in the United States, and sublingual or low-dose immunotherapy is unconventional and of unproved efficacy.
Adverse effects
Reactions to treatment may be local or systemic. Localized immediate and late-phase skin reactions occur at injection sites. These are not harmful, but the dose must be adjusted to avoid excessively large or prolonged local reactions. Immediate systemic reactions or anaphylaxis is a potential problem with each injection and must be prevented by monitoring of dosage. The patient remains at the treatment facility for at least 20 minutes after each injection so that drugs and equipment for treating anaphylaxis will be available if needed. No long-term adverse consequences of aqueous allergen extract immunotherapy are known to have occurred in immunocompetent individuals.

Nelson HS. Advances in upper airway diseases and allergen immunotherapy. J Allergy Clin Immunol. 2006 May;117(5):1047–53. [PMID: 16675331]

Spirometry

What does it mean?

In simple terms, spirometry measures two parameters fully inflated lungs and the total volume of air from maximum inhalation to maximum exhalation, force to blow all the air out as hard and as healthy individual this forced expiratory manoeuvre
be completed in three to four seconds, but with obstruction it takes longer to push all the air severe COPD it may take up to 15 seconds.

Spirometry and lung function tests

Main points

1 Spirometry measures airflow and lung volumes, and is the preferred lung function test in COPD.
2 The forced vital capacity (FVC) is the total volume of air that can be exhaled with maximum force, starting from maximum inhalation and continuing to maximum
exhalation.
3 The forced expiratory volume in one second (FEV1) is the amount of air that can be exhaled in the first second of a forced blow from maximum inhalation.
4 Both the FVC and the FEV1 are expressed as volumes (in litres) and as a percentage of the predicted values. Predicted values have been determined from large population studies, and are dependent on age, height,gender and ethnicity.
5 The ratio of FEV1 to FVC (FEV1/FVC) is expressed as a percentage.Values of less than 70% indicate airflow obstruction.
6 In diseases that cause airflow obstruction the FEV1 will be below 80% of the predicted value and the FEV1/FVC ratio will be less than 70%. (In severe COPD the FVC may also be less than 80% of predicted.)
7 In restrictive lung diseases both the FEV1 and the FVC will be below 80% of the predicted value but the FEV1/FVC ratio will be normal or high.
8 The volume/time trace must be smooth, upward and free of irregularities.The graph must reach a plateau, demonstrating that the patient has blown to FVC.

Chronic bronchitis

Chronic bronchitis is defined by the Medical Research Council as:
‘The production of sputum on most days for at least three months in at least two consecutive years.’

This definition describes a set of symptoms that are extremely common, if not universal, among long-term smokers and widely recognised as the ‘smoker’s cough’. Not all smokers whose illness fits the definition of chronic bronchitis will have an accelerated decline in lung function; 80% of smokers do not, after all, develop
COPD. However, the GOLD guidelines suggest that those with a persistent cough and sputum production and a history of exposure to risk factors should be considered ‘at risk’ and should be tested for airflow obstruction even if they do not complain of breathlessness. Recent research from the Netherlands has supported this suggestion.
Random testing of smokers aged between 35 and 70 years revealed a reduced FEV1 in 18% of all smokers. The percentage with a reduced FEV1 rose to 27% in smokers with cough and to 48% of smokers over 60 years who also had a cough.

Mucus in the airways is produced by mucus glands, situated mainly in the larger airways, and by goblet cells, found mainly in the lining of the smaller airways. Mucus glands produce about 40 times more mucus than the goblet cells, and it may be that the excess mucus production in smokers not affected by progressive airflow
obstruction reflects changes in the large airways.This chronic hypersecretion of mucus with little airflow obstruction, in the absence of other reasons for chronic mucus production such as bronchiectasis,is known as ‘simple bronchitis’. However, in at-risk smokers who are developing chronic airflow obstruction, excess mucus production seems to accelerate the rate of decline of their lung function.

Chronic production of mucus is unpleasant and may predispose the sufferer to lower respiratory tract infection, but on its own is not thought to be universally associated with the development of airflow obstruction. Excess production of mucus ceases in the majority of smokers when they stop smoking, although an initial
short-term increase is a common experience in smokers when they quit.

Emphysema

Emphysema is defined in structural and pathological terms as:
‘A condition of the lung characterised by abnormal,permanent enlargement of the air spaces distal to the terminal bronchiole, accompanied by destruction of their walls.’

This definition describes a destructive process that is largely associated with cigarette smoking.Cigarette smoke is an irritant and results in low-grade inflammation of the airways and alveoli. Bronchoalveolar lavage of smokers’ lungs reveals increased numbers of inflammatory cells, notably macrophages and neutrophils. These inflammatory cells produce elastases – proteolytic enzymes that
destroy elastin, the protein that makes up lung tissue. In health, these enzymes are neutralised by anti-elastases, anti-proteolytic enzymes, the most widely studied of which is alpha-1 antitrypsin show the histology of normal lung tissue and of emphysema.

Alpha-1 antitrypsin deficiency accounts for 1–2% of all cases of diagnosed COPD. It provides a good model for our current understanding of the role of elastases and anti-elastases in the development of emphysema.

In early experiments, elastases introduced into lung tissue deficient in alpha-1 antitrypsin digested that lung tissue, thus producing emphysema.When alpha-1 antitrypsin was introduced into the deficient lung tissue – thereby effectively making it ‘normal’ – it protected against the action of the elastases and thus prevented emphysema.

That elastases are responsible for the destruction of lung tissue was confirmed by further experiments. A purified elastase was derived from neutrophils, a white blood cell attracted into the lungs of smokers. This neutrophil elastase (NE) was instilled into the lungs of experimental animals, causing a transient decrease in lung elastin, which then gradually returned to normal. However, although the loss of elastin was temporary, the structure of the animals’ lungs was permanently damaged.

The elastase/anti-elastase hypothesis for the development of emphysema in humans is that the irritant effect of cigarette smoke increases the level of elastases in the lungs beyond the body’s ability to neutralise them. Over many years lung elastin is lost, lung tissue is destroyed and emphysema results.

Although these and other experiments helped to explain the mechanisms behind the development of emphysema in people who are deficient in alpha-1 antitrypsin, it remains less clear what happens in people who are not deficient in this anti-proteolytic enzyme. There are several theories but further investigation is needed.
One theory is that, in some smokers, excessive numbers of inflammatory cells are attracted into the lungs in response to the irritant effects of cigarette smoke.These inflammatory cells, particularly neutrophils, are responsible for the release of elastases into the lung tissue; if too many are attracted into the lung, the amount of elastase they produce may outstrip the protective capacity of the
anti-elastases. It is thought that in some individuals the inflammatory cells themselves produce excessive amounts of elastases.

Yet another hypothesis is that there is excessive inactivation of the protective anti-elastases such that the individual is somewhat deficient in these protective enzymes. It is thought that this inactivation may be caused by oxidants that are both present in cigarette smoke and released from the activated inflammatory cells
present in the airways of smokers.

These hypotheses can be summarised as:

Abnormally high numbers of inflammatory cells are attracted into the airways,resulting in excessive production of elastases.

The inflammatory cells in the airways produce abnormally large amounts of elastases.

Oxidants found in cigarette smoke and released from inflammatory cells inactivate the protective anti-elastases in the lung.

In practice, all these mechanisms may be interacting in a single individual.Elastases, NE in particular, have been implicated in the development of chronic bronchitis as well as emphysema. They have been found to produce an increase in the number of goblet cells, a feature of chronic bronchitis. NE is also a potent inducer of mucus secretion, and causes a reduction of ciliary beat frequency.

Thus elastase/anti-elastase imbalance may be implicated not only in the development of emphysema but also in the pathogenesis of chronic bronchitis.

Risk factors of COPD

Cigarette smoking

Cigarette smoking is overwhelmingly the most important risk factor for the development of COPD. Indeed, this is reflected in the GOLD and NICE guidelines’ definition of the disease.Although COPD can occur in non-smokers, about 90% of cases are thought to be a direct result of cigarette smoking.

Lung function declines after the age of 30–35 years as part of the ageing process

In normal, healthy non-smokers the rate of decline of FEV1 is about 25–30ml a year.

In ‘at-risk’ smokers the rate of decline may be double that, at about 50–60ml a year.

Why some smokers are at risk of this accelerated decline and others are not has been the subject of considerable research. Involvement of genetic factors is suggested by the ‘clustering’ of COPD cases in some families. Although some of this increased risk may be due to shared environmental factors, studies of diverse populations
suggest that shared environment does not provide a full Pathology and pathophysiology explanation. The search for a ‘COPD gene’ has revealed a number
of possible candidates, but has so far been inconclusive. What is known is that lung function declines steadily over the years of smoking but the FEV1 often drops below 50% of predicted before symptoms appear. Patients usually present with symptoms of
COPD between the ages of 50 and 70 years. Although lost lung function is not regained when smoking is stopped, the rate of decline returns to that of a non-smoker or nonsusceptible smoker. This highlights the importance of the early detection of such high-risk smokers and persuading them to stop smoking. If they can be persuaded to stop, they may never suffer from severe, disabling and symptomatic COPD.

Even when a smoker has developed symptomatic disease, stopping smoking will still result in worthwhile salvage of lung function and improved life expectancy.The main message for patients is: It is never too late to stop!

Increasing age

COPD is a slowly progressive disorder, so increasing age is another risk factor. Symptoms appearing in someone under the age of 40 years should be regarded with suspicion and investigated fully. The decline in lung function as part of the normal ageing process and as accelerated by cigarette smoking.

Gender

COPD is currently more common in men than women in the UK.A 1997 study of physician-diagnosed COPD showed a prevalence rate of:

1.7% of men,

1.4% of women.

However, the bad news is that, although the prevalence increased in men by 25% between 1990 and 1997, the increase in women during the same period was 69%. In men the prevalence of COPD levelled out in the mid-1990s but is continuing to rise in women.

It is also well recognised that physician-diagnosed COPD rates are an under-estimate of the true prevalence.A national study of ventilatory function in British adults in the mid-1980s – probably a truer picture of the prevalence of COPD – found reductions in lung function in the following proportions of people aged 40–65 years:

18% of male smokers,

7% of male non-smokers,

14% of female smokers,

6% of female non-smokers.

A population study from the USA, conducted in the mid-1990s, supports this earlier British study. It found prevalence rates of airflow limitation in white males of:

14.2% of current smokers,

6.9% of ex-smokers,

3.3% of non-smokers.
In white females the rates were:

13.6% of current smokers,

6.8% of ex-smokers,

3.1% of non-smokers.

These differences between male and female smokers might be related to the fact that in this age cohort smoking was more common in men than in women.With the increase in the number of
women smokers, the preponderance of males is changing. Some recent work has suggested that female smokers are at even greater risk of developing COPD than their male counterparts.

Airway hyper-responsiveness

Airway hyper-responsiveness (AHR) has been proposed as a risk factor for the development of COPD. Certainly AHR is not the sole preserve of the person with asthma. It has been demonstrated extensively in smokers. Smokers also have raised levels of IgE, the
antibody associated with atopy and asthma.

This observation forms the basis of the so-called Dutch hypothesis. Some doctors in the Netherlands have long regarded COPD and asthma as two aspects of the same process, and believe that atrisk smokers share an ‘allergic’ constitution that, when combined
with smoking, is expressed as COPD. However, this hypothesis iscontroversial and it has been argued that raised levels of IgE and increased AHR in COPD patients could be the result of smoking rather than a pre-existing factor.

Lower socio-economic status

The prevalence of COPD is highest among people in lower socioeconomic groups. Smoking rates are higher in these groups, but this may not be the sole causative factor. Low birth weight is associated with a reduced FEV1 in adult life. Airways develop in the first 16 weeks of gestation, and alveoli mature and increase in number in the last six weeks of gestation and
first three years of life.The number of alveoli reaches adult levels of about 300 million by the age of 8 years. Thus, malnutrition of the fetus and serious lower respiratory tract infection (LRTI) in infancy during these periods of lung development may result in lung function failing to reach full potential.This may be an independent risk factor for reduced lung function in adult life and increased risk of COPD.

Maternal smoking has been extensively linked with low birth weight and recurrent LRTI in infancy, as have poor housing and social deprivation.

Poor diet

It has been suggested that antioxidants in the diet protect against the harmful effects of smoking and that a low dietary intake of antioxidant vitamins, such as vitamin C, is associated with decreased lung function and increased risk of COPD. Poor diet is also associated with socio-economic deprivation.

Occupation

Certain jobs have been linked with COPD. Coal mining is probably the most well-recognised occupational risk factor, but cotton processing, farming and other dusty occupations may also be relevant,particularly when added to the effects of smoking.Welding fumes are highly toxic, and welding, particularly in confined spaces, is suspected of being a risk factor. However, in the UK at present the only occupational cause of COPD for which compensation may be paid is coal mining.

Air pollution

Air pollution is often blamed by COPD sufferers for their disease.Before the Clean Air Acts of the 1950s, urban dwelling was associated with an increased risk: the air was polluted with heavy particles, soot and sulphur oxides. The pollution now experienced is mainly from vehicle exhaust emissions and photochemical pollutants such as ozone, produced by the action of sunlight on exhaust fumes. It is seldom disputed that these are respiratory irritants and that episodes of high pollution are associated with increased hospital admissions for respiratory problems.The role of these irritants as a cause of COPD, however, is more controversial. Nowadays, urban dwelling in the UK does not seem to pose a greater risk of COPD than rural dwelling.

Outdoor and indoor air pollution may, however, be significant in Third World countries. Indoor air pollution from biomass fuels, such as charcoal burned for cooking and heating, may carry a risk for the development of COPD.

Deficiency of alpha-1 antitrypsin

A rare, but well-recognised, risk factor for COPD is the inherited deficiency of alpha-1 antitrypsin. This is a protective enzyme that counteracts the destructive action of proteolytic enzymes in the lung. Deficiency of it is associated with the early development –
between the ages of 20 and 40 years – of severe emphysema (see also the section ‘Emphysema’, below).The deficiency is inherited in a homozygous fashion with a frequency of 1:4000 of the population. Both parents will be carriers but the possession of a single abnormal chromosome does not seem to cause severe disease.There is usually a strong family history of COPD. Family members should be tested for alpha-1 antitrypsin deficiency and, if affected, must be very strongly advised never to smoke.

Genetics

Alpha-1 antitrypsin deficiency is an extensively studied genetic risk factor for COPD. It is now believed that many other genetic factors increase (and decrease) an individual’s risk of developing COPD. Why there seem to be familial clusters of COPD cases and why some smokers develop COPD and others do not has intrigued many researchers.The genetics of COPD is being investigated intensively.

Pathology and pathophysiology COPD

Main points

1 COPD is not a discrete clinical entity, but a combination of emphysema, chronic bronchitis, small airways disease and chronic asthma.
2 The most important risk factor is cigarette smoking.
3 Treating persistent asthma early and aggressively with inhaled steroids may reduce the development of chronic airflow limitation.
4 Chronic mucus production alone is not always associated with the development of progressive airflow limitation;however, when there is progressive airflow limitation,chronic mucus production may accelerate the decline in lung function.
5 Emphysema is thought to develop as a result of an imbalance between elastase and anti-elastase activity in the lung.
6 Loss of lung elastin, such as occurs in emphysema,contributes to airway collapse, particularly during exercise.
7 Hyperinflation of the lungs leads to increased breathlessness on exertion.
8 Disruption of gas exchange leads to polycythaemia, cor pulmonale and respiratory failure.

Identifying patients with COPD

People with or at risk of COPD can be identified by the following measures.


Evaluating and optimising treatment in those with an existing diagnosis of chronic bronchitis, emphysema or COAD.

Reviewing patients over 40 labelled as having asthma or those taking bronchodilators who also smoke.

Performing spirometry on smokers with breathlessness, cough,sputum or wheeze. Recalling smokers with acute bronchitis,when they are well, to perform lung function testing.

Screening of asymptomatic smokers over 35 – there may beas many as 20% with airflow obstruction. A case-controlledstudy by van Schayck in the Netherlands found that in smokers aged over 35 years who also have a persistent cough, 27% had airflow obstruction on spirometry.

Encouraging patients to report to their GP surgery if they have symptoms – the British Thoracic Society and the British Lung Foundation have posters that can be displayed in surgeries and pharmacies.

Why COPD is important

Chronic obstructive pulmonary disease (COPD) is one of the most common and important respiratory disorders in primary care. About 32,000 people die from COPD each year in the UK, and the disease results in considerable morbidity, impaired quality of life, time off work, and more hospital admissions and GP consultations than asthma. However, its diagnosis and effective management have been largely neglected, apart from patients being advised to stop smoking.

COPD is a spectrum of diseases that includes:

chronic bronchitis,

emphysema,

long-standing asthma that has become relatively unresponsive to treatment,

small airways disease.

The unifying feature of COPD is that it is a chronic, slowly progressive disorder characterised by airflow obstruction that is not fully reversible and varies very little from day to day and month to month.

COPD is caused mainly by cigarette smoking. However, only 20% of smokers will develop COPD and there are no clear pointers to what makes them particularly susceptible to the adverse effects of tobacco smoke. It is probable that there are genetic factors that increase susceptibility to smoking but, as yet, no chromosomal
abnormalities have been identified other than for alpha-1 antitrypsin deficiency. Family studies have found that siblings of people with emphysema are three to four times more likely than controls to develop COPD if they smoke. For people who are affected, stopping smoking is the only way to slow the progression of the disease.
There are as yet no drugs that significantly improve the disease or alter the rate of decline of lung function.

The 1990s saw great improvements in the management and organisation of asthma treatment in primary care. COPD, by contrast,has been largely ignored and rightly has been dubbed the ‘Cinderella respiratory disorder’. This situation began to change with the publication and widespread dissemination to GPs and practice
nurses of the British Thoracic Society (BTS) COPD Guidelines in December 1997. Since then there has been considerable interest in the disease and its management.

Research papers on COPD have flourished at both British and international meetings. The BTS Guidelines have set out five goals for COPD management:

early and accurate diagnosis,

best control of symptoms,

prevention of deterioration,

prevention of complications,

improved quality of life.

Guidelines are important in aiding accurate and appropriate clinical decision-making but are not useful unless disseminated to all primary care doctors and practice nurses in a simple, readily digestible format. The BTS COPD Consortium produced a four-page summary of the 1997 Guidelines, which was widely distributed to primary care. The Consortium will similarly distribute a short summary of the NICE guidelines shortly after publication, with more detailed information available to view and download from the BTS website. The full guideline appeared as a supplement of Thorax in March 2004.

COPD in Primary Care

1 COPD is a common and important respiratory disorder that causes considerable morbidity and patient suffering.

2 It comprises a spectrum of diseases, including chronic bronchitis, emphysema, long-standing asthma that is no longer reversible and small airways disease.

3 COPD is a chronic, slowly progressive disorder characterised by airflow obstruction that varies very little from month to month.

4 The main cause of COPD is cigarette smoking.

5 COPD is more common in men and with increasing age.The prevalence is 2% of men aged 45–65 and 7% of men over 75 years. Some 32,000 people die from COPD each year in the UK.

6 It results in a large economic burden to the nation in excess of £800 million per year for health care.

7 The symptoms of breathlessness and coughing increasingly affect levels of activity, work, lifestyle and social interaction.

8 The first set of British clinical guidelines was published by the British Thoracic Society in 1997. Much new therapy and clinical information has appeared since then, and new evidence-based guidelines have thus been compiled by the National Institute for Clinical Excellence (NICE) and were published in February 2004 to update knowledge and best management.The new material comprises Chapter 11.

How important is COPD?

The most up-to-date figures suggest that 1.5% of the UK population have been diagnosed with COPD – a total of 900,000 people. Men are more likely to be affected than women, with prevalence rates of 2% in men aged 45–65 years and 7% in men over 75. The rates for women are rising, however, which is probably related to their increased smoking over the last 20 years.These figures are likely to be an under-estimate of the true prevalence, because much COPD may be mis-labelled as asthma.Moreover, most mild COPD goes unrecognised because patients are relatively symptomatic, with only minor symptoms such as a smoker’s cough or mild breathlessness on exertion. As a result, they often don’t consult their doctor. Recent studies indicate that as few as 1 person in 4 with COPD is recognised.
In 1999, COPD accounted for 7.4% of all deaths among men and 4.1% among women in the UK. Mortality tends to be greater in urban areas, particularly in South Wales, the north-west of England and Scotland. There is a strong association with lower social class and poverty that can be explained only partly by the higher smoking rates of this group.

On a more global basis, the WHO estimates the prevalence of COPD to be 600 million world-wide. COPD is currently the fifth greatest cause of mortality world-wide, with over 2.5 million deaths recorded in 2000. By 2020, COPD is projected to become the third leading cause of death and the fifth leading cause of morbidity. Most other chronic diseases, including coronary artery disease, strokes and cancer, are likely to decrease over this period.

A project for the future – when suitable government funding ismade available – might be to screen smokers over the age of 45 years with spirometry (see Chapter 4) to detect early airflow obstruction before symptoms start. It will still be difficult to persuade people at risk to stop smoking but, if they are successful at this point of the disease, most of them will never develop symptomatic COPD. This will produce major personal benefits for them as well as a significant cost saving to the NHS.

As the disease progresses, patients become increasingly short of breath – washing, getting dressed and minimal exertion become difficult.The effect on lifestyle can be devastating, resulting in physical suffering, mood change and depression, together with social isolation. Many sufferers will have to accept early retirement, which
can create financial problems for them. Even at a less severe level,many activities are restricted:

doing jobs around the house,

hobbies (e.g. gardening),

choice of holiday venues.

When one partner is significantly restricted, a marriage may be put under considerable strain. An important part of COPD management is to be aware of these
problems. Addressing social and psychological needs as well as encouraging patients to take as much regular exercise as possible should form an integral part of their care. Information on disability grants and aids, such as the Blue (formerly Orange) Badge parking scheme for people with disabilities, may help improve their overall
quality of life.