Neurology_Adams

Neurology_Adams. The diagnosis of orthostatic hypotension from autonomic failure is established by measuring the blood pressure in the supine and then in the standing position and noting a substantial drop accompanied by symptoms of dizziness or syncope. It should be emphasized that the bedside testing of orthostatic blood pressure is best performed by having the patient stand quickly and taking readings immediately and again at 1 min and at 3 min, rather than using the lying-sitting-standing sequence.


Neurology_Adams

Neurology_Adams. Orthostatic hypotension involves the failure to maintain blood pressure in the upright posture. The maintenance of blood pressure during various levels of activity and with postural changes depends on pressure-sensitive receptors (baroreceptors) in the aortic arch and carotid sinus and mechanoreceptors in the walls of the heart. These receptors, which are the sensory nerve endings of the glossopharyngeal and vagus nerves, send afferent impulses to the vasomotor centers in the medulla, more specifically the NTS. Axons from the NTS project to the reticular formation of the ventrolateral medulla, which in turn, sends fibers to the intermediolateral cell column of the spinal cord, thereby controlling vasomotor tone in skeletal muscles, skin, and the splanchnic bed. A diminution of sensory impulses from baroreceptors increases the flow of excitatory signals, which raise the blood pressure and cardiac output, thus restoring cerebral perfusion. This subject is discussed further in relation


Neurology_Adams

Neurology_Adams. from baroreceptors increases the flow of excitatory signals, which raise the blood pressure and cardiac output, thus restoring cerebral perfusion. This subject is discussed further in relation to the regulation of blood pressure in Chap. 25.


Neurology_Adams

Neurology_Adams. As described by Low and colleagues, postural orthostatic tachycardia syndrome (POTS) consists of intolerance of the standing position accompanied by tachycardia up to 120 beats per minute or more, but without orthostatic hypotension. Dyspnea, fatigue, and tremulousness and a complaint of “dizziness” accompany the assumption of an upright posture, and the same constellation of symptoms may be brought out by upright tilting. There is a frequent association with longer term fatigue and with exercise intolerance. The situation is comparable to orthostatic intolerance in the chronic fatigue and postviral syndromes, with which POTS shares many features. An impairment of cerebral autoregulation has been hypothesized; others consider the condition to be a limited form of dysautonomia. The component of the syndrome that simulates anxiety makes it difficult in some cases to differentiate the anticipation of symptoms from a genuine form of autonomic dysfunction.


Neurology_Adams

Neurology_Adams. Goldstein and associates compared a cohort of POTS patients with a group that experienced recurrent postural near-syncope and found that in the former group there was increased myocardial epinephrine release from intact cardiac sympathetic nerves. The basis for this is not known, although the researchers did exclude the possibility of defects in the cardiac norepinephrine transporter membrane and in norepinephrine synthesis.


Neurology_Adams

Neurology_Adams. This presents in two forms. In one, there is a selective degeneration of neurons in the sympathetic ganglia with denervation of smooth muscle vasculature and adrenal glands. The pathology has not been fully delineated, but lesions in other parts of the nervous system are not evident. In the second type, there is a degeneration of preganglionic neurons in the lateral columns of gray matter in the spinal cord, leaving postganglionic neurons isolated from spinal control. The latter lesion is often associated with degeneration of other systems of neurons in the CNS, particularly the basal ganglia but also the cerebellum. These processes are subsumed under the term multiple system atrophy, as discussed in Chap. 38. Parkinson disease and Lewy-body dementia may be associated with the same type of central loss of sympathetic neurons, but orthostatic hypotension and a variety of other features of autonomic insufficiency are early, more pronounced, and progressive in multiple system atrophy


Neurology_Adams

Neurology_Adams. of central loss of sympathetic neurons, but orthostatic hypotension and a variety of other features of autonomic insufficiency are early, more pronounced, and progressive in multiple system atrophy than in the other diseases named. Most of the dopaminergic drugs used in the treatment of Parkinson disease can exaggerate the hypotension. There are cases in which neuronal degeneration is limited to the sympathetic neurons of the intermediolateral cell columns—the Shy-Drager syndrome. All of these forms of degenerative disease have their onset in adult life, and the associated hypotension and syncope are usually part of a more widespread autonomic dysfunction that includes other features such as a fixed cardiac rate, vocal cord paralysis, a loss of sweating in the lower parts of the body, redness of the digits, atonicity of the bladder, constipation, and erectile dysfunction.


Neurology_Adams

Neurology_Adams. Syncope of Cardiac Origin This is caused by a sudden reduction in cardiac output, usually because of an arrhythmia. Normally, a heart rate as low as 35 to 40 beats per minute or as high as 150 beats per minute is well tolerated, especially if the patient is recumbent. Changes in heart rate beyond these extremes impair cardiac output and may lead to syncope. Upright posture, anemia, and coronary, myocardial, and valvular disease all render the individual more susceptible to these alterations in heart rate and rhythm. Detailed discussions of the various valvular and myocardial abnormalities and arrhythmias that may compromise cardiac output and lead to syncope are to be found in the articles by Lipsitz, and by Kapoor and colleagues.


Neurology_Adams

Neurology_Adams. Cardiac syncope occurs most frequently in patients with complete atrioventricular block and a heart rate of 40 beats or less per minute (Stokes-Adams attacks, or Adams-Stokes-Morgagni syndrome). The block may be persistent or intermittent; it is often preceded by fascicular or second-degree heart block. Ventricular arrest of 4 to 8 s, if the patient is upright, is enough to cause syncope; if the patient is supine, the asystole must last 12 to 15 s. After asystole of 12 s, according to Engel, the patient turns pale and becomes momentarily weak or may lose consciousness without warning; this may occur regardless of the position of the body. If the duration of cerebral ischemia exceeds 15 to 20 s, there are a few clonic jerks. With still longer asystole, the clonic jerks merge with tonic spasms and stertorous respirations and the ashen-gray pallor gives way to cyanosis, incontinence, fixed pupils, and bilateral Babinski signs. As heart action resumes, the face and neck become flushed.


Neurology_Adams

Neurology_Adams. and stertorous respirations and the ashen-gray pallor gives way to cyanosis, incontinence, fixed pupils, and bilateral Babinski signs. As heart action resumes, the face and neck become flushed. The report of this sequence of signs by a dependable observer helps to distinguish syncope from epilepsy. In cases of even more prolonged asystole (4 to 5 min), or if the patient is trapped in an upright or seated position for briefer periods, there may be cerebral injury caused by a combination of hypoxia and ischemia. Coma may persist or may be replaced by confusion and other neurologic signs. Focal ischemic changes, often irreversible, may then be traced to the fields of occluded atherosclerotic cerebral arteries or the border zones between the areas of supply of major arteries. Cardiac faints of the Stokes-Adams type may recur several times a day. The heart block is usually intermittent at first, and between attacks the electrocardiogram (ECG) may show no evidence of heart disease. A


Neurology_Adams

Neurology_Adams. of the Stokes-Adams type may recur several times a day. The heart block is usually intermittent at first, and between attacks the electrocardiogram (ECG) may show no evidence of heart disease. A continuous ECG using a Holter monitor or telemetry is then needed to demonstrate the arrhythmia (see further on).


Neurology_Adams

Neurology_Adams. Less easily recognized are faintness and syncope caused by dysfunction of the sinus node, and manifested by marked sinus bradycardia, sinoatrial block, or sinus arrest (“sick sinus syndrome”). The nodal block results in prolonged atrial asystole. Supraventricular tachycardia or atrial fibrillation may occur, alternating with sinus bradycardia (bradycardia–tachycardia syndrome).


Neurology_Adams

Neurology_Adams. Tachyarrhythmias alone are less likely to produce syncope. Certainly, intermittent ventricular fibrillation can cause fainting, and supraventricular tachycardias with rapid ventricular responses (usually over 180 beats per minute) cause syncope when sustained, predominantly in patients who are upright at the time. The long QT syndrome is a rare familial condition in which syncope and ventricular arrhythmias are prone to occur. Mutations in at least six different genes encoding cardiac sodium and potassium channels cause this syndrome. Another inherited syndrome with right bundle branch block and ST-segment elevation in the right precordial leads is known to cause syncope and even sudden death (Brugada syndrome). Some patients with mitral valve prolapse seem disposed to syncope and presyncope and an inordinate number are also said to have panic attacks but these associations, like others with mitral valve prolapse, have never been adequately settled.


Neurology_Adams

Neurology_Adams. Aortic stenosis or subaortic stenosis from cardiomyopathy often sets the stage for exertional syncope, because cardiac output cannot keep pace with the demands of exercise. Primary pulmonary hypertension and obstruction of right ventricular outflow (pulmonic valvular or infundibular stenosis) or intracardiac tumors may also be associated with exertional syncope. Syncope may also be a manifestation of large pulmonary embolism. Vagal overactivity may be a factor contributing to the syncope in these conditions as well as in the syncope that may accompany acute aortic outflow obstruction. Tetralogy of Fallot is the congenital cardiac malformation that most often leads to syncope. Other cardiac causes are listed in the classification given at the opening of this chapter.


Neurology_Adams

Neurology_Adams. It is now widely appreciated that syncope is not a manifestation of conventional cerebrovascular disease (see further on for discussion and the problem of “drop attacks” that do not have loss of consciousness as a feature). Specifically, syncope does not occur as a manifestation of TIAs that are confined to the territory of the internal carotid arteries and it is rare, if ever, that pure syncopal attacks occur with vertebrobasilar ischemia (see further on). Cases of syncope that do occur are usually associated with multiple occlusions of the large arteries in the thorax or neck. The main examples are found in patients with the aortic-arch syndrome (Takayasu disease) in which the brachiocephalic, common carotid, and vertebral arteries have become narrowed. Physical activity may then critically reduce blood flow to the upper part of the brainstem, causing abrupt loss of consciousness. Stenosis or occlusion of vertebral arteries and the “subclavian steal syndrome” are other examples of


Neurology_Adams

Neurology_Adams. reduce blood flow to the upper part of the brainstem, causing abrupt loss of consciousness. Stenosis or occlusion of vertebral arteries and the “subclavian steal syndrome” are other examples of cerebrovascular diseases that may cause syncope under the special circumstance of overuse of an arm (see Chap. 33). Fainting also occurs occasionally in patients with congenital anomalies of the upper cervical spine (Klippel-Feil syndrome) or cervical spondylosis, in which the vertebral circulation is compromised. Head turning may then cause vertigo, nausea and vomiting, visual scotomas and, finally, unconsciousness.


Neurology_Adams

Neurology_Adams. The onset of a subarachnoid hemorrhage may be signaled by a syncopal episode, often with transient apnea. Because the bleeding is arterial, there is a momentary cessation of cerebral circulation as the levels of intracranial pressure and blood pressure approach one another. Unless there has been vomiting, a complaint of headache immediately preceding the syncope, or the discovery of severe hypertension or stiff neck when the patient awakens, the diagnosis may not be suspected until a CT scan or lumbar puncture is performed.


Neurology_Adams

Neurology_Adams. An associated problem, with which we have had numerous unsatisfactory encounters, is posed by the patient who falls suddenly forward, striking the head without apparent cause, has headache, and is found to have bifrontal hematomas and subarachnoid blood on CT. These cases highlight the difficulty of distinguishing a primary aneurysmal subarachnoid hemorrhage from an accidental fall or syncope with secondary frontal brain contusions; in almost every case, we have felt obliged to perform some form of cerebral angiography to exclude an anterior communicating artery aneurysm, but we have rarely found one.


Neurology_Adams

Neurology_Adams. Hysterical fainting is rather frequent and usually occurs under dramatic circumstances (see Chap. 47). The evident lack of change in pulse, blood pressure, or color of the skin or any outward display of anxiety distinguishes it from the vasodepressor faint. Irregular jerking movements and generalized spasms without loss of consciousness or change in the EEG are typical features (Linzer et al, 1992). The diagnosis is based on these negative findings in a person who exhibits the general personality and behavioral characteristics of hysteria. Several interesting instances of mass faintness and syncope of hysterical type have been described—for example, in school marching bands (R.J. Levine). Syncope of Unknown Cause


Neurology_Adams

Neurology_Adams. Syncope of Unknown Cause Finally, after careful evaluation of patients with syncope and the exclusion of the many forms of the condition described earlier, there remains a significant proportion (one-third to one-half, according to Kapoor and 40 percent in the earlier-noted Framingham Heart Study) in which a cause for the syncope cannot be ascertained. The question of whether a single positive tilt-table test signifies that a prior episode of syncope was neurocardiogenic is not resolved; this obviously has a bearing on the proportion of cases that remain without a diagnosis. If the episodes are repetitive and erratically spaced, a cardiac arrhythmia, intraventricular conduction defect, or seizure should be sought by use of prolonged cardiac rhythm monitoring and conduction studies as well as long-term EEG recordings. Anxiety Attacks and the Hyperventilation Syndrome


Neurology_Adams

Neurology_Adams. Anxiety Attacks and the Hyperventilation Syndrome These are probably the most important diagnostic considerations in unexplained faintness without syncope. The light-headedness of anxiety and hyperventilation are frequently described as a feeling of faintness, but a loss of consciousness does not follow (see Linzer et al, 1990). Such symptoms are not accompanied by facial pallor or relieved by recumbency. The diagnosis is made on the basis of the associated symptoms, the absence of laboratory and tilt-table abnormalities, and the finding that part of the attack can be reproduced by having the patient hyperventilate. The symptoms produced in this way mimic the persistent or episodic dizziness that accompanies anxiety and panic states (see Chap. 14). When anxiety attacks are combined with a Valsalva effect or prolonged standing, fainting may occur. The relationship of anxiety-panic to the previously described postural orthostatic tachycardia syndrome is uncertain.


Neurology_Adams

Neurology_Adams. In diabetics and some nondiabetics, hypoglycemia may be an obscure cause of episodic weakness and very rarely of syncope. With progressive lowering of blood glucose, the clinical picture is one of hunger, trembling, flushed facies, sweating, confusion, and, finally, after many minutes, seizures and coma. The diagnosis depends largely on the history, the documentation of reduced blood glucose during an attack, and reproduction of the patient’s spontaneous attacks by an injection of insulin or hypoglycemia-inducing drugs (or ingestion of a high-carbohydrate meal in the case of reactive hypoglycemia). Fasting hypoglycemia suggests the presence of an insulin-secreting tumor (insulinoma). Acute hemorrhage, usually within the gastrointestinal tract, is a cause of weakness, faintness, or even unconsciousness when the patient stands suddenly. The cause (gastric or duodenal ulcer is the most common) may remain inevident until the passage of black stools.


Neurology_Adams

Neurology_Adams. This term has been applied to falling spells that occur without warning and without loss of consciousness or postictal symptoms. The patient, usually elderly, suddenly falls down while walking or standing, rarely while stooping. The knees inexplicably buckle. There is no dizziness or impairment of consciousness, and the fall is usually forward, with scuffing of the knees and sometimes the nose. The patient, unless obese, is able to right himself and to rise immediately and go his way, quite embarrassed. There may be several attacks during a period of a few weeks and none thereafter. The interval EEGs and ECGs are normal. One potential mechanism is a lapse of tone in leg muscles during the silent phase of an unnoticed myoclonic or axterixis jerk. Primary orthostatic tremor (see Chap. 4) has a similar appearance. Drop attacks also occur in acute hydrocephalus, and with the Chiari malformation, and these patients, although conscious, may not be able to arise for several hours. Rare


Neurology_Adams

Neurology_Adams. 4) has a similar appearance. Drop attacks also occur in acute hydrocephalus, and with the Chiari malformation, and these patients, although conscious, may not be able to arise for several hours. Rare instances of Ménière disease, in which the patient is suddenly thrown to the ground (“otolithic catastrophe of Tumarkin,” see “Ménière Disease and Other Forms of Labyrinthine Vertigo” in Chap. 14) may be mistaken for a syncopal or drop attack, but only briefly, until vertigo becomes prominent.


Neurology_Adams

Neurology_Adams. Drop attacks as defined above are usually without an identifiable mechanism, requiring no treatment if cardiologic studies are normal. On uncertain grounds, they are often attributed to brainstem ischemia. In only about one-quarter of such cases, according to Meissner and coworkers, can an association be made with cardiovascular or cerebrovascular disease to which treatment should be directed. Orthopedic surgeons and rheumatologists are familiar with knee-buckling attacks, which they attribute to arthritic or tendinous disorders of the knee. Painful impulses arising in and around the knee could result in brief reflex silence of the antigravity muscles (primarily the quadriceps), producing a phenomenon akin to asterixis. Greenwood and Hopkins long ago proposed this mechanism. Although brief periods of silence have been recorded in the quadriceps muscles of patients with drop attacks, the reflex mechanism and its relationship to knee pain is speculative.


Neurology_Adams

Neurology_Adams. In epilepsy, whether convulsive or not, the arrest in consciousness is almost instantaneous and, as revealed by the EEG, is accompanied by a paroxysm of electrical activity occurring simultaneously in all of the cerebral cortex and thalamus. There are a number of important clinical distinctions between epileptic and syncopal attacks. The epileptic attack may occur day or night, regardless of the position of the patient; syncope rarely appears when the patient is recumbent, the only common exception being the Stokes-Adams attack. The patient’s color usually does not change at the onset of an epileptic attack; pallor is an early and almost invariable finding in most types of syncope except those caused by chronic orthostatic hypotension or hysteria, and it precedes unconsciousness. If an aura is present, it rarely lasts longer than a few seconds before consciousness is abolished. The onset of syncope is usually more gradual, and the prodromal symptoms are quite distinctive and different


Neurology_Adams

Neurology_Adams. is present, it rarely lasts longer than a few seconds before consciousness is abolished. The onset of syncope is usually more gradual, and the prodromal symptoms are quite distinctive and different from those of seizures. In general, injury from falling is more frequent in epilepsy than in syncope, because protective reflexes are instantaneously abolished in the former. (Nevertheless, cardiogenic syncope is an important cause of hurtful falls, especially in the elderly.) The return of consciousness is slow in epilepsy, prompt in syncope; mental confusion, headache, and drowsiness are common sequelae of seizures, and physical weakness with clear sensorium, of syncope (a brief period of grogginess may follow vasodepressor syncope). Biting of the tongue is well known, albeit not always present in convulsion; it is exceptional in syncope. Repeated spells of unconsciousness in a young person at a rate of several per day or month are much more suggestive of epilepsy than of syncope.


Neurology_Adams

Neurology_Adams. Tonic spasm of muscles with upturning of the eyes is a prominent and often initial feature of epilepsy, but also occurs in the course of a faint and cannot be depended upon to make the distinction between the two processes. Urinary incontinence is a frequent occurrence in epilepsy, but it need not occur during an epileptic attack and may occasionally occur with syncope, so that it also cannot be used as a means of separating the disorders.


Neurology_Adams

Neurology_Adams. The EEG may be helpful in differentiating syncope from epilepsy. In the interval between epileptic seizures, the EEG, particularly if repeated once or twice, shows some degree of abnormality in 50 to 75 percent of cases, whereas it should be normal between syncopal attacks. Sometimes one must resort to continuous EEG monitoring to clarify the situation (this can be combined with continuous ECG recording). Another useful laboratory marker of a seizure, especially if unwitnessed, is an elevation of the serum creatine kinase (CK) concentration; such a finding occurs only infrequently in the rare case of syncope associated with extensive muscle trauma. Elevated prolactin levels have not proved discriminating enough for routine use in separating seizure from syncope but remain useful in distinguishing both of these from other causes of loss of consciousness, particularly hysteria, in which such elevations do not occur.


Neurology_Adams

Neurology_Adams. No single criterion will absolutely differentiate epilepsy from syncope, but taken as a group and supplemented by the EEG, these criteria usually enable one to distinguish the two conditions. Cardiovascular structures represented in the insular cortex may give rise to seizures that produce cardiac arrhythmias, leading in turn to syncope. As a rule, seizures arising from the left insula prolong the QT interval and increase sympathetic tone, thereby lowering the threshold for ventricular arrhythmia, whereas those arising from the right insula shorten the QT interval and increase parasympathetic tone, thereby increasing the risk of vagally mediated syncope. Sympathetic storms may arise from the brain in circumstances of generalized injury (e.g., trauma, subarachnoid hemorrhage, infarction, or intracerebral hemorrhages). When severe, this sympathetic hyperactivity can cause acute left ventricular apical ballooning, known as takotsubo cardiomyopathy.


Neurology_Adams

Neurology_Adams. In patients who complain of recurrent faintness or syncope but do not have a spontaneous occurrence while under observation, an attempt to reproduce attacks may prove to be of great assistance in diagnosis. Here it is important to recall that normal persons can faint if made to squat and overbreathe and then to stand erect and hold their breath (especially if the Valsalva maneuver is added). Prolonged standing at attention in the heat often causes even well-conditioned soldiers to faint, as does compression of the chest and abdomen while holding one’s breath, as in the parlor trick of adolescents (“fainting lark”).


Neurology_Adams

Neurology_Adams. When an anxiety state is accompanied by faintness, the pattern of symptoms can often be reproduced by having the subject hyperventilate—that is, breathe rapidly and deeply for 2 to 3 min. This test may also be of therapeutic value, because the underlying anxiety tends to be lessened when the patient learns that the symptoms can be produced and alleviated at will simply by controlling breathing. Most patients with tussive syncope cannot reproduce an attack by the Valsalva maneuver but can sometimes do so by voluntary coughing, if severe enough. Another useful procedure is to have the patient perform the Valsalva maneuver for more than 10 s (thus trapping blood behind closed valves in the veins) while the pulse and blood pressure are measured (see “Tests for Abnormalities of the Autonomic Nervous System” in Chap. 25).


Neurology_Adams

Neurology_Adams. In each of the aforementioned instances, the crucial point is not whether symptoms are produced but whether they reproduce the exact pattern of symptoms that occurs in the spontaneous attacks. Other conditions in which the diagnosis is clarified by reproducing the attacks are carotid sinus hypersensitivity (massage of one or the other carotid sinus) and orthostatic hypotension (observations of pulse rate, blood pressure, and symptoms in the recumbent and standing positions or, even better, with the patient on a tilt table). The measurement of beat-to-beat variation in heart rate is a simple but sensitive means of detecting vagal dysfunction, as described in Chap. 25 but its role in the evaluation of syncope has not been established.


Neurology_Adams

Neurology_Adams. Careful, continuous monitoring of the ECG in the hospital or by using a portable (Holter) recorder may determine whether an arrhythmia is responsible for the syncopal episode. A continuous cardiac loop ECG recorder (which continually records and erases cardiac rhythm) permits prolonged (a month or longer) ambulatory monitoring at reasonable cost. The diagnostic yield from loop recording is modestly greater than that from Holter monitoring (Linzer et al, 1990). Upright tilting on a tilt table may cause, within seconds, up to 20 or 25 mm Hg drop in systolic blood pressure and 5 to 10 mm Hg in diastolic pressure in normal individuals, usually with only minor symptoms. In response, the heart rate rises 5 to 15 beats per minute.


Neurology_Adams

Neurology_Adams. There are two types of abnormal response to upright tilting: (1) early hypotension (occurring within moments of tilting) that slowly progresses with continued upright posture; this signifies inadequate sympathetic tone and baroreceptor function; and (2) a delayed (up to several minutes) hypotension that appears abruptly at the end of that period and indicates a neurocardiogenic mechanism.


Neurology_Adams

Neurology_Adams. The normal response to a 60to 80-degree head-up tilt after approximately 10 min is a transient drop in systolic blood pressure (5 to 15 mm Hg), a rise in diastolic pressure (5 to 10 mm Hg), and a rise in heart rate (10 to 15 beats per minute). Hypotension and fainting after tilting for this duration, a positive test, as already emphasized, is taken as a proclivity to neurocardiogenic fainting and at least an ostensible explanation for the problem. However, because it occurs in a proportion of individuals who have never fainted; it is not to be taken as incontrovertible evidence that a recent spell is explained by this mechanism. Although controversial, in some circumstances the infusion of the catecholamine isoproterenol (1 to 5 mcg/min for 30 min during head-up tilt) may be a more effective means of producing hypotension (and syncope) than the standard tilt test alone (Almquist et al; Waxman et al). While it brings out more cases of neurocardiogenic syncope, some of these are false


Neurology_Adams

Neurology_Adams. means of producing hypotension (and syncope) than the standard tilt test alone (Almquist et al; Waxman et al). While it brings out more cases of neurocardiogenic syncope, some of these are false positives.


Neurology_Adams

Neurology_Adams. Patients seen during the preliminary stages of fainting or after they have lost consciousness should be placed in a position that permits maximal cerebral blood flow, that is, with head lowered between the knees if sitting, or, far preferably, in the supine position with legs elevated. All tight clothing and other constrictions should be loosened and the head and body positioned so that the tongue does not fall back into the throat and the possible aspiration of vomitus is avoided. Nothing should be given by mouth until the patient has regained consciousness. The patient should not be permitted to rise until the sense of physical weakness and the appearance of pallor have passed and he should be watched carefully for a few minutes after arising.


Neurology_Adams

Neurology_Adams. As a rule, the physician sees the patient after recovery from the faint and is asked to explain why it happened and how it can be prevented in the future. One should think first of those causes of fainting that constitute a therapeutic emergency. Among them are massive internal hemorrhage and myocardial infarction, and cardiac arrhythmias. In an elderly person, a sudden faint without obvious cause must always arouse the suspicion of a complete heart block or other cardiac arrhythmia.


Neurology_Adams

Neurology_Adams. The prevention of fainting depends on the mechanisms involved. In the usual vasodepressor faint of adolescents—which tends to occur in circumstances favoring vasodilatation (warm environment, hunger, fatigue, alcohol intoxication) and periods of emotional excitement—it is enough to advise the patient to avoid such circumstances and to maintain adequate hydration. In postural hypotension, patients should be cautioned against arising suddenly from bed. Instead, they should first exercise the legs for a few seconds, then sit on the edge of the bed and make sure they are not light-headed or dizzy before starting to walk. Standing for prolonged periods can sometimes be tolerated without fainting by crossing the legs forcefully. The same regimen suffices for cases of syncope from deconditioning. Alternatives should be found for medications that are conceivable causes of orthostasis. β-Adrenergic blocking agents, diuretics, antidepressants, and sympatholytic antihypertensive drugs are the


Neurology_Adams

Neurology_Adams. Alternatives should be found for medications that are conceivable causes of orthostasis. β-Adrenergic blocking agents, diuretics, antidepressants, and sympatholytic antihypertensive drugs are the common culprits.


Neurology_Adams

Neurology_Adams. In the syndrome of chronic orthostatic hypotension, from central or peripheral sympathetic failure, special mineralocorticoid preparations—such as fludrocortisone acetate (Florinef) 0.05 to 0.4 mg/d in divided doses—and increased salt intake to expand blood volume are helpful. The α1-agonist midodrine, beginning with 2.5 mg every 4 h and slowly increasing the dose to 5 mg every 4 to 6 h, has been used successfully in several studies, but this medication has the potential to worsen the situation and must be used with care. Domperidone may be helpful in patients with parkinsonism but it may prolong the Q-T interval. Sleeping with the head posts of the bed elevated on wooden blocks 8 to 12 in high and wearing a snug elastic abdominal binder and elastic stockings are measures that often prove helpful. Tyramine and monoamine oxidase inhibitors have given limited relief in some cases of Shy-Drager syndrome, and β-blockers (propranolol or pindolol) and indomethacin (25 to 50 mg tid) in


Neurology_Adams

Neurology_Adams. prove helpful. Tyramine and monoamine oxidase inhibitors have given limited relief in some cases of Shy-Drager syndrome, and β-blockers (propranolol or pindolol) and indomethacin (25 to 50 mg tid) in others. These and other approaches that have proved useful in treating orthostatic hypotension are reviewed by Mathias and


Neurology_Adams

Neurology_Adams. Kimber. Anticholinesterase drugs such as pyridostigmine are entering a phase of popularity for the treatment of many forms of orthostatic hypotension (Singer and colleagues). Neurally mediated syncope (neurocardiogenic or vasodepressor syncope), identified largely by the clinical circumstances and by tilt-table testing, may be prevented by the use of β-adrenergic blocking agents. Our colleagues in cardiology have recently favored acebutolol 400 mg daily, in part because of its partial α-adrenergic activity, which raises baseline blood pressure, but atenolol 50 mg may be as effective. The anticholinergic agent disopyramide has also been used (Milstein et al). Several other drugs (e.g., ephedrine, metoclopramide, dihydroergotamine) have been variably successful in individual patients, but their utility as standard medications remains to be established; the β-blocking agents are generally preferred.


Neurology_Adams

Neurology_Adams. The treatment of carotid sinus syncope involves, first of all, instructing the patient in measures that minimize the hazards of a fall (see in the following text). A loose collar should be worn, and the patient should learn to turn his whole body, rather than the head alone, when looking to one side. Atropine or one of the sympathomimetic group of drugs may be used, respectively, in patients with pronounced bradycardia or hypotension during attacks. If atropine is not successful, and it is certainly not practical for any period of time, and the syncopal attacks are incapacitating, the insertion of a dual-chamber pacemaker should be considered. Radiation or surgical denervation of the carotid sinus had apparently yielded favorable results in some patients, but it is no longer practiced. Vagovagal attacks usually respond well to an anticholinergic agent (propantheline, 15 mg tid). Syncope arising from glossopharyngeal neuralgia tends to benefit from medications that reduce the incidence


Neurology_Adams

Neurology_Adams. attacks usually respond well to an anticholinergic agent (propantheline, 15 mg tid). Syncope arising from glossopharyngeal neuralgia tends to benefit from medications that reduce the incidence of episodes, such as gabapentin.


Neurology_Adams

Neurology_Adams. In the elderly person, a faint carries the additional hazard of a fracture or other trauma as a consequence of the fall. Therefore the patient subject to recurrent syncope should cover the bathroom floor and bathtub with mats and have as much of his home carpeted as is feasible. Especially important is the floor space between the bed and the bathroom, because this is the route along which faints in elderly persons most commonly occur. Outdoor walking should be on soft ground rather than hard surfaces, and the patient should avoid standing still for prolonged periods, which is more likely than walking to induce an attack. Padded hip protectors, now available as a commercial product, should be considered in elderly patients at risk of recurrent falls of any kind but evidence of their effectiveness in large populations is, so far lacking. Abboud FM: Neurocardiogenic syncope. N Engl J Med 328:1117, 1993.


Neurology_Adams

Neurology_Adams. Abboud FM: Neurocardiogenic syncope. N Engl J Med 328:1117, 1993. Almquist A, Goldenberg IF, Milstein S, et al: Provocation of bradycardia and hypotension by isoproterenol and upright posture in patients with unexplained syncope. N Engl J Med 320:346, 1989. Bannister R, Mathias W (eds): Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 4th ed. New York, Oxford University Press, 1999. Bechir M, Binggeli C, Corti R, et al: Dysfunctional baroreflex regulation of sympathetic nerve activity in patients with vasovagal syncope. Circulation 107:1620, 2003. Compton D, Hill PM, Sinclair JD: Weight-lifters’ blackout. Lancet 2:1234, 1973. Engel GL: Fainting, 2nd ed. Springfield, IL, Charles C Thomas, 1962. Frank JI, Ropper AH, Zuniga G: Vasodepressor carotid sinus syncope associated with a neck mass. Neurology 42:1194, 1992. Gastaut H, Fischer-Williams M: Electro-encephalographic study of syncope: Its differentiation from epilepsy. Lancet 2:1018, 1957.


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Neurology_Adams. Gastaut H, Fischer-Williams M: Electro-encephalographic study of syncope: Its differentiation from epilepsy. Lancet 2:1018, 1957. Goldstein DS, Holmes C, Frank SM, et al: Cardiac sympathetic dysautonomia in chronic orthostatic intolerance syndromes. Circulation 106:2358, 2002. Greenwood R, Hopkins A: Landing from an unexpected fall and voluntary step. Brain 99:375, 1976. Jarisch A, Zoterman Y: Depressor reflexes from the heart. Acta Physiol Scand 16:31, 1948. Kapoor WN: Evaluation and management of the patient with syncope. JAMA 268:2553, 1992. Kapoor WN, Karpf M, Maher Y, et al: Syncope of unknown origin. JAMA 247:2687, 1982. Kaufmann H: Neurally mediated syncope: Pathogenesis, diagnosis, and treatment. Neurology 45(Suppl 5):S12, 1995. Levin B, Posner JB: Swallow syncope: Report of a case and review of the literature. Neurology 22:1086, 1972. Levine RJ: Epidemic faintness and syncope in a school marching band. JAMA 238:2373, 1977.


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Neurology_Adams. Levine RJ: Epidemic faintness and syncope in a school marching band. JAMA 238:2373, 1977. Lewis T: A lecture on vasovagal syncope and the carotid sinus mechanism. Br Med J 1:873, 1932. Linzer M, Pritchett ELC, Pontinen M, et al: Incremental diagnostic yield of loop electrocardiographic recorders in unexplained syncope. Am J Cardiol 66:214, 1990. Linzer M, Varia I, Pontinen M, et al: Medically unexplained syncope: Relationship to psychiatric illness. Am J Med 92:185, 1992. Lipsitz LA: Orthostatic hypotension in the elderly. N Engl J Med 321:952, 1989. Low PA, Opfer-Gehrking TL, Textor SC, et al: Postural tachycardia syndrome (POTS). Neurology 45(Suppl 5):19, 1995. MacDonald DR, Strong E, Nielsen S, Posner JB: Syncope from head and neck cancer. J Neurooncol 1:257, 1983. Mark AL: The Bezold-Jarisch reflex revisited: Clinical implications of inhibitory reflexes originating in the heart. J Am Coll Cardiol 1:90, 1983.


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Neurology_Adams. Mark AL: The Bezold-Jarisch reflex revisited: Clinical implications of inhibitory reflexes originating in the heart. J Am Coll Cardiol 1:90, 1983. Mathias CJ, Keguchi K, Bleasdale-Barr K, Kimber JR: Frequency of family history in vasovagal syncope. Lancet 352:33, 1998. Mathias CJ, Kimber JR: Treatment of postural hypotension. J Neurol Neurosurg Psychiatry 65:285, 1998. Meissner L, Wiebers DO, Swanson JW, O’Fallon WM: The natural history of drop attacks. Neurology 36:1029, 1986. Milstein S, Buetikofer J, Dunnigan A, et al: Usefulness of disopyramide for prevention of upright tilt-induced hypotension bradycardia. Am J Cardiol 65:1339, 1990. Norcliffe-Kaufmann LJ, Kaufmann H, Hainsworth R: Enhanced vascular responses to hypocapnia in neurally medicated syncope. Ann Neurol 63:288, 2008.


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Neurology_Adams. Norcliffe-Kaufmann LJ, Kaufmann H, Hainsworth R: Enhanced vascular responses to hypocapnia in neurally medicated syncope. Ann Neurol 63:288, 2008. Oberg B, Thoren P: Increased activity in left ventricular receptors during hemorrhage or occlusion of caval veins in the cat: A possible cause of the vasovagal reaction. Acta Physiol Scand 85:164, 1972. Shy GM, Drager GA: A neurological syndrome associated with orthostatic hypotension: A clinical-pathologic study. Arch Neurol 2:511, 1960. Singer W, Sandroni P, Opfer-Gehrking TL, et al. Pyridostigmine treatment trial in neurogenic orthostatic hypotension. Archives of Neurology, 63:513, 2006. Soteriades ES, Evans JC, Larson MG, et al: Incidence and prognosis of syncope. N Engl J Med 347:878, 2002. Wallin BG, Sundlof G: Sympathetic outflow to muscles during vasovagal syncope. J Auton Nerv Syst 6:287, 1982.


Neurology_Adams

Neurology_Adams. Wallin BG, Sundlof G: Sympathetic outflow to muscles during vasovagal syncope. J Auton Nerv Syst 6:287, 1982. Wallin BG, Westerberg CE, Sundlof G: Syncope induced by glossopharyngeal neuralgia: Sympathetic outflow to muscle. Neurology 34:522, 1984. Waxman MB, Yao L, Cameron DA, et al: Isoproterenol induction of vasodepressor-type reaction in vasodepressor-prone persons. Am J Cardiol 63:58, 1989. Weiss S, Ferris EB Jr: Adams-Stokes syndrome with transient complete heart block of vagovagal reflex origin: Mechanism and treatment. Arch Intern Med 54:931, 1934.


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Neurology_Adams. Everyone, of course, has had a great deal of personal experience with sleep, or lack of it, and has observed people in sleep, so it requires no special knowledge to understand something about this condition or to appreciate its importance to health and well-being. Sleep, that familiar yet inexplicable condition of repose in which consciousness is in abeyance, is obviously not abnormal, yet it is connected with a number of interesting and common irregularities, some of which approach serious extremes. Furthermore, certain neurological conditions have special types of sleep disorders as common features. The psychologic and physiologic benefits of sleep are of paramount importance, and it is increasingly recognized that disruption of sleep increases the risks for several diseases, including stroke, hypertension, and coronary disease.


Neurology_Adams

Neurology_Adams. Physicians are frequently consulted by patients who suffer from some derangement of sleep. Most often, the problem is one of sleeplessness, but sometimes it concerns excessive sleepiness or some peculiar phenomenon occurring in connection with sleep. Certain points concerning normal sleep and the sleep–wake mechanisms are worth reviewing, as familiarity with them is necessary for an understanding of disorders of sleep. A great deal of information about sleep and sleep abnormalities is now available as a result of the development of the subspecialty of sleep medicine and the existence of centers for the diagnosis and treatment of sleep disorders. Most disorders of sleep can be readily recognized if one attends closely to the patient’s description of the disturbance. Cases requiring the documentation of apneic episodes or those with more complex disorders such as seizures and other motor symptoms during sleep, benefit from attention in sleep laboratories.


Neurology_Adams

Neurology_Adams. Sleep represents one of the basic 24-h (circadian) rhythms, traceable through all mammalian, avian, and reptilian species. The neural control of circadian rhythms is thought to reside in the ventral-anterior region of the hypothalamus, more specifically, in the suprachiasmatic nuclei. The intrinsic circadian rhythm of about 25 hours exists independent of light entrainment but is altered to conform to the day by light. Lesions in these nuclei result in a disorganization of the sleep–wake cycles as well as of the rest–activity, temperature, and feeding rhythms. Chapter 26 describes the ancillary role of melatonin and the pineal body in modulating this cyclic activity. There is also an important dimension of a homeostatic drive to sleep as the day wears on. Effects of Age


Neurology_Adams

Neurology_Adams. Effects of Age Observations of the human sleep–wake cycle show it to be closely age linked. The newborn baby sleeps from 16 to 20 h a day, and the child, 10 to 12 h. Total sleep time drops to 9 to 10 h by mid-adolescence and to about 7 to 7.5 h during young adulthood. A gradual decline to about 6.5 h develops in late adult life. However, there are wide individual differences in the length and depth of sleep, apparently as a result of genetic factors, early life conditioning, the amount of physical activity, and psychologic states.


Neurology_Adams

Neurology_Adams. The pattern of sleeping, which is adjusted to the 24-h day, also varies in the different epochs of life. The circadian rhythm, with predominance of daytime wakefulness and nighttime sleep, begins to appear only after the first few weeks of postnatal life of the full-term infant; as the child matures, the morning nap is omitted, then the afternoon nap; by the fourth or fifth year, sleep becomes consolidated into a single long nocturnal period. (Actually, a large part of the world’s population continues to have an afternoon nap, or siesta, as a lifelong sleep–wake pattern.) Fragmentation of the sleep pattern begins in late adult life. Over ensuing years, night awakenings tend to increase in frequency, and the daytime waking period may be interrupted by episodic sleep lasting seconds to minutes (microsleep), as well as by longer naps. From about 35 years of age onward, women tend to sleep slightly more than men. Stages of Sleep


Neurology_Adams

Neurology_Adams. Stages of Sleep Seminal contributions to our understanding of the physiology of sleep were made by Loomis and associates and by Aserinsky, Dement and Kleitman through electroencephalographic analysis and clinical observation. As a result of their studies, five stages of sleep have been defined. In each stage, the electrical activity of the brain occurs in organized and recurring cycles, referred to as the architecture of sleep. As the electrophysiologic stages of sleep progress, sleep becomes deeper, meaning that arousal requires a more intense stimulus. These findings put to rest the antiquated ideas that sleep is a purely passive state and reflects fatigue and reduction in environmental stimuli.


Neurology_Adams

Neurology_Adams. Relaxed wakefulness with the eyes closed is accompanied in the electroencephalogram (EEG) by posterior alpha waves of 9 to 11 Hz (cycles per second) and intermixed low-voltage fast activity of mixed frequency. Except for the facial muscles, the electromyogram (EMG) is silent when the patient is sitting or lying quietly. With drowsiness, as the first stage of sleep sets in, the eyelids begin to droop, the eyes may rove slowly from side to side, and the pupils become smaller. As the early stage of sleep evolves, the muscles relax and the EEG pattern changes to one of progressively lower voltage and mixed frequency with a loss of alpha waves; this is associated with slow, rolling eye movements and is stage 1 sleep. With progression to stage 2 sleep, there is the appearance of 0.5to 2-s bursts of biparietal 12to 14-Hz waves (sleep spindles) and intermittent high-amplitude, central-parietal sharp slow-wave complexes (vertex waves) (Fig. 18-1). Stage 3 represents slow-wave sleep with


Neurology_Adams

Neurology_Adams. bursts of biparietal 12to 14-Hz waves (sleep spindles) and intermittent high-amplitude, central-parietal sharp slow-wave complexes (vertex waves) (Fig. 18-1). Stage 3 represents slow-wave sleep with predominant theta rhythms and stage 4, deep slow wave sleep with a preponderance of delta frequency activity. Vertex waves and sleep spindles are no longer evident.


Neurology_Adams

Neurology_Adams. If the eyelids are raised gently during sleep, the globes are usually seen to be exotropic and the pupils are even smaller than before, but with retained responses to light. An additional stage of the sleep cycle, which follows the others intermittently throughout the night, is associated with further reduction in muscle tone except in the extraocular muscles and with bursts of rapid eye movement; thus the term rapid eye movement (REM) sleep designates this stage. The EEG becomes desynchronized, that is, it has a low-voltage, high-frequency discharge pattern. The first three stages of sleep are called nonrapid eye movement (NREM) sleep or synchronized sleep; the last stage, in addition to REM sleep, is variously designated as fast-wave, nonsynchronized, or desynchronized sleep. Figure 18-2 illustrates these features.


Neurology_Adams

Neurology_Adams. The American Academy of Sleep Medicine now recommends the following nomenclature: stage W (wakefulness), stage N1 (non-REM sleep, or NREM 1, formerly stage 1), stage N2 (NREM 2, formerly stage 2), stage N3 (NREM 3, combining former stages 3 and 4—or slow-wave sleep), and stage R (REM sleep) (Fig. 18-3). The essential difference between this new nomenclature and the one formerly used by neurologists is that stage N3 now represents slow-wave sleep, replacing stage 3 and stage 4 sleep, composed of an increasing proportion of high-amplitude delta waves (0.75 μV, 0.5 to 2 Hz) in the EEG (Table 18-1).


Neurology_Adams

Neurology_Adams. In the first portion of a typical night’s sleep, the normal young and middle-aged adult passes successively through stages N1, N2, N3, and R (REM) sleep. After about 70 to 100 min, a large proportion of which consists of stage N3 sleep, the first REM period occurs, usually heralded briefly by a transient increase in body movements and a shift in the EEG pattern from that of stage N3 to stage N2. This NREM–REM cycle is repeated at about the same interval four to six times during the night, depending on the total duration of sleep. The first REM period may be brief; the later cycles have less stage N3 sleep or none at all. In the latter portion of a night’s sleep, the cycles consist essentially of two alternating stages—REM sleep and stage N2 (spindle–K-complex) sleep. The relation of dreaming to these sleep stages is described further on.


Neurology_Adams

Neurology_Adams. Newborn full-term infants spend approximately 50 percent of their sleep in the REM stage (although their EEG and eye movements differ from those of adults). The newborn sleep cycle lasts about 60 min (50 percent REM, 50 percent NREM, generally alternating through a 3to 4-h interfeeding period); with age, the sleep cycle lengthens to 90 to 100 min. Approximately 20 to 25 percent of total sleep time in young adults is spent in REM sleep, 3 to 5 percent in stage N1, 50 to 60 percent in stage N2, and 10 to 20 percent in stage N3 combined. The amount of sleep in N3 decreases with age, and persons older than 70 years of age have virtually no very deep slow-wave sleep (Fig. 18-3). The 90to 100-min cycle is fairly stable in any one person and is believed to continue to operate to a less-perceptible degree during wakefulness in relation to a number of other cyclic phenomena, such as core body temperature, gastric motility, hunger, urinary output, alertness, and capacity for cognitive activity.


Neurology_Adams

Neurology_Adams. A comparison of the physiologic changes in NREM and REM sleep is of interest. The change in the EEG pattern has already been indicated. Cortical neurons tend to discharge in synchronized bursts during NREM sleep and in nonsynchronized bursts during wakefulness. In REM sleep, the EEG pattern is generally asynchronous as well. Much of the night’s complex visual dreaming has been found to occur in the REM period, with the qualifications noted below, and dreams are recalled most consistently if the subject is awakened during this time. It is important to point out, however, that dreaming activity is reported by subjects awakened from NREM sleep, although less consistently. Because the overall time spent in NREM is so much greater than that in REM, approximately 20 percent of dreaming occurs outside of REM periods but REM sleep nonetheless maintains a special relationship to dreaming.


Neurology_Adams

Neurology_Adams. Subjects are easily aroused from REM sleep, but arousing a person during stage N3 is more difficult; full arousal may take minutes or more, during which time the subject may be slightly disoriented and confused (for which reason, physicians called at night should, if possible, avoid making complex medical decisions during this brief period). As mentioned previously, tonic muscle activity is minimal during REM sleep, although small twitches in facial and digital muscles (hand and foot) can still be detected. Eye movements of REM sleep are conjugate and occur in all directions (horizontal more than vertical). They can be appreciated through the closed eyelids. Gross body movements occur every 15 min or so in all stages of sleep but are maximal in the transition between REM and NREM sleep, at which time the sleeping person changes position, usually from side to side (most people sleep on their sides).


Neurology_Adams

Neurology_Adams. On closer study, REM sleep has been found to have phasic and tonic components. In addition to the REMs, phasic phenomena include activation of the sympathetic nervous system with attendant alternate dilatation and constriction of the pupils and fluctuation of the blood pressure, heart rate, and respiration. The phasic activities are related to bursts of neuronal activity in the pontine, vestibular, and median raphe nuclei and are conducted through the corticobulbar and corticospinal tracts. In the nonphasic periods of REM sleep, alpha and gamma spinal neurons are inhibited, the H responses diminish (see Chap. 43), and the tendon and postural and flexor reflexes diminish or are abolished. This flaccidity and atonia, which are prominent in the abdominal, upper airway, and intercostal muscles, may compromise breathing during REM sleep and pose a threat to infants with respiratory difficulty and to adults who are obese or have respiratory difficulty as a result of kyphoscoliosis, muscular


Neurology_Adams

Neurology_Adams. may compromise breathing during REM sleep and pose a threat to infants with respiratory difficulty and to adults who are obese or have respiratory difficulty as a result of kyphoscoliosis, muscular dystrophy, hypoplastic or otherwise compromised airways, and neuromuscular paralyses.


Neurology_Adams

Neurology_Adams. It has long been known that body temperature falls slightly during sleep; however, if sleep does not occur, there is still a drop in body temperature as part of the circadian (24-h) temperature pattern. This reduction in temperature is also independent of the 24-h recumbency–ambulatory cycle. During sleep, the decline in temperature occurs mainly during the NREM period, and the same is true of the heartbeat and respiration, both of which become slow and more regular in this period. Cerebral blood flow and oxygen consumption in muscle diminish during NREM sleep and increase during REM sleep. Also, cerebral blood flow and metabolism are markedly reduced across the entire brain during deep NREM sleep; however, during REM sleep, metabolism and blood flow are restored to the levels of the waking state (Madsen and Vorstrup). Presumably, as a result of increased blood flow, intracranial pressure rises during REM sleep.


Neurology_Adams

Neurology_Adams. Urine excretion decreases during sleep and the absolute quantity of sodium and potassium that is eliminated also decreases; however, urine specific gravity and osmolality increase, presumably because of increased antidiuretic hormone excretion, and reabsorption of water. Parasympathetic outflow is activated periodically in REM sleep; sympathetic activity is suppressed. It has also been recognized that there is a drop in blood pressure and heart rate during slow-wave sleep and the loss of this dip, for example, as a result of sleep apnea, has been associated with daytime hypertension and increased risk for cardiovascular events. As mentioned, in REM sleep, there is an increase in sympathetic tone. Breathing is more irregular, and heart rate and blood pressure fluctuate. Penile erections appear periodically, usually during REM periods.


Neurology_Adams

Neurology_Adams. A number of endocrine changes also have a regular relationship to the sleep–wake cycle. During the first 2 h of sleep, there is a surge of growth hormone secretion, mainly during slow-wave sleep. In men, there tends to be a single peak, whereas women have a multiple episodes of increased secretion. This feature persists through middle and late adult life and then disappears. The secretion of cortisol and particularly of thyroid-stimulating hormone peaks at the onset of sleep. High concentrations of cortisol are also characteristically found on awakening. Melatonin, elaborated by the pineal gland, is produced at night and ceases upon retinal stimulation by sunlight (see Chap. 26).


Neurology_Adams

Neurology_Adams. Prolactin secretion increases during the night in both men and women, the highest plasma concentrations being found soon after the onset of sleep. Secretion of prolactin is influenced by sleep stages. Circadian mechanisms and the stages of sleep alter testosterone secretion and are therefore disrupted by sleep disorders, especially in younger individuals. Also, an increased sleep-associated secretion of luteinizing hormone occurs in pubertal boys and girls. Neurophysiology of Sleep and Dreaming


Neurology_Adams

Neurology_Adams. Hobson originally proposed that the basic oscillation of the sleep cycle is the result of reciprocal interaction of excitatory and inhibitory neurotransmitters. Single-cell recordings from the pontine reticular formation suggest that there are two interconnected neuronal populations whose levels of activity fluctuate periodically and reciprocally. During wakefulness, according to this conceptualization, the activity of monoaminergic (inhibitory) neurons is high; because of this inhibition, the activity of the cholinergic neurons is low. During NREM sleep, aminergic inhibition gradually declines and cholinergic excitation increases; REM sleep occurs when the shift is complete. It is likely that these monoaminergic neuronal circuits are modulated by input from orexin-secreting (also called hypocretin) neurons of the hypothalamus, but the details of this control system are not entirely known. Orexin, a peptide that assumes great importance in the pathophysiology of narcolepsy, is


Neurology_Adams

Neurology_Adams. called hypocretin) neurons of the hypothalamus, but the details of this control system are not entirely known. Orexin, a peptide that assumes great importance in the pathophysiology of narcolepsy, is discussed further on. There is also emerging evidence from animal work that orexin is involved in autonomic homeostatic control as reviewed by Grimaldi and colleagues.


Neurology_Adams

Neurology_Adams. A refinement of these views has elaborated the complex interaction of specially functioning nuclei in the hypothalamus, pons, and basal forebrain. Reciprocal connections among these areas, modulated by input from regions of the brain that sense environmental conditions, allow the organism to adapt sleep cycles to its needs and to external circumstances. The suprachiasmatic nucleus (SCN) of the hypothalamus has no direct influence on the sleep cycle but does integrate ambient light cues, and thereby affects various circadian rhythms, including sleep, as discussed in Chap. 26. Experiments in animals and analyses of cases of von Economo encephalitis (that caused a pathologic sleep syndrome) have indicated that the ventrolateral preoptic nucleus of the hypothalamus (VLPO) sends fibers to all the other major cell groups of the hypothalamus and brainstem that are engaged in arousal. Damage to the VLPO results in pathologic wakefulness and the virtual absence of sleep. The SCN has only


Neurology_Adams

Neurology_Adams. all the other major cell groups of the hypothalamus and brainstem that are engaged in arousal. Damage to the VLPO results in pathologic wakefulness and the virtual absence of sleep. The SCN has only minimal projections to the VLPO and to orexin-containing neurons (see further on), but it does strongly innervate the subparaventricular zone (SPZ) and the dorsomedial hypothalamic nuclei. The last of these areas integrates feeding, temperature, light, and other cues from SPZ and SCN. The brain contains a three-stage pathway for the control of the sleep rhythm.


Neurology_Adams

Neurology_Adams. The above-described interconnections and the action of the integrated system that causes the sleep state have been summarized by Saper and colleagues and schematically in Fig. 18-4, taken from their publication. The current conceptualization is one of an unstable “flip-flop” switch that depends on mutual inhibition of the monoaminergic system and the VLPO. (In engineering terms, a flip-flop switch favors one position or the other, avoiding intermediate states.) The state of the switch is indirectly stabilized by the orexin neurons. In this model, the awake state is maintained by monoaminergic activity (locus ceruleus, tuberomammillary nucleus [TMN], and the raphe nuclei) that inhibits the VLPO. Sleep occurs when the VLPO is activated, which reciprocally removes the tonic inhibitory action of the monoaminergic system. The orexin neurons act through the monoaminergic system as a stabilizing influence to prevent rapid transitions from one state to the other.


Neurology_Adams

Neurology_Adams. Apart from the overall diurnal sleep cycle, evidence from animal studies suggests that the physiologic mechanisms and transitions between NREM and REM sleep are governed by the pontine reticular formation and are influenced by acetylcholine. Cholinergic neurons are found in two major loci in the parabrachial region of the dorsolateral pontine tegmentum—in the pedunculopontine group of nuclei and the lateral dorsal tegmental group. The cholinergic cell groups project rostrally, but the precise anatomy of this projection system has not been defined. Cells from these groups make up parts of the ascending reticular activating system.


Neurology_Adams

Neurology_Adams. Despite the heuristic value of Hobson’s reciprocal interaction hypothesis, some of its features remain controversial. Although it is generally agreed that cholinergic mechanisms selectively promote REM sleep, and its components—rapid eye movements, absence of activity in the antigravity muscles (i.e., atonia), and desynchronized EEG—the role of amines has been more difficult to establish. Thus, lesions of the locus ceruleus and raphe nuclei, which contain neurons rich in norepinephrine, do not greatly alter REM sleep. Nevertheless, a considerable body of pharmacologic data suggests that a decrease in monoamines causes an increase in REM activity and vice versa. Insofar as the bulk of cholinergic and aminergic neurons are found in the pedunculopontine group of nuclei, Shiromani and colleagues have suggested that interaction between these neurons occurs in the region of the pedunculopontine nuclei rather than in the medial pontine reticular formation, as suggested by Hobson and


Neurology_Adams

Neurology_Adams. colleagues have suggested that interaction between these neurons occurs in the region of the pedunculopontine nuclei rather than in the medial pontine reticular formation, as suggested by Hobson and associates.


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Neurology_Adams. Yet another model of REM, based on experimental studies and not dependent on cholinergic mechanism, has been offered by Lu and colleagues, in which two small populations of GABA-ergic neurons in the pontine tegmentum have reciprocal innervation and act as a “flip-flop” mechanism similar to the one proposed for sleep initiation. This REM system runs in parallel to the sleep-wake system but is integrated into its functioning and may offer insights into some of the dysfunction syndromes of REM sleep.


Neurology_Adams

Neurology_Adams. Solms (1995, 1996) and others have questioned the traditional view that dreaming and REM sleep are obligately or even closely connected and has presented an alternative perspective. Among patients with cerebral lesions that eliminate or disrupt REM sleep, he cites several cases, in which dreaming was retained. Conversely, in his patients with basal forebrain (frontal) lesions, dreaming was lost, at least for a time, while REM periods remained undisturbed through the night. This same observation had been made in patients who had prefrontal leukotomies. Solms has proposed that the dopaminergic systems in the basal forebrain areas elicit or modulate dreaming. This view is supported by reports of diminished dreaming in patients being treated with dopaminergic blockers and the enhancement of dreaming reported by patients taking l-dopa or dopamine agonsits. Notable in this regard is the fact that major intracortical dopaminergic pathways originate in the frontal lobes.


Neurology_Adams

Neurology_Adams. In regard to the neurophysiology of the EEG and sleep rhythms, much has been gleaned from intracellular recordings in animals. As with the earlier-described anatomic and neurochemical data, the degree to which similar electrophysiologic changes are reflected in humans is not known. Most of the integrated rhythms of sleep that are recorded at the surface of the brain, including the background activity of slow-wave sleep and the faster and more synchronized sleep spindles and vertex waves, have their origins in the thalamus. Steriade and colleagues have performed a substantial amount of the modern work in this area and summarize it in their review. They make clear that these complex EEG rhythms, while apparent in nascent form in certain isolated neurons, are oscillations that arise from integrated ensembles of cells, with the thalamus as a nexus. It is evident that there is as yet no agreement concerning the integration of all these brainstem and thalamic–hypothalamic mechanisms in the


Neurology_Adams

Neurology_Adams. ensembles of cells, with the thalamus as a nexus. It is evident that there is as yet no agreement concerning the integration of all these brainstem and thalamic–hypothalamic mechanisms in the production of sleep or of dreams.


Neurology_Adams

Neurology_Adams. The Function of Sleep and Dreams These questions have been pondered endlessly by physiologists and psychiatrists (and philosophers). Parkes has reviewed the main theories—body restitution, facilitation of motor function, consolidation of learning and memory—and tends to agree with the ungrammatical but unambiguous conclusion of Popper and Eccles that “Sleep is a natural repeated unconsciousness that we do not even know the reason for.” One cannot logically entertain the notion that the function of sleep is to produce dreams, at least until the utility and meaning of dreams become known. There is, however, considerable support for the popular notion that we stabilize learned material while asleep.


Neurology_Adams

Neurology_Adams. Regarding neurophysiologic changes during dreaming, Braun and colleagues used positron emission tomography (PET) to study REM sleep; they observed selective activation of the extrastriate visual cortices and limbic–paralimbic regions, with attenuation of activity in the primary visual cortex and frontal association areas. Based on these and similar studies, several authors have speculated that the suppression of frontal lobe activity during dreaming, at a time when visual association areas and their paralimbic connections are activated, might explain the uncritical acceptance of the bizarre visual content, the disordered temporal relationships, and the heightened emotionality that characterize dreams. This would be in keeping with Hobson’s view of dreams as a form of delirium.


Neurology_Adams

Neurology_Adams. As an alternative that links dreams to inherent meaning for the individual, Solms suggested that activation of frontal dopaminergic systems during dreaming, the same pathways that participate in most biologic drives, implies that dreams express latent wishes and drives—a psychoanalytical interpretation expressed by Freud in his book The Interpretation of Dreams. The Effects of Sleep Deprivation Deprived of sleep, experimental animals will die within a few weeks, no matter how well they are fed, watered, and housed (Rechtschaffen et al), but whether a similar degree of sleep deprivation leads to death in humans is unknown. Nevertheless, humans beings deprived of sleep do suffer a variety of very unpleasant symptoms quite distinct from the effects of the usual types of insomnia.


Neurology_Adams

Neurology_Adams. Despite many studies of the deleterious emotional and cognitive effects of sleeplessness, we still know little about them. If deprived of sleep (NREM and REM) for periods of 60 to 200 h, human beings experience increasing sleepiness, fatigue, irritability, and difficulty in concentration. Performance of skilled motor activities also deteriorates; if the tasks are of short duration and slow pace, the subject can manage them, but if speed and perseverance are demanded, he cannot. Self-care is neglected, incentive to work wanes, sustained thought and action are interrupted by lapses of attention, judgment is impaired, and the subject becomes decreasingly inclined to communicate. With sustained deprivation, sleepiness becomes increasingly more intense, momentary periods of sleep (“microsleep”) become more intrusive, and the tendency to all types of accidents becomes more marked. Eventually, subjects fail to perceive inner and external experiences accurately and to maintain their


Neurology_Adams

Neurology_Adams. become more intrusive, and the tendency to all types of accidents becomes more marked. Eventually, subjects fail to perceive inner and external experiences accurately and to maintain their orientation. Illusions and hallucinations, mainly visual and tactile ones, intrude into consciousness and become more persistent as the period of sleeplessness is prolonged. This may be a component of the decompensation of individuals with bipolar psychiatric disease, sometimes triggering manic episodes.


Neurology_Adams

Neurology_Adams. Neurologic signs of sleep deprivation include mild and inconstant nystagmus, impairment of saccadic eye movements, loss of accommodation, exophoria, a slight tremor of the hands, ptosis of the eyelids, expressionless face, and thickness of speech, with mispronunciations, and incorrect choice of words. The EEG shows a decrement of alpha waves, and closing of the eyes no longer generates alpha activity. The seizure threshold is reduced, and seizure foci in the EEG may be activated. Rarely and probably only in predisposed persons, loss of sleep provokes a psychotic episode (2 to 3 percent of 350 sleep-deprived patients studied by Tyler); however, many sleep specialists dispute the production of psychosis.


Neurology_Adams

Neurology_Adams. During recovery from prolonged sleep deprivation, the amount of sleep obtained is never equal to the amount lost. This is probably a result of the intrusion of brief sleep periods during the waking state and represents a sizable amount of time if summated (it is virtually impossible to deprive a human being or animal totally of sleep). When falling asleep after a long period of deprivation, the subject rapidly enters N3 (NREM) sleep, which continues for several hours at the expense of N2 and REM sleep. But by the second recovery night, REM sleep rebounds and exceeds that of the predeprivation period. N3 seems to be the most important sleep stage in restoring the altered functions that result from prolonged sleep deprivation.


Neurology_Adams

Neurology_Adams. The effects of differential REM sleep deprivation are more difficult to interpret than the effects of total or near-total deprivation. Some subjects in whom REM sleep is prevented night after night show an increasing tendency to hyperactivity, emotional lability, and impulsivity—a state that has been compared to the heightened activity, excessive appetite, and hypersexuality of animals deprived of REM sleep. However, in humans, monoamine inhibitors are able to completely suppress REM sleep for months to years without obvious harm. Differential deprivation of NREM sleep (N3) leads, instead, to hyporesponsiveness and excessive daytime sleepiness as noted. Because the need for sleep varies considerably from person to person, it is difficult to decide what constitutes sleep deprivation. Certain individuals apparently function well on 4 h or even less of sleep per 24-h period, and others, who sleep long hours, claim not to obtain maximum benefit from it.


Neurology_Adams

Neurology_Adams. The term insomnia signifies a chronic inability to sleep despite adequate opportunity to do so; it is used popularly to indicate any impairment in the duration, depth, or restorative properties of sleep. There may be difficulty in falling asleep or remaining asleep, awakening may come too early, or there may be a combination of these complaints. Precision as to what constitutes pathologic insomnia is impossible at the present time because of our uncertainty as to the exact amounts of sleep required, and the role of sleep in the economy of the human body. All that can be said is that some form of sleeplessness is a frequent complaint (20 to 40 percent of the population) and is more prominent in the elderly and in women. Only a small proportion of persons who perceive their sleep to be inadequate seek professional help or use sleeping pills, according to Mellinger and colleagues.


Neurology_Adams

Neurology_Adams. Two general classes of insomnia can be recognized—one in which there appears to be a primary abnormality of the sleep mechanism, and another in which the sleep disturbance is secondary to, or perhaps more accurately comorbid with, a medical or psychologic disorder. Polysomnographic studies have defined yet another subgroup who actually sleep enough, but who perceive their sleep time to be shortened or disrupted (“paradoxical insomnia”).


Neurology_Adams

Neurology_Adams. This term is reserved for the condition in which nocturnal sleep is disturbed for prolonged periods and none of the symptoms of anxiety, depression, pain, or other psychiatric or medical diseases can be invoked to explain the sleep disturbance. In some patients, like those described by Hauri and Olmstead, the disorder is lifelong. Unlike the rare individuals who seem to be satisfied with 4 h or even less of sleep a night, insomniacs suffer the effects of partial sleep deprivation and resort to medications or alcohol. Their lives come to revolve around sleep to such an extent that they have been called “sleep pedants” or “sleep hypochondriacs.” Although statements on the quantity and quality of sleep given by insomniacs are often not to be taken as entirely valid, Rechtschaffen and Monroe have confirmed that most of them do, indeed, sleep for shorter periods, move and awaken more often, spend less time in N3 sleep than normal persons, and show a heightened physiologic arousal.


Neurology_Adams

Neurology_Adams. Monroe have confirmed that most of them do, indeed, sleep for shorter periods, move and awaken more often, spend less time in N3 sleep than normal persons, and show a heightened physiologic arousal. Personality inventories have disclosed a high incidence of psychologic disturbances in this group, but whether these are cause or effect is not clear.


Neurology_Adams

Neurology_Adams. Furthermore, a category of “conditioned,” or “psychophysiological” insomnia has been denominated, in which a situational trigger for insomnia has ceased, but the sleep disorder persists. Although insomniacs, regardless of the cause, tend to exaggerate the amount of sleep lost, primary insomnia should be recognized as a valid entity. This common type of insomnia, which is often transitory, can be ascribed to pain or some other recognizable bodily disorder, such as drug or alcohol abuse or, most commonly, to anxiety, worry, or depression. Of the medical disorders conducive to abnormal wakefulness, certain ones stand out—pain in the joints or in the spine, abdominal discomfort from peptic ulcer and carcinoma, pulmonary and cardiovascular insufficiency, and the nocturia engendered by prostatism. The “restless legs” syndrome and periodic leg movements of sleep are not considered in this category and have their own physiology, phenomenology, and treatment as noted below.


Neurology_Adams

Neurology_Adams. Other Causes of Secondary Insomnia Among the secondary insomnias, those caused by some type of psychologic disturbance are particularly common. Domestic or business worries may keep the patient’s mind in turmoil (situational insomnia). A strange bed or unfamiliar surroundings may prevent drowsiness and sleep. Under these circumstances, the main difficulty is in falling asleep, with a tendency to sleep late in the morning. These facts emphasize that conditioning and environmental factors (social and learned) are normally involved in readying the mind and body for sleep.


Neurology_Adams

Neurology_Adams. Illnesses in which anxiety and fear are prominent symptoms also result in difficulty in falling asleep and in light, fitful, or intermittent sleep. Disturbing dreams are frequent in these situations and may awaken the patient. Exceptionally, a patient may even try to stay awake in order to avoid them. In contrast, depressive illness produces early morning waking and inability to return to sleep; the quantity of sleep is reduced, and nocturnal motility is increased. REM sleep in depression, although not always reduced, comes earlier in the night. If anxiety is combined with depression, there is a tendency for both the above patterns to be observed. Yet another common pattern of disturbed sleep can be discerned in individuals who are under great tension and worry or are overworked and tired out. These people sink into bed and sleep through sheer exhaustion, but they awaken early with their worries and are unable to get back to sleep.


Neurology_Adams

Neurology_Adams. Chronic and even short-term use of alcohol, barbiturates, and certain nonbarbiturate sedative-hypnotic drugs markedly reduces REM sleep as well as stages 3 and 4 of NREM sleep (N3). Following withdrawal of these drugs, there is a rapid and marked increase of REM sleep, sometimes with vivid dreams and nightmares. “Rebound insomnia,” a worsening of sleep compared with pretreatment levels, has also been reported upon discontinuation of short-half-life benzodiazepine hypnotics, notably triazolam (Gillin et al) and including the newer sleep agents mentioned below. Furthermore, a form of drug-withdrawal or rebound insomnia may actually occur during the same night in which the drug is administered. The drug produces its hypnotic effect in the first half of the night and a worsening of sleep during the latter half of the night, as the effects of the drug wear off; the patient and the physician may be misled into thinking that these latter symptoms require more of the hypnotic drug or a


Neurology_Adams

Neurology_Adams. during the latter half of the night, as the effects of the drug wear off; the patient and the physician may be misled into thinking that these latter symptoms require more of the hypnotic drug or a different one. Alcohol taken in the evening acts in the same way. Rebound insomnia must be distinguished from the early morning awakening that accompanies anxiety and depressive states.


Neurology_Adams

Neurology_Adams. A wide variety of other pharmacologic agents may give rise to sporadic or persistent disturbances of sleep. Caffeine-containing beverages, corticosteroids, bronchodilators, central adrenergic-blocking agents, amphetamines, certain “activating” antidepressants such as fluoxetine, and cigarettes are the most common offenders. Others are listed in the extensive review of Kupfer and Reynolds. Acroparesthesias, a predominantly nocturnal tingling and numbness of the fingers and palms caused by tight carpal ligaments (carpal tunnel syndrome), may awaken the patient at night (see in the following text, under “Sleep Palsies and Acroparesthesias”). Cluster headaches characteristically awaken the patient within 1 to 2 h after falling asleep (see Chap. 9 for a fuller discussion). In a few patients, cluster headaches occur only during or immediately after the REM period.


Neurology_Adams

Neurology_Adams. The sleep rhythm is totally deranged in acute confusional states and especially in delirium, and the patient may doze for only short periods, both day and night, the total amount and depth of sleep in a 24-h period being reduced. Frightening hallucinations may prevent sleep. The senile patient tends to catnap during the day and to remain alert for progressively longer periods during the night, until sleep is obtained in a series of short naps throughout the 24 h; the total amount of sleep may be increased or decreased. Treatment of Insomnia


Neurology_Adams

Neurology_Adams. In general, a sedative-hypnotic drug for the management of insomnia should be prescribed only as a short-term aid during an illness or some unusual circumstance, that is, for acute insomnia. For patients who have difficulty falling asleep, a quick-acting, fairly rapidly metabolized hypnotic is useful. The most commonly used medications were the benzodiazepine receptor agonists, which act on the gamma-aminobutyric acid, GABA-A receptor complex. Benzodiazepines were popular but these have been largely replaced by nonbenzodiazepines, GABA-A α1-receptor agonists, with shorter half-lives and perhaps fewer side effects (e.g., zolpidem, zaleplon, and eszopiclone). Patients who do not respond to these medications may be given an intermediate-duration benzodiazepine such as temazepam. There is also a newer class of medications, which act as orexin receptor antagonists, typified by suvorexant. Hypnotic use is inadvisable during pregnancy and should be used cautiously in patients with alcoholism


Neurology_Adams

Neurology_Adams. a newer class of medications, which act as orexin receptor antagonists, typified by suvorexant. Hypnotic use is inadvisable during pregnancy and should be used cautiously in patients with alcoholism or advanced renal, hepatic, or pulmonary disease, and should be avoided in patients with sleep apnea syndrome.


Neurology_Adams

Neurology_Adams. Melatonin (3 to 12 mg) has reportedly been as effective as the sedative hypnotics and may cause fewer short-term side effects, but both of these statements are difficult to confirm. Melatonin has a short half-life, and it has only weak hypnotic effect. Therefore, for sleep rhythm disturbances, it is ideally taken 3 to 4 hours before sleep time. Tricyclic antidepressants appear to be sleep enhancing even in those who are not anxious or depressed. Tolerance develops to the drug, and there are morning side effects so the drug may find its best use in patients who are taking it for alternative reasons such as headache or depression. Some practitioners indicate that antidepressants may also worsen restless leg or periodic leg movement disorders. When pain is a factor in insomnia, the sedative may be combined with a suitable analgesic. Nonprescription drugs containing diphenhydramine (Benadryl), valerian, or doxylamine, which are minimally or not at all effective in inducing sleep, may


Neurology_Adams

Neurology_Adams. may be combined with a suitable analgesic. Nonprescription drugs containing diphenhydramine (Benadryl), valerian, or doxylamine, which are minimally or not at all effective in inducing sleep, may impair the quality of sleep and lead to drowsiness the following morning.


Neurology_Adams

Neurology_Adams. The chronic insomniac who has no other symptoms should be discouraged from using sedative drugs. The solution of this problem is rarely to be found in medication. One should search out and correct, if possible, any underlying situational or psychologic difficulty, using medication only as a temporary measure. Patients should be encouraged to regularize their daily schedules, including their bedtimes, and to be physically active during the day but to avoid strenuous physical and mental activity before bedtime. It has been suggested that illumination from broad-spectrum light (television) in the late evening is detrimental. Dietary excesses must be corrected, and all nonessential medications interdicted. Coffee and alcohol should be avoided at night, if not throughout the day. A number of simple behavioral modifications may be useful, such as using the bedroom only for sleeping, arising at the same time each morning regardless of the duration of sleep, avoiding daytime naps, and


Neurology_Adams

Neurology_Adams. of simple behavioral modifications may be useful, such as using the bedroom only for sleeping, arising at the same time each morning regardless of the duration of sleep, avoiding daytime naps, and limiting the time spent in bed strictly to the duration of sleep. A helpful approach is to lessen the patient’s concern about sleeplessness by pointing out that he will always get as much sleep as needed and that there is pleasure to be derived from staying awake and reading, or viewing a movie.


Neurology_Adams

Neurology_Adams. Restless Legs Syndrome, Periodic Leg Movements of Sleep, and Related Disorders


Neurology_Adams

Neurology_Adams. The disorder known as the restless legs syndrome may regularly delay the onset of sleep and usually occurs in its early stages. Ekbom called it asthenia crurum paresthetica and also, anxietas tibiarum. This disorder is surprisingly prevalent, affecting more than 2 percent of the population. The patient may complain of unpleasant aching and drawing sensations in the calves and thighs, often associated with creeping or crawling feelings; other descriptions have included “worms,” “internal itch,” and “coldness,” and the legs may feel tired, heavy, and weak. The location in the legs distinguishes the problem from the separate condition of acral paresthesias. The symptoms are provoked by rest, and rapidly, but temporarily, relieved by moving the legs. An urge to move the legs can be suppressed voluntarily for a brief period but is ultimately irresistible. Moving the limbs alleviates the sensation briefly. It is interesting that a small proportion of patients have similar symptoms in the


Neurology_Adams

Neurology_Adams. voluntarily for a brief period but is ultimately irresistible. Moving the limbs alleviates the sensation briefly. It is interesting that a small proportion of patients have similar symptoms in the arms after many years of symptoms. There may be variants of nocturnal restlessness in other parts of the body such as the abdomen, as suggested by Pérez-Díaz and colleagues. Their patients described an unpleasant abdominal musculature restlessness that required movement for relief and was eliminated with dopamine agonists.


Neurology_Adams

Neurology_Adams. Fatigue worsens restless legs syndrome, and there is a tendency for it to be worse in warm weather. In a few patients, mainly older ones with a severe form of the nighttime disorder, these movements and an associated myoclonus spill over into wakefulness and are accompanied by restlessness, foot spasms, foot stamping, body rocking, and marching that are only partly under voluntary control. The daytime phenomena may require several medications used simultaneously for control.


Neurology_Adams

Neurology_Adams. The syndrome is usually idiopathic and persists for years. However, iron-deficiency anemia and low ferritin levels are associated with the syndrome in many instances, as is renal failure, particularly with dialysis, alcohol before sleep, thyroid disease, pregnancy, and certain drugs, such as antidepressants and antihistamines. Occasionally, it is a prelude to a peripheral neuropathy, particularly in relation to uremia. Also, reduced levels of iron in the cerebrospinal fluid (CSF) have been found with restless legs syndrome and with periodic limb movements of sleep (see below). The basis for this relationship to iron is not well defined and the proportion of cases explained by this varies among studies, but it makes it advisable to check for reduced iron stores and anemia in most patients with restless leg syndrome. One hypothesis is that a disturbance of iron storage in the basal ganglia causes a decrement in dopamine binding by dopamine receptors and transporters, as has been


Neurology_Adams

Neurology_Adams. with restless leg syndrome. One hypothesis is that a disturbance of iron storage in the basal ganglia causes a decrement in dopamine binding by dopamine receptors and transporters, as has been described in studies using PET and single-photon emission tomography (SPECT) scans. Another potential relationship, unproved, is that iron is a cofactor for the enzyme, tyrosine hydroxylase, which is required to produce dopamine.


Neurology_Adams

Neurology_Adams. A closely related disturbance is periodic leg movements of sleep. Like the restless legs syndrome, it may result in sleep deprivation and daytime somnolence or, more often, in disturbance of a bed partner. However, the diagnosis of periodic leg movements depends on finding them during polysomnographic recordings, whereas restless leg syndrome is identified on clinical grounds. There is less certainty as to the importance of periodic compared to restless leg movements in disrupting sleep. Originally described as “nocturnal myoclonus,” periodic leg movements are slower than myoclonic jerks. They consist of a series of repetitive movements of the feet and legs occurring every 20 to 90 s for several minutes to an hour; mainly the anterior tibialis is involved, with dorsiflexion of the feet and big toes, sometimes followed by flexion of the hip and knee. The movements are similar to the triple-flexion (Babinski) response, which can be elicited in normal sleeping persons. These movements


Neurology_Adams

Neurology_Adams. and big toes, sometimes followed by flexion of the hip and knee. The movements are similar to the triple-flexion (Babinski) response, which can be elicited in normal sleeping persons. These movements may produce frequent microarousals or, if severe and periodic, full arousals. The patient, usually unaware of these sleep-related movements at the time they occur, is told of them by a bed mate or suspects their occurrence from the disarray of the bedclothes.


Neurology_Adams

Neurology_Adams. Periodic leg movement is closely associated with the restless legs syndrome and many sleep specialists consider it an integral part of the syndrome, but it also occurs independently with narcolepsy, sleep apnea, with the use of tricyclic and serotonin reuptake inhibiting antidepressants, and withdrawal from anticonvulsants and sedative-hypnotic drugs. Approximately 80 percent of individuals with restless leg syndrome will display periodic leg movements, but the opposite is not the case, as only 20 to 30 percent of patients with periodic leg movements have restless leg syndrome.


Neurology_Adams

Neurology_Adams. A genetic finding by Stefansson and colleagues derived from several populations, including the homogenous Icelandic, is that a nucleotide variant in a short segment of chromosome 6p is associated with periodic leg movements of sleep. This was found to hold in those with and without restless legs syndrome. If nothing else, as pointed out by the authors, this establishes that periodic limb movements are a distinct entity as defined in the era of genomics. The biologic significance and frequency in other populations of this variant is not yet known. Nonetheless, we continue to be impressed at the frequent cooccurrence of the two conditions and several shared underlying conditions such as iron deficiency, and treatments that are effective in both. Treatment of RLS and PLS


Neurology_Adams

Neurology_Adams. A search for iron deficiency, and its correction if present, is indicated in almost all cases. It is appropriate in many patients to explore the reason for iron deficiency. A large number of symptomatic medications have proved helpful in the treatment of both the restless legs syndrome and periodic leg movements. Until recently, many practitioners have favored treatment with either dopamine agonists such as pramipexole (0.25 to 0.75 mg) or ropinirole (0.5 to 1.5 mg) taken 1.5 to 2 h before bedtime. Long-acting combinations of l-dopa/carbidopa (12.5/50 or 25/100 mg dose) taken at bedtime have also been successful, but l-dopa, and sometimes the dopamine agonists, causes some patients to develop the movements earlier, that is, in the daytime, which become more intense and spread to other body parts. A longer acting dopamine agonist, rotigotine patch is available to treat patients who have this augmentation phenomenon. An association between augmentation, even mild forms and with low


Neurology_Adams

Neurology_Adams. body parts. A longer acting dopamine agonist, rotigotine patch is available to treat patients who have this augmentation phenomenon. An association between augmentation, even mild forms and with low doses of medication, and impulsive behavior has been noted by Heim and associates in a group of patients but the mechanism for their finding is not known.


Neurology_Adams

Neurology_Adams. The problem of augmentation, or enhancement of the restless leg syndrome with the long-term use of dopaminergic drugs has led to studies of alternatives, mainly gabapentin, pregabalin, but also diazepines such as clonazepam (0.5 to 2.0 mg), or temazepam (30 mg), taken 30 min before retiring. A clinical trial conducted by Allen and associates showed that pregabalin was as effective as pramipexole in reducing restless leg symptoms and had similar rates of augmentation as pramipexole 0.25 mg but lower rates than 0.5 mg. Suicidal ideation may have been more frequent as an adverse event with pregabalin. Other drugs—for example, baclofen, opioids, carbamazepine seem to be helpful in certain patients, but they are infrequently required. The lengthy list of medications that have been effective is given in Earley’s review. It is sometimes useful to give a medication in two divided doses, the first early in the evening, and the second just before sleep or, in severe cases, during the night by


Neurology_Adams

Neurology_Adams. given in Earley’s review. It is sometimes useful to give a medication in two divided doses, the first early in the evening, and the second just before sleep or, in severe cases, during the night by setting an alarm clock before the anticipated time of symptoms.


Neurology_Adams

Neurology_Adams. Disorders of Sleep Related to Neurologic Disease Many neurologic conditions seriously derange the total amount and patterns of sleep. Lesions in the upper pons, near the locus ceruleus, are particularly prone to do so. Markand and Dyken have described the most substantial of these, pontine infarction with involvement of the tegmental raphe nuclei. The clinical abnormality took the form of diminished NREM sleep and near abolition of REM sleep lasting for weeks or months. Bilateral lacunar infarctions in the pontine tegmentum also appear to be the basis of some instances of the REM sleep behavior disorder (Culebras and Moore) described further on with the other parasomnias. Bilateral paramedian thalamic infarctions are a potent cause of hypersomnolence as the result of disruption of both arousal mechanisms and NREM sleep (Bassetti et al).


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Neurology_Adams. Medullary lesions may affect sleep by altering automatic ventilation; the most extreme examples occur with bilateral tegmental lesions that may completely abolish breathing during sleep (“Ondine’s curse,” as described in Chap. 25). Lesser degrees of tegmental damage—as might occur with Chiari malformations, unilateral medullary infarction, syringobulbia, or poliomyelitis—may cause sleep apnea, and daytime drowsiness. Patients with large hemispheric strokes may also be left with daytime lethargy on the basis of inversion of sleep–wake rhythm. Certain instances of mesencephalic infarction that are characterized by vivid visual hallucinations (peduncular hallucinosis) may be associated with disruption of sleep.


Neurology_Adams

Neurology_Adams. von Economo encephalitis, now an extinct illness, was usually associated with a hypersomnolent state but caused persistent insomnia in some instances. The latter was related to a predominance of lesions in the anterior hypothalamus and basal frontal lobes, in distinction to hypersomnia, which was related to lesions mainly in dorsal hypothalamus and subthalamus. This subject and other forms of hypersomnia are elaborated further on under “Hypersomnia” (pathologic excessive sleep).


Neurology_Adams

Neurology_Adams. The remarkable illness, fatal familial insomnia, was initially described by Lugaresi and colleagues. This disorder, with onset in middle age and a clinical course of 7 to 36 months, is characterized by a progressive incapacity to sleep and to generate EEG sleep patterns. The cerebral changes consist mainly of profound neuronal loss in the anterior or anteroventral, and mediodorsal thalamic nuclei. These cases represent a usually familial form of prion disease similar to diseases that cause subacute spongiform encephalopathy (see Chap. 32). Interestingly, the alcoholic form of the Korsakoff amnesic state, associated with less severe lesions in the same thalamic nuclei, is also characterized by a sleep disturbance, taking the form of an increased frequency of intermittent periods of wakefulness (Martin et al). When carefully sought, similar sleep–wake disturbances have been found in sporadic Creutzfeldt-Jakob-prion disease (Landolt et al).


Neurology_Adams

Neurology_Adams. Major head injury is an important cause of sleep disturbance. The abnormalities, which may persist for months or years, consist mainly of a decrease in stages 1 and 2 sleep, and less than the expected amounts of REM sleep and dreaming. Some patients in the persistent vegetative state show a cycle of changes in the EEG, progressing from a picture of abortive spindles and K complexes with cyclic alterations in respiration and pupil size to the acquisition of a more normally structured sleep activity. This sequence usually presages the change from a state of coma to one of minimally conscious state (see Chap. 16). Organized sleep activity is absent in virtually all types of coma that are the result of anatomic damage to the brain. An exception, albeit a semantic one, occurs in the unusual condition known as “spindle coma,” in which persistent coma and the electrographic features of sleep coexist. This particular combination of events has been described after head trauma, and rarely, in