SECTION II Clinical Manifestations of Neurologic Disease132 The most common herniations are from the supra- drowsiness are the heralding signs. Both temporal and tentorial to the infratentorial compartments through central herniations have classically been considered to the tentorial opening, hence transtentorial. Uncal transten- cause a progressive compression of the brainstem from torial herniation refers to impaction of the anterior above in an orderly manner: first the midbrain, then the medial temporal gyrus (the uncus) into the tentorial pons, and finally the medulla.The result is a sequence of opening just anterior to and adjacent to the midbrain neurologic signs that corresponds to each affected level. (Fig. 14-1, A).The displaced brain tissue compresses the Other forms of herniation are transfalcial herniation (dis- third nerve as it traverses the subarachnoid space, and placement of the cingulate gyrus under the falx and results in enlargement of the ipsilateral pupil (putatively across the midline, Fig. 14-1, C), and foraminal herniation because the fibers subserving parasympathetic pupillary (downward forcing of the cerebellar tonsils into the function are located peripherally in the nerve). The foramen magnum, Fig. 14-1, D), which causes compres- coma that follows is due to compression of the mid- sion of the medulla and respiratory arrest. brain against the opposite tentorial edge by the dis- placed parahippocampal gyrus (Fig. 14-2). In some A direct relationship between the various configura- cases, the lateral displacement of the midbrain causes tions of transtentorial herniations and coma is not compression of the opposite cerebral peduncle, produc- always found. Drowsiness and stupor typically occur ing a Babinski sign and hemiparesis contralateral to the with moderate horizontal shifts at the level of the dien- original hemiparesis (the Kernohan-Woltman sign). In cephalon (thalami) well before transtentorial or other addition to compressing the upper brainstem, tissue herniations are evident. Lateral shift may be quantified shifts, including herniations, may compress major blood on axial images of CT and MRI scans (Fig. 14-2). In vessels, particularly the anterior and posterior cerebral cases of acutely appearing masses, horizontal displacement arteries as they pass over the tentorial reflections, thus of the pineal calcification of 3–5 mm is generally associ- producing brain infarctions. The distortions may also ated with drowsiness, 6–8 mm with stupor, and >9 mm entrap portions of the ventricular system, resulting in with coma. Intrusion of the medial temporal lobe into regional hydrocephalus. the tentorial opening may be apparent on MRI and CT Central transtentorial herniation denotes a symmetric scans by an obliteration of the cisterns that surround the downward movement of the thalamic medial structures upper brainstem. through the tentorial opening with compression of the upper midbrain (Fig. 14-1, B). Miotic pupils and Coma Due to Metabolic Disorders AB Many systemic metabolic abnormalities cause coma by FIGURE 14-2 interrupting the delivery of energy substrates (hypoxia, Coronal (A) and axial (B) magnetic resonance images from ischemia, hypoglycemia) or by altering neuronal excitabil- a stuporous patient with a left third nerve palsy as a result of ity (drug and alcohol intoxication, anesthesia, and epilepsy). a large left-sided subdural hematoma (seen as a gray-white rim). The same metabolic abnormalities that produce coma The upper midbrain and lower thalamic regions are com- may in milder form induce widespread cortical dysfunc- pressed and displaced horizontally away from the mass, and tion and an acute confusional state. Thus, in metabolic there is transtentorial herniation of the medial temporal lobe encephalopathies, clouded consciousness and coma are in structures, including the uncus anteriorly. The lateral ventricle a continuum. opposite to the hematoma has become enlarged as a result of compression of the third ventricle. Cerebral neurons are fully dependent on cerebral blood flow (CBF) and the related delivery of oxygen and glucose. CBF is ~75 mL per 100 g/min in gray mat- ter and 30 mL per 100 g/min in white matter (mean = 55 mL per 100 g/min); oxygen consumption is 3.5 mL per 100 g/min, and glucose utilization is 5 mg per 100 g/min. Brain stores of glucose provide energy for ~2 min after blood flow is interrupted, and oxygen stores last 8–10 s after the cessation of blood flow. Simultaneous hypoxia and ischemia exhaust glucose more rapidly. The elec- troencephalogram (EEG) rhythm in these circum- stances becomes diffusely slowed, typical of metabolic encephalopathies, and as conditions of substrate delivery worsen, eventually all recordable brain electrical activity ceases. In almost all instances of metabolic encephalo- pathy, the global metabolic activity of the brain is reduced in proportion to the degree of diminished consciousness.
Conditions such as hypoglycemia, hyponatremia, The postictal state produces a pattern of continuous, gen- 133CHAPTER 14 Coma hyperosmolarity, hypercapnia, hypercalcemia, and hepatic eralized slowing of the background EEG activity similar and renal failure are associated with a variety of alter- to that of other metabolic encephalopathies. ations in neurons and astrocytes. Unlike hypoxia-ischemia, which causes neuronal destruction, metabolic disorders Toxic Drug–Induced Coma generally cause only minor neuropathologic changes. The reversible effects of these conditions on the brain This common class of encephalopathy is in large mea- are not understood but may result from impaired energy sure reversible and leaves no residual damage providing supplies, changes in ion fluxes across neuronal mem- hypoxia does not supervene. Many drugs and toxins are branes, and neurotransmitter abnormalities. For example, capable of depressing nervous system function. Some the high brain ammonia concentration of hepatic coma produce coma by affecting both the brainstem nuclei, interferes with cerebral energy metabolism and with the including the RAS, and the cerebral cortex.The combi- Na+, K+-ATPase pump, increases the number and size of nation of cortical and brainstem signs, which occurs in astrocytes, alters nerve cell function, and causes increased certain drug overdoses, may lead to an incorrect diagno- concentrations of potentially toxic products of ammonia sis of structural brainstem disease. Overdose of medica- metabolism; it may also result in abnormalities of neuro- tions that have atropinic actions produces physical signs transmitters, including putative “false” neurotransmitters such as dilated pupils, tachycardia, and dry skin. that are active at receptor sites.Apart from hyperammone- mia, which of these mechanisms is of critical impor- Coma Due to Widespread Damage to the tance is not clear.The mechanism of the encephalopathy Cerebral Hemispheres of renal failure is also not known. Unlike ammonia, urea itself does not produce central nervous system (CNS) This special category, comprising a number of unrelated toxicity. A multifactorial causation has been proposed, disorders, results from widespread structural cerebral including increased permeability of the blood-brain bar- damage, thereby simulating a metabolic disorder of the rier to toxic substances such as organic acids and an increase cortex.The effect of prolonged hypoxia-ischemia is per- in brain calcium or cerebrospinal fluid (CSF) phosphate haps the best known and one in which it is not possible content. to distinguish the acute effects of hypoperfusion of the brain from the further effects of generalized neuronal Coma and seizures are a common accompaniment of damage. Similar bihemispheral damage is produced by any large shifts in sodium and water balance in the brain. disorders that occlude small blood vessels throughout These changes in osmolarity arise from systemic medical the brain; examples include cerebral malaria, thrombotic disorders including diabetic ketoacidosis, the nonketotic thrombocytopenic purpura, and hyperviscosity.The pres- hyperosmolar state, and hyponatremia from any cause ence of seizures and the bihemispheral damage are some- (e.g., water intoxication, excessive secretion of antidi- times an indication of this class of disorder. uretic hormone or atrial natriuretic peptides). Sodium levels <125 mmol/L induce confusion, and <115 mmol/L Approach to the Patient: are associated with coma and convulsions. In hyperosmo- COMA lar coma the serum osmolarity is generally >350 mosmol/L. Hypercapnia depresses the level of conscious- Acute respiratory and cardiovascular problems should ness in proportion to the rise in CO2 tension in the be attended to prior to neurologic assessment. In blood. In all of these metabolic encephalopathies, the degree of most instances, a complete medical evaluation, except neurologic change depends to a large extent on the rapidity with for vital signs, funduscopy, and examination for which the serum changes occur. The pathophysiology of nuchal rigidity, may be deferred until the neurologic other metabolic encephalopathies such as hypercalcemia, evaluation has established the severity and nature of hypothyroidism, vitamin B12 deficiency, and hypothermia coma. The approach to the patient with cranial are incompletely understood but must also reflect trauma is discussed in Chap. 31. derangements of CNS biochemistry and membrane function. HISTORY In many cases, the cause of coma is immediately evident (e.g., trauma, cardiac arrest, or Epileptic Coma known drug ingestion). In the remainder, certain points are especially useful: (1) the circumstances and Continuous, generalized electrical discharges of the cor- rapidity with which neurologic symptoms developed; tex (seizures) are associated with coma even in the absence (2) the antecedent symptoms (confusion, weakness, of epileptic motor activity (convulsions). The self-limited headache, fever, seizures, dizziness, double vision, or coma that follows seizures, termed the postictal state, may be due to exhaustion of energy reserves or effects of locally toxic molecules that are the byproduct of seizures.
SECTION II Clinical Manifestations of Neurologic Disease134 vomiting); (3) the use of medications, illicit drugs, or patient bilateral asterixis is a certain sign of metabolic alcohol; and (4) chronic liver, kidney, lung, heart, or encephalopathy or drug intoxication. other medical disease. Direct interrogation of family and observers on the scene, in person or by tele- The terms decorticate rigidity and decerebrate rigidity, phone, is an important part of the initial evaluation. or “posturing,” describe stereotyped arm and leg Ambulance technicians often provide the most useful movements occurring spontaneously or elicited by information. sensory stimulation. Flexion of the elbows and wrists and supination of the arm (decortication) suggests GENERAL PHYSICAL EXAMINATION The bilateral damage rostral to the midbrain, whereas temperature, pulse, respiratory rate and pattern, and extension of the elbows and wrists with pronation blood pressure should be measured quickly. Fever (decerebration) indicates damage to motor tracts in suggests a systemic infection, bacterial meningitis, or the midbrain or caudal diencephalon. The less fre- encephalitis; only rarely is it attributable to a brain quent combination of arm extension with leg flexion lesion that has disturbed hypothalamic temperature- or flaccid legs is associated with lesions in the pons. regulating centers (“central fever”). A slight elevation in These concepts have been adapted from animal work temperature may follow vigorous convulsions. High and cannot be applied with the same precision to body temperature, 42°–44°C, associated with dry skin coma in humans. In fact, acute and widespread disor- should arouse the suspicion of heat stroke or anti- ders of any type, regardless of location, frequently cholinergic drug intoxication. Hypothermia is observed cause limb extension, and almost all such extensor with alcoholic, barbiturate, sedative, or phenothiazine posturing becomes predominantly flexor as time intoxication; hypoglycemia; peripheral circulatory passes. Posturing may also be unilateral and may failure; or hypothyroidism. Hypothermia itself causes coexist with purposeful limb movements, usually coma only when the temperature is <31°C. Tachyp- reflecting incomplete damage to the motor system. nea may indicate systemic acidosis or pneumonia. Aberrant respiratory patterns that reflect brainstem LEVEL OF AROUSAL A sequence of increasingly disorders are discussed later. Marked hypertension intense stimuli is used to determine the threshold for either indicates hypertensive encephalopathy or is the arousal and the optimal motor response of each side result of a rapid rise in intracranial pressure (ICP; the of the body. The results of testing may vary from Cushing response) most often after cerebral hemor- minute to minute and serial examinations are most rhage or head injury. Hypotension is characteristic of useful. Tickling the nostrils with a cotton wisp is a coma from alcohol or barbiturate intoxication, inter- moderate stimulus to arousal—all but deeply stu- nal hemorrhage, myocardial infarction, sepsis, pro- porous and comatose patients will move the head found hypothyroidism, or Addisonian crisis. away and rouse to some degree. Using the hand to remove the offending stimulus represents an even The funduscopic examination can detect subarachnoid greater degree of responsiveness. Stereotyped postur- hemorrhage (subhyaloid hemorrhages), hypertensive ing in response to noxious stimuli indicates severe encephalopathy (exudates, hemorrhages, vessel-crossing dysfunction of the corticospinal system. Abduction- changes, papilledema), and increased ICP (papilledema). avoidance movement of a limb is usually purposeful Cutaneous petechiae suggest thrombotic thrombocy- and denotes an intact corticospinal system. Pressure topenic purpura, meningococcemia, or a bleeding on the knuckles or bony prominences and pinprick diathesis from which an intracerebral hemorrhage has stimulation are humane forms of noxious stimuli; arisen. pinching the skin causes unsightly ecchymoses and is generally not necessary but may be useful in eliciting NEUROLOGIC EXAMINATION First, the patient abduction withdrawal movements of the limbs. should be observed without intervention by the exam- iner. Tossing about in the bed, reaching up toward the BRAINSTEM REFLEXES Assessment of brainstem face, crossing legs, yawning, swallowing, coughing, or function is essential to localization of the lesion in coma moaning denotes a state close to normal awakeness. (Fig. 14-3). The brainstem reflexes that are conve- Lack of restless movements on one side or an out- niently examined are pupillary responses to light, spon- turned leg suggests a hemiplegia. Intermittent twitch- taneous and elicited eye movements, corneal responses, ing movements of a foot, finger, or facial muscle may and the respiratory pattern.As a rule, when these brain- be the only sign of seizures. Multifocal myoclonus stem activities are preserved, particularly the pupil reac- almost always indicates a metabolic disorder, particu- tions and eye movements, coma must be ascribed to larly uremia, anoxia, or drug intoxication (lithium and bilateral hemispheral disease. The converse, however, is haloperidol are particularly likely to cause this sign), or not always true, as a mass in the hemispheres may be the rare conditions of a prion disease (Chap. 38) or the underlying cause of coma but nonetheless produce “Hashimoto encephalopathy.” In a drowsy and confused brainstem signs by inducing transtentorial herniation.
Pupillary light reflex pupil is a transitional sign that accompanies early 135 midbrain–third nerve compression. The most extreme Corneal-blink III III Reflex conjugate pupillary sign, bilaterally dilated and unreactive pupils, CHAPTER 14 Coma reflex eye movements indicates severe midbrain damage, usually from com- M pression by a supratentorial mass. Ingestion of drugs V L Pons with anticholinergic activity, the use of mydriatic eye drops, and direct ocular trauma are among the causes F of misleading pupillary enlargement. Vll Vl Unilateral miosis in coma has been attributed to Vlll dysfunction of sympathetic efferents originating in the posterior hypothalamus and descending in the Medulla tegmentum of the brainstem to the cervical cord. It is an occasional finding with a large cerebral hemor- Respiratory rhage that affects the thalamus. Reactive and bilater- neurons ally small (1–2.5 mm) but not pinpoint pupils are seen in metabolic encephalopathies or in deep bilat- eral hemispheral lesions such as hydrocephalus or thalamic hemorrhage. Very small but reactive pupils (<1 mm) characterize narcotic or barbiturate over- doses but also occur with extensive pontine hemor- rhage. The response to naloxone and the presence of reflex eye movements (see below) distinguish these. FIGURE 14-3 Ocular Movements The eyes are first observed Examination of brainstem reflexes in coma. Midbrain and by elevating the lids and noting the resting position third nerve function are tested by pupillary reaction to light, and spontaneous movements of the globes. Lid tone, pontine function by spontaneous and reflex eye movements tested by lifting the eyelids and noting their resistance and corneal responses, and medullary function by respiratory to opening and the speed of closure, is reduced pro- and pharyngeal responses. Reflex conjugate, horizontal eye gressively as coma deepens. Horizontal divergence of movements are dependent on the medial longitudinal fasci- the eyes at rest is normal in drowsiness. As coma culus (MLF) interconnecting the sixth and contralateral third deepens, the ocular axes may become parallel again. nerve nuclei. Head rotation (oculocephalic reflex) or caloric stimulation of the labyrinths (oculovestibular reflex) elicits Spontaneous eye movements in coma often take contraversive eye movements (for details see text). the form of conjugate horizontal roving.This finding alone exonerates the midbrain and pons and has the Pupillary Signs Pupillary reactions are examined same significance as normal reflex eye movements with a bright, diffuse light (not an ophthalmoscope); if (see below). Conjugate horizontal ocular deviation to the response is absent, this should be confirmed by one side indicates damage to the pons on the oppo- observation through a magnifying lens. Normally site side or alternatively, to the frontal lobe on the reactive and round pupils of midsize (2.5–5 mm) same side. This phenomenon is summarized by the essentially exclude midbrain damage, either primary following maxim: The eyes look toward a hemispheral or secondary to compression. Reaction to light is lesion and away from a brainstem lesion. Seizures also often difficult to appreciate in pupils <2 mm in diam- drive the eyes to one side. On rare occasions, the eyes eter, and bright room lighting mutes pupillary reactiv- may turn paradoxically away from the side of a deep ity. One unreactive and enlarged pupil (>6 mm) or hemispheral lesion (“wrong-way eyes”). The eyes one that is poorly reactive signifies compression of the turn down and inward as a result of thalamic and third nerve from the effects of a mass above. Enlarge- upper midbrain lesions, typically with thalamic hem- ment of the pupil contralateral to a mass may occur orrhage. “Ocular bobbing” describes brisk downward first but is infrequent. An oval and slightly eccentric and slow upward movements of the eyes associated with loss of horizontal eye movements and is diag- nostic of bilateral pontine damage, usually from thrombosis of the basilar artery. “Ocular dipping” is a slower, arrhythmic downward movement followed by a faster upward movement in patients with normal reflex horizontal gaze; it indicates diffuse cortical anoxic damage. Many other complex eye movements
SECTION II Clinical Manifestations of Neurologic Disease136 are known but do not have the same clinical impor- Shallow, slow, but regular breathing suggests metabolic tance as those mentioned earlier. or drug depression. Cheyne-Stokes respiration in its The oculocephalic reflexes depend on the integrity classic cyclic form, ending with a brief apneic period, of the ocular motor nuclei and their interconnecting signifies bihemispheral damage or metabolic suppres- tracts that extend from the midbrain to the pons and sion and commonly accompanies light coma. Rapid, medulla. These reflexes are elicited by moving the deep (Kussmaul) breathing usually implies metabolic head from side to side or vertically and observing acidosis but may also occur with pontomesencephalic evoked eye movements in the direction opposite to lesions. Agonal gasps are the result of lower brainstem the head movement (Fig. 14-3). The movements, (medullary) damage and are well known as the termi- called somewhat inappropriately “doll’s eyes” (which nal respiratory pattern of severe brain damage.A num- refers more accurately to the reflex elevation of the ber of other cyclic breathing variations have been eyelids with flexion of the neck), are normally sup- described but are of lesser significance. pressed in the awake patient.The ability to elicit them therefore indicates a reduced cortical influence on the LABORATORY STUDIES AND IMAGING brainstem. Furthermore, preservation of evoked reflex eye movements signifies the integrity of the brainstem The studies that are most useful in the diagnosis of coma and implies that the origin of unconsciousness lies in are: chemical-toxicologic analysis of blood and urine, the cerebral hemispheres. The opposite, an absence of cranial CT or MRI, EEG, and CSF examination. Arter- reflex eye movements, usually signifies damage within ial blood-gas analysis is helpful in patients with lung dis- the brainstem but can be produced infrequently by ease and acid-base disorders. The metabolic aberrations profound overdoses of certain drugs. Normal pupillary commonly encountered in clinical practice require mea- size and light reaction distinguishes most drug- surements of electrolytes, glucose, calcium, osmolarity, induced comas from structural brainstem damage. and renal (blood urea nitrogen) and hepatic (NH3) func- Thermal, or “caloric,” stimulation of the vestibular tion. Toxicologic analysis is necessary in any case of apparatus (oculovestibular response) provides a more coma where the diagnosis is not immediately clear. intense stimulus for the oculocephalic reflex but gives However, the presence of exogenous drugs or toxins, fundamentally the same information. The test is per- especially alcohol, does not exclude the possibility that formed by irrigating the external auditory canal with other factors, particularly head trauma, are also contribut- cool water in order to induce convection currents in ing to the clinical state. An ethanol level of 43 mmol/L the labyrinths. After a brief latency, the result is tonic (0.2 g/dL) in nonhabituated patients generally causes deviation of both eyes to the side of cool-water irriga- impaired mental activity and of >65 mmol/L (0.3 g/dL) tion and nystagmus in the opposite direction. (The is associated with stupor. The development of tolerance acronym “COWS” has been used to remind generations may allow the chronic alcoholic to remain awake at levels of medical students of the direction of nystagmus— >87 mmol/L (0.4 g/dL). “cold water opposite, warm water same.”) The loss of conjugate ocular movements indicates brainstem dam- The availability of CT and MRI has focused attention age.The absence of nystagmus despite conjugate devia- on causes of coma that are radiologically detectable (e.g., tion of the globes indicates that the cerebral hemispheres hemorrhages, tumors, or hydrocephalus). Resorting pri- are damaged or metabolically suppressed. marily to this approach, although at times expedient, is By touching the cornea with a wisp of cotton, a imprudent because most cases of coma (and confusion) response consisting of brief bilateral lid closure is nor- are metabolic or toxic in origin.The notion that a normal mally observed. The corneal reflexes depend on the CT scan excludes anatomic lesions as the cause of coma is integrity of pontine pathways between the fifth also erroneous. Bilateral hemisphere infarction, acute (afferent) and both seventh (efferent) cranial nerves; brainstem infarction, encephalitis, meningitis, mechanical although rarely useful alone, in conjunction with shearing of axons as a result of closed head trauma, sagittal reflex eye movements they are important clinical tests sinus thrombosis, and subdural hematomas that are iso- of pontine function. CNS depressant drugs diminish dense to adjacent brain are some of the disorders that may or eliminate the corneal responses soon after reflex not be detected. Nevertheless, if the source of coma eye movements are paralyzed but before the pupils remains unknown, a scan should be obtained. become unreactive to light.The corneal (and pharyn- geal) response may be lost for a time on the side of an The EEG is useful in metabolic or drug-induced states acute hemiplegia. but is rarely diagnostic, except when coma is due to clini- cally unrecognized seizures, to herpesvirus encephalitis, or Respiratory Patterns These are of less localiz- to prion (Creutzfeldt-Jakob) disease.The amount of back- ing value in comparison to other brainstem signs. ground slowing of the EEG is a reflection of the severity of any diffuse encephalopathy. Predominant high-voltage
slowing (δ or triphasic waves) in the frontal regions is Lumbar puncture should therefore not be deferred if 137 CHAPTER 14 Coma typical of metabolic coma, as from hepatic failure, and meningitis is a possibility. widespread fast (β) activity implicates sedative drugs (e.g., diazepines, barbiturates).A special pattern of “alpha coma,” DIFFERENTIAL DIAGNOSIS OF COMA defined by widespread, variable 8- to 12-Hz activity, superficially resembles the normal α rhythm of waking (Table 14-1) The causes of coma can be divided into but is unresponsive to environmental stimuli. It results three broad categories: those without focal neurologic from pontine or diffuse cortical damage and is associated signs (e.g., metabolic encephalopathies); meningitis syn- with a poor prognosis. Most importantly, EEG recordings dromes, characterized by fever or stiff neck and an may reveal clinically inapparent epileptic discharges in a excess of cells in the spinal fluid (e.g., bacterial meningi- patient with coma. Normal α activity on the EEG, which tis, subarachnoid hemorrhage); and conditions associated is suppressed by stimulating the patient, also alerts the with prominent focal signs (e.g., stroke, cerebral hemor- clinician to the locked-in syndrome or to hysteria or rhage). In most instances coma is part of an obvious catatonia. medical problem such as drug ingestion, hypoxia, stroke, trauma, or liver or kidney failure. Conditions that cause Lumbar puncture is performed less frequently than in the sudden coma include drug ingestion, cerebral hemorrhage, past for coma diagnosis because neuroimaging effectively trauma, cardiac arrest, epilepsy, or basilar artery embolism. excludes intracerebral and extensive subarachnoid hemor- Coma that appears subacutely is usually related to a rhage. However, examination of the CSF remains indis- preceding medical or neurologic problem, including the pensable in the diagnosis of meningitis and encephalitis. TABLE 14-1 DIFFERENTIAL DIAGNOSIS OF COMA 1. Diseases that cause no focal or lateralizing neurologic signs, usually with normal brainstem functions; CT scan and cellular content of the CSF are normal a. Intoxications: alcohol, sedative drugs, opiates, etc. b. Metabolic disturbances: anoxia, hyponatremia, hypernatremia, hypercalcemia, diabetic acidosis, nonketotic hyperosmolar hyperglycemia, hypoglycemia, uremia, hepatic coma, hypercarbia, addisonian crisis, hypo- and hyperthyroid states, profound nutritional deficiency c. Severe systemic infections: pneumonia, septicemia, typhoid fever, malaria, Waterhouse-Friderichsen syndrome d. Shock from any cause e. Postseizure states, status epilepticus, subclinical epilepsy f. Hypertensive encephalopathy, eclampsia g. Severe hyperthermia, hypothermia h. Concussion i. Acute hydrocephalus 2. Diseases that cause meningeal irritation with or without fever, and with an excess of WBCs or RBCs in the CSF, usually without focal or lateralizing cerebral or brainstem signs; CT or MRI shows no mass lesion a. Subarachnoid hemorrhage from ruptured aneurysm, arteriovenous malformation, trauma b. Acute bacterial meningitis c. Viral encephalitis d. Miscellaneous: Fat embolism, cholesterol embolism, carcinomatous and lymphomatous meningitis, etc. 3. Diseases that cause focal brainstem or lateralizing cerebral signs, with or without changes in the CSF; CT and MRI are abnormal a. Hemispheral hemorrhage (basal ganglionic, thalamic) or infarction (large middle cerebral artery territory) with secondary brainstem compression b. Brainstem infarction due to basilar artery thrombosis or embolism c. Brain abscess, subdural empyema d. Epidural and subdural hemorrhage, brain contusion e. Brain tumor with surrounding edema f. Cerebellar and pontine hemorrhage and infarction g. Widespread traumatic brain injury h. Metabolic coma (see above) with preexisting focal damage i. Miscellaneous: cortical vein thrombosis, herpes simplex encephalitis, multiple cerebral emboli due to bacterial endocarditis, acute hemorrhagic leukoencephalitis, acute disseminated (postinfectious) encephalomyelitis, thrombotic thrombocytopenic purpura, cerebral vasculitis, gliomatosis cerebri, pituitary apoplexy, intravascular lymphoma, etc. Note: CSF, cerebrospinal fluid; WBCs, white blood cells; RBCs, red blood cells.
SECTION II Clinical Manifestations of Neurologic Disease138 secondary brain swelling of a mass lesion such as tumor Demonstration that apnea is due to irreversible or cerebral infarction. medullary damage requires that the PCO2 be high Cerebrovascular diseases cause the greatest difficulty in enough to stimulate respiration during a test of sponta- coma diagnosis (Chap. 21). The most common categories neous breathing. Apnea testing can be done safely by the are: (1) basal ganglia and thalamic hemorrhage (acute but use of diffusion oxygenation prior to removing the ven- not instantaneous onset, vomiting, headache, hemiplegia, tilator. This is accomplished by preoxygenation with and characteristic eye signs); (2) pontine hemorrhage (sud- 100% oxygen, which is then sustained during the test by den onset, pinpoint pupils, loss of reflex eye movements and oxygen administered through a tracheal cannula. CO2 corneal responses, ocular bobbing, posturing, hyperventila- tension increases ~0.3–0.4 kPa/min (2–3 mm Hg/min) tion, and excessive sweating); (3) cerebellar hemorrhage during apnea. At the end of the period of observation, (occipital headache, vomiting, gaze paresis, and inability to typically several minutes, arterial PCO2 should be at least stand); (4) basilar artery thrombosis (neurologic prodrome or >6.6–8.0 kPa (50–60 mm Hg) for the test to be valid. warning spells, diplopia, dysarthria, vomiting, eye movement Apnea is confirmed if no respiratory effort is observed and corneal response abnormalities, and asymmetric limb in the presence of a sufficiently elevated PCO2. paresis); and (5) subarachnoid hemorrhage (precipitous coma after headache and vomiting). The most common The possibility of profound drug-induced or hypother- stroke, infarction in the territory of the middle cerebral mic depression of the nervous system should be excluded, artery, does not generally cause coma, but edema surround- and some period of observation, usually 6–24 h, is desir- ing large infarcts may expand during the first few days and able during which the signs of brain death are sustained. It act as a mass.The syndrome of acute hydrocephalus accom- is advisable to delay clinical testing for at least 24 h if a car- panies many intracranial diseases, particularly subarachnoid diac arrest has caused brain death or if the inciting disease hemorrhage. It is characterized by headache and sometimes is not known.An isoelectric EEG may be used as a confir- vomiting that may progress quickly to coma, with extensor matory test for total cerebral damage. Radionuclide brain posturing of the limbs, bilateral Babinski signs, small unreac- scanning, cerebral angiography, or transcranial Doppler tive pupils, and impaired oculocephalic movements in the measurements may also be used to demonstrate the vertical direction. absence of cerebral blood flow but they have not been If the history and examination do not indicate the extensively correlated with pathologic changes. cause of coma, then information obtained from CT or MRI may be needed.The majority of medical causes of Although it is largely accepted in western society that coma can be established without a neuroimaging study. the respirator can be disconnected from a brain-dead patient, problems frequently arise because of poor com- BRAIN DEATH munication and inadequate preparation of the family by the physician. Reasonable medical practice allows the This is a state of cessation of cerebral function while removal of support or transfer out of an intensive care somatic function is maintained by artificial means and unit of patients who are not brain dead but whose con- the heart continues to pump. It is the only type of brain dition is nonetheless hopeless and are likely to live for damage that is recognized as equivalent to death. Several only a brief time. similar criteria have been advanced for the diagnosis of brain death, and it is essential to adhere to those standards Treatment: endorsed by the local medical community. Ideal criteria COMA are simple, can be assessed at the bedside, and allow no chance of diagnostic error. They contain three essential The immediate goal in a comatose patient is prevention elements of clinical evidence: (1) widespread cortical of further nervous system damage. Hypotension, hypo- destruction that is reflected by deep coma and unrespon- glycemia, hypercalcemia, hypoxia, hypercapnia, and siveness to all forms of stimulation; (2) global brainstem hyperthermia should be corrected rapidly. An oropha- damage demonstrated by absent pupillary light reaction ryngeal airway is adequate to keep the pharynx open in and by the loss of oculovestibular and corneal reflexes; drowsy patients who are breathing normally. Tracheal and (3) destruction of the medulla manifested by com- intubation is indicated if there is apnea, upper airway plete apnea. The pulse rate is invariant and unresponsive obstruction, hypoventilation, or emesis, or if the patient to atropine. Diabetes insipidus is often present but may is liable to aspirate because of coma. Mechanical ventila- develop hours or days after the other clinical signs of tion is required if there is hypoventilation or a need to brain death. The pupils are often enlarged but may be induce hypocapnia in order to lower ICP as described mid-sized; they should not, however, be constricted. The below. IV access is established, and naloxone and dextrose absence of deep tendon reflexes is not required because are administered if narcotic overdose or hypoglycemia are the spinal cord remains functional.There may or may not even remote possibilities; thiamine is given along with be Babinski signs.
glucose to avoid provoking Wernicke disease in malnour- vegetative. The uniformly poor outcome of the persis- 139 CHAPTER 14 Coma ished patients. In cases of suspected basilar thrombosis tent vegetative state has already been mentioned. Chil- with brainstem ischemia, IV heparin or a thrombolytic dren and young adults may have ominous early clinical agent is often utilized, after cerebral hemorrhage has findings such as abnormal brainstem reflexes and yet been excluded by a neuroimaging study. Physostigmine recover, so that temporization in offering a prognosis in may awaken patients with anticholinergic-type drug this group of patients is wise. Metabolic comas have a far overdose but should be used only by experienced better prognosis than traumatic ones.All systems for esti- physicians and with careful monitoring; many physi- mating prognosis in adults should be taken as approxi- cians believe that it should only be used to treat anti- mations, and medical judgments must be tempered by cholinergic overdose-associated cardiac arrhythmias. factors such as age, underlying systemic disease, and gen- The use of benzodiazepine antagonists offers some eral medical condition. In an attempt to collect prognos- prospect of improvement after overdoses of soporific tic information from large numbers of patients with drugs and has transient benefit in hepatic encephalopa- head injury, the Glasgow Coma Scale was devised; thy. IV administration of hypotonic solutions should be empirically it has predictive value in cases of brain monitored carefully in any serious acute brain illness trauma (Table 31-2). For anoxic and metabolic coma, because of the potential for exacerbating brain swelling. clinical signs such as the pupillary and motor responses Cervical spine injuries must not be overlooked, particu- after 1 day, 3 days, and 1 week have been shown to have larly prior to attempting intubation or evaluating of ocu- predictive value (Fig. 22-4). The absence of the cortical locephalic responses. Fever and meningismus indicate waves of the somatosensory evoked potentials has also an urgent need for examination of the CSF to diagnose proved a strong indicator of poor outcome in coma meningitis. If the lumbar puncture in a case of sus- from any cause. pected meningitis is delayed for any reason, an antibi- otic such as a third-generation cephalosporin should be FURTHER READINGS administered as soon as possible, preferably after obtaining blood cultures. The management of raised ICP LAUREYS S et al: Brain function in coma, vegetative state, and related is discussed in Chap. 22. disorders. Lancet Neurol 3:537, 2004 PROGNOSIS POSNER JB et al: Plum and Posner’s Diagnosis of Stupor and Coma, 4th ed. New York and London, Oxford Univ Press, 2007 One hopes to avoid the emotionally painful, hopeless outcome of a patient who is left severely disabled or ROPPER AH: Neurological and Neurosurgical Intensive Care, 4th ed. New York, Lippincott Williams & Wilkins, 2004 WIJDICKS EF et al: Neuropathology of brain death in the modern transplant era. Neurology 70:1234, 2008 YOUNG GB: Clinical Practice. Neurologic prognosis after cardiac arrest. N Engl J Med 361:605, 2009
CHAPTER 15 APHASIA, MEMORY LOSS, AND OTHER FOCAL CEREBRAL DISORDERS M. -Marsel Mesulam I The Left Perisylvian Network for Language: I The Occipitotemporal Network for Face and Object Aphasias and Related Conditions . . . . . . . . . . . . . . . . . . . . 140 Recognition: Prosopagnosia and Object Agnosia . . . . . . . . 150 Clinical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 I The Limbic Network for Memory: Amnesias . . . . . . . . . . . . . 150 I The Parietofrontal Network for Spatial Orientation: I The Prefrontal Network for Attention and Behavior . . . . . . . . 152 I Caring for the Patient with Deficits of Higher Neglect and Related Conditions . . . . . . . . . . . . . . . . . . . . . 147 Hemispatial Neglect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Cerebral Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 Bálint’s Syndrome, Simultanagnosia, Dressing Apraxia, I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 and Construction Apraxia . . . . . . . . . . . . . . . . . . . . . . . . . . 148 The cerebral cortex of the human brain contains ~20 other parts of the network undergo compensatory reor- billion neurons spread over an area of 2.5 m2.The primary ganization; and (4) individual anatomic sites within a sensory areas provide an obligatory portal for the entry of network display a relative (but not absolute) specializa- sensory information into cortical circuitry, whereas the tion for different behavioral aspects of the relevant func- primary motor areas provide final common pathways for tion. Five anatomically defined large-scale networks are coordinating complex motor acts. The primary sensory most relevant to clinical practice: a perisylvian network and motor areas constitute 10% of the cerebral cortex. for language; a parietofrontal network for spatial cogni- The rest is subsumed by unimodal, heteromodal, paral- tion; an occipitotemporal network for face and object imbic, and limbic areas, collectively known as the associa- recognition; a limbic network for retentive memory; and tion cortex (Fig. 15-1). The association cortex mediates a prefrontal network for attention and behavior. the integrative processes that subserve cognition, emo- tion, and behavior. A systematic testing of these mental THE LEFT PERISYLVIAN NETWORK FOR functions is necessary for the effective clinical assessment LANGUAGE: APHASIAS AND RELATED of the association cortex and its diseases. CONDITIONS According to current thinking, there are no centers Language allows the communication and elaboration of for “hearing words,”“perceiving space,” or “storing mem- thoughts and experiences by linking them to arbitrary ories.” Cognitive and behavioral functions (domains) are symbols known as words. The neural substrate of lan- coordinated by intersecting large-scale neural networks that guage is composed of a distributed network centered in contain interconnected cortical and subcortical compo- the perisylvian region of the left hemisphere. The poste- nents.The network approach to higher cerebral function rior pole of this network is located at the temporopari- has at least four implications of clinical relevance: (1) a etal junction and includes a region known as Wernicke’s single domain such as language or memory can be dis- area. An essential function of Wernicke’s area is to trans- rupted by damage to any one of several areas, as long as form sensory inputs into their lexical representations so these areas belong to the same network; (2) damage that these can establish the distributed associations that confined to a single area can give rise to multiple give the word its meaning.The anterior pole of the lan- deficits, involving the functions of all networks that guage network is located in the inferior frontal gyrus intersect in that region; (3) damage to a network com- ponent may give rise to minimal or transient deficits if 140
and Broca’s areas are interconnected with each other 141 CHAPTER 15 Aphasia, Memory Loss, and Other Focal Cerebral Disorders and with additional perisylvian, temporal, prefrontal, and posterior parietal regions, making up a neural network subserving the various aspects of language function. Damage to any one of these components or to their interconnections can give rise to language disturbances (aphasia). Aphasia should be diagnosed only when there are deficits in the formal aspects of language such as naming, word choice, comprehension, spelling, and syn- tax. Dysarthria and mutism do not, by themselves, lead to a diagnosis of aphasia.The language network shows a left hemisphere dominance pattern in the vast majority of the population. In ~90% of right handers and 60% of A left handers, aphasia occurs only after lesions of the left hemisphere. In some individuals no hemispheric domi- nance for language can be discerned, and in some others (including a small minority of right handers) there is a right hemisphere dominance for language. A language disturbance occurring after a right hemisphere lesion in a right hander is called crossed aphasia. B CLINICAL EXAMINATION FIGURE 15-1 The clinical examination of language should include the Lateral (A) and medial (B) views of the cerebral hemi- assessment of naming, spontaneous speech, comprehen- spheres. The numbers refer to the Brodmann cytoarchitec- sion, repetition, reading, and writing.A deficit of naming tonic designations. Area 17 corresponds to the primary (anomia) is the single most common finding in aphasic visual cortex, 41–42 to the primary auditory cortex, 1–3 to patients. When asked to name common objects (pencil the primary somatosensory cortex, and 4 to the primary or wristwatch), the patient may fail to come up with the motor cortex. The rest of the cerebral cortex contains associ- appropriate word, may provide a circumlocutious ation areas. AG, angular gyrus; B, Broca’s area; CC, corpus description of the object (“the thing for writing”), or callosum; CG, cingulate gyrus; DLPFC, dorsolateral pre- may come up with the wrong word (paraphasia). If the frontal cortex; FEF, frontal eye fields (premotor cortex); FG, patient offers an incorrect but legitimate word (“pen” fusiform gyrus; IPL, inferior parietal lobule; ITG, inferior tem- for “pencil”), the naming error is known as a semantic poral gyrus; LG, lingual gyrus; MPFC, medial prefrontal cor- paraphasia; if the word approximates the correct answer tex; MTG, middle temporal gyrus; OFC, orbitofrontal cortex; but is phonetically inaccurate (“plentil” for “pencil”), it PHG, parahippocampal gyrus; PPC, posterior parietal cortex; is known as a phonemic paraphasia. Asking the patient to PSC, peristriate cortex; SC, striate cortex; SMG, supramar- name body parts, geometric shapes, and component ginal gyrus; SPL, superior parietal lobule; STG, superior tem- parts of objects (lapel of coat, cap of pen) can elicit mild poral gyrus; STS, superior temporal sulcus; TP, temporopolar forms of anomia in patients who can otherwise name cortex; W, Wernicke’s area. common objects. In most anomias, the patient cannot retrieve the appropriate name when shown an object and includes a region known as Broca’s area. An essential but can point to the appropriate object when the name function of this area is to transform lexical representa- is provided by the examiner.This is known as a one-way tions into their articulatory sequences so that the words (or retrieval-based) naming deficit. A two-way naming can be uttered in the form of spoken language. The deficit exists if the patient can neither provide nor rec- sequencing function of Broca’s area also appears to ognize the correct name, indicating the presence of a involve the ordering of words into sentences that con- language comprehension impairment. Spontaneous speech tain a meaning-appropriate syntax (grammar).Wernicke’s is described as “fluent” if it maintains appropriate output volume, phrase length, and melody or as “nonfluent” if it is sparse, halting, and average utterance length is below four words.The examiner should also note if the speech is paraphasic or circumlocutious; if it shows a relative paucity of substantive nouns and action verbs versus function words (prepositions, conjunctions); and if word
142 TABLE 15-1 CLINICAL FEATURES OF APHASIAS AND RELATED CONDITIONS SECTION II Clinical Manifestations of Neurologic Disease Wernicke’s COMPREHENSION REPETITION OF NAMING FLUENCY Broca’s SPOKEN LANGUAGE Impaired Impaired Preserved or increased Global Preserved (except Impaired Impaired Decreased Conduction grammar) Impaired Nonfluent (motor) transcortical Impaired Impaired Decreased Fluent (sensory) transcortical Preserved Impaired Impaired Preserved Isolation Preserved Impaired Impaired Impaired Anomic Impaired Preserved Impaired Preserved Impaired Preserved Impaired No purposeful speech Preserved Echolalia Impaired Preserved except for Preserved word-finding pauses Preserved Pure word deafness Impaired only for Impaired Preserved Pure alexia spoken language Preserved Preserved Preserved Impaired only for reading order, tenses, suffixes, prefixes, plurals, and possessives are rigid one-to-one relationship and should be conceptual- appropriate. Comprehension can be tested by assessing the ized within the context of the distributed network model. patient’s ability to follow conversation, by asking yes-no Nonetheless, the classification of aphasias of acute onset questions (“Can a dog fly?”, “Does it snow in sum- into specific clinical syndromes helps to determine the mer?”) or asking the patient to point to appropriate most likely anatomic distribution of the underlying objects (“Where is the source of illumination in this neurologic disease and has implications for etiology room?”). Statements with embedded clauses or passive and prognosis (Table 15-1). The syndromes listed in voice construction (“If a tiger is eaten by a lion, which Table 15-1 are most applicable to aphasias caused by animal stays alive?”) help to assess the ability to compre- cerebrovascular accidents (CVA). They can be divided hend complex syntactic structure. Commands to close into “central” syndromes, which result from damage to or open the eyes, stand up, sit down, or roll over should the two epicenters of the language network (Broca’s and not be used to assess overall comprehension since appro- Wernicke’s areas), and “disconnection” syndromes, which priate responses aimed at such axial movements can be arise from lesions that interrupt the functional connec- preserved in patients who otherwise have profound tivity of these centers with each other and with the other comprehension deficits. components of the language network. The syndromes outlined below are idealizations; pure syndromes occur Repetition is assessed by asking the patient to repeat rarely. single words, short sentences, or strings of words such as “No ifs, ands, or buts.” The testing of repetition with Wernicke’s Aphasia tongue-twisters such as “hippopotamus” or “Irish con- stabulary” provides a better assessment of dysarthria and Comprehension is impaired for spoken and written lan- palilalia than aphasia. Aphasic patients may have little guage. Language output is fluent but is highly paraphasic difficulty with tongue-twisters but have a particularly and circumlocutious.The tendency for paraphasic errors hard time repeating a string of function words. It is may be so pronounced that it leads to strings of neolo- important to make sure that the number of words does gisms, which form the basis of what is known as “jargon not exceed the patient’s attention span. Otherwise, the aphasia.” Speech contains large numbers of function failure of repetition becomes a reflection of the nar- words (e.g., prepositions, conjunctions) but few substan- rowed attention span rather than an indication of an tive nouns or verbs that refer to specific actions. The aphasic deficit. Reading should be assessed for deficits in output is therefore voluminous but uninformative. For reading aloud as well as comprehension. Writing is example, a patient attempts to describe how his wife assessed for spelling errors, word order, and grammar. accidentally threw away something important, perhaps Alexia describes an inability to either read aloud or his dentures: “We don’t need it anymore, she says. And comprehend single words and simple sentences; agraphia with it when that was downstairs was my teeth-tick . . . a (or dysgraphia) is used to describe an acquired deficit in . . . den . . . dentith . . . my dentist. And they happened to the spelling or grammar of written language. be in that bag . . . see? How could this have happened? How could a thing like this happen . . . So she says we The correspondence between individual deficits of language function and lesion location does not display a
won’t need it anymore . . . I didn’t think we’d use it. And lead to a characteristic agrammatism. Speech is tele- 143 CHAPTER 15 Aphasia, Memory Loss, and Other Focal Cerebral Disorders now if I have any problems anybody coming a month graphic and pithy but quite informative. In the follow- from now, 4 months from now, or 6 months from now, I ing passage, a patient with Broca’s aphasia describes his have a new dentist. Where my two . . . two little pieces medical history: “I see . . . the dotor, dotor sent me . . . of dentist that I use . . . that I . . . all gone. If she throws Bosson. Go to hospital. Dotor . . . kept me beside. Two, the whole thing away . . . visit some friends of hers and tee days, doctor send me home.” she can’t throw them away.” Output may be reduced to a grunt or single word Gestures and pantomime do not improve communi- (“yes” or “no”), which is emitted with different intona- cation. The patient does not seem to realize that his or tions in an attempt to express approval or disapproval. In her language is incomprehensible and may appear angry addition to fluency, naming and repetition are also and impatient when the examiner fails to decipher the impaired. Comprehension of spoken language is intact, meaning of a severely paraphasic statement. In some except for syntactically difficult sentences with passive patients this type of aphasia can be associated with voice structure or embedded clauses. Reading compre- severe agitation and paranoid behaviors. One area of hension is also preserved, with the occasional exception of comprehension that may be preserved is the ability to a specific inability to read small grammatical words such as follow commands aimed at axial musculature.The disso- conjunctions and pronouns. The last two features indicate ciation between the failure to understand simple ques- that Broca’s aphasia is not just an “expressive” or “motor” tions (“What is your name?”) in a patient who rapidly disorder and that it may also involve a comprehension closes his or her eyes, sits up, or rolls over when asked to deficit for function words and syntax. Patients with Broca’s do so is characteristic of Wernicke’s aphasia and helps to aphasia can be tearful, easily frustrated, and profoundly differentiate it from deafness, psychiatric disease, or depressed. Insight into their condition is preserved, in con- malingering. Patients with Wernicke’s aphasia cannot trast to Wernicke’s aphasia. Even when spontaneous speech express their thoughts in meaning-appropriate words is severely dysarthric, the patient may be able to display a and cannot decode the meaning of words in any modal- relatively normal articulation of words when singing.This ity of input.This aphasia therefore has expressive as well dissociation has been used to develop specific therapeutic as receptive components. Repetition, naming, reading, approaches (melodic intonation therapy) for Broca’s apha- and writing are also impaired. sia. Additional neurologic deficits usually include right facial weakness, hemiparesis or hemiplegia, and a buccofa- The lesion site most commonly associated with Wer- cial apraxia characterized by an inability to carry out nicke’s aphasia is the posterior portion of the language net- motor commands involving oropharyngeal and facial mus- work and tends to involve at least parts of Wernicke’s area. culature (e.g., patients are unable to demonstrate how to An embolus to the inferior division of the middle cerebral blow out a match or suck through a straw).Visual fields are artery, and to the posterior temporal or angular branches in intact. The cause is most often infarction of Broca’s area particular, is the most common etiology (Chap. 21). Intrac- (the inferior frontal convolution;“B” in Fig. 15-1) and sur- erebral hemorrhage, severe head trauma, or neoplasm are rounding anterior perisylvian and insular cortex, due to other causes.A coexisting right hemi- or superior quadran- occlusion of the superior division of the middle cerebral tanopia is common, and mild right nasolabial flattening artery (Chap. 21). Mass lesions including tumor, intracere- may be found, but otherwise the examination is often bral hemorrhage, or abscess may also be responsible. Small unrevealing. The paraphasic, neologistic speech in an agi- lesions confined to the posterior part of Broca’s area may tated patient with an otherwise unremarkable neurologic lead to a nonaphasic and often reversible deficit of speech examination may lead to the suspicion of a primary psychi- articulation, usually accompanied by mild right facial atric disorder such as schizophrenia or mania, but the other weakness. When the cause of Broca’s aphasia is stroke, components characteristic of acquired aphasia and the recovery of language function generally peaks within 2–6 absence of prior psychiatric disease usually settle the issue. months, after which time further progress is limited. Some patients with Wernicke’s aphasia due to intracerebral hemorrhage or head trauma may improve as the hemor- Global Aphasia rhage or the injury heals. In most other patients, prognosis for recovery is guarded. Speech output is nonfluent, and comprehension of spo- ken language is severely impaired. Naming, repetition, Broca’s Aphasia reading, and writing are also impaired. This syndrome represents the combined dysfunction of Broca’s and Speech is nonfluent, labored, interrupted by many Wernicke’s areas and usually results from strokes that word-finding pauses, and usually dysarthric. It is impov- involve the entire middle cerebral artery distribution in erished in function words but enriched in meaning- the left hemisphere. Most patients are initially mute or say appropriate nouns and verbs. Abnormal word order and a few words, such as “hi” or “yes.” Related signs include the inappropriate deployment of bound morphemes (word right hemiplegia, hemisensory loss, and homonymous endings used to denote tenses, possessives, or plurals)
SECTION II Clinical Manifestations of Neurologic Disease144 hemianopia. Occasionally, a patient with a lesion in Wer- pathologic function of the language network when it is nicke’s area will present with a global aphasia that soon isolated from other regions of the brain. Broca’s and resolves into Wernicke’s aphasia. Wernicke’s areas tend to be spared, but there is damage to the surrounding frontal, parietal, and temporal cortex. Conduction Aphasia Lesions are patchy and can be associated with anoxia, carbon monoxide poisoning, or complete watershed Speech output is fluent but paraphasic, comprehension zone infarctions. of spoken language is intact, and repetition is severely impaired. Naming and writing are also impaired. Read- Anomic Aphasia ing aloud is impaired, but reading comprehension is pre- served.The lesion sites spare Broca’s and Wernicke’s areas This form of aphasia may be considered the “minimal but may induce a functional disconnection between the dysfunction” syndrome of the language network. Articu- two so that lexical representations formed in Wernicke’s lation, comprehension, and repetition are intact, but area and adjacent regions cannot be conveyed to Broca’s confrontation naming, word finding, and spelling are area for assembly into corresponding articulatory pat- impaired. Speech is enriched in function words but terns. Occasionally, a Wernicke’s area lesion gives rise to impoverished in substantive nouns and verbs denoting a transient Wernicke’s aphasia that rapidly resolves into a specific actions. Language output is fluent but parapha- conduction aphasia. The paraphasic output in conduc- sic, circumlocutious, and uninformative. The lesion sites tion aphasia interferes with the ability to express mean- can be anywhere within the left hemisphere language ing, but this deficit is not nearly as severe as the one dis- network, including the middle and inferior temporal played by patients with Wernicke’s aphasia. Associated gyri. Anomic aphasia is the single most common language dis- neurologic signs in conduction aphasia vary according turbance seen in head trauma, metabolic encephalopathy, and to the primary lesion site. Alzheimer’s disease. Nonfluent Transcortical Aphasia Pure Word Deafness (Transcortical Motor Aphasia) The most common causes are either bilateral or left- The features are similar to Broca’s aphasia, but repetition sided middle cerebral artery strokes affecting the supe- is intact and agrammatism may be less pronounced. The rior temporal gyrus. The net effect of the underlying neurologic examination may be otherwise intact, but a lesion is to interrupt the flow of information from the right hemiparesis can also exist.The lesion site disconnects unimodal auditory association cortex to Wernicke’s area. the intact language network from prefrontal areas of the Patients have no difficulty understanding written lan- brain and usually involves the anterior watershed zone guage and can express themselves well in spoken or between anterior and middle cerebral artery territories written language. They have no difficulty interpreting or the supplementary motor cortex in the territory of the and reacting to environmental sounds since primary anterior cerebral artery. auditory cortex and subcortical auditory relays are intact. Since auditory information cannot be conveyed Fluent Transcortical Aphasia to the language network, however, it cannot be decoded (Transcortical Sensory Aphasia) into lexical representations and the patient reacts to speech as if it were in an alien tongue that cannot be Clinical features are similar to those of Wernicke’s apha- deciphered. Patients cannot repeat spoken language but sia, but repetition is intact.The lesion site disconnects the have no difficulty naming objects. In time, patients with intact core of the language network from other tem- pure word deafness teach themselves lip reading and poroparietal association areas. Associated neurologic find- may appear to have improved. There may be no addi- ings may include hemianopia. Cerebrovascular lesions tional neurologic findings, but agitated paranoid reac- (e.g., infarctions in the posterior watershed zone) or neo- tions are frequent in the acute stages. Cerebrovascular plasms that involve the temporoparietal cortex posterior lesions are the most frequent cause. to Wernicke’s area are the most common causes. Pure Alexia without Agraphia Isolation Aphasia This is the visual equivalent of pure word deafness. The This rare syndrome represents a combination of the two lesions (usually a combination of damage to the left transcortical aphasias. Comprehension is severely impaired, occipital cortex and to a posterior sector of the corpus and there is no purposeful speech output. The patient callosum—the splenium) interrupt the flow of visual may parrot fragments of heard conversations (echolalia), input into the language network.There is usually a right indicating that the neural mechanisms for repetition are hemianopia, but the core language network remains at least partially intact. This condition represents the
unaffected. The patient can understand and produce necessary for the movement are intact. Some forms of 145 CHAPTER 15 Aphasia, Memory Loss, and Other Focal Cerebral Disorders spoken language, name objects in the left visual hemi- ideomotor apraxia represent a disconnection of the lan- field, repeat, and write. However, the patient acts as if guage network from pyramidal motor systems: commands illiterate when asked to read even the simplest sentence to execute complex movements are understood but can- because the visual information from the written words not be conveyed to the appropriate motor areas, even (presented to the intact left visual hemifield) cannot though the relevant motor mechanisms are intact. Bucco- reach the language network. Objects in the left hemi- facial apraxia involves apraxic deficits in movements of field may be named accurately because they activate the face and mouth. Limb apraxia encompasses apraxic nonvisual associations in the right hemisphere, which, in deficits in movements of the arms and legs. Ideomotor turn, can access the language network through transcal- apraxia is almost always caused by lesions in the left losal pathways anterior to the splenium. Patients with hemisphere and is commonly associated with aphasic this syndrome may also lose the ability to name colors, syndromes, especially Broca’s aphasia and conduction although they can match colors. This is known as a color aphasia. Its presence cannot be ascertained in patients anomia. The most common etiology of pure alexia is a with language comprehension deficits. The ability to vascular lesion in the territory of the posterior cerebral follow commands aimed at axial musculature (“close artery or an infiltrating neoplasm in the left occipital the eyes,” “stand up”) is subserved by different pathways cortex that involves the optic radiations as well as the and may be intact in otherwise severely aphasic and crossing fibers of the splenium. Since the posterior cere- apraxic patients. Patients with lesions of the anterior bral artery also supplies medial temporal components of corpus callosum can display a special type of ideomotor the limbic system, the patient with pure alexia may also apraxia confined to the left side of the body. Since the experience an amnesia, but this is usually transient handling of real objects is not impaired, ideomotor because the limbic lesion is unilateral. apraxia, by itself, causes no major limitation of daily liv- ing activities. Aphemia Ideational apraxia refers to a deficit in the execution of There is an acute onset of severely impaired fluency a goal-directed sequence of movements in patients who (often mutism), which cannot be accounted for by cor- have no difficulty executing the individual components ticobulbar, cerebellar, or extrapyramidal dysfunction. of the sequence. For example, when asked to pick up a Recovery is the rule and involves an intermediate stage pen and write, the sequence of uncapping the pen, plac- of hoarse whispering.Writing, reading, and comprehen- ing the cap at the opposite end, turning the point toward sion are intact, so this is not a true aphasic syndrome. the writing surface, and writing may be disrupted, and Partial lesions of Broca’s area or subcortical lesions that the patient may be seen trying to write with the wrong undercut its connections with other parts of the brain end of the pen or even with the removed cap. These may be present. Occasionally, the lesion site is on the motor sequencing problems are usually seen in the con- medial aspects of the frontal lobes and may involve the text of confusional states and dementias rather than focal supplementary motor cortex of the left hemisphere. lesions associated with aphasic conditions. Limb-kinetic apraxia involves a clumsiness in the actual use of tools that Apraxia cannot be attributed to sensory, pyramidal, extrapyramidal, or cerebellar dysfunction. This condition can emerge in This generic term designates a complex motor deficit the context of focal premotor cortex lesions or corticobasal that cannot be attributed to pyramidal, extrapyramidal, ganglionic degeneration. cerebellar, or sensory dysfunction and that does not arise from the patient’s failure to understand the nature Gerstmann’s Syndrome of the task. The form that is most frequently encoun- tered in clinical practice is known as ideomotor apraxia. The combination of acalculia (impairment of simple arith- Commands to perform a specific motor act (“cough,” metic), dysgraphia (impaired writing), finger anomia (an “blow out a match”) or to pantomime the use of a com- inability to name individual fingers such as the index or mon tool (a comb, hammer, straw, or toothbrush) in the thumb), and right-left confusion (an inability to tell whether absence of the real object cannot be followed. The a hand, foot, or arm of the patient or examiner is on the patient’s ability to comprehend the command is ascer- right or left side of the body) is known as Gerstmann’s tained by demonstrating multiple movements and estab- syndrome. In making this diagnosis it is important to lishing that the correct one can be recognized. Some establish that the finger and left-right naming deficits patients with this type of apraxia can imitate the appro- are not part of a more generalized anomia and that the priate movement (when it is demonstrated by the patient is not otherwise aphasic.When Gerstmann’s syn- examiner) and show no impairment when handed the drome is seen in isolation, it is commonly associated real object, indicating that the sensorimotor mechanisms with damage to the inferior parietal lobule (especially the angular gyrus) in the left hemisphere.
SECTION II Clinical Manifestations of Neurologic Disease146 Aprosodia to the point where customary daily living activities become compromised (Chap. 23). Alzheimer’s disease is Variations of melodic stress and intonation influence the the single most common cause of dementia. The neu- meaning and impact of spoken language. For example, ropathology of Alzheimer’s disease causes the earliest and the two statements “He is clever.” and “He is clever?” con- most profound neuronal loss in memory-related parts of tain an identical word choice and syntax but convey the brain such as the entorhinal cortex and the hip- vastly different messages because of differences in the pocampus. This is why progressive forgetfulness for intonation and stress with which the statements are recent events and experiences is the cardinal feature of uttered. This aspect of language is known as prosody. Alzheimer’s disease. In time, the neuronal pathology in Damage to perisylvian areas in the right hemisphere can Alzheimer’s disease spreads to the language network and a interfere with speech prosody and can lead to syndromes progressive aphasia, usually of the anomic type, becomes of aprosodia. Damage to right hemisphere regions corre- added to the progressive amnesia. There are other pat- sponding to Wernicke’s area can selectively impair decoding terns of dementia, however, where neurodegeneration of speech prosody, whereas damage to right hemisphere initially targets the language rather than memory net- regions corresponding to Broca’s area yields a greater impair- work of the brain, leading to the emergence of a pro- ment in the ability to introduce meaning-appropriate gressive aphasia that becomes the most prominent aspect prosody into spoken language. The latter deficit is the of the clinical picture during the initial phases of the most common type of aprosodia identified in clinical disease. Primary progressive aphasia (PPA) is the most practice—the patient produces grammatically correct lan- widely recognized syndrome with this pattern of selec- guage with accurate word choice but the statements are tive language impairment. uttered in a monotone that interferes with the ability to convey the intended stress and affect. Patients with this Clinical Presentation and Diagnosis of PPA type of aprosodia give the mistaken impression of being The patient with PPA comes to medical attention depressed or indifferent. because of word-finding difficulties, abnormal speech patterns, and spelling errors of recent onset. PPA is diag- Subcortical Aphasia nosed when other mental faculties such as memory for daily events, visuospatial skills (assessed by tests of draw- Damage to subcortical components of the language net- ing and face recognition), and comportment (assessed by work (e.g., the striatum and thalamus of the left hemi- history obtained from a third party) remain relatively sphere) can also lead to aphasia.The resulting syndromes intact; when language is the major area of dysfunction contain combinations of deficits in the various aspects of for the first few years of the disease; and when structural language but rarely fit the specific patterns described in brain imaging does not reveal a specific lesion, other than Table 15-1. In a patient with a CVA, an anomic aphasia atrophy, to account for the language deficit. Impairments accompanied by dysarthria or a fluent aphasia with in other cognitive functions may also emerge, but the hemiparesis should raise the suspicion of a subcortical language dysfunction remains the most salient feature lesion site. and deteriorates most rapidly throughout the illness. Progressive Aphasias Language in PPA The language impairment in PPA varies from patient to In clinical practice, acquired aphasias are most com- patient. Some patients cannot find the right words to monly encountered in one of two contexts: CVAs and express thoughts; others cannot understand the meaning degenerative diseases. Aphasias caused by CVAs start of heard or seen words; still others cannot name objects suddenly and display maximal deficits at the onset. The in the environment. The language impairment can be underlying lesion is relatively circumscribed and associ- fluent (that is, with normal articulation, flow, and num- ated with a total loss of neural function at the lesion site. ber of words per utterance) or nonfluent. The single These are the “classic” aphasias described earlier where rel- most common sign of primary progressive aphasia is atively reproducible relationships between lesion site and anomia, manifested by an inability to come up with the aphasia pattern can be discerned. Aphasias caused by right word during conversation and/or an inability to neurodegenerative diseases have an insidious onset and name objects shown by the examiner. Many patients relentless progression so that the symptomatology changes remain in an anomic phase through most of the disease over time. Since the neuronal loss within the areas and experience a gradual intensification of word-finding encompassed by the neurodegeneration is partial and deficits to the point of near-mutism. Others, however, since it tends to include multiple components of the proceed to develop distinct forms of agrammatism language network, distinctive clinical patterns and clinico- and/or word comprehension deficits. The agrammatism anatomic correlations are less obvious. consists of inappropriate word order and misuse of small Dementia is a generic term used to designate a neu- rodegenerative disease that impairs intellect and behavior
grammatical words. One patient, for example, sent the associated with neuronal loss in the lateral and anterior 147 CHAPTER 15 Aphasia, Memory Loss, and Other Focal Cerebral Disorders following e-mail to her daughter: “I will come my temporal cortex. house in your car and drive my car into chicago. . . .You will back get your car and my car park in my driveway. Neuropathology Love, Mom.” Comprehension deficits, if present, start Approximately 30% of patients have shown the micro- with an occasional inability to understand single low- scopic pathology of Alzheimer’s disease, presumably with frequency words and gradually progress to encompass an atypical distribution of lesions. In the majority of the comprehension of conversational speech. cases, the neuropathology falls within the family of fron- totemporal lobar degenerations (FTLD) and displays The impairments of syntax, comprehension, naming, various combinations of focal neuronal loss, gliosis, tau- or writing in PPA are no different from those seen in positive inclusions, Pick bodies, and tau-negative ubiqui- aphasias of cerebrovascular causes. However, they form tin inclusions (Chap. 23). Familial forms of PPA with slightly different patterns. According to a classification tau-negative ubiquinated inclusions have recently been proposed by Gorno-Tempini and colleagues, three vari- linked to mutations of the progranulin gene on chromo- ants of PPA can be recognized: an agrammatical variant some 17. Apolipoprotein E and prion protein genotyp- characterized by poor fluency and impaired syntax, a ing has shown differences between patients with typical semantic variant characterized by preserved fluency and clinical patterns of Alzheimer’s disease and those with a syntax but poor single word comprehension, and a diagnosis of PPA. The intriguing possibility has been logopenic variant characterized by preserved syntax and raised that a personal or family history of dyslexia may comprehension but frequent word-finding pauses dur- be a risk factor for primary progressive aphasia, at least ing spontaneous speech.The agrammatical variant is also in some patients, suggesting that this disease may arise known as progressive nonfluent aphasia and displays simi- on a background of genetic or developmental vulnera- larities to Broca’s aphasia. However, dysarthria is usually bility affecting language-related areas of the brain. absent. The semantic variant of PPA is also known as semantic dementia and displays similarities to Wernicke’s THE PARIETOFRONTAL NETWORK FOR aphasia, but the comprehension difficulty tends to be SPATIAL ORIENTATION: NEGLECT AND milder. The most obvious difference between aphasias RELATED CONDITIONS caused by CVA and those caused by neurodegenerative disease is the post-stroke improvement in CVA-related HEMISPATIAL NEGLECT aphasias, leading to a progressive crystallization of the subtypes listed in Table 15-1, versus the gradual deterio- Adaptive orientation to significant events within the ration that leads to a loss of syndromic specificity as the extrapersonal space is subserved by a large-scale network disease progresses. containing three major cortical components.The cingulate cortex provides access to a limbic-motivational mapping Pathophysiology of the extrapersonal space, the posterior parietal cortex to a Patients with PPA display progressive atrophy (indica- sensorimotor representation of salient extrapersonal tive of neuronal loss), electroencephalographic slowing, events, and the frontal eye fields to motor strategies for decreased blood flow (measured by single photon emis- attentional behaviors (Fig. 15-2). Subcortical compo- sion CT) and decreased glucose utilization (measured nents of this network include the striatum and the thala- by positron emission tomography) that are most pro- mus. Contralesional hemispatial neglect represents one nounced within the language network of the brain.The outcome of damage to any of the cortical or subcortical abnormalities may remain confined to left hemisphere components of this network. The traditional view that perisylvian and anterior temporal cortices for many hemispatial neglect always denotes a parietal lobe lesion is inac- years. The clinical focality of primary progressive aphasia curate. In keeping with this anatomic organization, the is thus matched by the anatomic selectivity of the under- clinical manifestations of neglect display three behavioral lying pathologic process. components: sensory events (or their mental representa- tions) within the neglected hemispace have a lesser impact The three variants display overlapping distributions of on overall awareness; there is a paucity of exploratory and neuronal loss but the agrammatical variant is most orienting acts directed toward the neglected hemispace; closely associated with atrophy in the anterior parts of and the patient behaves as if the neglected hemispace the language network (where Broca’s area is located), the was motivationally devalued. semantic variant with atrophy in the temporal compo- nents of the language network, and the logopenic vari- According to one model of spatial cognition, the ant with atrophy in the temporoparietal component of right hemisphere directs attention within the entire the language network. The relationship between poor extrapersonal space, whereas the left hemisphere directs language comprehension and damage to Wernicke’s area, attention mostly within the contralateral right hemispace. which is a feature of CVA-related aphasias, is not present in PPA. Instead, poor comprehension is most closely
SECTION II Clinical Manifestations of Neurologic Disease148 placed on the left side of the tray; and may fail to read the left half of sentences. When the examiner draws a A large circle [12–15 cm (5–6 in.) in diameter] and asks the patient to place the numbers 1–12 as if the circle B represented the face of a clock, there is a tendency to FIGURE 15-2 crowd the numbers on the right side and leave the left Functional magnetic resonance imaging of language side empty. When asked to copy a simple line drawing, and spatial attention in neurologically intact subjects. the patient fails to copy detail on the left; and when The dark areas show regions of task-related significant asked to write, there is a tendency to leave an unusually wide margin on the left. activation. (A) The subjects were asked to determine if two words were synonymous. This language task led to the Two bedside tests that are useful in assessing neglect simultaneous activation of the two epicenters of the lan- are simultaneous bilateral stimulation and visual target cancel- guage network, Broca’s area (B) and Wernicke’s area (W). lation. In the former, the examiner provides either uni- The activations are exclusively in the left hemisphere. (B ) lateral or simultaneous bilateral stimulation in the visual, The subjects were asked to shift spatial attention to a auditory, and tactile modalities. Following right hemi- peripheral target. This task led to the simultaneous activa- sphere injury, patients who have no difficulty detecting tion of the three epicenters of the attentional network, the unilateral stimuli on either side experience the bilater- posterior parietal cortex (P), the frontal eye fields (F), and ally presented stimulus as coming only from the right. the cingulate gyrus (CG). The activations are predominantly This phenomenon is known as extinction and is a mani- in the right hemisphere. (Courtesy of Darren Gitelman, MD; festation of the sensory-representational aspect of with permission.) hemispatial neglect. In the target detection task, targets (e.g., As) are interspersed with foils (e.g., other letters Consequently, unilateral left hemisphere lesions do not of the alphabet) on a 21.5 × 28.0 cm (8.5 × 11 in.) give rise to much contralesional neglect since the global sheet of paper and the patient is asked to circle all the attentional mechanisms of the right hemisphere can targets. A failure to detect targets on the left is a manifes- compensate for the loss of the contralaterally directed tation of the exploratory deficit in hemispatial neglect attentional functions of the left hemisphere. Unilateral (Fig. 15-3A). Hemianopia, by itself, does not interfere right hemisphere lesions, however, give rise to severe with performance in this task since the patient is free to contralesional left hemispatial neglect because the unaf- turn the head and eyes to the left.The normal tendency fected left hemisphere does not contain ipsilateral atten- in target detection tasks is to start from the left upper tional mechanisms.This model is consistent with clinical quadrant and move systematically in horizontal or ver- experience, which shows that contralesional neglect is tical sweeps. Some patients show a tendency to start the more common, severe, and lasting after damage to the process from the right and proceed in a haphazard fashion. right hemisphere than after damage to the left hemi- This represents a subtle manifestation of left neglect, sphere. Severe neglect for the right hemispace is rare, even if the patient eventually manages to detect all the even in left handers with left hemisphere lesions. appropriate targets. Some patients with neglect may also deny the existence of hemiparesis and may even deny Patients with severe neglect may fail to dress, shave, or ownership of the paralyzed limb, a condition known as groom the left side of the body; may fail to eat food anosognosia. Cerebrovascular lesions and neoplasms in the right hemisphere are the most common causes of hemispatial neglect. Depending on the site of the lesion, the patient with neglect may also have hemiparesis, hemihypesthesia, and hemianopia on the left, but these are not invariant findings. The majority of patients display considerable improvement of hemispatial neglect, usually within the first several weeks. BÁLINT’S SYNDROME, SIMULTANAGNOSIA, DRESSING APRAXIA, AND CONSTRUCTION APRAXIA Bilateral involvement of the network for spatial attention, especially its parietal components, leads to a state of severe spatial disorientation known as Bálint’s syndrome. Bálint’s syndrome involves deficits in the orderly visuomotor
149 A CHAPTER 15 Aphasia, Memory Loss, and Other Focal Cerebral Disorders FIGURE 15-3 Evidence of left hemispatial neglect and simultanagnosia. A. A 47-year-old man with a large frontoparietal lesion in the right hemisphere was asked to circle all the As. Only targets on the right are circled. This is a manifestation of left hemispatial neglect. B. A 70-year-old woman with a 2-year history of degener- ative dementia was able to circle most of the small targets but ignored the larger ones. This is a B manifestation of simultanagnosia. scanning of the environment (oculomotor apraxia) and in simultanagnosia report that objects they look at may accurate manual reaching toward visual targets (optic ataxia). suddenly vanish, probably indicating an inability to look The third and most dramatic component of Bálint’s syn- back at the original point of gaze after brief saccadic drome is known as simultanagnosia and reflects an inabil- displacements. Movement and distracting stimuli greatly ity to integrate visual information in the center of gaze exacerbate the difficulties of visual perception. Simul- with more peripheral information. The patient gets tanagnosia can sometimes occur without the other two stuck on the detail that falls in the center of gaze with- components of Bálint’s syndrome. out attempting to scan the visual environment for addi- tional information. The patient with simultanagnosia A modification of the letter cancellation task described “misses the forest for the trees.” Complex visual scenes above can be used for the bedside diagnosis of simul- cannot be grasped in their entirety, leading to severe tanagnosia. In this modification, some of the targets limitations in the visual identification of objects and (e.g., As) are made to be much larger than the others scenes. For example, a patient who is shown a table [7.5–10 cm vs 2.5 cm (3–4 in. vs 1 in.) in height], and all lamp and asked to name the object may look at its targets are embedded among foils. Patients with simul- circular base and call it an ash tray. Some patients with tanagnosia display a counterintuitive but characteristic tendency to miss the larger targets (Fig. 15-3B). This
SECTION II Clinical Manifestations of Neurologic Disease150 occurs because the information needed for the identifi- her own face in the mirror. This is not a perceptual cation of the larger targets cannot be confined to the deficit since prosopagnosic patients can easily tell if two immediate line of gaze and requires the integration of faces are identical or not. Furthermore, a prosopagnosic visual information across a more extensive field of view. patient who cannot recognize a familiar face by visual The greater difficulty in the detection of the larger tar- inspection alone can use auditory cues to reach appro- gets also indicates that poor acuity is not responsible for priate recognition if allowed to listen to the person’s the impairment of visual function and that the problem voice.The deficit in prosopagnosia is therefore modality- is central rather than peripheral. Bálint’s syndrome specific and reflects the existence of a lesion that prevents results from bilateral dorsal parietal lesions; common set- the activation of otherwise intact multimodal templates tings include watershed infarction between the middle by relevant visual input. Damasio has pointed out that and posterior cerebral artery territories, hypoglycemia, the deficit in prosopagnosia is not limited to the recog- sagittal sinus thrombosis, or atypical forms of Alzheimer’s nition of faces but that it can also extend to the recogni- disease. In patients with Bálint’s syndrome due to stroke, tion of individual members of larger generic object bilateral visual field defects (usually inferior quadran- groups. For example, prosopagnosic patients characteris- tanopias) are common. tically have no difficulty with the generic identification Another manifestation of bilateral (or right-sided) of a face as a face or of a car as a car, but they cannot dorsal parietal lobe lesions is dressing apraxia.The patient recognize the identity of an individual face or the make with this condition is unable to align the body axis with of an individual car. This reflects a visual recognition the axis of the garment and can be seen struggling as he deficit for proprietary features that characterize individ- or she holds a coat from its bottom or extends his or her ual members of an object class. When recognition prob- arm into a fold of the garment rather than into its lems become more generalized and extend to the generic sleeve. Lesions that involve the posterior parietal cortex identification of common objects, the condition is known also lead to severe difficulties in copying simple line as visual object agnosia. In contrast to prosopagnosic drawings. This is known as a construction apraxia and is patients, those with object agnosia cannot recognize a face much more severe if the lesion is in the right hemi- as a face or a car as a car. sphere. In some patients with right hemisphere lesions, the drawing difficulties are confined to the left side of It is important to distinguish visual object agnosia the figure and represent a manifestation of hemispatial from anomia.The patient with anomia cannot name the neglect; in others, there is a more universal deficit in object but can describe its use. In contrast, the patient reproducing contours and three-dimensional perspec- with visual agnosia is unable either to name a visually tive. Dressing apraxia and construction apraxia represent presented object or to describe its use.The characteristic special instances of a more general disturbance in spatial lesions in prosopagnosia and visual object agnosia consist orientation. of bilateral infarctions in the territory of the posterior cerebral arteries. Associated deficits can include visual THE OCCIPITOTEMPORAL NETWORK field defects (especially superior quadrantanopias) or a FOR FACE AND OBJECT RECOGNITION: centrally based color blindness known as achromatopsia. PROSOPAGNOSIA AND OBJECT Rarely, the responsible lesion is unilateral. In such cases, AGNOSIA prosopagnosia is associated with lesions in the right hemisphere and object agnosia with lesions in the left. Perceptual information about faces and objects is ini- tially encoded in primary (striate) visual cortex and THE LIMBIC NETWORK FOR MEMORY: adjacent (upstream) peristriate visual association areas. AMNESIAS This information is subsequently relayed first to the downstream visual association areas of occipitotemporal Limbic and paralimbic areas (such as the hippocampus, cortex and then to other heteromodal and paralimbic amygdala, and entorhinal cortex), the anterior and areas of the cerebral cortex. Bilateral lesions in the medial nuclei of the thalamus, the medial and basal parts fusiform and lingual gyri of the occipitotemporal cortex of the striatum, and the hypothalamus collectively con- disrupt this process and interfere with the ability of other- stitute a distributed network known as the limbic system. wise intact perceptual information to activate the distrib- The behavioral affiliations of this network include the uted multimodal associations that lead to the recognition coordination of emotion, motivation, autonomic tone, of faces and objects.The resultant face and object recog- and endocrine function. An additional area of specializa- nition deficits are known as prosopagnosia and visual object tion for the limbic network, and the one which is of agnosia. most relevance to clinical practice, is that of declarative (conscious) memory for recent episodes and experi- The patient with prosopagnosia cannot recognize famil- ences. A disturbance in this function is known as an iar faces, including, sometimes, the reflection of his or amnestic state. In the absence of deficits in motivation,
attention, language, or visuospatial function, the clinical hold the words online for at least 1 min.The final phase 151CHAPTER 15 Aphasia, Memory Loss, and Other Focal Cerebral Disorders diagnosis of a persistent global amnestic state is always of the testing involves a retention period of 5–10 min, associated with bilateral damage to the limbic network, during which the patient is engaged in other tasks. Ade- usually within the hippocampo-entorhinal complex or quate recall at the end of this interval requires offline the thalamus. storage, retention, and retrieval. Amnestic patients fail this phase of the task and may even forget that they Although the limbic network is the site of damage were given a list of words to remember. Accurate recog- for amnestic states, it is almost certainly not the storage nition of the words by multiple choice in a patient who site for memories. Memories are stored in widely dis- cannot recall them indicates a less severe memory dis- tributed form throughout the cerebral cortex. The role turbance that affects mostly the retrieval stage of memory. attributed to the limbic network is to bind these distrib- The retrograde component of an amnesia can be assessed uted fragments into coherent events and experiences that with questions related to autobiographical or historic can sustain conscious recall. Damage to the limbic net- events. The anterograde component of amnestic states is work does not necessarily destroy memories but inter- usually much more prominent than the retrograde com- feres with their conscious (declarative) recall in coherent ponent. In rare instances, usually associated with tempo- form. The individual fragments of information remain ral lobe epilepsy or benzodiazepine intake, the retro- preserved despite the limbic lesions and can sustain what grade component may dominate. is known as implicit memory. For example, patients with amnestic states can acquire new motor or perceptual The assessment of memory can be quite challenging. skills, even though they may have no conscious knowl- Bedside evaluations may only detect the most severe edge of the experiences that led to the acquisition of these impairments. Less severe memory impairments, as in the skills. case of patients with temporal lobe epilepsy, mild head injury, or early dementia, require quantitative evaluations The memory disturbance in the amnestic state is by neuropsychologists. Confusional states caused by toxic- multimodal and includes retrograde and anterograde metabolic encephalopathies and some types of frontal components. The retrograde amnesia involves an inability lobe damage interfere with attentional capacity and lead to recall experiences that occurred before the onset of to secondary memory impairments, even in the absence the amnestic state. Relatively recent events are more of any limbic lesions. This sort of memory impairment vulnerable to retrograde amnesia than more remote and can be differentiated from the amnestic state by the more extensively consolidated events. A patient who presence of additional impairments in the attention- comes to the emergency department complaining that related tasks described later in the section on the frontal he cannot remember his identity but who can remem- lobes. ber the events of the previous day is almost certainly not suffering from a neurologic cause of memory distur- Many neurologic diseases can give rise to an amnestic bance. The second and most important component of state. These include tumors (of the sphenoid wing, pos- the amnestic state is the anterograde amnesia, which indi- terior corpus callosum, thalamus, or medial temporal cates an inability to store, retain, and recall new knowl- lobe), infarctions (in the territories of the anterior or edge. Patients with amnestic states cannot remember posterior cerebral arteries), head trauma, herpes simplex what they ate a few minutes ago or the details of an encephalitis, Wernicke-Korsakoff encephalopathy, para- important event they may have experienced a few hours neoplastic limbic encephalitis, and degenerative ago. In the acute stages, there may also be a tendency to dementias such as Alzheimer’s or Pick’s disease.The one fill in memory gaps with inaccurate, fabricated, and common denominator of all these diseases is that they often implausible information. This is known as confabu- lead to the bilateral lesions within one or more compo- lation. Patients with the amnestic syndrome forget that nents in the limbic network, most commonly the hip- they forget and tend to deny the existence of a memory pocampus, entorhinal cortex, the mammillary bodies of problem when questioned. the hypothalamus, and the limbic thalamus. Occasion- ally, unilateral left-sided lesions can give rise to an The patient with an amnestic state is almost always amnestic state, but the memory disorder tends to be disoriented, especially to time. Accurate temporal orien- transient. Depending on the nature and distribution of tation and accurate knowledge of current news rule out the underlying neurologic disease, the patient may also a major amnestic state. The anterograde component of have visual field deficits, eye movement limitations, or an amnestic state can be tested with a list of four to five cerebellar findings. words read aloud by the examiner up to five times or until the patient can immediately repeat the entire list Transient global amnesia is a distinctive syndrome usu- without intervening delay. In the next phase of testing, ally seen in late middle age. Patients become acutely dis- the patient is allowed to concentrate on the words and oriented and repeatedly ask who they are, where they to rehearse them internally for 1 min before being asked to are, what they are doing. The spell is characterized by recall them. Accurate performance in this phase indicates anterograde amnesia (inability to retain new information) that the patient is motivated and sufficiently attentive to and a retrograde amnesia for relatively recent events that
SECTION II Clinical Manifestations of Neurologic Disease152 occurred before the onset. The syndrome usually the patient becomes socially disinhibited and shows resolves within 24–48 h and is followed by the filling-in severe impairments of judgment, insight, and foresight. of the period affected by the retrograde amnesia, The dissociation between intact cognitive function and although there is persistent loss of memory for the events a total lack of even rudimentary common sense is strik- that occurred during the ictus. Recurrences are noted in ing. Despite the preservation of all essential memory ~20% of patients. Migraine, temporal lobe seizures, and functions, the patient cannot learn from experience and transient ischemic events in the posterior cerebral terri- continues to display inappropriate behaviors without tory have been postulated as causes of transient global appearing to feel emotional pain, guilt, or regret when amnesia. The absence of associated neurologic findings such behaviors repeatedly lead to disastrous consequences. may occasionally lead to the incorrect diagnosis of a The impairments may emerge only in real-life situations psychiatric disorder. when behavior is under minimal external control and may not be apparent within the structured environment THE PREFRONTAL NETWORK FOR of the medical office. Testing judgment by asking ATTENTION AND BEHAVIOR patients what they would do if they detected a fire in a theater or found a stamped and addressed envelope on Approximately one-third of all the cerebral cortex in the road is not very informative since patients who answer the human brain is located in the frontal lobes. The these questions wisely in the office may still act very frontal lobes can be subdivided into motor-premotor, foolishly in the more complex real-life setting. The dorsolateral prefrontal, medial prefrontal, and orbitofrontal physician must therefore be prepared to make a diagno- components.The terms frontal lobe syndrome and prefrontal sis of frontal lobe disease on the basis of historic infor- cortex refer only to the last three of these four compo- mation alone even when the office examination of mental nents. These are the parts of the cerebral cortex that state may be quite intact. show the greatest phylogenetic expansion in primates and especially in humans. The dorsolateral prefrontal, medial The abulic syndrome tends to be associated with dam- prefrontal, and orbitofrontal areas, and the subcortical age to the dorsolateral prefrontal cortex, and the disinhibi- structures with which they are interconnected (i.e., the tion syndrome with the medial prefrontal or orbitofrontal head of the caudate and the dorsomedial nucleus of the cortex. These syndromes tend to arise almost exclusively thalamus), collectively make up a large-scale network after bilateral lesions, most frequently in the setting of head that coordinates exceedingly complex aspects of human trauma, stroke, ruptured aneurysms, hydrocephalus, tumors cognition and behavior. (including metastases, glioblastoma, and falx or olfactory groove meningiomas), or focal degenerative diseases. Uni- The prefrontal network plays an important role in lateral lesions confined to the prefrontal cortex may remain behaviors that require an integration of thought with silent until the pathology spreads to the other side. The emotion and motivation. There is no simple formula emergence of developmentally primitive reflexes, also for summarizing the diverse functional affiliations of known as frontal release signs, such as grasping (elicited the prefrontal network. Its integrity appears important by stroking the palm) and sucking (elicited by stroking for the simultaneous awareness of context, options, the lips) are seen primarily in patients with large struc- consequences, relevance, and emotional impact so as tural lesions that extend into the premotor components to allow the formulation of adaptive inferences, deci- of the frontal lobes or in the context of metabolic sions, and actions. Damage to this part of the brain encephalopathies.The vast majority of patients with pre- impairs mental flexibility, reasoning, hypothesis forma- frontal lesions and frontal lobe behavioral syndromes do tion, abstract thinking, foresight, judgment, the online not display these reflexes. (attentive) holding of information, and the ability to inhibit inappropriate responses. Behaviors impaired by Damage to the frontal lobe disrupts a variety of prefrontal cortex lesions, especially those related to the attention-related functions including working memory manipulation of mental content, are often referred to (the transient online holding of information), concentra- as “executive functions.” tion span, the scanning and retrieval of stored informa- tion, the inhibition of immediate but inappropriate Even very large bilateral prefrontal lesions may leave responses, and mental flexibility. The capacity for focus- all sensory, motor, and basic cognitive functions intact ing on a trend of thought and the ability to voluntarily while leading to isolated but dramatic alterations of per- shift the focus of attention from one thought or stimulus sonality and behavior. The most common clinical mani- to another can become impaired. Digit span (which festations of damage to the prefrontal network take the should be seven forward and five reverse) is decreased; form of two relatively distinct syndromes. In the frontal the recitation of the months of the year in reverse order abulic syndrome, the patient shows a loss of initiative, cre- (which should take less than 15 s) is slowed; and the flu- ativity, and curiosity and displays a pervasive emotional ency in producing words starting with a, f, or s that can blandness and apathy. In the frontal disinhibition syndrome, be generated in 1 min (normally Ն12 per letter) is diminished even in nonaphasic patients. Characteristically,
there is a progressive slowing of performance as the task it is advisable to use the diagnostic term frontal net- 153CHAPTER 15 Aphasia, Memory Loss, and Other Focal Cerebral Disorders proceeds; e.g., the patient asked to count backwards by work syndrome, with the understanding that the respon- 3s may say “100, 97, 94, . . . 91, . . . 88,” etc., and may not sible lesions can lie anywhere within this distributed complete the task. In “go–no-go” tasks (where the instruc- network. tion is to raise the finger upon hearing one tap but to keep it still upon hearing two taps), the patient shows a The patient with frontal lobe disease raises potential characteristic inability to keep still in response to the dilemmas in differential diagnosis: the abulia and bland- “no-go” stimulus; mental flexibility (tested by the ability ness may be misinterpreted as depression, and the disin- to shift from one criterion to another in sorting or match- hibition as idiopathic mania or acting-out. Appropriate ing tasks) is impoverished; distractibility by irrelevant stim- intervention may be delayed while a treatable tumor uli is increased; and there is a pronounced tendency for keeps expanding. An informed approach to frontal lobe impersistence and perseveration. disease and its behavioral manifestations may help to avoid such errors. These attentional deficits disrupt the orderly registra- tion and retrieval of new information and lead to sec- CARING FOR THE PATIENT WITH ondary memory deficits. Such memory deficits can be DEFICITS OF HIGHER CEREBRAL differentiated from the primary memory impairments of FUNCTION the amnestic state by showing that they improve when the attentional load of the task is decreased. Working Some of the deficits described in this chapter are so memory (also known as immediate memory) is an atten- complex that they may bewilder not only the patient tional function based on the temporary online holding of and family but also the physician. It is imperative to information. It is closely associated with the integrity of carry out a systematic clinical evaluation in order to the prefrontal network and the ascending reticular activat- characterize the nature of the deficits and explain them ing system. Retentive memory, on the other hand, depends in lay terms to the patient and family. Such an explana- on the stable (offline) storage of information and is associ- tion can allay at least some of the anxieties, address the ated with the integrity of the limbic network. The dis- mistaken impression that the deficit (e.g., social disinhi- tinction of the underlying neural mechanisms is illustrated bition or inability to recognize family members) is psy- by the observation that severely amnestic patients who chologically motivated, and lead to practical suggestions cannot remember events that occurred a few minutes ago for daily living activities. The consultation of a skilled may have intact if not superior working memory capacity neuropsychologist may aid in the formulation of diag- as shown in tests of digit span. nosis and management. Patients with simultanagnosia, for example, may benefit from the counterintuitive instruc- Lesions in the caudate nucleus or in the dorsomedial tion to stand back when they cannot find an item so nucleus of the thalamus (subcortical components of the that a greater search area falls within the immediate field prefrontal network) can also produce a frontal lobe syn- of gaze. Some patients with frontal lobe disease can be drome. This is one reason why the mental state changes extremely irritable and abusive to spouses and yet dis- associated with degenerative basal ganglia diseases, such play all the appropriate social graces during the visit to as Parkinson’s or Huntington’s disease, may take the the medical office. In such cases, the history may be form of a frontal lobe syndrome. Because of its wide- more important than the bedside examination in chart- spread connections with other regions of association ing a course of treatment. cortex, one essential computational role of the prefrontal network is to function as an integrator, or “orchestrator,” Reactive depression is common in patients with for other networks. Bilateral multifocal lesions of the cere- higher cerebral dysfunction and should be treated.These bral hemispheres, none of which are individually large patients may be sensitive to the usual doses of antide- enough to cause specific cognitive deficits such as aphasia pressants or anxiolytics and deserve a careful titration of or neglect, can collectively interfere with the connectivity dosage. Brain damage may cause a dissociation between and integrating function of the prefrontal cortex. A feeling states and their expression, so that a patient who frontal lobe syndrome is the single most common may superficially appear jocular could still be suffering behavioral profile associated with a variety of bilateral mul- from an underlying depression that deserves to be treated. tifocal brain diseases including metabolic encephalopathy, In many cases, agitation may be controlled with reassur- multiple sclerosis, vitamin B12 deficiency, and others. In ance. In other cases, treatment with sedating antidepres- fact, the vast majority of patients with the clinical diag- sants may become necessary. The use of neuroleptics for nosis of a frontal lobe syndrome tend to have lesions the control of agitation should be reserved for refractory that do not involve prefrontal cortex but involve either cases since extrapyramidal side effects are frequent in the subcortical components of the prefrontal network or patients with coexisting brain damage. its connections with other parts of the brain. In order to avoid making a diagnosis of “frontal lobe syndrome” Spontaneous improvement of cognitive deficits due in a patient with no evidence of frontal cortex disease, to acute neurologic lesions is common. It is most rapid
SECTION II Clinical Manifestations of Neurologic Disease154 in the first few weeks but may continue for up to 2 years, Alzheimer’s disease, for example, causes the greatest destruc- especially in young individuals with single brain lesions. tion in medial temporal areas belonging to the memory The mechanisms for this recovery are incompletely network and is clinically characterized by a correspond- understood. Some of the initial deficits appear to arise ingly severe amnesia. There are other dementias where from remote dysfunction (diaschisis) in parts of the brain memory is intact. Frontal lobe dementia results from a that are interconnected with the site of initial injury. selective degeneration of the frontal lobe and leads to a Improvement in these patients may reflect, at least in gradual dissolution of behavior and complex attention. part, a normalization of the remote dysfunction. Other Primary progressive aphasia is characterized by a gradual mechanisms may involve functional reorganization in atrophy of the left perisylvian language network and surviving neurons adjacent to the injury or the compen- leads to a progressive dissolution of language that can satory use of homologous structures, e.g., the right supe- remain isolated for up to 10 years. An enlightened rior temporal gyrus with recovery from Wernicke’s approach to the differential diagnosis and treatment of aphasia. In some patients with large lesions involving these patients requires an understanding of the principles Broca’s and Wernicke’s areas, only Wernicke’s area may that link neural networks to higher cerebral functions. show contralateral compensatory reorganization (or bilateral functionality), giving rise to a situation where a FURTHER READINGS lesion that should have caused a global aphasia becomes associated with a residual Broca’s aphasia. Prognosis for CATANI M, FFYCHTE H: The rises and falls of disconnection syn- recovery from aphasia is best when Wernicke’s area is dromes. Brain 128:2224, 2005 spared. Cognitive rehabilitation procedures have been used in the treatment of higher cortical deficits. There CRUTS M et al: Null mutations in progranulin cause ubiquitin- are few controlled studies, but some do show a benefit positive frontotemporal dementia linked to chromosome 17q21. of rehabilitation in the recovery from hemispatial Nature 442:916, 2006 neglect and aphasia. Some types of deficits may be more prone to recovery than others. For example, patients HILLIS AE: Aphasia: Progress in the last quarter of a century. Neurol- with nonfluent aphasias are more likely to benefit from ogy 69:200, 2007 speech therapy than patients with fluent aphasias and comprehension deficits. In general, lesions that lead to a KNIBB JA et al: Clinical and pathological characterization of progres- denial of illness (e.g., anosognosia) are associated with sive aphasia.Ann Neurol 59:156, 2006 cognitive deficits that are more resistant to rehabilita- tion. The recovery from higher cortical dysfunction is LE BER I et al: Phenotype variability in progranulin mutation carri- rarely complete. Periodic neuropsychological assessment ers: a clinical, neuropsychological, imaging and genetic study. is necessary for quantifying the pace of the improvement Brain 131:732, 2008 and for generating specific recommendations for cogni- tive rehabilitation, modifications in the home environ- MESULAM M-M: Behavioral neuroanatomy: Large-scale networks, ment, and the timetable for returning to school or work. association cortex, frontal syndromes, the limbic system and In general medical practice, most patients with deficits hemispheric specializations, in Principles of Behavioral and Cogni- in higher cognitive functions will be suffering from tive Neurology, 2d ed, M-M Mesulam (ed). New York, Oxford dementia. There is a mistaken belief that dementias are University Press, 2000, pp 1–120 anatomically diffuse and that they cause global cognitive impairments. This is only true at the terminal stages. ______: Representation, inference, and transcendent encoding in During most of the clinical course, dementias are exquisitely neurocognitive networks of the human brain. Ann Neurol selective with respect to anatomy and cognitive pattern. 64:367, 2008 ———: Current concepts: Primary progressive aphasia—a language- based dementia. New Engl J Med 348:1535, 2003 ———: The human frontal lobes: Transcending the default mode through contingent encoding, in Principles of Frontal Lobe Func- tion, DT Stuss, RT Knight (eds). New York, Oxford University Press, 2002, pp 8–30 ROGALSKI E, MESULAM M: An update on primary progressive apha- sia. Curr Neurol Neurosci Rep 7:388, 2007 SUMMERFIELD JJ et al: Orienting attention based on long-term memory experience. Neuron 49:905, 2006
CHAPTER 16 SLEEP DISORDERS Charles A. Czeisler I John W. Winkelman I Gary S. Richardson I Physiology of Sleep and Wakefulness . . . . . . . . . . . . . . . . . . 155 Comorbid Insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 States and Stages of Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . 155 Restless Legs Syndrome (RLS) . . . . . . . . . . . . . . . . . . . . . . . 162 Organization of Human Sleep . . . . . . . . . . . . . . . . . . . . . . . . 156 Periodic Limb Movement Disorder (PLMD) . . . . . . . . . . . . . . 163 Neuroanatomy of Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 Evaluation of Daytime Sleepiness . . . . . . . . . . . . . . . . . . . . . 163 Neurochemistry of Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 Narcolepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 Physiology of Circadian Rhythmicity . . . . . . . . . . . . . . . . . . . 157 Sleep Apnea Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 Behavioral Correlates of Sleep States and Stages . . . . . . . . . 158 Parasomnias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 Physiologic Correlates of Sleep States and Stages . . . . . . . . 158 I Circadian Rhythm Sleep Disorders . . . . . . . . . . . . . . . . . . . . 167 Medical Implications of Circadian Rhythmicity . . . . . . . . . . . . 169 I Disorders of Sleep and Wakefulness . . . . . . . . . . . . . . . . . . . 159 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 Evaluation of Insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 Primary Insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 Disturbed sleep is among the most frequent health com- a mid-afternoon nap and a shortened night sleep. Two plaints physicians encounter. More than one-half of principal systems govern the sleep-wake cycle: one adults in the United States experience at least intermit- actively generates sleep and sleep-related processes and tent sleep disturbances. For most, it is an occasional another times sleep within the 24-h day. Either intrinsic night of poor sleep or daytime sleepiness. However, the abnormalities in these systems or extrinsic disturbances Institute of Medicine estimates that 50–70 million (environmental, drug- or illness-related) can lead to Americans suffer from a chronic disorder of sleep and sleep or circadian rhythm disorders. wakefulness, which can lead to serious impairment of daytime functioning. In addition, such problems may STATES AND STAGES OF SLEEP contribute to or exacerbate medical or psychiatric con- ditions. Thirty years ago, many such complaints were States and stages of human sleep are defined on the basis treated with hypnotic medications without further diag- of characteristic patterns in the electroencephalogram nostic evaluation. Since then, a distinct class of sleep and (EEG), the electrooculogram (EOG—a measure of eye- arousal disorders has been identified. movement activity), and the surface electromyogram (EMG) measured on the chin and neck. The continuous recording of this array of electrophysiologic parameters to PHYSIOLOGY OF SLEEP AND define sleep and wakefulness is termed polysomnography. WAKEFULNESS Polysomnographic profiles define two states of sleep: (1) rapid-eye-movement (REM) sleep, and (2) non- Most adults sleep 7–8 h per night, although the timing, rapid-eye-movement (NREM) sleep. NREM sleep is duration, and internal structure of sleep vary among further subdivided into four stages, characterized by healthy individuals and as a function of age. At the increasing arousal threshold and slowing of the cortical extremes, infants and the elderly have frequent interrup- EEG. REM sleep is characterized by a low-amplitude, tions of sleep. In the United States, adults of intermedi- mixed-frequency EEG similar to that of NREM stage 1 ate age tend to have one consolidated sleep episode per sleep. The EOG shows bursts of REM similar to those day, although in some cultures sleep may be divided into seen during eyes-open wakefulness. Chin EMG activity 155
SECTION II Clinical Manifestations of Neurologic Disease156 is absent, reflecting the brainstem-mediated muscle atonia A different age profile exists for REM sleep than for that is characteristic of that state. slow-wave sleep. In infancy, REM sleep may comprise 50% of total sleep time, and the percentage is inversely ORGANIZATION OF HUMAN SLEEP proportional to developmental age. The amount of REM sleep falls off sharply over the first postnatal year Normal nocturnal sleep in adults displays a consistent as a mature REM-NREM cycle develops; thereafter, organization from night to night (Fig. 16-1). After sleep REM sleep occupies a relatively constant percentage of onset, sleep usually progresses through NREM stages total sleep time. 1–4 within 45–60 min. Slow-wave sleep (NREM stages 3 and 4) predominates in the first third of the night and NEUROANATOMY OF SLEEP comprises 15–25% of total nocturnal sleep time in young adults. The percentage of slow-wave sleep is Experimental studies in animals have variously impli- influenced by several factors, most notably age (see cated the medullary reticular formation, the thalamus, below). Prior sleep deprivation increases the rapidity of and the basal forebrain in the generation of sleep, while sleep onset and both the intensity and amount of slow- the brainstem reticular formation, the midbrain, the sub- wave sleep. thalamus, the thalamus, and the basal forebrain have all been suggested to play a role in the generation of wake- The first REM sleep episode usually occurs in the fulness or EEG arousal. second hour of sleep. More rapid onset of REM sleep in a young adult (particularly if <30 min) may suggest Current models suggest that the capacity for sleep pathology such as endogenous depression, narcolepsy, and wakefulness generation is distributed along an axial circadian rhythm disorders, or drug withdrawal. NREM “core” of neurons extending from the brainstem ros- and REM alternate through the night with an average trally to the basal forebrain. A cluster of γ-aminobutyric period of 90–110 min (the “ultradian” sleep cycle). acid (GABA) and galaninergic neurons in the ventrolat- Overall, REM sleep constitutes 20–25% of total sleep, eral preoptic (VLPO) hypothalamus is selectively acti- and NREM stages 1 and 2 are 50–60%. vated coincident with sleep onset.These neurons project to and inhibit multiple distinct wakefulness centers Age has a profound impact on sleep state organization including the tuberomammilary (histaminergic) nucleus (Fig. 16-1). Slow-wave sleep is most intense and promi- that are important to the ascending arousal system, indi- nent during childhood, decreasing sharply at puberty and cating that the hypothalamic VLPO neurons play a key across the second and third decades of life. After age 30, executive role in sleep regulation. there is a progressive decline in the amount of slow-wave sleep, and the amplitude of delta EEG activity comprising Specific regions in the pons are associated with the slow-wave sleep is profoundly reduced. The depth of neurophysiologic correlates of REM sleep. Small lesions in slow-wave sleep, as measured by the arousal threshold to the dorsal pons result in the loss of the descending muscle auditory stimulation, also decreases with age. In the other- inhibition normally associated with REM sleep; microin- wise healthy older person, slow-wave sleep may be com- jections of the cholinergic agonist carbachol into the pon- pletely absent, particularly in males. tine reticular formation appear to produce a state with all Awake Age 23 REM Sleep stage 1 2 3 4 Awake Age 68 REM 1 2 3 4 00:00 02:00 04:00 06:00 08:00 Clock time FIGURE 16-1 sleep, frequent spontaneous awakenings, early sleep onset, Stages of REM sleep (solid bars), the four stages of NREM and early morning awakening. (From the Division of Sleep sleep, and wakefulness over the course of the entire night for Medicine, Brigham and Women’s Hospital.) representative young and older adult men. Characteristic fea- tures of sleep in older people include reduction of slow-wave
of the features of REM sleep.These experimental manip- ? TIM ? PER3 157 ulations are mimicked by pathologic conditions in humans CRY1 PER2 and animals. In narcolepsy, for example, abrupt, complete, CRY2 PER1 CK1E or partial paralysis (cataplexy) occurs in response to a vari- ety of stimuli. In dogs with this condition, physostigmine, a – central cholinesterase inhibitor, increases the frequency of cataplectic attacks, while atropine decreases their fre- CLOCK CHAPTER 16 Sleep Disorders quency. Conversely, in REM sleep behavior disorder (see BMAL1 later), patients suffer from incomplete motor inhibition during REM sleep, resulting in involuntary, occasionally + violent movement during REM sleep. E-Box Per1 gene NEUROCHEMISTRY OF SLEEP FIGURE 16-2 Early experimental studies that focused on the raphe Model of the molecular feedback loop at the core of the nuclei of the brainstem appeared to implicate serotonin as mammalian circadian clock. The positive element of the the primary sleep-promoting neurotransmitter, while cat- feedback loop (+) is the transcriptional activation of the Per1 echolamines were considered to be responsible for wake- gene (and probably other clock genes) by a heterodimer of fulness. Simple neurochemical models have given way to the transcription factors CLOCK and BMAL1 (also called more complex formulations involving multiple parallel MOP3) bound to an E-box DNA regulatory element. The Per1 waking systems. Pharmacologic studies suggest that hista- transcript and its product, the clock component PER1 pro- mine, acetylcholine, dopamine, serotonin, and noradrena- tein, accumulate in the cell cytoplasm. As it accumulates, the line are all involved in wake promotion. In addition, pontine PER1 protein is recruited into a multiprotein complex thought cholinergic neurotransmission is known to play a role in to contain other circadian clock component proteins such as REM sleep generation.The alerting influence of caffeine cryptochromes (CRYs), Period proteins (PERs), and others. implicates adenosine, whereas the hypnotic effect of ben- This complex is then transported into the cell nucleus (across zodiazepines and barbiturates suggests a role for endogenous the dotted line), where it functions as the negative element in ligands of the GABAA receptor complex. A newly charac- the feedback loop (–) by inhibiting the activity of the CLOCK- terized neuropeptide, hypocretin (orexin), has recently been BMAL1 transcription factor heterodimer. As a consequence implicated in the pathophysiology of narcolepsy (see of this action, the concentration of PER1 and other clock later), but its role in normal sleep regulation remains to be proteins in the inhibitory complex falls, allowing CLOCK- defined. BMAL1 to activate transcription of Per1 and other genes and begin another cycle. The dynamics of the 24-h molecular A variety of sleep-promoting substances have been cycle are controlled at several levels, including regulation of identified, although it is not known whether they are the rate of PER protein degradation by casein kinase-1 involved in the endogenous sleep-wake regulatory process. epsilon (CK1E). Additional limbs of this genetic regulatory These include prostaglandin D2, delta sleep–inducing pep- network, omitted for the sake of clarity, are thought to con- tide, muramyl dipeptide, interleukin 1, fatty acid primary tribute stability. Question marks denote putative clock pro- amides, and melatonin. The hypnotic effect of these sub- teins, such as Timeless (TIM), as yet lacking genetic proof of stances is commonly limited to NREM or slow-wave a role in the mammalian clock mechanism. (Copyright Charles sleep, although peptides that increase REM sleep have also J. Weitz, Ph.D., Department of Neurobiology, Harvard Med- been reported. Many putative “sleep factors,” including ical School.) interleukin 1 and prostaglandin D2, are immunologically active as well, suggesting a link between immune function between those rhythmic components passively evoked and sleep-wake states. by periodic environmental or behavioral changes (e.g., the increase in blood pressure and heart rate upon PHYSIOLOGY OF CIRCADIAN RHYTHMICITY assumption of the upright posture) and those actively driven by an endogenous oscillatory process (e.g., the The sleep-wake cycle is the most evident of the many circadian variation in plasma cortisol that persists under 24-h rhythms in humans. Prominent daily variations also a variety of environmental and behavioral conditions). occur in endocrine, thermoregulatory, cardiac, pul- monary, renal, gastrointestinal, and neurobehavioral While it is now recognized that many peripheral functions. At the molecular level, endogenous circadian tissues in mammals have circadian clocks that regulate rhythmicity is driven by self-sustaining transcriptional/ diverse physiologic processes, these independent tissue- translational feedback loops (Fig. 16-2). In evaluating a specific oscillations are coordinated by a central neural daily variation in humans, it is important to distinguish pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Bilateral destruction of these nuclei results in a loss of the endogenous circadian rhythm of
SECTION II Clinical Manifestations of Neurologic Disease158 locomotor activity, which can be restored only by trans- PHYSIOLOGIC CORRELATES OF SLEEP plantation of the same structure from a donor animal. STATES AND STAGES The genetically determined period of this endogenous neural oscillator, which averages ~24.2 h in humans, is All major physiologic systems are influenced by sleep. normally synchronized to the 24-h period of the envi- Changes in cardiovascular function include a decrease in ronmental light-dark cycle. Small differences in circadian blood pressure and heart rate during NREM and partic- period underlie variations in diurnal preference, with ularly during slow-wave sleep. During REM sleep, pha- the circadian period shorter in individuals who typically sic activity (bursts of eye movements) is associated with rise early compared to those who typically go to bed late. variability in both blood pressure and heart rate medi- Entrainment of mammalian circadian rhythms by the ated principally by the vagus. Cardiac dysrhythmias may light-dark cycle is mediated via the retinohypothalamic occur selectively during REM sleep. Respiratory func- tract, a monosynaptic pathway that links specialized, pho- tion also changes. In comparison to relaxed wakefulness, toreceptive retinal ganglion cells directly to the SCN. respiratory rate becomes more regular during NREM Humans are exquisitely sensitive to the resetting effects sleep (especially slow-wave sleep) and tonic REM sleep of light, particularly at the blue end (~460–480 nm) of and becomes very irregular during phasic REM sleep. the visible spectrum. Minute ventilation decreases in NREM sleep out of The timing and internal architecture of sleep are proportion to the decrease in metabolic rate at sleep onset, directly coupled to the output of the endogenous circa- resulting in a higher PCO2. dian pacemaker. Paradoxically, the endogenous circadian rhythms of sleep tendency, sleepiness, and REM sleep Endocrine function also varies with sleep. Slow-wave propensity all peak near the habitual wake time, just sleep is associated with secretion of growth hormone, after the nadir of the endogenous circadian temperature while sleep in general is associated with augmented cycle, whereas the circadian wake propensity rhythm secretion of prolactin. Sleep has a complex effect on the peaks 1–3 h before the habitual bedtime.These rhythms secretion of luteinizing hormone (LH): during puberty, are thus timed to oppose the homeostatic decline of sleep is associated with increased LH secretion, whereas sleep tendency during the habitual sleep episode and the sleep in the postpubertal female inhibits LH secretion in rise of sleep tendency throughout the usual waking day, the early follicular phase of the menstrual cycle. Sleep respectively. Misalignment of the output of the endoge- onset (and probably slow-wave sleep) is associated with nous circadian pacemaker with the desired sleep-wake inhibition of thyroid-stimulating hormone and of the cycle can, therefore, induce insomnia, decreased alert- adrenocorticotropic hormone–cortisol axis, an effect that ness, and impaired performance evident in night-shift is superimposed on the prominent circadian rhythms in workers and airline travelers. the two systems. BEHAVIORAL CORRELATES OF SLEEP The pineal hormone melatonin is secreted predomi- STATES AND STAGES nantly at night in both day- and night-active species, reflecting the direct modulation of pineal activity by the Polysomnographic staging of sleep correlates with behav- circadian pacemaker through a circuitous neural pathway ioral changes during specific states and stages. During the from the SCN to the pineal gland. Melatonin secretion transitional state between wakefulness and sleep (stage is not dependent upon the occurrence of sleep, persist- 1 sleep), subjects may respond to faint auditory or visual ing in individuals kept awake at night. In addition, exoge- signals without “awakening.” Memory incorporation is nous melatonin increases sleepiness and increases sleep inhibited at the onset of NREM stage 1 sleep, which may duration when administered to healthy adults attempting explain why individuals aroused from that transitional sleep to sleep during daylight hours, at a time when endoge- stage frequently deny having been asleep. Such transitions nous melatonin levels are low. The efficacy of melatonin may intrude upon behavioral wakefulness after sleep depri- as a sleep-promoting therapy for patients with insomnia vation, notwithstanding attempts to remain continuously is currently not known. awake (see Shift-Work Disorder, later in the chapter). Sleep is also accompanied by alterations of ther- Awakenings from REM sleep are associated with recall moregulatory function. NREM sleep is associated with of vivid dream imagery >80% of the time.The reliability an attenuation of thermoregulatory responses to either of dream recall increases with REM sleep episodes occur- heat or cold stress, and animal studies of thermosensitive ring later in the night. Imagery may also be reported after neurons in the hypothalamus document an NREM- NREM sleep interruptions, though these typically lack sleep-dependent reduction of the thermoregulatory set- the detail and vividness of REM sleep dreams. The inci- point. REM sleep is associated with complete absence dence of NREM sleep dream recall can be increased by of thermoregulatory responsiveness, effectively resulting selective REM sleep deprivation, suggesting that REM in functional poikilothermy. However, the potential sleep and dreaming per se are not inexorably linked. adverse impact of this failure of thermoregulation is blunted by inhibition of REM sleep by extreme ambient temperatures.
DISORDERS OF SLEEP AND can be invaluable; some patients may be unaware of, 159 WAKEFULNESS or will underreport, such potentially embarrassing symptoms as heavy snoring or falling asleep while CHAPTER 16 Sleep Disorders Approach to the Patient: driving. SLEEP DISORDERS Patients with excessive sleepiness should be advised Patients may seek help from a physician because of to avoid all driving until effective therapy has been one of several symptoms: (1) an acute or chronic achieved. inability to initiate or maintain sleep adequately at night (insomnia); (2) chronic fatigue, sleepiness, or Completion by the patient of a day-by-day sleep- tiredness during the day; or (3) a behavioral manifes- work-drug log for at least 2 weeks can help the physi- tation associated with sleep itself. Complaints of cian understand the nature of the complaint better. insomnia or excessive daytime sleepiness should be Work times and sleep times (including daytime naps approached as symptoms (much like fever or pain) of and nocturnal awakenings) as well as drug and alco- underlying disorders. Knowledge of the differential hol use, including caffeine and hypnotics, should be diagnosis of these presenting complaints is essential to noted each day. identify any underlying medical disorder. Only then can appropriate treatment, rather than nonspecific Polysomnography is necessary for the diagnosis of approaches (e.g., over-the-counter sleeping aids), be specific disorders such as narcolepsy and sleep apnea applied. Diagnoses of exclusion, such as primary and may be of utility in other settings as well. In insomnia, should be made only after other diagnoses addition to the three electrophysiologic variables used have been ruled out. Table 16-1 outlines the diag- to define sleep states and stages, the standard clinical nostic and therapeutic approach to the patient with a polysomnogram includes measures of respiration (res- complaint of excessive daytime sleepiness. piratory effort, air flow, and oxygen saturation), ante- rior tibialis EMG, and electrocardiogram. A careful history is essential. In particular, the dura- tion, severity, and consistency of the symptoms are EVALUATION OF INSOMNIA important, along with the patient’s estimate of the consequences of the sleep disorder on waking func- Insomnia is the complaint of inadequate sleep; it can be tion. Information from a friend or family member classified according to the nature of sleep disruption and the duration of the complaint. Insomnia is subdivided into difficulty falling asleep (sleep onset insomnia), frequent or sustained awakenings (sleep maintenance insomnia), early TABLE 16-1 EVALUATION OF THE PATIENT WITH THE COMPLAINT OF EXCESSIVE DAYTIME SOMNOLENCE FINDINGS ON HISTORY AND DIAGNOSTIC EVALUATION DIAGNOSIS THERAPY PHYSICAL EXAMINATION Polysomnography with Obstructive Continuous positive airway pressure; Obesity, snoring, hypertension respiratory monitoring sleep apnea ENT surgery (e.g., uvulopalatopharyngoplasty); dental appliance; pharmacologic therapy (e.g., Cataplexy, hypnogogic Polysomnography with Narcolepsy- protriptyline); weight loss hallucinations, sleep multiple sleep latency cataplexy Stimulants (e.g., modafinil, methylphenidate); paralysis, family history testing syndrome REM-suppressant antidepressants (e.g., protriptyline); genetic counseling Restless legs, disturbed Assesment for Restless legs Treatment of predisposing condition, if possible; sleep, predisposing predisposing medical syndrome dopamine agonists (e.g., pramipexole, medical condition (e.g., iron conditions ropinirole) deficiency or renal failure) Insomnias Disturbed sleep, predisposing Sleep-wake diary (see text) Treatment of predisposing condition and/or medical conditions (e.g., recording change in therapy, if possible; behavioral asthma) and/or predisposing therapy; short-acting benzodiazepine receptor medical therapies (e.g., agonist (e.g., zolpidem) theophylline) Note: ENT, ears, nose, throat; REM, rapid eye movement; EMG, electromyogram.
SECTION II Clinical Manifestations of Neurologic Disease160 morning awakenings (sleep offset insomnia), or persistent occurring at other times. Subsyndromal psychiatric sleepiness/fatigue despite sleep of adequate duration disorders (e.g., anxiety and mood complaints), negative (nonrestorative sleep). Similarly, the duration of the symp- conditioning to the sleep environment (psychophysio- tom influences diagnostic and therapeutic considera- logic insomnia, see later in the chapter), amplification of tions. An insomnia complaint lasting one to several the time spent awake (paradoxical insomnia), physiologic nights (within a single episode) is termed transient insom- hyperarousal, and poor sleep hygiene (see earlier) may all nia and is typically the result of situational stress or a be present. As these processes may be both causes and change in sleep schedule or environment (e.g., jet lag consequences of chronic insomnia, many individuals disorder). Short-term insomnia lasts from a few days to will have a progressive course to their symptoms in 3 weeks. Disruption of this duration is usually associated which the severity is proportional to the chronicity, and with more protracted stress, such as recovery from much of the complaint may persist even after effective surgery or short-term illness. Long-term insomnia, or treatment of the initial inciting etiology. Treatment of chronic insomnia, lasts for months or years and, in contrast insomnia is often directed to each of the putative con- with short-term insomnia, requires a thorough evalua- tributing factors: behavior therapies for anxiety and neg- tion of underlying causes (see below). Chronic insomnia ative conditioning (see later), pharmacotherapy and/or is often a waxing and waning disorder, with spontaneous psychotherapy for mood/anxiety disorders, and an or stressor-induced exacerbations. emphasis on maintenance of good sleep hygiene. An occasional night of poor sleep, typically in the set- ting of stress or excitement about external events, is both If insomnia persists after treatment of these contribut- common and without lasting consequences. However, ing factors, empirical pharmacotherapy is often used on persistent insomnia can lead to impaired daytime func- a nightly or intermittent basis. A variety of sedative tion, injury due to accidents, and the development of compounds are used for this purpose. Alcohol and anti- major depression. In addition, there is emerging evidence histamines are the most commonly used nonprescrip- that individuals with chronic insomnia have increased uti- tion sleep aids. The former may help with sleep onset lization of health care resources, even after controlling for but is associated with sleep disruption during the night co-morbid medical and psychiatric disorders. and can escalate into abuse, dependence, and withdrawal All insomnias can be exacerbated and perpetuated by in the predisposed individual. Antihistamines may be of behaviors that are not conducive to initiating or main- benefit when used intermittently but often produce taining sleep. Inadequate sleep hygiene is characterized by a rapid tolerance and may have multiple side effects (espe- behavior pattern prior to sleep or a bedroom environ- cially anticholinergic), which limit their use, particularly ment that is not conducive to sleep. Noise or light in the in the elderly. Benzodiazepine-receptor agonists are the bedroom can interfere with sleep, as can a bed partner most effective and well-tolerated class of medications for with periodic limb movements during sleep or one who insomnia. The broad range of half-lives allows flexibility snores loudly. Clocks can heighten the anxiety about the in the duration of sedative action. The most commonly time it has taken to fall asleep. Drugs that act on the prescribed agents in this family are zaleplon (5–20 mg), central nervous system, large meals, vigorous exercise, or with a half-life of 1–2 h; zolpidem (5–10 mg) and tria- hot showers just before sleep may all interfere with sleep zolam (0.125–0.25 mg), with half-lives of 2–3 h; eszopi- onset. Many individuals participate in stressful work- clone (1–3 mg), with a half-life of 5.5–8 h; and related activities in the evening, producing a state temazepam (15–30 mg) and lorazepam (0.5–2 mg), with incompatible with sleep onset. In preference to hypnotic half-lives of 6–12 h. Generally, side effects are minimal medications, patients should be counseled to avoid when the dose is kept low and the serum concentration stressful activities before bed, develop a soporific bed- is minimized during the waking hours (by using the time ritual, and to prepare and reserve the bedroom shortest-acting, effective agent). Recent data suggest that environment for sleeping. Consistent, regular rising at least one benzodiazepine receptor agonist (eszopi- times should be maintained daily, including weekends. clone) continues to be effective for 6 months of nightly use. However, longer durations of use have not been PRIMARY INSOMNIA evaluated, and it is unclear whether this is true of other agents in this class. Moreover, with even brief continu- Many patients with chronic insomnia have no clear, ous use of benzodiazepine-receptor agonists, rebound single identifiable underlying cause for their difficulties insomnia can occur upon discontinuation. The likeli- with sleep. Rather, such patients often have multiple eti- hood of rebound insomnia and tolerance can be mini- ologies for their insomnia, which may evolve over the mized by short durations of treatment, intermittent use, years. In addition, the chief sleep complaint may change or gradual tapering of the dose. For acute insomnia, over time, with initial insomnia predominating at one nightly use of a benzodiazepine receptor agonist for a max- point, and multiple awakenings or nonrestorative sleep imum of 2–4 weeks is advisable. For chronic insomnia, intermittent use is recommended, unless the consequences
of untreated insomnia outweigh concerns regarding latency, frequent awakenings from sleep, and early morn- 161 CHAPTER 16 Sleep Disorders chronic use. Benzodiazepine receptor agonists should be ing awakening can all occur. Recovery is generally avoided, or used very judiciously, in patients with a his- rapid, usually within a few weeks. Treatment is sympto- tory of substance or alcohol abuse. The heterocyclic matic, with intermittent use of hypnotics and resolution antidepressants (trazodone, amitriptyline, and doxepin) of the underlying stress. Altitude insomnia describes a are the most commonly prescribed alternatives to ben- sleep disturbance that is a common consequence of zodiazepine receptor agonists due to their lack of abuse exposure to high altitude. Periodic breathing of the potential and lower cost.Trazodone (25–100 mg) is used Cheyne-Stokes type occurs during NREM sleep about more commonly than the tricyclic antidepressants as it half the time at high altitude, with restoration of a regu- has a much shorter half-life (5–9 h), has much less anti- lar breathing pattern during REM sleep. Both hypoxia cholinergic activity (sparing patients, particularly the and hypocapnia are thought to be involved in the devel- elderly, constipation, urinary retention, and tachycardia), opment of periodic breathing. Frequent awakenings and is associated with less weight gain, and is much safer in poor quality sleep characterize altitude insomnia, which is overdose.The risk of priapism is small (~1 in 10,000). generally worse on the first few nights at high altitude but may persist. Treatment with acetazolamide can decrease Psychophysiologic Insomnia time spent in periodic breathing and substantially reduce hypoxia during sleep. Persistent psychophysiologic insomnia is a behavioral disorder in which patients are preoccupied with a perceived inabil- COMORBID INSOMNIA ity to sleep adequately at night.This sleep disorder begins like any other acute insomnia; however, the poor sleep Insomnia Associated with Mental Disorders habits and sleep-related anxiety (“insomnia phobia”) per- sist long after the initial incident. Such patients become Approximately 80% of patients with psychiatric disorders hyperaroused by their own efforts to sleep or by the sleep describe sleep complaints. There is considerable hetero- environment, and the insomnia becomes a conditioned or geneity, however, in the nature of the sleep disturbance learned response. Patients may be able to fall asleep more both between conditions and among patients with the easily at unscheduled times (when not trying) or outside same condition. Depression can be associated with sleep the home environment. Polysomnographic recording in onset insomnia, sleep maintenance insomnia, or early patients with psychophysiologic insomnia reveals an morning wakefulness. However, hypersomnia occurs in objective sleep disturbance, often with an abnormally long some depressed patients, especially adolescents and those sleep latency; frequent nocturnal awakenings; and an with either bipolar or seasonal (fall/winter) depression increased amount of stage 1 transitional sleep. Rigorous (Chap. 49). Indeed, sleep disturbance is an important attention should be paid to improving sleep hygiene, cor- vegetative sign of depression and may commence before rection of counterproductive, arousing behaviors before any mood changes are perceived by the patient. Consis- bedtime, and minimizing exaggerated beliefs regarding the tent polysomnographic findings in depression include negative consequences of insomnia. Behavioral therapies decreased REM sleep latency, lengthened first REM are the treatment modality of choice, with intermittent use sleep episode, and shortened first NREM sleep episode; of medications. When patients are awake for >20 min, however, these findings are not specific for depression, they should read or perform other relaxing activities to and the extent of these changes varies with age and distract themselves from insomnia-related anxiety. In addi- symptomatology. Depressed patients also show decreased tion, bedtime and wake time should be scheduled to slow-wave sleep and reduced sleep continuity. restrict time in bed to be equal to their perceived total sleep time. This will generally produce sleep deprivation, In mania and hypomania, sleep latency is increased and greater sleep drive, and, eventually, better sleep. Time in total sleep time can be reduced. Patients with anxiety disor- bed can then be gradually expanded. In addition, methods ders tend not to show the changes in REM sleep and slow- directed toward producing relaxation in the sleep setting wave sleep seen in endogenously depressed patients. Chronic (e.g., meditation, muscle relaxation) are encouraged. alcoholics lack slow-wave sleep, have decreased amounts of REM sleep (as an acute response to alcohol), and have fre- Adjustment Insomnia (Acute Insomnia) quent arousals throughout the night.This is associated with impaired daytime alertness.The sleep of chronic alcoholics This typically develops after a change in the sleeping may remain disturbed for years after discontinuance of environment (e.g., in an unfamiliar hotel or hospital alcohol usage. Sleep architecture and physiology are dis- bed) or before or after a significant life event, such as a turbed in schizophrenia (with a decreased amount of stage 4 change of occupation, loss of a loved one, illness, or anx- sleep and a lack of augmentation of REM sleep following iety over a deadline or examination. Increased sleep REM sleep deprivation); chronic schizophrenics often show day-night reversal, sleep fragmentation, and insomnia.
SECTION II Clinical Manifestations of Neurologic Disease162 Insomnia Associated with Neurologic Cardiac ischemia may also be associated with sleep dis- Disorders ruption. The ischemia itself may result from increases in sympathetic tone as a result of sleep apnea. Patients may A variety of neurologic diseases result in sleep disruption present with complaints of nightmares or vivid, disturbing through both indirect, nonspecific mechanisms (e.g., pain dreams, with or without awareness of the more classic in cervical spondylosis or low back pain) or by impair- symptoms of angina or of the sleep disordered breathing. ment of central neural structures involved in the genera- Treatment of the sleep apnea may substantially improve tion and control of sleep itself. For example, dementia the angina and the nocturnal sleep quality. Paroxysmal from any cause has long been associated with distur- nocturnal dyspnea can also occur as a consequence of sleep- bances in the timing of the sleep-wake cycle, often char- associated cardiac ischemia that causes pulmonary conges- acterized by nocturnal wandering and an exacerbation of tion exacerbated by the recumbent posture. symptomatology at night (so-called sundowning). Chronic obstructive pulmonary disease is also associated Epilepsy may rarely present as a sleep complaint with sleep disruption, as is cystic fibrosis, menopause, hyper- (Chap. 20). Often the history is of abnormal behavior, at thyroidism, gastroesophageal reflux, chronic renal failure, and times with convulsive movements during sleep. The dif- liver failure. ferential diagnosis includes REM sleep behavior disor- der, sleep apnea syndrome, and periodic movements of Medication-, Drug-, or Alcohol-Dependent sleep (see earlier). Diagnosis requires nocturnal polysomno- Insomnia graphy with a full EEG montage. Other neurologic dis- eases associated with abnormal movements, such as Disturbed sleep can result from ingestion of a wide vari- Parkinson’s disease, hemiballismus, Huntington’s chorea, and ety of agents. Caffeine is perhaps the most common phar- Tourette syndrome (Chaps. 24 and 25), are also associated macologic cause of insomnia. It produces increased with disrupted sleep, presumably through secondary mech- latency to sleep onset, more frequent arousals during anisms. However, the abnormal movements themselves are sleep, and a reduction in total sleep time for up to 8–14 h greatly reduced during sleep. Headache syndromes (migraine after ingestion. Even small amounts of coffee can signifi- or cluster headache) may show sleep-associated exacerba- cantly disturb sleep in some patients; therefore, a 1- to tions (Chap. 6) by unknown mechanisms. 2-month trial without caffeine should be attempted in patients with these symptoms. Similarly, alcohol and nico- Fatal familial insomnia is a rare hereditary disorder caused tine can interfere with sleep, despite the fact that many by degeneration of anterior and dorsomedial nuclei of the patients use them to relax and promote sleep. Although thalamus. Insomnia is a prominent early symptom. Patients alcohol can increase drowsiness and shorten sleep latency, develop progressive autonomic dysfunction, followed by even moderate amounts of alcohol increase awakenings in dysarthria, myoclonus, coma, and death. The pathogenesis the second half of the night. In addition, alcohol ingestion is a mutation in the prion gene (Chap. 38). prior to sleep is contraindicated in patients with sleep apnea because of the inhibitory effects of alcohol on Insomnia Associated with Other upper airway muscle tone. Acutely, amphetamines and Medical Disorders cocaine suppress both REM sleep and total sleep time, which return to normal with chronic use. Withdrawal A number of medical conditions are associated with dis- leads to a REM sleep rebound. A number of prescribed ruptions of sleep. The association is frequently nonspe- medications can produce insomnia. Antidepressants, sym- cific, e.g., sleep disruption due to chronic pain from pathomimetics, and glucocorticoids are common causes. rheumatologic disorders. Attention to this association is In addition, severe rebound insomnia can result from the important in that sleep-associated symptoms are often acute withdrawal of hypnotics, especially following the the presenting or most bothersome complaint.Treatment use of high doses of benzodiazepines with a short half- of the underlying medical problem is the most useful life. For this reason, hypnotic doses should be low to approach. Sleep disruption can also result from the use of moderate and prolonged drug tapering is encouraged. medications such as glucocorticoids (see later). RESTLESS LEGS SYNDROME (RLS) One prominent association is between sleep disrup- tion and asthma. In many asthmatics there is a prominent Patients with this sensory-motor disorder report an irre- daily variation in airway resistance that results in marked sistible urge to move the legs, or sometimes the upper increases in asthmatic symptoms at night, especially during extremities that is often associated with a creepy-crawling sleep. In addition, treatment of asthma with theophylline- or aching dysesthesias deep within the affected limbs. For based compounds, adrenergic agonists, or glucocorticoids most patients with RLS, the dysesthesias and restlessness can independently disrupt sleep. When sleep disruption are much worse in the evening or night compared to the is a side effect of asthma treatment, inhaled glucocorti- daytime and frequently interferes with the ability to fall coids (e.g., beclomethasone) that do not disrupt sleep may provide a useful alternative.
asleep.The symptoms appear with inactivity and are tem- 5.0-s extensions of the great toe and dorsiflexion of the 163 CHAPTER 16 Sleep Disorders porarily relieved by movement. In contrast, paresthesias foot, which recur every 20–40 s during NREM sleep, in secondary to peripheral neuropathy persist with activity. episodes lasting from minutes to hours, as documented The severity of this chronic disorder may wax and wane by bilateral surface EMG recordings of the anterior tib- over time and can be exacerbated by sleep deprivation, ialis on polysomnography. PLMS is the principal objec- caffeine, alcohol, serotonergic antidepressants, and preg- tive polysomnographic finding in 17% of patients with nancy. The prevalence is 1–5% of young to middle-aged insomnia and 11% of those with excessive daytime som- adults and 10–20% of those >60 years.There appear to be nolence (Fig. 16-3). It is often unclear whether it is an important differences in RLS prevalence among racial incidental finding or the cause of disturbed sleep. When groups, with higher prevalence in those of Northern deemed to be the latter, PLMS is called PLMD. PLMS European ancestry. Roughly one-third of patients (partic- occurs in a wide variety of sleep disorders (including ularly those with an early age of onset) will have multiple narcolepsy, sleep apnea, REM sleep behavior disorder, affected family members.At least three separate chromoso- and various forms of insomnia) and may be associated mal loci have been identified in familial RLS, though no with frequent arousals and an increased number of gene has been identified to date. Iron deficiency and renal sleep-stage transitions. The pathophysiology is not well failure may cause RLS, which is then considered sec- understood, though individuals with high spinal transec- ondary RLS.The symptoms of RLS are exquisitely sensi- tions can exhibit periodic leg movements during sleep, tive to dopaminergic drugs (e.g., pramipexole 0.25–0.5 suggesting the existence of a spinal generator.Treatment mg q8PM or ropinirole 0.5–4.0 mg q8PM), which are the options include dopaminergic medications or benzodi- treatments of choice. Opiods, benzodiazepines, and azepines. gabapentin may also be of therapeutic value. Most patients with restless legs also experience periodic limb movements EVALUATION OF DAYTIME SLEEPINESS of sleep, although the reverse is not the case. Daytime impairment due to sleep loss may be difficult PERIODIC LIMB MOVEMENT DISORDER to quantify for several reasons. First, sleepiness is not (PLMD) necessarily proportional to subjectively assessed sleep deprivation. In obstructive sleep apnea, for example, the Periodic limb movements of sleep (PLMS), previously known repeated brief interruptions of sleep associated with as nocturnal myoclonus, consists of stereotyped, 0.5- to resumption of respiration at the end of apneic episodes Snoring sounds Nasal/oral airflow Respiratory effort Arterial O2 saturation 95 98 97 96 95 97 98 97 95 94 92 90 92 97 98 98 98 95 93 89 92 90 94 93 93 90 90 91 88 86 A 30 s EEG 30 s Chin EMG with a relatively constant intermovement interval and are associated with changes in the EEG and heart rate accelera- Heart Rate tion (lower panel). R.A.T., right anterior tibialis; L.A.T., left R.A.T. EMG anterior tibialis. (From the Division of Sleep Medicine, Brigham and Women’s Hospital.) L.A.T. EMG B FIGURE 16-3 Polysomnographic recordings of (A) obstructive sleep apnea and (B) periodic limb movement of sleep. Note the snoring and reduction in air flow in the presence of continued respiratory effort, associated with the subsequent oxygen desaturation (upper panel). Periodic limb movements occur
SECTION II Clinical Manifestations of Neurologic Disease164 result in daytime sleepiness, despite the fact that the driving be suspended until successful treatment or a patient may be unaware of the sleep fragmentation. schedule modification can be instituted. Second, subjective descriptions of waking impairment vary from patient to patient. Patients may describe them- The distinction between fatigue and sleepiness can be selves as “sleepy,” “fatigued,” or “tired” and may have a useful in the differentiation of patients with complaints clear sense of the meaning of those terms, while others of fatigue or tiredness in the setting of disorders such as may use the same terms to describe a completely differ- fibromyalgia, chronic fatigue syndrome (Chap. 47), or ent condition. Third, sleepiness, particularly when pro- endocrine deficiencies such as hypothyroidism or Addi- found, may affect judgment in a manner analogous to son’s disease. Although patients with these disorders can ethanol, such that subjective awareness of the condition typically distinguish their daytime symptoms from the and the consequent cognitive and motor impairment is sleepiness that occurs with sleep deprivation, substantial reduced. Finally, patients may be reluctant to admit that overlap can occur.This is particularly true when the pri- sleepiness is a problem, both because they are generally mary disorder also results in chronic sleep disruption unaware of what constitutes normal alertness and (e.g., sleep apnea in hypothyroidism) or in abnormal because sleepiness is generally viewed pejoratively, sleep (e.g., fibromyalgia). ascribed more often to a deficit in motivation than to an inadequately addressed physiologic sleep need. Although clinical evaluation of the complaint of Specific questioning about the occurrence of sleep excessive sleepiness is usually adequate, objective quan- episodes during normal waking hours, both intentional tification is sometimes necessary. Assessment of daytime and unintentional, is necessary to determine the extent functioning as an index of the adequacy of sleep can be of the adverse effects of sleepiness on a patient’s daytime made with the multiple sleep latency test (MSLT), which function. Specific areas to be addressed include the involves repeated measurement of sleep latency (time to occurrence of inadvertent sleep episodes while driving onset of sleep) under standardized conditions during a or in other safety-related settings, sleepiness while at day following quantified nocturnal sleep. The average work or school (and the relationship of sleepiness to latency across four to six tests (administered every 2 h work and school performance), and the effect of sleepi- across the waking day) provides an objective measure of ness on social and family life. Driving is particularly haz- daytime sleep tendency. Disorders of sleep that result in ardous for patients with increased sleepiness. Reaction pathologic daytime somnolence can be reliably distin- time is equally impaired by 24 h of sleep loss as by a guished with the MSLT. In addition, the multiple mea- blood alcohol level of 0.10 g/dL. More than half of surements of sleep onset may identify direct transitions Americans admit to driving when drowsy. An estimated from wakefulness to REM sleep that are suggestive of 250,000 motor vehicle crashes per year are due to specific pathologic conditions (e.g., narcolepsy). drowsy drivers, thus causing 20% of all serious crash injuries. Drowsy driving legislation, aimed at improving NARCOLEPSY education of all drivers about the hazards of driving drowsy and establishing sanctions comparable to those Narcolepsy is both a disorder of the ability to sustain for drunk driving, is pending in several states. Screening wakefulness voluntarily and a disorder of REM sleep for sleep disorders, provision of an adequate number of regulation (Table 16-2). The classic “narcolepsy tetrad” safe highway rest areas, maintenance of unobstructed consists of excessive daytime somnolence plus three spe- shoulder rumble strips, and strict enforcement and com- cific symptoms related to an intrusion of REM sleep pliance monitoring of hours-of-service policies are characteristics (e.g., muscle atonia, vivid dream imagery) needed to reduce the risk of sleep-related transportation into the transition between wakefulness and sleep: crashes. Evidence for significant daytime impairment [in association either with the diagnosis of a primary sleep TABLE 16-2 disorder, such as narcolepsy or sleep apnea, or with PREVALENCE OF SYMPTOMS IN NARCOLEPSY imposed or self-selected sleep-wake schedules (see Shift- Work Disorder, later)] raises the issue of the physician’s SYMPTOM PREVALENCE, % responsibility to notify motor vehicle licensing authori- ties of the increased risk of sleepiness-related vehicle Excessive daytime somnolence 100 accidents. As with epilepsy, legal requirements vary from Disturbed sleep 87 state to state, and existing legal precedents do not pro- Cataplexy 76 vide a consistent interpretation of the balance between Hypnagogic hallucinations 68 the physician’s responsibility and the patient’s right to Sleep paralysis 64 privacy. At a minimum, physicians should document dis- Memory problems 50 cussions with the patient regarding the increased risk of operating a vehicle, as well as a recommendation that Source: Modified from TA Roth, L Merlotti in SA Burton et al (eds), Narcolepsy 3rd International Symposium: Selected Symposium Pro- ceedings, Chicago, Matrix Communications, 1989.
(1) sudden weakness or loss of muscle tone without loss reliably. Hypnogogic and hypnopompic hallucinations 165 CHAPTER 16 Sleep Disorders of consciousness, often elicited by emotion (cataplexy); and sleep paralysis are often found in nonnarcoleptic (2) hallucinations at sleep onset (hypnogogic hallucina- individuals and may be present in only one-half of nar- tions) or upon awakening (hypnopompic hallucinations); coleptics. Nocturnal sleep disruption is commonly and (3) muscle paralysis upon awakening (sleep paralysis). observed in narcolepsy but is also a nonspecific symp- The severity of cataplexy varies, as patients may have two tom. Similarly, a history of “automatic behavior” during to three attacks per day or per decade. Some patients wakefulness (a trancelike state during which simple with objectively confirmed narcolepsy (see later) may motor behaviors persist) is not specific for narcolepsy show no evidence of cataplexy. In those with cataplexy, and serves principally to corroborate the presence of the extent and duration of an attack may also vary, from daytime somnolence. a transient sagging of the jaw lasting a few seconds to rare cases of flaccid paralysis of the entire voluntary Treatment: musculature for up to 20–30 min. Symptoms of nar- NARCOLEPSY colepsy typically begin in the second decade, although the onset ranges from ages 5–50. Once established, the The treatment of narcolepsy is symptomatic. Somno- disease is chronic without remissions. Secondary forms lence is treated with wake-promoting therapeutics. of narcolepsy have been described (e.g., after head Modafinil is now the drug of choice, principally because trauma). it is associated with fewer side effects than older stimu- lants and has a long half-life; 200–400 mg is given as a Narcolepsy affects about 1 in 4000 people in the single daily dose. Older drugs such as methylphenidate United States and appears to have a genetic basis. (10 mg bid to 20 mg qid) or dextroamphetamine (10 mg Recently, several convergent lines of evidence suggest bid) are still used as alternatives, particularly in refrac- that the hypothalamic neuropeptide hypocretin (orexin) tory patients. These latter medications are now available is involved in the pathogenesis of narcolepsy: (1) a muta- in slow-release formulations, extending their duration of tion in the hypocretin receptor 2 gene has been associ- action and allowing once daily dosing. ated with canine narcolepsy; (2) hypocretin “knockout” mice that are genetically unable to produce this neu- Treatment of the REM-related phenomena cataplexy, ropeptide exhibit behavioral and electrophysiologic fea- hypnogogic hallucinations, and sleep paralysis requires tures resembling human narcolepsy; and (3) cerebrospinal the potent REM sleep suppression produced by antide- fluid levels of hypocretin are reduced in most patients pressant medications. The tricyclic antidepressants who have narcolepsy with cataplexy. The inheritance [e.g., protriptyline (10–40 mg/d) and clomipramine pattern of narcolepsy in humans is more complex than in (25–50 mg/d)] and the selective serotonin reuptake the canine model. However, almost all narcoleptics with inhibitors (SSRIs) [e.g., fluoxetine (10–20 mg/d)] are cataplexy are positive for HLA DQB1∗0602, suggesting commonly used for this purpose. Efficacy of the antide- that an autoimmune process may be responsible. pressants is limited largely by anticholinergic side effects (tricyclics) and by sleep disturbance and sexual dysfunc- Diagnosis tion (SSRIs). Alternately, gamma hydroxybutyrate (GHB), given at bed time, and 4 h later, is effective in reducing The diagnostic criteria continue to be a matter of daytime cataplectic episodes. Adequate nocturnal sleep debate. Certainly, objective verification of excessive day- time and planned daytime naps (when possible) are time somnolence, typically with MSLT mean sleep important preventative measures. latencies <8 min, is an essential if nonspecific diagnostic feature. Other conditions that cause excessive sleepiness, SLEEP APNEA SYNDROMES such as sleep apnea or chronic sleep deprivation, must be rigorously excluded. The other objective diagnostic Respiratory dysfunction during sleep is a common, seri- feature of narcolepsy is the presence of REM sleep in at ous cause of excessive daytime somnolence as well as of least two of the naps during the MSLT. Abnormal regu- disturbed nocturnal sleep. An estimated 2–5 million lation of REM sleep is also manifested by the appear- individuals in the United States have a reduction or ces- ance of REM sleep immediately or within minutes after sation of breathing for 10–150 s, from thirty to several sleep onset in 50% of narcoleptic patients, a rarity in hundred times every night during sleep. These episodes unaffected individuals maintaining a conventional sleep- may be due to either an occlusion of the airway (obstructive wake schedule.The REM-related symptoms of the classic sleep apnea), absence of respiratory effort (central sleep narcolepsy tetrad are variably present. There is increasing apnea), or a combination of these factors (mixed sleep apnea) evidence that narcoleptics with cataplexy (one-half to (Fig. 16-3). Failure to recognize and treat these conditions two-thirds of patients) may represent a more homoge- neous group than those without this symptom. How- ever, a history of cataplexy can be difficult to establish
SECTION II Clinical Manifestations of Neurologic Disease166 appropriately may lead to impairment of daytime alert- patient is usually unaware of the problem. The typical ness, increased risk of sleep-related motor vehicle acci- age of onset is 17–20 years, and spontaneous remission dents, hypertension and other serious cardiovascular usually occurs by 40 years. Sex distribution appears to complications, and increased mortality. Sleep apnea is be equal. In many cases, the diagnosis is made during particularly prevalent in overweight men and in the dental examination, damage is minor, and no treatment elderly, yet it is estimated to remain undiagnosed in is indicated. In more severe cases, treatment with a rub- 80–90% of affected individuals.This is unfortunate since ber tooth guard is necessary to prevent disfiguring tooth effective treatments are available. injury. Stress management or, in some cases, biofeedback can be useful when bruxism is a manifestation of psy- PARASOMNIAS chological stress. There are anecdotal reports of benefit using benzodiazepines. The term parasomnia refers to abnormal behaviors or experiences that arise from or occur during sleep. A Sleep Enuresis continuum of parasomnias arises from NREM sleep, from brief confusional arousals to sleepwalking and Bedwetting, like sleepwalking and night terrors, is night terrors.The presenting complaint is usually related another parasomnia that occurs during sleep in the to the behavior itself, but the parasomnias can disturb young. Before age 5 or 6, nocturnal enuresis should sleep continuity or lead to mild impairments in daytime probably be considered a normal feature of develop- alertness. Two main parasomnias occur in REM sleep: ment. The condition usually improves spontaneously by REM sleep behavior disorder (RBD), which will be puberty, has a prevalence in late adolescence of 1–3%, described later, and nightmare disorder. and is rare in adulthood. In older patients with enuresis a distinction must be made between primary and sec- Sleepwalking (Somnambulism) ondary enuresis, the latter being defined as bedwetting in patients who have previously been fully continent for Patients affected by this disorder carry out automatic 6–12 months. Treatment of primary enuresis is reserved motor activities that range from simple to complex. for patients of appropriate age (>5 or 6 years) and con- Individuals may walk, urinate inappropriately, eat, or exit sists of bladder training exercises and behavioral therapy. from the house while remaining only partially aware. Urologic abnormalities are more common in primary Full arousal may be difficult, and individuals may rarely enuresis and must be assessed by urologic examination. respond to attempted awakening with agitation or even Important causes of secondary enuresis include emo- violence. Sleepwalking arises from stage 3 or 4 NREM tional disturbances, urinary tract infections or malforma- sleep, usually in the first 2 hours of the night, and is tions, cauda equina lesions, epilepsy, sleep apnea, and most common in children and adolescents, when these certain medications. Symptomatic pharmacotherapy is sleep stages are most robust. Episodes are usually isolated usually accomplished with desmopressin (0.2 mg qhs), but may be recurrent in 1–6% of patients. The cause is oxybutynin chloride (5–10 mg qhs) or imipramine unknown, though it has a familial basis in roughly one- (10–50 mg qhs). third of cases. Miscellaneous Parasomnias Sleep Terrors Other clinical entities may be characterized as a para- This disorder, also called pavor nocturnus, occurs primarily somnia or a sleep-related movement disorder in that in young children during the first several hours after sleep they occur selectively during sleep and are associated onset, in stages 3 and 4 of NREM sleep. The child sud- with some degree of sleep disruption. Examples include denly screams, exhibiting autonomic arousal with sweat- jactatio capitis nocturna (nocturnal headbanging, rhythmic ing, tachycardia, and hyperventilation. The individual may movement disorder), confusional arousals, sleep-related be difficult to arouse and rarely recalls the episode on eating disorder, and nocturnal leg cramps. awakening in the morning. Parents are usually reassured to learn that the condition is self-limited and benign and that REM Sleep Behavior Disorder (RBD) no specific therapy is indicated. Both sleep terrors and sleepwalking represent abnormalities of arousal. In con- RBD is a rare condition that is distinct from other para- trast, nightmares occur during REM sleep and cause full somnias in that it occurs during REM sleep. It primarily arousal, with intact memory for the unpleasant episode. afflicts men of middle age or older, many of whom have an existing, or developing, neurologic disease. Approxi- Sleep Bruxism mately one-half of patients with RBD will develop Parkinson’s disease (Chap. 24) within 10–20 years. Pre- Bruxism is an involuntary, forceful grinding of teeth senting symptoms consist of agitated or violent behavior during sleep that affects 10–20% of the population. The
during sleep, as reported by a bed partner. In contrast to rhythms. A large-scale clinical trial evaluating the safety 167CHAPTER 16 Sleep Disorders typical somnambulism, injury to the patient or bed part- and efficacy of melatonin as a treatment for jet lag disor- ner is not uncommon, and, upon awakening, the patient der and other circadian sleep disorders is needed. reports vivid, often unpleasant, dream imagery. The principal differential diagnosis is nocturnal seizures, Shift-Work Disorder which can be excluded with polysomnography. In RBD, seizure activity is absent on the EEG, and disinhibition More than 7 million workers in the United States regu- of the usual motor atonia is observed in the EMG dur- larly work at night, either on a permanent or rotating ing REM sleep, at times associated with complex motor schedule. In addition, each week millions more elect to behaviors. The pathogenesis is unclear, but damage to remain awake at night to meet deadlines, drive long dis- brainstem areas mediating descending motor inhibition tances, or participate in recreational activities. This during REM sleep may be responsible. In support of this results in both sleep loss and misalignment of the circa- hypothesis are the remarkable similarities between RBD dian rhythm with respect to the sleep-wake cycle. and the sleep of animals with bilateral lesions of the pon- tine tegmentum in areas controlling REM sleep motor Studies of regular night-shift workers indicate that inhibition.Treatment with clonazepam (0.5–1.0 mg qhs) the circadian timing system usually fails to adapt success- provides sustained improvement in almost all reported fully to such inverted schedules.This leads to a misalign- cases. ment between the desired work-rest schedule and the output of the pacemaker and in disturbed daytime sleep CIRCADIAN RHYTHM SLEEP in most individuals. Sleep deprivation, increased length DISORDERS of time awake prior to work, and misalignment of circa- dian phase produce decreased alertness and perfor- A subset of patients presenting with either insomnia or mance, increased reaction time, and increased risk of hypersomnia may have a disorder of sleep timing rather performance lapses, thereby resulting in greater safety than sleep generation. Disorders of sleep timing can be hazards among night workers and other sleep-deprived either organic (i.e., due to an intrinsic defect in the cir- individuals. Sleep disturbance nearly doubles the risk of cadian pacemaker or its input from entraining stimuli) a fatal work accident. Additional problems include or environmental (i.e., due to a disruption of exposure to higher rates of cancer and of cardiac, gastrointestinal, and entraining stimuli from the environment). Regardless of reproductive disorders in chronic night-shift workers. etiology, the symptoms reflect the influence of the underlying circadian pacemaker on sleep-wake function. Sleep onset is associated with marked attenuation in Thus, effective therapeutic approaches should aim to perception of both auditory and visual stimuli and lapses entrain the oscillator at an appropriate phase. of consciousness.The sleepy individual may thus attempt to perform routine and familiar motor tasks during the transi- Jet Lag Disorder tion state between wakefulness and sleep (stage 1 sleep) in the absence of adequate processing of sensory input More than 60 million persons experience transmeridian from the environment. Motor vehicle operators are espe- air travel annually, which is often associated with exces- cially vulnerable to sleep-related accidents since the sleep- sive daytime sleepiness, sleep onset insomnia, and fre- deprived driver or operator often fails to heed the warning quent arousals from sleep, particularly in the latter half of signs of fatigue. Such attempts to override the powerful the night. Gastrointestinal discomfort is common. The biologic drive for sleep by the sheer force of will can yield syndrome is transient, typically lasting 2–14 d depending a catastrophic outcome when sleep processes intrude on the number of time zones crossed, the direction of involuntarily upon the waking brain. Such sleep-related travel, and the traveler’s age and phase-shifting capacity. attentional failures typically last only seconds but are Travelers who spend more time outdoors reportedly known on occasion to persist for longer durations. These adapt more quickly than those who remain in hotel frequent brief intrusions of stage 1 sleep into behavioral rooms, presumably due to bright (outdoor) light expo- wakefulness are a major component of the impaired psy- sure. Avoidance of antecedent sleep loss and obtaining chomotor performance seen with sleepiness. There is a nap sleep on the afternoon prior to overnight travel significant increase in the risk of sleep-related, fatal-to- greatly reduces the difficulty of extended wakefulness. the-driver highway crashes in the early morning and late Laboratory studies suggest that sub-milligram doses of afternoon hours, coincident with bimodal peaks in the the pineal hormone melatonin can enhance sleep effi- daily rhythm of sleep tendency. ciency, but only if taken when endogenous melatonin concentrations are low (i.e., during biologic daytime), Medical housestaff constitute another group of work- and that melatonin may induce phase shifts in human ers at risk for accidents and other adverse consequences of lack of sleep and misalignment of the circadian rhythm. Recent research has demonstrated that the practice of scheduling interns and residents to work shifts of 30 consecutive hours both doubles the risk of
SECTION II Clinical Manifestations of Neurologic Disease168 attentional failures among intensive care unit interns night work, (2) the frequency of shift rotation so that working at night and significantly increases the risk of shifts do not rotate more than once every 2–3 weeks, (3) serious medical errors in intensive care units. Moreover, the number of consecutive night shifts, and (4) the working for >24 h consecutively increases the risk of duration of night shifts. Shift durations of >16 h should needlestick injuries and more than doubles the risk of be universally recognized as increasing the risk of sleep- motor vehicle crashes on the commute home. Some related errors and performance lapses to a level that is 20% of hospital interns report making a fatigue-related unacceptable in nonemergency circumstances. mistake that injured a patient, and 5% admit making a mistake that results in the death of a patient. Delayed Sleep Phase Disorder From 5–10% of individuals scheduled to work at night or in the early morning hours have much greater Delayed sleep phase disorder is characterized by: (1) than average difficulties remaining awake during night reported sleep onset and wake times intractably later work and sleeping during the day; these individuals are than desired, (2) actual sleep times at nearly the same diagnosed with chronic and severe shift-work disorder clock hours daily, and (3) essentially normal all-night (SWD). Patients with this disorder have a level of exces- polysomnography except for delayed sleep onset. sive sleepiness during night work and insomnia during Patients exhibit an abnormally delayed endogenous cir- day sleep that the physician judges to be clinically signif- cadian phase, with the temperature minimum during icant; the condition is associated with an increased risk the constant routine occurring later than normal. This of sleep-related accidents and with some of the illnesses delayed phase could be due to: (1) an abnormally long, associated with night-shift work. Patients with chronic genetically determined intrinsic period of the endoge- and severe SWD are profoundly sleepy at night. In fact, nous circadian pacemaker; (2) an abnormally reduced their sleep latencies during night work average just 2 min, phase-advancing capacity of the pacemaker; or (3) an comparable to mean sleep latency durations of patients irregular prior sleep-wake schedule, characterized by with narcolepsy or severe daytime sleep apnea. frequent nights when the patient chooses to remain awake well past midnight (for social, school, or work Treatment: reasons). In most cases, it is difficult to distinguish SHIFT-WORK DISORDER among these factors, since patients with an abnormally long intrinsic period are more likely to “choose” such Caffeine is frequently used to promote wakefulness. late-night activities because they are unable to sleep at However, it cannot forestall sleep indefinitely, and it that time. Patients tend to be young adults. This self- does not shield users from sleep-related performance perpetuating condition can persist for years and does lapses. Postural changes, exercise, and strategic place- not usually respond to attempts to reestablish normal ment of nap opportunities can sometimes temporarily bedtime hours. Treatment methods involving bright- reduce the risk of fatigue-related performance lapses. light phototherapy during the morning hours or mela- Properly timed exposure to bright light can facilitate tonin administration in the evening hours show promise rapid adaptation to night-shift work. in these patients, although the relapse rate is high. While many techniques (e.g., light treatment) used to Advanced Sleep Phase Disorder facilitate adaptation to night shift work may help patients with this disorder, modafinil is the only thera- Advanced sleep phase disorder (ASPD) is the converse peutic intervention that has ever been evaluated as a of the delayed sleep phase syndrome. Most commonly, treatment for this specific patient population. Modafinil this syndrome occurs in older people, 15% of whom (200 mg, taken 30–60 min before the start of each night report that they cannot sleep past 5 A.M., with twice that shift) is approved by the U.S. Food and Drug Administra- number complaining that they wake up too early at least tion as a treatment for the excessive sleepiness during several times per week. Patients with ASPD experience night work in patients with SWD. Although treatment excessive daytime sleepiness during the evening hours, with modafinil significantly increases sleep latency and when they have great difficulty remaining awake, even reduces the risk of lapses of attention during night in social settings.Typically, patients awaken from 3–5 A.M. work, SWD patients remain excessively sleepy at night, each day, often several hours before their desired wake even while being treated with modafinil. times. In addition to age-related ASPD, an early-onset familial variant of this condition has also been reported. Safety programs should promote education about In one such family, autosomal dominant ASPD was due sleep and increase awareness of the hazards associated to a missense mutation in a circadian clock component with night work. The goal should be to minimize both (PER2, as shown in Fig. 16-2) that altered the circadian sleep deprivation and circadian disruption. Work sched- ules should be designed to minimize: (1) exposure to
period. Patients with ASPD may benefit from bright- understanding of the possible role of circadian rhythmic- 169 CHAPTER 16 Sleep Disorders light phototherapy during the evening hours, designed ity in the acute destabilization of a chronic condition to reset the circadian pacemaker to a later hour. such as atherosclerotic disease could improve the under- standing of the pathophysiology. Non-24-Hour Sleep-Wake Disorder Diagnostic and therapeutic procedures may also be This condition can occur when the maximal phase- affected by the time of day at which data are collected. advancing capacity of the circadian pacemaker is not ade- Examples include blood pressure, body temperature, the quate to accommodate the difference between the 24-h dexamethasone suppression test, and plasma cortisol levels. geophysical day and the intrinsic period of the pacemaker The timing of chemotherapy administration has been in the patient.Alternatively, patients’ self-selected exposure reported to have an effect on the outcome of treatment. to artificial light may drive the circadian pacemaker to a Few physicians realize the extent to which routine mea- >24-h schedule.Affected patients are not able to maintain sures are affected by the time (or sleep/wake state) when a stable phase relationship between the output of the the measurement is made. pacemaker and the 24-h day. Such patients typically pre- sent with an incremental pattern of successive delays in In addition, both the toxicity and effectiveness of sleep onsets and wake times, progressing in and out of drugs can vary during the day. For example, more than a phase with local time. When the patient’s endogenous fivefold difference has been observed in mortality rates rhythms are out of phase with the local environment, following administration of toxic agents to experimental insomnia coexists with excessive daytime sleepiness. Con- animals at different times of day. Anesthetic agents are versely, when the endogenous rhythms are in phase with particularly sensitive to time-of-day effects. Finally, the the local environment, symptoms remit. The intervals physician must be increasingly aware of the public between symptomatic periods may last several weeks to health risks associated with the ever-increasing demands several months. Blind individuals unable to perceive light made by the duty-rest-recreation schedules in our are particularly susceptible to this disorder. Nightly low- round-the-clock society. dose (0.5 mg) melatonin administration has been reported to improve sleep and, in some cases, to induce synchro- FURTHER READINGS nization of the circadian pacemaker. BLOOM HG et al: Evidence-based recommendations for the assess- MEDICAL IMPLICATIONS OF CIRCADIAN ment and management of sleep disorders in older persons. J Am RHYTHMICITY Geriatr Soc 57:761, 2009 Prominent circadian variations have been reported in BRADLEY TD, FLORAS JS: Obstructive sleep apnoea and its cardiovas- the incidence of acute myocardial infarction, sudden cular consequences. Lancet 373:82, 2009 cardiac death, and stroke, the leading causes of death in the United States. Platelet aggregability is increased after FLEMONS WW: Clinical practice. Obstructive sleep apnea. N Engl J arising in the early morning hours, coincident with the Med 347:498, 2002 peak incidence of these cardiovascular events. A better SCAMMELL TE: The neurobiology, diagnosis, and treatment of nar- colepsy.Ann Neurol 53:154, 2003 SILBER MH: Clinical practice. Chronic insomnia. N Engl J Med 353:803, 2005 WISE MS et al: Treatment of narcolepsy and other hypersomnias of central origin. Sleep 30: 1712, 2009
CHAPTER 17 DISORDERS OF VISION Jonathan C. Horton I The Human Visual System . . . . . . . . . . . . . . . . . . . . . . . . . . 170 I Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 I Clinical Assessment of Visual Function . . . . . . . . . . . . . . . . . 171 Red or Painful Eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 Transient or Sudden Visual Loss . . . . . . . . . . . . . . . . . . . . . . 178 Refractive State . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 Chronic Visual Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 Visual Acuity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 Proptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 Pupils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172 Ptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 Eye Movements and Alignment . . . . . . . . . . . . . . . . . . . . . . . 173 Double Vision (Diplopia) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 Stereopsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Color Vision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 Visual Fields . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 THE HUMAN VISUAL SYSTEM impinging upon the retina into a continuously varying bar- rage of action potentials that propagates along the primary The visual system provides a supremely efficient means optic pathway to visual centers within the brain.There are for the rapid assimilation of information from the envi- a million ganglion cells in each retina, and hence a million ronment to aid in the guidance of behavior. The act of fibers in each optic nerve. seeing begins with the capture of images focused by the cornea and lens upon a light-sensitive membrane in the Ganglion cell axons sweep along the inner surface of back of the eye, called the retina. The retina is actually the retina in the nerve fiber layer, exit the eye at the optic part of the brain, banished to the periphery to serve as a disc, and travel through the optic nerve, optic chiasm, and transducer for the conversion of patterns of light energy optic tract to reach targets in the brain. The majority of into neuronal signals. Light is absorbed by photopigment fibers synapse upon cells in the lateral geniculate body, a in two types of receptors: rods and cones. In the human thalamic relay station. Cells in the lateral geniculate body retina there are 100 million rods and 5 million cones. project in turn to the primary visual cortex.This massive The rods operate in dim (scotopic) illumination. The afferent retinogeniculocortical sensory pathway provides cones function under daylight (photopic) conditions. the neural substrate for visual perception. Although the The cone system is specialized for color perception and lateral geniculate body is the main target of the retina, separate classes of ganglion cells project to other subcorti- high spatial resolution.The majority of cones are located cal visual nuclei involved in different functions. Ganglion within the macula, the portion of the retina serving the cells that mediate pupillary constriction and circadian central 10° of vision. In the middle of the macula a small rhythms are light sensitive, owing to a novel visual pig- pit termed the fovea, packed exclusively with cones, pro- ment, melanopsin. Pupil responses are mediated by input vides best visual acuity. to the pretectal olivary nuclei in the midbrain. The pre- Photoreceptors hyperpolarize in response to light, acti- tectal nuclei send their output to the Edinger-Westphal vating bipolar, amacrine, and horizontal cells in the inner nuclei, which in turn provide parasympathetic innerva- nuclear layer. After processing of photoreceptor responses tion to the iris sphincter via an interneuron in the ciliary by this complex retinal circuit, the flow of sensory infor- ganglion. Circadian rhythms are timed by a retinal projec- mation ultimately converges upon a final common path- tion to the suprachiasmatic nucleus.Visual orientation and way: the ganglion cells.These cells translate the visual image eye movements are served by retinal input to the superior 170
colliculus. Gaze stabilization and optokinetic reflexes are VISUAL ACUITY 171 governed by a group of small retinal targets known col- lectively as the brainstem accessory optic system. The Snellen chart is used to test acuity at a distance of CHAPTER 17 Disorders of Vision 6 m (20 ft). For convenience, a scale version of the Snellen The eyes must be rotated constantly within their chart, called the Rosenbaum card, is held at 36 cm (14 in) orbits to place and maintain targets of visual interest from the patient (Fig. 17-1). All subjects should be able upon the fovea. This activity, called foveation, or looking, to read the 6/6 m (20/20 ft) line with each eye using is governed by an elaborate efferent motor system. Each their refractive correction, if any. Patients who need read- eye is moved by six extraocular muscles, supplied by cra- ing glasses because of presbyopia must wear them for nial nerves from the oculomotor (III), trochlear (IV), accurate testing with the Rosenbaum card. If 6/6 (20/20) and abducens (VI) nuclei. Activity in these ocular motor nuclei is coordinated by pontine and midbrain mecha- nisms for smooth pursuit, saccades, and gaze stabilization during head and body movements. Large regions of the frontal and parietooccipital cortex control these brain- stem eye movement centers by providing descending supranuclear input. CLINICAL ASSESSMENT OF VISUAL FIGURE 17-1 FUNCTION The Rosenbaum card is a miniature, scale version of the Snellen chart for testing visual acuity at near. When the REFRACTIVE STATE visual acuity is recorded, the Snellen distance equivalent should bear a notation indicating that vision was tested at In approaching the patient with reduced vision, the first near, not at 6 m (20 ft), or else the Jaeger number system step is to decide whether refractive error is responsible. In should be used to report the acuity. emmetropia, parallel rays from infinity are focused perfectly upon the retina. Sadly, this condition is enjoyed by only a minority of the population. In myopia, the globe is too long, and light rays come to a focal point in front of the retina. Near objects can be seen clearly, but distant objects require a diverging lens in front of the eye. In hyperopia, the globe is too short, and hence a converging lens is used to supplement the refractive power of the eye. In astigma- tism, the corneal surface is not perfectly spherical, necessi- tating a cylindrical corrective lens. In recent years it has become possible to correct refractive error with the excimer laser by performing LASIK (laser in situ ker- atomileusis) to alter the curvature of the cornea. With the onset of middle age, presbyopia develops as the lens within the eye becomes unable to increase its refractive power to accommodate upon near objects. To compensate for presbyopia, the emmetropic patient must use reading glasses. The patient already wearing glasses for distance correction usually switches to bifocals. The only exception is the myopic patient, who may achieve clear vision at near simply by removing glasses containing the distance prescription. Refractive errors usually develop slowly and remain stable after adolescence, except in unusual circum- stances. For example, the acute onset of diabetes mellitus can produce sudden myopia because of lens edema induced by hyperglycemia.Testing vision through a pin- hole aperture is a useful way to screen quickly for refractive error. If the visual acuity is better through a pinhole than with the unaided eye, the patient needs a refraction to obtain best corrected visual acuity.
SECTION II Clinical Manifestations of Neurologic Disease172 acuity is not present in each eye, the deficiency in vision A must be explained. If worse than 6/240 (20/800), acuity should be recorded in terms of counting fingers, hand B motions, light perception, or no light perception. Legal blindness is defined by the Internal Revenue Service as a C best corrected acuity of 6/60 (20/200) or less in the bet- FIGURE 17-2 ter eye, or a binocular visual field subtending 20° or less. Demonstration of a relative afferent pupil defect (Marcus For driving the laws vary by state, but most require a Gunn pupil) in the left eye, done with the patient fixating corrected acuity of 6/12 (20/40) in at least one eye for upon a distant target. A. With dim background lighting, the unrestricted privileges. Patients with a homonymous pupils are equal and relatively large. B. Shining a flashlight hemianopia should not drive. into the right eye evokes equal, strong constriction of both pupils. C. Swinging the flashlight over to the damaged left PUPILS eye causes dilation of both pupils, although they remain smaller than in A. Swinging the flashlight back over to the The pupils should be tested individually in dim light healthy right eye would result in symmetric constriction back with the patient fixating on a distant target. If they to the appearance shown in B. Note that the pupils always respond briskly to light, there is no need to check the remain equal; the damage to the left retina/optic nerve is near response, because isolated loss of constriction (mio- revealed by weaker bilateral pupil constriction to a flashlight sis) to accommodation does not occur. For this reason, in the left eye compared with the right eye. (From P Levatin, the ubiquitous abbreviation PERRLA (pupils equal, Arch Ophthalmol 62:768, 1959.) round, and reactive to light and accommodation) implies a wasted effort with the last step. However, it is impor- are infection (herpes zoster, influenza), trauma (blunt, pen- tant to test the near response if the light response is poor or etrating, surgical), or ischemia (diabetes, temporal arteritis). absent. Light-near dissociation occurs with neurosyphilis After denervation of the iris sphincter the pupil does not (Argyll Robertson pupil), lesions of the dorsal midbrain respond well to light, but the response to near is often (obstructive hydrocephalus, pineal region tumors), and relatively intact. When the near stimulus is removed, the after aberrant regeneration (oculomotor nerve palsy,Adie’s pupil redilates very slowly compared with the normal pupil, tonic pupil). hence the term tonic pupil. In Adie’s syndrome, a tonic pupil occurs in conjunction with weak or absent tendon reflexes An eye with no light perception has no pupillary in the lower extremities.This benign disorder, which occurs response to direct light stimulation. If the retina or optic nerve is only partially injured, the direct pupillary response will be weaker than the consensual pupillary response evoked by shining a light into the other eye.This relative afferent pupillary defect (Marcus Gunn pupil) can be elicited with the swinging flashlight test (Fig. 17-2). It is an extremely useful sign in retrobulbar optic neuritis and other optic nerve diseases, where it may be the sole objective evidence for disease. Subtle inequality in pupil size, up to 0.5 mm, is a fairly common finding in normal persons.The diagnosis of essential or physiologic anisocoria is secure as long as the relative pupil asymmetry remains constant as ambi- ent lighting varies. Anisocoria that increases in dim light indicates a sympathetic paresis of the iris dilator muscle. The triad of miosis with ipsilateral ptosis and anhidrosis constitutes Horner’s syndrome, although anhidrosis is an inconstant feature. Brainstem stroke, carotid dissection, or neoplasm impinging upon the sympathetic chain are occasionally identified as the cause of Horner’s syn- drome, but most cases are idiopathic. Anisocoria that increases in bright light suggests a parasympathetic palsy. The first concern is an oculomotor nerve paresis.This possibility is excluded if the eye move- ments are full and the patient has no ptosis or diplopia. Acute pupillary dilation (mydriasis) can occur from damage to the ciliary ganglion in the orbit. Common mechanisms
predominantly in healthy young women, is assumed to STEREOPSIS 173 represent a mild dysautonomia. Tonic pupils are also asso- ciated with Shy-Drager syndrome, segmental hypohidrosis, Stereoacuity is determined by presenting targets with reti- CHAPTER 17 Disorders of Vision diabetes, and amyloidosis. Occasionally, a tonic pupil is dis- nal disparity separately to each eye using polarized images. covered incidentally in an otherwise completely normal, The most popular office tests measure a range of thresh- asymptomatic individual. The diagnosis is confirmed by olds from 800–40 seconds of arc. Normal stereoacuity is placing a drop of dilute (0.125%) pilocarpine into each 40 seconds of arc. If a patient achieves this level of eye. Denervation hypersensitivity produces pupillary con- stereoacuity, one is assured that the eyes are aligned striction in a tonic pupil, whereas the normal pupil shows orthotropically and that vision is intact in each eye. Ran- no response. Pharmacologic dilation from accidental or dom dot stereograms have no monocular depth cues and deliberate instillation of anticholinergic agents (atropine, provide an excellent screening test for strabismus and scopolamine drops) into the eye can also produce pupillary amblyopia in children. mydriasis. In this situation, normal strength (1%) pilo- carpine causes no constriction. COLOR VISION Both pupils are affected equally by systemic medica- The retina contains three classes of cones, with visual tions. They are small with narcotic use (morphine, pigments of differing peak spectral sensitivity: red (560 nm), heroin) and large with anticholinergics (scopolamine). green (530 nm), and blue (430 nm). The red and green Parasympathetic agents (pilocarpine, demecarium bro- cone pigments are encoded on the X chromosome; the mide) used to treat glaucoma produce miosis. In any blue cone pigment on chromosome 7. Mutations of the patient with an unexplained pupillary abnormality, a blue cone pigment are exceedingly rare. Mutations of slit-lamp examination is helpful to exclude surgical the red and green pigments cause congenital X-linked trauma to the iris, an occult foreign body, perforating color blindness in 8% of men. Affected individuals are injury, intraocular inflammation, adhesions (synechia), not truly color blind; rather, they differ from normal angle-closure glaucoma, and iris sphincter rupture from subjects in how they perceive color and how they com- blunt trauma. bine primary monochromatic lights to match a given color. Anomalous trichromats have three cone types, EYE MOVEMENTS AND ALIGNMENT but a mutation in one cone pigment (usually red or green) causes a shift in peak spectral sensitivity, alter- Eye movements are tested by asking the patient with ing the proportion of primary colors required to both eyes open to pursue a small target such as a penlight achieve a color match. Dichromats have only two into the cardinal fields of gaze. Normal ocular versions cone types and will therefore accept a color match are smooth, symmetric, full, and maintained in all direc- based upon only two primary colors. Anomalous tions without nystagmus. Saccades, or quick refixation trichromats and dichromats have 6/6 (20/20) visual eye movements, are assessed by having the patient look acuity, but their hue discrimination is impaired. Ishi- back and forth between two stationary targets. The eyes hara color plates can be used to detect red-green color should move rapidly and accurately in a single jump to blindness. The test plates contain a hidden number, their target. Ocular alignment can be judged by holding visible only to subjects with color confusion from red- a penlight directly in front of the patient at about 1 m. If green color blindness. Because color blindness is almost the eyes are straight, the corneal light reflex will be cen- exclusively X-linked, it is worth screening only male tered in the middle of each pupil. To test eye alignment children. more precisely, the cover test is useful. The patient is instructed to gaze upon a small fixation target in the dis- The Ishihara plates are often used to detect acquired tance. One eye is covered suddenly while observing the defects in color vision, although they are intended as a second eye. If the second eye shifts to fixate upon the screening test for congenital color blindness. Acquired target, it was misaligned. If it does not move, the first eye defects in color vision frequently result from disease of is uncovered and the test is repeated on the second eye. If the macula or optic nerve. For example, patients with a neither eye moves, the eyes are aligned orthotropically. If history of optic neuritis often complain of color desat- the eyes are orthotropic in primary gaze but the patient uration long after their visual acuity has returned to complains of diplopia, the cover test should be per- normal. Color blindness can also occur from bilateral formed with the head tilted or turned in whatever direc- strokes involving the ventral portion of the occipital tion elicits diplopia. With practice the examiner can lobe (cerebral achromatopsia). Such patients can per- detect an ocular deviation (heterotropia) as small as 1–2° ceive only shades of gray and may also have difficulty with the cover test. Deviations can be measured by plac- recognizing faces (prosopagnosia). Infarcts of the domi- ing prisms in front of the misaligned eye to determine nant occipital lobe sometimes give rise to color the power required to neutralize the fixation shift evoked anomia. Affected patients can discriminate colors, but by covering the other eye. they cannot name them.
SECTION II Clinical Manifestations of Neurologic Disease174 VISUAL FIELDS (Fig. 17-3A). By generating an automated printout of light thresholds, these static perimeters provide a sensi- Vision can be impaired by damage to the visual system tive means of detecting scotomas in the visual field. anywhere from the eyes to the occipital lobes. One can They are exceedingly useful for serial assessment of localize the site of the lesion with considerable accuracy visual function in chronic diseases such as glaucoma or by mapping the visual field deficit by finger confronta- pseudotumor cerebri. tion and then correlating it with the topographic anatomy of the visual pathway (Fig. 17-3). Quantitative The crux of visual field analysis is to decide whether visual field mapping is performed by computer-driven a lesion is before, at, or behind the optic chiasm. If a perimeters (Humphrey, Octopus) that present a target of scotoma is confined to one eye, it must be due to a variable intensity at fixed positions in the visual field lesion anterior to the chiasm, involving either the optic FIGURE 17-3 using a gray scale format. Areas of visual field loss are Ventral view of the brain, correlating patterns of visual shown in black. The examples of common monocular, field loss with the sites of lesions in the visual pathway. prechiasmal field defects are all shown for the right eye. By The visual fields overlap partially, creating 120° of central convention, the visual fields are always recorded with the left binocular field flanked by a 40° monocular crescent on either eye’s field on the left, and the right eye’s field on the right, side. The visual field maps in this figure were done with a just as the patient sees the world. computer-driven perimeter (Humphrey Instruments, Carl Zeiss, Inc.). It plots the retinal sensitivity to light in the central 30°
nerve or retina. Retinal lesions produce scotomas that homonymous hemianopia, i.e., a temporal hemifield defect 175 CHAPTER 17 Disorders of Vision correspond optically to their location in the fundus. For in the contralateral eye and a matching nasal hemifield example, a superior-nasal retinal detachment results in defect in the ipsilateral eye (Fig. 17-3I). A unilateral an inferior-temporal field cut. Damage to the macula postchiasmal lesion leaves the visual acuity in each eye causes a central scotoma (Fig. 17-3B). unaffected, although the patient may read the letters on only the left or right half of the eye chart. Lesions of the Optic nerve disease produces characteristic patterns optic radiations tend to cause poorly matched or of visual field loss. Glaucoma selectively destroys axons incongruous field defects in each eye. Damage to the optic that enter the superotemporal or inferotemporal poles of radiations in the temporal lobe (Meyer’s loop) produces a the optic disc, resulting in arcuate scotomas shaped like a superior quadrantic homonymous hemianopia (Fig. 17-3J), Turkish scimitar, which emanate from the blind spot and whereas injury to the optic radiations in the parietal lobe curve around fixation to end flat against the horizontal results in an inferior quadrantic homonymous hemianopia meridian (Fig. 17-3C). This type of field defect mirrors (Fig. 17-3K ). Lesions of the primary visual cortex give rise the arrangement of the nerve fiber layer in the temporal to dense, congruous hemianopic field defects. Occlusion retina. Arcuate or nerve fiber layer scotomas also occur of the posterior cerebral artery supplying the occipital lobe from optic neuritis, ischemic optic neuropathy, optic is a frequent cause of total homonymous hemianopia. disc drusen, and branch retinal artery or vein occlusion. Some patients with hemianopia after occipital stroke have macular sparing, because the macular representation at the Damage to the entire upper or lower pole of the tip of the occipital lobe is supplied by collaterals from optic disc causes an altitudinal field cut that follows the the middle cerebral artery (Fig. 17-3L). Destruction of horizontal meridian (Fig. 17-3D). This pattern of visual both occipital lobes produces cortical blindness.This con- field loss is typical of ischemic optic neuropathy but also dition can be distinguished from bilateral prechiasmal occurs from retinal vascular occlusion, advanced glau- visual loss by noting that the pupil responses and optic coma, and optic neuritis. fundi remain normal. About half the fibers in the optic nerve originate DISORDERS from ganglion cells serving the macula. Damage to papillomacular fibers causes a cecocentral scotoma RED OR PAINFUL EYE encompassing the blind spot and macula (Fig. 17-3E). If the damage is irreversible, pallor eventually appears in Corneal Abrasions the temporal portion of the optic disc. Temporal pallor from a cecocentral scotoma may develop in optic neuri- These are seen best by placing a drop of fluorescein in tis, nutritional optic neuropathy, toxic optic neuropathy, the eye and looking with the slit lamp using a cobalt- Leber’s hereditary optic neuropathy, and compressive blue light. A penlight with a blue filter will suffice if no optic neuropathy. It is worth mentioning that the tem- slit lamp is available. Damage to the corneal epithelium is poral side of the optic disc is slightly more pale than the revealed by yellow fluorescence of the exposed basement nasal side in most normal individuals. Therefore, it can membrane underlying the epithelium. It is important to sometimes be difficult to decide whether the temporal check for foreign bodies.To search the conjunctival for- pallor visible on fundus examination represents a patho- nices, the lower lid should be pulled down and the logic change. Pallor of the nasal rim of the optic disc is a upper lid everted. A foreign body can be removed with less equivocal sign of optic atrophy. a moistened cotton-tipped applicator after placing a drop of topical anesthetic, such as proparacaine, in the At the optic chiasm, fibers from nasal ganglion cells eye. Alternatively, it may be possible to flush the foreign decussate into the contralateral optic tract. Crossed fibers body from the eye by irrigating copiously with saline or are damaged more by compression than uncrossed fibers. artificial tears. If the corneal epithelium has been As a result, mass lesions of the sellar region cause a tempo- abraded, antibiotic ointment and a patch should be applied ral hemianopia in each eye. Tumors anterior to the optic to the eye. A drop of an intermediate-acting cycloplegic, chiasm, such as meningiomas of the tuberculum sella, pro- such as cyclopentolate hydrochloride 1%, helps to reduce duce a junctional scotoma characterized by an optic neu- pain by relaxing the ciliary body.The eye should be reex- ropathy in one eye and a superior-temporal field cut in amined the next day. Minor abrasions may not require the other eye (Fig. 17-3G). More symmetric compression patching and cycloplegia. of the optic chiasm by a pituitary adenoma, meningioma, craniopharyngioma, glioma, or aneurysm results in a Subconjunctival Hemorrhage bitemporal hemianopia (Fig. 17-3H).The insidious devel- opment of a bitemporal hemianopia often goes unnoticed This results from rupture of small vessels bridging the by the patient and will escape detection by the physician potential space between the episclera and conjunctiva. unless each eye is tested separately. It is difficult to localize a postchiasmal lesion accurately, because injury anywhere in the optic tract, lateral genicu- late body, optic radiations, or visual cortex can produce a
SECTION II Clinical Manifestations of Neurologic Disease176 Blood dissecting into this space can produce a spectacu- slightly. The most common viral etiology is adenovirus lar red eye, but vision is not affected and the hemorrhage infection. It causes a watery discharge, mild foreign- resolves without treatment. Subconjunctival hemorrhage body sensation, and photophobia. Bacterial infection is usually spontaneous but can occur from blunt trauma, tends to produce a more mucopurulent exudate. Mild eye rubbing, or vigorous coughing. Occasionally it is a cases of infectious conjunctivitis are usually treated empir- clue to an underlying bleeding disorder. ically with broad-spectrum topical ocular antibiotics, such as sulfacetamide 10%, polymixin-bacitracin-neomycin, Pinguecula or trimethoprim-polymixin combination. Smears and cultures are usually reserved for severe, resistant, or recur- This is a small, raised conjunctival nodule at the temporal rent cases of conjunctivitis.To prevent contagion, patients or nasal limbus. In adults such lesions are extremely com- should be admonished to wash their hands frequently, mon and have little significance, unless they become not to touch their eyes, and to avoid direct contact with inflamed (pingueculitis).A pterygium resembles a pinguecula others. but has crossed the limbus to encroach upon the corneal surface. Removal is justified when symptoms of irritation Allergic Conjunctivitis or blurring develop, but recurrence is a common problem. This condition is extremely common and often mistaken Blepharitis for infectious conjunctivitis. Itching, redness, and epiphora are typical. The palpebral conjunctiva may become This refers to inflammation of the eyelids. The most hypertropic with giant excrescences called cobblestone common form occurs in association with acne rosacea or papillae. Irritation from contact lenses or any chronic for- seborrheic dermatitis.The eyelid margins are usually col- eign body can also induce formation of cobblestone onized heavily by staphylococci. Upon close inspection, papillae. Atopic conjunctivitis occurs in subjects with atopic they appear greasy, ulcerated, and crusted with scaling dermatitis or asthma. Symptoms caused by allergic con- debris that clings to the lashes.Treatment consists of warm junctivitis can be alleviated with cold compresses, topical compresses, strict eyelid hygiene, and topical antibiotics vasoconstrictors, antihistamines, and mast cell stabilizers such as erythromycin. An external hordeolum (sty) is caused such as cromolyn sodium. Topical glucocorticoid solu- by staphylococcal infection of the superficial accessory tions provide dramatic relief of immune-mediated forms glands of Zeis or Moll located in the eyelid margins. An of conjunctivitis, but their long-term use is ill-advised internal hordeolum occurs after suppurative infection of because of the complications of glaucoma, cataract, and the oil-secreting meibomian glands within the tarsal plate secondary infection. Topical nonsteroidal anti-inflamma- of the eyelid. Systemic antibiotics, usually tetracyclines, are tory agents (NSAIDs) such as ketorolac tromethamine sometimes necessary for treatment of meibomian gland are a better alternative. inflammation (meibomitis) or chronic, severe blepharitis. A chalazion is a painless, granulomatous inflammation of a Keratoconjunctivitis Sicca meibomian gland that produces a pealike nodule within the eyelid. It can be incised and drained, or injected with Also known as dry eye, it produces a burning, foreign- glucocorticoids. Basal cell, squamous cell, or meibomian body sensation, injection, and photophobia. In mild gland carcinoma should be suspected for any nonhealing, cases the eye appears surprisingly normal, but tear pro- ulcerative lesion of the eyelids. duction measured by wetting of a filter paper (Schirmer strip) is deficient. A variety of systemic drugs, including Dacrocystitis antihistaminic, anticholinergic, and psychotropic med- ications, result in dry eye by reducing lacrimal secretion. An inflammation of the lacrimal drainage system, this can Disorders that involve the lacrimal gland directly, such as produce epiphora (tearing) and ocular injection. Gentle sarcoidosis or Sjögren’s syndrome, also cause dry eye. pressure over the lacrimal sac evokes pain and reflux of Patients may develop dry eye after radiation therapy if mucus or pus from the tear puncta. Dacrocystitis usually the treatment field includes the orbits. Problems with occurs after obstruction of the lacrimal system. It is treated ocular drying are also common after lesions affecting with topical and systemic antibiotics, followed by probing cranial nerves V or VII. Corneal anesthesia is particularly or surgery to reestablish patency. Entropion (inversion of dangerous, because the absence of a normal blink reflex the eyelid) or ectropion (sagging or eversion of the eyelid) exposes the cornea to injury without pain to warn the can also lead to epiphora and ocular irritation. patient. Dry eye is managed by frequent and liberal application of artificial tears and ocular lubricants. In Conjunctivitis severe cases the tear puncta can be plugged or cauterized to reduce lacrimal outflow. This is the most common cause of a red, irritated eye. Pain is minimal, and the visual acuity is reduced only
Keratitis zoster eruption in any branch of the trigeminal nerve 177 CHAPTER 17 Disorders of Vision but are particularly common when vesicles form on the This is a threat to vision because of the risk of corneal nose, reflecting nasociliary (V1) nerve involvement clouding, scarring, and perforation. Worldwide, the two (Hutchinson’s sign). Herpes zoster ophthalmicus pro- leading causes of blindness from keratitis are trachoma duces corneal dendrites, which can be difficult to distin- from chlamydial infection and vitamin A deficiency guish from those seen in herpes simplex. Stromal keratitis, related to malnutrition. In the United States, contact lenses anterior uveitis, raised intraocular pressure, ocular motor play a major role in corneal infection and ulceration.They nerve palsies, acute retinal necrosis, and postherpetic should not be worn by anyone with an active eye infec- scarring and neuralgia are other common sequelae. tion. In evaluating the cornea, it is important to differenti- Herpes zoster ophthalmicus is treated with antiviral ate between a superficial infection (keratoconjunctivitis) and agents and cycloplegics. In severe cases, glucocorticoids a deeper, more serious ulcerative process. The latter is may be added to prevent permanent visual loss from accompanied by greater visual loss, pain, photophobia, corneal scarring. redness, and discharge. Slit-lamp examination shows dis- ruption of the corneal epithelium, a cloudy infiltrate or Episcleritis abscess in the stroma, and an inflammatory cellular reac- tion in the anterior chamber. In severe cases, pus settles at This is an inflammation of the episclera, a thin layer of the bottom of the anterior chamber, giving rise to a connective tissue between the conjunctiva and sclera. hypopyon. Immediate empirical antibiotic therapy should Episcleritis resembles conjunctivitis but is a more local- be initiated after corneal scrapings are obtained for Gram’s ized process and discharge is absent. Most cases of epis- stain, Giemsa stain, and cultures. Fortified topical antibi- cleritis are idiopathic, but some occur in the setting of otics are most effective, supplemented with subconjuncti- an autoimmune disease. Scleritis refers to a deeper, more val antibiotics as required. A fungal etiology should always severe inflammatory process, frequently associated with a be considered in the patient with keratitis. Fungal infec- connective tissue disease such as rheumatoid arthritis, tion is common in warm humid climates, especially after lupus erythematosus, polyarteritis nodosa, Wegener’s penetration of the cornea by plant or vegetable material. granulomatosis, or relapsing polychondritis. The inflam- mation and thickening of the sclera can be diffuse or Herpes Simplex nodular. In anterior forms of scleritis, the globe assumes a violet hue and the patient complains of severe ocular The herpes viruses are a major cause of blindness from tenderness and pain.With posterior scleritis the pain and keratitis. Most adults in the United States have serum redness may be less marked, but there is often proptosis, antibodies to herpes simplex, indicating prior viral infec- choroidal effusion, reduced motility, and visual loss. tion. Primary ocular infection is generally caused by her- Episcleritis and scleritis should be treated with NSAIDs. pes simplex type 1, rather than type 2. It manifests as a If these agents fail, topical or even systemic glucocorti- unilateral follicular blepharoconjunctivitis, easily con- coid therapy may be necessary, especially if an underly- fused with adenoviral conjunctivitis unless telltale vesicles ing autoimmune process is active. appear on the periocular skin or conjunctiva. A dendritic pattern of corneal epithelial ulceration revealed by fluo- Uveitis rescein staining is pathognomonic for herpes infection but is seen in only a minority of primary infections. Involving the anterior structures of the eye, this is also Recurrent ocular infection arises from reactivation of the called iritis or iridocyclitis. The diagnosis requires slit-lamp latent herpes virus.Viral eruption in the corneal epithe- examination to identify inflammatory cells floating in the lium may result in the characteristic herpes dendrite. aqueous humor or deposited upon the corneal endothe- Involvement of the corneal stroma produces edema, vas- lium (keratic precipitates). Anterior uveitis develops in cularization, and iridocyclitis. Herpes keratitis is treated sarcoidosis, ankylosing spondylitis, juvenile rheumatoid with topical antiviral agents, cycloplegics, and oral acy- arthritis, inflammatory bowel disease, psoriasis, Reiter’s clovir. Topical glucocorticoids are effective in mitigating syndrome, and Behçet’s disease. It is also associated with corneal scarring but must be used with extreme caution herpes infections, syphilis, Lyme disease, onchocerciasis, because of the danger of corneal melting and perfora- tuberculosis, and leprosy. Although anterior uveitis can tion. Topical glucocorticoids also carry the risk of pro- occur in conjunction with many diseases, no cause is longing infection and inducing glaucoma. found to explain the majority of cases. For this reason, laboratory evaluation is usually reserved for patients with Herpes Zoster recurrent or severe anterior uveitis.Treatment is aimed at reducing inflammation and scarring by judicious use of Herpes zoster from reactivation of latent varicella (chick- topical glucocorticoids. Dilation of the pupil reduces enpox) virus causes a dermatomal pattern of painful pain and prevents the formation of synechiae. vesicular dermatitis. Ocular symptoms can occur after
SECTION II Clinical Manifestations of Neurologic Disease178 Posterior Uveitis headache, prompting a fruitless workup for abdominal or neurologic disease. The diagnosis is made by measur- This is diagnosed by observing inflammation of the ing the intraocular pressure during an acute attack or by vitreous, retina, or choroid on fundus examination. It is observing a narrow chamber angle by means of a spe- more likely than anterior uveitis to be associated with cially mirrored contact lens. Acute angle closure is an identifiable systemic disease. Some patients have treated with acetazolamide (PO or IV), topical beta panuveitis, or inflammation of both the anterior and blockers, prostaglandin analogues, α2-adrenergic ago- posterior segments of the eye. Posterior uveitis is a nists, and pilocarpine to induce miosis. If these measures manifestation of autoimmune diseases such as sarcoido- fail, a laser can be used to create a hole in the peripheral sis, Behçet’s disease, Vogt-Koyanagi-Harada syndrome, iris to relieve pupillary block. Many physicians are reluc- and inflammatory bowel disease (Fig. 17-4). It also tant to dilate patients routinely for fundus examination accompanies diseases such as toxoplasmosis, onchocer- because they fear precipitating an angle-closure glaucoma. ciasis, cysticercosis, coccidioidomycosis, toxocariasis, and The risk is actually remote and more than outweighed histoplasmosis; infections caused by organisms such as by the potential benefit to patients of discovering a Candida, Pneumocystis carinii, Cryptococcus, Aspergillus, her- hidden fundus lesion visible only through a fully dilated pes, and cytomegalovirus; and other diseases such as pupil. Moreover, a single attack of angle closure after syphilis, Lyme disease, tuberculosis, cat-scratch disease, pharmacologic dilation rarely causes any permanent dam- Whipple’s disease, and brucellosis. In multiple sclerosis, age to the eye and serves as an inadvertent provocative chronic inflammatory changes can develop in the extreme test to identify patients with narrow angles who would periphery of the retina (pars planitis or intermediate benefit from prophylactic laser iridectomy. uveitis). Endophthalmitis Acute Angle-Closure Glaucoma This occurs from bacterial, viral, fungal, or parasitic This is a rare and frequently misdiagnosed cause of a infection of the internal structures of the eye. It is usu- red, painful eye. Susceptible eyes have a shallow anterior ally acquired by hematogenous seeding from a remote chamber, either because the eye has a short axial length site. Chronically ill, diabetic, or immunosuppressed (hyperopia) or a lens enlarged by the gradual develop- patients, especially those with a history of indwelling IV ment of cataract. When the pupil becomes mid-dilated, catheters or positive blood cultures, are at greatest risk the peripheral iris blocks aqueous outflow via the ante- for endogenous endophthalmitis. Although most patients rior chamber angle and the intraocular pressure rises have ocular pain and injection, visual loss is sometimes abruptly, producing pain, injection, corneal edema, the only symptom. Septic emboli, from a diseased heart obscurations, and blurred vision. In some patients, ocular valve or a dental abscess, that lodge in the retinal circula- symptoms are overshadowed by nausea, vomiting, or tion can give rise to endophthalmitis. White-centered retinal hemorrhages (Roth’s spots) are considered pathog- nomonic for subacute bacterial endocarditis, but they also appear in leukemia, diabetes, and many other condi- tions. Endophthalmitis also occurs as a complication of ocular surgery, occasionally months or even years after the operation. An occult penetrating foreign body or unrecognized trauma to the globe should be considered in any patient with unexplained intraocular infection or inflammation. FIGURE 17-4 TRANSIENT OR SUDDEN VISUAL LOSS Retinal vasculitis, uveitis, and hemorrhage in a 32-year- old woman with Crohn’s disease. Note that the veins are Amaurosis Fugax frosted with a white exudate. Visual acuity improved from 20/400 to 20/20 following treatment with intravenous methyl- This term refers to a transient ischemic attack of the prednisolone. retina (Chap. 21). Because neural tissue has a high rate of metabolism, interruption of blood flow to the retina for more than a few seconds results in transient monocular blindness, a term used interchangeably with amaurosis fugax. Patients describe a rapid fading of vision like a curtain descending, sometimes affecting only a portion
FIGURE 17-5 in patients with diseased valves, atrial fibrillation, or wall 179CHAPTER 17 Disorders of Vision Hollenhorst plaque lodged at the bifurcation of a retinal motion abnormalities. arteriole proves that a patient is shedding emboli from either the carotid artery, great vessels, or heart. In rare instances, amaurosis fugax occurs from low central retinal artery perfusion pressure in a patient with of the visual field. Amaurosis fugax usually occurs from a critical stenosis of the ipsilateral carotid artery and an embolus that becomes stuck within a retinal arteriole poor collateral flow via the circle of Willis. In this situa- (Fig. 17-5). If the embolus breaks up or passes, flow is tion, amaurosis fugax develops when there is a dip in restored and vision returns quickly to normal without systemic blood pressure or a slight worsening of the permanent damage. With prolonged interruption of carotid stenosis. Sometimes there is contralateral motor blood flow, the inner retina suffers infarction. Ophthal- or sensory loss, indicating concomitant hemispheric moscopy reveals zones of whitened, edematous retina cerebral ischemia. following the distribution of branch retinal arterioles. Complete occlusion of the central retinal artery pro- Retinal arterial occlusion also occurs rarely in associa- duces arrest of blood flow and a milky retina with a tion with retinal migraine, lupus erythematosus, anticar- cherry-red fovea (Fig. 17-6). Emboli are composed of diolipin antibodies (Fig. 17-6), anticoagulant deficiency either cholesterol (Hollenhorst plaque), calcium, or states (protein S, protein C, and antithrombin III defi- platelet-fibrin debris. The most common source is an ciency), pregnancy, IV drug abuse, blood dyscrasias, dys- atherosclerotic plaque in the carotid artery or aorta, proteinemias, and temporal arteritis. although emboli can also arise from the heart, especially Marked systemic hypertension causes sclerosis of retinal arterioles, splinter hemorrhages, focal infarcts of the nerve fiber layer (cotton-wool spots), and leakage of lipid and fluid (hard exudate) into the macula (Fig. 17-7). In hypertensive crisis, sudden visual loss can result from vasospasm of retinal arterioles and retinal ischemia. In addition, acute hypertension may produce visual loss from ischemic swelling of the optic disc. Patients with acute hypertensive retinopathy should be treated by lowering the blood pressure. However, the blood pressure should not be reduced precipitously, because there is a danger of optic disc infarction from sudden hypoperfusion. Impending branch or central retinal vein occlusion can produce prolonged visual obscurations that resemble those described by patients with amaurosis fugax. The veins appear engorged and phlebitic, with numerous retinal hemorrhages (Fig. 17-8). In some patients, venous blood FIGURE 17-6 FIGURE 17-7 Central retinal artery occlusion combined with ischemic Hypertensive retinopathy with scattered flame (splinter) optic neuropathy in a 19-year-old woman with an elevated hemorrhages and cotton-wool spots (nerve fiber layer titer of anticardiolipin antibodies. Note the orange dot (rather infarcts) in a patient with headache and a blood pressure of than cherry red) corresponding to the fovea and the spared 234/120. patch of retina just temporal to the optic disc.
SECTION II Clinical Manifestations of Neurologic Disease180 into two forms: arteritic and nonarteritic. The nonar- teritic form of AION is most common. No specific cause FIGURE 17-8 can be identified, although diabetes and hypertension are Central retinal vein occlusion can produce massive retinal frequent risk factors. No treatment is available. About 5% hemorrhage (“blood and thunder”), ischemia, and vision loss. of patients, especially those older than 60 years, develop the arteritic form of AION in conjunction with giant cell flow recovers spontaneously, while others evolve a frank (temporal) arteritis. It is urgent to recognize arteritic obstruction with extensive retinal bleeding (“blood and AION so that high doses of glucocorticoids can be insti- thunder” appearance), infarction, and visual loss. Venous tuted immediately to prevent blindness in the second eye. occlusion of the retina is often idiopathic, but hyperten- Symptoms of polymyalgia rheumatica may be present; the sion, diabetes, and glaucoma are prominent risk factors. sedimentation rate and C-reactive protein level are usually Polycythemia, thrombocythemia, or other factors leading elevated. In a patient with visual loss from suspected to an underlying hypercoagulable state should be cor- arteritic AION, temporal artery biopsy is mandatory to rected; aspirin treatment may be beneficial. confirm the diagnosis. Glucocorticoids should be started Anterior Ischemic Optic Neuropathy (AION) immediately, without waiting for the biopsy to be com- This is caused by insufficient blood flow through the pos- pleted. The diagnosis of arteritic AION is difficult to terior ciliary arteries supplying the optic disc. It produces sustain in the face of a negative temporal artery biopsy, painless, monocular visual loss that is usually sudden, but such cases do occur rarely. although some patients have progressive worsening. The optic disc appears swollen and surrounded by nerve fiber Posterior Ischemic Optic Neuropathy layer splinter hemorrhages (Fig. 17-9). AION is divided This is an infrequent cause of acute visual loss, induced FIGURE 17-9 by the combination of severe anemia and hypotension. Anterior ischemic optic neuropathy from temporal arteri- Cases have been reported after major blood loss during tis in a 78-year-old woman with pallid disc swelling, hemor- surgery, exsanguinating trauma, gastrointestinal bleeding, rhage, visual loss, myalgia, and an erythrocyte sedimentation and renal dialysis. The fundus usually appears normal, rate of 86 mm/h. although optic disc swelling develops if the process extends far enough anteriorly.Vision can be salvaged in some patients by prompt blood transfusion and reversal of hypotension. Optic Neuritis This is a common inflammatory disease of the optic nerve. In the Optic Neuritis Treatment Trial (ONTT), the mean age of patients was 32 years, 77% were women, 92% had ocular pain (especially with eye movements), and 35% had optic disc swelling. In most patients, the demyelinating event was retrobulbar and the ocular fun- dus appeared normal on initial examination (Fig. 17-10), although optic disc pallor slowly developed over subse- quent months. Virtually all patients experience a gradual recovery of vision after a single episode of optic neuritis, even with- out treatment.This rule is so reliable that failure of vision to improve after a first attack of optic neuritis casts doubt upon the original diagnosis. Treatment with high-dose IV methylprednisolone (250 mg every 6 h for 3 days) followed by oral prednisone (1 mg/kg per day for 11 days) makes no difference in final acuity (measured 6 months after the attack), but the recovery of visual function occurs more rapidly. For some patients, optic neuritis remains an isolated event. However, the ONTT showed that the 10-year cumulative probability of developing clinically definite multiple sclerosis following optic neuritis is 38%. In
181 FIGURE 17-10 FIGURE 17-11 CHAPTER 17 Disorders of Vision Retrobulbar optic neuritis is characterized by a normal fun- Optic atrophy is not a specific diagnosis, but refers to the dus examination initially, hence the rubric, “the doctor sees combination of optic disc pallor, arteriolar narrowing, and nothing, and the patient sees nothing.” Optic atrophy devel- nerve fiber layer destruction produced by a host of eye dis- ops after severe or repeated attacks. eases, especially optic neuropathies. patients with two or more demyelinating plaques on visual loss can also develop gradually and produce optic brain magnetic resonance (MR) imaging, treatment with atrophy (Fig. 17-11) without a phase of acute optic disc interferon beta-1a can retard the development of more edema. Many agents have been implicated as a cause of lesions. In summary, an MR scan is recommended in toxic optic neuropathy, but the evidence supporting the every patient with a first attack of optic neuritis. When association for many is weak. The following is a partial visual loss is severe (worse than 20/100), treatment with list of potential offending drugs or toxins: disulfiram, intravenous followed by oral glucocorticoids hastens ethchlorvynol, chloramphenicol, amiodarone, monoclonal recovery. If multiple lesions are present on the MR scan, anti-CD3 antibody, ciprofloxacin, digitalis, streptomycin, treatment with interferon beta-1a should be considered. lead, arsenic, thallium, D-penicillamine, isoniazid, eme- tine, and sulfonamides. Deficiency states, induced either Leber’s Hereditary Optic Neuropathy by starvation, malabsorption, or alcoholism, can lead to insidious visual loss. Thiamine, vitamin B12, and folate This disease usually affects young men, causing gradual, levels should be checked in any patient with unex- painless, severe, central visual loss in one eye, followed plained, bilateral central scotomas and optic pallor. weeks or months later by the same process in the other eye. Acutely, the optic disc appears mildly plethoric with Papilledema surface capillary telangiectases, but no vascular leakage on fluorescein angiography. Eventually optic atrophy ensues. This connotes bilateral optic disc swelling from raised Leber’s optic neuropathy is caused by a point mutation at intracranial pressure (Fig. 17-12). Headache is a frequent, codon 11778 in the mitochondrial gene encoding nicoti- but not invariable, accompaniment. All other forms of namide adenine dinucleotide dehydrogenase (NADH) optic disc swelling, e.g., from optic neuritis or ischemic subunit 4.Additional mutations responsible for the disease optic neuropathy, should be called “optic disc edema.” have been identified, most in mitochondrial genes encod- This convention is arbitrary but serves to avoid confusion. ing proteins involved in electron transport. Mitochondrial Often it is difficult to differentiate papilledema from other mutations causing Leber’s neuropathy are inherited from forms of optic disc edema by fundus examination alone. the mother by all her children, but usually only sons Transient visual obscurations are a classic symptom of develop symptoms. There is no treatment. papilledema. They can occur in only one eye or simulta- neously in both eyes. They usually last seconds but can Toxic Optic Neuropathy persist longer. Obscurations follow abrupt shifts in posture or happen spontaneously. When obscurations are pro- This can result in acute visual loss with bilateral optic longed or spontaneous, the papilledema is more threaten- disc swelling and central or cecocentral scotomas. Such ing. Visual acuity is not affected by papilledema unless cases have been reported to result from exposure to the papilledema is severe, long-standing, or accompanied ethambutol, methyl alcohol (moonshine), ethylene glycol by macular edema and hemorrhage. Visual field testing (antifreeze), or carbon monoxide. In toxic optic neuropathy,
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