Harrison Neurology in Clinical Medicine Second Edition

SECTION II Clinical Manifestations of Neurologic Disease82 older age, prior history of back pain, restricted spinal good evidence to suggest that one NSAID is more effective than another. Bed rest should not exceed mobility, pain radiating into a leg, high levels of psycho- 2 days. Activity tolerance is the primary goal, while logical distress, poor self-rated health, minimal physical pain relief is secondary. Exercise programs can reverse activity, smoking, job dissatisfaction, and widespread atrophy in paraspinal muscles and strengthen exten- pain. Combinations of these premorbid factors have sors of the trunk. Intensive physical exercise or “work been used to predict which individuals with ALBP are hardening” regimens (under the guidance of a physical likely to develop CLBP. The initial approach to these therapist) have been effective in returning some patients patients is similar to that for ALBP. Treatment of this het- to work, improving walking distances, and diminishing erogeneous group of patients is directed toward the pain. The benefit can be sustained with home exercise underlying cause when known; the ultimate goal is to regimens. It is difficult to endorse one specific exercise restore function to the maximum extent possible. or PT regimen given the heterogeneous nature of this patient group. The role of manipulation, back school, Many conditions that produce CLBP can be identified or epidural steroid injections in the treatment of CLBP by a combination of neuroimaging and electrophysio- is unproven. There is no strong evidence to support logic studies. Spine MRI and CT-myelography are almost the use of acupuncture or traction. A reduction in sick always the imaging techniques of choice. Imaging stud- leave days, long-term health care utilization, and pen- ies should be performed only in circumstances when sion expenditures may offset the initial expense of the results are likely to influence management. multidisciplinary treatment programs. Studies of hydrotherapy for CLBP have yielded mixed results; Injection studies can be used diagnostically to however, given its low risk and cost, hydrotherapy can help determine the anatomic source of back pain. be considered as a treatment option. Transcutaneous Reproduction of the patient’s typical pain with electrical nerve stimulation (TENS) has not been ade- diskography has been used as evidence that a spe- quately studied in CLBP. cific disk is the pain generator. Pain relief following a foraminal nerve root block or glucocorticoid injection PAIN IN THE NECK AND SHOULDER into a facet has been similarly used as evidence that (Table 7-4) the facet joint or nerve root is the source. However, the possibility that the injection response was a Neck pain, which usually arises from diseases of the cer- placebo effect or due to systemic absorption of the vical spine and soft tissues of the neck, is common (4.6% glucocorticoids is usually not considered. The value of of adults in one study). Neck pain arising from the cer- these procedures in the treatment of CLBP or in the vical spine is typically precipitated by movement and selection of candidates for surgery is largely unknown may be accompanied by focal tenderness and limitation despite their widespread use. The value of thermog- of motion. Pain arising from the brachial plexus, shoul- raphy in the assessment of radiculopathy also has not der, or peripheral nerves can be confused with cervical been rigorously studied. spine disease, but the history and examination usually identify a more distal origin for the pain. Cervical spine The diagnosis of nerve root injury is most secure trauma, disk disease, or spondylosis may be asympto- when the history, examination, results of imaging matic or painful and can produce a myelopathy, radicu- studies, and the EMG are concordant. The correlation lopathy, or both. The nerve roots most commonly between CT and EMG for localization of nerve root injury affected are C7 and C6. is between 65 and 73%. Up to one-third of asympto- matic adults have a disk protrusion detected by CT or TRAUMA TO THE CERVICAL SPINE MRI scans. Thus, surgical intervention based solely upon radiologic findings increases the likelihood of an unsuc- Trauma to the cervical spine (fractures, subluxation) cessful outcome. places the spinal cord at risk for compression. Motor vehicle accidents, violent crimes, or falls account for 87% An unblinded study in patients with chronic sciatica of spinal cord injuries (Chap. 30). Immediate immobi- found that surgery could hasten relief of symptoms by lization of the neck is essential to minimize further spinal ~2 months; however, at 1 year there was no advantage cord injury from movement of unstable cervical spine of surgery over conservative medical therapy, and segments. A CT scan is the diagnostic procedure of nearly all patients (95%) in both groups made a full choice for detection of acute fractures. Following major recovery regardless of the treatment approach. A large observational cohort study of patients with lumbar spinal stenosis showed surgery to be relatively safe, likely reducing pain at 2 years with little effect on func- tion or disability. CLBP can be treated with a variety of conservative measures. Acute and subacute exacerbations are man- aged with NSAIDs and comfort measures. There is no

TABLE 7-4 83 CERVICAL RADICULOPATHY—NEUROLOGIC FEATURES CERVICAL EXAMINATION FINDINGS PAIN NERVE ROOTS DISTRIBUTION REFLEX SENSORY MOTOR Lateral arm, medial scapula C5 Biceps Over lateral deltoid Supraspinatusa (initial arm abduction) Lateral forearm, thumb, C6 Biceps Infraspinatusa (arm external rotation) index finger CHAPTER 7 Back and Neck Pain Thumb, index fingers Deltoida (arm abduction) C7 Triceps Radial hand/forearm Biceps (arm flexion) Posterior arm, dorsal Biceps (arm flexion) forearm, lateral hand C8 Finger Middle fingers Pronator teres (internal forearm flexors Dorsum forearm 4th and 5th fingers, medial rotation) forearm T1 Finger Little finger Tricepsa (arm extension) flexors Medial hand Wrist extensorsa Medial arm, axilla and forearm Extensor digitoruma (finger extension) Axilla and Abductor pollicis brevis (abduction D1) medial arm First dorsal interosseous (abduction D2) Abductor digiti minimi (abduction D5) Abductor pollicis brevis (abduction D1) First dorsal interosseous (abduction D2) Abductor digiti minimi (abduction D5) aThese muscles receive the majority of innervation from this root. trauma to the cervical spine, injury to the vertebral nerve root territory, and (3) the location of pain is the arteries is common; most lesions are asymptomatic and most variable of the clinical features. can be visualized by MRI and angiography. CERVICAL SPONDYLOSIS Whiplash injury is due to trauma (usually automobile accidents) causing cervical musculoligamental sprain or Osteoarthritis of the cervical spine may produce neck strain due to hyperflexion or hyperextension. This diag- pain that radiates into the back of the head, shoulders, or nosis should not be applied to patients with fractures, arms, or may be the source of headaches in the posterior disk herniation, head injury, focal neurologic findings, or occipital region (supplied by the C2-C4 nerve roots). altered consciousness. Imaging of the cervical spine is Osteophytes, disk protrusions, and hypertrophic facet or not cost-effective acutely but is useful to detect disk uncovertebral joints may compress one or several nerve herniations when symptoms persist for >6 weeks fol- roots at the intervertebral foramina (Fig. 7-7); this com- lowing the injury. Severe initial symptoms have been pression accounts for 75% of cervical radiculopathies. associated with a poor long-term outcome. The roots most commonly affected are C7 and C6. Narrowing of the spinal canal by osteophytes, ossifica- CERVICAL DISK DISEASE tion of the posterior longitudinal ligament (OPLL), or a large central disk may compress the cervical spinal cord. Herniation of a lower cervical disk is a common cause of Combinations of radiculopathy and myelopathy may neck, shoulder, arm, or hand pain or tingling. Neck pain, also be present. Spinal cord involvement is suggested by stiffness, and a range of motion limited by pain are the Lhermitt’s symptom, an electrical sensation elicited by usual manifestations. A herniated cervical disk is respon- neck flexion and radiating down the spine from the sible for ~25% of cervical radiculopathies. Extension and neck. When little or no neck pain accompanies cord lateral rotation of the neck narrows the ipsilateral inter- compression, the diagnosis may be confused with amy- vertebral foramen and may reproduce radicular symp- otrophic lateral sclerosis (Chap. 27), multiple sclerosis toms (Spurling’s sign). In young persons, acute nerve root (Chap. 34), spinal cord tumors, or syringomyelia (Chap. 30). compression from a ruptured cervical disk is often due to The possibility of cervical spondylosis should be consid- trauma. Cervical disk herniations are usually posterolat- ered even when the patient presents with symptoms or eral near the lateral recess and intervertebral foramen. signs in the legs only. MRI is the study of choice to Typical patterns of reflex, sensory, and motor changes define the anatomic abnormalities, but plain CT is ade- that accompany specific cervical nerve root lesions are quate to assess bony spurs, foraminal narrowing, or summarized in Table 7-4; however, (1) overlap in func- OPLL. EMG and nerve conduction studies can localize tion between adjacent nerve roots is common, (2) symp- and assess the severity of the nerve root injury. toms and signs may be evident in only part of the injured

84 SECTION II Clinical Manifestations of Neurologic Disease FIGURE 7-7 Cervical spondylosis; left C6 radiculopathy. A. Sagittal T2 fast spin echo magnetic resonance imaging reveals a hypointense osteophyte that pro- trudes from the C5–C6 level into the thecal sac, displacing the spinal cord posteriorly (white arrow). B. Axial 2-mm section from a 3-D volume gradient echo sequence of the cervical spine. The high signal of the right C5–C6 intervertebral foramen contrasts with the narrow high signal of the left C5–C6 intervertebral foramen produced by osteophytic spurring (arrows). OTHER CAUSES OF NECK PAIN lung apex. Injury to these structures may result in pos- tural or movement-induced pain around the shoulder Rheumatoid arthritis (RA) of the cervical apophyseal and supraclavicular region. True neurogenic thoracic outlet joints produces neck pain, stiffness, and limitation of syndrome (TOS) results from compression of the lower motion. In advanced RA, synovitis of the atlantoaxial trunk of the brachial plexus or ventral rami of the C8 or joint (C1-C2; Fig. 7-2) may damage the transverse liga- T1 nerve roots by an anomalous band of tissue connect- ment of the atlas, producing forward displacement of the ing an elongate transverse process at C7 with the first atlas on the axis (atlantoaxial subluxation). Radiologic rib. Signs include weakness of intrinsic muscles of the evidence of atlantoaxial subluxation occurs in 30% of hand and diminished sensation on the palmar aspect of patients with RA. Not surprisingly, the degree of sub- the fourth and fifth digits. EMG and nerve conduction luxation correlates with the severity of erosive disease. studies confirm the diagnosis. Treatment consists of sur- When subluxation is present, careful assessment is gical resection of the anomalous band. The weakness important to identify early signs of myelopathy. Occa- and wasting of intrinsic hand muscles typically does not sional patients develop high spinal cord compression improve, but surgery halts the insidious progression of leading to quadriparesis, respiratory insufficiency, and weakness. Arterial TOS results from compression of the death. Surgery should be considered when myelopathy subclavian artery by a cervical rib; the compression or spinal instability is present. results in poststenotic dilatation of the artery and throm- bus formation. Blood pressure is reduced in the affected Ankylosing spondylitis can cause neck pain and less com- limb, and signs of emboli may be present in the hand. monly atlantoaxial subluxation; surgery may be required Neurologic signs are absent. Ultrasound can confirm the to prevent spinal cord compression. Acute herpes zoster diagnosis noninvasively. Treatment is with thrombolysis presents as acute posterior occipital or neck pain prior to or anticoagulation (with or without embolectomy) and the outbreak of vesicles. Neoplasms metastatic to the cervi- surgical excision of the cervical rib compressing the cal spine, infections (osteomyelitis and epidural abscess), and subclavian artery or vein. Disputed TOS includes a large metabolic bone diseases may be the cause of neck pain. Neck number of patients with chronic arm and shoulder pain pain may also be referred from the heart with coronary of unclear cause. The lack of sensitive and specific find- artery ischemia (cervical angina syndrome). ings on physical examination or laboratory markers for this condition frequently results in diagnostic uncer- THORACIC OUTLET tainty.The role of surgery in disputed TOS is controver- sial. Multidisciplinary pain management is a conservative The thoracic outlet contains the first rib, the subclavian approach, although treatment is often unsuccessful. artery and vein, the brachial plexus, the clavicle, and the

BRACHIAL PLEXUS AND NERVES improved neurologic function are reasonable goals. 85 Symptomatic treatment includes the use of analgesic Pain from injury to the brachial plexus or peripheral medications and/or a soft cervical collar. Most treatment CHAPTER 7 Back and Neck Pain nerves of the arm can occasionally mimic pain of cervi- recommendations reflect anecdotal experience, case cal spine origin. Neoplastic infiltration of the lower series, or conclusions derived from studies of the lumbar trunk of the brachial plexus may produce shoulder pain spine. Controlled studies of oral prednisone or trans- radiating down the arm, numbness of the fourth and foraminal glucocorticoid injections have not been per- fifth fingers, and weakness of intrinsic hand muscles formed. Reasonable indications for cervical disk surgery innervated by the ulnar and median nerves. Postradia- include a progressive radicular motor deficit, pain that tion fibrosis (most commonly from treatment of breast fails to respond to conservative management and limits cancer) may produce similar findings, although pain is activities of daily living, or cervical spinal cord compres- less often present. A Pancoast tumor of the lung is sion. Surgical management of herniated cervical disks another cause and should be considered, especially when usually consists of an anterior approach with diskec- a Horner’s syndrome is present. Suprascapular neuropathy tomy followed by anterior interbody fusion. A simple may produce severe shoulder pain, weakness, and wast- posterior partial laminectomy with diskectomy is an ing of the supraspinatous and infraspinatous muscles. acceptable alternative approach. Another surgical Acute brachial neuritis is often confused with radiculopa- approach involves implantation of an artificial disk; in thy; the acute onset of severe shoulder or scapular pain is one prospective trial, outcomes after 2 years favored the followed over days to weeks by weakness of the proxi- implant over a traditional anterior cervical discectomy mal arm and shoulder girdle muscles innervated by the with fusion. The artificial disk is not yet approved for upper brachial plexus.The onset is often preceded by an general use in the United States. The risk of subsequent infection.The suprascapular and long thoracic nerves are radiculopathy or myelopathy at cervical segments adja- most often affected; the latter results in a winged cent to the fusion is ~3% per year and 26% per decade. scapula. Brachial neuritis may also present as an isolated Although this risk is sometimes portrayed as a late com- paralysis of the diaphragm. Complete recovery occurs in plication of surgery, it may also reflect the natural his- 75% of patients after 2 years and in 89% after 3 years. tory of degenerative cervical disk disease. Occasional cases of carpal tunnel syndrome produce Nonprogressive cervical radiculopathy due to a her- pain and paresthesias extending into the forearm, arm, niated cervical disk may be treated conservatively, even and shoulder resembling a C5 or C6 root lesion. Lesions if a focal neurologic deficit is present, with a high rate of of the radial or ulnar nerve can mimic a radiculopathy at success. However, if the cervical radiculopathy is due to C7 or C8, respectively. EMG and nerve conduction bony compression from cervical spondylosis, then surgi- studies can accurately localize lesions to the nerve roots, cal decompression is generally indicated to forestall the brachial plexus, or peripheral nerves. For further discus- progression of neurologic signs. sion of peripheral nerve disorders, see Chap. 40. Cervical spondylotic myelopathy is typically man- SHOULDER aged with either anterior decompression and fusion or laminectomy in order to forestall progression of the Pain arising from the shoulder can on occasion mimic pain myelopathy known to occur in 20–30% of untreated from the spine. If symptoms and signs of radiculopathy are patients. However, one prospective study comparing absent, then the differential diagnosis includes mechanical surgery vs. conservative treatment for mild cervical shoulder pain (tendonitis, bursitis, rotator cuff tear, disloca- spondylotic myelopathy showed no difference in out- tion, adhesive capsulitis, and cuff impingement under the come after 2 years of follow-up. acromion) and referred pain (subdiaphragmatic irritation, angina, Pancoast tumor). Mechanical pain is often worse at FURTHER READINGS night, associated with local shoulder tenderness and aggra- vated by abduction, internal rotation, or extension of the BAGLEY LJ: Imaging of spinal trauma. Radiol Clin North Am 44:1, 2006 arm. Pain from shoulder disease may radiate into the arm BHANGLE SD et al: Back pain made simple: an approach based on or hand, but sensory, motor, and reflex changes are absent. principles and evidence. Cleve Clin J Med 76:393, 2009 Treatment: CASSIDY JD et al: Effect of eliminating compensation for pain and NECK PAIN suffering on the outcome of insurance claims for whiplash There are few well-designed clinical trials that address injury. N Engl J Med 342:1179, 2000 optimal treatment of neck pain or cervical radiculopa- CAVALIER R et al: Spondylolysis and spondylolisthesis in children and thy. Relief of pain, prevention of recurrence, and adolescents: Diagnosis, natural history, and non-surgical manage- ment. J Am Acad Orthop Surg 14:417, 2006 COWAN JA JR et al: Changes in the utilization of spinal fusion in the United States. Neurosurgery 59:1, 2006

86 DATTA S et al: Systematic assessment of diagnostic accuray and thera- VAN ALFEN N,VAN ENGELEN BG:The clinical spectrum of neuralgic amyotrophy in 246 cases. Brain 129:438, 2006 peutic utility of lumbar facet joint interventions. Pain Physician 12:437, 2009 WEINSTEIN JN et al: Surgical versus nonsurgical therapy for lumbar MUMMANENI PV et al: Clinical and radiographic analysis of cervi- spinal stenosis. N Engl J Med 358:794, 2008 cal disk arthroplasty compared with allograft fusion: A ran- domized controlled clinical trial. J Neurosurg Spine 6:198, __________ et al: Surgical versus nonsurgical treatment for lumbar 2007 degenerative spondylolisthesis. N Engl J Med 356:2257, 2007 PEUL WC et al: Surgery versus prolonged conservative treatment for sciatica. N Engl J Med 356:2245, 2007 __________ et al: Surgical vs nonoperative treatment for lumbar disc herniation. The spine patient outcomes research trial (SPORT): A randomized trial. JAMA 296:2441, 2006 SECTION II Clinical Manifestations of Neurologic Disease

CHAPTER 8 SYNCOPE Mark D. Carlson Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 I Causes of Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 Disorders of Vascular Tone or Blood Volume . . . . . . . . . . . . . . 88 I Cardiovascular Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Cerebrovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 I Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Anxiety Attacks and Hyperventilation Syndrome . . . . . . . . . . . 91 Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Hysterical Fainting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 Syncope, a transient loss of consciousness and postural tone renin-aldosterone-angiotensin system. Knowledge of due to reduced cerebral blood flow, is associated with spon- the processes is important to understanding the patho- taneous recovery. It may occur suddenly, without warning, physiology of syncope. Approximately three-fourths of or may be preceded by symptoms of faintness (“presyn- the systemic blood volume is contained in the venous cope”).These symptoms include lightheadedness, dizziness, bed, and any interference in venous return may lead to a feeling of warmth, diaphoresis, nausea, and visual blurring a reduction in cardiac output. Cerebral blood flow can occasionally proceeding to transient blindness. Presyncopal be maintained if cardiac output and systemic arterial symptoms vary in duration and may increase in severity vasoconstriction compensate, but when these adjust- until loss of consciousness occurs, or they may resolve prior ments fail, hypotension with resultant cerebral under- to loss of consciousness if the cerebral ischemia is cor- perfusion to less than half of normal results in syncope. rected. The differentiation of syncope from seizure is an Normally, the pooling of blood in the lower parts of important, sometimes difficult, diagnostic problem. the body is prevented by (1) pressor reflexes that Syncope may be benign when it occurs as a result of induce constriction of peripheral arterioles and venules, normal cardiovascular reflex effects on heart rate and (2) reflex acceleration of the heart by means of aortic vascular tone, or serious when due to a life-threatening and carotid reflexes, and (3) improvement of venous cardiac arrhythmia. Syncope may occur as a single event return to the heart by activity of the muscles of the or may be recurrent. Recurrent, unexplained syncope, limbs. Tilting a normal person upright on a tilt table particularly in an individual with structural heart disease, causes some blood to accumulate in the lower limbs is associated with a high risk of death (40% mortality and diminishes cardiac output slightly; this may be fol- within 2 years). lowed by a slight transitory fall in systolic blood pres- sure. However, in a patient with defective vasomotor PATHOPHYSIOLOGY reflexes, upright tilt may produce an abrupt and sustained fall in blood pressure, precipitating a faint. A recent Under normal circumstances systemic blood pressure is study suggests that susceptibility to neurally-mediated regulated by a complex process that includes the mus- syncope is driven partly by an enhanced vascular response culature, venous valves, autonomic nervous system, and to hypocapnia. 87

SECTION II Clinical Manifestations of Neurologic Disease88 CAUSES OF SYNCOPE TABLE 8-1 Transiently decreased cerebral blood flow is usually due CAUSES OF SYNCOPE to one of three general mechanisms: disorders of vascu- lar tone or blood volume, cardiovascular disorders I. Disorders of Vascular Tone or Blood Volume including obstructive lesions and cardiac arrhythmias, or A. Reflex syncopes cerebrovascular disease (Table 8-1). Not infrequently, 1. Neurocardiogenic however, the cause of syncope is multifactorial. 2. Situational Cough DISORDERS OF VASCULAR TONE OR Micturition BLOOD VOLUME Defecation Valsalva Disorders of vascular tone or blood volume that can Deglutition cause syncope include the reflex syncopes and a number 3. Carotid sinus hypersensitivity of conditions resulting in orthostatic intolerance. The B. Orthostatic hypotension reflex syncopes—including neurocardiogenic syncope, 1. Drug-induced (antihypertensive or vasodilator situational syncope, and carotid sinus hypersensitivity— drugs) share common autonomic nervous system pathophysio- 2. Pure autonomic failure (idiopathic orthostatic logic mechanisms: a cardioinhibitory component (e.g., hypotension) bradycardia due to increased vagal activity), a vasodepres- 3. Multisystem atrophies sor component (e.g., inappropriate vasodilatation due to 4. Peripheral neuropathy (diabetic, alcoholic, sympathetic withdrawal), or both. nutritional, amyloid) 5. Physical deconditioning Neurocardiogenic (Vasovagal and 6. Sympathectomy Vasodepressor) Syncope 7. Decreased blood volume The term neurocardiogenic is generally used to encompass II. Cardiovascular Disorders both vasovagal and vasodepressor syncope. Strictly speak- A. Structural and obstructive causes ing, vasovagal syncope is associated with both sympathetic 1. Pulmonary embolism withdrawal (vasodilatation) and increased parasympa- 2. Pulmonary hypertension thetic activity (bradycardia), whereas vasodepressor syn- 3. Atrial myxoma cope is associated with sympathetic withdrawal alone. 4. Mitral valvular stenosis 5. Myocardial disease (massive acute myocardial These forms of syncope are the common faint that infarction) may be experienced by normal persons; they account for 6. Left ventricular myocardial restriction or approximately half of all episodes of syncope. Neurocar- constriction diogenic syncope is frequently recurrent and commonly 7. Pericardial constriction or tamponade precipitated by a hot or crowded environment, alcohol, 8. Aortic outflow tract obstruction extreme fatigue, severe pain, hunger, prolonged standing, 9. Aortic valvular stenosis and emotional or stressful situations. Episodes are often 10. Hypertrophic obstructive cardiomyopathy preceded by a presyncopal prodrome lasting seconds to B. Cardiac arrhythmias minutes, and rarely occur in the supine position. The 1. Bradyarrhythmias individual is usually sitting or standing and experiences a. Sinus bradycardia, sinoatrial block, sinus weakness, nausea, diaphoresis, lightheadedness, blurred arrest, sick-sinus syndrome vision, and often a forceful heartbeat with tachycardia b. Atrioventricular block followed by cardiac slowing and decreasing blood pres- 2. Tachyarrhythmias sure prior to loss of consciousness.The individual appears a. Supraventricular tachycardia with structural pale or ashen; in dark-skinned individuals, the pallor may cardiovascular disease only be notable in the conjunctivae and lips. Patients b. Atrial fibrillation with the Wolff-Parkinson-White with a gradual onset of presyncopal symptoms have time syndrome to protect themselves against injury; in others, syncope c. Atrial flutter with 1:1 atrioventricular occurs suddenly, without warning. conduction d. Ventricular tachycardia The depth and duration of unconsciousness vary. Sometimes the patient remains partly aware of the sur- III. Cerebrovascular Disease roundings, or there may be complete unresponsiveness. A. Vertebrobasilar insufficiency The unconscious patient usually lies motionless, with B. Basilar artery migraine IV. Other Disorders that May Resemble Syncope A. Metabolic 1. Hypoxia 2. Anemia 3. Diminished carbon dioxide due to hyperventilation 4. Hypoglycemia B. Psychogenic 1. Anxiety attacks 2. Hysterical fainting C. Seizures

skeletal muscles relaxed, but a few clonic jerks of the and defecation are associated with maneuvers (such as 89 CHAPTER 8 Syncope limbs and face may occur. Sphincter control is usually Valsalva’s, straining, and coughing) that may contribute maintained, in contrast to a seizure. The pulse may be to hypotension and syncope by decreasing venous feeble or apparently absent, the blood pressure low or return. Increased intracranial pressure secondary to the undetectable, and breathing may be almost impercepti- increased intrathoracic pressure may also contribute by ble. The duration of unconsciousness is rarely longer decreasing cerebral blood flow. than a few minutes if the conditions that provoke the episode are reversed. Once the patient is placed in a Cough syncope typically occurs in men with chronic horizontal position, the strength of the pulse improves, bronchitis or chronic obstructive lung disease during or color begins to return to the face, breathing becomes after prolonged coughing fits. Micturition syncope quicker and deeper, and consciousness is restored. Some occurs predominantly in middle-aged and older men, patients may experience a sense of residual weakness particularly those with prostatic hypertrophy and after regaining consciousness, and rising too soon may obstruction of the bladder neck; loss of consciousness precipitate another faint. Unconsciousness may be pro- usually occurs at night during or immediately after longed if an individual remains upright; thus, it is essen- voiding. Deglutition syncope and defecation syncope tial that individuals with vasovagal syncope assume a occur in men and women. Deglutition syncope may be recumbent position as soon as possible. Although usually associated with esophageal disorders, particularly benign, neurocardiogenic syncope can be associated esophageal spasm. In some individuals, particular foods with prolonged asystole and hypotension, resulting in and carbonated or cold beverages initiate episodes by hypoxic-ischemic injury. activating esophageal sensory receptors that trigger reflex sinus bradycardia or atrioventricular (AV) block. Neurocardiogenic syncope often occurs in the setting Defecation syncope is probably secondary to Valsalva’s of increased peripheral sympathetic activity and venous maneuver in older individuals with constipation. pooling. Under these conditions, vigorous myocardial contraction of a relatively empty left ventricle is thought Carotid Sinus Hypersensitivity to activate myocardial mechanoreceptors and vagal affer- ent nerve fibers that inhibit sympathetic activity and Syncope due to carotid sinus hypersensitivity is precipi- increase parasympathetic activity.The resultant vasodilata- tated by pressure on the carotid sinus baroreceptors, tion and bradycardia induce hypotension and syncope. which are located just cephalad to the bifurcation of the Although the reflex involving myocardial mechanore- common carotid artery.This typically occurs in the setting ceptors is the mechanism usually accepted as responsible of shaving, a tight collar, or turning the head to one side. for neurocardiogenic syncope, other reflexes may also be Carotid sinus hypersensitivity occurs predominantly in operative. Patients with transplanted (denervated) hearts men Ն50 years. Activation of carotid sinus baroreceptors have experienced cardiovascular responses identical to gives rise to impulses carried via the nerve of Hering, a those present during neurocardiogenic syncope. This branch of the glossopharyngeal nerve, to the medulla in should not be possible if the response depends solely on the brainstem. These afferent impulses activate efferent the reflex mechanisms described above, unless the trans- sympathetic nerve fibers to the heart and blood vessels, planted heart has become reinnervated. Moreover, neu- cardiac vagal efferent nerve fibers, or both. In patients rocardiogenic syncope often occurs in response to stimuli with carotid sinus hypersensitivity, these responses may (fear, emotional stress, or pain) that may not be associated cause sinus arrest or AV block (a cardioinhibitory response), with venous pooling in the lower extremities, which vasodilatation (a vasodepressor response), or both (a mixed suggests a cerebral component to the reflex. response).The underlying mechanisms responsible for the carotid sinus hypersensitivity are not clear, and validated As distinct from the peripheral mechanisms, the cen- diagnostic criteria do not exist. tral nervous system (CNS) mechanisms responsible for neurocardiogenic syncope are uncertain, but a sudden Postural (Orthostatic) Hypotension surge in central serotonin levels may contribute to the sympathetic withdrawal. Endogenous opiates (endor- Orthostatic intolerance can result from hypovolemia or phins) and adenosine are also putative participants in the from disturbances in vascular control. The latter may pathogenesis. occur due to agents that affect the vasculature or due to primary or secondary abnormalities of autonomic con- Situational Syncope trol. Sudden rising from a recumbent position or stand- ing quietly are precipitating circumstances. Orthostatic A variety of activities, including cough, deglutition, mic- hypotension may be the cause of syncope in up to 30% of the turition, and defecation, are associated with syncope in elderly; polypharmacy with antihypertensive or antidepressant susceptible individuals. Like neurocardiogenic syncope, drugs is often a contributor in these patients. these syndromes may involve a cardioinhibitory response, a vasodepressor response, or both. Cough, micturition,

SECTION II Clinical Manifestations of Neurologic Disease90 Postural syncope may occur in otherwise normal per- especially if the person is in the supine position. As the sons with defective postural reflexes. Pure autonomic heart rate decreases, ventricular filling time and stroke failure (formerly called idiopathic postural hypotension) is volume increase to maintain normal cardiac output. At characterized by orthostatic hypotension, syncope and rates <30 beats/min, stroke volume can no longer near syncope, neurocardiogenic bladder, constipation, increase to compensate adequately for the decreased heat intolerance, inability to sweat, and erectile dysfunc- heart rate. At rates greater than ~180 beats/min, ventric- tion (Chap. 28). The disorder is more common in men ular filling time is inadequate to maintain adequate than women and typically begins between 50 and 75 years stroke volume. In either case, cerebral hypoperfusion and of age. syncope may occur. Upright posture; cerebrovascular Orthostatic hypotension, often accompanied by distur- disease; anemia; loss of atrioventricular synchrony; and bances in sweating, impotence, and sphincter difficulties, coronary, myocardial, or valvular disease all reduce the is also a primary feature of a variety or other autonomic tolerance to alterations in rate. nervous system disorders (Chap. 28). Among the most common causes of neurogenic orthostatic hypotension Bradyarrhythmias may occur as a result of an abnor- are chronic diseases of the peripheral nervous system mality of impulse generation (e.g., sinoatrial arrest) or that involve postganglionic unmyelinated fibers (e.g., impulse conduction (e.g., AV block). Either may cause diabetic, nutritional, and amyloid polyneuropathy). syncope if the escape pacemaker rate is insufficient to Much less common are the multiple system atrophies; maintain cardiac output. Syncope due to bradyarrhyth- these are CNS disorders in which orthostatic hypoten- mias may occur abruptly, without presyncopal symp- sion is associated with (1) parkinsonism (Shy-Drager toms, and recur several times daily. Patients with sick syndrome), (2) progressive cerebellar degeneration, or (3) sinus syndrome may have sinus pauses (>3 s), and those a more variable parkinsonian and cerebellar syndrome with syncope due to high-degree AV block (Stokes- (Chap. 28).A rare, acute postganglionic dysautonomia may Adams-Morgagni syndrome) may have evidence of con- represent a variant of Guillain-Barré syndrome (Chaps. 28 duction system disease (e.g., prolonged PR interval, and 41); a related disorder, autoimmune autonomic neu- bundle branch block). However, the arrhythmia is often ropathy, is associated with autoantibodies to the ganglionic transitory, and the surface electrocardiogram or continu- acetylcholine receptor. ous electrocardiographic monitor (Holter monitor) taken There are several additional causes of postural syn- later may not reveal the abnormality. The bradycardia- cope: (1) after physical deconditioning (such as after tachycardia syndrome is a common form of sinus node prolonged illness with recumbency, especially in elderly dysfunction in which syncope generally occurs as a individuals with reduced muscle tone) or after pro- result of marked sinus pauses, some following termina- longed weightlessness, as in space flight; (2) after sympa- tion of paroxysms of atrial tachyarrhythmias. Drugs thectomy that has abolished vasopressor reflexes; and (3) are a common cause for bradyarrhythmias, particularly in patients receiving antihypertensive or vasodilator drugs in patients with underlying structural heart disease. and those who are hypovolemic because of diuretics, Digoxin, β-adrenergic receptor antagonists, calcium chan- excessive sweating, diarrhea, vomiting, hemorrhage, or nel blockers, and many antiarrhythmic drugs may sup- adrenal insufficiency. press sinoatrial node impulse generation or slow AV nodal conduction. Glossopharyngeal Neuralgia Syncope due to a tachyarrhythmia is usually preceded Syncope due to glossopharyngeal neuralgia (Chap. 29) is by palpitation or lightheadedness but may occur abruptly preceded by pain in the oropharynx, tonsillar fossa, or with no warning symptoms. Supraventricular tach- tongue. Loss of consciousness is usually associated with yarrhythmias are unlikely to cause syncope in individu- asystole rather than vasodilatation. The mechanism is als with structurally normal hearts but may do so if thought to involve activation of afferent impulses in the they occur in patients with (1) heart disease that also glossopharyngeal nerve that terminate in the nucleus compromises cardiac output, (2) cerebrovascular dis- solitarius of the medulla and, via collaterals, activate the ease, (3) a disorder of vascular tone or blood volume, dorsal motor nucleus of the vagus nerve. or (4) a rapid ventricular rate. These tachycardias result most commonly from paroxysmal atrial flutter, atrial CARDIOVASCULAR DISORDERS fibrillation, or reentry involving the AV node or acces- sory pathways that bypass part or all of the AV conduc- Cardiac syncope results from a sudden reduction in car- tion system. Patients with Wolff-Parkinson-White syndrome diac output, caused most commonly by a cardiac arrhyth- may experience syncope when a very rapid ventricular mia. In normal individuals, heart rates between 30 and rate occurs due to reentry across an accessory AV 180 beats/min do not reduce cerebral blood flow, connection. In patients with structural heart disease, ventricular tachycardia is a common cause of syncope, particularly in those with a prior myocardial infarction. Patients with

aortic valvular stenosis and hypertrophic obstructive car- DIFFERENTIAL DIAGNOSIS 91 diomyopathy are also at risk for ventricular tachycardia. Individuals with abnormalities of ventricular repolariza- ANXIETY ATTACKS AND tion (prolongation of the QT interval) are at risk to HYPERVENTILATION SYNDROME develop polymorphic ventricular tachycardia (torsades des pointes). Those with the inherited form of this syn- Anxiety, such as occurs in panic attacks, is frequently CHAPTER 8 Syncope drome often have a family history of sudden death in interpreted as a feeling of faintness or dizziness resem- young individuals. Genetic markers can identify some bling presyncope. However, the symptoms are not patients with familial long-QT syndrome, but the clini- accompanied by facial pallor and are not relieved by cal utility of these markers remains unproven. Drugs recumbency. The diagnosis is made on the basis of the (i.e., certain antiarrhythmics and erythromycin) and associated symptoms such as a feeling of impending electrolyte disorders (i.e., hypokalemia, hypocalcemia, doom, air hunger, palpitations, and tingling of the fingers hypomagnesemia) can prolong the QT interval and pre- and perioral region. Attacks can often be reproduced dispose to torsades des pointes. Antiarrhythmic medica- by hyperventilation, resulting in hypocapnia, alkalosis, tions may precipitate ventricular tachycardia, particularly increased cerebrovascular resistance, and decreased cere- in patients with structural heart disease. bral blood flow. The release of epinephrine also con- tributes to the symptoms. In addition to arrhythmias, syncope may also occur with a variety of structural cardiovascular disorders. SEIZURES Episodes are usually precipitated when the cardiac out- put cannot increase to compensate adequately for A seizure may be heralded by an aura, which is caused peripheral vasodilatation. Peripheral vasodilatation may by a focal seizure discharge and hence has localizing be appropriate, such as following exercise, or may occur significance (Chap. 20). The aura is usually followed by due to inappropriate activation of left ventricular a rapid return to normal or by a loss of consciousness. mechanoreceptor reflexes, as occurs in aortic outflow Injury from falling is frequent in a seizure and rare in tract obstruction (aortic valvular stenosis or hyper- syncope, since only in generalized seizures are protective trophic obstructive cardiomyopathy). Obstruction to reflexes abolished instantaneously. Sustained tonic-clonic forward flow is the most common reason that cardiac movements are characteristic of convulsive seizures, but output cannot increase. Pericardial tamponade is a rare brief clonic, or tonic-clonic, seizure-like activity can cause of syncope. Syncope occurs in up to 10% of accompany fainting episodes. The period of uncon- patients with massive pulmonary embolism and may sciousness in seizures tends to be longer than in syn- occur with exertion in patients with severe primary pul- cope. Urinary incontinence is frequent in seizures and monary hypertension. The cause is an inability of the rare in syncope. The return of consciousness is prompt right ventricle to provide appropriate cardiac output in in syncope and slow after a seizure. Mental confusion, the presence of obstruction or increased pulmonary vascu- headache, and drowsiness are common sequelae of seizures, lar resistance. Loss of consciousness is usually accompanied whereas physical weakness with a clear sensorium char- by other symptoms such as chest pain and dyspnea. Atrial acterizes the postsyncopal state. Repeated spells of uncon- myxoma, a prosthetic valve thrombus, and, rarely, mitral sciousness in a young person at a rate of several per stenosis may impair left ventricular filling, decrease cardiac day or month are more suggestive of epilepsy than output, and cause syncope. syncope. See Table 20-7 for a comparison of seizures and syncope. CEREBROVASCULAR DISEASE HYPOGLYCEMIA Cerebrovascular disease alone rarely causes syncope but may lower the threshold for syncope in patients with Severe hypoglycemia is usually due to a serious disease other causes. The vertebrobasilar arteries, which supply such as a tumor of the islets of Langerhans or advanced brainstem structures responsible for maintaining con- adrenal, pituitary, or hepatic disease; or to excessive sciousness, are usually involved when cerebrovascular administration of insulin. diseases causes or contributes to syncope. An exception is the rare patient with tight bilateral carotid stenosis and HYSTERICAL FAINTING recurrent syncope, often precipitated by standing or walking. Most patients who experience lightheadedness The attack is usually unattended by an outward display or syncope due to cerebrovascular disease also have of anxiety. Lack of change in pulse and blood pressure or symptoms of focal neurologic ischemia, such as arm or color of the skin and mucous membranes distinguish it leg weakness, diplopia, ataxia, dysarthria, or sensory dis- from the vasodepressor faint. turbances. Basilar artery migraine is a rare disorder that causes syncope in adolescents.

SECTION II Clinical Manifestations of Neurologic Disease92 The physical examination should include evalua- tion of heart rate and blood pressure in the supine, Approach to the Patient: sitting, and standing positions. In patients with unex- plained recurrent syncope, an attempt to reproduce SYNCOPE an attack may assist in diagnosis. Anxiety attacks induced by hyperventilation can be reproduced read- The diagnosis of syncope is often challenging. The ily by having the patient breathe rapidly and deeply cause may be apparent only at the time of the event, for 2–3 min. Cough syncope may be reproduced by leaving few, if any, clues when the patient is seen later inducing the Valsalva’s maneuver. Carotid sinus mas- by the physician. The physician should think first of sage should generally be avoided, unless carotid ultra- those causes that constitute a therapeutic emergency, sound is negative for atheroma, because its diagnostic including massive internal hemorrhage or myocardial specificity is unknown and it may provoke a transient infarction, which may be painless, and cardiac arrhyth- ischemic attack (TIA) or stroke in individuals with mias. In elderly persons, a sudden faint, without obvi- carotid atheromas. ous cause, should arouse the suspicion of complete heart block or a tachyarrhythmia, even though all DIAGNOSTIC TESTS The choice of diagnostic findings are negative when the patient is seen. tests should be guided by the history and the physical examination. Measurements of serum electrolytes, Figure 8-1 depicts an algorithmic approach to syn- glucose, and the hematocrit are usually indicated. cope. A careful history is the most important diagnos- Cardiac enzymes should be evaluated if myocardial tic tool, both to suggest the correct cause and to ischemia is suspected. Blood and urine toxicology exclude important potential causes (Table 8-1). The screens may reveal the presence of alcohol or other nature of the events and their time course immedi- drugs. In patients with possible adrenocortical insuffi- ately prior to, during, and after an episode of syncope ciency, plasma aldosterone and mineralocorticoid often provide valuable etiologic clues. Loss of con- levels should be obtained. sciousness in particular situations, such as during venipuncture or micturition or with volume deple- Although the surface electrocardiogram is unlikely tion, suggests an abnormality of vascular tone. The to provide a definitive diagnosis, it may provide clues position of the patient at the time of the syncopal to the cause of syncope and should be performed in episode is important; syncope in the supine position is almost all patients. The presence of conduction abnor- unlikely to be vasovagal and suggests an arrhythmia or malities (PR prolongation and bundle branch block) a seizure. Syncope due to carotid sinus syndrome may suggests a bradyarrhythmia, whereas pathologic Q occur when the individual is wearing a shirt with a waves or prolongation of the QT interval suggests a tight collar, turning the head (turning to look while ventricular tachyarrhythmia. Inpatients should undergo driving in reverse), or manipulating the neck (as in continuous electrocardiographic monitoring; outpa- shaving). The patient’s medications must be noted, tients should wear a Holter monitor for 24–48 h. including nonprescription drugs or health store sup- Whenever possible, symptoms should be correlated plements, with particular attention to recent changes. with the occurrence of arrhythmias. Continuous elec- trocardiographic monitoring may establish the cause Syncope of syncope in as many as 15% of patients. Cardiac event monitors may be useful in patients with infre- Normal history History, physical Examination Review quent symptoms, particularly in patients with presyn- and physical exam, ECG reveals medication cope. An implantable event monitor may be necessary examination for patients with extremely infrequent episodes. The suggest cardiac orthostatic presence of a late potential on a signal-averaged elec- disease hypotension trocardiogram is associated with increased risk for ventricular tachyarrhythmias in patients with a prior Reflex Echocardiogram, Normal Abnormal myocardial infarction. Low-voltage (visually inapparent) syncope 24-h Holter neurologic neurologic T wave alternans is also associated with development of sustained ventricular arrhythmias. Tilt testing if monitor, stress test, exam exam severe or other cardiac Invasive cardiac electrophysiologic testing provides diag- recurrent Consider Peripheral nostic and prognostic information regarding sinus testing as indicated postganglionic neuropathy node function, AV conduction, and supraventricular (consider diabetic, and ventricular arrhythmias. Prolongation of the sinus autonomic nutritional, node recovery time (>1500 ms) is a specific finding insufficiency amyloid, etc.) Central nervous sytem findings Consider multiple system atrophy FIGURE 8-1 Approach to the patient with syncope.

(85–100%) for diagnosis of sinus node dysfunction arrhythmias. In some patients, cardiac catheterization 93 but has a low sensitivity; continuous electrocardio- may be necessary to diagnose the presence or severity graphic monitoring is usually more effective for diag- of coronary artery disease or valvular abnormalities. CHAPTER 8 Syncope nosing this abnormality. Prolongation of the HV Ultrafast CT scan, ventilation-perfusion scan, or pul- interval and conduction block below the His bundle monary angiography is indicated in patients in whom indicate that His-Purkinje disease may be responsible syncope may be due to pulmonary embolus. for syncope. Programmed stimulation for ventricular arrhythmias is most useful in patients who have expe- In cases of possible cerebrovascular syncope, neu- rienced a myocardial infarction; the sensitivity and roimaging tests may be indicated, including Doppler specificity of this technique is lower in patients with ultrasound studies of the carotid and vertebrobasilar normal hearts or those with heart disease other than systems, MRI, magnetic resonance angiography, and coronary artery disease. x-ray angiography of the cerebral vasculature (Chap. 2). Electroencephalography is indicated if seizures are Upright tilt table testing is indicated for recurrent syn- suspected. cope, a single syncopal episode that caused injury, or a single syncopal event in a “high-risk” setting (pilot, Treatment: commercial vehicle driver, etc.), whether or not there SYNCOPE is a history of preexisting heart disease or prior vaso- vagal episodes. In susceptible patients, upright tilt at an The treatment of syncope is directed at the underlying angle between 60° and 80° for 30–60 min induces a cause. This discussion will focus on disorders of auto- vasovagal episode. The protocol can be shortened if nomic control. Cerebrovascular disorders are discussed upright tilt is combined with administration of drugs in Chap. 21. that cause venous pooling or increase adrenergic stim- ulation (isoproterenol, nitroglycerin, edrophonium, or Certain precautions should be taken regardless of adenosine). The sensitivity and specificity of tilt-table the cause of syncope. At the first sign of symptoms, testing is difficult to ascertain because of the lack of patients should make every effort to avoid injury should validated criteria. Moreover, the reflexes responsible they lose consciousness. Patients with frequent for vasovagal syncope can be elicited in most, if not episodes, or those who have experienced syncope with- all, individuals given the appropriate stimulus. The out warning symptoms, should avoid situations in specificity of tilt-table testing has been reported to be which sudden loss of consciousness might result in near 90%, but it is lower when pharmacologic provo- injury (e.g., climbing ladders, swimming alone, operat- cation is employed.The reported sensitivity of the test ing heavy machinery, driving). Patients should lower ranges between 20 and 74%, the variability due to dif- their head to the extent possible and preferably should ferences in populations studied, techniques used, and lie down. Lowering the head by bending at the waist the absence of a true “gold standard” against which to should be avoided because it may further compromise compare test results. The reproducibility (in a time venous return to the heart. When appropriate, family ranging from several hours to weeks) is 80–90% for an members or other close contacts should be educated as initially positive response, but may be less for an ini- to the problem. This will ensure appropriate therapy tially negative response (ranging from 30 to 90%). and may prevent delivery of inappropriate therapy (chest compressions associated with cardiopulmonary A variety of other tests may be useful to determine resuscitation) that may inflict trauma. the presence of structural heart disease that may cause syncope. The echocardiogram with Doppler examina- Patients who have lost consciousness should be tion detects valvular, myocardial, and pericardial abnor- placed in a position that maximizes cerebral blood flow, malities.The echocardiogram is the “gold standard” for offers protection from trauma, and secures the airway. the diagnosis of hypertrophic cardiomyopathy and Whenever possible, the patient should be placed supine atrial myxoma. Cardiac cine MRI provides an alterna- with the head turned to the side to prevent aspiration tive noninvasive modality that may be useful for and the tongue from blocking the airway. Assessment patients in whom diagnostic-quality echocardiographic of the pulse and direct cardiac auscultation may assist images cannot be obtained. This test is also indicated in determining if the episode is associated with a brad- for patients suspected of having arrhythmogenic right yarrhythmia or a tachyarrhythmia. Clothing that fits ventricular dysplasia or right ventricular outflow tract tightly around the neck or waist should be loosened. ventricular tachycardia. Both are associated with right Peripheral stimulation, such as sprinkling cold water on ventricular structural abnormalities that are better visu- the face, may be helpful. Patients should not be given alized on MR imaging than by echocardiogram. Exer- cise testing may detect ischemia or exercise-induced

SECTION II Clinical Manifestations of Neurologic Disease94 anything by mouth or be permitted to rise until the Although several clinical trials have suggested that pharmacologic therapy for neurocardiogenic syncope is sense of physical weakness has passed. effective, the few long-term prospective randomized Patients with vasovagal syncope should be instructed controlled trials have yielded mixed results. In the Pre- vention of Syncope Trial (POST), metoprolol was ineffec- to avoid situations or stimuli that have caused them to tive in patients <42 years but decreased the incidence lose consciousness and to assume a recumbent position of syncope in patients >42 years, raising the possibility when premonitory symptoms occur. These behavioral that there may be significant age-related differences in modifications alone may be sufficient for patients with response to pharmacologic therapy. infrequent and relatively benign episodes of vasovagal syncope, particularly when loss of consciousness occurs Studies of permanent pacing for neurocardiogenic in response to a specific stimulus. Tilt training (standing syncope have also yielded mixed results. Dual-chamber and leaning against a wall for progressively longer peri- cardiac pacing may be effective for patients with fre- ods each day) has been used with limited success, par- quent episodes of vasovagal syncope, particularly for ticularly for patients with orthostatic intolerance. those with prolonged asystole associated with vasova- Episodes associated with intravascular volume deple- gal episodes. Pacemakers that can be programmed to tion may be prevented by salt and fluid loading prior to transiently pace at a high rate (90–100 beats/min) after provocative events. a profound drop in the patient’s intrinsic heart rate are most effective. Drug therapy may be necessary when vasovagal syn- cope is resistant to the above measures, when episodes Patients with orthostatic hypotension should be occur frequently, or when syncope is associated with a instructed to rise slowly and systematically (supine to significant risk for injury. β-Adrenergic receptor antago- seated, seated to standing) from the bed or a chair. nists (metoprolol, 25–50 mg bid; atenolol, 25–50 mg qd; Movement of the legs prior to rising facilitates venous or nadolol, 10–20 mg bid; all starting doses), the most return from the lower extremities. Whenever possible, widely used agents, mitigate the increase in myocardial medications that aggravate the problem (vasodilators, contractility that stimulates left ventricular mechanore- diuretics, etc.) should be discontinued. Elevation of the ceptors and also block central serotonin receptors. Sero- head of the bed [20–30 cm (8–12 in.)] and use of com- tonin reuptake inhibitors (paroxetine, 20–40 mg qd; or pression stockings may help. sertraline, 25–50 mg qd), appear to be effective for some patients. Bupropion SR (150 mg qd), another anti- Additional therapeutic modalities include salt load- depressant, has also been used with success. β-Adrener- ing and a variety of pharmacologic agents including gic receptor antagonists and serotonin reuptake sympathomimetic amines, monamine oxidase inhibitors, inhibitors are well tolerated and are often used as first- beta blockers, and levodopa. The treatment of orthosta- line agents for younger patients. Hydrofludrocortisone tic hypotension secondary to central or peripheral (0.1–0.2 mg qd), a mineralocorticoid, promotes sodium disorders of the autonomic nervous system is discussed retention, volume expansion, and peripheral vasocon- in Chap. 28. striction by increasing β-receptor sensitivity to endoge- nous catecholamines. Hydrofludrocortisone is useful for Glossopharyngeal neuralgia is treated with carba- patients with intravascular volume depletion and for mazepine, which is effective for syncope as well as for those who also have postural hypotension. Proamatine pain. Patients with carotid sinus hypersensitivity should (2.5–10 mg bid or tid), an α-agonist, has been used as a be instructed to avoid clothing and situations that first-line agent for some patients. In a randomized con- stimulate carotid sinus baroreceptors. They should turn trolled trial, proamatine was more effective than their entire body, rather than just their head, when look- placebo in preventing syncope during an upright tilt- ing to the side. Those with intractable syncope due test. However, in some patients, proamatine and to the cardioinhibitory response to carotid sinus hydrofludrocortisone may increase resting supine sys- stimulation should undergo permanent pacemaker temic blood pressure, which may be problematic for implantation. those with hypertension. Patients with syncope should be hospitalized when Disopyramide (150 mg bid), a vagolytic antiarrhyth- there is a possibility that the episode may have resulted mic drug with negative inotropic properties, and trans- from a life-threatening abnormality or if recurrence with dermal scopolamine, another vagolytic, have been used significant injury seems likely. These individuals should to treat vasovagal syncope, as have theophylline and be admitted to a bed with continuous electrocardio- ephedrine. Side effects associated with these drugs graphic monitoring. Patients who are known to have a have limited their use for this indication. Disopyramide normal heart and for whom the history strongly sug- is a type 1A antiarrhythmic drug and should be used gests vasovagal or situational syncope may be treated with great caution, if at all, in patients who are at risk for as outpatients if the episodes are neither frequent nor ventricular arrhythmias. severe.

FURTHER READINGS NORCLIFFE-KAUFMANN LJ et al: Enhanced vascular responses to 95 CHAPTER 8 Syncope BENDITT DG, NGUYEN JT: Syncope:Therapeutic approaches. J Am Coll hypocapnia in neurally mediated syncope.Ann Neurol 63:288, 2008 Cardiol. 53:1741, 2009 SOTERIADES E et al: Incidence and prognosis of syncope. N Engl J GRUBB BP: Neurocardiogenic syncope and related disorders of Med 347:878, 2002 orthostatic intolerance. Circulation 111:2997, 2005 STRICKBERGER SA et al: AHA/ACCF scientific statement on the ———, OLSHANSKY B (eds): Syncope: Mechanisms and Management, evaluation of syncope: From the American Heart Association 2d ed. Malden, Mass., Blackwell Futura, 2005 Councils on Clinical Cardiology, Cardiovascular Nursing, Car- diovascular Disease in the Young, and Stroke, and the Quality of KAPOOR WN: Current evaluation in management of syncope. Circu- Care and Outcomes Research Interdisciplinary Working Group; lation 106:1606, 2002 and the American College of Cardiology Foundation: In collab- oration with the Heart Rhythm Society: Endorsed by the Amer- KERR SRJ et al: Carotid sinus hypersensitivity in asymptomatic older ican Autonomic Society. Circulation 113(2):316, 2006 persons: Implications for diagnosis of syncope and falls. Arch VAN DIJK N et al: Quality of life within one year following presenta- Intern Med 166:515, 2006 tion after transient loss of consciousness. Am J Cardiol 100:672, 2007 MAISEL W, STEBENSON W: Syncope—getting to the heart of the matter. N Engl J Med 347:931, 2002

CHAPTER 9 DIZZINESS AND VERTIGO Robert B. Daroff Faintness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 Vertigo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 Miscellaneous Head Sensations . . . . . . . . . . . . . . . . . . . . . . . 99 Global Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 Dizziness is a common and often vexing symptom. FAINTNESS Patients use the term to encompass a variety of sensa- Prior to an actual faint (syncope), there are often pro- tions, including those that seem semantically appropriate dromal presyncopal symptoms (faintness) reflecting (e.g., lightheadedness, faintness, spinning, giddiness) and ischemia to a degree insufficient to impair conscious- those that are misleadingly inappropriate, such as mental ness. These include lightheadedness, “dizziness” without confusion, blurred vision, headache, or tingling. More- true vertigo, a feeling of warmth, diaphoresis, nausea, over, some individuals with gait disorders caused by and visual blurring occasionally proceeding to blindness. peripheral neuropathy, myelopathy, spasticity, parkinson- Presyncopal symptoms vary in duration and may ism, or cerebellar ataxia have complaint of “dizziness” increase in severity until loss of consciousness occurs or despite the absence of vertigo or other abnormal may resolve prior to loss of consciousness if the cerebral cephalic sensations. In this context, the term dizziness is ischemia is corrected. Faintness and syncope are dis- being used to describe disturbed ambulation.There may cussed in detail in Chap. 8. be mild associated lightheadedness, particularly with impaired sensation from the feet or poor vision; this is known as multiple-sensory-defect dizziness and occurs in VERTIGO elderly individuals who complain of dizziness only when walking. Decreased position sense (secondary to Vertigo is usually due to a disturbance in the vestibular neuropathy or myelopathy) and poor vision (from system. The end organs of this system, situated in the cataracts or retinal degeneration) create an overreliance bony labyrinths of the inner ears, consist of the three on the aging vestibular apparatus. A less precise but semicircular canals and the otolithic apparatus (utricle sometimes comforting designation to patients is benign and saccule) on each side. The canals transduce angular dysequilibrium of aging.Thus, a careful history is necessary acceleration, while the otoliths transduce linear accelera- to determine exactly what a patient who states,“Doctor, tion and the static gravitational forces that provide a I’m dizzy,” is experiencing. After eliminating the mis- sense of head position in space.The neural output of the leading symptoms or gait disturbance, “dizziness” usually end organs is conveyed to the vestibular nuclei in the means either faintness (presyncope) or vertigo (an illusory brainstem via the eighth cranial nerves. The principal or hallucinatory sense of movement of the body or projections from the vestibular nuclei are to the nuclei of environment, most often a feeling of spinning). Opera- cranial nerves III, IV, and VI; spinal cord; cerebral cortex; tionally, after obtaining the history, dizziness may be and cerebellum.The vestibuloocular reflex (VOR) serves classified into three categories: (1) faintness, (2) vertigo, to maintain visual stability during head movement and and (3) miscellaneous head sensations. depends on direct projections from the vestibular nuclei 96

to the sixth cranial nerve (abducens) nuclei in the pons associated with jerk nystagmus and is frequently accom- 97 CHAPTER 9 Dizziness and Vertigo and, via the medial longitudinal fasciculus, to the third panied by nausea, postural unsteadiness, and gait ataxia. (oculomotor) and fourth (trochlear) cranial nerve nuclei Since vertigo increases with rapid head movements, in the midbrain. These connections account for the nys- patients tend to hold their heads still. tagmus (to-and-fro oscillation of the eyes) that is an almost invariable accompaniment of vestibular dysfunction. The Labyrinthine Dysfunction vestibular nerves and nuclei project to areas of the cerebel- This causes severe rotational or linear vertigo.When rota- lum (primarily the flocculus and nodulus) that modulate tional, the hallucination of movement, whether of envi- the VOR. The vestibulospinal pathways assist in the ronment or self, is directed away from the side of the maintenance of postural stability. Projections to the cere- lesion. The fast phases of nystagmus beat away from the bral cortex, via the thalamus, provide conscious awareness lesion side, and the tendency to fall is toward the side of of head position and movement. the lesion, particularly in darkness or with the eyes closed. The vestibular system is one of three sensory systems Under normal circumstances, when the head is straight subserving spatial orientation and posture; the other two and immobile, the vestibular end organs generate a tonic are the visual system (retina to occipital cortex) and the resting firing frequency that is equal from the two sides. somatosensory system that conveys peripheral informa- With any rotational acceleration, the anatomic positions tion from skin, joint, and muscle receptors.The three sta- of the semicircular canals on each side necessitate an bilizing systems overlap sufficiently to compensate (partially increased firing rate from one and a commensurate or completely) for each other’s deficiencies.Vertigo may decrease from the other.This change in neural activity is represent either physiologic stimulation or pathologic ultimately projected to the cerebral cortex, where it is dysfunction in any of the three sensory systems. summed with inputs from the visual and somatosensory systems to produce the appropriate conscious sense of Physiologic Vertigo rotational movement. After cessation of prolonged rota- tion, the firing frequencies of the two end organs This occurs in normal individuals when (1) the brain is reverse; the side with the initially increased rate decreases, confronted with an intersensory mismatch among the and the other side increases. A sense of rotation in the three stabilizing sensory systems; (2) the vestibular sys- opposite direction is experienced; since there is no tem is subjected to unfamiliar head movements to actual head movement, this hallucinatory sensation is which it is unadapted, such as in seasickness; (3) unusual physiologic postrotational vertigo. head/neck positions, such as the extreme extension when painting a ceiling; or (4) following a spin. Inter- Any disease state that changes the firing frequency of sensory mismatch explains carsickness, height vertigo, an end organ, producing unequal neural input to the and the visual vertigo most commonly experienced dur- brainstem and ultimately the cerebral cortex, causes ver- ing motion picture chase scenes; in the latter, the visual tigo. The symptom can be conceptualized as the cortex sensation of environmental movement is unaccompa- inappropriately interpreting the abnormal neural input nied by concomitant vestibular and somatosensory as indicating actual head rotation. Transient abnormali- movement cues. Space sickness, a frequent transient effect ties produce short-lived symptoms. With a fixed unilat- of active head movement in the weightless zero-gravity eral deficit, central compensatory mechanisms ultimately environment, is another example of physiologic vertigo. diminish the vertigo. Since compensation depends on the plasticity of connections between the vestibular Pathologic Vertigo nuclei and the cerebellum, patients with brainstem or cerebellar disease have diminished adaptive capacity, and This results from lesions of the visual, somatosensory, or symptoms may persist indefinitely. Compensation is vestibular systems. Visual vertigo is caused by new or always inadequate for severe fixed bilateral lesions incorrect eyeglasses or by the sudden onset of an despite normal cerebellar connections; these patients are extraocular muscle paresis with diplopia; in either permanently symptomatic when they move their heads. instance, central nervous system (CNS) compensation rapidly counteracts the vertigo. Somatosensory vertigo, Acute unilateral labyrinthine dysfunction is caused by rare in isolation, is usually due to a peripheral neuropa- infection, trauma, and ischemia. Often, no specific etiol- thy or myelopathy that reduces the sensory input neces- ogy is uncovered, and the nonspecific terms acute sary for central compensation when there is dysfunction labyrinthitis, acute peripheral vestibulopathy, or vestibular neu- of the vestibular or visual systems. ritis are used to describe the event. The vertiginous attacks are brief and leave the patient with mild vertigo The most common cause of pathologic vertigo is for several days. Infection with herpes simplex virus type vestibular dysfunction involving either its end organ 1 has been implicated. It is impossible to predict (labyrinth), nerve, or central connections. The vertigo is whether a patient recovering from the first bout of ver- tigo will have recurrent episodes.

SECTION II Clinical Manifestations of Neurologic Disease98 Labyrinthine ischemia, presumably due to occlusion the vertical nystagmus in the upper eye increases in of the labyrinthine branch of the internal auditory amplitude. Mild dysequilibrium when upright may also artery, may be the sole manifestation of vertebrobasilar be present. insufficiency (Chap. 21); patients with this syndrome present with the abrupt onset of severe vertigo, nausea, A perilymphatic fistula should be suspected when and vomiting, but without tinnitus or hearing loss. episodic vertigo is precipitated by Valsalva or exertion, Acute bilateral labyrinthine dysfunction is usually the particularly upon a background of a stepwise progressive result of toxins such as drugs or alcohol.The most com- sensory-neural hearing loss. The condition is usually mon offending drugs are the aminoglycoside antibiotics caused by head trauma or barotrauma or occurs after that damage the hair cells of the vestibular end organs middle ear surgery. and may cause a permanent disorder of equilibrium. Recurrent unilateral labyrinthine dysfunction, in associa- Vertigo of Vestibular Nerve Origin tion with signs and symptoms of cochlear disease (pro- This occurs with diseases that involve the nerve in the gressive hearing loss and tinnitus), is usually due to petrous bone or the cerebellopontine angle. Although Ménière’s disease (Chap. 18). When auditory manifesta- less severe and less frequently paroxysmal, it has many of tions are absent, the term vestibular neuronitis denotes the characteristics of labyrinthine vertigo. The adjacent recurrent monosymptomatic vertigo. Transient ischemic auditory division of the eighth cranial nerve is usually attacks of the posterior cerebral circulation (verte- affected, which explains the frequent association of ver- brobasilar insufficiency) only infrequently cause recur- tigo with unilateral tinnitus and hearing loss. The most rent vertigo without concomitant motor, sensory, visual, common cause of eighth cranial nerve dysfunction is a cranial nerve, or cerebellar signs (Chap. 21). tumor, usually a schwannoma (acoustic neuroma) or a Positional vertigo is precipitated by a recumbent head meningioma. These tumors grow slowly and produce position, either to the right or to the left. Benign parox- such a gradual reduction of labyrinthine output that ysmal positional (or positioning) vertigo (BPPV) of the central compensatory mechanisms can prevent or mini- posterior semicircular canal is particularly common. mize the vertigo; auditory symptoms are the most com- Although the condition may be due to head trauma, mon manifestations. usually no precipitating factors are identified. It generally abates spontaneously after weeks or months. The vertigo Central Vertigo and accompanying nystagmus have a distinct pattern of Lesions of the brainstem or cerebellum can cause acute latency, fatigability, and habituation that differs from the vertigo, but associated signs and symptoms usually permit less common central positional vertigo (Table 9-1) due distinction from a labyrinthine etiology (Table 9-2). to lesions in and around the fourth ventricle. Moreover, Occasionally, an acute lesion of the vestibulocerebellum the pattern of nystagmus in posterior canal BPPV is dis- may present with monosymptomatic vertigo indistin- tinctive. When supine, with the head turned to the side guishable from a labyrinthopathy. of the offending ear (bad ear down), the lower eye dis- plays a large-amplitude torsional nystagmus, and the upper Vertigo may be a manifestation of a migraine aura eye has a lesser degree of torsion combined with upbeat- (Chap. 6), but some patients with migraine have ing nystagmus. If the eyes are directed to the upper ear, episodes of vertigo unassociated with their headaches. Antimigrainous treatment should be considered in such TABLE 9-1 patients with otherwise enigmatic vertiginous episodes. BENIGN PAROXYSMAL POSITIONAL VERTIGO AND Vestibular epilepsy, vertigo secondary to temporal lobe CENTRAL POSITIONAL VERTIGO epileptic activity, is rare and almost always intermixed with other epileptic manifestations. FEATURES BPPV CENTRAL Psychogenic Vertigo Latencya 3–40 s None: immediate This is sometimes called phobic postural vertigo and is vertigo and nystagmus usually a concomitant of panic attacks (Chap. 49) or Fatigabilityb Yes No agoraphobia (fear of large open spaces, crowds, or leav- Habituationc Yes No ing the safety of home). It should be suspected in Intensity of vertigo Severe Mild patients so “incapacitated” by their symptoms that they Reproducibilityd Variable Good adopt a prolonged housebound status. Most patients with organic vertigo attempt to function despite their aTime between attaining head position and onset of symptoms. discomfort. Organic vertigo is accompanied by nystag- bDisappearance of symptoms with maintenance of offending posi- mus; a psychogenic etiology is almost certain when nys- tagmus is absent during a vertiginous episode. The tion. symptoms often develop after an episode of acute cLessening of symptoms with repeated trials. labyrinthine dysfunction. dLikelihood of symptom production during any examination session.

TABLE 9-2 99 FEATURES OF PERIPHERAL AND CENTRAL VERTIGO CENTRAL (BRAINSTEM SIGN OR SYMPTOM PERIPHERAL (LABYRINTH) OR CEREBELLUM) CHAPTER 9 Dizziness and Vertigo Unidirectional; fast phase opposite lesiona Direction of associated nystagmus Uncommon Bidirectional or unidirectional Purely horizontal nystagmus without Common Never present torsional component May be present Vertical or purely torsional Inhibits nystagmus and vertigo Marked No inhibition nystagmus Toward fast phase Often mild Visual fixation Toward slow phase Variable Severity of vertigo Finite (minutes, days, weeks) but recurrent Variable Direction of spin Often present May be chronic Direction of fall Usually absent Duration of symptoms None Tinnitus and/or Extremely common (e.g., diplopia, BPPV, infection (labyrinthitis), Ménière’s, hiccups, cranial neuropathies, deafness neuronitis, ischemia, trauma, toxin dysarthria) Associated CNS Vascular, demyelinating, abnormalities neoplasm Common causes aIn Ménière’s disease, the direction of the fast phase is variable. MISCELLANEOUS HEAD SENSATIONS simulate either cephalic ischemia or vestibular dys- function. Cephalic ischemia is obvious if the dizziness This designation is used, primarily for purposes of initial is duplicated during maneuvers that produce ortho- classification, to describe dizziness that is neither faint- static hypotension. Further provocation involves the ness nor vertigo. Cephalic ischemia or vestibular dys- Valsalva maneuver, which decreases cerebral blood function may be of such low intensity that the usual flow and should reproduce ischemic symptoms. symptomatology is not clearly identified. For example, a small decrease in blood pressure or a slight vestibular Hyperventilation is the cause of dizziness in many imbalance may cause sensations different from distinct anxious individuals; tingling of the hands and face faintness or vertigo but that may be identified properly may be absent. Forced hyperventilation for 1 min is by provocative testing techniques (see below). Other indicated for patients with enigmatic dizziness and causes of dizziness in this category are hyperventilation normal neurologic examinations. syndrome, hypoglycemia, and the somatic symptoms of a clinical depression; these patients should all have normal The simplest provocative test for vestibular dys- neurologic examinations and vestibular function tests. function is rapid rotation and abrupt cessation of Depressed patients often insist that the depression is movement in a swivel chair. This always induces ver- “secondary” to the dizziness. tigo that the patients can compare with their sympto- matic dizziness. The intense induced vertigo may be Approach to the Patient: unlike the spontaneous symptoms, but shortly there- DIZZINESS AND VERTIGO after, when the vertigo has all but subsided, a light- headedness supervenes that may be identified as “my The most important diagnostic tool is a detailed history dizziness.” When this occurs, the dizzy patient, origi- focused on the meaning of “dizziness” to the patient. Is nally classified as suffering from “miscellaneous head it faintness (presyncope)? Is there a sensation of spin- sensations,” is now properly diagnosed as having mild ning? If either of these is affirmed and the neurologic vertigo secondary to a vestibulopathy. examination is normal, appropriate investigations for the multiple causes of cephalic ischemia, presyncope Patients with symptoms of positional vertigo should (Chap. 8), or vestibular dysfunction are undertaken. be appropriately tested (Table 9-1). A final provoca- tive and diagnostic vestibular test, requiring the use of When the meaning of “dizziness” is uncertain, Frenzel eyeglasses (self-illuminated goggles with con- provocative tests may be helpful.These office procedures vex lenses that blur out the patient’s vision, but allow the examiner to see the eyes greatly magnified), is vigorous head shaking in the horizontal plane for

100 about 10 s. If nystagmus develops after the shaking TABLE 9-3 stops, even in the absence of vertigo, vestibular dys- TREATMENT OF VERTIGO function is demonstrated. The maneuver can then be repeated in the vertical plane. If the provocative tests AGENTa DOSEb establish the dizziness as a vestibular symptom, an evaluation of vestibular vertigo is undertaken. Antihistamines EVALUATION OF PATIENTS WITH PATHO- Meclizine 25–50 mg 3 times/day LOGIC VESTIBULAR VERTIGO The evaluation Dimenhydrinate 50 mg 1–2 times/day depends on whether a central etiology is suspected (Table 9-2). If so, MRI of the head is mandatory. Such Promethazinec 25–50-mg suppository an examination is rarely helpful in cases of recurrent monosymptomatic vertigo with a normal neurologic or IM examination. Typical BPPV requires no investigation SECTION II Clinical Manifestations of Neurologic Disease after the diagnosis is made (Table 9-1). Benzodiazepines Vestibular function tests serve to (1) demonstrate an Diazepam 2.5 mg 1–3 times/day abnormality when the distinction between organic and psychogenic is uncertain, (2) establish the side of Clonazepam 0.25 mg 1–3 times/day the abnormality, and (3) distinguish between peripheral and central etiologies. The standard test is electronys- Phenothiazines tagmography (calorics), where warm and cold water (or air) are applied, in a prescribed fashion, to the Prochlorperazinec 5 mg IM or 25 mg tympanic membranes, and the slow-phase velocities of the resultant nystagmus from the two are com- suppository pared. A velocity decrease from one side indicates hypofunction (“canal paresis”). An inability to induce Anticholinergicd nystagmus with ice water denotes a “dead labyrinth.” Some institutions have the capability of quantitatively Scopolamine transdermal Patch determining various aspects of the VOR using com- puter-driven rotational chairs and precise oculo- Sympathomimeticsd graphic recording of the eye movements. Ephedrine 25 mg/d CNS disease can produce dizzy sensations of all types. Consequently, a neurologic examination is always Combination preparationsd required even if the history or provocative tests suggest a cardiac, peripheral vestibular, or psychogenic etiology. Ephedrine and promethazine 25 mg/d of each Any abnormality on the neurologic examination should prompt appropriate neurodiagnostic studies. Exercise therapy Repositioning maneuverse Vestibular rehabilitationf Other Diuretics or low-salt (1 g/d) dietg Antimigrainous drugsh Inner ear surgeryi Prednisonec 100 mg/d for 3 days, tapered by 20 mg every 3 days aAll listed drugs are U.S. Food and Drug Administration approved, but most are not approved for the treatment of vertigo. bUsual oral (unless otherwise stated) starting dose in adults; mainte- nance dose can be reached by a gradual increase. cFor acute vertigo only. dFor motion sickness only. eFor benign paroxysmal positional vertigo. fFor vertigo other than Ménière’s and positional. gFor Ménière’s disease. hFor migraine-associated vertigo (see Chap. 6 for a listing of prophy- lactic antimigrainous drugs). iFor perilymphatic fistula and refractory cases of Ménière’s disease. Treatment: Posterior semicircular canal BPPV, the most common VERTIGO type, is often self-limited but, when persistent, may respond dramatically to specific repositioning exercise Treatment of acute vertigo consists of bed rest (1–2 days programs designed to empty particulate debris from maximum) and vestibular suppressant drugs such as the canal. One of these exercises, the Epley procedure, is antihistaminics (meclizine, dimenhydrinate, promet- graphically demonstrated, in four languages, on a website hazine), tranquilizers with GABA-ergic effects (diazepam, for use in both physicians’ offices and self-treatment: clonazepam), phenothiazines (prochlorperazine), or glu- www.charite.de/ch/neuro/vertigo.html cocorticoids (Table 9-3). If the vertigo persists beyond a few days, most authorities advise ambulation in an Prophylactic measures to prevent recurrent vertigo attempt to induce central compensatory mechanisms, are variably effective. Antihistamines are commonly uti- despite the short-term discomfort to the patient. lized but are of limited value. Ménière’s disease may Chronic vertigo of labyrinthine origin may be treated respond to a diuretic or, more effectively, to a very low with a systematized vestibular rehabilitation program to salt diet (1 g/d). Recurrent episodes of migraine-associ- facilitate central compensation. ated vertigo should be treated with antimigrainous

therapy (Chap. 6). There are a variety of inner ear surgi- number of reports of horizontal (lateral) BPPV from 101 CHAPTER 9 Dizziness and Vertigo cal procedures for refractory Ménière’s disease, but Italy and Korea. these are only rarely necessary. FURTHER READINGS Psychogenic (“phobic postural”) vertigo is best treated with cognitive-behavioral therapy. FIFE TD et al: Practice parameter: Therapies for benign paroxysmal positional vertigo (an evidence-based review). Neurology Helpful websites for both physicians and vertigo 70:2067, 2008 patients: www.iVertigo.net and www.tchain.com. HALMAGI GM: Diagnosis and management of vertigo. Clin Med GLOBAL CONSIDERATIONS 5:159, 2005 There are no epidemiologic studies indicating an LEIGH RJ, ZEE DS: Neurology of Eye Movement, 4th ed. New York, increased frequency of specific types of vertigo Oxford, 2006, 76–79; 559–597 in different geographical areas. However, whereas BPPV of the posterior semicircular canal is overwhelm- SAJJADI H, PAPARELLA MM: Meniere’s disease. Lancet 372:406, 2008 ingly the most common form of positional vertigo in STRUPP M et al: Methylprednisolone, valacyclovir, or the combina- most countries, there seems to be an unusually large tion for vestibular neuritis. N Engl J Med 351:354, 2004 ———, BRANDT T: Pharmacological advances in the treatment of neuro-otological and eye movement disorders. Curr Opin Neu- rol 19:33, 2006 ZINGLER VC et al: Causative factors and epidemiology of bilateral vestibulopathy in 255 patients.Ann Neurol 61:524, 2007

CHAPTER 10 WEAKNESS AND PARALYSIS Michael J. Aminoff Normal motor function involves integrated muscle weakness generally produce spasticity, an increase in tone activity that is modulated by the activity of the cerebral associated with disease of upper motor neurons. Spastic- cortex, basal ganglia, cerebellum, and spinal cord. Motor ity is velocity-dependent, has a sudden release after system dysfunction leads to weakness or paralysis, which reaching a maximum (the “clasp-knife” phenomenon), is discussed in this chapter, or to ataxia (Chap. 26) or and predominantly affects the antigravity muscles (i.e., abnormal movements (Chaps. 24 and 25). The mode of upper-limb flexors and lower-limb extensors). Spasticity onset, distribution, and accompaniments of weakness is distinct from rigidity and paratonia, two other types of help to suggest its cause. hypertonia. Rigidity is increased tone that is present throughout the range of motion (a “lead pipe” or “plas- Weakness is a reduction in the power that can be tic” stiffness) and affects flexors and extensors equally; it exerted by one or more muscles. Increased fatigability sometimes has a cogwheel quality that is enhanced by or limitation in function due to pain or articular stiff- voluntary movement of the contralateral limb (rein- ness is often confused with weakness by patients. forcement). Rigidity occurs with certain extrapyramidal Increased fatigability is the inability to sustain the perfor- disorders such as Parkinson’s disease. Paratonia (or gegen- mance of an activity that should be normal for a person halten) is increased tone that varies irregularly in a man- of the same age, gender, and size. Increased time is ner that may seem related to the degree of relaxation, is sometimes required for full power to be exerted, and present throughout the range of motion, and affects this bradykinesia may be misinterpreted as weakness. flexors and extensors equally; it usually results from dis- Severe proprioceptive sensory loss may also lead to ease of the frontal lobes. Weakness with decreased tone complaints of weakness because adequate feedback (flaccidity) or normal tone occurs with disorders of motor information about the direction and power of move- units. A motor unit consists of a single lower motor neu- ments is lacking. Finally, apraxia, a disorder of planning ron and all of the muscle fibers that it innervates. and initiating a skilled or learned movement unrelated to a significant motor or sensory deficit (Chap. 15), is Muscle bulk is generally unaffected in patients with sometimes mistaken for weakness by inexperienced upper motor neuron lesions, although mild disuse atro- medical staff. phy may eventually occur. By contrast, atrophy is often conspicuous when a lower motor neuron lesion is Paralysis indicates weakness that is so severe that the responsible for weakness and may also occur with muscle cannot be contracted at all, whereas paresis refers advanced muscle disease. to weakness that is mild or moderate.The prefix “hemi- ” refers to one half of the body, “para-” to both legs, and Muscle stretch (tendon) reflexes are usually increased “quadri-” to all four limbs. The suffix “-plegia” signifies with upper motor neuron lesions, although they may be severe weakness or paralysis. decreased or absent for a variable period immediately after onset of an acute lesion. This is usually—but not Weakness or paralysis is typically accompanied by invariably—accompanied by abnormalities of cutaneous other neurologic abnormalities that help to indicate the reflexes (such as superficial abdominals; Chap. 1) and, in site of the responsible lesion. These include changes in particular, by an extensor plantar (Babinski) response. tone, muscle bulk, muscle stretch reflexes, and cutaneous The muscle stretch reflexes are depressed in patients reflexes (Table 10-1). with lower motor neuron lesions when there is direct involvement of specific reflex arcs. The stretch reflexes Tone is the resistance of a muscle to passive stretch. Central nervous system (CNS) abnormalities that cause 102

TABLE 10-1 103 SIGNS THAT DISTINGUISH ORIGIN OF WEAKNESS SIGN UPPER MOTOR NEURON LOWER MOTOR NEURON MYOPATHIC CHAPTER 10 Weakness and Paralysis Atrophy None Severe Mild Fasciculations None Common None Tone Spastic Decreased Normal/decreased Distribution of Pyramidal/regional Distal/segmental Proximal weakness Hyperactive Hypoactive/absent Normal/hypoactive Tendon reflexes Present Absent Absent Babinski’s sign are generally preserved in patients with myopathic Lower Motor Neuron Weakness weakness except in advanced stages, when they are sometimes attenuated. In disorders of the neuromuscular This pattern results from disorders of cell bodies of junction, the intensity of the reflexes may be affected by lower motor neurons in the brainstem motor nuclei and preceding voluntary activity of affected muscles—such the anterior horn of the spinal cord, or from dysfunction activity may lead to enhancement of initially depressed of the axons of these neurons as they pass to skeletal reflexes in Lambert-Eaton myasthenic syndrome and, muscle (Fig. 10-2).Weakness is due to a decrease in the conversely, to depression of initially normal reflexes in number of muscle fibers that can be activated, through a myasthenia gravis (Chap. 42). loss of γ motor neurons or disruption of their connec- tions to muscle. Loss of γ motor neurons does not cause The distinction of neuropathic (lower motor neuron) weakness but decreases tension on the muscle spindles, from myopathic weakness is sometimes difficult clinically, which decreases muscle tone and attenuates the stretch although distal weakness is likely to be neuropathic and reflexes elicited on examination. An absent stretch reflex symmetric proximal weakness myopathic. Fasciculations suggests involvement of spindle afferent fibers. (visible or palpable twitch within a muscle due to the spontaneous discharge of a motor unit) and early atro- When a motor unit becomes diseased, especially in phy indicate that weakness is neuropathic. anterior horn cell diseases, it may spontaneously dis- charge, producing fasciculations that may be seen or felt PATHOGENESIS clinically or recorded by electromyography (EMG). When α motor neurons or their axons degenerate, the Upper Motor Neuron Weakness denervated muscle fibers may also discharge sponta- neously. These single muscle fiber discharges, or fibrilla- This pattern of weakness results from disorders that affect tion potentials, cannot be seen or felt but can be recorded the upper motor neurons or their axons in the cerebral with EMG. If lower motor neuron weakness is present, cortex, subcortical white matter, internal capsule, brain- recruitment of motor units is delayed or reduced, with stem, or spinal cord (Fig. 10-1). Such lesions produce fewer than normal activated at a given discharge fre- weakness through decreased activation of the lower quency. This contrasts with weakness of upper motor motor neurons. In general, distal muscle groups are neuron type, in which a normal number of motor units affected more severely than proximal ones, and axial is activated at a given frequency but with a diminished movements are spared unless the lesion is severe and maximal discharge frequency. bilateral. With corticobulbar involvement, weakness is usually observed only in the lower face and tongue; Myopathic Weakness extraocular, upper facial, pharyngeal, and jaw muscles are almost always spared.With bilateral corticobulbar lesions, Myopathic weakness is produced by disorders of the pseudobulbar palsy often develops: dysarthria, dysphagia, muscle fibers. Disorders of the neuromuscular junctions dysphonia, and emotional lability accompany bilateral also produce weakness, but this is variable in degree and facial weakness and a brisk jaw jerk. Spasticity accompa- distribution and is influenced by preceding activity of nies upper motor neuron weakness but may not be pre- the affected muscle.At a muscle fiber, if the nerve termi- sent in the acute phase. Upper motor neuron lesions also nal releases a normal number of acetylcholine molecules affect the ability to perform rapid repetitive movements. presynaptically and a sufficient number of postsynaptic Such movements are slow and coarse, but normal rhyth- acetylcholine receptors are opened, the end plate micity is maintained. Finger-nose-finger and heel-knee- reaches threshold and thereby generates an action shin maneuvers are performed slowly but adequately. potential that spreads across the muscle fiber membrane

104 Corticospinal Hip ShoulTrduernk tract Knee ThFiunmgbWerErilssbtow Ankle Toes Neck Brow Eyelid Nares Lips Tongue Larynx SECTION II Clinical Manifestations of Neurologic Disease Red nucleus Rubrospinal tract Reticular nuclei Vestibular nuclei Lateral corticospinal Vestibulospinal tract tract Reticulospinal tract Ventromedial Lateral bulbospinal corticospinal tract tracts Rubrospinal FIGURE10-1 (ventrolateral) The corticospinal and bulbospinal upper motor neuron tract pathways. Upper motor neurons have their cell bodies in layer V of the primary motor cortex (the precentral gyrus, or are involved in the execution of learned, fine movements. Brodmann’s area 4) and in the premotor and supplemental Corticobulbar neurons are similar to corticospinal neurons motor cortex (area 6). The upper motor neurons in the primary but innervate brainstem motor nuclei. motor cortex are somatotopically organized as illustrated on the right side of the figure. Bulbospinal upper motor neurons influence strength and tone but are not part of the pyramidal system. The Axons of the upper motor neurons descend through the descending ventromedial bulbospinal pathways originate in subcortical white matter and the posterior limb of the internal the tectum of the midbrain (tectospinal pathway), the capsule. Axons of the pyramidal or corticospinal system vestibular nuclei (vestibulospinal pathway), and the reticular descend through the brainstem in the cerebral peduncle of formation (reticulospinal pathway). These pathways influ- the midbrain, the basis pontis, and the medullary pyramids. ence axial and proximal muscles and are involved in the At the cervicomedullary junction, most pyramidal axons maintenance of posture and integrated movements of the decussate into the contralateral corticospinal tract of the lat- limbs and trunk. The descending ventrolateral bulbospinal eral spinal cord, but 10–30% remains ipsilateral in the ante- pathways, which originate predominantly in the red nucleus rior spinal cord. Pyramidal neurons make direct monosynap- (rubrospinal pathway), facilitate distal limb muscles. The tic connections with lower motor neurons. They innervate bulbospinal system is sometimes referred to as the most densely the lower motor neurons of hand muscles and extrapyramidal upper motor neuron system. In all figures, nerve cell bodies and axon terminals are shown, respec- tively, as closed circles and forks. and into the transverse tubular system. This electrical within motor units.With muscular dystrophies, inflamma- excitation activates intracellular events that produce an tory myopathies, or myopathies with muscle fiber necrosis, energy-dependent contraction of the muscle fiber (exci- the number of muscle fibers is reduced within many tation-contraction coupling). motor units. On EMG, the size of each motor unit action potential is decreased, and motor units must be recruited Myopathic weakness is produced by a decrease in the more rapidly than normal to produce the desired power. number or contractile force of muscle fibers activated

Hemiparesis 105 Afferent Hemiparesis results from an upper motor neuron lesion CHAPTER 10 Weakness and Paralysis neuron above the midcervical spinal cord; most such lesions are above the foramen magnum. The presence of other neu- γ rologic deficits helps to localize the lesion.Thus, language α disorders, cortical sensory disturbances, cognitive abnor- malities, disorders of visual-spatial integration, apraxia, or Alpha and gamma seizures point to a cortical lesion. Homonymous visual motor neurons field defects reflect either a cortical or a subcortical hemi- spheric lesion. A “pure motor” hemiparesis of the face, Motor end plates on arm, or leg is often due to a small, discrete lesion in the voluntary muscle posterior limb of the internal capsule, cerebral peduncle, (extrafusal fibers) or upper pons. Some brainstem lesions produce “crossed paralyses,” consisting of ipsilateral cranial nerve signs and Muscle spindle contralateral hemiparesis. The absence of cranial nerve (intrafusal fibers) signs or facial weakness suggests that a hemiparesis is due FIGURE 10-2 to a lesion in the high cervical spinal cord, especially if associated with ipsilateral loss of proprioception and con- Lower motor neurons are divided into α and γ types. The tralateral loss of pain and temperature sense (the Brown- larger α motor neurons are more numerous and innervate the Séquard syndrome). extrafusal muscle fibers of the motor unit. Loss of α motor Acute or episodic hemiparesis usually results from ischemic neurons or disruption of their axons produces lower motor or hemorrhagic stroke, but may also relate to hemor- rhage occurring into brain tumors or as a result of neuron weakness. The smaller, less numerous γ motor neu- trauma; other causes include a focal structural lesion or inflammatory process as in multiple sclerosis, abscess, or rons innervate the intrafusal muscle fibers of the muscle spin- sarcoidosis. Evaluation begins immediately with a CT scan of the brain (Fig. 10-3) and laboratory studies. If dle and contribute to normal tone and stretch reflexes. The α the CT is normal and an ischemic stroke is unlikely, MRI of the brain or cervical spine is performed. motor neuron receives direct excitatory input from corticomo- Subacute hemiparesis that evolves over days or weeks toneurons and primary muscle spindle afferents. The α and γ has an extensive differential diagnosis. A common cause is subdural hematoma, especially in elderly or anticoagu- motor neurons also receive excitatory input from other lated patients, even when there is no history of trauma. descending upper motor neuron pathways, segmental sen- Infectious possibilities include cerebral abscess, fungal granuloma or meningitis, and parasitic infection. Weak- sory inputs, and interneurons. The α motor neurons receive ness from primary and metastatic neoplasms may evolve over days to weeks. AIDS may present with subacute direct inhibition from Renshaw cell interneurons, and other hemiparesis due to toxoplasmosis or primary CNS lym- phoma. Noninfectious inflammatory processes, such as interneurons indirectly inhibit the α and γ motor neurons. multiple sclerosis or, less commonly, sarcoidosis, merit consideration. If the brain MRI is normal and there are A tendon reflex requires the function of all illustrated struc- no cortical and hemispheric signs, MRI of the cervical tures. A tap on a tendon stretches muscle spindles (which spine should be undertaken. are tonically activated by γ motor neurons) and activates the Chronic hemiparesis that evolves over months is usually primary spindle afferent neurons. These stimulate the α due to a neoplasm or vascular malformation, a chronic subdural hematoma, or a degenerative disease. If an motor neurons in the spinal cord, producing a brief muscle MRI of the brain is normal, the possibility of a foramen contraction, which is the familiar tendon reflex. magnum or high cervical spinal cord lesion should be considered. Some myopathies produce weakness through loss of con- tractile force of muscle fibers or through relatively selec- Paraparesis tive involvement of the type II (fast) fibers.These may not affect the size of individual motor unit action potentials An intraspinal lesion at or below the upper thoracic and are detected by a discrepancy between the electrical spinal cord level is most commonly responsible, but a activity and force of a muscle. paraparesis may also result from lesions at other locations Diseases of the neuromuscular junction, such as myas- thenia gravis, produce weakness in a similar manner, but the loss of muscle fibers is functional (due to inability to activate them) rather than related to muscle fiber loss.The number of muscle fibers that are activated varies over time, depending on the state of rest of the neuromuscular junc- tions. Thus, fatigable weakness is suggestive of myasthenia gravis or other disorders of the neuromuscular junction.

106 DISTRIBUTION OF WEAKNESS Hemiparesis Paraparesis Quadriparesis Monoparesis Distal Proximal Restricted Alert UMN signs LMN signs* Yes No UMN signs LMN signs* SECTION II Clinical Manifestations of Neurologic Disease Cerebral signs UMN signs LMN signs* Yes No EMG and NCS UMN pattern LMN pattern Myopathic pattern Brain CT Spinal MRI‡ Anterior horn, Muscle or or MRI† root, or peripheral neuromuscular nerve disease junction disease * or signs of myopathy † If no abnormality detected, consider spinal MRI. ‡ If no abnormality detected, consider myelogram or brain MRI. FIGURE 10-3 neuron; NCS, nerve conduction studies; UMN, upper motor An algorithm for the initial workup of a patient with neuron. weakness. EMG, electromyography; LMN, lower motor that disturb upper motor neurons (especially parasagittal confusion, seizures, or other hemispheric signs, MRI of intracranial lesions) and lower motor neurons [anterior the brain should be undertaken. horn cell disorders, cauda equina syndromes due to involvement of nerve roots derived from the lower spinal Paraparesis may result from a cauda equina syndrome, cord (Chap. 30), and peripheral neuropathies]. for example, following trauma to the low back, a mid- line disk herniation, or an intraspinal tumor; although Acute paraparesis may not be recognized as due to sphincters are affected, hip flexion is often spared, as is spinal cord disease at an early stage if the legs are flaccid sensation over the anterolateral thighs. Rarely, paraparesis and areflexic. Usually, however, there is sensory loss in is caused by a rapidly evolving anterior horn cell disease the legs with an upper level on the trunk; a dissociated (such as poliovirus or West Nile virus infection), periph- sensory loss suggestive of a central cord syndrome; or eral neuropathy (such as Guillain-Barré syndrome; exaggerated stretch reflexes in the legs with normal Chap. 41) or myopathy (Chap. 43). In such cases, elec- reflexes in the arms. It is important to image the spinal trophysiologic studies are diagnostically helpful and cord (Fig. 10-3). Compressive lesions (particularly epidural refocus the subsequent evaluation. tumor, abscess, or hematoma, but also a prolapsed inter- vertebral disk and vertebral involvement by malignancy Subacute or chronic paraparesis with spasticity is caused or infection), spinal cord infarction (proprioception is by upper motor neuron disease. When there is associ- usually spared), an arteriovenous fistula or other vascular ated lower-limb sensory loss and sphincter involvement, anomaly, and transverse myelitis, are among the possible a chronic spinal cord disorder is likely (Chap. 30). If an causes (Chap. 30). MRI of the spinal cord is normal, MRI of the brain may be indicated. If hemispheric signs are present, a Diseases of the cerebral hemispheres that produce parasagittal meningioma or chronic hydrocephalus is acute paraparesis include anterior cerebral artery ischemia likely and MRI of the brain is the initial test. In the (shoulder shrug is also affected), superior sagittal sinus or rare situation in which a longstanding paraparesis has a cortical venous thrombosis, and acute hydrocephalus. If lower motor neuron or myopathic etiology, the local- upper motor neuron signs are associated with drowsiness, ization is usually suspected on clinical grounds by the

absence of spasticity and confirmed by EMG and nerve but the patient is alert, the initial test is usually an MRI 107CHAPTER 10 Weakness and Paralysis conduction tests. of the cervical cord. If weakness is lower motor neuron, myopathic, or uncertain in origin, the clinical approach Quadriparesis or Generalized Weakness begins with blood studies to determine the level of muscle enzymes and electrolytes and an EMG and nerve Generalized weakness may be due to disorders of the conduction study. CNS or of the motor unit.Although the terms quadripare- sis and generalized weakness are often used interchangeably, Subacute or Chronic Quadriparesis quadriparesis is commonly used when an upper motor When quadriparesis due to upper motor neuron disease neuron cause is suspected, and generalized weakness develops over weeks, months, or years, the distinction when a disease of the motor unit is likely.Weakness from between disorders of the cerebral hemispheres, brain- CNS disorders is usually associated with changes in con- stem, and cervical spinal cord is usually possible clinically. sciousness or cognition, with spasticity and brisk stretch An MRI is obtained of the clinically suspected site of reflexes, and with alterations of sensation. Most neuro- pathology. EMG and nerve conduction studies help to muscular causes of generalized weakness are associated distinguish lower motor neuron disease (which usually with normal mental function, hypotonia, and hypoactive presents with weakness that is most profound distally) muscle stretch reflexes. The major causes of intermittent from myopathic weakness, which is typically proximal. weakness are listed in Table 10-2.A patient with general- ized fatigability without objective weakness may have the Monoparesis chronic fatigue syndrome (Chap. 47). This is usually due to lower motor neuron disease, with Acute Quadriparesis or without associated sensory involvement. Upper Acute quadriparesis with onset over minutes may result motor neuron weakness occasionally presents as a from disorders of upper motor neurons (e.g., anoxia, monoparesis of distal and nonantigravity muscles. Myo- hypotension, brainstem or cervical cord ischemia, trauma, pathic weakness is rarely limited to one limb. and systemic metabolic abnormalities) or muscle (elec- trolyte disturbances, certain inborn errors of muscle Acute Monoparesis energy metabolism, toxins, or periodic paralyses). Onset If the weakness is predominantly in distal and nonanti- over hours to weeks may, in addition to the above, be due gravity muscles and not associated with sensory impair- to lower motor neuron disorders. Guillain-Barré syn- ment or pain, focal cortical ischemia is likely (Chap. 21); drome (Chap. 41) is the most common lower motor neu- diagnostic possibilities are similar to those for acute hemi- ron weakness that progresses over days to 4 weeks; the paresis. Sensory loss and pain usually accompany acute finding of an elevated protein level in the cerebrospinal lower motor neuron weakness; the weakness is commonly fluid is helpful but may be absent early in the course. localized to a single nerve root or peripheral nerve within the limb but occasionally reflects plexus involvement. If In obtunded patients, evaluation begins with a CT lower motor neuron weakness is suspected, or the pattern scan of the brain. If upper motor neuron signs are present of weakness is uncertain, the clinical approach begins with an EMG and nerve conduction study. TABLE 10-2 Subacute or Chronic Monoparesis CAUSES OF EPISODIC GENERALIZED WEAKNESS Weakness and atrophy that develop over weeks or months are usually of lower motor neuron origin. If 1. Electrolyte disturbances, e.g., hypokalemia, they are associated with sensory symptoms, a peripheral hyperkalemia, hypercalcemia, hypernatremia, cause (nerve, root, or plexus) is likely; in the absence of hyponatremia, hypophosphatemia, hypermagnesemia such symptoms, anterior horn cell disease should be considered. In either case, an electrodiagnostic study is 2. Muscle disorders indicated. If weakness is of upper motor neuron type, a a. Channelopathies (periodic paralyses) discrete cortical (precentral gyrus) or cord lesion may be b. Metabolic defects of muscle (impaired carbohydrate responsible, and an imaging study is performed of the or fatty acid utilization; abnormal mitochondrial appropriate site. function) Distal Weakness 3. Neuromuscular junction disorders a. Myasthenia gravis Involvement of two or more limbs distally suggests b. Lambert-Eaton myasthenic syndrome lower motor neuron or peripheral nerve disease. Acute 4. Central nervous system disorders a. Transient ischemic attacks of the brainstem b. Transient global cerebral ischemia c. Multiple sclerosis

SECTION II Clinical Manifestations of Neurologic Disease108 distal lower limb weakness occurs occasionally from an Weakness in a Restricted Distribution acute toxic polyneuropathy or cauda equina syndrome. Distal symmetric weakness usually develops over weeks, Weakness may not fit any of the above patterns, being months, or years and, when associated with numbness, is limited, for example, to the extraocular, hemifacial, bul- due to metabolic, toxic, hereditary, degenerative, or bar, or respiratory muscles. If unilateral, restricted weak- inflammatory diseases of peripheral nerves (Chap. 40). ness is usually due to lower motor neuron or peripheral Anterior horn cell disease may begin distally but is typi- nerve disease, such as in a facial palsy (Chap. 29) or an cally asymmetric and without accompanying numbness isolated superior oblique muscle paresis (Chap. 17). (Chap. 27). Rarely, myopathies present with distal weak- Weakness of part of a limb is usually due to a peripheral ness (Chap. 43). Electrodiagnostic studies help to localize nerve lesion such as carpal tunnel syndrome or another the disorder (Fig. 10-3). entrapment neuropathy. Relatively symmetric weakness of extraocular or bulbar muscles is usually due to a Proximal Weakness myopathy (Chap. 43) or neuromuscular junction disor- der (Chap. 42). Bilateral facial palsy with areflexia sug- Myopathy often produces symmetric weakness of the gests Guillain-Barré syndrome (Chap. 41). Worsening of pelvic or shoulder girdle muscles (Chap. 43). Diseases of relatively symmetric weakness with fatigue is character- the neuromuscular junction [such as myasthenia gravis istic of neuromuscular junction disorders. Asymmetric (Chap. 42)], may present with symmetric proximal bulbar weakness is usually due to motor neuron disease. weakness often associated with ptosis, diplopia, or bulbar Weakness limited to respiratory muscles is uncommon weakness and fluctuating in severity during the day. and is usually due to motor neuron disease, myasthenia Extreme fatigability present in some cases of myasthenia gravis, or polymyositis/dermatomyositis (Chap. 44). gravis may even suggest episodic weakness, but strength rarely returns fully to normal. In anterior horn cell dis- ACKNOWLEDGMENT ease proximal weakness is usually asymmetric, but may be symmetric if familial. Numbness does not occur with Richard K. Olney, MD, was the author of this chapter any of these diseases.The evaluation usually begins with in previous editions, and his contributions in the last three determination of the serum creatine kinase level and editions of Harrison’s Principles of Internal Medicine are electrophysiologic studies. appreciated.

CHAPTER 11 GAIT AND BALANCE DISORDERS Lewis Sudarsky Prevalence, Morbidity, and Mortality . . . . . . . . . . . . . . . . . . . 109 Anatomy and Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Disorders of Gait . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 Disorders of Balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 Falls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 PREVALENCE, MORBIDITY, AND are widely distributed in the central nervous system.The MORTALITY biomechanics of bipedal walking are complex, and the Gait and balance problems are common in the elderly performance is easily compromised by injury at any and contribute to the risk of falls and injury. Gait disor- level. Command and control centers in the brainstem, ders have been described in 15% of individuals older than cerebellum, and forebrain modify the action of spinal 65 years. By 80 years, one person in four will use a pattern generators to promote stepping.While a form of mechanical aid to assist ambulation.Among those 85 years “fictive locomotion” can be elicited from quadrupedal and older, the prevalence of gait abnormality approaches animals after spinal transection, this capacity is limited in 40%. In epidemiologic studies, gait disorders are consis- primates. Step generation in primates is dependent on tently identified as a major risk factor for falls and injury. locomotor centers in the pontine tegmentum, midbrain, and subthalamic region. Locomotor synergies are exe- A substantial number of older persons report insecure cuted through the reticular formation and descending balance and experience falls and fear of falling. Prospec- pathways in the ventromedial spinal cord. Cerebral con- tive studies indicate that 20–30% of individuals >65 years trol provides a goal and purpose for walking and is involved fall each year, and the proportion is even higher in hos- in avoidance of obstacles and adaptation of locomotor pitalized elderly and nursing home patients. Each year programs to context and terrain. 8% of individuals >75 years suffer a serious fall-related injury. Hip fractures often result in hospitalization and Postural control requires the maintenance of the cen- nursing home admission. For each person who is physi- ter of mass over the base of support through the gait cally disabled, there are others whose functional inde- cycle. Unconscious postural adjustments maintain stand- pendence is constrained by anxiety and fear of falling. ing balance: long latency responses are measurable in the Nearly one in five of elderly individuals voluntarily leg muscles, beginning 110 ms after a perturbation. For- limit their activity because of fear of falling.With loss of ward motion of the center of mass provides propulsive ambulation, there is a diminished quality of life and force for stepping, but failure to maintain the center of increased morbidity and mortality. mass within stability limits results in falls. The anatomic substrate for dynamic balance has not been well defined, ANATOMY AND PHYSIOLOGY but the vestibular nucleus and midline cerebellum con- tribute to balance control in animals. Human patients Upright bipedal gait depends on the successful integra- with damage to these structures have impaired balance tion of postural control and locomotion.These functions with standing and walking. 109

110 Standing balance depends on good quality sensory TABLE 11-1 information about the position of the body center with ETIOLOGY OF GAIT DISORDER respect to the environment, support surface, and gravita- SECTION II Clinical Manifestations of Neurologic Disease tional forces. Sensory information for postural control is Sensory deficits CASES PERCENT primarily generated by the visual system, the vestibular Myelopathy system, and by proprioceptive receptors in the muscle Multiple infarcts 22 18.3 spindles and joints. A healthy redundancy of sensory Parkinsonism 20 16.7 afferent information is generally available, but loss of Cerebellar degeneration 18 15.0 two of the three pathways is sufficient to compromise Hydrocephalus 14 11.7 standing balance. Balance disorders in older individuals Toxic/metabolic sometimes result from multiple insults in the peripheral Psychogenic 8 6.7 sensory systems (e.g., visual loss, vestibular deficit, Other 8 6.7 peripheral neuropathy), critically degrading the quality Unknown cause 3 2.5 of afferent information needed for balance stability. 4 3.3 Older patients with mental status abnormalities and Total 6 5.0 dementia from neurodegenerative diseases appear to be 17 14.2 particularly prone to falls and injury. Frailty, muscle weak- ness, and deconditioning undoubtedly contribute to the 120 100% risk.There is a growing literature on the use of attentional resources to manage locomotion. The ability to walk Source: Reproduced with permission from Masdeu et al. while attending to a cognitive task (dual tasking) may be particularly compromised in older adults with a history of level gait disturbance. Physical therapy often improves falls. Walking is generally considered to be unconscious walking to the degree that follow-up observation may and automatic, but older patients with deficits in execu- reveal a more specific underlying disorder. tive function may be unable to manage the attention needed for dynamic balance when distracted. Stiff-Legged Gait DISORDERS OF GAIT Spastic gait is characterized by stiffness in the legs, an imbalance of muscle tone, and a tendency to circumduct The heterogeneity of gait disorders observed in clinical and scuff the feet. The disorder reflects compromise of practice reflects the large network of neural systems corticospinal command and overactivity of spinal involved in the task. There is the potential for abnor- reflexes. The patient may walk on his or her toes. In malities to develop, and walking is vulnerable to neuro- extreme instances, the legs cross due to increased tone in logic disease at every level. Gait disorders have been the adductors. Upper motor neuron signs are present on classified descriptively, based on the abnormal physiol- physical examination. Shoes often reflect an uneven pat- ogy and biomechanics. One problem with this approach tern of wear across the outside. The disorder may be is that many failing gaits look fundamentally similar. cerebral or spinal in origin. This overlap reflects common patterns of adaptation to threatened balance stability and declining performance. Myelopathy from cervical spondylosis is a common The gait disorder observed clinically must be viewed as the cause of spastic or spastic-ataxic gait. Demyelinating dis- product of a neurologic deficit and a functional adaptation. ease and trauma are the leading causes of myelopathy in Unique features of the failing gait are often over- younger patients. In a chronic progressive myelopathy of whelmed by the adaptive response. Some of the com- unknown cause, workup with laboratory and imaging mon patterns of abnormal gait are summarized below. tests may establish a diagnosis of multiple sclerosis. A Gait disorders can also be classified by etiology, as listed family history should suggest hereditary spastic paraple- in Table 11-1. gia (HSP). Genetic testing is now available for some of the common HSP mutations.Tropical spastic paraparesis Cautious Gait related to the retrovirus HTLV-I is endemic in parts of the Caribbean and South America. A structural lesion, The term cautious gait is used to describe the patient such as tumor or spinal vascular malformation, should who walks with an abbreviated stride and lowered center be excluded with appropriate testing. Spinal cord disor- of mass, as if walking on a slippery surface.This disorder ders are discussed in detail in Chap. 30. is both common and nonspecific. It is, in essence, an adaptation to a perceived postural threat. A fear of falling With cerebral spasticity asymmetry is common, involve- may be associated. In one study, this disorder was observed ment of the upper extremities is usually observed, and in more than one-third of older patients with a higher dysarthria is often an associated feature. Common causes include vascular disease (stroke), multiple sclerosis, and perinatal injury to the nervous system (cerebral palsy). Other stiff-legged gaits include dystonia (Chap. 25) and stiff-person syndrome. Dystonia is a disorder characterized

by sustained muscle contractions, resulting in repetitive disease). The clinical syndrome includes mental change 111 CHAPTER 11 Gait and Balance Disorders twisting movements and abnormal posture. It often has a (variable in degree), dysarthria, pseudobulbar affect (emo- genetic basis. Dystonic spasms produce plantar flexion tional disinhibition), increased tone, and hyperreflexia in and inversion of the feet, sometimes with torsion of the the lower limbs. trunk. In autoimmune stiff-person syndrome, there is exaggerated lordosis of the lumbar spine and overactiva- Communicating hydrocephalus in the adult also pre- tion of antagonist muscles, which restricts trunk and sents with a gait disorder of this type. Other features of lower limb movement and results in a wooden or fixed the diagnostic triad (mental change, incontinence) may posture. be absent in the initial stages. MRI demonstrates ven- tricular enlargement, an enlarged flow void about the Parkinsonism and Freezing Gait aqueduct, and a variable degree of periventricular white matter change. A lumbar puncture or dynamic test is Parkinson’s disease (Chap. 24) is common, affecting 1% necessary to confirm the presence of hydrocephalus. of the population >55 years. The stooped posture and shuffling gait are characteristic and distinctive features. Cerebellar Gait Ataxia Patients sometimes accelerate (festinate) with walking or display retropulsion. There may be difficulty with gait Disorders of the cerebellum have a dramatic impact on initiation (freezing) and a tendency to turn en bloc. gait and balance. Cerebellar gait ataxia is characterized Imbalance and falls may develop as the disease progresses by a wide base of support, lateral instability of the trunk, over years. Other progressive neurodegenerative disorders erratic foot placement, and decompensation of balance may also involve a freezing gait; these include progressive when attempting to walk tandem. Difficulty maintain- supranuclear palsy, multiple system atrophy, corticobasal ing balance when turning is often an early feature. degeneration, and primary pallidal degeneration. Such Patients are unable to walk tandem heel to toe, and dis- patients with atypical parkinsonian syndromes frequently play truncal sway in narrow-based or tandem stance. present with axial stiffness, postural instability, and a They show considerable variation in their tendency to shuffling gait but tend to lack the characteristic pill-rolling fall in daily life. tremor of Parkinson’s disease. Falls within the first year suggest the possibility of progressive supranuclear palsy. Causes of cerebellar ataxia in older patients include stroke, trauma, tumor, and neurodegenerative disease, Hyperkinetic movement disorders also produce char- including multiple system atrophy (Chaps. 24 and 26) acteristic and recognizable disturbances in gait. In Hunt- and various forms of hereditary cerebellar degeneration ington’s disease (Chap. 25), the unpredictable occurrence (Chap. 24). MRI demonstrates the extent and topogra- of choreic movements gives the gait a dancing quality. phy of cerebellar atrophy. A short expansion at the site Tardive dyskinesia is the cause of many odd, stereotypic of the fragile X mutation (fragile X pre-mutation) has gait disorders seen in chronic psychiatric patients. been associated with gait ataxia in older men. Alcoholic cerebellar degeneration can be screened by history and Frontal Gait Disorder often confirmed by MRI. Frontal gait disorder, sometimes known as “gait apraxia,” Sensory Ataxia is common in the elderly and has a variety of causes. Typical features include a wide base of support, short As reviewed above, balance depends on high-quality stride, shuffling along the floor, and difficulty with starts afferent information from the visual and the vestibular and turns. Many patients exhibit difficulty with gait ini- systems and proprioception. When this information is tiation, descriptively characterized as the “slipping lost or degraded, balance during locomotion is impaired clutch” syndrome or “gait ignition failure.” The term and instability results. The sensory ataxia of tabetic neu- lower body parkinsonism is also used to describe such rosyphilis is a classic example.The contemporary equiva- patients. Strength is generally preserved, and patients are lent is the patient with neuropathy affecting large fibers. able to make stepping movements when not standing Vitamin B12 deficiency is a treatable cause of large-fiber and maintaining balance at the same time. This disorder sensory loss in the spinal cord and peripheral nervous is a higher level motor control disorder, as opposed to an system. Joint position and vibration sense are diminished apraxia. in the lower limbs.The stance in such patients is destabi- lized by eye closure; they often look down at their feet The most common cause of frontal gait disorder is when walking and do poorly in the dark. Patients have vascular disease, particularly subcortical small-vessel dis- been described with imbalance from bilateral vestibular ease. Lesions are frequently found in the deep frontal loss, caused by disease or by exposure to ototoxic drugs. white matter and centrum ovale. Gait disorder may be Table 11-2 compares sensory ataxia with cerebellar ataxia the salient feature in hypertensive patients with ischemic and frontal gait disorder. Some patients exhibit a syndrome lesions of the deep hemisphere white matter (Binswanger’s of imbalance from the combined effect of multiple sensory

112 TABLE 11-2 FEATURES OF CEREBELLAR ATAXIA, SENSORY ATAXIA, AND FRONTAL GAIT DISORDERS SECTION II Clinical Manifestations of Neurologic Disease Base of support CEREBELLAR ATAXIA SENSORY ATAXIA FRONTAL GAIT Velocity Stride Wide-based Narrow base, looks down Wide-based Variable Slow Very slow Romberg Irregular, lurching Regular with path Short, shuffling Heel → shin deviation Initiation +/– Unsteady, falls +/– Turns Abnormal +/– Normal Postural instability Normal Normal Hesitant Unsteady +/– Hesitant, multistep + +++ ++++ Poor postural synergies Falls Late event Frequent getting up from a chair Frequent deficits. Such patients, often elderly and diabetic, have patients with extreme anxiety or phobia walk with disturbances in proprioception, vision, and vestibular exaggerated caution with abduction of the arms, as if sense that impair postural support. walking on ice. This inappropriately overcautious gait differs in degree from the gait of the patient who is Neuromuscular Disease insecure and making adjustments for imbalance. Depressed patients exhibit primarily slowness, a manifes- Patients with neuromuscular disease often have an abnor- tation of psychomotor retardation, and lack of purpose mal gait, occasionally as a presenting feature. With distal in their stride. Hysterical gait disorders are among the weakness (peripheral neuropathy) the step height is most spectacular encountered. Odd gyrations of posture increased to compensate for foot drop, and the sole of with wastage of muscular energy (astasia-abasia), the foot may slap on the floor during weight acceptance. extreme slow motion, and dramatic fluctuations over Neuropathy may be associated with a degree of sensory time may be observed in patients with somatoform dis- imbalance, as described earlier. Patients with myopathy or orders and conversion reaction. muscular dystrophy more typically exhibit proximal weakness. Weakness of the hip girdle may result in a Approach to the Patient: degree of excess pelvic sway during locomotion. SLOWLY PROGRESSIVE DISORDER OF GAIT Toxic and Metabolic Disorders When reviewing the history it is helpful to inquire about the onset and progression of disability. Initial Alcohol intoxication is the most common cause of acute awareness of an unsteady gait often follows a fall. walking difficulty. Chronic toxicity from medications Stepwise evolution or sudden progression suggest vas- and metabolic disturbances can impair motor function cular disease. Gait disorder may be associated with and gait. Mental status changes may be present, and urinary urgency and incontinence, particularly in examination may reveal asterixis or myoclonus. Static patients with cervical spine disease or hydrocephalus. equilibrium is disturbed, and such patients are easily It is always important to review the use of alcohol thrown off balance. Disequilibrium is particularly evi- and medications that affect gait and balance. Informa- dent in patients with chronic renal disease and those tion on localization derived from the neurologic with hepatic failure, in whom asterixis may impair pos- examination can be helpful to narrow the list of pos- tural support. Sedative drugs, especially neuroleptics and sible diagnoses. long-acting benzodiazepines, affect postural control and increase the risk for falls. These disorders are important Gait observation provides an immediate sense of to recognize because they are often treatable. the patient’s degree of disability. Characteristic pat- terns of abnormality are sometimes observed, though Psychogenic Gait Disorder failing gaits often look fundamentally similar. Cadence Psychogenic disorders are common in outpatient prac- tice, and the presentation often involves gait. Some

(steps/min), velocity, and stride length can be recorded Somatosensory deficits also produce imbalance and 113 CHAPTER 11 Gait and Balance Disorders by timing a patient over a fixed distance. Watching falls.There is often a subjective sense of insecure balance the patient get out of a chair provides a good func- and fear of falling. Postural control is compromised by tional assessment of balance. eye closure (Romberg’s sign); these patients also have dif- ficulty navigating in the dark. A dramatic example is the Brain imaging studies may be informative in patients patient with autoimmune subacute sensory neuropathy, with an undiagnosed disorder of gait. MRI is sensitive sometimes a paraneoplastic disorder (Chap. 39). Com- for cerebral lesions of vascular or demyelinating disease pensatory strategies enable such patients to walk in the and is a good screening test for occult hydrocephalus. virtual absence of proprioception, but the task requires Patients with recurrent falls are at risk for subdural active visual monitoring. Patients with higher level disor- hematoma. Many elderly patients with gait and balance ders of equilibrium have difficulty maintaining balance difficulty have white matter abnormalities in the in daily life and may present with falls. There may be periventricular region and centrum semiovale. While reduced awareness of balance impairment. Classic exam- these lesions may be an incidental finding, a substantial ples include patients with progressive supranuclear palsy burden of white matter disease will ultimately impact and normal pressure hydrocephalus. Patients on sedating cerebral control of locomotion. medications are also in this category. In prospective stud- ies, cognitive impairment and the use of sedative medica- DISORDERS OF BALANCE tions substantially increase the risk for falls. Balance is the ability to maintain equilibrium: a state in FALLS which opposing physical forces cancel. In physiology, this is taken to mean the ability of the organism to con- Falls are a common event, particularly among the trol the center of mass with respect to gravity and the elderly. Modest changes in balance function have been support surface. In reality, no one is aware of what or described in fit older subjects as a result of normal where the center of mass is, but everyone, including aging. Subtle deficits in sensory systems, attention, and gymnasts, figure skaters, and platform divers, move so as motor reaction time contribute to the risk, and environ- to manage it. Imbalance implies a disturbance of equi- mental hazards abound. Epidemiologic studies have librium. Disorders of balance present with difficulty identified a number of risk factors for falls, summarized maintaining posture standing and walking and with a in Table 11-3. A fall is not a neurologic problem, nor subjective sense of disequilibrium, a form of dizziness. reason for referral to a specialist, but there are circum- stances in which neurologic evaluation is appropriate. In The cerebellum and vestibular system organize anti- a classic study, 90% of fall events occurred among 10% gravity responses needed to maintain the upright pos- of individuals, a group known as recurrent fallers. Some of ture. As reviewed earlier, these responses are physiologi- these are frail older persons with chronic diseases. cally complex, and the anatomic representation is not Recurrent falls sometimes indicate the presence of seri- well understood. Failure, resulting in disequilibrium, can ous balance impairment. Syncope, seizure, or falls related occur at several levels: cerebellar, vestibular, somatosen- to loss of consciousness require appropriate evaluation sory, and higher level disequilibrium. Patients with and treatment (Chaps. 8 and 20). hereditary ataxia or alcoholic cerebellar degeneration do not generally complain of dizziness, but balance is visi- TABLE 11-3 bly impaired. Neurologic examination will reveal a vari- ety of cerebellar signs. Postural compensation may pre- RISK FACTORS FOR FALLS, A META-ANALYSIS: vent falls early on, but falls inevitably occur with disease SUMMARY OF SIXTEEN CONTROLLED STUDIES progression. The progression of a neurodegenerative ataxia is often measured by the number of years to loss RISK FACTOR MEAN RR (OR) RANGE of stable ambulation.Vestibular disorders have symptoms and signs in three categories: vertigo, the subjective Weakness 4.9 1.9–10.3 appreciation or illusion of movement; nystagmus, a Balance deficit 3.2 1.6–5.4 vestibulo-oculomotor sign; and poor balance, an impair- Gait disorder 3.0 1.7–4.8 ment of vestibulospinal function. Not every patient has Visual deficit 2.8 1.1–7.4 all manifestations. Patients with vestibular deficits related Mobility limitation 2.5 1.0–5.3 to ototoxic drugs may lack vertigo or obvious nystag- Cognitive impairment 2.4 2.0–4.7 mus, but balance is impaired on standing and walking, Impaired functional status 2.0 1.0–3.1 and the patient cannot navigate in the dark. Laboratory Postural hypotension 1.9 1.0–3.4 testing is available to explore vestibulo-oculomotor and vestibulospinal deficits. Note: RR, relative risks from prospective studies; OR, odds ratios from retrospective studies. Source: Reprinted from Masdeu et al, with permission.

SECTION II Clinical Manifestations of Neurologic Disease114 The descriptive classification of falls is as difficult as Falls of this nature occur in patients with advanced the classification of gait disorders, for many of the same Parkinson’s disease once postural instability has developed. reasons. Postural control systems are widely distributed, and a number of disease-related abnormalities occur. Gait Freezing Unlike gait problems that are apparent on observation, falls are rarely observed in the office. The patient and Another fall pattern in Parkinson’s disease and related family may have limited information about what trig- disorders is the fall due to freezing of gait.The feet stick gered the fall. Injuries can complicate the physical to the floor and the center of mass keeps moving, result- examination. Although there is no standard nosology of ing in a disequilibrium from which the patient cannot falls, common patterns can be identified. recover. This can result in a forward fall. Gait freezing can also occur as the patient attempts to turn and Slipping, Tripping, and “Mechanical Falls” change direction. Similarly, the patient with Parkinson’s disease and festinating gait may find his feet unable to Slipping on icy pavement, tripping on obstacles, and falls keep up, resulting in a forward fall. related to obvious environmental factors are often termed mechanical falls. They occasionally occur in Falls Related to Sensory Deficit healthy individuals with good balance compensation. Frequent tripping falls raise suspicion about an underly- Patients with somatosensory, visual, or vestibular deficits ing neurologic deficit. Patients with spasticity, leg weak- are prone to falls. These patients have particular difficulty ness, or foot drop experience tripping falls. dealing with poor illumination or walking on uneven ground.These patients often express subjective imbalance, Weakness and Frailty apprehension, and fear of falling. Deficits in joint position and vibration sense are apparent on physical examination. Patients who lack strength in antigravity muscles have difficulty rising from a chair, fatigue easily when walk- Treatment: ing, and have difficulty maintaining their balance after a INTERVENTIONS TO REDUCE perturbation. These patients are often unable to get up THE RISK OF FALLS AND INJURY after a fall and may be on the floor for an hour or more before help arrives. Deconditioning of this sort is often Efforts should be made to define the etiology of the gait treatable. Resistance strength training can increase mus- disorder and mechanism of the falls. Standing blood cle mass and leg strength in people in their 80s and 90s. pressure should be recorded. Specific treatment may be possible, once a diagnosis is established. Therapeutic Drop Attacks and Collapsing Falls intervention is often recommended for older patients at substantial risk for falls, even if no neurologic disease is Drop attacks are sudden collapsing falls without loss of identified. A home visit to look for environmental hazards consciousness. Patients who collapse from lack of pos- can be helpful. A variety of modifications may be recom- tural tone present a diagnostic challenge.The patient may mended to improve safety, including improved lighting report that his or her legs just gave out underneath; the and the installation of grab bars and nonslip surfaces. family may describe the patient as “collapsing in a heap.” Orthostatic hypotension may be a factor in some such Rehabilitation interventions attempt to improve muscle falls. Asterixis or epilepsy may impair postural support. strength and balance stability and to make the patient A colloid cyst of the third ventricle can present with inter- more resistant to injury. High-intensity resistance strength mittent obstruction of the foramen of Monroe, resulting in training with weights and machines is useful to improve a drop attack. While collapsing falls are more common in muscle mass, even in frail older patients. Improvements older patients with vascular risk factors, they should not be are realized in posture and gait, which should translate to confused with vertebrobasilar ischemic attacks. reduced risk of falls and injury. The goal of sensory bal- ance training is to improve balance stability. Measurable Toppling Falls gains can be achieved in a few weeks of training, and benefits can be maintained over 6 months by a 10- to Some patients maintain tone in antigravity muscles but 20-min home exercise program.This strategy is particularly fall over like a tree trunk, as if postural defenses had disen- successful in patients with vestibular and somatosensory gaged. There may be a consistent direction to such falls. balance disorders. The Yale Health and Aging study used The patient with cerebellar pathology may lean and top- a strategy of targeted, multiple risk factor abatement to ple over toward the side of the lesion. Patients with reduce falls in the elderly. Prescription medications were lesions of the vestibular system or its central pathways adjusted, and home-based exercise programs were may experience lateral pulsion and toppling falls. Patients with progressive supranuclear palsy often fall over backwards.

tailored to the patient’s need, based on an initial geriatric BRONSTEIN A et al: Clinical Disorders of Balance, Posture and Gait. 115 CHAPTER 11 Gait and Balance Disorders assessment. The program realized a 44% reduction in falls, in comparison with a control group of patients who London,Arnold Press, 2003 had periodic social visits. GANZ DA et al:Will my patient fall? JAMA 297:77, 2007 Horlings CG et al: A weak balance: the contribution of muscle FURTHER READINGS BISCHOFF-FERRARI HA et al: Fall prevention with supplemental and weakness to postural instability and falls. Nat Clin Pract Neurol 4:504, 2008 active forms of vitamin D: a meta-analysis of randomised controlled MASDEU J et al: Gait Disorders of Aging:With Special Reference to Falls. trials. BMJ 339:3692, 2009 Boston, Little Brown, 1995 SNIJDERS AH et al: Neurological gait disorders in elderly people: Clinical approach and classification. Lancet Neurol 6:63, 2007 TINETTI ME: Preventing falls in elderly persons. N Engl J Med 348:42, 2003

CHAPTER 12 NUMBNESS, TINGLING, AND SENSORY LOSS Michael J. Aminoff I Arthur K. Asbury Positive and Negative Symptoms . . . . . . . . . . . . . . . . . . . . . 116 Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 Anatomy of Sensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 I Examination of Sensation . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 I Localization of Sensory Abnormalities . . . . . . . . . . . . . . . . . . 120 Normal somatic sensation reflects a continuous moni- Negative phenomena represent loss of sensory func- toring process, little of which reaches consciousness tion and are characterized by diminished or absent feel- under ordinary conditions. By contrast, disordered sen- ing, often experienced as numbness, and by abnormal sation, particularly when experienced as painful, is findings on sensory examination. In disorders affecting alarming and dominates the sufferer’s attention. Physi- peripheral sensation, it is estimated that at least half the cians should be able to recognize abnormal sensations by afferent axons innervating a given site are lost or func- how they are described, know their type and likely site tionless before a sensory deficit can be demonstrated by of origin, and understand their implications. Pain is con- clinical examination. This threshold varies according to sidered separately in Chap. 5. how rapidly function is lost in sensory nerve fibers. If the rate of loss is slow, lack of cutaneous feeling may be POSITIVE AND NEGATIVE SYMPTOMS unnoticed by the patient and difficult to demonstrate on examination, even though few sensory fibers are func- Abnormal sensory symptoms may be divided into two tioning; if rapid, both positive and negative phenomena categories, positive and negative. The prototypical posi- are usually conspicuous. Subclinical degrees of sensory tive symptom is tingling (pins-and-needles); other posi- dysfunction may be revealed by sensory nerve conduction tive sensory phenomena include altered sensations that studies or somatosensory evoked potentials (Chap. 3). are described as pricking, bandlike, lightning-like shoot- ing feelings (lancinations), aching, knifelike, twisting, Whereas sensory symptoms may be either positive or drawing, pulling, tightening, burning, searing, electrical, negative, sensory signs on examination are always a mea- or raw feelings. Such symptoms are often painful. sure of negative phenomena. Positive phenomena usually result from trains of TERMINOLOGY impulses generated at sites of lowered threshold or heightened excitability along a peripheral or central Words used to characterize sensory disturbance are sensory pathway. The nature and severity of the abnor- descriptive and based on convention. Paresthesias and mal sensation depend on the number, rate, timing, and dysesthesias are general terms used to denote positive sen- distribution of ectopic impulses and the type and func- sory symptoms. The term paresthesias typically refers to tion of nervous tissue in which they arise. Because posi- tingling or pins-and-needles sensations but may include a tive phenomena represent excessive activity in sensory wide variety of other abnormal sensations, except pain; it pathways, they are not necessarily associated with a sen- sometimes implies that the abnormal sensations are per- sory deficit (loss) on examination. ceived spontaneously. The more general term dysesthesias 116

denotes all types of abnormal sensations, including painful spinal cord (Fig.12-1). From there the smaller fibers 117 CHAPTER 12 Numbness, Tingling, and Sensory Loss ones, regardless of whether a stimulus is evident. take a different route to the parietal cortex than the larger fibers. The polysynaptic projections of the smaller Another set of terms refers to sensory abnormalities fibers (unmyelinated and small myelinated), which sub- found on examination. Hypesthesia or hypoesthesia refers to serve mainly nociception, temperature sensibility, and a reduction of cutaneous sensation to a specific type of touch, cross and ascend in the opposite anterior and lat- testing such as pressure, light touch, and warm or cold eral columns of the spinal cord, through the brainstem, stimuli; anesthesia, to a complete absence of skin sensation to the ventral posterolateral (VPL) nucleus of the thala- to the same stimuli plus pinprick; and hypalgesia or analge- mus, and ultimately project to the postcentral gyrus of the sia to reduced or absent pain perception (nociception), parietal cortex. This is the spinothalamic pathway or antero- such as perception of the pricking quality elicited by a lateral system.The larger fibers, which subserve tactile and pin. Hyperesthesia means pain or increased sensitivity in position sense and kinesthesia, project rostrally in the response to touch. Similarly, allodynia describes the situa- posterior column on the same side of the spinal cord tion in which a nonpainful stimulus, once perceived, is experienced as painful, even excruciating. An example is Leg Post-central elicitation of a painful sensation by application of a vibrat- Trunk cortex ing tuning fork. Hyperalgesia denotes severe pain in response to a mildly noxious stimulus, and hyperpathia, a Thalamus Arm broad term, encompasses all the phenomena described by hyperesthesia, allodynia, and hyperalgesia. With hyper- Internal Face pathia, the threshold for a sensory stimulus is increased capsule and perception is delayed, but once felt, is unduly painful. Ventral Reticulothalamic pathway posterolateral Disorders of deep sensation, arising from muscle spin- Principal sensory dles, tendons, and joints, affect proprioception (position nucleus of V nucleus of sense). Manifestations include imbalance (particularly thalamus with eyes closed or in the dark), clumsiness of precision Nucleus of MIDBRAIN movements, and unsteadiness of gait, which are referred funiculus gracilis to collectively as sensory ataxia. Other findings on exami- Nucleus of PONS nation usually, but not invariably, include reduced or funiculus cuneatus Medial lemniscus absent joint position and vibratory sensibility and absent deep tendon reflexes in the affected limbs. Romberg’s Nucleus of MEDULLA sign is positive, which means that the patient sways spinal tract V Spinothalamic tract markedly or topples when asked to stand with feet close together and eyes closed. In severe states of deafferenta- SPINAL CORD tion involving deep sensation, the patient cannot walk or stand unaided or even sit unsupported. Continuous invol- Spinothalamic tract untary movements (pseudoathetosis) of the outstretched hands and fingers occur, particularly with eyes closed. FIGURE12-1 The main somatosensory pathways. The spinothalamic tract ANATOMY OF SENSATION (pain, thermal sense) and the posterior column–lemniscal sys- tem (touch, pressure, joint position) are shown. Offshoots from Cutaneous afferent innervation is conveyed by a rich variety the ascending anterolateral fasciculus (spinothalamic tract) to of receptors, both naked nerve endings (nociceptors and nuclei in the medulla, pons, and mesencephalon and nuclear thermoreceptors) and encapsulated terminals (mechanore- terminations of the tract are indicated. (From AH Ropper, RH ceptors). Each type of receptor has its own set of sensitivities Brown, in Adams and Victor’s Principles of Neurology, 8th ed. to specific stimuli, size and distinctness of receptive fields, New York, McGraw-Hill, 2007.) and adaptational qualities. Much of the knowledge about these receptors has come from the development of tech- niques to study single intact nerve fibers intraneurally in awake, unanesthetized human subjects. It is possible not only to record from but also to stimulate single fibers in isolation. A single impulse, whether elicited by a natural stimulus or evoked by electrical microstimulation in a large myelinated afferent fiber may be both perceived and localized. Afferent fibers of all sizes in peripheral nerve trunks traverse the dorsal roots and enter the dorsal horn of the

SECTION II Clinical Manifestations of Neurologic Disease118 and make their first synapse in the gracile or cuneate sensation, but some idea of proprioceptive function may nucleus of the lower medulla. Axons of the second- be gained by noting the patient’s best performance of order neuron decussate and ascend in the medial lem- movements requiring balance and precision. Frequently, niscus located medially in the medulla and in the patients present with sensory symptoms that do not fit an tegmentum of the pons and midbrain and synapse in the anatomic localization and that are accompanied by either VPL nucleus; the third-order neurons project to parietal no abnormalities or gross inconsistencies on examination. cortex.This large-fiber system is referred to as the poste- The examiner should then consider whether the sensory rior column–medial lemniscal pathway (lemniscal, for short). symptoms are a disguised request for help with psycholog- Note that although the lemniscal and the anterolateral ical or situational problems. Discretion must be used in pathways both project up the spinal cord to the thala- pursuing this possibility. Finally, sensory examination of a mus, it is the (crossed) anterolateral pathway that is patient who has no neurologic complaints can be brief referred to as the spinothalamic tract, by convention. and consist of pinprick, touch, and vibration testing in the Although the fiber types and functions that make up hands and feet plus evaluation of stance and gait, including the spinothalamic and lemniscal systems are relatively the Romberg maneuver. Evaluation of stance and gait also well known, many other fibers, particularly those associ- tests the integrity of motor and cerebellar systems. ated with touch, pressure, and position sense, ascend in a diffusely distributed pattern both ipsilaterally and con- Primary Sensation tralaterally in the anterolateral quadrants of the spinal cord. This explains why a complete lesion of the poste- (See Table 12-1) The sense of pain is usually tested with rior columns of the spinal cord may be associated with a clean pin, asking the patient to focus on the pricking little sensory deficit on examination. or unpleasant quality of the stimulus and not just the pressure or touch sensation elicited. Areas of hypalgesia EXAMINATION OF SENSATION should be mapped by proceeding radially from the most hypalgesic site (Figs. 12-2 and 12-3). The main components of the sensory examination are tests of primary sensation (pain, touch, vibration, joint Temperature sensation, to both hot and cold, is best position, and thermal sensation; Table 12-1). tested with small containers filled with water of the desired temperature. This is impractical in most settings. Some general principles pertain. The examiner must An alternative way to test cold sensation is to touch a depend on patient responses, particularly when testing metal object, such as a tuning fork at room temperature, cutaneous sensation (pin, touch, warm, or cold), which to the skin. For testing warm temperatures, the tuning complicates interpretation. Further, examination may be fork or other metal object may be held under warm limited in some patients. In a stuporous patient, for exam- water of the desired temperature and then used. The ple, sensory examination is reduced to observing the brisk- appreciation of both cold and warmth should be tested ness of withdrawal in response to a pinch or other noxious because different receptors respond to each. stimulus. Comparison of response on one side of the body to the other is essential. In the alert but uncooperative Touch is usually tested with a wisp of cotton or a fine patient, it may not be possible to examine cutaneous camelhair brush. In general, it is better to avoid testing touch on hairy skin because of the profusion of sensory endings that surround each hair follicle. TABLE 12-1 TESTING PRIMARY SENSATION SENSE TEST DEVICE ENDINGS ACTIVATED FIBER SIZE CENTRAL PATHWAY MEDIATING Pain Pinprick Cutaneous nociceptors SpTh, also D Temperature, heat Warm metal object Cutaneous thermoreceptors for hot Small SpTh Temperature, cold Cold metal object Cutaneous thermoreceptors for cold Small SpTh Touch Cotton wisp, Cutaneous mechanoreceptors, Small Lem, also D and SpTh fine brush also naked endings Large and Vibration Tuning fork, 128 Hz Mechanoreceptors, especially small Lem, also D pacinian corpuscles Large Joint position Passive movement Joint capsule and tendon endings, Lem, also D of specific joints muscle spindles Large Note: D, diffuse ascending projections in ipsilateral and contralateral anterolateral columns; SpTh, spinothalamic projection, contralateral; Lem, posterior column and lemniscal projection, ipsilateral.

Ophthalmic n. Greater occipital n. 119 Greater auricular n. C2 Lesser occipital n. Maxillary n. Greater auricular n. Mandibular n. C2 Great auricular n. Transverse colli n. C3 C4 Transverse colli n. Cutaneous branches of C3 dorsal rami of spinal nn. C5 Supraclavicular nn. T2 C4 T2 Supraclavicular n. CHAPTER 12 Numbness, Tingling, and Sensory Loss T1 T4 Intercostal nn. C5 T4 C6 T6 1. Ant cutaneous rami T6 Lat. cutaneous branches C7 T8 2. Lat cutaneous rami T1 T8 of intercostal n. T10 L1 Axillary n. C6 T10 Axillary n. T12 C7 Med. brachial cutaneous T12 Post. brachial cutaneous n. and intercostobrachial nn. L1 L2 Med. brachial cutaneous Med. antebrachial and intercostobrachial nn. cutaneous n. S4 Post. antebrachial Lat. antebrachial S3 cutaneous n. cutaneous n. Lat. antebrachial Radial n. cutaneous n. Median n. Med antebrachial Ulnar n. cutaneous n. Iliohypogastric n. Ilioinguinal n. Radial n. Genitofemoral n. Ulnar n. C8 L2 Lat femoral cutaneous n. C8 S2 Median n. L3 Obturator n. L2 Iliohypogastric n. L5 Ant femoral cutaneous n. Saphenous n. Cluneal nn. Lat. sural cutaneous n. Obturator n. Ant. femoral cutaneous n. L3 Lat. femoral cutaneous n. L4 L4 Post. femoral cutaneous n. L5 Lat. sural cutaneous n. Superficial peroneal n. S1 Sural n. Saphenous n. S1 Sural n. L5 Calcaneal nn. Medial plantar n. Deep peroneal n. Saphenous n. Plantar branches of tibial n. FIGURE 12-2 Anterior view of dermatomes (left) and cutaneous areas FIGURE 12-3 (right) supplied by individual peripheral nerves. (Modified Posterior view of dermatomes (left) and cutaneous areas from MB Carpenter and J Sutin, in Human Neuroanatomy, (right) supplied by individual peripheral nerves. (Modified 8th ed. Baltimore, Williams & Wilkins, 1983.) from MB Carpenter and J Sutin, in Human Neuroanatomy, 8th ed. Baltimore, Williams & Wilkins, 1983.) Joint position testing is a measure of proprioception, Vibratory thresholds at the same site in the patient and one of the most important functions of the sensory sys- the examiner may be compared for control purposes. tem.With the patient’s eyes closed, joint position is tested in the distal interphalangeal joint of the great toe and fin- Quantitative Sensory Testing gers. If errors are made in recognizing the direction of passive movements, more proximal joints are tested. A test Effective sensory testing devices are now available com- of proximal joint position sense, primarily at the shoulder, mercially. Quantitative sensory testing is particularly use- is performed by asking the patient to bring the two index ful for serial evaluation of cutaneous sensation in clinical fingers together with arms extended and eyes closed. trials. Threshold testing for touch and vibratory and Normal individuals can do this accurately, with errors of thermal sensation is the most widely used application. 1 cm or less. Cortical Sensation The sense of vibration is tested with a tuning fork that vibrates at 128 Hz. Vibration is usually tested over The most commonly used tests of cortical function are bony points, beginning distally; in the feet, it is tested two-point discrimination, touch localization, and bilat- over the dorsal surface of the distal phalanx of the big eral simultaneous stimulation and tests for graphesthesia toes and at the malleoli of the ankles, and in the hands and stereognosis. Abnormalities of these sensory tests, in dorsally at the distal phalanx of the fingers. If abnormali- the presence of normal primary sensation in an alert ties are found, more proximal sites can be examined.

SECTION II Clinical Manifestations of Neurologic Disease120 cooperative patient, signify a lesion of the parietal cortex dysesthesias can also be an early event in an evolving or thalamocortical projections to the parietal lobe. If polyneuropathy or may herald a myelopathy, such as from primary sensation is altered, these cortical discriminative vitamin B12 deficiency. Sometimes distal dysesthesias have functions will usually be abnormal also. Comparisons no definable basis. In contrast, dysesthesias that corre- should always be made between analogous sites on the spond to a particular peripheral nerve territory denote a two sides of the body because the deficit with a specific lesion of that nerve trunk. For instance, dysesthesias parietal lesion is likely to be unilateral. Interside com- restricted to the fifth digit and the adjacent one-half of parisons are important for all cortical sensory testing. the fourth finger on one hand reliably point to disorder Two-point discrimination is tested by special calipers, the of the ulnar nerve, most commonly at the elbow. points of which may be set from 2 mm to several cen- timeters apart and then applied simultaneously to the Nerve and Root site to be tested.The pulp of the fingertips is a common site to test; a normal individual can distinguish about In focal nerve trunk lesions severe enough to cause a 3-mm separation of points there. deficit, sensory abnormalities are readily mapped and gen- Touch localization is performed by light pressure for an erally have discrete boundaries (Figs. 12-2 and 12-3). instant with the examiner’s fingertip or a wisp of cotton- Root (“radicular”) lesions are frequently accompanied by wool; the patient, whose eyes are closed, is required to deep, aching pain along the course of the related nerve identify the site of touch with the fingertip. Bilateral simul- trunk. With compression of a fifth lumbar (L5) or first taneous stimulation at analogous sites (e.g., the dorsum of sacral (S1) root, as from a ruptured intervertebral disc, sci- both hands) can be carried out to determine whether the atica (radicular pain relating to the sciatic nerve trunk) is a perception of touch is extinguished consistently on one frequent manifestation (Chap. 7).With a lesion affecting a side or the other. The phenomenon is referred to as single root, sensory deficits may be minimal or absent extinction. Graphesthesia means the capacity to recognize because adjacent root territories overlap extensively. with eyes closed letters or numbers drawn by the exam- iner’s fingertip on the palm of the hand. Once again, With polyneuropathies, sensory deficits are generally interside comparison is of prime importance. Inability to graded, distal, and symmetric in distribution (Chap. 40). recognize numbers or letters is termed agraphesthesia. Dysesthesias, followed by numbness, begin in the toes Stereognosis refers to the ability to identify common and ascend symmetrically. When dysesthesias reach the objects by palpation, recognizing their shape, texture, knees, they have usually also appeared in the fingertips. and size. Common standard objects, such as a key, paper The process appears to be nerve length–dependent, and clip, or coins, are best used. Patients with normal stere- the deficit is often described as “stocking-glove” in type. ognosis should be able to distinguish a dime from a Involvement of both hands and feet also occurs with penny and a nickel from a quarter without looking. lesions of the upper cervical cord or the brainstem, but Patients should only be allowed to feel the object with an upper level of the sensory disturbance may then be one hand at a time. If they are unable to identify it in found on the trunk and other evidence of a central one hand, it should be placed in the other for compari- lesion may be present, such as sphincter involvement or son. Individuals unable to identify common objects and signs of an upper motor neuron lesion (Chap. 10). coins in one hand and who can do so in the other are Although most polyneuropathies are pansensory and said to have astereognosis of the abnormal hand. affect all modalities of sensation, selective sensory dys- function according to nerve fiber size may occur. Small- LOCALIZATION OF SENSORY fiber polyneuropathies are characterized by burning, ABNORMALITIES painful dysesthesias with reduced pinprick and thermal sensation but sparing of proprioception, motor function, Sensory symptoms and signs can result from lesions at and deep tendon reflexes. Touch is involved variably; almost any level of the nervous system from parietal when spared, the sensory pattern is referred to as exhibit- cortex to the peripheral sensory receptor. Noting the ing sensory dissociation. Sensory dissociation may occur distribution and nature of sensory symptoms and signs is with spinal cord lesions as well as small-fiber neu- the most important way to localize their source. Their ropathies. Large-fiber polyneuropathies are characterized extent, configuration, symmetry, quality, and severity are by vibration and position sense deficits, imbalance, absent the key observations. tendon reflexes, and variable motor dysfunction but preservation of most cutaneous sensation. Dysesthesias, if Dysesthesias without sensory findings by examina- present at all, tend to be tingling or bandlike in quality. tion may be difficult to interpret. To illustrate, tingling dysesthesias in an acral distribution (hands and feet) can Spinal Cord be systemic in origin, e.g., secondary to hyperventilation, or induced by a medication such as acetazolamide. Distal (See Chap. 30) If the spinal cord is transected, all sensation is lost below the level of transection. Bladder and bowel

function are also lost, as is motor function. Hemisection Thalamus 121 of the spinal cord produces the Brown-Séquard syn- drome, with absent pain and temperature sensation con- Hemisensory disturbance with tingling numbness from CHAPTER 12 Numbness, Tingling, and Sensory Loss tralaterally and loss of proprioceptive sensation and power head to foot is often thalamic in origin but can also arise ipsilaterally below the lesion (see Figs. 12-1 and 30-1). from the anterior parietal region. If abrupt in onset, the lesion is likely to be due to a small stroke (lacunar Numbness or paresthesias in both feet may arise from a infarction), particularly if localized to the thalamus. spinal cord lesion; this is especially likely when the upper Occasionally, with lesions affecting the VPL nucleus or level of the sensory loss extends to the trunk. When all adjacent white matter, a syndrome of thalamic pain, also extremities are affected, the lesion is probably in the cer- called Déjerine-Roussy syndrome, may ensue. The persis- vical region or brainstem unless a peripheral neuropathy tent, unrelenting unilateral pain is often described in is responsible. The presence of upper motor neuron signs dramatic terms. (Chap. 10) supports a central lesion; a hyperesthetic band on the trunk may suggest the level of involvement. Cortex A dissociated sensory loss can reflect spinothalamic With lesions of the parietal lobe involving either the tract involvement in the spinal cord, especially if the cortex or subjacent white matter, the most prominent deficit is unilateral and has an upper level on the torso. symptoms are contralateral hemineglect, hemi-inatten- Bilateral spinothalamic tract involvement occurs with tion, and a tendency not to use the affected hand and lesions affecting the center of the spinal cord, such as in arm. On cortical sensory testing (e.g., two-point dis- syringomyelia. There is a dissociated sensory loss with crimination, graphesthesia), abnormalities are often impairment of pinprick and temperature appreciation found but primary sensation is usually intact. Anterior but relative preservation of light touch, position sense, parietal infarction may present as a pseudothalamic syn- and vibration appreciation. drome with contralateral loss of primary sensation from head to toe. Dysesthesias or a sense of numbness may Dysfunction of the posterior columns in the spinal also occur, and rarely, a painful state. cord or of the posterior root entry zone may lead to a bandlike sensation around the trunk or a feeling of tight Focal Sensory Seizures pressure in one or more limbs. Flexion of the neck sometimes leads to an electric shock–like sensation that These are generally due to lesions in the area of the radiates down the back and into the legs (Lhermitte’s postcentral or precentral gyrus. The principal symptom sign) in patients with a cervical lesion affecting the pos- of focal sensory seizures is tingling, but additional, more terior columns, such as from multiple sclerosis, cervical complex sensations may occur, such as a rushing feeling, spondylosis, or recent irradiation to the cervical region. a sense of warmth, or a sense of movement without detectable motion. Symptoms typically are unilateral; Brainstem commonly begin in the arm or hand, face, or foot; and often spread in a manner that reflects the cortical repre- Crossed patterns of sensory disturbance, in which one side sentation of different bodily parts, as in a Jacksonian of the face and the opposite side of the body are affected, march. Duration of seizures is variable; they may be localize to the lateral medulla. Here a small lesion may transient, lasting only for seconds, or persist for an hour damage both the ipsilateral descending trigeminal tract or more. Focal motor features may supervene, often and ascending spinothalamic fibers subserving the oppo- becoming generalized with loss of consciousness and site arm, leg, and hemitorso (see Lateral medullary syn- tonic-clonic jerking. drome in Fig. 21-10). A lesion in the tegmentum of the pons and midbrain, where the lemniscal and spinothalamic tracts merge, causes pansensory loss contralaterally.

CHAPTER 13 CONFUSION AND DELIRIUM Scott Andrew Josephson I Bruce L. Miller Clinical Features of Delirium . . . . . . . . . . . . . . . . . . . . . . . . . 122 Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 Confusion, a mental and behavioral state of reduced Delirium is a clinical diagnosis that can only be made comprehension, coherence, and capacity to reason, is at the bedside. Two broad clinical categories of delirium one of the most common problems encountered in have been described, hyperactive and hypoactive sub- medicine, accounting for a large number of emergency types, based on differential psychomotor features. The department visits, hospital admissions, and inpatient con- cognitive syndrome associated with severe alcohol with- sultations. Delirium, a term used to describe an acute drawal remains the classic example of the hyperactive confusional state, remains a major cause of morbidity subtype, featuring prominent hallucinations, agitation, and mortality, contributing billions of dollars yearly to and hyperarousal, often accompanied by life-threatening health care costs in the United States alone. Delirium autonomic instability. In striking contrast is the hypoac- often goes unrecognized despite clear evidence that it is tive subtype of delirium, exemplified by opiate intoxica- usually the cognitive manifestation of serious underlying tion, in which patients are withdrawn and quiet, with medical or neurologic illness. prominent apathy and psychomotor slowing. CLINICAL FEATURES OF DELIRIUM This dichotomy between subtypes of delirium is a useful construct, but patients often fall somewhere along A multitude of terms are used to describe delirium, a spectrum between the hyperactive and hypoactive including encephalopathy, acute brain failure, acute con- extremes, sometimes fluctuating from one to the other fusional state, and postoperative or intensive care unit within minutes. Therefore, clinicians must recognize the (ICU) psychosis. Delirium has many clinical manifesta- broad range of presentations of delirium in order to tions, but essentially it is defined as a relatively acute identify all patients with this potentially reversible cog- decline in cognition that fluctuates over hours or days. nitive disturbance. Hyperactive patients, such as those The hallmark of delirium is a deficit of attention, with delirium tremens, are easily recognized by their although all cognitive domains—including memory, characteristic severe agitation, tremor, hallucinations, and executive function, visuospatial tasks, and language—are autonomic instability. Patients who are quietly disturbed variably involved. Associated symptoms may include are more often overlooked on the medical wards and in altered sleep-wake cycles, perceptual disturbances such the ICU, yet multiple studies suggest that this under- as hallucinations or delusions, affect changes, and auto- recognized hypoactive subtype is associated with worse nomic findings including heart rate and blood pressure outcomes. instability. The reversibility of delirium is emphasized because many etiologies, such as systemic infection and medication 122

effects, can be easily treated. However, the long-term prominent visual hallucinations, parkinsonism, and an 123 CHAPTER 13 Confusion and Delirium cognitive effects of delirium remain largely unknown and attentional deficit that clinically resembles hyperactive understudied. Some episodes of delirium continue for delirium. Delirium in the elderly often reflects an insult weeks, months, or even years. The persistence of delir- to the brain that is vulnerable due to an underlying ium in some patients and its high recurrence rate may neurodegenerative condition. Therefore, the develop- be due to inadequate treatment of the underlying etiol- ment of delirium sometimes heralds the onset of a pre- ogy for the syndrome. In some instances, delirium does viously unrecognized brain disorder. not disappear because there is underlying permanent neuronal damage. Even after an episode of delirium EPIDEMIOLOGY resolves, there may still be lingering effects of the disor- der. A patient’s recall of events after delirium varies Delirium is a common disease, but its reported inci- widely, ranging from complete amnesia to repeated dence has varied widely based on the criteria used to reexperiencing of the frightening period of confusion in define the disorder. Estimates of delirium in hospitalized a disturbing manner, similar to what is seen in patients patients range from 14 to 56%, with higher rates with posttraumatic stress disorder. reported for elderly patients and patients undergoing hip surgery. Older patients in the ICU have especially high RISK FACTORS rates of delirium ranging from 70 to 87%.The condition is not recognized in up to one-third of delirious inpa- An effective primary prevention strategy for delirium tients, and the diagnosis is especially problematic in the begins with identification of patients at highest risk, includ- ICU environment where cognitive dysfunction is often ing those preparing for elective surgery or being admitted difficult to appreciate in the setting of serious systemic to the hospital.Although no single validated scoring system illness and sedation. Delirium in the ICU should be has been widely accepted as a screen for asymptomatic viewed as an important manifestation of organ dysfunc- patients, there are multiple well-established risk factors for tion not unlike liver, kidney, or heart failure. Outside delirium. of the acute hospital setting, delirium occurs in nearly two-thirds of patients in nursing homes and in over 80% The two most consistently identified risks are older age of those at the end of life.These estimates emphasize the and baseline cognitive dysfunction. Individuals who are remarkably high frequency of this cognitive syndrome in older than 65 years or exhibit low scores on standardized older patients, a population expected to grow in the tests of cognition develop delirium upon hospitalization at upcoming decade with the aging of the “baby boom” a rate approaching 50%. Whether age and baseline cogni- generation. tive dysfunction are truly independent risk factors is uncertain. Other predisposing factors include sensory In previous decades an episode of delirium was viewed deprivation, such as preexisting hearing and visual impair- as a transient condition that carried a benign prognosis. ment, as well as indices for poor overall health, including Delirium has now been clearly associated with substan- baseline immobility, malnutrition, and underlying medical tial morbidity and increased mortality, and is increasingly or neurologic illness. recognized as a sign of serious underlying illness. Recent estimates of in-hospital mortality among delirious patients In-hospital risks for delirium include the use of blad- have ranged from 25–33%, a rate that is similar to patients der catheterization, physical restraints, sleep and sensory with sepsis. Patients with an in-hospital episode of delir- deprivation, and the addition of three or more new ium have a higher mortality in the months and years medications. Avoiding such risks remains a key compo- following their illness compared with age-matched non- nent of delirium prevention as well as treatment. Surgi- delirious hospitalized patients. Delirious hospitalized cal and anesthetic risk factors for the development of patients have a longer length of stay, are more likely to postoperative delirium include specific procedures such be discharged to a nursing home, and are more likely to as those involving cardiopulmonary bypass and inade- experience subsequent episodes of delirium; as a result, quate or excessive treatment of pain in the immediate this condition has enormous economic implications. postoperative period. PATHOGENESIS The relationship between delirium and dementia (Chap. 23) is complicated by significant overlap between The pathogenesis and anatomy of delirium are incom- these two conditions, and it is not always simple to dis- pletely understood. The attentional deficit that serves as tinguish between the two. Dementia and preexisting the neuropsychological hallmark of delirium appears to cognitive dysfunction serve as major risk factors for have a diffuse localization with the brainstem, thalamus, delirium, and at least two-thirds of cases of delirium prefrontal cortex, thalamus, and parietal lobes. Rarely, occur in patients with coexisting underlying dementia. A form of dementia with parkinsonism, termed dementia with Lewy bodies, is characterized by a fluctuating course,

SECTION II Clinical Manifestations of Neurologic Disease124 focal lesions such as ischemic strokes have led to delir- Approach to the Patient: ium in otherwise healthy persons; right parietal and DELIRIUM medial dorsal thalamic lesions have been reported most commonly, stressing the relevance of these areas to delir- As the diagnosis of delirium is clinical and made at ium pathogenesis. In most cases, delirium results from the bedside, a careful history and physical examina- widespread disturbances in cortical and subcortical tion is necessary when evaluating patients with possi- regions, rather than a focal neuroanatomic cause. Elec- ble confusional states. Screening tools can aid physi- troencephalogram (EEG) data in persons with delirium cians and nurses in identifying patients with delirium, usually show symmetric slowing, a nonspecific finding including the Confusion Assessment Method (CAM) supporting diffuse cerebral dysfunction. (Table 13-1); the Organic Brain Syndrome Scale; the Deficiency of acetylcholine often plays a key role in Delirium Rating Scale; and, in the ICU, the Delirium delirium pathogenesis. Medications with anticholinergic Detection Score and the ICU version of the CAM. properties can precipitate delirium in susceptible indi- These scales are based on criteria from the American viduals, and therapies designed to boost cholinergic tone Psychiatric Association’s Diagnostic and Statistical Man- such as cholinesterase inhibitors have, in small trials, ual of Mental Disorders (DSM) or the World Health been shown to relieve symptoms of delirium. Dementia Organization’s International Classification of Diseases patients are susceptible to episodes of delirium, and (ICD). Unfortunately, these scales themselves do not those with Alzheimer’s pathology are known to have a identify the full spectrum of patients with delirium. chronic cholinergic deficiency state due to degeneration All patients who are acutely confused should be pre- of acetylcholine-producing neurons in the basal fore- sumed delirious regardless of their presentation due brain. Another common dementia associated with to the wide variety of possible clinical features.A course decreased acetylcholine levels, dementia with Lewy bod- ies, clinically mimics delirium in some patients. Other TABLE 13-1 neurotransmitters are also likely involved in this diffuse cerebral disorder. For example, increases in dopamine THE CONFUSION ASSESSMENT METHOD (CAM) can also lead to delirium. Patients with Parkinson’s dis- DIAGNOSTIC ALGORITHM ease treated with dopaminergic medications can develop a delirious-like state that features visual hallucinations, The diagnosis of delirium requires the presence of fluctuations, and confusion. In contrast, reducing dopamin- features 1 and 2 and of either 3 or 4.a ergic tone with dopamine antagonists such as typical and Feature 1: Acute onset and fluctuating course atypical antipsychotic medications has long been recog- This feature is satisfied by positive responses to nized as effective symptomatic treatment in patients with these questions: Is there evidence of an acute delirium. change in mental status from the patient’s baseline? Not all individuals exposed to the same insult will Did the (abnormal) behavior fluctuate during the develop signs of delirium. A low dose of an anticholin- day—that is, tend to come and go—or did it ergic medication may have no cognitive effects on a increase and decrease in severity? healthy young adult but may produce a florid delirium Feature 2: Inattention in an elderly person with known underlying dementia. This feature is satisfied by a positive response to this However, an extremely high dose of the same anti- question: Did the patient have difficulty focusing cholinergic medication may lead to delirium even in attention—for example, was easily distractible—or healthy young persons. This concept of delirium devel- have difficulty keeping track of what was being oping as the result of an insult in predisposed individu- said? als is currently the most widely accepted pathogenic Feature 3: Disorganized thinking construct. Therefore, if a previously healthy individual This feature is satisfied by a positive response to this with no known history of cognitive illness develops question: Was the patient’s thinking disorganized delirium in the setting of a relatively minor insult such or incoherent, such as rambling or irrelevant as elective surgery or hospitalization, then an unrecog- conversation, unclear or illogical flow of ideas, or nized underlying neurologic illness such as a neurode- unpredictable switching from subject to subject? generative disease, multiple previous strokes, or another Feature 4: Altered level of consciousness diffuse cerebral cause should be considered. In this con- This feature is satisfied by any answer other than text, delirium can be viewed as the symptom resulting “alert” to this question: Overall, how would you rate from a “stress test for the brain” induced by the insult. this patient’s level of consciousness: alert (normal), Exposure to known inciting factors such as systemic vigilant (hyperalert), lethargic (drowsy, easily infection or offending drugs can unmask a decreased cere- aroused), stupor (difficult to arouse), or coma bral reserve and herald a serious underlying and poten- (unarousable)? tially treatable illness. aInformation is usually obtained from a reliable reporter, such as a family member, caregiver, or nurse. Source: Modified from Inouye SK et al: Ann Intern Med 113:941, 1990.

that fluctuates over hours or days and may worsen at Other important elements of the history include 125 night (termed sundowning) is typical but not essential screening for symptoms of organ failure or systemic for the diagnosis. Observation of the patient will usu- infection, which often contributes to delirium in the CHAPTER 13 Confusion and Delirium ally reveal an altered level of consciousness or a deficit elderly. A history of illicit drug use, alcoholism, or of attention. Other hallmark features that may be pre- toxin exposure is common in younger delirious sent in the delirious patient include alteration of patients. Finally, asking the patient and collateral sleep-wake cycles, thought disturbances such as hallu- source about other symptoms that may accompany cinations or delusions, autonomic instability, and delirium, such as depression or hallucinations, may changes in affect. help identify potential therapeutic targets. HISTORY It may be difficult to elicit an accurate PHYSICAL EXAMINATION The general physical history in delirious patients who have altered levels of examination in a delirious patient should include a consciousness or impaired attention. Information careful screening for signs of infection such as fever, from a collateral source such as a spouse or other tachypnea, pulmonary consolidation, heart murmur, family member is therefore invaluable.The three most or stiff neck. The patient’s fluid status should be important pieces of history include the patient’s base- assessed; both dehydration and fluid overload with line cognitive function, the time course of the present resultant hypoxia have been associated with delirium, illness, and current medications. and each is usually easily rectified. The appearance of the skin can be helpful, showing jaundice in hepatic Premorbid cognitive function can be assessed encephalopathy, cyanosis in hypoxia, or needle tracks through the collateral source or, if needed, via a in patients using intravenous drugs. review of outpatient records. Delirium by definition represents a change that is relatively acute, usually over The neurologic examination requires a careful hours to days, from a cognitive baseline. As a result, an assessment of mental status. Patients with delirium acute confusional state is nearly impossible to diagnose often present with a fluctuating course; therefore the without some knowledge of baseline cognitive func- diagnosis can be missed when relying on a single tion. Without this information, many patients with time point of evaluation. Some but not all patients dementia or depression may be mistaken as delirious exhibit the characteristic pattern of sundowning, a during a single initial evaluation. Patients with a more worsening of their condition in the evening. In these hypoactive, apathetic presentation with psychomotor cases, assessment only during morning rounds may be slowing may only be identified as being different from falsely reassuring. baseline through conversations with family members. A number of validated instruments have been shown An altered level of consciousness ranging from to accurately diagnose cognitive dysfunction using a hyperarousal to lethargy to coma is present in most collateral source including the modified Blessed patients with delirium and can be easily assessed at Dementia Rating Scale and Clinical Dementia Rating the bedside. In the patient with a relatively normal (CDR). Baseline cognitive impairment is common in level of consciousness, a screen for an attentional patients with delirium. Even when no such history of deficit is in order, as this deficit is the classic neu- cognitive impairment is elicited, there should still be a ropsychological hallmark of delirium. Attention can high suspicion for previously unrecognized underlying be assessed while taking a history from the patient. neurologic disorder. Tangential speech, a fragmentary flow of ideas, or inability to follow complex commands often signifies Establishing the time course of cognitive change is an attentional problem. Formal neuropsychological important not only to make a diagnosis of delirium tests to assess attention exist, but a simple bedside test but also to correlate the onset of the illness with of digit span forward is quick and fairly sensitive. In potentially treatable etiologies such as recent medica- this task, patients are asked to repeat successively tion changes or symptoms of systemic infection. longer random strings of digits beginning with two digits in a row. Average adults can repeat a string of Medications remain a common cause of delirium, between five to seven digits before faltering; a digit especially those compounds with anticholinergic or span of four or less usually indicates an attentional sedative properties. It is estimated that nearly one- deficit unless hearing or language barriers are present. third of all cases of delirium are secondary to medica- tions, especially in the elderly. Medication histories More formal neuropsychological testing can be should include all prescription as well as over-the- extraordinarily helpful in assessing the delirious counter and herbal substances taken by the patient patient, but it is usually too cumbersome and time- and any recent changes in dosing or formulation, consuming in the inpatient setting. A simple Mini including substitution of generics for brand-name Mental Status Examination (MMSE) (Table 23-5) can medications. provide some information regarding orientation,

SECTION II Clinical Manifestations of Neurologic Disease126 language, and visuospatial skills; however, perfor- TABLE 13-2 mance of some tasks on the MMSE such as spelling “world” backwards or serial subtraction of digits will COMMON ETIOLOGIES OF DELIRIUM be impaired by delirious patients’ attentional deficits alone and are therefore unreliable. Toxins The remainder of the screening neurologic exami- Prescription medications: especially those with nation should focus on identifying new focal neuro- anticholinergic properties, narcotics and logic deficits. Focal strokes or mass lesions in isolation benzodiazepines are rarely the cause of delirium, but patients with Drugs of abuse: alcohol intoxication and alcohol underlying extensive cerebrovascular disease or neu- withdrawal, opiates, ecstasy, LSD, GHB, PCP, rodegenerative conditions may not be able to cogni- ketamine, cocaine tively tolerate even relatively small new insults. Poisons: inhalants, carbon monoxide, ethylene glycol, Patients should also be screened for additional signs pesticides of neurodegenerative conditions such as parkinson- ism, which is seen not only in idiopathic Parkinson’s Metabolic conditions disease but also in other dementing conditions such Electrolyte disturbances: hypoglycemia, hyperglycemia, as Alzheimer’s disease, dementia with Lewy bodies, hyponatremia, hypernatremia, hypercalcemia, and progressive supranuclear palsy. The presence of hypocalcemia, hypomagnesemia multifocal myoclonus or asterixis on the motor Hypothermia and hyperthermia examination is nonspecific but usually indicates a Pulmonary failure: hypoxemia and hypercarbia metabolic or toxic etiology of the delirium. Liver failure/hepatic encephalopathy Renal failure/uremia ETIOLOGY Some etiologies can be easily dis- Cardiac failure cerned through a careful history and physical exami- Vitamin deficiencies: B12, thiamine, folate, niacin nation, while others require confirmation with labo- Dehydration and malnutrition ratory studies, imaging, or other ancillary tests. A Anemia large, diverse group of insults can lead to delirium, and the cause in many patients is often multifactorial. Infections Common etiologies are listed in Table 13-2. Systemic infections: urinary tract infections, pneumonia, skin and soft tissue infections, sepsis Prescribed, over-the-counter, and herbal medica- CNS infections: meningitis, encephalitis, brain abscess tions are common precipitants of delirium. Drugs with anticholinergic properties, narcotics, and benzo- Endocrinologic conditions diazepines are especially frequent offenders, but Hyperthyroidism, hypothyroidism nearly any compound can lead to cognitive dysfunc- Hyperparathyroidism tion in a predisposed patient.While an elderly patient Adrenal insufficiency with baseline dementia may become delirious upon exposure to a relatively low dose of a medication, Cerebrovascular disorders other less-susceptible individuals may only become Global hypoperfusion states delirious with very high doses of the same medica- Hypertensive encephalopathy tion. This observation emphasizes the importance of Focal ischemic strokes and hemorrhages, especially correlating the timing of recent medication changes, nondominant parietal and thalamic lesions including dose and formulation, with the onset of cognitive dysfunction. Autoimmune disorders CNS vasculitis In younger patients especially, illicit drugs and Cerebral lupus toxins are common causes of delirium. In addition to more classic drugs of abuse, the recent rise in Seizure-related disorders availability of so-called club drugs, such as methyl- Nonconvulsive status epilepticus enedioxymethamphetamine (MDMA, ecstasy), γ- Intermittent seizures with prolonged post-ictal states hydroxybutyrate (GHB), and the PCP-like agent ketamine, has led to an increase in delirious young Neoplastic disorders persons presenting to acute care settings. Many com- Diffuse metastases to the brain mon prescription drugs such as oral narcotics and Gliomatosis cerebri benzodiazepines are now often abused and readily Carcinomatous meningitis available on the street. Alcohol intoxication with high serum levels can cause confusion, but more commonly Hospitalization Terminal end of life delirium Note: LSD, lysergic acid diethylamide; GHB, γ-hydroxybutyrate; PCP, phencyclidine; CNS, central nervous system. it is withdrawal from alcohol that leads to a classic hyperactive delirium. Alcohol and benzodiazepine withdrawal should be considered in all cases of delir- ium as even patients who drink only a few servings of alcohol every day can experience relatively severe withdrawal symptoms upon hospitalization.

Metabolic abnormalities such as electrolyte distur- It is very common for patients to experience delir- 127 bances of sodium, calcium, magnesium, or glucose can ium at the end of life in palliative care settings. This cause delirium, and mild derangements can lead to condition, sometimes described as terminal restlessness, substantial cognitive disturbances in susceptible indi- must be identified and treated aggressively as it is an viduals. Other common metabolic etiologies include important cause of patient and family discomfort at liver and renal failure, hypercarbia and hypoxia, vitamin the end of life. It should be remembered that these deficiencies of thiamine and B12, autoimmune disor- patients may also be suffering from more common ders including CNS vasculitis, and endocrinopathies etiologies of delirium such as systemic infection. such as thyroid and adrenal disorders. LABORATORY AND DIAGNOSTIC EVALUA- CHAPTER 13 Confusion and Delirium Systemic infections often cause delirium, especially in the elderly. A common scenario involves the devel- TION A cost-effective approach to the diagnostic opment of an acute cognitive decline in the setting of evaluation of delirium allows the history and physical a urinary tract infection in a patient with baseline examination to guide tests. No established algorithm dementia. Pneumonia, skin infections such as celluli- for workup will fit all delirious patients due to the tis, and frank sepsis can also lead to delirium.This so- staggering number of potential etiologies, but one called septic encephalopathy, often seen in the ICU, is step-wise approach is detailed in Table 13-3. If a likely due to the release of proinflammatory cytokines clear precipitant is identified early, such as an offend- and their diffuse cerebral effects. CNS infections such ing medication, then little further workup is required. as meningitis, encephalitis, and abscess are less-com- If, however, no likely etiology is uncovered with ini- mon etiologies of delirium; however, given the high tial evaluation, an aggressive search for an underlying mortality associated with these conditions when not cause should be initiated. treated quickly, clinicians must always maintain a high index of suspicion. Basic screening labs, including a complete blood count, electrolyte panel, and tests of liver and renal In some susceptible individuals, exposure to the function, should be obtained in all patients with delir- unfamiliar environment of a hospital can lead to delir- ium. In elderly patients, screening for systemic infection, ium.This etiology usually occurs as part of a multifac- including chest radiography, urinalysis and culture, and torial delirium and should be considered a diagnosis of possibly blood cultures, is important. In younger indi- exclusion after all other causes have been thoroughly viduals, serum and urine drug and toxicology screen- investigated. Many primary prevention and treatment ing may be appropriate early in the workup. Addi- strategies for delirium involve relatively simple meth- tional laboratory tests addressing other autoimmune, ods to address those aspects of the inpatient setting that endocrinologic, metabolic, and infectious etiologies are most confusing. should be reserved for patients in whom the diagnosis remains unclear after initial testing. Cerebrovascular etiologies are usually due to global hypoperfusion in the setting of systemic hypotension Multiple studies have demonstrated that brain from heart failure, septic shock, dehydration, or ane- imaging in patients with delirium is often unhelpful. mia. Focal strokes in the right parietal lobe and However, if the initial workup is unrevealing, most medial dorsal thalamus can rarely lead to a delirious clinicians quickly move toward imaging of the brain state. A more common scenario involves a new focal in order to exclude structural causes. A noncontrast stroke or hemorrhage causing confusion in a patient CT scan can identify large masses and hemorrhages who has decreased cerebral reserve. In these individu- but is otherwise relatively insensitive for discovering als, it is sometimes difficult to distinguish between an etiology of delirium. The ability of MRI to iden- cognitive dysfunction resulting from the new neu- tify most acute ischemic strokes as well as to provide rovascular insult itself and delirium due to the infec- neuroanatomic detail that gives clues to possible tious, metabolic, and pharmacologic complications infectious, inflammatory, neurodegenerative, and neo- that can accompany hospitalization after stroke. plastic conditions makes it the test of choice. Since MRI techniques are limited by availability, speed of Because a fluctuating course is often seen in delir- imaging, patient cooperation, and contraindications ium, intermittent seizures may be overlooked when to magnetic exposure, many clinicians begin with CT considering potential etiologies. Both nonconvulsive scanning and proceed to MRI if the etiology of delir- status epilepticus as well as recurrent focal or general- ium remains elusive. ized seizures followed by post-ictal confusion can cause delirium; EEG remains essential for this diag- Lumbar puncture (LP) must be obtained immedi- nosis. Seizure activity spreading from an electrical ately, after appropriate neuroimaging, in all patients in focus in a mass or infarct can explain global cognitive whom CNS infection is suspected. Spinal fluid exam- dysfunction caused by relatively small lesions. ination can also be useful in identifying inflammatory and neoplastic conditions as well as in the diagnosis

SECTION II Clinical Manifestations of Neurologic Disease128 TABLE 13-3 infections should be given appropriate antibiotics and underlying electrolyte disturbances judiciously cor- STEP-WISE EVALUATION OF A PATIENT WITH rected). These treatments often lead to prompt resolu- DELIRIUM tion of delirium. Blindly targeting the symptoms of delir- ium pharmacologically only serves to prolong the time Initial evaluation patients remain in the confused state and may mask History with special attention to medications (including important diagnostic information. Recent trials of med- over-the-counter and herbals) ications used to boost cholinergic tone in delirious General physical examination and neurologic patients have led to mixed results, and this strategy is examination not currently recommended. Complete blood count Electrolyte panel including calcium, magnesium, Relatively simple methods of supportive care can be phosphorus highly effective in treating patients with delirium. Reori- Liver function tests including albumin entation by the nursing staff and family combined with Renal function tests visible clocks, calendars, and outside-facing windows can reduce confusion. Sensory isolation should be pre- First-tier further evaluation guided by initial evaluation vented by providing glasses and hearing aids to those Systemic infection screen patients who need them. Sundowning can be Urinalysis and culture addressed to a large extent through vigilance to appro- Chest radiograph priate sleep-wake cycles. During the day, a well-lit room Blood cultures should be accompanied by activities or exercises to pre- Electrocardiogram vent napping. At night, a quiet, dark environment with Arterial blood gas limited interruptions by staff can assure proper rest. Serum and/or urine toxicology screen (perform earlier in These sleep-wake cycle interventions are especially young persons) important in the ICU setting as the usual constant 24-h Brain imaging with MRI with diffusion and gadolinium activity commonly provokes delirium. Attempting to (preferred) or CT mimic the home environment as much as possible has Suspected CNS infection: lumbar puncture following also been shown to help treat and even prevent delir- brain imaging ium. Visits from friends and family throughout the day Suspected seizure-related etiology: electroencephalogram minimize the anxiety associated with the constant flow (EEG) (if high suspicion should be performed of new faces of staff and physicians. Allowing hospital- immediately) ized patients to have access to home bedding, clothing, and nightstand objects makes the hospital environment Second-tier further evaluation less foreign and therefore less confusing. Simple stan- Vitamin levels: B12, folate, thiamine dard nursing practices such as maintaining proper Endocrinologic laboratories: thyroid-stimulating nutrition and volume status as well as managing incon- hormone (TSH) and free T4; cortisol tinence and skin breakdown also help to alleviate dis- Serum ammonia comfort and resulting confusion. Sedimentation rate Autoimmune serologies: antinuclear antibodies (ANA), In some instances, patients pose a threat to their own complement levels; p-ANCA, c-ANCA safety or to the safety of staff members, and acute man- Infectious serologies: rapid plasmin reagin (RPR); fungal agement is required. Bed alarms and personal sitters are and viral serologies if high suspicion; HIV antibody more effective and much less disorienting than physical Lumbar puncture (if not already performed) restraints. Chemical restraints should be avoided, but, Brain MRI with and without gadolinium (if not already when necessary, very-low-dose typical or atypical performed) antipsychotic medications administered on an as- needed basis are effective. The recent association of Note: p-ANCA, perinuclear antineutrophil cytoplasmic antibody; atypical antipsychotic use in the elderly with increased c-ANCA, cytoplasmic antineutrophil cytoplasmic antibody. mortality underscores the importance of using these medications judiciously and only as a last resort. Benzo- of hepatic encephalopathy through elevated CSF glu- diazepines are not as effective as antipsychotics and tamine levels. As a result, LP should be considered in often worsen confusion via their sedative properties. any delirious patient with a negative workup. EEG Although many clinicians still use benzodiazepines to does not have a routine role in the workup of delir- treat acute confusion, their use should be limited only ium, but it remains invaluable if seizure-related eti- to cases in which delirium is caused by alcohol or ben- ologies are considered. zodiazepine withdrawal. Treatment: DELIRIUM Management of delirium begins with treatment of the underlying inciting factor (e.g., patients with systemic

PREVENTION standardized protocols to address common risk factors 129 CHAPTER 13 Confusion and Delirium with the goal of decreasing the incidence of delirium. Given the high morbidity associated with delirium and the tremendously increased health care costs that ACKNOWLEDGMENT accompany it, development of an effective strategy to prevent delirium in hospitalized patients is extremely In the previous edition, Allan H. Ropper contributed to a sec- important. Successful identification of high-risk patients tion on acute confusional states that was incorporated into this is the first step, followed by initiation of appropriate current chapter. interventions. One trial randomized more than 850 elderly inpatients to simple standardized protocols used FURTHER READINGS to manage risk factors for delirium, including cognitive impairment, immobility, visual impairment, hearing FONG TG et al: Delirium in elderly adults: diagnosis, prevention, and impairment, sleep deprivation, and dehydration. Signifi- treatment. Nat Rev Neurol 5:210, 2009 cant reductions in the number and duration of episodes of delirium were observed in the treatment group, but GIRARD TD et al: Delirium in the intensive care unit. Crit Care 12 unfortunately delirium recurrence rates were unchanged. Suppl 3:S3, 2008 Recent trials in the ICU have focused on identifying sedatives, such as dexmedetomidine, that are less likely INOUYE SK et al: A multicomponent intervention to prevent delir- to lead to delirium in critically ill patients. All hospitals ium in hospitalized older patients. N Engl J Med 340:669, 1999 and health care systems should work toward developing LAT I et al:The impact of delirium on clinical outcomes in mechani- cally ventilated surgical and trauma patients. Crit Care Med 37:1898, 2009 RIKER RR et al: Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 301:489, 2009

CHAPTER 14 COMA Allan H. Ropper The Anatomy and Physiology of Coma . . . . . . . . . . . . . . . . . 131 Laboratory Studies and Imaging . . . . . . . . . . . . . . . . . . . . . . 136 Differential Diagnosis of Coma . . . . . . . . . . . . . . . . . . . . . . . 137 Brain Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 Coma is among the most common and striking prob- Yawning, coughing, swallowing, as well as limb and head lems in general medicine. It accounts for a substantial movements persist, but there are few, if any, meaningful portion of admissions to emergency departments and responses to the external and internal environment—in occurs on all hospital services. Because coma demands essence, an “awake coma.” Respiratory and autonomic immediate attention, the physician must employ an orga- functions are retained. The term “vegetative” is unfortu- nized approach. nate as it is subject to misinterpretation by laypersons. The possibility of incorrectly attributing meaningful There is a continuum of states of reduced alertness, behavior to these patients has created inordinate prob- the severest form being coma, a deep sleeplike state from lems. There are always accompanying signs that indicate which the patient cannot be aroused. Stupor refers to a extensive damage in both cerebral hemispheres, e.g., higher degree of arousability in which the patient can decerebrate or decorticate limb posturing and absent be awakened only by vigorous stimuli, accompanied by responses to visual stimuli (see later). In the closely motor behavior that leads to avoidance of uncomfort- related but less severe minimally conscious state the patient able or aggravating stimuli. Drowsiness, which is familiar may make intermittent rudimentary vocal or motor to all persons, simulates light sleep and is characterized responses. Cardiac arrest with cerebral hypoperfusion and by easy arousal and the persistence of alertness for brief head injuries are the most common causes of the vegeta- periods. Drowsiness and stupor are usually attended by tive and minimally conscious states (Chaps. 22 and 31). some degree of confusion (Chap. 13).A narrative descrip- The prognosis for regaining mental faculties once the tion of the level of arousal and of the type of responses vegetative state has supervened for several months is very evoked by various stimuli, precisely as observed at the poor, and after a year, almost nil, hence the term persistent bedside, is preferable to ambiguous terms such as lethargy, vegetative state. Most reports of dramatic recovery, when semicoma, or obtundation. investigated carefully, are found to yield to the usual rules for prognosis, but there have been rare instances in which Several other neurologic conditions render patients recovery has occurred to a demented condition and, in apparently unresponsive and thereby simulate coma, and rare childhood cases, to an even better state. certain subsyndromes of coma must be considered sepa- rately because of their special significance. Among the Quite apart from the above conditions, certain syn- latter, the vegetative state signifies an awake but nonre- dromes that affect alertness are prone to be misinterpreted sponsive state. These patients have emerged from coma as stupor or coma. Akinetic mutism refers to a partially or after a period of days or weeks to a state in which the fully awake state in which the patient is able to form eyelids are open, giving the appearance of wakefulness. 130

impressions and think but remains virtually immobile and damage the RAS or its projections; (2) destruction of 131 CHAPTER 14 Coma mute. The condition results from damage in the regions large portions of both cerebral hemispheres; and (3) sup- of the medial thalamic nuclei or the frontal lobes (partic- pression of reticulo-cerebral function by drugs, toxins, or ularly lesions situated deeply or on the orbitofrontal sur- metabolic derangements such as hypoglycemia, anoxia, faces), or from hydrocephalus. The term abulia is in uremia, and hepatic failure. essence a milder form of akinetic mutism, used to describe mental and physical slowness and diminished The proximity of the RAS to structures that control ability to initiate activity. It is also generally the result of pupillary function and eye movements permits clinical damage to the frontal lobe network (Chap. 15). Catatonia localization of the cause of coma in many cases. Pupillary is a curious hypomobile and mute syndrome that arises as enlargement with loss of light reaction and loss of verti- part of a major psychosis, usually schizophrenia or major cal and adduction movements of the eyes suggests that depression. Catatonic patients make few voluntary or the likely location of the lesion is in the upper brainstem. responsive movements, although they blink, swallow, and Conversely, preservation of pupillary reactivity and eye may not appear distressed.There are nonetheless signs that movements absolves the upper brainstem and indicates the patient is responsive, although it may take some inge- that widespread structural lesions or metabolic suppres- nuity on the part of the examiner to demonstrate them. sion of the cerebral hemispheres is responsible. For example, eyelid elevation is actively resisted, blinking occurs in response to a visual threat, and the eyes move Coma Due to Cerebral Mass Lesions concomitantly with head rotation, all of which are incon- and Herniations sistent with the presence of a brain lesion. It is character- The cranial cavity is separated into compartments by istic but not invariable in catatonia for the limbs to retain infoldings of the dura.The two cerebral hemispheres are the postures in which they have been placed by the separated by the falx, and the anterior and posterior fos- examiner (“waxy flexibility,” or catalepsy). Upon recovery, sae by the tentorium. Herniation refers to displacement such patients have some memory of events that occurred of brain tissue into a compartment that it normally does during their catatonic stupor. The appearance is superfi- not occupy. Many of the signs associated with coma, and cially similar to akinetic mutism, but clinical evidence of indeed coma itself, can be attributed to these tissue cerebral damage such as Babinski signs and hypertonicity shifts, and certain clinical configurations are characteristic of the limbs is lacking. The singular problem of brain of specific herniations (Fig. 14-1). They are in essence death is discussed later. “false localizing” signs since they derive from compres- sion of brain structures at a distance from the mass. The locked-in state describes yet another type of pseudocoma in which an awake patient has no means of C producing speech or volitional movement, but retains voluntary vertical eye movements and lid elevation, thus B allowing the patient to signal with a clear mind. The pupils are normally reactive. Such individuals have writ- A ten entire treatises using Morse code. The usual cause is an infarction or hemorrhage of the ventral pons, which D transects all descending corticospinal and corticobulbar pathways. A similar awake but de-efferented state occurs FIGURE 14-1 as a result of total paralysis of the musculature in severe Types of cerebral herniation. (A) uncal; (B) central; cases of Guillain-Barré syndrome (Chap. 41), critical ill- (C) transfalcial; (D) foraminal. ness neuropathy (Chap. 22), and pharmacologic neuro- muscular blockade. THE ANATOMY AND PHYSIOLOGY OF COMA Almost all instances of diminished alertness can be traced to widespread abnormalities of the cerebral hemispheres or to reduced activity of a special thalamocortical alert- ing system termed the reticular activating system. The proper functioning of this system, its ascending projec- tions to the cortex, and the cortex itself are required to maintain alertness and coherence of thought. It follows that the principal causes of coma are (1) lesions that