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InternalMed_Harrison. Inf. med. cluneal n. Inf. med. n. of thigh Post cut. n. of thigh Lat. cut. n.of calf (from common femoral n.) Saphenous n. (from femoral n.) Superficial peroneal n. (from common peroneal n.) Sural n. (from tibial n.) Calcanean branches of sural & tibial n’s. Ulnar n. Inf. lat. cluneal n’s. Median n. Obturator n. Med. cut. n. of thigh (from femoral n.) Lat. plantar n. Med. plantar n. Lat. plantar n. Superficial peroneal n. Saphenous n. Calcanean branches of tibial & sural n’s. Sural n. FIguRE 31-2 The cutaneous fields of peripheral nerves. (Reproduced by permission from W Haymaker, B Woodhall: Peripheral Nerve Injuries, 2nd ed. Philadelphia, Saunders, 1953.) FIguRE 31-3 Distribution of the sensory spinal roots on the surface of the body (dermatomes). (From D Sinclair: Mechanisms of Cutaneous Sensation. Oxford, UK, Oxford University Press, 1981; with permission from Dr. David Sinclair.)


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InternalMed_Harrison. Distal dysesthesias can also be an early event in an evolving polyneuropathy or may herald a myelopathy, such as from vitamin B12 deficiency. Sometimes distal dysesthesias have no definable basis. In contrast, dysesthesias that correspond in distribution to that of a particular peripheral nerve structure denote a lesion at that site. For instance, dysesthesias restricted to the fifth digit and the adjacent one-half of the fourth finger on one hand reliably point to disorder of the ulnar nerve, most commonly at the elbow.


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InternalMed_Harrison. Nerve and Root In focal nerve trunk lesions, sensory abnormalities are readily mapped and generally have discrete boundaries (Figs. 31-2 and 31-3). Root (“radicular”) lesions frequently are accompanied by deep, aching pain along the course of the related nerve trunk. With compression of a fifth lumbar (L5) or first sacral (S1) root, as from a ruptured intervertebral disk, sciatica (radicular pain relating to the sciatic nerve trunk) is a common manifestation (Chap. 22). With a lesion affecting a single root, sensory deficits may be minimal or absent because adjacent root territories overlap extensively.


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InternalMed_Harrison. Isolated mononeuropathies may cause symptoms beyond the territory supplied by the affected nerve, but abnormalities on examination typically are confined to appropriate anatomic boundaries. In multiple mononeuropathies, symptoms and signs occur in discrete territories supplied by different individual nerves and—as more nerves are affected—may simulate a polyneuropathy if deficits become confluent. With polyneuropathies, sensory deficits are generally graded, distal, and symmetric in distribution (Chap. 459). Dysesthesias, followed by numbness, begin in the toes and ascend symmetrically. When dysesthesias reach the knees, they usually also have appeared in the fingertips. The process is nerve length–dependent, and the deficit is often described as “stocking-glove” in type. Involvement of both hands and feet also occurs with lesions of the upper cervical cord or the brainstem, but an upper level of the sensory disturbance may then be found on the trunk and other evidence of a central


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InternalMed_Harrison. both hands and feet also occurs with lesions of the upper cervical cord or the brainstem, but an upper level of the sensory disturbance may then be found on the trunk and other evidence of a central lesion may be present, such as sphincter involvement or signs of an upper motor neuron lesion (Chap. 30). Although most polyneuropathies are pansensory and affect all modalities of sensation, selective sensory dysfunction according to nerve fiber size may occur. Small-fiber polyneuropa-161 thies are characterized by burning, painful dysesthesias with reduced pinprick and thermal sensation but with sparing of proprioception, motor function, and deep tendon reflexes. Touch is involved variably; when it is spared, the sensory pattern is referred to as exhibiting sensory dissociation. Sensory dissociation may occur also with spinal cord lesions as well as small-fiber neuropathies. Large-fiber polyneuropathies are characterized by vibration and position sense deficits, imbalance, absent tendon


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InternalMed_Harrison. may occur also with spinal cord lesions as well as small-fiber neuropathies. Large-fiber polyneuropathies are characterized by vibration and position sense deficits, imbalance, absent tendon reflexes, and variable motor dysfunction but preservation of most cutaneous sensation. Dysesthesias, if present at all, tend to be tingling or bandlike in quality.


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InternalMed_Harrison. Sensory neuronopathy (or ganglionopathy) is characterized by widespread but asymmetric sensory loss occurring in a non-lengthdependent manner so that it may occur proximally or distally and in the arms, legs, or both. Pain and numbness progress to sensory ataxia and impairment of all sensory modalities with time. This condition is usually paraneoplastic or idiopathic in origin (Chaps. 122 and 459) or related to an autoimmune disease, particularly Sjögren’s syndrome. Spinal Cord (See also Chap. 456) If the spinal cord is transected, all sensation is lost below the level of transection. Bladder and bowel function also are lost, as is motor function. Lateral hemisection of the spinal cord produces the Brown-Séquard syndrome, with absent pain and temperature sensation contralaterally and loss of proprioceptive sensation and power ipsilaterally below the lesion (see Figs. 31-1 and 456-1).


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InternalMed_Harrison. Numbness or paresthesias in both feet may arise from a spinal cord lesion; this is especially likely when the upper level of the sensory loss extends to the trunk. When all extremities are affected, the lesion is probably in the cervical region or brainstem unless a peripheral neuropathy is responsible. The presence of upper motor neuron signs (Chap. 30) supports a central lesion; a hyperesthetic band on the trunk may suggest the level of involvement. A dissociated sensory loss can reflect spinothalamic tract involvement in the spinal cord, especially if the deficit is unilateral and has an upper level on the torso. Bilateral spinothalamic tract involvement occurs with lesions affecting the center of the spinal cord, such as in syringomyelia. There is a dissociated sensory loss with impairment of pinprick and temperature appreciation but relative preservation of light touch, position sense, and vibration appreciation.


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InternalMed_Harrison. Dysfunction of the posterior columns in the spinal cord or of the posterior root entry zone may lead to a bandlike sensation around the trunk or a feeling of tight pressure in one or more limbs. Flexion of the neck sometimes leads to an electric shock–like sensation that radiates down the back and into the legs (Lhermitte’s sign) in patients with a cervical lesion affecting the posterior columns, such as from multiple sclerosis, cervical spondylosis, or recent irradiation to the cervical region.


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InternalMed_Harrison. Brainstem Crossed patterns of sensory disturbance, in which one side of the face and the opposite side of the body are affected, localize to the lateral medulla. Here a small lesion may damage both the ipsilateral descending trigeminal tract and the ascending spinothalamic fibers subserving the opposite arm, leg, and hemitorso (see “Lateral medullary syndrome” in Fig. 446-10). A lesion in the tegmentum of the pons and midbrain, where the lemniscal and spinothalamic tracts merge, causes pansensory loss contralaterally.


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InternalMed_Harrison. Thalamus Hemisensory disturbance with tingling numbness from head to foot is often thalamic in origin but also can arise from the anterior parietal region. If abrupt in onset, the lesion is likely to be due to a small stroke (lacunar infarction), particularly if localized to the thalamus. Occasionally, with lesions affecting the VPL nucleus or adjacent white matter, a syndrome of thalamic pain, also called Déjerine-Roussy syndrome, may ensue. The persistent, unrelenting unilateral pain often is described in dramatic terms. Cortex With lesions of the parietal lobe involving either the cortex or the subjacent white matter, the most prominent symptoms are contralateral hemineglect, hemi-inattention, and a tendency not to use


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InternalMed_Harrison. CHAPTER 31 Numbness, Tingling, and Sensory Loss 162 the affected hand and arm. On cortical sensory testing (e.g., two-point discrimination, graphesthesia), abnormalities are often found but primary sensation is usually intact. Anterior parietal infarction may present as a pseudothalamic syndrome with contralateral loss of primary sensation from head to toe. Dysesthesias or a sense of numbness and, rarely, a painful state may also occur.


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InternalMed_Harrison. Focal Sensory Seizures These seizures generally are due to lesions in the area of the postcentral or precentral gyrus. The principal symptom of focal sensory seizures is tingling, but additional, more complex sensations may occur, such as a rushing feeling, a sense of warmth, or a sense of movement without detectable motion. Symptoms typically are unilateral; commonly begin in the arm or hand, face, or foot; and often spread in a manner that reflects the cortical representation of different bodily parts, as in a Jacksonian march. Their duration is variable; seizures may be transient, lasting only for seconds, or persist for an hour or more. Focal motor features may supervene, often becoming generalized with loss of consciousness and tonic-clonic jerking. Arthur Asbury authored or co-authored this chapter in earlier editions of this book. PART 2 Cardinal Manifestations and Presentation of Diseases PREVALENCE, MORBIDITY, AND MORTALITY


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InternalMed_Harrison. Arthur Asbury authored or co-authored this chapter in earlier editions of this book. PART 2 Cardinal Manifestations and Presentation of Diseases PREVALENCE, MORBIDITY, AND MORTALITY Gait and balance problems are common in the elderly and contribute to the risk of falls and injury. Gait disorders have been described in 15% of individuals older than 65. By age 80 one person in four will use a mechanical aid to assist with ambulation. Among those 85 and older, the prevalence of gait abnormality approaches 40%. In epidemiologic studies, gait disorders are consistently identified as a major risk factor for falls and injury.


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InternalMed_Harrison. A substantial number of older persons report insecure balance and experience falls and fear of falling. Prospective studies indicate that 30% of those older than 65 fall each year. The proportion is even higher in frail elderly and nursing home patients. Each year, 8% of individuals older than 75 suffer a serious fall-related injury. Hip fractures result in hospitalization, can lead to nursing home admission, and are associated with an increased mortality risk in the subsequent year. For each person who is physically disabled, there are others whose functional independence is limited by anxiety and fear of falling. Nearly one in five elderly individuals voluntarily restricts his or her activity because of fear of falling. With loss of ambulation, the quality of life diminishes, and rates of morbidity and mortality increase.


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InternalMed_Harrison. An upright bipedal gait depends on the successful integration of postural control and locomotion. These functions are widely distributed in the central nervous system. The biomechanics of bipedal walking are complex, and the performance is easily compromised by a neurologic deficit at any level. Command and control centers in the brain-stem, cerebellum, and forebrain modify the action of spinal pattern generators to promote stepping. While a form of “fictive locomotion” can be elicited from quadrupedal animals after spinal transection, this capacity is limited in primates. Step generation in primates is dependent on locomotor centers in the pontine tegmentum, midbrain, and subthalamic region. Locomotor synergies are executed through the reticular formation and descending pathways in the ventromedial spinal cord. Cerebral control provides a goal and purpose for walking and is involved in avoidance of obstacles and adaptation of locomotor programs to context and terrain.


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InternalMed_Harrison. Postural control requires the maintenance of the center of mass over the base of support through the gait cycle. Unconscious postural adjustments maintain standing balance: long latency responses are measurable in the leg muscles, beginning 110 milliseconds after a perturbation. Forward motion of the center of mass provides propulsive force for stepping, but failure to maintain the center of mass within stability limits results in falls. The anatomic substrate for dynamic balance has not been well defined, but the vestibular nucleus and midline cerebellum contribute to balance control in animals. Patients with damage to these structures have impaired balance while standing and walking.


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InternalMed_Harrison. Standing balance depends on good-quality sensory information about the position of the body center with respect to the environment, support surface, and gravitational forces. Sensory information for postural control is primarily generated by the visual system, the vestibular system, and proprioceptive receptors in the muscle spindles and joints. A healthy redundancy of sensory afferent information is generally available, but loss of two of the three pathways is sufficient to compromise standing balance. Balance disorders in older individuals sometimes result from multiple insults in the peripheral sensory systems (e.g., visual loss, vestibular deficit, peripheral neuropathy) that critically degrade the quality of afferent information needed for balance stability.


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InternalMed_Harrison. Older patients with cognitive impairment from neurodegenerative diseases appear to be particularly prone to falls and injury. There is a growing body of literature on the use of attentional resources to manage gait and balance. Walking is generally considered to be unconscious and automatic, but the ability to walk while attending to a cognitive task (dual-task walking) may be compromised in frail elderly individuals with a history of falls. Older patients with deficits in executive function may have particular difficulty in managing the attentional resources needed for dynamic balance when distracted.


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InternalMed_Harrison. Disorders of gait may be attributed to frailty, fatigue, arthritis, and orthopedic deformity, but neurologic causes are disabling and important to address. The heterogeneity of gait disorders observed in clinical practice reflects the large network of neural systems involved in the task. Walking is vulnerable to neurologic disease at every level. Gait disorders have been classified descriptively on the basis of abnormal physiology and biomechanics. One problem with this approach is that many failing gaits look fundamentally similar. This overlap reflects common patterns of adaptation to threatened balance stability and declining performance. The gait disorder observed clinically must be viewed as the product of a neurologic deficit and a functional adaptation. Unique features of the failing gait are often overwhelmed by the adaptive response. Some common patterns of abnormal gait are summarized next. Gait disorders can also be classified by etiology (Table 32-1).


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InternalMed_Harrison. Etiology No. of Cases Percent Source: Reproduced with permission from J Masdeu, L Sudarsky, L Wolfson: Gait Disorders of Aging. Lippincott Raven, 1997. The term cautious gait is used to describe the patient who walks with an abbreviated stride and lowered center of mass, as if walking on a slippery surface. This disorder is both common and nonspecific. It is, in essence, an adaptation to a perceived postural threat. There may be an associated fear of falling. This disorder can be observed in more than one-third of older patients with gait impairment. Physical therapy often improves walking to the degree that follow-up observation may reveal a more specific underlying disorder.


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InternalMed_Harrison. Spastic gait is characterized by stiffness in the legs, an imbalance of muscle tone, and a tendency to circumduct and scuff the feet. The disorder reflects compromise of corticospinal command and overactivity of spinal reflexes. The patient may walk on the toes. In extreme instances, the legs cross due to increased tone in the adductors. Upper motor neuron signs are present on physical examination. Shoes often reflect an uneven pattern of wear across the outside. The disorder may be cerebral or spinal in origin.


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InternalMed_Harrison. Myelopathy from cervical spondylosis is a common cause of spastic or spastic-ataxic gait in the elderly. Demyelinating disease and trauma are the leading causes of myelopathy in younger patients. In chronic progressive myelopathy of unknown cause, a workup with laboratory and imaging tests may establish a diagnosis. A family history should suggest hereditary spastic paraplegia (Chap. 452); genetic testing is now available for some of the common mutations responsible for this disorder. Tropical spastic paraparesis related to the retrovirus human T-cell lymphotropic virus 1 (HTLV-1) is endemic in parts of the Caribbean and South America. A structural lesion, such as a tumor or a spinal vascular malformation, should be excluded with appropriate testing. Spinal cord disorders are discussed in detail in Chap. 456.


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InternalMed_Harrison. With cerebral spasticity, asymmetry is common, the upper extremities are usually involved, and 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. 449) and stiff-person syndrome (Chap. 122). Dystonia is a disorder characterized by sustained muscle contractions resulting in repetitive twisting movements and abnormal posture. It often has a genetic basis. Dystonic spasms can produce plantar flexion and inversion of the feet, sometimes with torsion of the trunk. In autoimmune stiff-person syndrome, exaggerated lordosis of the lumbar spine and overactivation of antagonist muscles restrict trunk and lower-limb movement and result in a wooden or fixed posture.


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InternalMed_Harrison. Parkinson’s disease (Chap. 449) is common, affecting 1% of the population >55 years of age. The stooped posture and shuffling gait are characteristic and distinctive features. Patients sometimes accelerate (festinate) with walking, display retropulsion, or exhibit a tendency to turn en bloc. A National Institutes of Health workshop defined freezing of gait as “brief, episodic absence of forward progression of the feet, despite the intention to walk.” Gait freezing occurs in 26% of Parkinson’s patients by the end of 5 years and develops in most such patients eventually. Postural instability and falling occur as the disease progresses; some falls are precipitated by freezing of gait.


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InternalMed_Harrison. Freezing of gait is even more common in some Parkinson’s-related neurodegenerative disorders, such as progressive supranuclear palsy, multiple-system atrophy, and corticobasal degeneration. Patients with these disorders frequently present with axial stiffness, postural instability, and a shuffling, freezing gait while lacking the characteristic pill-rolling tremor of Parkinson’s disease. Falls within the first year suggest the possibility of progressive supranuclear palsy. Hyperkinetic movement disorders also produce characteristic and recognizable disturbances in gait. In Huntington’s disease (Chap. 449), the unpredictable occurrence of choreic movements gives the gait a dancing quality. Tardive dyskinesia is the cause of many odd, stereotypic gait disorders seen in patients chronically exposed to antipsychotics and other drugs that block the D2 dopamine receptor.


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InternalMed_Harrison. Frontal gait disorder, sometimes known as gait apraxia, is common in the elderly and has a variety of causes. The term is used to describe a shuffling, freezing gait with imbalance and other signs of higher cerebral dysfunction. Typical features include a wide base of support, a short stride, shuffling along the floor, and difficulty with starts and turns. Many patients exhibit a difficulty with gait initiation that is descriptively characterized as the “slipping clutch” syndrome or gait ignition failure. The term lower-body parkinsonism is also used to describe such patients. Strength is generally preserved, and patients are able to make stepping movements when not standing and maintaining their balance at the same time. This disorder is best considered a higher-level motor control disorder, as opposed to an apraxia (Chap. 36).


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InternalMed_Harrison. The most common cause of frontal gait disorder is vascular disease, particularly subcortical small-vessel disease. Lesions are frequently found in the deep frontal white matter and centrum ovale. Gait disorder may be the salient feature in hypertensive patients with ischemic lesions of the deep-hemisphere white matter (Binswanger’s disease). The clinical syndrome includes mental changes (variable in degree), dysarthria, pseudobulbar affect (emotional disinhibition), increased tone, and hyperreflexia in the lower limbs. Communicating hydrocephalus in adults also presents with a gait disorder of this type. Other features of the diagnostic triad (mental changes, incontinence) may be absent in the initial stages. MRI demonstrates ventricular enlargement, an enlarged flow void about the aqueduct, and a variable degree of periventricular white-matter change. A lumbar puncture or dynamic test is necessary to confirm hydrocephalus.


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InternalMed_Harrison. Disorders of the cerebellum have a dramatic impact on gait and balance. Cerebellar gait ataxia is characterized by a wide base of support, lateral instability of the trunk, erratic foot placement, and decompensation of balance when attempting to walk on a narrow base. Difficulty maintaining balance when turning is often an early feature. Patients are unable to walk tandem heel to toe and display truncal sway in narrow-based or tandem stance. They show considerable variation in their tendency to fall in daily life.


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InternalMed_Harrison. Causes of cerebellar ataxia in older patients include stroke, trauma, tumor, and neurodegenerative disease such as multiple-system atrophy (Chaps. 449 and 454) and various forms of hereditary cerebellar degeneration (Chap. 450). A short expansion at the site of the fragile X mutation (fragile X pre-mutation) has been associated with gait ataxia in older men. Alcoholic cerebellar degeneration can be screened by history and often confirmed by MRI. In patients with ataxia, MRI demonstrates the extent and topography of cerebellar atrophy.


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InternalMed_Harrison. As reviewed earlier in this chapter, balance depends on high-quality afferent information from the visual and the vestibular systems and proprioception. When this information is lost or degraded, balance during locomotion is impaired and instability results. The sensory ataxia of tabetic neurosyphilis is a classic example. The contemporary equivalent is the patient with neuropathy affecting large fibers. Vitamin B12 deficiency is a treatable cause of large-fiber sensory loss in the spinal cord and peripheral nervous system. Joint position and vibration sense are diminished in the lower limbs. The stance in such patients is destabilized by eye closure; they often look down at their feet when walking and do poorly in the dark. Table 32-2 compares sensory ataxia with cerebellar ataxia and frontal gait disorder. Some frail older patients exhibit a syndrome of imbalance from the combined effect of multiple sensory deficits. Such patients have disturbances in proprioception, vision, and


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InternalMed_Harrison. frontal gait disorder. Some frail older patients exhibit a syndrome of imbalance from the combined effect of multiple sensory deficits. Such patients have disturbances in proprioception, vision, and vestibular sense that impair postural support.


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InternalMed_Harrison. Patients with neuromuscular disease often have an abnormal gait, occasionally as a presenting feature. With distal weakness (peripheral neuropathy), the step height is increased to compensate for footdrop, and the sole of the foot may slap on the floor during weight acceptance. Neuropathy may be associated with a degree of sensory imbalance, as described earlier. Patients with myopathy or muscular dystrophy more TABLE 32-2 fEATuRES of CEREBELLAR ATAxiA, SEnSoRy ATAxiA, AnD fRonTAL gAiT DiSoRDERS Base of Wide-based Narrow base, Wide-based support Stride Irregular, Regular with Short, shuffling lurching path deviation Romberg test +/− Unsteady, falls +/− Turns Unsteady +/− Hesitant, multistep typically exhibit proximal weakness. Weakness of the hip girdle may result in some degree of excess pelvic sway during locomotion.


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InternalMed_Harrison. Turns Unsteady +/− Hesitant, multistep typically exhibit proximal weakness. Weakness of the hip girdle may result in some degree of excess pelvic sway during locomotion. Alcohol intoxication is the most common cause of acute walking difficulty. Chronic toxicity from medications and metabolic disturbances can impair motor function and gait. Mental status changes may be found, and examination may reveal asterixis or myoclonus. Static equilibrium is disturbed, and such patients are easily thrown off balance. Disequilibrium is particularly evident in patients with chronic renal disease and those with hepatic failure, in whom asterixis may impair postural support. Sedative drugs, especially neuroleptics and long-acting benzodiazepines, affect postural control and increase the risk for falls. These disorders are especially important to recognize because they are often treatable.


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InternalMed_Harrison. Psychogenic disorders are common in neurologic practice, and the presentation often involves gait. Some patients with extreme anxiety or phobia walk with exaggerated caution with abduction of the arms, as if walking on ice. This inappropriately overcautious gait differs in degree from the gait of the patient who is insecure and making adjustments for imbalance. Depressed patients exhibit primarily slowness, a manifestation of psychomotor retardation, and lack of purpose in their stride. Hysterical gait disorders are among the most spectacular encountered. Odd gyrations of posture with wastage of muscular energy (astasia–abasia), extreme slow motion, and dramatic fluctuations over time may be observed in patients with somatoform disorders and conversion reactions. APPROACH TO THE PATIENT: Slowly Progressive Disorder of gait PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. APPROACH TO THE PATIENT: Slowly Progressive Disorder of gait PART 2 Cardinal Manifestations and Presentation of Diseases When reviewing the history, it is helpful to inquire about the onset and progression of disability. Initial awareness of an unsteady gait often follows a fall. Stepwise evolution or sudden progression suggests vascular disease. Gait disorder may be associated with urinary urgency and incontinence, particularly in patients with cervical spine disease or hydrocephalus. It is always important to review the use of alcohol and medications that affect gait and balance. Information on localization derived from the neurologic examination can be helpful in narrowing the list of possible diagnoses.


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InternalMed_Harrison. Gait observation provides an immediate sense of the patient’s degree of disability. Arthritic and antalgic gaits are recognized by observation, though neurologic and orthopedic problems may coexist. Characteristic patterns of abnormality are sometimes seen, though, as stated previously, failing gaits often look fundamentally similar. Cadence (steps per minute), velocity, and stride length can be recorded by timing a patient over a fixed distance. Watching the patient rise from a chair provides a good functional assessment of balance.


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InternalMed_Harrison. Brain imaging studies may be informative in patients with an undiagnosed disorder of gait. MRI is sensitive for cerebral lesions of vascular or demyelinating disease and is a good screening test for occult hydrocephalus. Patients with recurrent falls are at risk for subdural hematoma. As mentioned earlier, many elderly patients with gait and balance difficulty have white matter abnormalities in the periventricular region and centrum semiovale. While these lesions may be an incidental finding, a substantial burden of white matter disease will ultimately impact cerebral control of locomotion. DEFINITION, ETIOLOgY, AND MANIFESTATIONS


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InternalMed_Harrison. DEFINITION, ETIOLOgY, AND MANIFESTATIONS Balance is the ability to maintain equilibrium—a state in which opposing physical forces cancel one another out. In physiology, this term is taken to mean the ability to control the center of mass with respect to gravity and the support surface. In reality, people are not consciously aware of their center of mass, but everyone (particularly gymnasts, figure skaters, and platform divers, for example) move so as to manage it. Disorders of balance present as difficulty maintaining posture while standing and walking and as a subjective sense of disequilibrium, which is a form of dizziness. The cerebellum and vestibular system organize antigravity responses needed to maintain an upright posture. These responses are physiologically complex, and the anatomic representation they entail is not well understood. Failure, resulting in disequilibrium, can occur at several levels: cerebellar, vestibular, somatosensory, and higher-level disequilibrium.


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InternalMed_Harrison. Patients with cerebellar ataxia do not generally complain of dizziness, though balance is visibly impaired. Neurologic examination reveals a variety of cerebellar signs. Postural compensation may prevent falls early on, but falls are inevitable with disease progression. The progression of neurodegenerative ataxia is often measured by the number of years to loss of stable ambulation. Vestibular disorders (Chap. 28) have symptoms and signs that fall into three categories: (1) vertigo (the subjective inappropriate perception or illusion of movement); (2) nystagmus (involuntary eye movements); and (3) impaired standing balance. Not every patient has all manifestations. Patients with vestibular deficits related to ototoxic drugs may lack vertigo or obvious nystagmus, but their balance is impaired on standing and walking, and they cannot navigate in the dark. Laboratory testing is available to investigate vestibular deficits.


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InternalMed_Harrison. Somatosensory deficits also produce imbalance and falls. There is often a subjective sense of insecure balance and fear of falling. Postural control is compromised by eye closure (Romberg’s sign); these patients also have difficulty navigating in the dark. A dramatic example is provided by the patient with autoimmune subacute sensory neuropathy, which is sometimes a paraneoplastic disorder (Chap. 122). Compensatory strategies enable such patients to walk in the virtual absence of proprioception, but the task requires active visual monitoring. Patients with higher-level disorders of equilibrium have difficulty maintaining balance in daily life and may present with falls. Their awareness of balance impairment may be reduced. Patients taking sedating medications are in this category. In prospective studies, dementia and sedating medications substantially increase the risk for falls.


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InternalMed_Harrison. Falls are common in the elderly; 30% of people older than 65 who are living in the community fall each year. Modest changes in balance function have been described in fit older individuals as a result of normal aging. Subtle deficits in sensory systems, attention, and motor reaction time contribute to the risk, and environmental hazards abound. Many falls by older adults are episodes of tripping or slipping, often designated mechanical falls. A fall is not a neurologic problem per se, but there are events for which neurologic evaluation is appropriate. It is important to distinguish falls associated with loss of consciousness (syncope, seizure), which require appropriate evaluation and intervention (Chaps. 27 and 445). In most prospective studies, a small subset of individuals experience a large number of fall events. These individuals with recurrent falls often have gait and balance issues that need to be addressed.


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InternalMed_Harrison. Fall Patterns: The Event description The history of a fall is often problematic or incomplete, and the underlying mechanism or cause may be difficult to establish in retrospect. The patient and family may have limited information about what triggered the fall. Injuries can complicate the physical examination. While there is no standard nosology of falls, some common clinical patterns may emerge and provide a clue.


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InternalMed_Harrison. drop attacks and collapsIng falls Drop attacks are sudden collapsing falls without loss of consciousness. Patients who collapse from lack of postural tone present a diagnostic challenge. Patients may report that their legs just “gave out” underneath them; their families may describe these patients as “collapsing in a heap.” Orthostatic hypotension may be a factor in some such falls, and this possibility should be thoroughly evaluated. Rarely, a colloid cyst of the third ventricle can present with intermittent obstruction of the foramen of Monro, with a consequent drop attack. While collapsing falls are more common among older patients with vascular risk factors, they should not be confused with vertebrobasilar ischemic attacks.


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InternalMed_Harrison. topplIng falls Some patients maintain tone in antigravity muscles but fall over like a tree trunk, as if postural defenses had disengaged. There may be a consistent direction to such falls. The patient with cerebellar pathology may lean and topple over toward the side of the lesion. Patients with lesions of the vestibular system or its central pathways may experience lateral pulsion and toppling falls. Patients with progressive supranuclear palsy often fall over backward. Falls of this nature occur in patients with advanced Parkinson’s disease once postural instability has developed.


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InternalMed_Harrison. falls due to gaIt freezIng Another fall pattern in Parkinson’s disease and related disorders is the fall due to freezing of gait. The feet stick to the floor and the center of mass keeps moving, resulting in a disequilibrium from which the patient has difficulty recovering. This sequence of events can result in a forward fall. Gait freezing can also occur as the patient attempts to turn and change direction. Similarly, patients with Parkinson’s disease and festinating gait may find their feet unable to keep up and may thus fall forward.


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InternalMed_Harrison. falls related to sensory loss Patients with somatosensory, visual, or vestibular deficits are prone to falls. These patients have particular difficulty dealing with poor illumination or walking on uneven ground. They often report subjective imbalance, apprehension, and fear of falling. Deficits in joint position and vibration sense are apparent on physical examination. These patients may be especially responsive to a rehabilitation-based intervention. weakness and fraIlty Patients who lack strength in antigravity muscles have difficulty rising from a chair, tire easily when walking, and have difficulty maintaining their balance after a perturbation. These patients are often unable to get up after a fall and may have to remain on the floor for a prolonged period until help arrives. Deconditioning of this sort is often treatable. Resistance strength training can increase muscle mass and leg strength, even for people in their eighties and nineties.


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InternalMed_Harrison. The most productive approach is to identify the high-risk patient prospectively, before there is a serious injury. Patients at particular risk include hospitalized patients with mental status changes, nursing home residents, patients with dementia, and those taking medications that compromise attention and alertness. Patients with Parkinson’s disease and other gait disorders are also at increased risk. (Table 32-3) summarizes a meta-analysis of prospective studies establishing the principal risk factors for falls. It is often possible to address and mitigate some of the major risk factors. Medication overuse may be the most important remediable risk factor for falls. Abbreviations: OR, odds ratio from retrospective studies; RR, relative risk from prospective studies. Source: Reproduced with permission from J Masdeu, L Sudarsky, L Wolfson: Gait Disorders of Aging. Lippincott Raven, 1997.


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InternalMed_Harrison. Source: Reproduced with permission from J Masdeu, L Sudarsky, L Wolfson: Gait Disorders of Aging. Lippincott Raven, 1997. Efforts should be made to define the etiology of the gait disorder and the mechanism underlying the falls by a given patient. Orthostatic changes in blood pressure and pulse should be recorded. Rising from a chair and walking should be evaluated for safety. Specific treatment may be possible once a diagnosis is established. Therapeutic intervention is often recommended for older patients at substantial risk for falls, even if no neurologic disease is identified. A home visit to look for environmental hazards can be helpful. A variety of modifications may be recommended to improve safety, including improved lighting and the installation of grab bars and nonslip surfaces.


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InternalMed_Harrison. Rehabilitative interventions aim to improve muscle strength and balance stability and to make the patient more resistant to injury. High-intensity resistance strength training with weights and machines is useful to improve muscle mass, even in frail older patients. Improvements realized in posture and gait should translate to reduced risk of falls and injury. Sensory balance training is another approach to improving balance stability. Measurable gains can be made in a few weeks of training, and benefits can be maintained over 6 months by a 10to 20-min home exercise program. This strategy is particularly successful in patients with vestibular and somatosensory balance disorders. A Tai Chi exercise program has been demonstrated to reduce the risk of falls and injury in patients with Parkinson’s disease. Video Library of Gait Disorders Gail Kang, Nicholas B. Galifianakis, Michael D. Geschwind


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InternalMed_Harrison. Video Library of Gait Disorders Gail Kang, Nicholas B. Galifianakis, Michael D. Geschwind Problems with gait and balance are major causes of falls, accidents, and resulting disability, especially in later life, and are often harbingers of neurologic disease. Early diagnosis is essential, especially for treatable conditions, because it may permit the institution of prophylactic measures to prevent dangerous falls and also to reverse or ameliorate the underlying cause. In this video, examples of gait disorders due to Parkinson’s disease, other extrapyramidal disorders, and ataxias, as well as other common gait disorders, are presented. CHAPTER 33e Video Library of Gait Disorders


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InternalMed_Harrison. CHAPTER 33e Video Library of Gait Disorders Confusion and Delirium S. Andrew Josephson, Bruce L. Miller Confusion, a mental and behavioral state of reduced comprehen-sion, coherence, and capacity to reason, is one of the most common problems encountered in medicine, accounting for a large number of emergency department visits, hospital admissions, and inpatient 34166 consultations. Delirium, a term used to describe an acute confusional state, remains a major cause of morbidity and mortality, costing over $150 billion dollars yearly in health care costs in the United States alone. Despite increased efforts targeting awareness of this condition, delirium often goes unrecognized in the face of evidence that it is usually the cognitive manifestation of serious underlying medical or neurologic illness.


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InternalMed_Harrison. A multitude of terms are used to describe patients with delirium, including encephalopathy, acute brain failure, acute confusional state, and postoperative or intensive care unit (ICU) psychosis. Delirium has many clinical manifestations, but is defined as a relatively acute decline in cognition that fluctuates over hours or days. The hallmark of delirium is a deficit of attention, although all cognitive domains—including memory, executive function, visuospatial tasks, and language—are variably involved. Associated symptoms that may be present in some cases include altered sleep-wake cycles, perceptual disturbances such as hallucinations or delusions, affect changes, and autonomic findings that include heart rate and blood pressure instability.


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InternalMed_Harrison. Delirium is a clinical diagnosis that is made only at the bedside. Two subtypes have been described—hyperactive and hypoactive—based on differential psychomotor features. The cognitive syndrome associated with severe alcohol withdrawal (i.e., “delirium tremens”) remains the classic example of the hyperactive subtype, featuring prominent hallucinations, agitation, and hyperarousal, often accompanied by life-threatening autonomic instability. In striking contrast is the hypoactive subtype, exemplified by benzodiazepine intoxication, in which patients are withdrawn and quiet, with prominent apathy and psychomotor slowing.


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InternalMed_Harrison. This dichotomy between subtypes of delirium is a useful construct, but patients often fall somewhere along a spectrum between the hyperactive and hypoactive extremes, sometimes fluctuating from one to the other. Therefore, clinicians must recognize this broad range of presentations of delirium to identify all patients with this potentially reversible cognitive disturbance. Hyperactive patients are often easily recognized by their characteristic severe agitation, tremor, hallucinations, and autonomic instability. Patients who are quietly hypoactive are more often overlooked on the medical wards and in the ICU.


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InternalMed_Harrison. The reversibility of delirium is emphasized because many etiologies, such as systemic infection and medication effects, can be treated easily. The long-term cognitive effects of delirium remain largely unknown. Some episodes of delirium continue for weeks, months, or even years. The persistence of delirium in some patients and its high recurrence rate may be due to inadequate initial treatment of the underlying etiology. In other instances, delirium appears to cause permanent neuronal damage and cognitive decline. Even if an episode of delirium completely resolves, there may be lingering effects of the disorder; a patient’s recall of events after delirium varies widely, ranging from complete amnesia to repeated re-experiencing of the frightening period of confusion, similar to what is seen in patients with posttraumatic stress disorder.


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InternalMed_Harrison. An effective primary prevention strategy for delirium begins with identification of patients at high risk for this disorder, including those preparing for elective surgery or being admitted to the hospital. Although no single validated scoring system has been widely accepted as a screen for asymptomatic patients, there are multiple well-established risk factors for delirium. PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases The two most consistently identified risks are older age and baseline cognitive dysfunction. Individuals who are over age 65 or exhibit low scores on standardized tests of cognition develop delirium upon hospitalization at a rate approaching 50%. Whether age and baseline cognitive dysfunction are truly independent risk factors is uncertain. Other predisposing factors include sensory deprivation, such as preexisting hearing and visual impairment, as well as indices for poor overall health, including baseline immobility, malnutrition, and underlying medical or neurologic illness.


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InternalMed_Harrison. In-hospital risks for delirium include the use of bladder catheterization, physical restraints, sleep and sensory deprivation, and the addition of three or more new medications. Avoiding such risks remains a key component of delirium prevention as well as treatment. Surgical and anesthetic risk factors for the development of postoperative delirium include specific procedures such as those involving cardiopulmonary bypass, inadequate or excessive treatment of pain in the immediate postoperative period, and perhaps specific agents such as inhalational anesthetics.


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InternalMed_Harrison. The relationship between delirium and dementia (Chap. 448) is complicated by significant overlap between the two conditions, and it is not always simple to distinguish between them. Dementia and preexisting cognitive dysfunction serve as major risk factors for delirium, and at least two-thirds of cases of delirium occur in patients with coexisting underlying dementia. A form of dementia with parkinsonism, termed dementia with Lewy bodies, is characterized by a fluctuating course, prominent visual hallucinations, parkinsonism, and an attentional deficit that clinically resembles hyperactive delirium; patients with this condition are particularly vulnerable to delirium. Delirium in the elderly often reflects an insult to the brain that is vulnerable due to an underlying neurodegenerative condition. Therefore, the development of delirium sometimes heralds the onset of a previously unrecognized brain disorder.


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InternalMed_Harrison. Delirium is common, but its reported incidence has varied widely with the criteria used to define this disorder. Estimates of delirium in hospitalized patients range from 18 to 64%, with higher rates reported for elderly patients and patients undergoing hip surgery. Older patients in the ICU have especially high rates of delirium that approach 75%. The condition is not recognized in up to one-third of delirious inpatients, and the diagnosis is especially problematic in the ICU environment, where cognitive dysfunction is often difficult to appreciate in the setting of serious systemic illness and sedation. Delirium in the ICU should be viewed as an important manifestation of organ dysfunction not unlike liver, kidney, or heart failure. Outside the acute hospital setting, delirium occurs in nearly one-quarter of patients in nursing homes and in 50 to 80% of those at the end of life. These estimates emphasize the remarkably high frequency of this cognitive syndrome in older patients, a


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InternalMed_Harrison. nearly one-quarter of patients in nursing homes and in 50 to 80% of those at the end of life. These estimates emphasize the remarkably high frequency of this cognitive syndrome in older patients, a population expected to grow in the upcoming decades.


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InternalMed_Harrison. Until recently, an episode of delirium was viewed as a transient condition that carried a benign prognosis. It is now recognized as a disorder with a substantial morbidity rate and increased mortality rate and often represents the first manifestation of a serious underlying illness. Recent estimates of in-hospital mortality rates among delirious patients have ranged from 25 to 33%, a rate similar to that of patients with sepsis. Patients with an in-hospital episode of delirium have a fivefold higher mortality rate in the months after their illness compared with age-matched nondelirious hospitalized patients. Delirious hospitalized patients have a longer length of stay, are more likely to be discharged to a nursing home, and are more likely to experience subsequent episodes of delirium and cognitive decline; as a result, this condition has enormous economic implications.


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InternalMed_Harrison. The pathogenesis and anatomy of delirium are incompletely understood. The attentional deficit that serves as the neuropsychological hallmark of delirium has a diffuse localization within the brainstem, thalamus, prefrontal cortex, and parietal lobes. Rarely, focal lesions such as ischemic strokes have led to delirium in otherwise healthy persons; right parietal and medial dorsal thalamic lesions have been reported most commonly, pointing to the importance of these areas to delirium pathogenesis. In most cases, delirium results from widespread disturbances in cortical and subcortical regions rather than a focal neuroanatomic cause. Electroencephalogram (EEG) data in persons with delirium usually show symmetric slowing, a nonspecific finding that supports diffuse cerebral dysfunction.


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InternalMed_Harrison. Multiple neurotransmitter abnormalities, proinflammatory factors, and specific genes likely play a role in the pathogenesis of delirium. Deficiency of acetylcholine may play a key role, and medications with anticholinergic properties also can precipitate delirium. Dementia patients are susceptible to episodes of delirium, and those with Alzheimer’s pathology and dementia with Lewy bodies or Parkinson’s disease dementia are known to have a chronic cholinergic deficiency state due to degeneration of acetylcholine-producing neurons in the basal forebrain. Additionally, other neurotransmitters are also likely to be involved in this diffuse cerebral disorder. For example, increases in dopamine can also lead to delirium. Patients with Parkinson’s disease treated with dopaminergic medications can develop a delirium-like state that features visual hallucinations, fluctuations, and confusion.


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InternalMed_Harrison. Not all individuals exposed to the same insult will develop signs of delirium. A low dose of an anticholinergic medication may have no cognitive effects on a healthy young adult but produce a florid delirium in an elderly person with known underlying dementia, although even healthy young persons develop delirium with very high doses of anticholinergic medications. This concept of delirium developing as the result of an insult in predisposed individuals is currently the most widely accepted pathogenic construct. Therefore, if a previously healthy individual with no known history of cognitive illness develops delirium in the setting of a relatively minor insult such as elective surgery or hospitalization, an unrecognized underlying neurologic illness such as a neurodegenerative disease, multiple previous strokes, or another diffuse cerebral cause should be considered. In this context, delirium can be viewed as a “stress test for the brain” whereby exposure to known inciting factors such


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InternalMed_Harrison. previous strokes, or another diffuse cerebral cause should be considered. In this context, delirium can be viewed as a “stress test for the brain” whereby exposure to known inciting factors such as systemic infection and offending drugs can unmask a decreased cerebral reserve and herald a serious underlying and potentially treatable illness.


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APPROACH TO THE PATIENT:

InternalMed_Harrison. APPROACH TO THE PATIENT:


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InternalMed_Harrison. Because the diagnosis of delirium is clinical and is made at the bedside, a careful history and physical examination are necessary in evaluating patients with possible confusional states. Screening tools can aid physicians and nurses in identifying patients with delirium, including the Confusion Assessment Method (CAM) (Table 34-1); the Organic Brain Syndrome Scale; the Delirium Rating Scale; and, in the ICU, the ICU version of the CAM and the Delirium Detection Score. Using the well-validated CAM, a diagnosis of delirium is made if there is (1) an acute onset and fluctuating course and (2) inattention accompanied by either (3) disorganized thinking or (4) an altered level of consciousness. These scales may not identify the full spectrum of patients with delirium, and all patients who are acutely confused should be presumed delirious regardless of their presentation due to the wide variety of possible clinical features. A course that fluctuates over hours or days and may worsen at


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InternalMed_Harrison. are acutely confused should be presumed delirious regardless of their presentation due to the wide variety of possible clinical features. A course that fluctuates over hours or days and may worsen at night (termed sundowning) is typical but not essential for the diagnosis. Observation of the patient usually will reveal an altered level of consciousness or a deficit of attention. Other features that are sometimes present include alteration of sleep-wake cycles, thought disturbances such as hallucinations or delusions, autonomic instability, and changes in affect.


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InternalMed_Harrison. It may be difficult to elicit an accurate history in delirious patients who have altered levels of consciousness or impaired attention. Information from a collateral source such as a spouse or another The diagnosis of delirium requires the presence of features 1 and 2 and of either feature 3 or 4. Feature 1. Acute onset and fluctuating course This feature is satisfied by positive responses to the following questions: Is there evidence of an acute change in mental status from the patient’s baseline? Did the (abnormal) behavior fluctuate during the day, that is, tend to come and go, or did it increase and decrease in severity? Feature 2. Inattention This feature is satisfied by a positive response to the following question: Did the patient have difficulty focusing attention, for example, being easily distractible, or have difficulty keeping track of what was being said? Feature 3. Disorganized thinking


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InternalMed_Harrison. Feature 3. Disorganized thinking This feature is satisfied by a positive response to the following question: Was the patient’s thinking disorganized or incoherent, such as rambling or irrelevant conversation, unclear or illogical flow of ideas, or unpredictable switching from subject to subject? Feature 4. Altered level of consciousness This feature is satisfied by any answer other than “alert” to the following question: Overall, how would you rate the patient’s level of consciousness: alert (normal), vigilant (hyperalert), lethargic (drowsy, easily aroused), stupor (difficult to arouse), or coma (unarousable)? aInformation is usually obtained from a reliable reporter, such as a family member, caregiver, or nurse. Source: Modified from SK Inouye et al: Clarifying confusion: The Confusion Assessment Method. A new method for detection of delirium. Ann Intern Med 113:941, 1990.


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InternalMed_Harrison. Source: Modified from SK Inouye et al: Clarifying confusion: The Confusion Assessment Method. A new method for detection of delirium. Ann Intern Med 113:941, 1990. family member is therefore invaluable. The three most important pieces of history are the patient’s baseline cognitive function, the time course of the present illness, and current medications.


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InternalMed_Harrison. Premorbid cognitive function can be assessed through the collateral source or, if needed, via a review of outpatient records. Delirium by definition represents a change that is relatively acute, usually over hours to days, from a cognitive baseline. As a result, an acute confusional state is nearly impossible to diagnose without some knowledge of baseline cognitive function. Without this information, many patients with dementia or depression may be mistaken as delirious during a single initial evaluation. Patients with a more hypoactive, apathetic presentation with psychomotor slowing may be identified as being different from baseline only through conversations with family members. A number of validated instruments have been shown to diagnose cognitive dysfunction accurately using a collateral source, including the modified Blessed Dementia Rating Scale and the Clinical Dementia Rating (CDR). Baseline cognitive impairment is common in patients with delirium. Even when no such history


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InternalMed_Harrison. source, including the modified Blessed Dementia Rating Scale and the Clinical Dementia Rating (CDR). Baseline cognitive impairment is common in patients with delirium. Even when no such history of cognitive impairment is elicited, there should still be a high suspicion for a previously unrecognized underlying neurologic disorder.


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InternalMed_Harrison. Establishing the time course of cognitive change is important not only to make a diagnosis of delirium but also to correlate the onset of the illness with potentially treatable etiologies such as recent medication changes or symptoms of systemic infection. Medications remain a common cause of delirium, especially compounds with anticholinergic or sedative properties. It is estimated that nearly one-third of all cases of delirium are secondary to medications, especially in the elderly. Medication histories should include all prescription as well as over-the-counter and herbal substances taken by the patient and any recent changes in dosing or formulation, including substitution of generics for brand-name medications.


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InternalMed_Harrison. Other important elements of the history include screening for symptoms of organ failure or systemic infection, which often contributes to delirium in the elderly. A history of illicit drug use, alcoholism, or toxin exposure is common in younger delirious patients. Finally, asking the patient and collateral source about other symptoms that may accompany delirium, such as depression, may help identify potential therapeutic targets. The general physical examination in a delirious patient should include careful screening for signs of infection such as fever, tachypnea, pulmonary consolidation, heart murmur, and stiff neck. The patient’s fluid status should be assessed; both dehydration and fluid overload with resultant hypoxemia have been associated with delirium, and each is usually easily rectified. The appearance of the skin can be helpful, showing jaundice in hepatic encephalopathy, cyanosis in hypoxemia, or needle tracks in patients using intravenous drugs.


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InternalMed_Harrison. The neurologic examination requires a careful assessment of mental status. Patients with delirium often present with a fluctuating course; therefore, the diagnosis can be missed when one relies on a single time point of evaluation. Some but not all patients exhibit the characteristic pattern of sundowning, a worsening of their condition in the evening. In these cases, assessment only during morning rounds may be falsely reassuring.


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InternalMed_Harrison. An altered level of consciousness ranging from hyperarousal to lethargy to coma is present in most patients with delirium and can be assessed easily at the bedside. In a patient with a relatively normal level of consciousness, a screen for an attentional deficit is in order, because this deficit is the classic neuropsychological hallmark of delirium. Attention can be assessed while taking a history from the patient. Tangential speech, a fragmentary flow of ideas, or inability to follow complex commands often signifies an attentional problem. There are formal neuropsychological tests to assess attention, but a simple bedside test of digit span forward is quick and fairly sensitive. In this task, patients are asked to repeat successively longer random strings of digits beginning with two digits in a row, said to the patient at 1-second intervals. Healthy adults can repeat a string of five to seven digits before faltering; a digit span of four or less usually indicates an attentional


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InternalMed_Harrison. digits in a row, said to the patient at 1-second intervals. Healthy adults can repeat a string of five to seven digits before faltering; a digit span of four or less usually indicates an attentional deficit unless hearing or language barriers are present, and many patients with delirium have digit spans of three or fewer digits.


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InternalMed_Harrison. More formal neuropsychological testing can be helpful in assessing a delirious patient, but it is usually too cumbersome and time-consuming in the inpatient setting. A Mini-Mental State Examination (MMSE) provides information regarding orientation, language, and visuospatial skills; however, performance of many tasks on the MMSE, including the spelling of “world” backward and serial subtraction of digits, will be impaired by delirious patients’ attentional deficits, rendering the test unreliable.


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InternalMed_Harrison. The remainder of the screening neurologic examination should focus on identifying new focal neurologic deficits. Focal strokes or mass lesions in isolation are rarely the cause of delirium, but patients with underlying extensive cerebrovascular disease or neurodegenerative conditions may not be able to cognitively tolerate even relatively small new insults. Patients should be screened for other signs of neurodegenerative conditions such as parkinsonism, which is seen not only in idiopathic Parkinson’s disease but also in other dementing conditions such as Alzheimer’s disease, dementia with Lewy bodies, and progressive supranuclear palsy. The presence of multifocal myoclonus or asterixis on the motor examination is nonspecific but usually indicates a metabolic or toxic etiology of the delirium.


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InternalMed_Harrison. Some etiologies can be easily discerned through a careful history and physical examination, whereas others require confirmation with laboratory studies, imaging, or other ancillary tests. A large, diverse group of insults can lead to delirium, and the cause in many patients is often multifactorial. Common etiologies are listed in Table 34-2. Prescribed, over-the-counter, and herbal medications all can precipitate delirium. Drugs with anticholinergic properties, narcotics, and benzodiazepines are particularly common offenders, but nearly any compound can lead to cognitive dysfunction in a predisposed patient. Whereas an elderly patient with baseline dementia PART 2 Cardinal Manifestations and Presentation of Diseases CoMMon ETioLogiES of DELiRiuM


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases CoMMon ETioLogiES of DELiRiuM Prescription medications: especially those with anticholinergic properties, narcotics, and benzodiazepines Drugs of abuse: alcohol intoxication and alcohol withdrawal, opiates, ecstasy, LSD, GHB, PCP, ketamine, cocaine, “bath salts,” marijuana and its synthetic forms Poisons: inhalants, carbon monoxide, ethylene glycol, pesticides Metabolic conditions Electrolyte disturbances: hypoglycemia, hyperglycemia, hyponatremia, hypernatremia, hypercalcemia, hypocalcemia, hypomagnesemia Hypothermia and hyperthermia Pulmonary failure: hypoxemia and hypercarbia Liver failure/hepatic encephalopathy Renal failure/uremia Cardiac failure Vitamin deficiencies: B12, thiamine, folate, niacin Dehydration and malnutrition Anemia Systemic infections: urinary tract infections, pneumonia, skin and soft tissue infections, sepsis CNS infections: meningitis, encephalitis, brain abscess


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InternalMed_Harrison. Systemic infections: urinary tract infections, pneumonia, skin and soft tissue infections, sepsis CNS infections: meningitis, encephalitis, brain abscess Endocrine conditions Hyperthyroidism, hypothyroidism Hyperparathyroidism Adrenal insufficiency Cerebrovascular disorders Global hypoperfusion states Hypertensive encephalopathy Focal ischemic strokes and hemorrhages (rare): especially nondominant Seizure-related disorders Nonconvulsive status epilepticus Intermittent seizures with prolonged postictal states Neoplastic disorders Diffuse metastases to the brain Gliomatosis cerebri Carcinomatous meningitis CNS lymphoma Hospitalization Terminal end-of-life delirium Abbreviations: CNS, central nervous system; GHB, γ-hydroxybutyrate; LSD, lysergic acid diethylamide; PCP, phencyclidine.


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InternalMed_Harrison. Hospitalization Terminal end-of-life delirium Abbreviations: CNS, central nervous system; GHB, γ-hydroxybutyrate; LSD, lysergic acid diethylamide; PCP, phencyclidine. may become delirious upon exposure to a relatively low dose of a medication, less susceptible individuals may become delirious only with very high doses of the same medication. This observation emphasizes the importance of correlating the timing of recent medication changes, including dose and formulation, with the onset of cognitive dysfunction.


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InternalMed_Harrison. In younger patients, illicit drugs and toxins are common causes of delirium. In addition to more classic drugs of abuse, the recent rise in availability of methylenedioxymethamphetamine (MDMA, ecstasy), γ-hydroxybutyrate (GHB), “bath salts,” synthetic cannabis, and the phencyclidine (PCP)-like agent ketamine, has led to an increase in delirious young persons presenting to acute care settings (Chap. 469e). Many common prescription drugs such as oral narcotics and benzodiazepines are often abused and readily available on the street. Alcohol abuse leading to high serum levels causes confusion, but more commonly, it is withdrawal from alcohol that leads to a hyperactive delirium. Alcohol and benzodiazepine withdrawal should be considered in all cases of delirium because even patients who drink only a few servings of alcohol every day can experience relatively severe withdrawal symptoms upon hospitalization.


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InternalMed_Harrison. Metabolic abnormalities such as electrolyte disturbances of sodium, calcium, magnesium, or glucose can cause delirium, and mild derangements can lead to substantial cognitive disturbances in susceptible individuals. Other common metabolic etiologies include liver and renal failure, hypercarbia and hypoxemia, vitamin deficiencies of thiamine and B12, autoimmune disorders including central nervous system (CNS) vasculitis, and endocrinopathies such as thyroid and adrenal disorders.


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InternalMed_Harrison. Systemic infections often cause delirium, especially in the elderly. A common scenario involves the development of an acute cognitive decline in the setting of a urinary tract infection in a patient with baseline dementia. Pneumonia, skin infections such as cellulitis, and frank sepsis also lead to delirium. This so-called septic encephalopathy, often seen in the ICU, is probably due to the release of proinflammatory cytokines and their diffuse cerebral effects. CNS infections such as meningitis, encephalitis, and abscess are less common etiologies of delirium; however, in light of the high mortality rates associated with these conditions when they are not treated quickly, clinicians must always maintain a high index of suspicion.


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InternalMed_Harrison. In some susceptible individuals, exposure to the unfamiliar environment of a hospital itself can lead to delirium. This etiology usually occurs as part of a multifactorial delirium and should be considered a diagnosis of exclusion after all other causes have been thoroughly investigated. Many primary prevention and treatment strategies for delirium involve relatively simple methods to address the aspects of the inpatient setting that are most confusing.


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InternalMed_Harrison. Cerebrovascular etiologies of delirium are usually due to global hypoperfusion in the setting of systemic hypotension from heart failure, septic shock, dehydration, or anemia. Focal strokes in the right parietal lobe and medial dorsal thalamus rarely can lead to a delirious state. A more common scenario involves a new focal stroke or hemorrhage causing confusion in a patient who has decreased cerebral reserve. In these individuals, it is sometimes difficult to distinguish between cognitive dysfunction resulting from the new neurovascular insult itself and delirium due to the infectious, metabolic, and pharmacologic complications that can accompany hospitalization after stroke.


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InternalMed_Harrison. Because a fluctuating course often is seen in delirium, intermittent seizures may be overlooked when one is considering potential etiologies. Both nonconvulsive status epilepticus and recurrent focal or generalized seizures followed by postictal confusion can cause delirium; EEG remains essential for this diagnosis. Seizure activity spreading from an electrical focus in a mass or infarct can explain global cognitive dysfunction caused by relatively small lesions. It is very common for patients to experience delirium at the end of life in palliative care settings. This condition, sometimes described as terminal restlessness, must be identified and treated aggressively because it is an important cause of patient and family discomfort at the end of life. It should be remembered that these patients also may be suffering from more common etiologies of delirium such as systemic infection.


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InternalMed_Harrison. A cost-effective approach to the diagnostic evaluation of delirium allows the history and physical examination to guide further tests. No established algorithm for workup will fit all delirious patients due to the staggering number of potential etiologies, but one stepwise approach is detailed in Table 34-3. If a clear precipitant is STEPwiSE EvALuATion of A PATiEnT wiTH DELiRiuM History with special attention to medications (including over-the-counter and herbals) General physical examination and neurologic examination Complete blood count Electrolyte panel including calcium, magnesium, phosphorus Liver function tests, including albumin Renal function tests


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InternalMed_Harrison. Electrocardiogram Arterial blood gas Serum and/or urine toxicology screen (perform earlier in young persons) Brain imaging with MRI with diffusion and gadolinium (preferred) or CT Suspected CNS infection: lumbar puncture after brain imaging Suspected seizure-related etiology: electroencephalogram (EEG) (if high suspicion, should be performed immediately) Second-tier further evaluation Vitamin levels: B12, folate, thiamine Endocrinologic laboratories: thyroid-stimulating hormone (TSH) and free T4; cortisol Serum ammonia Sedimentation rate Autoimmune serologies: antinuclear antibodies (ANA), complement levels; p-ANCA, c-ANCA. consider paraneoplastic serologies Infectious serologies: rapid plasmin reagin (RPR); fungal and viral serologies if high suspicion; HIV antibody Lumbar puncture (if not already performed) Brain MRI with and without gadolinium (if not already performed)


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InternalMed_Harrison. Abbreviations: c-ANCA, cytoplasmic antineutrophil cytoplasmic antibody; CNS, central nervous system; CT, computed tomography; MRI, magnetic resonance imaging; p-ANCA, perinuclear antineutrophil cytoplasmic antibody. identified, such as an offending medication, further testing may not be required. If, however, no likely etiology is uncovered with initial evaluation, an aggressive search for an underlying cause should be initiated.


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InternalMed_Harrison. Basic screening labs, including a complete blood count, electrolyte panel, and tests of liver and renal function, should be obtained in all patients with delirium. In elderly patients, screening for systemic infection, including chest radiography, urinalysis and culture, and possibly blood cultures, is important. In younger individuals, serum and urine drug and toxicology screening may be appropriate early in the workup. Additional laboratory tests addressing other autoimmune, endocrinologic, metabolic, and infectious etiologies should be reserved for patients in whom the diagnosis remains unclear after initial testing.


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InternalMed_Harrison. Multiple studies have demonstrated that brain imaging in patients with delirium is often unhelpful. If, however, the initial workup is unrevealing, most clinicians quickly move toward imaging of the brain to exclude structural causes. A noncontrast computed tomography (CT) scan can identify large masses and hemorrhages but is otherwise unlikely to help determine an etiology of delirium. The ability of magnetic resonance imaging (MRI) to identify most acute ischemic strokes as well as to provide neuroanatomic detail that gives clues to possible infectious, inflammatory, neurodegenerative, and neoplastic conditions makes it the test of choice. Because MRI techniques are limited by availability, speed of imaging, patient cooperation, and contraindications, many clinicians begin with CT scanning and proceed to MRI if the etiology of delirium remains elusive.


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InternalMed_Harrison. Lumbar puncture (LP) must be obtained immediately after appropriate neuroimaging in all patients in whom CNS infection is suspected. Spinal fluid examination can also be useful in identifying inflammatory and neoplastic conditions. As a result, LP should be considered in any delirious patient with a negative workup. EEG does not have a routine role in the workup of delirium, but it remains invaluable if seizure-related etiologies are considered. PART 2 Cardinal Manifestations and Presentation of Diseases Management of delirium begins with treatment of the underlying inciting factor (e.g., patients with systemic infections should be given appropriate antibiotics, and underlying electrolyte disturbances judiciously corrected). These treatments often lead to prompt resolution of delirium. Blindly targeting the symptoms of delirium pharmacologically only serves to prolong the time patients remain in the confused state and may mask important diagnostic information.


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InternalMed_Harrison. Relatively simple methods of supportive care can be highly effective in treating patients with delirium. Reorientation by the nursing staff and family combined with visible clocks, calendars, and outside-facing windows can reduce confusion. Sensory isolation should be prevented by providing glasses and hearing aids to patients who need them. Sundowning can be addressed to a large extent through vigilance to appropriate sleep-wake cycles. During the day, a well-lit room should be accompanied by activities or exercises to prevent napping. At night, a quiet, dark environment with limited interruptions by staff can assure proper rest. These sleep-wake cycle interventions are especially important in the ICU setting as the usual constant 24-h activity commonly provokes delirium. Attempting to mimic the home environment as much as possible also has been shown to help treat and even prevent delirium. Visits from friends and family throughout the day minimize the anxiety associated with the


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InternalMed_Harrison. mimic the home environment as much as possible also has been shown to help treat and even prevent delirium. Visits from friends and family throughout the day minimize the anxiety associated with the constant flow of new faces of staff and physicians. Allowing hospitalized patients to have access to home bedding, clothing, and nightstand objects makes the hospital environment less foreign and therefore less confusing. Simple standard nursing practices such as maintaining proper nutrition and volume status as well as managing incontinence and skin breakdown also help alleviate discomfort and resulting confusion.


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InternalMed_Harrison. In some instances, patients pose a threat to their own safety or to the safety of staff members, and acute management is required. Bed alarms and personal sitters are more effective and much less disorienting than physical restraints. Chemical restraints should be avoided, but only when necessary, very-low-dose typical or atypical antipsychotic medications administered on an as-needed basis are effective. The recent association of antipsychotic use in the elderly with increased mortality rates underscores the importance of using these medications judiciously and only as a last resort. Benzodiazepines often worsen confusion through their sedative properties. Although many clinicians still use benzodiazepines to treat acute confusion, their use should be limited to cases in which delirium is caused by alcohol or benzodiazepine withdrawal.


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InternalMed_Harrison. In light of the high morbidity associated with delirium and the tremendously increased health care costs that accompany it, development of an effective strategy to prevent delirium in hospitalized patients is extremely important. Successful identification of high-risk patients is the first step, followed by initiation of appropriate interventions. Simple standardized protocols used to manage risk factors for delirium, including sleep-wake cycle reversal, immobility, visual impairment, hearing impairment, sleep deprivation, and dehydration, have been shown to be effective. Recent trials in the ICU have focused both on identifying sedatives, such as dexmedetomidine, that are less likely to lead to delirium in critically ill patients and on developing protocols for daily awakenings in which infusions of sedative medications are interrupted and the patient is reorientated by the staff. All hospitals and health care systems should work toward decreasing the incidence of delirium.


InternalMed_Harrison

William W. Seeley, Bruce L. Miller

InternalMed_Harrison. William W. Seeley, Bruce L. Miller


InternalMed_Harrison

InternalMed_Harrison. Dementia, a syndrome with many causes, affects >5 million people in the United States and results in a total annual health care cost between $157 and $215 billion. Dementia is defined as an acquired deterioration in cognitive abilities that impairs the successful performance of activities of daily living. Episodic memory, the ability to recall events specific in time and place, is the cognitive function most commonly lost; 10% of persons age >70 years and 20–40% of individuals age >85 years have clinically identifiable memory loss. In addition to memory, dementia may erode other mental faculties, including language, visuospatial, praxis, calculation, judgment, and problem-solving abilities. Neuropsychiatric and social deficits also arise in many dementia syndromes, manifesting as depression, apathy, anxiety, hallucinations, delusions, agitation, insomnia, sleep disturbances, compulsions, or disinhibition. The clinical course may be slowly progressive, as in Alzheimer’s disease (AD);


InternalMed_Harrison

InternalMed_Harrison. apathy, anxiety, hallucinations, delusions, agitation, insomnia, sleep disturbances, compulsions, or disinhibition. The clinical course may be slowly progressive, as in Alzheimer’s disease (AD); static, as in anoxic encephalopathy; or may fluctuate from day to day or minute to minute, as in dementia with Lewy bodies. Most patients with AD, the most prevalent form of dementia, begin with episodic memory impairment, although in other dementias, such as frontotemporal dementia, memory loss is not typically a presenting feature. Focal cerebral disorders are discussed in Chap. 36 and illustrated in a video library in Chap. 37e; the pathogenesis of AD and related disorders is discussed in Chap. 448.


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InternalMed_Harrison. Dementia syndromes result from the disruption of specific large-scale neuronal networks; the location and severity of synaptic and neuronal loss combine to produce the clinical features (Chap. 36). Behavior, mood, and attention are modulated by ascending noradrenergic, serotonergic, and dopaminergic pathways, whereas cholinergic signaling is critical for attention and memory functions. The dementias differ in the relative neurotransmitter deficit profiles; accordingly, accurate diagnosis guides effective pharmacologic therapy.


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InternalMed_Harrison. AD begins in the entorhinal region of the medial temporal lobe, spreads to the hippocampus, and then moves to lateral and posterior temporal and parietal neocortex, eventually causing a more widespread degeneration. Vascular dementia is associated with focal damage in a variable patchwork of cortical and subcortical regions or white matter tracts that disconnect nodes within distributed networks. In keeping with its anatomy, AD typically presents with episodic memory loss accompanied later by aphasia or navigational problems. In contrast, dementias that begin in frontal or subcortical regions, such as frontotemporal dementia (FTD) or Huntington’s disease (HD), are less likely to begin with memory problems and more likely to present with difficulties with judgment, mood, executive control, movement, and behavior.


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InternalMed_Harrison. Lesions of frontal-striatal1 pathways produce specific and predictable effects on behavior. The dorsolateral prefrontal cortex has connections with a central band of the caudate nucleus. Lesions of either the caudate or dorsolateral prefrontal cortex, or their connecting white matter pathways, may result in executive dysfunction, manifesting as poor organization and planning, decreased cognitive flexibility, and impaired working memory. The lateral orbital frontal cortex connects with the ventromedial caudate, and lesions of this system cause impulsiveness, distractibility, and disinhibition. The anterior cingulate cortex and adjacent medial prefrontal cortex project to the nucleus accumbens, and interruption of this system produces apathy, poverty of speech, emotional blunting, or even akinetic mutism. All corticostriatal systems also include topographically organized projections through the globus pallidus and thalamus, and damage to these nodes 1The striatum comprises the


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InternalMed_Harrison. or even akinetic mutism. All corticostriatal systems also include topographically organized projections through the globus pallidus and thalamus, and damage to these nodes 1The striatum comprises the caudate/putamen.


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InternalMed_Harrison. can likewise reproduce the clinical syndrome of cortical or striatal injury. The single strongest risk factor for dementia is increasing age. The prevalence of disabling memory loss increases with each decade over age 50 and is usually associated with the microscopic changes of AD at autopsy. Yet some centenarians have intact memory function and no evidence of clinically significant dementia. Whether dementia is an inevitable consequence of normal human aging remains controversial. The many causes of dementia are listed in Table 35-1. The frequency of each condition depends on the age group under study, access of the group to medical care, country of origin, and perhaps racial or ethnic background. AD is the most common cause of dementia in Western Most Common Causes of Dementia Less Common Causes of Dementia Thiamine (B1): Wernicke’s encephalopathya B12 (subacute combined multifocal leukoencephalopathy) Tuberculosis, fungal, and protozoala Whipple’s diseasea


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InternalMed_Harrison. Less Common Causes of Dementia Thiamine (B1): Wernicke’s encephalopathya B12 (subacute combined multifocal leukoencephalopathy) Tuberculosis, fungal, and protozoala Whipple’s diseasea Drug, medication, and narcotic poisoninga Heavy metal intoxicationa Organic toxins degeneration spectrum Multiple sclerosis Adult Down’s syndrome with ALS-parkinsonism-dementia complex of Guam Prion (Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases) Miscellaneous Sarcoidosisa Vasculitisa CADASIL, etc. Acute intermittent porphyriaa


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InternalMed_Harrison. Metabolic disorders (e.g., Wilson’s and Leigh’s diseases, leukodystrophies, lipid storage diseases, mitochondrial mutations) countries, accounting for more than half of all patients. Vascular dis-171 ease is considered the second most frequent cause for dementia and is particularly common in elderly patients or populations with limited access to medical care, where vascular risk factors are undertreated. Often, vascular brain injury is mixed with neurodegenerative disorders, making it difficult, even for the neuropathologist, to estimate the contribution of cerebrovascular disease to the cognitive disorder in an individual patient. Dementias associated with Parkinson’s disease (PD) (Chap. 449) are common and may develop years after onset of a parkinsonian disorder, as seen with PD-related dementia (PDD), or can occur concurrently with or preceding the motor syndrome, as in dementia with Lewy bodies (DLB). In patients under the age of 65, FTD rivals AD as the most common cause of


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InternalMed_Harrison. dementia (PDD), or can occur concurrently with or preceding the motor syndrome, as in dementia with Lewy bodies (DLB). In patients under the age of 65, FTD rivals AD as the most common cause of dementia. Chronic intoxications, including those resulting from alcohol and prescription drugs, are an important and often treatable cause of dementia. Other disorders listed in Table 35-1 are uncommon but important because many are reversible. The classification of dementing illnesses into reversible and irreversible disorders is a useful approach to differential diagnosis. When effective treatments for the neurodegenerative conditions emerge, this dichotomy will become obsolete.


InternalMed_Harrison

InternalMed_Harrison. In a study of 1000 persons attending a memory disorders clinic, 19% had a potentially reversible cause of the cognitive impairment and 23% had a potentially reversible concomitant condition that may have contributed to the patient’s impairment. The three most common potentially reversible diagnoses were depression, normal pressure hydrocephalus (NPH), and alcohol dependence; medication side effects are also common and should be considered in every patient (Table 35-1).


InternalMed_Harrison

InternalMed_Harrison. Subtle cumulative decline in episodic memory is a common part of aging. This frustrating experience, often the source of jokes and humor, is referred to as benign forgetfulness of the elderly. Benign means that it is not so progressive or serious that it impairs reasonably successful and productive daily functioning, although the distinction between benign and more significant memory loss can be difficult to make. At age 85, the average person is able to learn and recall approximately one-half of the items (e.g., words on a list) that he or she could at age 18. A measurable cognitive problem that does not seriously disrupt daily activities is often referred to as mild cognitive impairment (MCI). Factors that predict progression from MCI to an AD dementia include a prominent memory deficit, family history of dementia, presence of an apolipoprotein ε4 (Apo ε4) allele, small hippocampal volumes, an AD-like signature of cortical atrophy, low cerebrospinal fluid Aβ, and elevated tau or


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InternalMed_Harrison. family history of dementia, presence of an apolipoprotein ε4 (Apo ε4) allele, small hippocampal volumes, an AD-like signature of cortical atrophy, low cerebrospinal fluid Aβ, and elevated tau or evidence of brain amyloid deposition on positron emission tomography (PET) imaging.


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InternalMed_Harrison. The major degenerative dementias include AD, DLB, FTD and related disorders, HD, and prion diseases, including Creutzfeldt-Jakob disease (CJD). These disorders are all associated with the abnormal aggregation of a specific protein: Aβ42 and tau in AD; α-synuclein in DLB; tau, TAR DNA-binding protein of 43 kDa (TDP-43), or fused in sarcoma (FUS) in FTD; huntingtin in HD; and misfolded prion protein (PrPsc) in CJD (Table 35-2). APPROACH TO THE PATIENT: Three major issues should be kept at the forefront: (1) What is the best fit for a clinical diagnosis? (2) What component of the dementia syndrome is treatable or reversible? (3) Can the physician help to alleviate the burden on caregivers? A broad overview of the approach to dementia is shown in Table 35-3. The major degenerative dementias can usually be distinguished by the initial symptoms; neuropsychological, neuropsychiatric, and neurologic findings; and neuroimaging features (Table 35-4).


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InternalMed_Harrison. The history should concentrate on the onset, duration, and tempo of progression. An acute or subacute onset of confusion may be due to delirium (Chap. 34) and should trigger the search for intoxication, infection, or metabolic derangement. An elderly person aPotentially reversible dementia. Abbreviations: ALS, amyotrophic lateral sclerosis; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; LBD, Lewy body disease; PDD, Parkinson’s disease dementia. PART 2 Cardinal Manifestations and Presentation of Diseases Abbreviations: AD, Alzheimer’s disease; CJD, Creutzfeldt-Jakob disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia.


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InternalMed_Harrison. with slowly progressive memory loss over several years is likely to suffer from AD. Nearly 75% of patients with AD begin with memory symptoms, but other early symptoms include difficulty with managing money, driving, shopping, following instructions, finding words, or navigating. Personality change, disinhibition, and weight gain or compulsive eating suggest FTD, not AD. FTD is also suggested by prominent apathy, compulsivity, loss of empathy for others, or progressive loss of speech fluency or single-word comprehension and by a relative sparing of memory and visuospatial abilities. The diagnosis of DLB is suggested by early visual hallucinations; parkinsonism; proneness to delirium or sensitivity to psychoactive medications; rapid eye movement (REM) behavior disorder (RBD; the loss of skeletal muscle paralysis during dreaming); or Capgras syndrome, the delusion that a familiar person has been replaced by an impostor.


InternalMed_Harrison

InternalMed_Harrison. A history of stroke with irregular stepwise progression suggests vascular dementia. Vascular dementia is also commonly seen in the setting of hypertension, atrial fibrillation, peripheral vascular disease, and diabetes. In patients suffering from cerebrovascular disease, it can be difficult to determine whether the dementia is due to AD, vascular disease, or a mixture of the two because many of the risk factors for vascular dementia, including diabetes, high cholesterol, elevated homocysteine, and low exercise, are also putative risk factors for AD. Moreover, many patients with a major vascular contribution to their dementia lack a history of stepwise decline. Rapid progression with motor rigidity and myoclonus suggests CJD (Chap. 453e). Seizures may indicate strokes or neoplasm but also occur in AD, particularly early-age-of-onset AD. Gait disturbance is common in vascular dementia, PD/DLB, or NPH. A history of high-risk sexual behaviors or intravenous drug use


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InternalMed_Harrison. Abbreviations: CT, computed tomography; EEG, electroencephalogram; MRI, magnetic resonance imaging; PET, positron emission tomography; RBC, red blood cell; RPR, rapid plasma reagin (test); SPECT, single-photon emission computed tomography; TSH, thyroid-stimulating hormone; VDRL, Venereal Disease Research Laboratory (test for syphilis). Abbreviations: AD, Alzheimer’s disease; CBD, cortical basal degeneration; CJD, Creutzfeldt-Jakob disease; DLB, dementia with Lewy bodies; FLAIR, fluid-attenuated inversion recovery; FTD, frontotemporal dementia; MND, motor neuron disease; MRI, magnetic resonance imaging; PSP, progressive supranuclear palsy; REM, rapid eye movement.


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InternalMed_Harrison. should trigger a search for central nervous system (CNS) infection, especially HIV or syphilis. A history of recurrent head trauma could indicate chronic subdural hematoma, chronic traumatic encephalopathy (a progressive dementia best characterized in contact sport athletes such as boxers and American football players), intracranial hypotension, or NPH. Subacute onset of severe amnesia and psychosis with mesial temporal T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities on magnetic resonance imaging (MRI) should raise concern for paraneoplastic limbic encephalitis, especially in a long-term smoker or other patients at risk for cancer. Related autoimmune conditions, such as voltage-gated potassium channel (VGKC)or N-methyl-d-aspartate (NMDA)-receptor antibody-mediated encephalopathy, can present with a similar tempo and imaging signature with or without characteristic motor manifestations such as myokymia (anti-VGKC) and faciobrachial dystonic seizures (anti-NMDA). Alcohol


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InternalMed_Harrison. can present with a similar tempo and imaging signature with or without characteristic motor manifestations such as myokymia (anti-VGKC) and faciobrachial dystonic seizures (anti-NMDA). Alcohol abuse creates risk for malnutrition and thiamine deficiency. Veganism, bowel irradiation, an autoimmune diathesis, a remote history of gastric surgery, and chronic antihistamine therapy for dyspepsia or gastroesophageal reflux predispose to B12 deficiency. Certain occupations, such as working in a battery or chemical factory, might indicate heavy metal intoxication. Careful review of medication intake, especially for sedatives and analgesics, may raise the issue of chronic drug intoxication. An autosomal dominant family history is found in HD and in familial forms of AD, FTD, DLB, or prion disorders. A history of mood disorders, the recent death of a loved one, or depressive signs, such as insomnia or weight loss, raise the possibility of depression-related cognitive impairments.


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InternalMed_Harrison. A thorough general and neurologic examination is essential to document dementia, to look for other signs of nervous system involvement, and to search for clues suggesting a systemic disease that might be responsible for the cognitive disorder. Typical AD spares motor systems until later in the course. In contrast, FTD patients often develop axial rigidity, supranuclear gaze palsy, or a motor neuron disease reminiscent of amyotrophic lateral sclerosis (ALS). In DLB, the initial symptoms may include the new onset of a parkinsonian syndrome (resting tremor, cogwheel rigidity, bradykinesia, festinating gait), but DLB often starts with visual hallucinations or dementia. Symptoms referable to the lower brainstem (RBD, gastrointestinal or autonomic problems) may arise years or even decades before parkinsonism or dementia. Corticobasal syndrome (CBS) features asymmetric akinesia and rigidity, dystonia, myoclonus, alien limb phenomena, pyramidal signs, and prefrontal deficits such as nonfluent


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InternalMed_Harrison. parkinsonism or dementia. Corticobasal syndrome (CBS) features asymmetric akinesia and rigidity, dystonia, myoclonus, alien limb phenomena, pyramidal signs, and prefrontal deficits such as nonfluent aphasia with or without motor speech impairment, executive dysfunction, apraxia, or a behavioral disorder. Progressive supranuclear palsy (PSP) is associated with unexplained falls, axial rigidity, dysphagia, and vertical gaze deficits. CJD is suggested by the presence of diffuse rigidity, an akinetic-mute state, and prominent, often startle-sensitive myoclonus.


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InternalMed_Harrison. Hemiparesis or other focal neurologic deficits suggest vascular dementia or brain tumor. Dementia with a myelopathy and peripheral neuropathy suggests vitamin B12 deficiency. Peripheral neuropathy could also indicate another vitamin deficiency, heavy metal intoxication, thyroid dysfunction, Lyme disease, or vasculitis. Dry, cool skin, hair loss, and bradycardia suggest hypothyroidism. Fluctuating confusion associated with repetitive stereotyped movements may indicate ongoing limbic, temporal, or frontal seizures. In the elderly, hearing impairment or visual loss may produce confusion and disorientation misinterpreted as dementia. Profound bilateral sensorineural hearing loss in a younger patient with short stature or myopathy, however, should raise concern for a mitochondrial disorder.


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InternalMed_Harrison. Brief screening tools such as the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MOCA), and Cognistat can be used to capture dementia and follow progression. None of these tests is highly sensitive to early-stage dementia or discriminates between dementia syndromes. The MMSE is a 30 point test of cognitive function, with each correct answer being scored as 1 point. It includes tests in the areas of: orientation (e.g., identify season/date/month/year/floor/hospital/town/state/ country); registration (e.g., name and restate 3 objects); recall (e.g., remember the same three objects 5 minutes later); and language (e.g., name pencil and watch; repeat “no if ’s and’s or but’s”; follow a 3-step command; obey a written command; and write a sentence and copy a design). In most patients with MCI and some with clinically apparent AD, bedside screening tests may be normal, and a more challenging and comprehensive set of neuropsychological tests will be required. When the