Harrison Neurology in Clinical Medicine Second Edition

CHAPTER 22 NEUROLOGIC CRITICAL CARE, INCLUDING HYPOXIC-ISCHEMIC ENCEPHALOPATHY AND SUBARACHNOID HEMORRHAGE J. Claude Hemphill, III ■ Wade S. Smith Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 Wernicke’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 ■ Critical Care Disorders of the Central Nervous System . . . . . 287 ■ Critical Care Disorders of the Peripheral Nervous System . . . . 291 Hypoxic-Ischemic Encephalopathy . . . . . . . . . . . . . . . . . . . . 287 Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 Delayed Postanoxic Encephalopathy . . . . . . . . . . . . . . . . . . 289 Disorders of Neuromuscular Transmission . . . . . . . . . . . . . . 292 Metabolic Encephalopathies . . . . . . . . . . . . . . . . . . . . . . . . . 289 Myopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 Septic Encephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 ■ Subarachnoid Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . 292 Central Pontine Myelinolysis . . . . . . . . . . . . . . . . . . . . . . . . . 290 ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Life-threatening neurologic illness may be caused by a Early astrocytic swelling is a hallmark of ischemia. Brain primary disorder affecting any region of the neuraxis or edema that is clinically significant usually represents a may occur as a consequence of a systemic disorder such combination of vasogenic and cellular components. as hepatic failure, multisystem organ failure, or cardiac Edema can lead to increased ICP as well as tissue shifts arrest (Table 22-1). Neurologic critical care focuses on and brain displacement from focal processes (Chap. 14). preservation of neurologic tissue and prevention of sec- These tissue shifts can cause injury by mechanical dis- ondary brain injury caused by ischemia, edema, and ele- traction and compression in addition to the ischemia of vated intracranial pressure (ICP). impaired perfusion consequent to the elevated ICP. PATHOPHYSIOLOGY Ischemic Cascade and Cellular Injury Brain Edema When delivery of substrates, principally oxygen and glu- cose, is inadequate to sustain cellular function, a series of Swelling, or edema, of brain tissue occurs with many interrelated biochemical reactions known as the ischemic types of brain injury. The two principal types of edema cascade is initiated (see Fig. 21-2).The release of excitatory are vasogenic and cytotoxic. Vasogenic edema refers to the amino acids, especially glutamate, leads to influx of cal- influx of fluid and solutes into the brain through an cium and sodium ions, which disrupt cellular homeostasis. incompetent blood-brain barrier (BBB). In the normal An increased intracellular calcium concentration may acti- cerebral vasculature, endothelial tight junctions associ- vate proteases and lipases, which then lead to lipid peroxi- ated with astrocytes create an impermeable barrier (the dation and free radical–mediated cell membrane injury. BBB), through which access into the brain interstitium Cytotoxic edema ensues, and ultimately necrotic cell death is dependent upon specific transport mechanisms and tissue infarction occur.This pathway to irreversible cell (Chap. 19).The BBB may be compromised in ischemia, death is common to ischemic stroke, global cerebral trauma, infection, and metabolic derangements. Typi- ischemia, and traumatic brain injury. Penumbra refers to cally, vasogenic edema develops rapidly following injury. ischemic brain tissue that has not yet undergone irre- Cytotoxic edema refers to cellular swelling and occurs in a versible infarction, implying that the region is potentially variety of settings including brain ischemia and trauma. salvageable if ischemia can be reversed. Factors that may 282

TABLE 22-1 283 NEUROLOGIC DISORDERS IN CRITICAL ILLNESS LOCALIZATION SYNDROME ALONG NEUROAXIS Central Nervous System Global encephalopathy CHAPTER 22 Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy and Subarachnoid Hemorrhage Brain: Cerebral hemispheres Sepsis Organ failure—hepatic, renal Brainstem Medication related Spinal cord Sedatives/hypnotics/analgesics H2 blockers, antihypertensives Peripheral Nervous System Drug overdose Peripheral nerve Electrolyte disturbance—hyponatremia, hypoglycemia Hypotension/hypoperfusion Axonal Hypoxia Demyelinating Meningitis Neuromuscular junction Subarachnoid hemorrhage Muscle Wernicke’s disease Seizure—postictal or nonconvulsive status Hypertensive encephalopathy Hypothyroidism—myxedema Focal deficits Ischemic stroke Tumor Abscess, subdural empyema Subdural/epidural hematoma Mass effect and compression Ischemic stroke, intraparenchymal hemorrhage Hypoxia Mass effect and compression Disc herniation Epidural hematoma Ischemia—hypotension/embolic Subdural empyema Trauma, central cord syndrome Critical illness polyneuropathy Possible neuromuscular blocking agent complication Metabolic disturbances, uremia, hyperglycemia Medication effects—chemotherapeutic, antiretroviral Guillian-Barré syndrome Chronic inflammatory demyelinating polyneuropathy Prolonged effect of neuromuscular blockade Medication effects—aminoglycosides Myasthenia-gravis, Lambert-Eaton syndrome Critical illness myopathy Septic myopathy Cachectic myopathy—with or without disuse atrophy Electrolyte disturbances—hypokalemia/hyperkalemia, hypophosphatemia Acute quadriplegic myopathy exacerbate ischemic brain injury include systemic to exacerbation of the primary brain injury. Prevention, hypotension and hypoxia, which further reduce substrate identification, and treatment of secondary brain insults are delivery to vulnerable brain tissue, and fever, seizures, and fundamental goals of management. hyperglycemia, which can increase cellular metabolism outstripping compensatory processes. Clinically, these An alternative pathway of cellular injury is apoptosis. events are known as secondary brain insults because they lead This process implies programmed cell death, which may occur in the setting of ischemic stroke, global cerebral

SECTION III Diseases of the Central Nervous System284 ischemia, traumatic brain injury, and possibly intracerebral and decreases with hypocapnia and alkalosis. This forms hemorrhage. Apoptotic cell death can be distinguished the basis for the use of hyperventilation to lower ICP, histologically from the necrotic cell death of ischemia and and this effect on ICP is mediated through a decrease in is mediated through a different set of biochemical path- intracranial blood volume. Cerebral autoregulation is ways. At present, interventions for prevention and treat- critical to the normal homeostatic functioning of the ment of apoptotic cell death remain less well defined than brain, and this process may be disordered focally and those for ischemia. Excitotoxicity and mechanisms of cell unpredictably in disease states such as traumatic brain death are discussed in more detail in Chap. 19. injury and severe focal cerebral ischemia. Cerebral Perfusion and Autoregulation Cerebrospinal Fluid and Intracranial Pressure Brain tissue requires constant perfusion in order to The cranial contents consist essentially of brain, cere- ensure adequate delivery of substrate. The hemodynamic brospinal fluid (CSF), and blood. CSF is produced prin- response of the brain has the capacity to preserve perfu- cipally in the choroid plexus of each lateral ventricle, sion across a wide range of systemic blood pressures. exits the brain via the foramina of Luschka and Magendi, Cerebral perfusion pressure (CPP), defined as the mean and flows over the cortex to be absorbed into the venous systemic arterial pressure (MAP) minus the ICP, provides system along the superior sagittal sinus. Approximately the driving force for circulation across the capillary beds 150 mL of CSF are contained within the ventricles and of the brain. Autoregulation refers to the physiologic surrounding the brain and spinal cord; the cerebral blood response whereby cerebral blood flow (CBF) remains volume is also ~150 mL. The bony skull offers excellent relatively constant over a wide range of blood pressures as protection for the brain but allows little tolerance for a consequence of alterations of cerebrovascular resistance additional volume. Significant increases in volume even- (Fig. 22-1). If systemic blood pressure drops, cerebral tually result in increased ICP. Obstruction of CSF out- perfusion is preserved through vasodilatation of arterioles flow, edema of cerebral tissue, or increases in volume in the brain; likewise, arteriolar vasoconstriction occurs at from tumor or hematoma may increase ICP. Elevated high systemic pressures to prevent hyperperfusion. At the ICP diminishes cerebral perfusion and can lead to tissue extreme limits of MAP or CPP (high or low), flow ischemia. Ischemia in turn may lead to vasodilatation via becomes directly related to perfusion pressure. These autoregulatory mechanisms designed to restore cerebral autoregulatory changes occur in the microcirculation and perfusion. However, vasodilatation also increases cerebral are mediated by vessels below the resolution of those seen blood volume, which in turn then increases ICP, lowers on angiography. CBF is also strongly influenced by pH CPP, and provokes further ischemia (Fig. 22-2). This and PCO2. CBF increases with hypercapnia and acidosis vicious cycle is commonly seen in traumatic brain injury, massive intracerebral hemorrhage, and large hemispheric infarcts with significant tissue shifts. 125 PaCO2 PaO2 CBF, mL/100g per min ↓SABP Spontaneous 75 ↓CPP Dehydration Pharmacologic Mechanical ↓Metabolism ↑Edema ↑ICP ↑Vasodilatation ↑CMR-O2/Metabolism ↑CSF ↑Viscosity ↓O2 delivery 25 Hypercapnia 25 75 125 175 Pharmacologic BP, mmHg ↑CBV FIGURE 22-1 Autoregulation of cerebral blood flow (solid line). Cerebral FIGURE 22-2 perfusion is constant over a wide range of systemic blood Ischemia and vasodilatation. Reduced cerebral perfusion pressure. Perfusion is increased in the setting of hypoxia or pressure (CPP) leads to increased ischemia, vasodilatation, hypercarbia. BP, blood pressure; CBF, cerebral blood flow. increased intracranial pressure (ICP), and further reductions (Reprinted with permission from Anesthesiology 43:447, in CPP, a cycle leading to further neurologic injury. CBV, cere- 1975. Copyright 1975, Lippincott Company.) bral blood volume; CMR, cerebral metabolic rate; CSF, cere- brospinal fluid; SABP, systolic arterial blood pressure. (Adapted from MJ Rosner et al: J Neurosurg 83:949, 1995; with permission.)

Approach to the Patient: metabolic encephalopathy typically reveals generalized 285 slowing. One of the most important uses of EEG is to SEVERE CNS DYSFUNCTION help exclude inapparent seizures, especially nonconvul- CHAPTER 22 Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy and Subarachnoid Hemorrhage sive status epilepticus. Untreated continuous or fre- Critically ill patients with severe central nervous system quently recurrent seizures may cause neuronal injury, dysfunction require rapid evaluation and intervention making the diagnosis and treatment of seizures crucial in in order to limit primary and secondary brain injury. this patient group. Lumbar puncture (LP) may be neces- Initial neurologic evaluation should be performed con- sary to exclude infectious processes, and an elevated current with stabilization of basic respiratory, cardiac, opening pressure may be an important clue to cerebral and hemodynamic parameters. Significant barriers venous sinus thrombosis. In patients with coma or pro- may exist to neurologic assessment in the critical care found encephalopathy, it is preferable to perform a neu- unit, including endotracheal intubation and the use of roimaging study prior to LP. If bacterial meningitis is sedative or paralytic agents to facilitate procedures. suspected, an LP may be performed first or antibiotics may be empirically administered before the diagnostic An impaired level of consciousness is common in studies are completed. Standard laboratory evaluation of critically ill patients. The essential first task in assess- critically ill patients should include assessment of serum ment is to determine whether the cause of dysfunc- electrolytes (especially sodium and calcium), glucose, tion is related to a diffuse, usually metabolic, process renal and hepatic function, complete blood count, and or whether a focal, usually structural, process is impli- coagulation. Serum or urine toxicology screens should cated. Examples of diffuse processes include meta- be performed in patients with encephalopathy of bolic encephalopathies related to organ failure, drug unknown cause. EEG, LP, and other specific laboratory overdose, or hypoxia-ischemia. Focal processes include tests are most useful when the mechanism of the altered ischemic and hemorrhagic stroke and traumatic level of consciousness is uncertain; they are not routinely brain injury, especially with intracranial hematomas. performed in clear-cut cases of stroke or traumatic brain Since these two categories of disorders have funda- injury. mentally different causes, treatments, and prognoses, the initial focus is on making this distinction rapidly Monitoring of ICP can be an important tool in and accurately. The approach to the comatose selected patients. In general, patients who should be patient is discussed in Chap. 14; etiologies are listed in considered for ICP monitoring are those with pri- Table 14-1. mary neurologic disorders, such as stroke or traumatic brain injury, who are at significant risk for secondary Minor focal deficits may be present on the neuro- brain injury due to elevated ICP and decreased CPP. logic examination in patients with metabolic Included are patients with the following: severe trau- encephalopathies. However, the finding of prominent matic brain injury [Glasgow Coma Scale (GCS) score focal signs such as pupillary asymmetry, hemiparesis, Յ8 (Table 31-2)]; large tissue shifts from supratentorial gaze palsy, or paraplegia should suggest the possibility ischemic or hemorrhagic stroke; or hydrocephalus of a structural lesion. All patients with a decreased from subarachnoid hemorrhage (SAH), intraventricu- level of consciousness associated with focal findings lar hemorrhage, or posterior fossa stroke.An additional should undergo an urgent neuroimaging procedure, disorder in which ICP monitoring can add important as should all patients with coma of unknown etiology. information is fulminant hepatic failure, in which ele- CT scanning is usually the most appropriate initial vated ICP may be treated with barbiturates or, eventu- study because it can be performed quickly in criti- ally, liver transplantation. In general, ventriculostomy is cally ill patients and demonstrates hemorrhage, hydro- preferable to ICP monitoring devices that are placed cephalus, and intracranial tissue shifts well. MRI may in the brain parenchyma, because ventriculostomy provide more specific information in some situations, allows CSF drainage as a method of treating elevated such as acute ischemic stroke (diffusion-weighted ICP. However, parenchymal ICP monitoring is most imaging, DWI) and cerebral venous sinus thrombosis appropriate for patients with diffuse edema and small (magnetic resonance venography, MRV). Any sugges- ventricles (which may make ventriculostomy place- tion of trauma from the history or examination ment more difficult) or any degree of coagulopathy should alert the examiner to the possibility of cervical (in which ventriculostomy carries a higher risk of spine injury and prompt an imaging evaluation using hemorrhagic complications) (Fig 22-3). plain x-rays, MRI, or CT. TREATMENT OF ELEVATED ICP Elevated ICP Other diagnostic studies are best utilized in specific may occur in a wide range of disorders including circumstances, usually when neuroimaging studies fail to head trauma, intracerebral hemorrhage, SAH with reveal a structural lesion and the etiology of the altered hydrocephalus, and fulminant hepatic failure. Because mental state remains uncertain. Electroencephalography (EEG) can be important in the evaluation of critically ill patients with severe brain dysfunction. The EEG of

286 TABLE 22-2 Lateral ventricle STEPWISE APPROACH TO TREATMENT OF ELEVATED INTRACRANIAL PRESSUREa Ventriculostomy Brain tissue oxygen probe Insert ICP monitor—ventriculostomy versus parenchymal device SECTION III Diseases of the Central Nervous System Fiberoptic intraparenchymal General goals: maintain ICP <20 mmHg and CPP Ն60 mmHg ICP monitor For ICP > 20–25 mmHg for >5 min: FIGURE 22-3 1. Drain CSF via ventriculostomy (if in place) Intracranial pressure and brain tissue oxygen monitoring. 2. Elevate head of the bed; midline head position A ventriculostomy allows for drainage of cerebrospinal fluid 3. Osmotherapy—mannitol 25–100 g q4h as needed— to treat elevated intracranial pressure (ICP). Fiberoptic ICP (maintain serum osmolality <320 mosmol) or hyper- and brain tissue oxygen monitors are usually secured using a tonic saline (30 mL, 23.4% NaCl bolus) screwlike skull bolt. Cerebral blood flow and microdialysis 4. Glucocorticoids—dexamethasone 4 mg q6h for probes (not shown) may be placed in a manner similar to the vasogenic edema from tumor, abscess (avoid brain tissue oxygen probe. glucocorticoids in head trauma, ischemic and hemorrhagic stroke) CSF and blood volume can be redistributed initially, 5. Sedation (e.g., morphine, propofol, or midazolam); by the time elevated ICP occurs intracranial compli- add neuromuscular paralysis if necessary (patient will ance is severely impaired. At this point, any small require endotracheal intubation and mechanical venti- increase in the volume of CSF, intravascular blood, lation at this point, if not before) edema, or a mass lesion may result in a significant 6. Hyperventilation—to Paco2 30–35 mmHg increase in ICP and a decrease in cerebral perfusion. 7. Pressor therapy—phenylephrine, dopamine, or This is a fundamental mechanism of secondary norepinephrine to maintain adequate MAP to ensure ischemic brain injury and constitutes an emergency CPP Ն60 mmHg (maintain euvolemia to minimize that requires immediate attention. In general, ICP deleterious systemic effects of pressors) should be maintained at <20 mm Hg and CPP 8. Consider second-tier therapies for refractory elevated should be maintained at >60 mm Hg. ICP a. High-dose barbiturate therapy (“pentobarb coma”) Interventions to lower ICP are ideally based on the b. Aggressive hyperventilation to Paco2 <30 mmHg underlying mechanism responsible for the elevated c. Hypothermia ICP (Table 22-2). For example, in hydrocephalus d. Hemicraniectomy from SAH, the principal cause of elevated ICP is impairment of CSF drainage. In this setting, ventricu- aThroughout ICP treatment algorithm, consider repeat head CT to lar drainage of CSF is likely to be sufficient and most identify mass lesions amenable to surgical evacuation. appropriate. In head trauma and stroke, cytotoxic Note: CPP, cerebral perfusion pressure; CSF, cerebrospinal fluid; edema may be most responsible, and the use of MAP, mean arterial pressure; Paco2, arterial partial pressure of carbon osmotic diuretics such as mannitol becomes an dioxide. appropriate early step. As described above, elevated ICP may cause tissue ischemia, and, if cerebral studies may reveal evidence of edema and mass effect. autoregulation is intact, the resulting vasodilatation Hypotonic IV fluids should be avoided, and elevation can lead to a cycle of worsening ischemia. Paradoxi- of the head of the bed is recommended. Patients must cally, administration of vasopressor agents to increase be carefully observed for risk of aspiration and com- mean arterial pressure may actually lower ICP by promise of the airway as the level of alertness improving perfusion, thereby allowing autoregulatory declines. Coma and unilateral pupillary changes are vasoconstriction as ischemia is relieved and ultimately late signs and require immediate intervention. Emer- decreasing intracranial blood volume. gent treatment of elevated ICP is most quickly achieved by intubation and hyperventilation, which Early signs of elevated ICP include drowsiness and causes vasoconstriction and reduces cerebral blood a diminished level of consciousness. Neuroimaging volume. In order to avoid provoking or worsening cerebral ischemia, hyperventilation is best used for short periods of time until a more definitive treat- ment can be instituted. Furthermore, the effects of hyperventilation on ICP are short-lived, often lasting only for several hours because of the buffering capac- ity of the cerebral interstitium, and rebound eleva- tions of ICP may accompany abrupt discontinuation

of hyperventilation. As the level of consciousness CRITICAL CARE DISORDERS OF THE 287 declines to coma, the ability to follow the neurologic CENTRAL NERVOUS SYSTEM status of the patient by examination deteriorates and measurement of ICP assumes greater importance. If a HYPOXIC-ISCHEMIC ENCEPHALOPATHY ventriculostomy device is in place, direct drainage of CSF to reduce ICP is possible. Finally, high-dose bar- This occurs from lack of delivery of oxygen to the brain biturates, decompressive hemicraniectomy, or hypother- because of hypotension or respiratory failure. Causes mia are sometimes used for refractory elevations of include myocardial infarction, cardiac arrest, shock, asphyx- ICP, although these have significant side effects and iation, paralysis of respiration, and carbon monoxide or have not been proven to improve outcome. cyanide poisoning. In some circumstances, hypoxia may predominate. Carbon monoxide and cyanide poisoning SECONDARY BRAIN INSULTS Patients with are termed histotoxic hypoxia since they cause a direct primary brain injuries, whether due to trauma or impairment of the respiratory chain. stroke, are at risk for ongoing secondary ischemic brain injury. Because secondary brain injury can be a major Clinical Manifestations CHAPTER 22 Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy and Subarachnoid Hemorrhage determinant of a poor outcome, strategies for minimiz- ing secondary brain insults are an integral part of the Mild degrees of pure hypoxia, such as occur at high alti- critical care of all patients.While elevated ICP may lead tudes, cause impaired judgment, inattentiveness, motor to secondary ischemia, most secondary brain injury is incoordination, and, at times, euphoria. However, with mediated through other clinical events that exacerbate hypoxia-ischemia, such as occurs with circulatory arrest, the ischemic cascade already initiated by the primary consciousness is lost within seconds. If circulation is brain injury. Episodes of secondary brain insults are restored within 3–5 min, full recovery may occur, but if usually not associated with apparent neurologic wors- hypoxia-ischemia lasts beyond 3–5 min, some degree of ening. Rather, they lead to cumulative injury, which permanent cerebral damage is the rule. Except in manifests as higher mortality or worsened long-term extreme cases, it may be difficult to judge the precise functional outcome. Thus, close monitoring of vital degree of hypoxia-ischemia, and some patients make a signs is important, as is early intervention to prevent relatively full recovery after even 8–10 min of global secondary ischemia. Avoiding hypotension and hypoxia cerebral ischemia.The distinction between pure hypoxia is critical, as significant hypotensive events (systolic and hypoxia-ischemia is important, since a Pao2 as low as blood pressure <90 mm Hg) as short as 10 min in 20 mmHg (2.7 kPa) can be well tolerated if it develops duration have been shown to adversely influence out- gradually and normal blood pressure is maintained, but come after traumatic brain injury. Even in patients with short durations of very low or absent cerebral circula- stroke or head trauma who do not require ICP moni- tion may result in permanent impairment. toring, close attention to adequate cerebral perfusion is warranted. Hypoxia (pulse oximetry saturation < 90%), Clinical examination at different time points after a particularly in combination with hypotension, also leads hypoxic-ischemic insult (especially cardiac arrest) is useful to secondary brain injury. Likewise, fever and hyper- in assessing prognosis for long-term neurologic outcome. glycemia both worsen experimental ischemia and have The prognosis is better for patients with intact brainstem been associated with worsened clinical outcome after function, as indicated by normal pupillary light responses stroke and head trauma.Aggressive control of fever with and intact oculocephalic (doll’s-eyes), oculovestibular a goal of normothermia is warranted but may be diffi- (caloric), and corneal reflexes (Fig. 22-4). Absence of cult to achieve with antipyretic medications and cool- these reflexes and the presence of persistently dilated ing blankets.The value of newer surface or intravascular pupils that do not react to light are grave prognostic signs. temperature control devices for the management of A uniformly dismal prognosis from hypoxic-ischemic refractory fever is under investigation. The use of IV coma is conveyed by an absent pupillary light reflex or insulin infusion is encouraged for control of hyper- extensor or absent motor response to pain on day 3 fol- glycemia as this allows better regulation of serum glu- lowing the injury. Electrophysiologically, the bilateral absence cose levels than subcutaneous insulin. A reasonable goal of the N20 component of the somatosensory evoked is to maintain the serum glucose level at <7.8 mmol/L response (SSEPs) in the first several days also conveys a (<140 mg/dL), although some have suggested that even poor prognosis.A very elevated serum level (>33 μg/L) of tighter control is warranted. New cerebral monitoring the biochemical marker neuron-specific enolase (NSE) is tools that allow continuous evaluation of brain tissue indicative of brain damage after resuscitation from cardiac oxygen tension, CBF, and metabolism (via microdialysis) arrest and predicts a poor outcome. However, at present, may further improve the management of secondary SSEPs and NSE levels may be difficult to obtain in a brain injury. timely fashion, with SSEP testing requiring substantial expertise in interpretation and NSE measurements not yet standardized.Whether administration of mild hypothermia

288 Coma Exclude major confounders SECTION III Diseases of the Central Nervous System No brain stem reflexes at Yes Brain death FPR FIGURE 22-5 any time (pupil, cornea, Yes testing 0% Cortical laminar necrosis in hypoxic-ischemic encephalopa- oculocephalic, cough) Yes (0–8.8) thy. T1-weighted postcontrast MRI shows cortical enhance- Yes Poor ment in a watershed distribution consistent with laminar or Yes outcome FPR necrosis. 0.7% Day 1 Poor (0–3.7) or brainstem. In some cases, extensive bilateral thalamic Myoclonus, status epilepticus outcome scarring may affect pathways that mediate arousal, and FPR this pathology may be responsible for the persistent veg- or Poor 0% etative state. A specific form of hypoxic-ischemic outcome (0–3) encephalopathy, so-called watershed infarcts, occurs at Day 1–3 the distal territories between the major cerebral arteries SSEP Poor FPR and can cause cognitive deficits, including visual agnosia, outcome 0% and weakness that is greater in proximal than in distal absent N20 responses∗ (0–3) muscle groups. or Diagnosis Day 1–3 Diagnosis is based upon the history of a hypoxic- Serum NSE > 33 μg/L∗ ischemic event such as cardiac arrest. Blood pressure <70 mmHg systolic or Pao2 <40 mmHg is usually nec- or essary, although both absolute levels as well as duration Day 3 of exposure are important determinants of cellular injury. Carbon monoxide intoxication can be confirmed Absent pupil or corneal by measurement of carboxyhemoglobin and is suggested reflexes; extensor or absent by a cherry red color of the skin, although the latter is an inconsistent clinical finding. motor response Treatment: no HYPOXIC-ISCHEMIC ENCEPHALOPATHY Treatment should be directed at restoration of normal Indeterminate outcome cardiorespiratory function. This includes securing a clear airway, ensuring adequate oxygenation and ventilation, FIGURE 22-4 and restoring cerebral perfusion, whether by cardiopul- Prognostication of outcome in comatose survivors of car- monary resuscitation, fluid, pressors, or cardiac pacing. diopulmonary resuscitation. Numbers in parentheses are 95% confidence intervals. Confounders could include use of sedatives or neuromuscular blocking agents, hypothermia therapy, organ failure, or shock. Tests denoted with an * may not be available in a timely and standardized manner. SSEP, somatosensory evoked potentials; NSE, neuron-specific enolase; FPR, false-positive rate. (From Wijdicks et al, with permission.) after cardiac arrest (see Treatment) will alter the usefulness of these clinical and electrophysiologic predictors is unknown. Long-term consequences of hypoxic-ischemic encephalopathy include persistent coma or a vegetative state (Chap. 14), dementia, visual agnosia (Chap. 15), parkinsonism, choreoathetosis, cerebellar ataxia, myoclonus, seizures, and an amnestic state, which may be a conse- quence of selective damage to the hippocampus. Pathology Principal histologic findings are extensive multifocal or diffuse laminar cortical necrosis (Fig. 22-5), with almost invariable involvement of the hippocampus. The hip- pocampal CA1 neurons are vulnerable to even brief episodes of hypoxia-ischemia, perhaps explaining why selective persistent memory deficits may occur after brief cardiac arrest. Scattered small areas of infarction or neuronal loss may be present in the basal ganglia, hypothalamus,

Hypothermia may target the neuronal cell injury cascade disturbance. This is often attributed to medication 289 CHAPTER 22 Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy and Subarachnoid Hemorrhage and has substantial neuroprotective properties in experi- effects, sleep deprivation, pain, and anxiety. The term mental models of brain injury. In two trials, mild ICU psychosis has been used to describe a mental state hypothermia (33°C) improved functional outcome in with profound agitation occurring in this setting. The patients who remained comatose after resuscitation presence of family members in the ICU may help to from a cardiac arrest. Treatment was initiated within min- calm and orient agitated patients, and in severe cases, utes of cardiac resuscitation and continued for 12 h in low doses of neuroleptics (e.g., haloperidol 0.5–1 mg) one study and 24 h in the other. Potential complications can be useful. Ultimately, the psychosis resolves with of hypothermia include coagulopathy and an increased improvement in the underlying illness and a return to risk of infection. Based upon these studies, the Interna- familiar surroundings. tional Liaison Committee on Resuscitation issued the fol- lowing advisory statement in 2003: “Unconscious adult In the ICU setting, several metabolic causes of an patients with spontaneous circulation after out-of-hospital altered level of consciousness predominate. Hypercarbic cardiac arrest should be cooled to 32°–34°C for 12–24 h encephalopathy can present with headache, confusion, when the initial rhythm was ventricular fibrillation.” stupor, or coma. Hypoventilation syndrome occurs most frequently in patients with a history of chronic CO2 Severe carbon monoxide intoxication may be treated retention who are receiving oxygen therapy for emphy- with hyperbaric oxygen. Anticonvulsants may be needed sema or chronic pulmonary disease. The elevated Paco2 to control seizures, although these are not usually given leading to CO2 narcosis may have a direct anesthetic prophylactically. Posthypoxic myoclonus may respond to effect, and cerebral vasodilatation from increased Paco2 oral administration of clonazepam at doses of 1.5–10 mg can lead to increased ICP. Hepatic encephalopathy is daily or valproate at doses of 300–1200 mg daily in suggested by asterixis and can occur in chronic liver fail- divided doses. Myoclonic status epilepticus within 24 h ure or acute fulminant hepatic failure. Both hyper- after a primary circulatory arrest portends a universally glycemia and hypoglycemia can cause encephalopathy, as poor prognosis, even if seizures are controlled. can hypernatremia and hyponatremia. Confusion, impair- ment of eye movements, and gait ataxia are the hallmarks of acute Wernicke’s disease (see later in the chapter). DELAYED POSTANOXIC ENCEPHALOPATHY SEPTIC ENCEPHALOPATHY Delayed postanoxic encephalopathy is an uncommon Pathogenesis phenomenon in which patients appear to make an ini- tial recovery from hypoxic-ischemic insult but then In patients with sepsis, the systemic response to infectious develop a relapse characterized by apathy, confusion, and agents leads to the release of circulating inflammatory agitation. Progressive neurologic deficits may include mediators that appear to contribute to encephalopathy. shuffling gait, diffuse rigidity and spasticity, persistent Critical illness, in association with the systemic inflamma- parkinsonism or myoclonus, and, on occasion, coma and tory response syndrome (SIRS), can lead to multisystem death after 1–2 weeks. Widespread cerebral demyelina- organ failure. This syndrome can occur in the setting of tion may be present. apparent sepsis, severe burns, or trauma, even without clear identification of an infectious agent. Many patients with Carbon monoxide and cyanide intoxication can also critical illness, sepsis, or SIRS develop encephalopathy cause a delayed encephalopathy. Little clinical impairment without obvious explanation. This condition is broadly is evident when the patient first regains consciousness, termed septic encephalopathy. While the specific mediators but a parkinsonian syndrome characterized by akinesia leading to neurologic dysfunction remain uncertain, it is and rigidity without tremor may develop. Symptoms clear that the encephalopathy is not simply the result of can worsen over months, accompanied by increasing metabolic derangements of multiorgan failure. The evidence of damage in the basal ganglia as seen on both cytokines tumor necrosis factor , interleukin (IL) 1, IL-2, CT and MRI. and IL-6 are thought to play a role in this syndrome. METABOLIC ENCEPHALOPATHIES Diagnosis Altered mental states, variously described as confusion, Septic encephalopathy presents clinically as a diffuse delirium, disorientation, and encephalopathy, are present dysfunction of the brain without prominent focal find- in many patients with severe illness in an intensive care ings. Confusion, disorientation, agitation, and fluctuations unit (ICU). Older patients are particularly vulnerable to in level of alertness are typical. In more profound cases, delirium, a confusional state characterized by disordered especially with hemodynamic compromise, the decrease perception, frequent hallucinations, delusions, and sleep in level of alertness can be more prominent, at times

SECTION III Diseases of the Central Nervous System290 resulting in coma. Hyperreflexia and frontal release signs should aim for gradual correction, i.e., by Ն10 mmol/L such as a grasp or snout reflex (Chap. 15) can be seen. (10 meq/L) within 24 h and 20 mmol/L (20 meq/L) Abnormal movements such as myoclonus, tremor, or within 48 h. asterixis can occur. Septic encephalopathy is quite com- mon, occurring in the majority of patients with sepsis WERNICKE’S DISEASE and multisystem organ failure. Diagnosis is often difficult because of the multiple potential causes of neurologic Wernicke’s disease is a common and preventable disor- dysfunction in critically ill patients and requires exclu- der due to a deficiency of thiamine. In the United States, sion of structural, metabolic, toxic, and infectious (e.g., alcoholics account for most cases, but patients with mal- meningitis or encephalitis) causes. The mortality of nutrition due to hyperemesis, starvation, renal dialysis, patients with septic encephalopathy severe enough to cancer, AIDS, or rarely gastric surgery are also at risk. produce coma approaches 50%, although this principally The characteristic clinical triad is that of ophthalmople- reflects the severity of the underlying critical illness and gia, ataxia, and global confusion. However, only one- is not a singular result of the septic encephalopathy. third of patients with acute Wernicke’s disease present Patients dying from severe sepsis or septic shock may with the classic clinical triad. Most patients are profoundly have elevated levels of the serum brain injury biomarker disoriented, indifferent, and inattentive, although rarely S-100β and neuropathologic findings of neuronal apop- they have an agitated delirium related to ethanol with- tosis and cerebral ischemic injury. However, successful drawal. If the disease is not treated, stupor, coma, and treatment of the underlying critical illness almost always death may ensue. Ocular motor abnormalities include results in complete resolution of the encephalopathy, horizontal nystagmus on lateral gaze, lateral rectus palsy with profound long-term cognitive disability being (usually bilateral), conjugate gaze palsies, and rarely pto- uncommon. sis. Gait ataxia probably results from a combination of polyneuropathy, cerebellar involvement, and vestibular CENTRAL PONTINE MYELINOLYSIS paresis. The pupils are usually spared, but they may This disorder typically presents in a devastating fashion become miotic with advanced disease. as quadriplegia and pseudobulbar palsy. Predisposing fac- tors include severe underlying medical illness or nutri- Wernicke’s disease is usually associated with other tional deficiency; most cases are associated with rapid cor- manifestations of nutritional disease, such as polyneu- rection of hyponatremia or with hyperosmolar states. ropathy. Rarely, amblyopia or myelopathy occurs.Tachy- The pathology consists of demyelination without inflam- cardia and postural hypotension may be related to mation in the base of the pons, with relative sparing of impaired function of the autonomic nervous system or axons and nerve cells. MRI is useful in establishing the to the coexistence of cardiovascular beriberi. Patients diagnosis (Fig. 22-6) and may also identify partial forms who recover show improvement in ocular palsies within that present as confusion, dysarthria, and/or disturbances hours after the administration of thiamine, but horizon- of conjugate gaze without quadriplegia. Occasional cases tal nystagmus may persist. Ataxia improves more slowly present with lesions outside of the brainstem. Therapeu- than the ocular motor abnormalities. Approximately half tic guidelines for the restoration of severe hyponatremia recover incompletely and are left with a slow, shuffling, wide-based gait and an inability to tandem walk. Apathy, FIGURE 22-6 drowsiness, and confusion improve more gradually. As Central pontine myelinolysis. Axial T2-weighted MR scan these symptoms recede, an amnestic state with impair- through the pons reveals a symmetric area of abnormal high ment in recent memory and learning may become more signal intensity within the basis pontis (arrows). apparent (Korsakoff’s psychosis). Korsakoff ’s psychosis is frequently persistent; the residual mental state is charac- terized by gaps in memory, confabulation, and disor- dered temporal sequencing. Pathology Periventricular lesions surround the third ventricle, aqueduct, and fourth ventricle, with petechial hemor- rhages in occasional acute cases and atrophy of the mammillary bodies in most chronic cases. There is fre- quently endothelial proliferation, demyelination, and some neuronal loss. These changes may be detected by MRI scanning (Fig. 22-7). The amnestic defect is related to lesions in the dorsal medial nuclei of the thalamus.

FIGURE 22-7 (2) secondary PNS manifestations of systemic critical 291 CHAPTER 22 Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy and Subarachnoid Hemorrhage Wernicke’s disease. Coronal T1-weighted postcontrast MRI illness, often involving multisystem organ failure. The reveals abnormal enhancement of the mammillary bodies former include acute polyneuropathies such as Guillain- (arrows), typical of acute Wernicke’s encephalopathy. Barré syndrome (Chap. 41), neuromuscular junction disorders including myasthenia gravis (Chap. 42) and bot- Pathogenesis ulism, and primary muscle disorders such as polymyositis Thiamine is a cofactor of several enzymes, including trans- (Chap. 44). The latter result either from the systemic dis- ketolase, pyruvate dehydrogenase, and α-ketoglutarate ease itself or as a consequence of interventions. dehydrogenase. Thiamine deficiency produces a diffuse decrease in cerebral glucose utilization and results in General principles of respiratory evaluation in patients mitochondrial damage. Glutamate accumulates owing to with PNS involvement, regardless of cause, include assess- impairment of α-ketoglutarate dehydrogenase activity ment of pulmonary mechanics, such as maximal inspiratory and, in combination with the energy deficiency, may force (MIF) and vital capacity (VC), and evaluation of result in excitotoxic cell damage. strength of bulbar muscles. Regardless of the cause of weakness, endotracheal intubation should be considered Treatment: when the MIF falls to <25 cmH2O or the VC is <1 L. WERNICKE’S DISEASE Also, patients with severe palatal weakness may require Wernicke’s disease is a medical emergency and requires endotracheal intubation in order to prevent acute upper immediate administration of thiamine, in a dose of 100 mg airway obstruction or recurrent aspiration. Arterial blood either IV or IM. The dose should be given daily until the gases and oxygen saturation from pulse oximetry are used patient resumes a normal diet and should be begun to follow patients with potential respiratory compromise prior to treatment with IV glucose solutions. Glucose from PNS dysfunction. However, intubation and mechani- infusions may precipitate Wernicke’s disease in a previ- cal ventilation should be undertaken based on clinical ously unaffected patient or cause a rapid worsening of assessment rather than waiting until oxygen saturation an early form of the disease. For this reason, thiamine drops or CO2 retention develops from hypoventilation. should be administered to all alcoholic patients requir- Noninvasive mechanical ventilation may be considered ing parenteral glucose. initially in lieu of endotracheal intubation but is generally insufficient in patients with severe bulbar weakness or CRITICAL CARE DISORDERS OF THE ventilatory failure with hypercarbia. PERIPHERAL NERVOUS SYSTEM NEUROPATHY Critical illness with disorders of the peripheral nervous system (PNS) arises in two contexts: (1) primary neuro- Although encephalopathy may be the most obvious logic diseases that require critical care interventions neurologic dysfunction in critically ill patients, dysfunc- such as intubation and mechanical ventilation, and tion of the PNS is also quite common. It is typically present in patients with prolonged critical illnesses last- ing several weeks and involving sepsis; clinical suspicion is aroused when there is failure to wean from mechani- cal ventilation despite improvement of the underlying sepsis and critical illness. Critical illness polyneuropathy refers to the most common PNS complication related to critical illness; it is seen in the setting of prolonged criti- cal illness, sepsis, and multisystem organ failure. Neuro- logic findings include diffuse weakness, decreased reflexes, and distal sensory loss. Electrophysiologic studies demon- strate a diffuse, symmetric, distal axonal sensorimotor neuropathy, and pathologic studies have confirmed axonal degeneration. The precise mechanism of critical illness polyneuropathy remains unclear, but circulating factors such as cytokines, which are associated with sepsis and SIRS, are thought to play a role. It has been reported that up to 70% of patients with the sepsis syndrome have some degree of neuropathy, although far fewer have a clinical syndrome profound enough to cause severe respiratory muscle weakness requiring prolonged mechanical ventilation or resulting in failure to wean. Recent studies suggest that aggressive glycemic control

SECTION III Diseases of the Central Nervous System292 with insulin infusions decreases the risk of critical illness muscle biopsy may be normal initially but eventually polyneuropathy. Treatment is supportive, with specific show abnormal spontaneous activity and panfascicular intervention directed at treating the underlying illness. necrosis with an accompanying inflammatory reaction. While spontaneous recovery is usually seen, the time Both of these myopathic syndromes may be considered course may extend over weeks to months and necessi- under the broader heading of critical illness myopathy. tate long-term ventilatory support and care even after the underlying critical illness has resolved. Acute quadriplegic myopathy describes a clinical syn- drome of severe weakness seen in the setting of glucocor- DISORDERS OF NEUROMUSCULAR ticoid and nd-NMBA use.The most frequent scenario in TRANSMISSION which this is encountered is the asthmatic patient who requires high-dose glucocorticoids and nd-NMBA to A defect in neuromuscular transmission may be a source facilitate mechanical ventilation. This muscle disorder is of weakness in critically ill patients. Myasthenia gravis not due to prolonged action of nd-NMBAs at the neu- may be a consideration; however, persistent weakness romuscular junction but, rather, is an actual myopathy secondary to impaired neuromuscular junction transmis- with muscle damage; it has occasionally been described sion is almost always due to administration of drugs. A with high-dose glucocorticoid use alone. Clinically this number of medications impair neuromuscular transmis- syndrome is most often recognized when a patient fails sion; these include antibiotics, especially aminoglycosides, to wean from mechanical ventilation despite resolution and beta-blocking agents. In the ICU, the nondepolariz- of the primary pulmonary process. Pathologically, there ing neuromuscular blocking agents (nd-NMBAs), also may be vacuolar changes in both type I and type II mus- known as muscle relaxants, are most commonly respon- cle fibers with evidence of regeneration. Acute quadri- sible. Included in this group of drugs are such agents as plegic myopathy has a good prognosis. If patients survive pancuronium, vecuronium, rocuronium, and atracurium. their underlying critical illness, the myopathy invariably They are often used to facilitate mechanical ventilation improves and most patients return to normal. However, or other critical care procedures, but with prolonged use because this syndrome is a result of true muscle damage, persistent neuromuscular blockade may result in weak- not just prolonged blockade at the neuromuscular junc- ness even after discontinuation of these agents hours or tion, this process may take weeks or months, and tra- days earlier. Risk factors for this prolonged action of cheostomy with prolonged ventilatory support may be neuromuscular blocking agents include female sex, meta- necessary. Some patients do have residual long-term bolic acidosis, and renal failure. weakness, with atrophy and fatigue limiting ambulation. At present, it is unclear how to prevent this myopathic Prolonged neuromuscular blockade does not appear complication, except by avoiding use of nd-NMBAs, a to produce permanent damage to the PNS. Once the strategy not always possible. Monitoring with a periph- offending medications are discontinued, full strength is eral nerve stimulator can help to avoid the overuse of restored, although this may take days. In general, the low- these agents. However, this is more likely to prevent the est dose of neuromuscular blocking agent should be used complication of prolonged neuromuscular junction to achieve the desired result, and, when these agents are blockade than it is to prevent this myopathy. used in the ICU, a peripheral nerve stimulator should be used to monitor neuromuscular junction function. SUBARACHNOID HEMORRHAGE MYOPATHY Subarachnoid hemorrhage (SAH) renders the brain crit- ically ill from both primary and secondary brain insults. Critically ill patients, especially those with sepsis, fre- Excluding head trauma, the most common cause of quently develop muscle wasting, often in the face of SAH is rupture of a saccular aneurysm. Other causes seemingly adequate nutritional support. The assumption include bleeding from a vascular malformation (arteri- has been that this represents a catabolic myopathy ovenous malformation or dural arterial-venous fistula) brought about as a result of multiple factors, including and extension into the subarachnoid space from a pri- elevated cortisol and catecholamine release and other cir- mary intracerebral hemorrhage. Some idiopathic SAHs culating factors induced by the SIRS. In this syndrome, are localized to the perimesencephalic cisterns and are known as cachectic myopathy, serum creatine kinase levels benign; they probably have a venous or capillary source, and electromyography (EMG) are normal. Muscle biopsy and angiography is unrevealing. shows type II fiber atrophy. Panfascicular muscle fiber necrosis may also occur in the setting of profound sepsis. Saccular (“Berry”) Aneurysm This so-called septic myopathy is characterized clinically by weakness progressing to a profound level over just a Autopsy and angiography studies have found that about few days. There may be associated elevations in serum 2% of adults harbor intracranial aneurysms, for a prevalence creatine kinase and urine myoglobin. Both EMG and

of 4 million persons in the United States; the aneurysm site of rupture (most often the dome) the wall thins, 293 CHAPTER 22 Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy and Subarachnoid Hemorrhage will rupture, producing SAH, in 25,000–30,000 cases and the tear that allows bleeding is often Յ0.5 mm per year. For patients who arrive alive at hospital, the long. Aneurysm size and site are important in predicting mortality rate over the next month is about 45%. Of risk of rupture. Those >7 mm in diameter and those at those who survive, more than half are left with major the top of the basilar artery and at the origin of the neurologic deficits as a result of the initial hemorrhage, posterior communicating artery are at greater risk of cerebral vasospasm with infarction, or hydrocephalus. If rupture. the patient survives but the aneurysm is not obliterated, the rate of rebleeding is about 20% in the first 2 weeks, Clinical Manifestations 30% in the first month, and about 3% per year afterwards. Most unruptured intracranial aneurysms are completely Given these alarming figures, the major therapeutic asymptomatic. Symptoms are usually due to rupture emphasis is on preventing the predictable early complica- and resultant SAH, although some present with mass tions of the SAH. effect on cranial nerves or brain parenchyma. At the moment of aneurysmal rupture with major SAH, the Unruptured, asymptomatic aneurysms are much less ICP suddenly rises. This may account for the sudden dangerous than a recently ruptured aneurysm. The transient loss of consciousness that occurs in nearly half annual risk of rupture for aneurysms <10 mm in size is of patients. Sudden loss of consciousness may be pre- ~0.1%, and for aneurysms Ն10 mm in size is ~0.5–1%; ceded by a brief moment of excruciating headache, but the surgical morbidity far exceeds these percentages. most patients first complain of headache upon regain- Because of the longer length of exposure to risk of rup- ing consciousness. In 10% of cases, aneurysmal bleeding ture, younger patients with aneurysms >10 mm in size is severe enough to cause loss of consciousness for sev- may benefit from prophylactic treatment. As with the eral days. In ~45% of cases, severe headache associated treatment of asymptomatic carotid stenosis, this risk- with exertion is the presenting complaint. The patient benefit strongly depends on the complication rate of often calls the headache “the worst headache of my treatment. life”; however, the most important characteristic is sud- den onset. Occasionally these ruptures may present as Giant aneurysms, those >2.5 cm in diameter, occur at headache of only moderate intensity or as a change in the same sites (see later) as small aneurysms and account the patient’s usual headache pattern. The headache is for 5% of cases. The three most common locations are usually generalized, often with neck stiffness, and vom- the terminal internal carotid artery, middle cerebral iting is common. artery (MCA) bifurcation, and top of the basilar artery. Their risk of rupture is ~6% in the first year after identi- Although sudden headache in the absence of focal fication and may remain high indefinitely. They often neurologic symptoms is the hallmark of aneurysmal cause symptoms by compressing the adjacent brain or rupture, focal neurologic deficits may occur. Anterior cranial nerves. communicating artery or MCA bifurcation aneurysms may rupture into the adjacent brain or subdural space Mycotic aneurysms are usually located distal to the and form a hematoma large enough to produce mass first bifurcation of major arteries of the circle of Willis. effect. The common deficits that result include hemi- Most result from infected emboli due to bacterial endo- paresis, aphasia, and abulia. carditis causing septic degeneration of arteries and sub- sequent dilatation and rupture. Whether these lesions Occasionally, prodromal symptoms suggest the loca- should be sought and repaired prior to rupture or left to tion of a progressively enlarging unruptured aneurysm. heal spontaneously is controversial. A third cranial nerve palsy, particularly when associated with pupillary dilatation, loss of ipsilateral (but retained Pathophysiology contralateral) light reflex, and focal pain above or behind Saccular aneurysms occur at the bifurcations of the the eye, may occur with an expanding aneurysm at the large to medium-sized intracranial arteries; rupture is junction of the posterior communicating artery and the into the subarachnoid space in the basal cisterns and internal carotid artery. A sixth nerve palsy may indicate often into the parenchyma of the adjacent brain. an aneurysm in the cavernous sinus, and visual field Approximately 85% of aneurysms occur in the anterior defects can occur with an expanding supraclinoid circulation, mostly on the circle of Willis. About 20% of carotid or anterior cerebral artery aneurysm. Occipital patients have multiple aneurysms, many at mirror sites and posterior cervical pain may signal a posterior infe- bilaterally. As an aneurysm develops, it typically forms a rior cerebellar artery or anterior inferior cerebellar neck with a dome. The length of the neck and the size artery aneurysm. Pain in or behind the eye and in the of the dome vary greatly and are factors that are impor- low temple can occur with an expanding MCA tant in planning neurosurgical obliteration or endovas- aneurysm.Thunderclap headache is a variant of migraine cular embolization. The arterial internal elastic lamina that simulates a SAH. Before concluding that a patient disappears at the base of the neck.The media thins, and with sudden, severe headache has thunderclap migraine, connective tissue replaces smooth-muscle cells. At the

294 TABLE 22-3 GRADING SCALES FOR SUBARACHNOID HEMORRHAGE GRADE HUNT-HESS SCALE WORLD FEDERATION OF NEUROSURGICAL 1 SOCIETIES (WFNS) SCALE Mild headache, normal mental Glasgow Coma Scalea (GCS) score 15, no 2 status, no cranial nerve or motor findings motor deficits 3 Severe headache, normal mental GCS 13–14, no motor deficits 4 status, may have cranial nerve deficit GCS 13–14, with motor deficits 5 Somnolent, confused, may have GCS 7–12, with or without motor deficits cranial nerve or mild motor deficit Stupor, moderate to severe motor GCS 3–6, with or without motor deficits deficit, may have intermittent reflex posturing Coma, reflex posturing or flaccid SECTION III Diseases of the Central Nervous System aGlasgow Coma Scale: See Table 31-2. a definitive workup for aneurysm or other intracranial hydrocephalus may develop weeks to months after pathology is required. SAH and manifest as gait difficulty, incontinence, or impaired mentation. Subtle signs may be a lack of Aneurysms can undergo small ruptures and leaks of initiative in conversation or a failure to recover blood into the subarachnoid space, so-called sentinel independence. bleeds. Sudden unexplained headache at any location 3. Vasospasm. Narrowing of the arteries at the base of should raise suspicion of SAH and be investigated, the brain following SAH causes symptomatic because a major hemorrhage may be imminent. ischemia and infarction in ~30% of patients and is the major cause of delayed morbidity and death. Signs of The initial clinical manifestations of SAH can be graded ischemia appear 4–14 days after the hemorrhage, using the Hunt-Hess or World Federation of Neurosurgi- most often at 7 days.The severity and distribution of cal Societies classification schemes (Table 22-3). For rup- vasospasm determine whether infarction will occur. tured aneurysms, prognosis for good outcomes falls as the grade increases. For example it is unusual for a Delayed vasospasm is believed to result from Hunt-Hess grade 1 patient to die if the aneurysm is direct effects of clotted blood and its breakdown treated, but the mortality for grade 4 and 5 patients may products on the arteries within the subarachnoid be as high as 80%. space. In general, the more blood that surrounds the arteries, the greater the chance of symptomatic Delayed Neurologic Deficits vasospasm. Spasm of major arteries produces symp- There are four major causes of delayed neurologic deficits: toms referable to the appropriate vascular territory rerupture, hydrocephalus, vasospasm, and hyponatremia. (Chap. 21). All of these focal symptoms may present abruptly, fluctuate, or develop over a few days. In 1. Rerupture. The incidence of rerupture of an most cases, focal spasm is preceded by a decline in untreated aneurysm in the first month following mental status. SAH is ~30%, with the peak in the first 7 days. Rerupture is associated with a 60% mortality and Vasospasm can be detected reliably with conven- poor outcome. Early treatment eliminates this risk. tional x-ray angiography, but this invasive procedure is expensive and carries the risk of stroke and other 2. Hydrocephalus. Acute hydrocephalus can cause stupor complications. TCD ultrasound is based on the and coma and can be mitigated by placement of an principle that the velocity of blood flow within an external ventricular drain. More often, subacute artery will rise as the lumen diameter is narrowed. hydrocephalus may develop over a few days or By directing the probe along the MCA and proxi- weeks and causes progressive drowsiness or slowed mal anterior cerebral artery (ACA), carotid termi- mentation (abulia) with incontinence. Hydro- nus, and vertebral and basilar arteries on a daily or cephalus is differentiated from cerebral vasospasm every-other-day basis, vasospasm can be reliably with a CT scan, CT angiogram, transcranial Doppler detected and treatments initiated to prevent cerebral (TCD) ultrasound, or conventional x-ray angiogra- ischemia (see later). CT angiography is another phy. Hydrocephalus may clear spontaneously or method that can detect vasospasm. require temporary ventricular drainage. Chronic

Severe cerebral edema in patients with infarction blood to be visualized on a high-quality noncontrast 295 CHAPTER 22 Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy and Subarachnoid Hemorrhage from vasospasm may increase the ICP enough to reduce CT scan obtained within 72 h. If the scan fails to estab- cerebral perfusion pressure. Treatment may include lish the diagnosis of SAH and no mass lesion or mannitol, hyperventilation, and hemicraniectomy; obstructive hydrocephalus is found, a lumbar puncture moderate hypothermia may have a role as well. should be performed to establish the presence of sub- 4. Hyponatremia. Hyponatremia may be profound and arachnoid blood. Lysis of the red blood cells and subse- can develop quickly in the first 2 weeks following quent conversion of hemoglobin to bilirubin stains the SAH. There is both natriuresis and volume deple- spinal fluid yellow within 6–12 h. This xanthochromic tion with SAH, so that patients become both spinal fluid peaks in intensity at 48 h and lasts for 1–4 hyponatremic and hypovolemic. Both atrial natri- weeks, depending on the amount of subarachnoid uretic peptide and brain natriuretic peptide have a blood. role in producing this “cerebral salt-wasting syn- drome.” Typically it clears over the course of 1–2 The extent and location of subarachnoid blood on weeks and, in the setting of SAH, should not be noncontrast CT scan help locate the underlying treated with free-water restriction as this may aneurysm, identify the cause of any neurologic deficit, increase the risk of stroke (see later). and predict delayed vasospasm.A high incidence of symp- tomatic vasospasm in the MCA and ACA has been found Laboratory Evaluation and Imaging when early CT scans show subarachnoid clots >5 × 3 (Fig. 22-8) The hallmark of aneurysmal rupture is mm in the basal cisterns or layers of blood >1 mm thick blood in the CSF. More than 95% of cases have enough in the cerebral fissures. CT scans less reliably predict vasospasm in the vertebral, basilar, or posterior cerebral AB arteries. CD Lumbar puncture prior to an imaging procedure is FIGURE 22-8 indicated only if a CT scan is not available at the time of Subarachnoid hemorrhage. A. CT angiography revealing an the suspected SAH. Once the diagnosis of hemorrhage aneurysm of the left superior cerebellar artery. B. Noncontrast from a ruptured saccular aneurysm is suspected, four-vessel CT scan at the level of the third ventricle revealing subarach- conventional x-ray angiography (both carotids and both noid blood (bright) in the left sylvian fissure and within the left vertebrals) is generally performed to localize and define lateral ventricle. C. Conventional anteroposterior x-ray the anatomic details of the aneurysm and to determine if angiogram of the right vertebral and basilar artery showing other unruptured aneurysms exist (Fig. 22-8C). At some the large aneurysm. D. Conventional angiogram following coil centers, the ruptured aneurysm can be treated using embolization of the aneurysm, whereby the aneurysm body is endovascular techniques at the time of the initial angiogram filled with platinum coils delivered through a microcatheter as a way to expedite treatment and minimize the number navigated from the femoral artery into the aneurysm neck. of invasive procedures. CT angiography is an alternative method for locating the aneurysm and may be sufficient to plan definitive therapy. Close monitoring (daily or twice daily) of electrolytes is important because hyponatremia can occur precipitously during the first 2 weeks following SAH (see above). The electrocardiogram (ECG) frequently shows ST- segment and T-wave changes similar to those associated with cardiac ischemia. Prolonged QRS complex, increased QT interval, and prominent “peaked” or deeply inverted symmetric T waves are usually secondary to the intracra- nial hemorrhage.There is evidence that structural myocar- dial lesions produced by circulating catecholamines and excessive discharge of sympathetic neurons may occur after SAH, causing these ECG changes and a reversible cardiomyopathy sufficient to cause shock or congestive heart failure. Echocardiography reveals a pattern of regional wall motion abnormalities that follow the distrib- ution of sympathetic nerves rather than the major coro- nary arteries, with relative sparing of the ventricular wall apex. The sympathetic nerves themselves appear to be injured by direct toxicity from the excessive catecholamine release. An asymptomatic troponin elevation is common. Serious ventricular dysrhythmias are unusual.

SECTION III Diseases of the Central Nervous System296 depressed level of consciousness, ICP should be mea- sured and the cerebral perfusion pressure targeted to Treatment: 60–70 mm Hg. SUBARACHNOID HEMORRHAGE Because rebleeding is common, all patients who are Early aneurysm repair prevents rerupture and allows the not candidates for early aneurysm repair are put on bed safe application of techniques to improve blood flow rest in a quiet room and are given stool softeners to (e.g., induced hypertension and hypervolemia) should prevent straining. If headache or neck pain is severe, symptomatic vasospasm develop. An aneurysm can be mild sedation and analgesia are prescribed. Extreme “clipped” by a neurosurgeon or “coiled” by an endovas- sedation is avoided because it can obscure changes in cular surgeon. Surgical repair involves placing a metal neurologic status. Adequate hydration is necessary to clip across the aneurysm neck, thereby immediately avoid a decrease in blood volume predisposing to brain eliminating the risk of rebleeding. This approach ischemia. requires craniotomy and brain retraction, which is asso- ciated with neurologic morbidity. Endovascular tech- Seizures are uncommon at the onset of aneurysmal niques involve placing platinum coils, or other embolic rupture. The quivering, jerking, and extensor posturing material, within the aneurysm via a catheter that is that often accompany loss of consciousness with SAH passed from the femoral artery. The aneurysm is packed are probably related to the sharp rise in ICP or, perhaps, tightly to enhance thrombosis and over time is walled- acute generalized vasospasm rather than seizure. How- off from the circulation (Fig. 22-8D).The only prospective ever, phenytoin is often given as prophylactic therapy randomized trial of surgery versus endovascular treat- since a seizure may promote rebleeding. ment for ruptured aneurysm, the International Sub- arachnoid Aneurysm Trial (ISAT), was terminated early Glucocorticoids may help reduce the head and neck when 24% of patients treated with endovascular ther- ache caused by the irritative effect of the subarachnoid apy were dead or dependent at 1 year compared to 31% blood. There is no good evidence that they reduce cere- treated with surgery, a significant 23% relative reduc- bral edema, are neuroprotective, or reduce vascular tion. Follow-up for these patients, now complete, reveals injury, and their routine use therefore is not recom- that the benefit of endovascular therapy is durable. mended. However, some aneurysms have a morphology that is not amenable to endovascular treatment. Thus, surgery Antifibrinolytic agents are not routinely prescribed remains an important treatment option. Centers that but may be considered in patients in whom aneurysm combine both endovascular and neurosurgical exper- treatment cannot proceed immediately. They are associ- tise likely offer the best outcomes for patients, and there ated with a reduced incidence of aneurysmal rerupture are good data showing that centers that specialize in but may also increase the risk of delayed cerebral infarc- aneurysm treatment have improved mortality rates. tion and deep vein thrombosis (DVT). The medical management of SAH focuses on protect- Vasospasm remains the leading cause of morbidity ing the airway, managing blood pressure before and and mortality following aneurysmal SAH. Treatment after aneurysm treatment, preventing rebleeding prior with the calcium channel antagonist nimodipine (60 mg to treatment, managing vasospasm, treating hydro- PO every 4 h) improves outcome, perhaps by preventing cephalus, treating hyponatremia, and preventing pul- ischemic injury rather than reducing the risk of monary embolus. vasospasm. Nimodipine can cause significant hypoten- sion in some patients, which may worsen cerebral Intracranial hypertension following aneurysmal rup- ischemia in patients with vasospasm. Symptomatic cere- ture occurs secondary to subarachnoid blood, parenchy- bral vasospasm can also be treated by increasing the mal hematoma, acute hydrocephalus, or loss of vascular cerebral perfusion pressure by raising mean arterial autoregulation. Patients who are stuporous should pressure through plasma volume expansion and the undergo emergent ventriculostomy to measure ICP and judicious use of IV vasopressor agents, usually phenyle- to treat high ICP in order to prevent cerebral ischemia. phrine or norepinephrine. Raised perfusion pressure has Medical therapies designed to combat raised ICP (e.g., been associated with clinical improvement in many mild hyperventilation, mannitol, and sedation) can also patients, but high arterial pressure may promote be used as needed. High ICP refractory to treatment is a rebleeding in unprotected aneurysms. Treatment with poor prognostic sign. induced hypertension and hypervolemia generally requires monitoring of arterial and central venous pres- Prior to definitive treatment of the ruptured sures; it is best to infuse pressors through a central aneurysm, care is required to maintain adequate cere- venous line as well. Volume expansion helps prevent bral perfusion pressure while avoiding excessive eleva- hypotension, augments cardiac output, and reduces tion of arterial pressure. If the patient is alert, it is reason- blood viscosity by reducing the hematocrit. This method able to lower the blood pressure to normal using is called “triple-H” (hypertension, hemodilution, and nicardipine, labetolol, or esmolol. If the patient has a hypervolemic) therapy.

If symptomatic vasospasm persists despite optimal has been treated and whether or not the patient has 297 medical therapy, intraarterial vasodilators and percuta- had a craniotomy. Systemic anticoagulation with heparin neous transluminal angioplasty are considered. Vasodi- is contraindicated in patients with ruptured and latation by direct angioplasty appears to be permanent, untreated aneurysms. It is a relative contraindication fol- allowing triple-H therapy to be tapered sooner. The lowing craniotomy for several days or perhaps weeks, pharmacologic vasodilators (verapamil and nicardipine) and it may delay thrombosis of a coiled aneurysm. Fol- do not last more than 8–24 h, and therefore multiple lowing craniotomy, use of inferior vena cava filters is treatments may be required until the subarachnoid preferred to prevent further pulmonary emboli, while blood is reabsorbed. Although intraarterial papaverine is systemic anticoagulation with heparin is preferred fol- an effective vasodilator, there is evidence that papaver- lowing successful endovascular treatment. ine may be neurotoxic so its use should be reserved for refractory cases. FURTHER READINGS CHAPTER 22 Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy and Subarachnoid Hemorrhage Acute hydrocephalus can cause stupor or coma. It HERMANS G et al: Clinical review. Critical illness polyneuropathy may clear spontaneously or require temporary ventricu- and myopathy. Crit Care 12:238, 2008 lar drainage. When chronic hydrocephalus develops, ventricular shunting is the treatment of choice. LIOU AK et al:To die or not to die for neurons in ischemia, traumatic brain injury and epilepsy: A review on the stress-activated signal- Free-water restriction is contraindicated in patients ing pathways and apoptotic pathways. Prog Neurobiol 69:103, with SAH at risk for vasospasm because hypovolemia 2003 and hypotension may occur and precipitate cerebral ischemia. Many patients continue to experience a MOLYNEUX A et al: International Subarachnoid Aneurysm Trial decline in serum sodium despite receiving parenteral (ISAT) of neurosurgical clipping versus endovascular coiling in fluids containing normal saline. Frequently, supplemen- 2143 patients with ruptured intracranial aneurysms: A random- tal oral salt coupled with normal saline will mitigate ized trial. Lancet 360:1267, 2002 hyponatremia, but often patients also require hyper- tonic saline. Care must be taken not to correct serum PANDHARIPANDE PP et al: Effect of sedation with dexmedetomidine sodium too quickly in patients with marked hypona- versus lorazepam on acute brain dysfunction in mechanically tremia of several days’ duration, as central pontine ventilated patients: The MENDS randomized controlled trial. myelinolysis may occur. JAMA 298:2654, 2007 All patients should have pneumatic compression PUTTGEN HA et al: Management of cardiac arrest patients to maxi- stockings applied to prevent pulmonary embolism. mize neurologic outcome. Curr Opin Crit Care 15:118, 2009 Unfractionated heparin administered subcutaneously for DVT prophylaxis can be initiated immediately follow- POSNER JB et al: Plum and Posner’s Diagnosis of Stupor and Coma, ing endovascular treatment and within days following 4th ed. New York, Oxford University Press, 2007 craniotomy and surgical clipping and is a useful adjunct to pneumatic compression stockings. Treatment of SAFE STUDY INVESTIGATORS et al: Saline or albumin for fluid resusci- pulmonary embolus depends on whether the aneurysm tation in patients with traumatic brain injury. N Engl J Med 357:874, 2007 WOLF SJ et al: Blast injuries. Lancet 374:405, 2009 WIJDICKS EFM et al: Practice parameter: Prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review). Neurology 67:203, 2006

CHAPTER 23 AL ZHEIMER’S DISEASE AND OTHER DEMENTIAS Thomas D. Bird I Bruce L. Miller I Functional Anatomy of the Dementias . . . . . . . . . . . . . . . . . . 298 The Causes of Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 I Specific Dementias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 Genetic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 Vascular Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310 Frontotemporal Dementia, Progressive Supranuclear Palsy, and Corticobasal Degeneration . . . . . . . . . . . . . . . . . 311 Dementia with Lewy Bodies . . . . . . . . . . . . . . . . . . . . . . . . . 313 I Other Causes of Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . 314 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319 Dementia, a syndrome with many causes, affects >4 mil- affected regions are factors that combine to cause the spe- lion Americans and results in a total health care cost of cific disorder (Chap. 15). Behavior and mood are modu- >$100 billion annually. It is defined as an acquired deteri- lated by noradrenergic, serotonergic, and dopaminergic oration in cognitive abilities that impairs the successful pathways, while acetylcholine seems to be particularly performance of activities of daily living. Memory is the important for memory. Therefore, the loss of cholinergic most common cognitive ability lost with dementia; 10% neurons in Alzheimer’s disease (AD) may underlie the of persons >70 years and 20–40% of individuals >85 memory impairment, while in patients with non-AD years have clinically identifiable memory loss. In addition dementias, the loss of serotonergic and glutaminergic to memory, other mental faculties are also affected in neurons causes primarily behavioral symptoms, leaving dementia; these include language, visuospatial ability, cal- memory relatively spared. Neurotrophins (Chap. 19) are culation, judgment, and problem solving. Neuropsychi- also postulated to play a role in memory function, in part atric and social deficits also develop in many dementia by preserving cholinergic neurons, and therefore represent syndromes, resulting in depression, withdrawal, hallucina- a pharmacologic pathway toward slowing or reversing the tions, delusions, agitation, insomnia, and disinhibition.The effects of AD. most common forms of dementia are progressive, but some dementing illnesses are static and unchanging or Dementias have anatomically specific patterns of neu- fluctuate dramatically from day to day. Most diagnoses of ronal degeneration that dictate the clinical symptoma- dementia require some sort of memory deficit, although tology. AD begins in the entorhinal cortex, spreads to there are many dementias, such as frontotemporal demen- the hippocampus, and then moves to posterior temporal tia, where memory loss is not a presenting feature. and parietal neocortex, eventually causing a relatively diffuse degeneration throughout the cerebral cortex. Multi-infarct dementia is associated with focal damage in a random patchwork of cortical regions. Diffuse white FUNCTIONAL ANATOMY OF THE matter damage may disrupt intracerebral connections DEMENTIAS and cause dementia syndromes similar to those associ- ated with leukodystrophies, multiple sclerosis, and Bin- Dementia results from the disruption of cerebral neuronal swanger’s disease (see later). Subcortical structures, circuits; the quantity of neuronal loss and the location of including the caudate, putamen, thalamus, and substantia 298

nigra, also modulate cognition and behavior in ways that dementia. Other disorders listed in the table are uncom- 299 CHAPTER 23 Alzheimer’s Disease and Other Dementias are not yet well understood. The effect that these pat- mon but important because many are reversible.The clas- terns of cortical degeneration have on disease sympto- sification of dementing illnesses into two broad groups of matology is clear: AD primarily presents as memory loss reversible and irreversible disorders is a useful approach to and is often associated with aphasia or other distur- the differential diagnosis of dementia. bances of language. In contrast, patients with frontal lobe or subcortical dementias such as frontotemporal dementia In a study of 1000 persons attending a memory disor- (FTD) or Huntington’s disease (HD) are less likely to ders clinic, 19% had a potentially reversible cause of the begin with memory problems and more likely to have cognitive impairment and 23% had a potentially reversible difficulties with attention, judgment, awareness, and concomitant condition.The three most common poten- behavior. tially reversible diagnoses were depression, hydrocephalus, and alcohol dependence (Table 23-1). Lesions of specific cortical-subcortical pathways have equally specific effects on behavior.The dorsolateral pre- Subtle cumulative decline in episodic memory is a frontal cortex has connections with dorsolateral caudate, natural part of aging. This frustrating experience, often globus pallidus, and thalamus. Lesions of these pathways the source of jokes and humor, is referred to as benign result in poor organization and planning, decreased cog- forgetfulness of the elderly. Benign means that it is not so nitive flexibility, and impaired judgment. The lateral progressive or serious that it impairs reasonably success- orbital frontal cortex connects with the ventromedial ful and productive daily functioning, although the dis- caudate, globus pallidus, and thalamus. Lesions of these tinction between benign and more significant memory connections cause irritability, impulsiveness, and dis- loss can be difficult to make. At 85 years, the average tractibility. The anterior cingulate cortex connects with person is able to learn and recall approximately one-half the nucleus accumbens, globus pallidus, and thalamus. the number of items (e.g., words on a list) that he or she Interruption of these connections produces apathy and could at 18 years. A cognitive problem that has begun to poverty of speech or even akinetic mutism. subtly interfere with daily activities is referred to as mild cognitive impairment (MCI). A sizeable proportion of per- The single strongest risk factor for dementia is sons with MCI will progress to frank dementia, usually increasing age. The prevalence of disabling memory loss caused by AD. The conversion rate from MCI to AD is increases with each decade after 50 years of age and is ~12% per year. It remains unclear why some individuals associated most often with the microscopic changes of show progression and others do not. Factors that predict AD at autopsy. Slow accumulation of mutations in neu- progression from MCI to AD include a memory deficit ronal mitochondria is also hypothesized to contribute to >1.5 standard deviations from the norm, family history the increasing prevalence of dementia with age.Yet some of dementia, the presence of an apolipoprotein ε4 (Apo centenarians have intact memory function and no evi- ε4), and small hippocampal volumes. There is optimism dence of clinically significant dementia.Whether demen- that new positron emission tomography (PET) imaging tia is an inevitable consequence of normal human aging techniques that label amyloid or tau in vivo might aid in remains controversial. early diagnosis of AD in the future. THE CAUSES OF DEMENTIA The major degenerative dementias include AD, FTD and related disorders, DLB, HD, and prion disorders The many causes of dementia are listed in Table 23-1. including Creutzfeldt-Jakob disease (CJD). These disor- The frequency of each condition depends on the age ders are all associated with the abnormal aggregation of group under study, the access of the group to medical a specific protein: Aβ42 in AD, tau or TDP-43 in FTD, care, the country of origin, and perhaps racial or ethnic α-synuclein in DLB, polyglutamine repeats in HD, and background. AD is the most common cause of dementia prions in CJD (Table 23-2). in Western countries, representing more than half of demented patients. Vascular disease is the second most Approach to the Patient: common cause of dementia in the United States, repre- DEMENTIA senting 10–20%. In populations with limited access to medical care, where vascular risk factors are undertreated, Three major issues should be kept in the forefront: the prevalence of vascular dementia can be much higher. (1) What is the most accurate diagnosis? (2) Is there a Dementia associated with Parkinson’s disease (PD) is the treatable or reversible component to the dementia? next most common category, and in many instances these (3) Can the physician help to alleviate the burden on patients suffer from dementia with Lewy bodies (DLB). caregivers? A broad overview of the approach to In patients younger than 60 years, FTD rivals AD as the dementia is shown in Table 23-3. The major degen- most common cause of dementia. Chronic intoxications, erative dementias can usually be distinguished by the including those resulting from alcohol and prescription drugs, are an important and often treatable cause of

300 TABLE 23-1 DIFFERENTIAL DIAGNOSIS OF DEMENTIA SECTION III Diseases of the Central Nervous System Most Common Causes of Dementia Alcoholisma Parkinson’s disease Alzheimer’s disease Drug/medication intoxicationa Vascular dementia Toxic disorders Multi-infarct Drug, medication, and narcotic poisoninga Diffuse white matter disease (Binswanger’s) Heavy metal intoxicationa Dialysis dementia (aluminum) Less Common Causes of Dementia Organic toxins Vitamin deficiencies Psychiatric Thiamine (B1): Wernicke’s encephalopathya Depression (pseudodementia)a B12 (pernicious anemia)a Schizophreniaa Nicotinic acid (pellagra)a Conversion reactiona Endocrine and other organ failure Degenerative disorders Hypothyroidisma Huntington’s disease Adrenal insufficiency and Cushing’s syndromea Pick’s disease Hypo- and hyperparathyroidisma Dementia with Lewy bodies Renal failurea Progressive supranuclear palsy (Steel-Richardson syndrome) Liver failurea Multisystem degeneration (Shy-Drager syndrome) Pulmonary failurea Hereditary ataxias (some forms) Motor neuron disease [amyotrophic lateral sclerosis (ALS); Chronic infections some forms] HIV Frontotemporal dementia Neurosyphilisa Cortical basal degeneration Papovavirus (progressive multifocal Multiple sclerosis leukoencephalopathy) Adult Down’s syndrome with Alzheimer’s Prion (Creutzfeldt-Jakob and Gerstmann- ALS–Parkinson’s–Dementia complex of Guam Sträussler-Scheinker diseases) Tuberculosis, fungal, and protozoala Miscellaneous Whipple’s diseasea Sarcoidosisa Vasculitisa Head trauma and diffuse brain damage CADASIL etc Dementia pugilistica Acute intermittent porphyriaa Chronic subdural hematomaa Recurrent nonconvulsive seizuresa Postanoxia Postencephalitis Additional conditions in children or adolescents Normal-pressure hydrocephalusa Hallervorden-Spatz disease Subacute sclerosing panencephalitis Neoplastic Metabolic disorders (e.g., Wilson’s and Leigh’s diseases, Primary brain tumora leukodystrophies, lipid storage diseases, mitochondrial Metastatic brain tumora mutations) Paraneoplastic limbic encephalitis aPotentially reversible dementia. initial symptoms; neuropsychological, neuropsychi- loss over several years is likely to suffer from AD. atric, and neurologic findings; and neuroimaging Nearly 75% of AD patients begin with memory features (Table 23-4). symptoms, but other early symptoms include difficulty with managing money, driving, shopping, following HISTORY The history should concentrate on the instructions, finding words, or navigating. A change in onset, duration, and tempo of progression of the personality, disinhibition, and gain of weight or food dementia. An acute or subacute onset of confusion obsession suggests FTD, not AD. FTD is also suggested may represent delirium and should trigger the search by the finding of apathy, loss of executive function, or for intoxication, infection, or metabolic derangement. progressive abnormalities in speech, or by a relative An elderly person with slowly progressive memory sparing of memory or spatial abilities. The diagnosis

TABLE 23-2 301 THE MOLECULAR BASIS FOR DEGENERATIVE DEMENTIA PATHOLOGY DEMENTIA MOLECULAR CAUSAL GENES AND SUSCEPTIBILITY Amyloid plaques, neurofibrillary tangles AD BASIS (CHROMOSOME) GENES Apo ε4 (19) Tau inclusions, Pick bodies, Aβ <2% carry these mutations. neurofibrillary tangles APP (21), PS-1 (14), PS-2 (1) H1 tau FTD Tau (most mutations are in PS-1) haplotypes α-synuclein inclusions Tau exon and intron mutations (Lewy bodies) DLB α-synuclein (17) (about 10% of Unknown CJD familial cases) Tau inclusions, spongiform changes, PrPSC Progranulin (17) (10% of Codon 129 gliosis proteins familial cases) homozygosity Very rare α-synuclein (4) for methionine (dominant) or valine Prion (20) (up to 15% of cases carry these dominant mutations) Note: AD, Alzheimer’s disease; FTD, frontotemporal dementia; DLB, dementia with Lewy bodies; CJD, Creutzfeldt-Jakob disease. CHAPTER 23 Alzheimer’s Disease and Other Dementias TABLE 23-3 EVALUATION OF THE PATIENT WITH DEMENTIA ROUTINE EVALUATION OPTIONAL OCCASIONALLY FOCUSED TESTS HELPFUL TESTS History Physical examination Psychometric testing EEG Laboratory tests Chest x-ray Parathyroid function Lumbar puncture Adrenal function Thyroid function (TSH) Liver function Urine heavy metals Vitamin B12 Renal function RBC sedimentation rate Complete blood count Urine toxin screen Angiogram Electrolytes HIV Brain biopsy CT/MRI Apolipoprotein E SPECT RPR or VDRL PET Diagnostic Categories PSYCHIATRIC REVERSIBLE CAUSES IRREVERSIBLE/ DISORDERS DEGENERATIVE Examples DEMENTIAS Depression Hypothyroidism Schizophrenia Thiamine deficiency Examples Conversion reaction Vitamin B12 deficiency Alzheimer’s Normal-pressure hydrocephalus Frontotemporal dementia Subdural hematoma Huntington’s Chronic infection Dementia with Lewy bodies Brain tumor Vascular Drug intoxication Leukoencephalopathies Parkinson’s Associated Treatable Conditions Agitation Depression Caregiver “burnout” Seizures Drug side effects Insomnia Note: PET, positron emission tomography; RPR, rapid plasma reagin (test); SPECT, single photon emission CT; VDRL, Venereal Disease Research Laboratory (test for syphilis).

302 TABLE 23-4 CLINICAL DIFFERENTIATION OF THE MAJOR DEMENTIAS DISEASE FIRST SYMPTOM MENTAL STATUS NEUROPSYCHIATRY NEUROLOGY IMAGING AD Initially normal FTD Memory loss Episodic Initially normal Entorhinal cortex and memory loss Due to PSP/CBD hippocampal atrophy DLB Apathy; poor Frontal/executive, Apathy, disinhibition, overlap; vertical Frontal and/or temporal judgment/insight, language; hyperorality, gaze palsy, axial atrophy; spares CJD speech/language; spares drawing euphoria, depression rigidity, dystonia, posterior parietal lobe hyperorality alien hand Vascular Parkinsonism Posterior parietal Visual hallucina- Drawing and Visual hallucinations, atrophy; hippocampi tions, REM sleep frontal/executive; depression, sleep Myoclonus, rigidity, larger than in AD disorder, delirium, spares memory; disorder, delusions parkinsonism Capgras’ delirium prone Cortical ribboning and syndrome, Depression, anxiety Usually motor basal ganglia or parkinsonism Variable, frontal/ slowing, thalamus SECTION III Diseases of the Central Nervous System executive, focal spasticity; hyperintensity on Dementia, mood, cortical, memory can be normal diffusion/flare MRI anxiety, Cortical and/or movement subcortical disorders infarctions, confluent white Often but not Frontal/executive, Apathy, delusions, matter disease always sudden; cognitive slowing; anxiety variable; apathy, can spare falls, focal memory weakness Note: AD, Alzheimer’s disease; FTD, frontotemporal dementia; PSP, progressive supranuclear palsy; CBD, cortical basal degeneration; DLB, dementia with Lewy bodies; CJD, Creutzfeldt-Jakob disease. of DLB is suggested by the early presence of visual HIV. A history of recurrent head trauma could indi- hallucinations; parkinsonism; delirium; REM sleep cate chronic subdural hematoma, dementia pugilis- disorder (the merging of dream-states into wakeful- tica, or NPH. Alcoholism may suggest malnutrition ness); or Capgras’ syndrome, the delusion that a famil- and thiamine deficiency. A remote history of gastric iar person has been replaced by an impostor. surgery resulting in loss of intrinsic factor can bring about vitamin B12 deficiency. Certain occupations A history of sudden stroke with irregular stepwise such as working in a battery or chemical factory progression suggests multi-infarct dementia. Multi- might indicate heavy metal intoxication. Careful infarct dementia is also commonly seen in the setting review of medication intake, especially of sedatives of hypertension, atrial fibrillation, peripheral vascular and tranquilizers, may raise the issue of chronic drug disease, and diabetes. In patients suffering from cere- intoxication. A positive family of dementia is found in brovascular disease, it can be difficult to determine HD and in forms of familial Alzheimer’s disease whether the dementia is due to AD, multi-infarct (FAD), FTD, or prion disorders.The recent death of a dementia, or a mixture of the two as many of the risk loved one, or depressive signs such as insomnia or factors for vascular dementia, including diabetes, high weight loss, raises the possibility of pseudodementia cholesterol, elevated homocysteine and low exercise, due to depression. are also risk factors for AD. Rapid progression of the dementia in association with motor rigidity and PHYSICAL AND NEUROLOGIC EXAMINATION myoclonus suggests CJD. Seizures may indicate strokes or neoplasm. Gait disturbance is commonly A thorough general and neurologic examination is seen with multi-infarct dementia, PD, or normal- essential to document dementia, look for other signs pressure hydrocephalus (NPH). Multiple sex partners of nervous system involvement, and search for clues or intravenous drug use should trigger a search for suggesting a systemic disease that might be responsi- central nervous system (CNS) infection, especially for ble for the cognitive disorder. AD does not affect

motor systems until later in the course. In contrast, COGNITIVE AND NEUROPSYCHIATRIC 303 FTD patients often develop axial rigidity, supranu- clear gaze palsy, or features of amyotrophic lateral EXAMINATION Brief screening tools such as the CHAPTER 23 Alzheimer’s Disease and Other Dementias sclerosis (ALS). In DLB, initial symptoms may be the mini-mental state examination (MMSE) help to con- new onset of a parkinsonian syndrome (resting firm the presence of cognitive impairment and to fol- tremor, cogwheel rigidity, bradykinesia, festinating low the progression of dementia (Table 23-5). The gait) with the dementia following later, or vice versa. MMSE, an easily administered 30-point test of cogni- Corticobasal degeneration (CBD) is associated with tive function, contains tests of orientation, working dystonia, alien hand, and asymmetric extrapyramidal, memory (e.g., spell world backwards), episodic mem- pyramidal, or sensory deficits or myoclonus. Progres- ory (orientation and recall), language comprehension, sive supranuclear palsy (PSP) is associated with unex- naming, and copying. In most patients with MCI and plained falls, axial rigidity, dysphagia, and vertical gaze some with clinically apparent AD, the MMSE may be deficits. CJD is suggested by the presence of diffuse normal and a more rigorous set of neuropsychologi- rigidity, an akinetic state, and myoclonus. cal tests will be required. Additionally, when the etiol- ogy for the dementia syndrome remains in doubt, a Hemiparesis or other focal neurologic deficits may specially tailored evaluation should be performed that occur in multi-infarct dementia or brain tumor. includes tasks of working and episodic memory, Dementia with a myelopathy and peripheral neuropa- frontal executive function, language, and visuospatial thy suggests vitamin B12 deficiency. A peripheral neu- and perceptual abilities. In AD the deficits involve ropathy could also indicate an underlying vitamin episodic memory, category generation (“name as deficiency or heavy metal intoxication. Dry, cool skin, many animals as you can in one minute”), and visuo- hair loss, and bradycardia suggest hypothyroidism. constructive ability. Deficits in verbal or visual Confusion associated with repetitive stereotyped move- episodic memory are often the first neuropsychologi- ments may indicate ongoing seizure activity. Hearing cal abnormalities seen with AD, and tasks that require impairment or visual loss may produce confusion and the patient to recall a long list of words or a series of disorientation misinterpreted as dementia. Such sen- pictures after a predetermined delay will demonstrate sory deficits are common in the elderly but can be a deficits in most AD patients. In FTD, the earliest manifestation of mitochondrial disorders. deficits often involve frontal executive or language TABLE 23-5 THE MINI-MENTAL STATUS EXAMINATION Orientation POINTS Name: season/date/day/month/year Name: hospital/floor/town/state/country 5 (1 for each name) 5 (1 for each name) Registration 3 (1 for each object) Identify three objects by name and ask patient to repeat 5 (1 for each subtraction) Attention and calculation 3 (1 for each object) Serial 7s; subtract from 100 2 (1 for each object) (e.g., 93–86–79–72–65) 1 3 (1 for each command) Recall Recall the three objects presented earlier 1 1 Language 1 Name pencil and watch Repeat “No ifs, ands, or buts” 30 Follow a 3-step command (e.g., “Take this paper, fold it in half, and place it on the table”) Write “close your eyes” and ask patient to obey written command Ask patient to write a sentence Ask patient to copy a design (e.g., intersecting pentagons) Total

SECTION III Diseases of the Central Nervous System304 (speech or naming) function. DLB patients have more discourage multiple tests. Nevertheless, even a test severe deficits in visuospatial function but do better with only a 1–2% positive rate is probably worth on episodic memory tasks than patients with AD. undertaking if the alternative is missing a treatable Patients with vascular dementia often demonstrate a cause of dementia. Table 23-3 lists most screening mixture of frontal executive and visuospatial deficits. tests for dementia. Recently the American Academy In delirium, deficits tend to fall in the area of atten- of Neurology recommended the routine measure- tion, working memory, and frontal function. ment of thyroid function, a vitamin B12 level test, and A functional assessment should also be performed. a neuroimaging study (CT or MRI). The physician should determine the day-to-day impact of the disorder on the patient’s memory, com- Neuroimaging studies will identify primary and munity affairs, hobbies, judgment, dressing, and eat- secondary neoplasms, locate areas of infarction, diag- ing. Knowledge of the patient’s day-to-day function nose subdural hematomas, and suggest NPH or dif- will help the clinician and the family to organize a fuse white matter disease. They also lend support to therapeutic approach. the diagnosis of AD, especially if there is hippocampal Neuropsychiatric assessment is important for diag- atrophy in addition to diffuse cortical atrophy. Focal nosis, prognosis, and treatment. In the early stages of frontal and/or anterior temporal atrophy suggests AD, mild depressive features, social withdrawal, and FTD. There is no specific pattern yet determined for denial of illness are the most prominent psychiatric DLB, although these patients tend to have less hip- changes. However, patients often maintain their social pocampal atrophy than patients with AD. The use of skills into the middle stages of the illness, when delu- diffusion-weighted imaging with MRI will detect sions, agitation, and sleep disturbance become more abnormalities in the cortical ribbon and basal ganglia common. In FTD, dramatic personality change, apa- in the vast majority of patients with CJD. Large thy, overeating, repetitive compulsions, disinhibition, white-matter abnormalities correlate with a vascular euphoria, and loss of empathy are common. DLB etiology for dementia.The role of functional imaging shows visual hallucinations, delusions related to per- in the diagnosis of dementia is still under study. Single sonal identity, and day-to-day fluctuation. Vascular photon emission computed tomography (SPECT) and dementia can present with psychiatric symptoms such PET scanning will show temporal-parietal hypoper- as depression, delusions, disinhibition, or apathy. fusion or hypometabolism in AD and frontotemporal hypoperfusion or hypometabolism in FTD, but most LABORATORY TESTS The choice of laboratory of these changes reflect atrophy. Recently, amyloid tests in the evaluation of dementia is complex. The imaging has shown promise for the diagnosis of AD, physician does not want to miss a reversible or treat- and Pittsburgh Agent B appears to be a reliable agent able cause, yet no single etiology is common; thus, a for detecting brain amyloid due to the accumulation screen must employ multiple tests, each of which has of Aβ42 within plaques (Fig. 23-1). Similarly, MRI a low yield. Cost/benefit ratios are difficult to assess, and perfusion and brain activation studies using functional many laboratory screening algorithms for dementia MRI are under active study as potential early diag- nostic tools. AB C FIGURE 23-1 have control-like levels of amyloid, some have AD-like lev- PET images obtained with the amyloid-imaging agent els of amyloid, and some have intermediate levels. PET, Pittsburgh Compound-B ([11C]PIB) in a normal control (A); positron emission tomography; MCI, mild cognitive impair- three different patients with mild cognitive impairment ment; AD, Alzheimer’s disease. (MCI, B); and a mild AD patient (C). Some MCI patients

Lumbar puncture need not be done routinely in However, ~20% of AD patients present with nonmem- 305 CHAPTER 23 Alzheimer’s Disease and Other Dementias the evaluation of dementia, but it is indicated if CNS ory complaints such as word-finding, organizational, or infection is a serious consideration. Cerebrospinal navigational difficulty. In the early stages of the disease, fluid (CSF) levels of tau protein and Aβ42 amyloid the memory loss may go unrecognized or be ascribed to show differing patterns with the various dementias; benign forgetfulness. Once the memory loss begins to however, the sensitivity and specificity of these mea- affect day-to-day activities or falls below 1.5 standard sures are not sufficiently high to warrant routine deviations from normal on standardized memory tasks, measurement. Formal psychometric testing, though the disease is defined as MCI. Approximately 50% of not necessary in every patient with dementia, helps to MCI individuals will progress to AD within 5 years. document the severity of dementia, suggest psychogenic Slowly the cognitive problems begin to interfere with causes, and provide a semiquantitative method for fol- daily activities, such as keeping track of finances, follow- lowing the disease course. EEG is rarely helpful except ing instructions on the job, driving, shopping, and to suggest CJD (repetitive bursts of diffuse high volt- housekeeping. Some patients are unaware of these diffi- age sharp waves) or an underlying nonconvulsive culties (anosognosia), while others have considerable insight. seizure disorder (epileptiform discharges). Brain biopsy Change of environment may be bewildering, and the (including meninges) is not advised except to diag- patient may become lost on walks or while driving an nose vasculitis, potentially treatable neoplasms, automobile. In the middle stages of AD, the patient is unusual infections, or systemic disorders such as vas- unable to work, is easily lost and confused, and requires culitis or sarcoid, or in young persons where the daily supervision. Social graces, routine behavior, and diagnosis is uncertain. Angiography should be consid- superficial conversation may be surprisingly intact. Lan- ered when cerebral vasculitis is a possible cause of the guage becomes impaired—first naming, then compre- dementia. hension, and finally fluency. In some patients, aphasia is an early and prominent feature.Word finding difficulties SPECIFIC DEMENTIAS and circumlocution may be a problem even when for- mal testing demonstrates intact naming and fluency. ALZHEIMER’S DISEASE Apraxia emerges, and patients have trouble performing sequential motor tasks. Visuospatial deficits begin to Approximately 10% of all persons older than 70 years interfere with dressing, eating, solving simple puzzles, have significant memory loss and in more than one-half and copying geometric figures. Patients may be unable the cause is AD. It is estimated that the annual total cost to do simple calculations or tell time. of caring for a single AD patient in an advanced stage of the disease is >$50,000. The disease also exacts a heavy In the late stages of the disease, some persons remain emotional toll on family members and caregivers. AD ambulatory but wander aimlessly. Loss of judgment, rea- can occur in any decade of adulthood, but it is the most son, and cognitive abilities is inevitable. Delusions are common cause of dementia in the elderly. AD most common and usually simple in quality, such as delusions often presents with subtle onset of memory loss fol- of theft, infidelity, or misidentification. Approximately lowed by a slowly progressive dementia that has a course 10% of AD patients develop Capgras’ syndrome, believing of several years. Pathologically, there is diffuse atrophy of that a caregiver has been replaced by an impostor. In the cerebral cortex with secondary enlargement of the contrast to DLB, where Capgras’ syndrome is an early ventricular system. Microscopically, there are neuritic feature, in AD this syndrome emerges later in the course plaques containing Aβ amyloid, silver-staining neurofib- of the illness. Loss of inhibitions and aggression may rillary tangles (NFTs) in neuronal cytoplasm, and accu- occur and alternate with passivity and withdrawal. mulation of Aβ42 amyloid in arterial walls of cerebral Sleep-wake patterns are prone to disruption, and night- blood vessels (see Pathogenesis, later). The identification time wandering becomes disturbing to the household. of four different susceptibility genes for AD has provided Some patients develop a shuffling gait with generalized a foundation for rapid progress in understanding AD’s muscle rigidity associated with slowness and awkward- biologic basis. ness of movement. Patients often look parkinsonian (Chap. 24) but rarely have a rapid, rhythmic, resting Clinical Manifestations tremor. In end-stage AD, patients become rigid, mute, incontinent, and bedridden. Help may be needed with The cognitive changes with AD tend to follow a charac- the simplest tasks, such as eating, dressing, and toilet teristic pattern, beginning with memory impairment function. They may show hyperactive tendon reflexes. and spreading to language and visuospatial deficits. Myoclonic jerks (sudden brief contractions of various muscles or the whole body) may occur spontaneously or in response to physical or auditory stimulation. Myoclonus raises the possibility of CJD (Chap. 38), but the course of AD is much more prolonged. Generalized

SECTION III Diseases of the Central Nervous System306 seizures may also occur. Often death results from malnu- AB trition, secondary infections, pulmonary emboli, or heart disease.The typical duration of AD is 8–10 years, but the CD course can range from 1 to 25 years. For unknown rea- FIGURE 23-2 sons, some AD patients show a steady downhill decline Alzheimer’s disease. Axial T1weighted MR images through in function, while others have prolonged plateaus with- the midbrain of a normal 86-year-old athlete (A) and a out major deterioration. 77-year-old male (B) with AD. Note that both individuals have prominent sulci and slight dilatation of the lateral ventri- Differential Diagnosis cles. However, there is a reduction in the volume of the hip- pocampus of the patient with AD (arrows) compared with Early in the disease course, other etiologies of dementia that of the normal-for-age hippocampus (A). Fluorodeoxyglu- should be excluded. These include treatable entities such cose PET scans of a normal control (C) and a patient with AD as thyroid disease, vitamin deficiencies, brain tumor, drug (D). Note that the patient with AD has decreased activity in and medication intoxication, chronic infection, and the parietal lobes bilaterally (arrows), a typical finding in this severe depression (pseudodementia). Neuroimaging stud- condition. AD, Alzheimer’s disease; PET, positron emission ies (CT and MRI) do not show a single specific pattern tomography. (Images courtesy of TF Budinger, University of with AD and may be normal early in the course of the California; with permission.) disease. As AD progresses, diffuse cortical atrophy becomes apparent, and MRI scans show atrophy of the depression suggests pseudodementia (see later). A history hippocampus (Fig. 23-2A, B). Imaging helps to exclude of treatment for insomnia, anxiety, psychiatric disturbance, other disorders, such as primary and secondary neo- or epilepsy suggests chronic drug intoxication. Rapid pro- plasms, multiinfarct dementia, diffuse white matter dis- gression over a few weeks or months associated with ease, and NPH; it also helps to distinguish AD from other rigidity and myoclonus suggests CJD (Chap. 38). Promi- degenerative disorders with distinctive imaging patterns nent behavioral changes with intact memory and lobar such as FTD or CJD. Functional imaging studies in AD atrophy on brain imaging are typical of FTD. A positive reveal hypoperfusion or hypometabolism in the posterior family history of dementia suggests either one of the temporal-parietal cortex (Fig. 23-2C, D). The EEG in familial forms of AD or one of the other genetic disorders AD is normal or shows nonspecific slowing. Routine associated with dementia, such as HD (see later), FTD spinal fluid examination is also normal. CSF Aβ amyloid (see later), familial forms of prion diseases, or rare forms levels are reduced, whereas levels of tau protein are of hereditary ataxias (Chap. 26). increased, but the considerable overlap of these levels with those of the normal aged population limits the use- Epidemiology fulness of these measurements in diagnosis. The use of The most important risk factors for AD are old age and blood Apo ε genotyping is discussed under Pathogenesis, a positive family history. The frequency of AD increases later. Slowly progressive decline in memory and orientation, normal results on laboratory tests, and an MRI or CT scan showing only diffuse or posteriorly predominant cortical and hip- pocampal atrophy is highly suggestive of AD. A clinical diag- nosis of AD reached after careful evaluation is confirmed at autopsy about 90% of the time, with misdiagnosed cases usually representing one of the other dementing disorders described later in this chapter, a mixture of AD with vascular pathology, or DLB. Relatively simple clinical clues are useful in the differ- ential diagnosis. Early prominent gait disturbance with only mild memory loss suggests vascular dementia or, rarely, NPH (see later). Resting tremor with stooped posture, bradykinesia, and masked facies suggest PD (Chap. 24).The early appearance of parkinsonian features, visual hallucinations, delusional misidentification, or REM sleep disorders suggest DLB. Chronic alcoholism should prompt the search for vitamin deficiency. Loss of sensi- bility to position and vibration stimuli accompanied by Babinski responses suggests vitamin B12 deficiency (Chap. 30). Early onset of a seizure suggests a metastatic or primary brain neoplasm (Chap. 32). A past history of

with each decade of adult life, reaching 20–40% of the 307CHAPTER 23 Alzheimer’s Disease and Other Dementias population older than 85 years. A positive family history of dementia suggests a genetic cause of AD. Female gen- FIGURE 23-3 der may also be a risk factor independent of the greater Mature neuritic plaque with a dense central amyloid core longevity of women. Some AD patients have a past his- surrounded by dystrophic neurites (thioflavin S stain). (Image tory of head trauma with concussion, but this appears to courtesy of S DeArmond, University of California; with per- be a relatively minor risk factor. AD is more common in mission.) groups with very low educational attainment, but edu- cation influences test-taking ability, and it is clear that phosphorylated tau (τ) protein and appear as paired heli- AD can affect persons of all intellectual levels. One cal filaments by electron microscopy. Tau is a micro- study found that the capacity to express complex writ- tubule associated protein that may function to assemble ten language in early adulthood correlated with a and stabilize the microtubules that convey cell organelles, decreased risk for AD. Numerous environmental factors, glycoproteins, and other important materials throughout including aluminum, mercury, and viruses, have been the neuron. The ability of tau protein to bind to micro- proposed as causes of AD, but none has been demon- tubule segments is determined partly by the number of strated to play a significant role. Similarly, several studies phosphate groups attached to it. Increased phosphoryla- suggest that the use of nonsteroidal anti-inflammatory tion of tau protein disturbs this normal process. Finally, agents is associated with a decreased risk of AD, but this the co-association of AD with DLB and vascular pathol- has not been confirmed in large prospective studies.Vas- ogy is extremely common. cular disease, in particular stroke, seems to lower the threshold for the clinical expression of AD. Also, in many Biochemically, AD is associated with a decrease in the AD patients, amyloid angiopathy can lead to ischemic cerebral cortical levels of several proteins and neuro- infarctions or hemorrhages. Diabetes increases the risk transmitters, especially acetylcholine, its synthetic of AD threefold. Elevated homocysteine and cholesterol enzyme choline acetyltransferase, and nicotinic choliner- levels; hypertension; diminished serum levels of folic gic receptors. Reduction of acetylcholine may be related acid; low dietary intake of fruits, vegetables, and red in part to degeneration of cholinergic neurons in the wine; and low levels of exercise are all being explored as nucleus basalis of Meynert that project to many areas of potential risk factors for AD. cortex. There is also reduction in norepinephrine levels in brainstem nuclei such as the locus coeruleus. Pathology GENETIC CONSIDERATIONS At autopsy, the most severe pathology is usually found in Several genetic factors play important roles in the the hippocampus, temporal cortex, and nucleus basalis of pathogenesis of at least some cases of AD. One is Meynert (lateral septum). The most important micro- the APP gene on chromosome 21. Adults with tri- scopic findings are neuritic “senile” plaques and NFTs. These lesions accumulate in small numbers during nor- somy 21 (Down’s syndrome) consistently develop the mal aging of the brain but occur in excess in AD. There typical neuropathologic hallmarks of AD if they survive is increasing evidence to suggest that soluble amyloid beyond age 40. Many develop a progressive dementia fibrils called oligomers lead to the dysfunction of the cell superimposed on their baseline mental retardation. APP and may be the first biochemical injury in AD. Mis- is a membrane-spanning protein that is subsequently folded Aβ42 molecules may be the most toxic form of processed into smaller units, including Aβ amyloid that is this protein. Accumulation of oligomers eventually leads deposited in neuritic plaques. Aβ peptide results from to formation of neuritic plaques (Fig. 23-3). The neu- cleavage of APP by β and γ secretases (Fig. 23-4). Pre- ritic plaques contain a central core that includes Aβ sumably the extra dose of the APP gene on chromosome amyloid, proteoglycans, Apo ε4, α1 antichymotrypsin, 21 is the initiating cause of AD in adult Down’s syndrome and other proteins. Aβ amyloid is a protein of 39–42 amino acids that is derived proteolytically from a larger transmembrane protein named amyloid precursor protein (APP) when APP is cleaved by β and γ secretases. The normal function of Aβ amyloid is unknown. APP has neurotrophic and neuroprotective activities. The plaque core is surrounded by the debris of degenerating neu- rons, microglia, and macrophages. The accumulation of Aβ amyloid in cerebral arterioles is termed amyloid angiopathy. NFTs are silverstaining, twisted neurofila- ments in neuronal cytoplasm that represent abnormally

308 Step 1: Cleavage by either α- or β-secretase homologous to a cell-trafficking protein, sel 12, found in the nematode Coenorhabditis elegans. Patients with muta- APP β α Cell tions in these genes have elevated plasma levels of Aβ42 membrane amyloid, and PS-1 mutations in cell cultures produce increased Aβ42 amyloid in the media. There is evidence γ that PS-1 is involved in the cleavage of APP at the gamma secretase site and mutations in either gene (PS-1 β-Secretase product α-Secretase product or APP) may disturb this function. Mutations in PS-1 Step 2: Cleavage by γ-secretase have thus far proved to be the most common cause of earlyonset FAD, representing perhaps 40–70% of this rel- Aβ42 Aβ40 P3 atively rare syndrome. Mutations in PS-1 tend to produce Nontoxic Nontoxic AD with an earlier age of onset (mean onset 45 years) Toxic and a shorter, more rapidly progressive course (mean Amyloidogenic duration 6–7 years) than the disease caused by mutations in PS-2 (mean onset 53 years; duration 11 years). Some SECTION III Diseases of the Central Nervous System FIGURE 23-4 carriers of uncommon PS-2 mutations have had onset of dementia after the age of 70. Mutations in the prese- Amyloid precursor protein (APP) is catabolized by α-, β-, nilins are rarely involved in the more common sporadic and γ-secretases. A key initial step is the digestion by either cases of late-onset AD occurring in the general popula- β-secretase (BASE) or α-secretase [ADAM10 or ADAM17 tion. Molecular DNA blood testing for these uncom- (TACE)], producing smaller nontoxic products. Cleavage of mon mutations is now possible on a research basis, and the β-secretase product by γ-secretase (step 2) results in mutation analysis of PS-1 is commercially available. either the toxic Aβ42 or the nontoxic Aβ40 peptide; cleavage Such testing is likely to be positive only in early-onset of the α-secretase product by γ-secretase produces the non- familial cases of AD. Any testing of asymptomatic per- toxic P3 peptide. Excess production of Aβ42 is a key initiator sons at risk must be done in the context of formal, of cellular damage in Alzheimer’s disease. Current AD research thoughtful genetic counseling. is focused on developing therapies designed to reduce accu- A discovery of great importance has implicated the Apo ε gene on chromosome 19 in the pathogenesis of mulation of Aβ42 by antagonizing β- or γ-secretases, promot- late onset familial and sporadic forms of AD. Apo ε is ing α-secretase, or clearing Aβ42 that has already formed by involved in cholesterol transport and has three alleles: 2, use of specific antibodies. 3, and 4.The Apo ε4 allele has a strong association with AD in the general population, including sporadic and and results in an excess of cerebral amyloid. Furthermore, late-onset familial cases. Approximately 24–30% of the a few families with early onset FAD have been discovered nondemented white population has at least one ε4 allele to have point mutations in the APP gene. Although very (12–15% allele frequency), and about 2% are ε4/4 rare, these families were the first examples of a single- homozygotes. Approximately 40–65% of AD patients gene autosomal dominant genetic transmission of AD. have at least one ε4 allele, a highly significant difference compared with controls. On the other hand, many AD Investigation of large families with multigenerational patients have no ε4 allele, and individuals with ε4 may FAD led to the discovery of two additional AD genes, never develop AD. Therefore, ε4 is neither necessary termed the presenilins. Presenilin-1 (PS-1) is on chromo- nor sufficient as a cause of AD. Nevertheless, it is clear some 14 and encodes a protein called S182. Mutations that the Apo ε4 allele, especially in the homozygous 4/4 in this gene cause an early-onset AD (onset before age state, is an important risk factor for AD. It appears to act 60 and often before age 50) transmitted in an autosomal as a dose-dependent modifier of age of onset, with the dominant, highly penetrant fashion. More than 100 dif- earliest onset associated with the ε4/4 homozygous ferent mutations have been found in the PS-1 gene in state. It is unknown how Apo ε functions as a risk factor families from a wide range of ethnic backgrounds. Pre- modifying age of onset, but it may be involved with the senilin-2 (PS-2) is on chromosome 1 and encodes a clearance of amyloid, less efficiently in the case of Apo protein called STM2. A mutation in the PS-2 gene was ε4. Apo ε is present in the neuritic amyloid plaques of first found in a group of American families with Volga AD, and it may also be involved in neurofibrillary tangle German ethnic background. Mutations in PS-1 are formation, because it binds to tau protein. Apo ε4 much more common than those in PS-2.The two genes decreases neurite outgrowth in cultures of dorsal root (PS-1 and PS-2) are highly homologous and encode ganglion neurons, perhaps indicating a deleterious role similar proteins that at first appeared to have seven trans- in the brain’s response to injury. There is some evidence membrane domains (hence the designation STM), but that the ε2 allele may be “protective,” but that remains subsequent studies have suggested eight such domains, to be clarified.The use of Apo ε testing in the diagnosis with a ninth submembrane region. Both S182 and STM2 are cytoplasmic neuronal proteins that are widely expressed throughout the nervous system. They are

of AD is controversial. It is not indicated as a predictive The pharmacologic action of donepezil, rivastigmine, 309 test in normal persons because its precise predictive and galantamine is inhibition of cholinesterase, with a value is unclear, and many individuals with the ε4 allele resulting increase in cerebral levels of acetylcholine. CHAPTER 23 Alzheimer’s Disease and Other Dementias never develop dementia. However, some cognitively Memantine appears to act by blocking overexcited normal ε4 heterozygotes and homozygotes have been N-methyl-D-aspartate (NMDA) channels. Double-blind, found by PET to have decreased cerebral cortical meta- placebo-controlled, crossover studies with cholinesterase bolic rates, suggesting possible presymptomatic abnor- inhibitors and memantine have shown them to be asso- malities compatible with the earliest stage of AD. In ciated with improved caregiver ratings of patients’ func- demented persons who meet clinical criteria for AD, the tioning and with an apparent decreased rate of decline finding of an ε4 allele increases the reliability of diagno- in cognitive test scores over periods of up to 3 years. The sis. However, the absence of an ε4 allele does not elimi- average patient on an anticholinesterase compound nate the diagnosis of AD. Furthermore, all patients with maintains his or her MMSE score for close to a year, dementia, including those with an ε4 allele, require a whereas a placebo-treated patient declines 2–3 points search for reversible causes of their cognitive impair- over the same time period. Memantine, used in conjunc- ment. Nevertheless, Apo ε4 remains the single most tion with cholinesterase inhibitors or by itself, seems to important biologic marker associated with risk for AD, slow cognitive deterioration in patients with moderate and studies of its functional role and diagnostic useful- to severe AD and is not approved for mild AD. These ness are progressing rapidly. Its association (or lack compounds have only modest efficacy for AD and offer thereof) with other dementing illnesses needs to be fully even less benefit in the late stages. All the cholinesterase evaluated. The ε4 allele is not associated with FTD, inhibitors are relatively easy to administer, and their DLB, or CJD. Additional genes are also likely to be major side effects are gastrointestinal symptoms (nau- involved in AD, but none have been reliably identified. sea, diarrhea, cramps), altered sleep with bad dreams, bradycardia (usually benign), and sometimes muscle Treatment: cramps. ALZHEIMER’S DISEASE In a prospective observational study, the use of estro- The management of AD is challenging and gratifying, gen replacement therapy appeared to protect—by despite the absence of a cure or a robust pharmaco- about 50%—against development of AD in women. This logic treatment. The primary focus is on long-term study seemed to confirm the results of two earlier amelioration of associated behavioral and neurologic case-controlled studies. Sadly, a prospective placebo- problems. controlled study of a combined estrogen-progesterone therapy for asymptomatic postmenopausal women Building rapport with the patient, family members, increased, rather than decreased, the prevalence of and other caregivers is essential to successful manage- dementia. This study markedly dampened enthusiasm ment. In the early stages of AD, memory aids such as for hormone treatments for the prevention of dementia. notebooks and posted daily reminders can be helpful. Additionally, no benefit has been found in the treatment Common sense and clinical studies show that family of AD with estrogen. members should emphasize activities that are pleasant and deemphasize those that are unpleasant. Kitchens, In patients with moderately advanced AD, a prospec- bathrooms, and bedrooms need to be made safe, and tive trial of the antioxidants selegiline, α-tocopherol eventually patients must stop driving. Loss of indepen- (vitamin E), or both, slowed institutionalization and pro- dence and change of environment may worsen confu- gression to death. Because vitamin E has less potential sion, agitation, and anger. Communication and repeated for toxicity than selegiline and is cheaper, the doses calm reassurance are necessary. Caregiver “burnout” is used in this study of 1000 IU twice daily are offered to common, often resulting in nursing home placement of many patients with AD. However, the beneficial effects the patient, and respite breaks for the caregiver help to of vitamin E remain controversial, and most investiga- maintain successful long-term management of the tors no longer give it in these high doses because of patient. Use of adult day-care centers can be most help- potential cardiovascular complications. ful. Local and national support groups, such as the Alzheimer’s Association, are valuable resources. A randomized, double-blind, placebo-controlled trial of an extract of Ginkgo biloba found modest improve- Donepezil, rivastigmine, galantamine, memantine, ment in cognitive function in subjects with AD and vas- and tacrine are the drugs presently approved by the cular dementia. This study requires confirmation before Food and Drug Administration (FDA) for treatment of Ginkgo biloba is used as a treatment for dementia AD. Due to hepatotoxicity, tacrine is no longer used. because there was a high subject dropout rate and no improvement on a clinician’s judgment scale. A compre- hensive 6-year multicenter prevention study using Ginkgo biloba is underway.

SECTION III Diseases of the Central Nervous System310 Vaccination against Aβ42 has proved highly effica- several strokes may develop chronic cognitive deficits, commonly called multi-infarct dementia. The strokes may cious in mouse models of AD; it helped to clear amyloid be large or small (sometimes lacunar) and usually involve from the brain and prevent further accumulation of several different brain regions. The occurrence of amyloid. However, in human trials this approach led to dementia depends partly on the total volume of dam- life-threatening complications, including meningoen- aged cortex, but it is also more common in individuals cephalitis. Modifications of the vaccine approach using with left-hemisphere lesions, independent of any lan- passive immunization with monoclonal antibodies are guage disturbance. Patients typically report a history of currently being evaluated in phase 3 trials. Another discrete episodes of sudden neurologic deterioration. experimental approach to the treatment of AD has been Many multi-infarct dementia patients have a history of the use of β and γ secretase inhibitors that diminish the hypertension, diabetes, coronary artery disease, or other production of Aβ42. manifestations of widespread atherosclerosis. Physical examination usually shows focal neurologic deficits such Several retrospective studies suggest that nons- as hemiparesis, a unilateral Babinski reflex, a visual field teroidal anti-inflammatory agents and statins (HMG-CoA defect, or pseudobulbar palsy. Recurrent strokes result in reductase inhibitors) may have a protective effect on a stepwise progression of disease. Neuroimaging studies dementia, and controlled prospective studies are being show multiple areas of infarction. Thus, the history and conducted. Similarly, prospective studies with the goal neuroimaging findings differentiate this condition from of lowering serum homocysteine levels are underway, AD. However, both AD and multiple infarctions are suggesting an association of elevated homocysteine common and sometimes occur together. With normal with dementia progression based on epidemiologic aging, there is also an accumulation of amyloid in cere- studies. Finally, there is now a strong interest in the rela- bral blood vessels, leading to a condition called cerebral tionship between diabetes and AD, and insulin-regulat- amyloid angiopathy of aging (not associated with demen- ing studies are being conducted. tia), which predisposes older persons to hemorrhagic lobar stroke. AD patients with amyloid angiopathy may Mild to moderate depression is common in the early be at increased risk for cerebral infarction. stages of AD and responds to antidepressants or cholinesterase inhibitors. Selective serotonin reuptake Some individuals with dementia are discovered on inhibitors (SSRIs) are commonly used due to their low MRI to have bilateral abnormalities of subcortical white anticholinergic side effects. Generalized seizures should matter, termed diffuse white matter disease, often occurring be treated with an appropriate anticonvulsant, such as in association with lacunar infarctions (Fig. 23-5). The phenytoin or carbamazepine. Agitation, insomnia, hallu- dementia may be insidious in onset and progress slowly, cinations, and belligerence are especially troublesome features that distinguish it from multi-infarct dementia, characteristics of some AD patients, and these behaviors but other patients show a stepwise deterioration more can lead to nursing home placement. The newer genera- typical of multi-infarct dementia. Early symptoms are tion of atypical antipsychotics, such as risperidone, mild confusion, apathy, changes in personality, depres- quetiapine, and olanzapine, are being used in low doses sion, psychosis, memory, and spatial or executive deficits. to treat these neuropsychiatric symptoms. The few con- Marked difficulties in judgment and orientation and trolled studies comparing drugs against behavioral dependence on others for daily activities develop later. intervention in the treatment of agitation suggest mild Euphoria, elation, depression, or aggressive behaviors are efficacy with significant side effects related to sleep, gait, common as the disease progresses. Both pyramidal and and cardiovascular complications. All of the antipsy- cerebellar signs may be present in the same patient. A chotics carry a black-box warning and are associated gait disorder is present in at least half of these patients. with increased deaths in AD patients; therefore, they With advanced disease, urinary incontinence and dysarthria should be used with caution. However, careful, daily, with or without other pseudobulbar features (e.g., dys- nonpharmacologic behavior management is often not phagia, emotional lability) are frequent. Seizures and available, rendering medications necessary. myoclonic jerks appear in a minority of patients. This disorder appears to result from chronic ischemia due to VASCULAR DEMENTIA occlusive disease of small, penetrating cerebral arteries and arterioles (microangiopathy). Any disease-causing Dementia associated with cerebral vascular disease can stenosis of small cerebral vessels may be the critical be divided into two general categories: multi-infarct underlying factor, though most typically hypertension is dementia and diffuse white matter disease (also called the main cause. The term Binswanger’s disease should be leukoaraiosis, subcortical arteriosclerotic encephalopathy or Bin- used with caution, because it does not really identify a swanger’s disease). Cerebral vascular disease appears to be single entity. a more common cause of dementia in Asia than in Europe and North America. Individuals who have had Other rare causes of white matter disease also present with dementia, such as adult metachromatic leukodystrophy

FRONTOTEMPORAL DEMENTIA, 311 PROGRESSIVE SUPRANUCLEAR PALSY, AND CORTICOBASAL DEGENERATION FIGURE 23-5 Frontotemporal dementia (FTD) often begins when the CHAPTER 23 Alzheimer’s Disease and Other Dementias Diffuse white matter disease (Binswanger’s disease). Axial patient is in the fifth to seventh decades, and in this age T2-weighted MR image through the lateral ventricles reveals group it is nearly as common as AD. Most studies suggest multiple areas of abnormal high signal intensity involving the that FTD is twice as common in men as it is in women. periventricular white matter as well as the corona radiata and Unlike AD, behavioral symptoms predominate in the early lentiform nuclei (arrows). While seen in some individuals with stages of FTD. Genetics play a significant role in a sizable normal cognition, this appearance is more pronounced in minority of cases. The clinical heterogeneity in familial patients with dementia of a vascular etiology. and sporadic forms of FTD is remarkable, with patients demonstrating variable mixtures of disinhibition, demen- (arylsulfatase A deficiency) and progressive multifocal tia, PSP, CBD, and motor neuron disease. The most leukoencephalopathy (papovavirus infection). A domi- common genetic mutations that cause an autosomal nantly inherited form of diffuse white matter disease is dominant form of FTD involve the tau or progranulin known as cerebral autosomal dominant arteriopathy with sub- genes, both on chromosome 17. Tau mutations lead to a cortical infarcts and leukoencephalopathy (CADASIL). Clini- change in the alternate splicing of tau or cause loss of cally, there is a progressive dementia developing in the function in the tau molecule.With progranulin, a missense fifth to seventh decades in multiple family members mutation in the coding sequence of the gene is the who may also have a history of migraine and recurrent underlying cause for the neurodegeneration. Progranulin stroke without hypertension. Skin biopsy may show appears to be a rare example of an autosomal dominant characteristic dense bodies in the media of arterioles. mutation leading to haploinsufficiency—too little of the The disease is caused by mutations in the notch 3 gene, progranulin protein. Both tau and progranulin mutations and there is a commercially available genetic test. The are associated with parkinsonian features, while ALS is frequency of this disorder is unknown, and there are no rare in the setting of these mutations. In contrast, familial known treatments. FTD with ALS has been linked to chromosome 9. Muta- tions in the valosin (chromosome 9) and ESCRTII mol- Mitochondrial disorders can present with strokelike ecules (chromosome 3) also lead to autosomal dominant episodes and can selectively injure basal ganglia or cor- forms of familial FTD. tex. Many such patients show other findings suggestive of a neurologic or systemic disorder such as ophthalmople- In FTD, early symptoms are divided among cognitive, gia, retinal degeneration, deafness, myopathy, neuropathy, behavioral, and sometimes motor abnormalities, reflect- or diabetes. Diagnosis is difficult but serum—especially ing degeneration of the anterior frontal and temporal CSF—levels of lactate and pyruvate may be abnormal, regions, basal ganglia, and motor neurons. Cognitive and biopsy of affected tissue is often diagnostic. testing typically reveals spared memory but impaired planning, judgment, or language. Poor business decisions Treatment of vascular dementia must be focused on the and difficulty organizing work tasks are common, and underlying causes, such as hypertension, atherosclerosis, speech and language deficits often emerge. Patients with and diabetes. Recovery of lost cognitive function is not FTD often show an absence of insight into their condi- likely to occur, although fluctuations with periods of tion. Common behavioral deficits include apathy, disin- improvement are common. Anticholinesterase compounds hibition, weight gain, food fetishes, compulsions, and are being studied as a treatment for vascular dementia. euphoria. Findings at the bedside are dictated by the anatomic localization of the disorder. Asymmetric left-frontal cases present with nonfluent aphasias, while left anterior tem- poral degeneration is characterized by loss of words and concepts related to language (semantic dementia). Non- fluent patients quickly progress to mutism, while those with semantic dementia develop features of multimodal- ity agnosia, losing the ability to recognize faces, objects, words, and the emotions of others. Copying, calculating, and navigation often remain normal into later in the ill- ness. Recently it has become apparent that many if not most patients with nonfluent aphasia progress to clinical syndromes that overlap with PSP and CBD and show these pathologies at autopsy. This left-hemisphere

SECTION III Diseases of the Central Nervous System312 presentation of FTD has been called primary progressive FIGURE 23-7 aphasia. In contrast, right-frontal or temporal cases show Voxel-based morphometry analysis showing differing pat- profound alterations in social conduct, with loss of terns of brain atrophy in the frontal variant of frontotemporal empathy, disinhibition, and antisocial behaviors predom- dementia (red), temporal variant of frontotemporal dementia inating. Memory and visuospatial skills are relatively (green), and Alzheimer’s disease (blue). This technique allows spared in most FTD patients. There is a striking overlap comparison of MRI gray matter volumes between groups of among FTD, PSP, CBD, and motor neuron disease; oph- subjects. (Image courtesy of M Gorno-Tempini, University of thalmoplegia, dystonia, swallowing symptoms, and fasci- California at San Francisco; with permission. culations are common at presentation of FTD or emerge during the course of the illness. cholinergic system is relatively spared in FTD, whereas The distinguishing anatomic hallmark of FTD is a serotonergic and glutaminergic neurons are depleted in marked lobar atrophy of temporal and/or frontal lobes, many patients. which can be visualized by neuroimaging studies and is readily apparent at autopsy (Figs. 23-6 and 23-7). The Historically, Pick’s disease was described as a progressive atrophy is sometimes asymmetric and may involve the degenerative disorder characterized clinically by selective basal ganglia.Two major pathologies have been linked to involvement of the anterior frontal and temporal neo- the clinical syndrome, one associated with tau inclu- cortex and pathologically by intracellular inclusions sions, the other with inclusions that stain negatively for (Pick bodies). Classic Pick bodies stain positive with silver tau but positively for ubiquitin and TDP-43. Micro- (argyrophilic) and tau, but many of the tau-positive scopic findings that are seen across all FTD cases include gliosis, neuronal loss, and spongiosus. Approximately one-half of all cases show swollen or ballooned neurons containing cytoplasmic inclusions that stain positively for tau. These aggregates sometimes resemble those found in PSP and CBD, and tau plays a major role in the pathogenesis of all three conditions. A toxic gain of function related to tau underlies the patho- genesis of many familial cases and is presumed to be a factor in sporadic cases as well. Nearly 80% of FTD patients show involvement of the basal ganglia at autopsy, and 15% go on to develop motor neuron dis- ease, underscoring the multisystem nature of this illness. Serotonergic losses are seen in many patients, and gluta- minergic neurons are depleted. In contrast to AD, the A B FIGURE 23-6 disinhibition and antisocial behavior. In the temporally pre- Frontotemporal dementia (FTD). Coronal MRI sections dominant patient, severe atrophy in the left temporal lobe from one patient with frontally predominant FTD (A) and (open arrows) and amygdala (white arrowheads) is present; another with temporally predominant FTD (B). Prominent this patient presented with progressive aphasia. (Images atrophy affecting the frontal gyri (white arrows) is present in courtesy of H Rosen and G Schauer, University of California frontally predominant FTD, particularly affecting the right at San Francisco; with permission.) frontal region; note also the thinning of the corpus callosum superior to the lateral ventricles. This patient presented with

FIGURE 23-8 no other effective treatments exist. Death occurs within 313CHAPTER 23 Alzheimer’s Disease and Other Dementias 5–10 years of onset. At autopsy, abnormal accumulation Classic intraneuronal Pick body (tau2 stain). These con- of tau is found within neurons and glia, often in the form of neurofibrillary tangles (NFTs).These tangles are sist of loosely arranged paired and straight-helical filaments found in multiple subcortical structures (including the subthalamus, globus pallidus, substantia nigra, locus and stain positive for tau. Classic Pick bodies are seen in coeruleus, periaqueductal gray, superior colliculi, and oculomotor nuclei) as well as in the neocortex. The ~20% of all frontotemporal dementia cases. NFTs have similar staining characteristics to those of AD, but on electron microscopy they are generally seen inclusions in FTD cases are not labeled with silver stains to consist of straight tubules rather than the paired heli- (Fig. 23-8).Although the nomenclature for these patients cal filaments found in AD. has remained controversial, the term FTD is increasingly used to describe the clinical syndrome, while Pick’s dis- In addition to its overlap with FTD and CBD (see ease is used to classify patients in whom the pathology below), PSP is often confused with idiopathic Parkinson’s shows classic Pick bodies (only a minority of patients disease (PD). Although elderly Parkinson’s patients may with the clinical features of FTD). have some difficulty with upgaze, they do not develop downgaze paresis or other abnormalities of voluntary The burden on caregivers of FTD patients is eye movements typical of PSP. Dementia does occur in extremely high. Treatment is symptomatic, and there are ~20% of PD patients, often secondary to DLB. Further- currently no therapies known to slow progression or more, the behavioral syndromes seen with DLB differ improve cognitive symptoms. Many of the behaviors from PSP (see later).The occurrence of dementia in PD that accompany FTD, such as depression, hyperorality, is more likely with increasing age, increasing severity of compulsions, and irritability, can be ameliorated with extrapyramidal signs, a long duration of disease, and the serotonin-modifying antidepressants. The co-association presence of depression.These patients also show cortical with motor disorders necessitates the careful use of atrophy on brain imaging. Neuropathologically, there antipsychotics, which can exacerbate this problem. may be Alzheimer changes in the cortex (amyloid plaques and NFTs), neuronal Lewy body inclusions in Progressive supranuclear palsy (PSP) is a degenerative both the substantia nigra and the cortex, or no specific disease that involves the brainstem, basal ganglia, and microscopic changes other than gliosis and neuronal neocortex. Clinically, this disorder begins with falls and loss. Progressive supranuclear palsy and Parkinson’s dis- vertical supranuclear gaze paresis and progresses to sym- ease are discussed in detail in Chap. 24. metrical rigidity and dementia. A stiff, unstable posture with hyperextension of the neck and slow gait with fre- Cortical basal degeneration (CBD) is a slowly progres- quent falls is characteristic of PSP. Early in the disease, sive dementing illness associated with severe gliosis and patients have difficulty with downgaze and lose vertical neuronal loss in both the neocortex and basal ganglia opticokinetic nystagmus on downward movement of a (substantia nigra and striatum). Occasionally there is a target. Frequent unexplained and sometimes spectacular unilateral onset with rigidity, dystonia, and apraxia of falls are common secondary to a combination of axial one arm and hand, sometimes called the alien hand, rigidity, inability to look down, and bad judgment. while in other instances the disease presents as a pro- Although the patients have very limited voluntary eye gressive frontal syndrome or as progressive symmetrical movements, their eyes still retain oculocephalic reflexes parkinsonism. Some patients begin with a progressive (doll’s head maneuver); thus, the eye-movement disorder nonfluent aphasia or a progressive motor disorder of is supranuclear. The dementia is similar to FTD with speech. Eventually CBD becomes bilateral and leads to apathy, frontal/executive dysfunction, poor judgment, dysarthria, slow gait, action tremor, and dementia. The slowed thought processes, impaired verbal fluency, and microscopic features include enlarged, achromatic neu- difficulty with sequential actions and with shifting from rons in the cortex with tau inclusions. Glial plaques with one task to another all common at the time of presenta- tau inclusions are pathognomonic of CBD. The condi- tion and often preceding the motor syndrome. Some tion is rarely familial, the cause is unknown, and there is patients begin with a nonfluent aphasia and progress to no specific treatment. classical PSP.There is only a limited response to L-dopa; DEMENTIA WITH LEWY BODIES The parkinsonian dementia syndromes are under increas- ing study, with many cases unified by the presence of Lewy bodies in both the substantia nigra and the cortex at pathology. The clinical syndrome is characterized by visual hallucinations, parkinsonism, fluctuating alertness,

SECTION III Diseases of the Central Nervous System314 falls, and often REM sleep behavior disorder. Dementia must be carefully titrated; tolerability may be improved can precede or follow the appearance of parkinsonism. by concomitant AD medications. Hence, one pathway to DLB occurs in patients with longstanding PD without cognitive impairment who OTHER CAUSES OF DEMENTIA slowly develop a dementia that is associated with visual hallucinations, parkinsonism, and fluctuating alertness. In Prion disorders such as Creutzfeldt-Jakob disease (CJD) are others, the dementia and neuropsychiatric syndrome rare conditions (~1 per million population) that produce precede the parkinsonism. DLB patients are highly sus- dementia. CJD is a rapidly progressive disorder associ- ceptible to metabolic perturbations, and in some patients ated with dementia, focal cortical signs, rigidity, and the first manifestation of illness is a delirium, often pre- myoclonus, causing death in <1 year from the first cipitated by an infection or other systemic disturbance. symptoms. The rapidity of progression seen with CJD is A delirium induced by L-dopa, prescribed for parkin- uncommon in AD so that distinction between the two sonian symptoms attributed to PD, may be the initial disorders is usually possible. However, CBD and DLB, clue that the correct diagnosis is DLB. Even without an more rapid degenerative dementias with prominent underlying precipitant, fluctuations can be marked in abnormalities in movement, are more likely to be mis- DLB patients, with the occurrence of episodic confu- taken for CJD.The differential diagnosis for CJD usually sion admixed with lucid intervals. However, despite the includes other rapidly progressive dementing conditions fluctuating pattern, the clinical features persist over a such as viral or bacterial encephalitides, Hashimoto’s long period of time, unlike delirium, which resolves encephalitis, CNS vasculitis, lymphoma, or paraneoplas- following correction of the underlying precipitant. Cog- tic syndromes. The markedly abnormal periodic EEG nitively, DLB patients tend to have relatively better discharges and cortical and basal ganglia abnormalities memory but more severe visuospatial deficits than indi- on diffusion-weighted MRI are unique diagnostic fea- viduals with AD. tures of CJD. Transmission from infected cattle to the The key neuropathologic feature is the presence of human population in the United Kingdom has caused a Lewy bodies throughout the cortex, amygdala, cingulate small epidemic of atypical CJD in young adults. Prion cortex, and substantia nigra. Lewy bodies are intraneu- diseases are discussed in detail in Chap. 38. ronal cytoplasmic inclusions that stain with periodic acid–Schiff (PAS) and ubiquitin. They are composed of Huntington’s disease (HD) (Chap. 25) is an autosomal straight neurofilaments 7–20 nm long with surrounding dominant, degenerative brain disorder. A DNA repeat amorphous material. They contain epitopes recognized expansion (CAG repeat) of the mutant gene on chro- by antibodies against phosphorylated and nonphospho- mosome 4 forms the basis of a diagnostic blood test for rylated neurofilament proteins, ubiquitin, and a presy- the disease gene.The clinical hallmarks of the disease are naptic protein called α-synuclein. Lewy bodies are tradi- chorea, behavioral disturbance, and frontal executive dis- tionally found in the substantia nigra of patients with order. Onset is usually in the fourth or fifth decade, but idiopathic PD. A profound cholinergic deficit is present there is a wide range in age of onset, from childhood to in many patients with DLB and may be a factor respon- >70 years. Memory is frequently not impaired until late sible for the fluctuations and visual hallucinations pre- in the disease, but attention, judgment, awareness, and sent in these patients. In patients without other pathologic executive functions may be seriously deficient at an features, the condition is referred to as diffuse Lewy body early stage. Depression, apathy, social withdrawal, irri- disease. In patients whose brains also contain excessive tability, and intermittent disinhibition are common. amounts of amyloid plaques and NFTs, the condition is Delusions and obsessive compulsive behavior may occur. called the Lewy body variant of Alzheimer’s disease. The The disease duration is typically about 15 years but is quantity of Lewy bodies required to establish the diag- quite variable. There is no specific treatment, but the nosis is controversial, but a definite diagnosis requires adventitious movements may partially respond to first- pathology. At autopsy, 10–30% of demented patients and second-generation antipsychotics. Treatment of show cortical Lewy bodies. behavioral changes are discussed in “General Sympto- Due to the overlap with AD and the cholinergic matic Treatment of the Patient with Dementia,” later. deficit in DLB, anticholinesterase compounds may be Asymptomatic adult children at risk for HD should helpful. Exercise programs maximize the motor function receive careful genetic counseling prior to DNA testing, of these patients. Similarly, antidepressants are often nec- because a positive result may have serious emotional and essary to treat the depressive syndromes that accompany social consequences. DLB. Atypical antipsychotics in low doses are sometimes needed to alleviate psychosis, although even low doses Normal-pressure hydrocephalus (NPH) is a relatively can increase extrapyramidal syndromes and may rarely uncommon syndrome with clinical, physiologic, and lead to death. As noted above, patients with DLB are neuroimaging characteristics. Historically, many of the extremely sensitive to dopaminergic medications, which individuals who have been treated for NPH have suf- fered from other dementias, particularly AD, multi-infarct

315 FIGURE 23-9 dilatation of the lateral, third, and fourth ventricles with a CHAPTER 23 Alzheimer’s Disease and Other Dementias Normal-pressure hydrocephalus. A. Sagittal T1-weighted patent aqueduct, typical of communicating hydrocephalus. MR image demonstrates dilatation of the lateral ventricle and B. Axial T2-weighted MR images demonstrate dilatation of stretching of the corpus callosum (arrows), depression of the the lateral ventricles. This patient underwent successful ven- floor of the third ventricle (single arrowhead), and enlarge- triculoperitoneal shunting. ment of the aqueduct (double arrowheads). Note the diffuse dementia, and DLB. For NPH the clinical triad includes A number of attempts have been made to use various an abnormal gait (ataxic or apractic), dementia (usually special studies to improve the diagnosis of NPH and pre- mild to moderate), and urinary incontinence. Neu- dict the success of ventricular shunting. These include roimaging studies reveal enlarged lateral ventricles radionuclide cisternography (showing a delay in CSF (hydrocephalus) with little or no cortical atrophy. This absorption over the convexity) and various attempts to syndrome is a communicating hydrocephalus with a monitor and alter CSF flow dynamics, including a con- patent aqueduct of Sylvius (Fig. 23-9), in contrast to stant-pressure infusion test. None has proven to be spe- congenital aqueductal stenosis, where the aqueduct is cific or consistently useful.There is sometimes a transient small. In many cases, periventricular edema is present. improvement in gait or cognition following lumbar Lumbar puncture opening pressure is in the high normal puncture (or serial punctures) with removal of 30–50 mL range, and the CSF protein, sugar concentrations, and cell of CSF, but this finding also has not proven to be consis- count are normal. NPH is presumed to be caused by tently predictive of post-shunt improvement. AD often obstruction to normal flow of CSF over the cerebral masquerades as NPH, because the gait may be abnormal convexity and delayed absorption into the venous sys- in AD and cortical atrophy sometimes is difficult to tem. The indolent nature of the process results in determine by CT or MRI early in the disease. Hip- enlarged lateral ventricles but relatively little increase in pocampal atrophy on MRI is a clue favoring AD. CSF pressure. There is presumed stretching and distor- Approximately 30–50% of patients identified by careful tion of white matter tracts in the corona radiata, but the diagnosis as having NPH will show improvement with a exact physiologic cause of the clinical syndrome is ventricular shunting procedure. Gait may improve more unclear. Some patients have a history of conditions pro- than memory. Transient, short-lasting improvement is ducing scarring of the basilar meninges (blocking common. Patients should be carefully selected for this upward flow of CSF) such as previous meningitis, sub- operation, because subdural hematoma and infection are arachnoid hemorrhage, or head trauma. Others with known complications. longstanding but asymptomatic congenital hydrocephalus may have adult-onset deterioration in gait or memory Dementia can accompany chronic alcoholism (Chap. 50). that is confused with NPH. In contrast to AD, the NPH This may be a result of associated malnutrition, especially patient has an early and prominent gait disturbance of B vitamins and particularly thiamine. However, other and no evidence of cortical atrophy on CT or MRI. poorly defined aspects of chronic alcohol ingestion may also produce cerebral damage. A rare idiopathic syndrome

SECTION III Diseases of the Central Nervous System316 of dementia and seizures with degeneration of the corpus Deficiency of nicotinic acid (pellagra) is associated callosum has been reported primarily in male Italian with sun-exposed skin rash, glossitis, and angular stom- drinkers of red wine (Marchiafava-Bignami disease). atitis. Severe dietary deficiency of nicotinic acid along Thiamine (vitamin B1) deficiency causes Wernicke’s with other B vitamins such as pyridoxine may result in encephalopathy (Chap. 22).The clinical presentation is a spastic paraparesis, peripheral neuropathy, fatigue, irri- malnourished individual (frequently but not necessarily tability, and dementia. This syndrome has been seen in alcoholic) with confusion, ataxia, and diplopia from prisoner-of-war and concentration camps. Low serum ophthalmoplegia.Thiamine deficiency damages the thal- folate levels appear to be a rough index of malnutrition, amus, mammillary bodies, midline cerebellum, periaque- but isolated folate deficiency has not been proven to be ductal grey matter of the midbrain, and peripheral specific cause of dementia. nerves. Damage to the dorsomedial thalamic region cor- relates most closely with the memory loss. Prompt Infections of the CNS usually cause delirium and other administration of parenteral thiamine (100 mg intra- acute neurologic syndromes (Chap. 13). However, some venously for 3 days followed by daily oral dosage) may chronic CNS infections, particularly those associated with reverse the disease if given in the first days of symptom chronic meningitis (Chap. 36), may produce a dementing onset. However, prolonged untreated thiamine defi- illness. The possibility of chronic infectious meningitis ciency can result in an irreversible dementia/amnestic should be suspected in patients presenting with a demen- syndrome (Korsakoff ’s psychosis) or even death. tia or behavioral syndrome who also have headache, In Korsakoff’s syndrome, the patient is unable to recall meningismus, cranial neuropathy, and/or radiculopathy. new information despite normal immediate memory, Between 20 and 30% of patients in the advanced stages of attention span, and level of consciousness. Memory for infection with HIV become demented (Chap. 37). Cardi- new events is seriously impaired, whereas memory of nal features include psychomotor retardation, apathy, and knowledge prior to the illness is relatively intact. Patients impaired memory. This syndrome may result from sec- are easily confused, disoriented, and incapable of recall- ondary opportunistic infections but can also be caused ing new information for more than a brief interval. by direct infection of CNS neurons with HIV. CNS Superficially, they may be conversant, entertaining, and syphilis was a common cause of dementia in the prean- able to perform simple tasks and follow immediate com- tibiotic era; it is uncommon nowadays but can still be mands. Confabulation is common, although not always encountered in patients with multiple sex partners. Char- present, and may result in obviously erroneous state- acteristic CSF changes consist of pleocytosis, increased ments and elaborations. There is no specific treatment protein, and a positive venereal disease research laboratory because the previous thiamine deficiency has produced (VDRL) test. irreversible damage to the medial thalamic nuclei and mammillary bodies. Mammillary body atrophy may be Primary and metastatic neoplasms of the CNS (Chap. 32) visible on high-resolution MRI. usually produce focal neurologic findings and seizures Vitamin B12 deficiency, as can occur in pernicious anemia, rather than dementia. However, if tumor growth begins causes a macrocytic anemia and may also damage the ner- in the frontal or temporal lobes, the initial manifesta- vous system (Chap. 30). Neurologically, it most commonly tions may be memory loss or behavioral changes. A produces a spinal cord syndrome (myelopathy) affecting the paraneoplastic syndrome of dementia associated with posterior columns (loss of position and vibratory sense) and occult carcinoma (often small cell lung cancer) is termed corticospinal tracts (hyperactive tendon reflexes with limbic encephalitis (Chap. 39). In this syndrome, confusion, Babinski responses); it also damages peripheral nerves, agitation, seizures, poor memory, movement disorders, resulting in sensory loss with depressed tendon reflexes. and frank dementia may occur in association with sen- Damage to cerebral myelinated fibers may also cause sory neuropathy. dementia.The mechanism of neurologic damage is unclear but may be related to a deficiency of S-adenosylmethionine A nonconvulsive seizure disorder may underlie a syn- (required for methylation of myelin phospholipids) due to drome of confusion, clouding of consciousness, and gar- reduced methionine synthase activity or accumulation of bled speech. Psychiatric disease is often suspected, but an methylmalonate, homocysteine, and propionate, providing EEG demonstrates the seizure discharges. If recurrent or abnormal substrates for fatty acids synthesis in myelin. persistent, the condition may be termed complex partial The neurologic signs of vitamin B12 deficiency are usually status epilepticus.The cognitive disturbance often responds associated with macrocytic anemia but on occasion may to anticonvulsant therapy. The etiology may be previous occur in its absence.Treatment with parenteral vitamin B12 small strokes or head trauma; some cases are idiopathic. (1000 μg intramuscularly daily for a week, weekly for a month, and monthly for life for pernicious anemia) stops It is important to recognize systemic diseases that indi- progression of the disease if instituted promptly, but reversal rectly affect the brain and produce chronic confusion or of advanced nervous system damage will not occur. dementia. Such conditions include hypothyroidism; vas- culitis; and hepatic, renal, or pulmonary disease. Hepatic encephalopathy may begin with irritability and confu- sion and slowly progress to agitation, lethargy, and coma (Chaps. 14, 45).

Isolated vasculitis of the CNS (CNS granulomatous vas- of bouts. Early in the condition, a personality change 317CHAPTER 23 Alzheimer’s Disease and Other Dementias culitis) (Chap. 21) occasionally causes a chronic associated with social instability and sometimes paranoia encephalopathy associated with confusion, disorienta- and delusions occurs. Later, memory loss progresses to tion, and cloudiness of consciousness. Headache is com- full dementia, often associated with parkinsonian signs mon, and strokes and cranial neuropathies may occur. and ataxia or intention tremor. At autopsy, the cerebral Brain imaging studies may be normal or nonspecifically cortex may show changes similar to AD, although NFTs abnormal. CSF studies reveal a mild pleocytosis or ele- are usually more prominent than amyloid plaques vation in the protein level. Cerebral angiography often (which are usually diffuse rather than neuritic). There shows multifocal stenosis and narrowing of vessels. A may also be loss of neurons in the substantia nigra. few patients have only small-vessel disease that is not Chronic subdural hematoma (Chap. 31) is also occasion- revealed on angiography.The angiographic appearance is ally associated with dementia, often in the context of not specific and may be mimicked by atherosclerosis, underlying cortical atrophy from conditions such as AD infection, or other causes of vascular disease. Brain or or HD. In these latter cases, evacuation of subdural meningeal biopsy demonstrates abnormal arteries with hematoma will not alter the underlying degenerative endothelial cell proliferation and infiltrates of mononu- process. clear cells.The prognosis is often poor, although the dis- order may remit spontaneously. Some patients respond Transient global amnesia (TGA) is characterized by the to glucocorticoids or chemotherapy. sudden onset of a severe episodic memory deficit, usu- ally occurring in persons >50 years. Often the memory Chronic metal exposure may produce a dementing syn- loss occurs in the setting of an emotional stimulus or drome.The key to diagnosis is to elicit a history of expo- physical exertion. During the attack, the individual is sure at work or home, or even as a consequence of a alert and communicative, general cognition seems intact, medical procedure such as dialysis. Chronic lead poison- and there are no other neurologic signs or symptoms. ing from inadequately fired glazed pottery has been The patient may seem confused and repeatedly ask reported. Fatigue, depression, and confusion may be asso- about present events.The ability to form new memories ciated with episodic abdominal pain and peripheral returns after a period of hours, and the individual neuropathy. Gray lead lines appear in the gums. There is returns to normal with no recall for the period of the usually an anemia with basophilic stippling of red cells. attack. Frequently no cause is determined, but cere- The clinical presentation can resemble that of acute brovascular disease, epilepsy (7% in one study), migraine, intermittent porphyria, including elevated levels of urine or cardiac arrhythmias have all been implicated. A Mayo porphyrins as a result of the inhibition of δ-aminole- Clinic review of 277 patients with TGA found a past vulinic acid dehydrase.The treatment is chelation therapy history of migraine in 14% and cerebrovascular disease with agents such as ethylenediamine tetraacetic acid in 11%, but these conditions were not temporally related (EDTA). Chronic mercury poisoning produces demen- to the TGA episodes. Approximately one-quarter of the tia, peripheral neuropathy, ataxia, and tremulousness that patients had recurrent attacks, but they were not at may progress to a cerebellar intention tremor or choreoa- increased risk for subsequent stroke. Rare instances of thetosis. The confusion and memory loss of chronic permanent memory loss after sudden onset have been arsenic intoxication is also associated with nausea, weight reported, usually representing ischemic infarction of the loss, peripheral neuropathy, pigmentation and scaling of hippocampi or medial thalamic nuclei bilaterally. the skin, and transverse white lines of the fingernails (Mees’ lines).Treatment is chelation therapy with dimer- The ALS/parkinsonian/dementia complex of Guam is a caprol (BAL). Aluminum poisoning has been best docu- rare degenerative disease that has occurred in the mented with the dialysis dementia syndrome, in which Chamorro natives on the island of Guam. Individuals water used during renal dialysis was contaminated with may have any combination of parkinsonian features, excessive amounts of aluminum. This poisoning resulted dementia, and motor neuron disease. The most charac- in a progressive encephalopathy associated with confu- teristic pathologic features are the presence of NFTs in sion, nonfluent aphasia, memory loss, agitation, and, later, degenerating neurons of the cortex and substantia nigra lethargy and stupor. Speech arrest and myoclonic jerks and loss of motor neurons in the spinal cord. Epidemio- were common and associated with severe and general- logic evidence supports a possible environmental cause, ized EEG changes.The condition has been eliminated by such as exposure to a neurotoxin with a long latency the use of deionized water for dialysis. period. One interesting but unproven candidate neuro- toxin occurs in the seed of the false palm tree, which Recurrent head trauma in professional boxers may Guamanians traditionally used to make flour. The ALS lead to a dementia sometimes called the “punch drunk” syndrome is decreasing in frequency in Guam, but a syndrome, or dementia pugilistica. The symptoms can be dementing illness with rigidity continues to be seen. progressive, beginning late in a boxer’s career or even long after retirement.The severity of the syndrome cor- Rarely, adult-onset leukodystrophies, neuronal storage relates with the length of the boxing career and number diseases, and other genetic disorders can present as dementia late in life. Metachromatic leukodystrophy can

SECTION III Diseases of the Central Nervous System318 present as a dementia associated with large frontal white third decades) than most dementing illnesses, and is matter lesions.This syndrome is diagnosed by measuring associated with intact memory.The delusions and hallu- arylsulfatase A enzyme activity in white blood cells. Adult cinations of schizophrenia are usually more complex and presentations of adrenal leukodystrophy have been bizarre than those of dementia. Some chronic schizo- reported, and in these cases involvement of the spinal cord phrenics develop an unexplained progressive dementia and posterior white matter is common. Adrenoleukodys- late in life that is not related to AD. Conversely, FTD, trophy is diagnosed with measurement of plasma very HD, vascular dementia, DLB, AD, or leukoencephalopa- long-chain fatty acids. CADASIL is another genetic thy can begin with schizophrenia-like features, leading syndrome associated with white matter disease, often to the misdiagnosis of a psychiatric condition. The later frontally and temporally predominant. Diagnosis is made age of onset, presence of significant deficits on cognitive with biopsy of skin which shows osmophilic granules in testing, or the presence of abnormal neuroimaging find- arterioles; genetic testing for mutations in notch 3 is also ings point toward a degenerative condition. Memory possible (see earlier). The neuronal cerebrolipofuscinoses loss may also be part of a conversion reaction. In this sit- are a genetically heterogeneous group of disorders asso- uation, patients commonly complain bitterly of memory ciated with myoclonus, seizures, and progressive demen- loss, but careful cognitive testing either does not con- tia. Diagnosis is made by finding curvilinear inclusions firm the deficits or demonstrates inconsistent or unusual within white blood cells or neuronal tissue. patterns of cognitive problems. The patient’s behavior Psychogenic amnesia for personally important memo- and “wrong” answers to questions often indicate that he ries is common, although whether this results from or she understands the question and knows the correct deliberate avoidance of unpleasant memories or from answer. unconscious repression is currently unknown. The event-specific amnesia is more likely to occur after vio- Clouding of cognition by chronic drug or medication use, lent crimes such as homicide of a close relative or friend often prescribed by physicians, is an important cause of or sexual abuse. It may also develop in association with dementia. Sedatives, tranquilizers, and analgesics used to severe drug or alcohol intoxication and sometimes with treat insomnia, pain, anxiety, or agitation may cause con- schizophrenia. More prolonged psychogenic amnesia fusion, memory loss, and lethargy, especially in the occurs in fugue states that also commonly follow severe elderly. Discontinuation of the offending medication emotional stress. The patient with a fugue state suffers often improves mentation. from a sudden loss of personal identity and may be found wandering far from home. In contrast to organic Treatment: amnesia, fugue states are associated with amnesia for personal DEMENTIA identity and events closely associated with the personal past. At the same time, memory for other recent events and the The major goals of management are to treat any cor- ability to learn and use new information are preserved. rectable causes of the dementia and to provide comfort The episodes usually last hours or days and occasionally and support to the patient and caregivers. Treatment of weeks or months while the patient takes on a new iden- underlying causes might include thyroid replacement tity. On recovery, there is a residual amnesia gap for the for hypothyroidism; vitamin therapy for thiamine or B12 period of the fugue.Very rarely, selective loss of autobio- deficiency or for elevated serum homocysteine; antibi- graphic information represents a focal injury in the otics for opportunistic infections; ventricular shunting brain areas involved with these functions. for NPH; and appropriate surgical, radiation, and/or Psychiatric diseases may mimic dementia. Severely chemotherapeutic treatment for CNS neoplasms. Removal depressed individuals may appear demented, a phenom- of sedating or cognition-impairing drugs and medica- enon called pseudodementia. Memory and language are tions is often beneficial. If the patient is depressed rather usually intact when carefully tested in depressed persons, than demented (pseudodementia), the depression and a significant memory disturbance usually suggests an should be vigorously treated. Patients with degenerative underlying dementia, even if the patient is depressed. diseases may also be depressed, and that portion of The pseudodemented patient may feel confused and their condition may respond to antidepressant therapy. unable to accomplish routine tasks.Vegetative symptoms, Antidepressants that are low in cognitive side effects, such as insomnia, lack of energy, poor appetite, and con- such as SSRIs (Chap. 49), are advisable when treatment is cern with bowel function, are common. The onset is necessary. Anticonvulsants are used to control seizures. often abrupt, and the psychosocial milieu may suggest prominent reasons for depression. Such patients respond Agitation, hallucinations, delusions, and confusion are to treatment of the depression. Schizophrenia is usually difficult to treat. These behavioral problems represent not difficult to distinguish from dementia, but occasion- major causes for nursing home placement and institu- ally the distinction can be problematic. Schizophrenia tionalization. Before treating these behaviors with med- generally has a much earlier age of onset (second and ications, a thorough search for potentially modifiable

environmental or metabolic factors should be sought. with complaints, depression, or anger. Hostile responses 319 Hunger, lack of exercise, toothache, constipation, urinary on the part of the caretaker are useless and sometimes tract infection, or drug toxicity all represent easily harmful. Explanation, reassurance, distraction, and calm CHAPTER 23 Alzheimer’s Disease and Other Dementias correctable factors that can be treated without psy- statements are more productive responses in this set- choactive drugs. Drugs such as phenothiazines and ben- ting. Eventually, tasks such as finances and driving must zodiazepines may ameliorate the behavior problems be assumed by others, and the patient will conform and but have untoward side effects such as sedation, rigidity, adjust. Safety is an important issue that includes not and dyskinesias. Despite their unfavorable side-effect only driving but the environment of the kitchen, bath- profile, second-generation antipsychotics such as queti- room, and sleeping area. These areas need to be moni- apine (25 mg qd starting dose) are increasingly being tored, supervised, and made as safe as possible. A move used for patients with agitation, aggression, and psy- to a retirement home, assisted-living center, or nursing chosis. When patients do not respond to treatment, it is home can initially increase confusion and agitation. usually a mistake to advance to higher doses or to use Repeated reassurance, reorientation, and careful intro- anticholinergics or sedatives (such as barbiturates or duction to the new personnel will help to smooth the benzodiazepines). It is important to recognize and treat process. Provision of activities that are known to be depression; initial treatment can be with a low dose of enjoyable to the patient can be of considerable bene- an SSRI (e.g., escitalopram 10 mg/d) while monitoring fit. Attention should also be paid to frustration and for efficacy and toxicity. Sometimes apathy, visual hallu- depression in family members and caregivers. Caregiver cinations, depression, and other psychiatric symptoms guilt and burnout are common. Family members often respond to the cholinesterase inhibitors, obviating the feel overwhelmed and helpless and may vent their need for other more toxic therapies. frustrations on the patient, each other, and health care providers. Caregivers should be encouraged to Cholinesterase inhibitors are being used to treat AD, take advantage of day-care facilities and respite breaks. and other drugs, such as anti-inflammatory agents, are Education and counseling about dementia are impor- being investigated in the treatment or prevention of AD. tant. Local and national support groups can be of con- Depression should be recognized and treated, initially siderable help, such as the Alzheimer’s Association with a low dose of an SSRI (Lexapro 10 mg), closely mon- (www.alz.org). itoring for efficacy and toxicity. These approaches are reviewed in the treatment section for AD, earlier. FURTHER READINGS A proactive strategy has been shown to reduce the BALLARD C et al: The dementia antipsychotic withdrawal trial occurrence of delirium in hospitalized patients. This (DART-AD): Long-term follow-up of a randomised placebo- strategy includes frequent orientation, cognitive activi- controlled trial. Lancet Neurol 8:151, 2009 ties, sleep-enhancement measures, vision and hearing aids, and correction of dehydration. CASELLI RJ et al: Longitudinal Modeling of Age-Related Memory Decline and the APOE ε4 Effect. N Engl J Med 361:255, 2009 Nondrug behavior therapy has an important place in the management of dementia. The primary goal is to KNOPMAN DS et al: Incidence and causes of nondegenerative nonva- make the demented patient’s life comfortable, uncom- scular dementia: A population-based study. Arch Neurol 63:218, plicated, and safe. Preparing lists, schedules, calendars, 2006 and labels can be helpful. It is also useful to stress famil- iar routines, short-term tasks, walks, and simple physical ROBERSON ED, MUCKE L: 100 years and counting: Prospects for exercises. For many demented patients, memory for defeating Alzheimer’s disease. Science 314:781, 2006 facts is worse than that for routine activities, and they may still be able to take part in preserved physical activ- SAVVA GM et al: Age, neuropathology, and dementia. N Engl J Med ities such as walking, bowling, dancing, and golf. 360:2302, 2009 Demented patients usually object to losing control over familiar tasks such as driving, cooking, and handling SEELEY WW et al: Early frontotemporal dementia targets neurons finances. Attempts to help or take over may be greeted unique to apes and humans.Ann Neurol 60:660, 2006 SMALL GW et al: PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med 355:2652, 2007 VAN OIJEN M et al: Atherosclerosis and risk for dementia. Ann Neurol 61:403, 2007

CHAPTER 24 PARKINSON’S DISEASE AND OTHER EXTRAPYRAMIDAL MOVEMENT DISORDERS Mahlon R. DeLong ■ Jorge L. Juncos ■ Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 Differential Diagnosis and Screening Evaluation . . . . . . . . . . . 325 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 ■ Dementia in Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . 334 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 ■ Other Parkinsonian Disorders . . . . . . . . . . . . . . . . . . . . . . . . 334 Motor Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 Non-motor Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 Parkinsonian Disorders Associated with Abnormal Neuropsychiatric Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . 322 Metabolism of α-Synuclein (α-Synucleinopathies) . . . . . . . 334 Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323 Parkinsonian Disorders Associated with Abnormalities Genetic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323 of Tau Metabolism (Tauopathies) . . . . . . . . . . . . . . . . . . . . . 335 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 Secondary Parkinsonism . . . . . . . . . . . . . . . . . . . . . . . . . . . 336 ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336 PARKINSON’S DISEASE autosomal dominant and recessive forms of PD (now numbering >10) comprise ~5% of cases (Table 24-1).These Parkinson’s disease (PD) is the most common form of a are generally characterized by an earlier age of onset (typ- group of progressive neurodegenerative disorders charac- ically <45 years) and a longer course than cases of “spo- terized by the clinical features of parkinsonism, including radic” PD, although one genetic form, LLRK-2, causes bradykinesia (a paucity and slowness of movement), rest PD in the same age range as sporadic PD. Although most tremor, muscular rigidity, shuffling gait, and flexed pos- patients with PD appear to have no strong genetic deter- ture. Although defined clinically as a movement disorder, minant, epidemiologic evidence points to a complex inter- it is now widely appreciated that PD can be accompa- action between genetic vulnerability and environmental nied by a variety of non-motor symptoms, including factors. Risk factors include a positive family history, male autonomic, sensory, sleep, cognitive, and psychiatric dis- gender, head injury, exposure to pesticides, consumption turbances. Nearly all forms of parkinsonism result from a of well water, and rural living. Factors associated with a reduction of dopaminergic transmission within the basal reduced incidence of PD include coffee drinking, smok- ganglia. The discovery of dopamine in the brain, the ing, use of nonsteroidal anti-inflammatory drugs, and demonstration of its depletion in PD, and the success of estrogen replacement in postmenopausal women. dopamine replacement therapy by its precursor, lev- odopa, are all major landmarks in the field of neurology. CLINICAL FEATURES A diagnosis of PD can be made with some confidence in EPIDEMIOLOGY patients who present with at least two of the three cardinal signs—rest tremor, rigidity, and bradykinesia.Tremor is par- PD afflicts ~1 million individuals in the United States ticularly important, as it is present in 85% of patients with (~1% of those older than 55 years). Its peak age of onset is true PD; a diagnosis of PD is particularly difficult when in the early 60s (range 35–85 years), and the course of the tremor is absent.A unilateral and gradual onset of symptoms illness ranges between 10 and 25 years. PD accounts further supports the diagnosis. Masked facies, decreased eye for ~75% of all cases of parkinsonism; the remaining blinking, stooped posture, and decreased arm swing com- cases result from other neurodegenerative disorders, cere- plete the early picture. The onset may also be heralded by brovascular disease, and drugs. Familial forms of known vague feelings of weakness, fatigue, aching, and discomfort. 320

TABLE 24-1 321 GENETICALLY BASED PARKINSON’S DISEASE LOCUS GENE PROTEIN FUNCTION INHERITANCE PARK1 SNCA α-Synuclein Uncertain; vesicle trafficking AD PARK2 PRKN Parkin E3 ubiquitin ligase AR PARK4 SNCA α-Synuclein (triplication Uncertain; vesicle trafficking AD PARK5 UCH-L1 or duplication) Proteosomal processing AD UCH-L1 (Ubiquitin carboxy- PARK6 PINK1 Mitochondrial kinase AR PARK7 DJ-1 terminal hydroxylase L1) Oxidative stress response AR PARK8 LRRK2 PINK1 Cytosolic kinase AD DJ-1 Dardarin Note: See text for details. AD, autosomal dominant; AR, autosomal recessive. MOTOR FEATURES changes in the posture of the fingers, hand, and arm. Pos- CHAPTER 24 Parkinson’s Disease and Other Extrapyramidal Movement Disorders tural instability is one of the most disabling features of The most disabling motor feature of PD is bradykinesia, advanced PD, contributing to falls and injuries and lead- which interferes with all aspects of daily living including ing to major morbidity and mortality. It can be tested in rising from a chair, walking, turning in bed, and dress- the office with the “pull test” (Fig. 24-1). The develop- ing. Fine motor control is also impaired, as evidenced by ment of postural instability and falls in the first years of decreased manual dexterity and micrographia. Soft the illness, however, strongly suggest a diagnosis of atypical speech (hypophonia) and sialorrhea are other troubling PD. Patients are also at risk for hip fractures, which are manifestations of (bulbar) bradykinesia. Rest tremor, at a associated with osteoporosis and vitamin D deficiency. frequency of 4–6 Hz, typically appears unilaterally, first distally, involving the digits and wrist, where it may have Testing for Postural Instability a “pill-rolling” character. Tremor usually spreads proxi- I. Practice session mally and occasionally to the ipsilateral leg before Explanation must be given that the patient will be pulled appearing on the other side after a year or more. It may forcefully backward to test balance and that the patient appear later in the lips, tongue, and jaw but spares the must prevent himself or herself from falling, if necessary, head and neck. Rigidity is felt as a uniform resistance to by taking a step backward after he or she is pulled. At passive movement about a joint throughout the full least one good practice session is carried out before the range of motion, accompanied by a characteristic “plastic” final test. quality to the movement. Brief, regular interruptions of resistance during passive movement, due to subclinical II. Patient stance tremor, may give rise to a “cogwheeling” sensation. Dys- Patient must be upright and cannot lean forward in any tonia involving the distal arm or leg may occur early in way unless axial flexion prevents upright posture. Patient the disease, unrelated to treatment, especially in younger must not be pulled while off balance from a previous pull. patients. It can also be provoked by antiparkinsonian Stance should be with feet comfortably apart. drug therapy. III. Pull Gait disturbance with shuffling short steps and a ten- Patient is pulled briskly and forcefully enough to trigger dency to turn en bloc is a prominent feature of PD. Fes- one step back. tinating gait, a classic sign of parkinsonism, results from the combination of flexed posture and loss of postural IV. Examiner’s response reflexes, which cause the patient to accelerate in an Examiner is ready to catch the patient but allows enough effort to “catch up” with the body’s center of gravity. space to move backward with the patient for at least three Freezing of gait, a feature of more advanced PD, occurs steps of recovery. The test is to be performed in a space commonly at the onset of locomotion (start hesitation), long enough to differentiate between persistent but when attempting to change direction or turn around, recovering retropulsion and no recovery. and upon entering a crowded room or narrow space such as a doorway. FIGURE 24-1 Testing for postural instability. (From: RP Munhox et al. Abnormalities of balance and posture tend to increase Neurology 62:125, 2004; with permission.) as the disease progresses. Flexion of the head, stooping and tilting of the upper trunk, and a tendency to hold the arm in a flexed posture while walking are common, as are

SECTION III Diseases of the Central Nervous System322 NON-MOTOR FEATURES somatic and vegetative symptoms of PD and depression. As a result, depression may go unrecognized and untreated. Non-motor aspects of PD include depression and anxi- There is compelling evidence that depression in PD is an ety, cognitive impairment, sleep disturbances, sensory intrinsic part of the illness and not simply a reaction to abnormalities and pain, loss of smell (anosmia), and dis- disability. Recognizing even mild depression is particularly turbances of autonomic function. Together these may important since it can account for otherwise unexplained contribute as much to the burden of the disease as the albeit reversible worsening of parkinsonian motor symp- more obvious motor abnormalities. Some of these non- toms, new somatic symptoms, and sleep disruption. motor disturbances may be present long before the onset Depression can also be induced or aggravated iatrogeni- of motor signs. The physiologic basis of the non-motor cally by antiparkinsonian and psychotropic agents used to signs and symptoms are explained in part by widespread treat other symptoms. Finally, other causes for depressive involvement of brainstem, olfactory, thalamic, and corti- symptoms and refractory depression should always be cal structures, as discussed later in the chapter. considered, including hypothyroidism, hypogonadism, and vitamin B12 deficiency. Sensory symptoms often manifest as a distressing sensa- tion of inner restlessness presumed to be a form of Anxiety disorders in PD can appear in isolation or as akathisia. Aching pain and discomfort in the extremities an accompaniment of depression or progressive cogni- can be a prominent presenting symptom or develop when tive impairment. They can also be due to an akathisia antiparkinsonian medications are wearing off. Some equivalent provoked in part by undertreatment of motor patients may develop a subjective shortness of breath in symptoms. The development of drug-induced motor the absence of any underlying cardiorespiratory pathology. fluctuations can compound the problem by precipitating anxiety during the off periods that, in severe cases, may Sleep disorders and impaired daytime alertness are com- mimic panic attacks. mon in PD. Factors that disrupt sleep include nighttime reemergence of bradykinesia and rigidity, with difficulty Mild or moderate cognitive abnormalities affect many turning in bed, as well as tremor and involuntary move- patients with PD.These occur in the later stages of the ill- ments (e.g., myoclonic jerks or periodic leg movements). ness and present as frontal lobe dysfunction. Difficulties Restless legs and rapid eye movement behavioral disorder with complex tasks, long-term planning, and memorizing often precede the onset of motor signs of PD.Vivid dreams or retrieving new information are common. Although and hallucinations related to dopaminomimetic therapy some of these symptoms represent bradyphrenia (the cog- may also contribute to sleep disruption. Finally, sleep apnea nitive equivalent of bradykinesia), it is now clear that the and other sleep disturbances can also occur. Correction of dysfunction also includes working memory, executive these sleep disorders may improve daytime functioning, but function, attention, mental flexibility, visuospatial func- often alertness remains impaired, pointing to a separate dis- tion, and word fluency. In contrast, language and simple order of arousal or to drug-induced sedation. mathematical skills are relatively spared, unlike in patients with AD. Iatrogenic contributors to cognitive decline in Autonomic dysfunction can produce diverse manifes- vulnerable patients include the use of anticholinergics, tations, including orthostatic hypotension, constipation, amantadine, psychotropics, and even dopaminomimetic urinary urgency and frequency, excessive sweating, and medications. Depression and intercurrent medical ill- seborrhea. Orthostatic hypotension is present in many nesses, especially infections (of the urinary tract or else- patients resulting from impaired vasomotor reflexes, sym- where) and dehydration, are important reversible causes pathetic denervation of the heart, or as a side effect of of an acute change in cognitive function in PD. dopaminomimetic therapy. This rarely leads to syncope unless the patient has developed true autonomic failure or The incidence of significant dementia in PD may be has an unrelated cardiac problem. Paroxysms of drenching as high as six times that in age-matched controls and, in sweats may occur in advanced PD, often related to the subspecialty clinics, can be as high as 70% or greater wearing off of antiparkinsonian medications. with long-term observation (Ն8 years). In late stages the presence of substantial cognitive impairment may limit NEUROPSYCHIATRIC SYMPTOMS therapeutic options and contribute more to overall dis- ability than the motor symptoms in PD. Predictors of Changes in mood, cognition, and behavior are common dementia include late age of onset, akinetic-rigid phe- accompaniments of PD, especially in its later stages, and notype, presence of severe depression, persistent halluci- may be the direct result of PD or its comorbid patholo- nations, and advanced stages of disease. In most instances, gies [e.g., Alzheimer’s disease (AD), cortical dementia accumulating amyloid and α-synuclein pathologies in with Lewy bodies (DLB)] or may occur as a side effect the frontal lobes, basal forebrain, hippocampus, and of antiparkinsonian or concomitant therapy. amygdala account for the progression of these symptoms (see Pathology, below). Depression affects approximately one-half of patients with PD and can occur at any phase of the illness. It is Psychotic symptoms affect up to 40% of patients with often difficult to diagnose due to the overlap between the PD, depending on the age, disease duration, and prevalence

of dementia in the population surveyed. Early symptoms Pathology Hippocampus & basal forebrain 323 include visual illusions (e.g., shadows of the edge of the Cholinergic pathology visual field) and formed visual hallucinations (usually Brainstem and cortex people and animals), both with retained insight.Although Lewy depression and dementia are the most important risk factors for psychotic symptoms in PD, the symptoms are Protofibrils, fibers bodies often triggered by drug therapy. Dopaminomimetics (especially dopamine agonists), anticholinergics, amanta- Clinical course dine, and psychotropics are the chief drug offenders. Delusions are more disturbing than hallucinations Non-motor symptoms because they place an even heavier burden on the family and caregivers. The prodrome to these psychotic symp- Early motor symptoms toms includes sleep disturbances and subtle erratic behaviors with temperamental and sometimes unreason- Clinical Dx Fluctuations, dyskinesias, and falls able outbursts. Decreasing motor response, In recent years there has been increased recognition of dementia & insidious behavioral disturbances in a subset of patients with PD, referred to collectively as impulse control disorders psychotic symptoms (ICDs); these include pathologic gambling, hypersexuality, compulsive shopping, and compulsive eating and are asso- 60 75 ciated primarily with the use of dopaminergic agents. A related disorder, termed punding, consists of stereotypical Age motor behavior in which there is an intense fascination with repetitive handling and examining of mechanical FIGURE 24-2 CHAPTER 24 Parkinson’s Disease and Other Extrapyramidal Movement Disorders objects, such as picking at oneself, taking apart watches Proposed stages of Parkinson’s disease (PD) based on and radios, or sorting and arranging common objects. extrapolations from pathologic, clinical and brain imaging Current therapeutic approaches to these disorders include studies. Broken black lines indicate that, by itself, Lewy (α- reduction or discontinuation of dopamine agonist ther- synuclein) protofibril or fiber pathology is not sufficient to apy, psychosocial interventions, and in some cases consid- make the pathologic diagnosis of PD. Broken blue lines rep- eration of deep brain stimulation with a goal of reducing resent non-motor signs that usually precede clinical recogni- the requirement for drugs. tion of PD, including impaired olfaction, sleep and mood dis- turbances, and constipation. Broken yellow lines indicate that PATHOLOGY fluctuations may be less apparent in the late stages of PD. Gross examination of the brain in PD reveals mild play a role in the non-motor (e.g., autonomic, sleep, emo- frontal atrophy with loss of the normal dark melanin tional, and cognitive) and levodopa unresponsive motor pigment of the midbrain. Microscopically there is aspects (e.g., postural instability, gait, and bulbar distur- degeneration of the dopaminergic cells with the pres- bances) of PD. ence of Lewy bodies (LBs) in the remaining neurons and processes of the substantia nigra pars compacta The biochemical consequence of dopaminergic cell (SNpc); other brainstem nuclei; and regions such as the loss in the SNpc is gradual denervation of the striatum, medial temporal, limbic, and frontal cortices. LBs have a the main target projection for the SNpc neurons. Other high concentration of α-synuclein and are the patho- target regions of these neurons include the intralaminar logic hallmark of the disorder. Mutations in the α- and parafascicular nuclei of the thalamus, the globus pal- synuclein gene can cause familial PD by promoting the lidus, and the subthalamic nucleus (STN). Dopamine formation of α-synuclein-positive filaments that aggre- denervation of the putamen, the motor portion of the gate into LBs and Lewy neurites (Fig. 24-2). It is now striatum, leads to many of the motor symptoms of PD. generally accepted that this pathology appears first in Symptoms develop when striatal dopamine depletion the anterior olfactory nuclei and lower brainstem (glos- reaches 50–70% of normal. Pharmacologic restoration sopharyngeal and vagal nerve nuclei), with ascending of dopamine transmission is the basis for symptomatic brainstem involvement of the locus coeruleus, n. gigan- drug treatment of PD. tocellularis, and the raphe, before extending to the mag- nocellular nuclei of the basal forebrain, the central GENETIC CONSIDERATIONS nucleus of the amygdala, and the SNpc. Further progres- sion extends to the thalamus and cerebral cortex. Although the vast majority of cases of PD appear Involvement of these extranigral areas is postulated to to be sporadic, increasing evidence indicates that genetic factors play an important role in many forms of PD. Much of this evidence comes from studies of the concordance rates for PD among monozygotic and dizygotic twins. These studies suggest that heredity plays an important role in cases with age of onset <45 years and a less important role in older patients. Eight genes have been clearly linked to familial forms of PD (Table 24-1), and a number of other candidate genes or

324 genetic loci have been identified as possibly causative of carboxy-terminal hydroxylase L1 (UCH-L1), another PD. Among the former, PARK1, PARK4, and PARK5 component of the ubiquitin proteasomal system. lead to an autosomal dominant form of PD with atypi- Because ubiquitination of proteins targets them for cal features such as early age of onset and rapid progres- degradation in the proteasome system, these findings sion of symptoms. PARK1 is due to a mutation in the suggest that abnormal proteasomal processing is impor- gene for α-synuclein leading to abnormal aggregation tant in the pathogenesis of at least some forms of PD. of this protein (Fig. 24-3). PARK2 and PARK7 lead to The most recently identified mutation is the gene for autosomal recessive disorders also with atypical features, LRRK2. Most cases are slowly progressive and begin in including juvenile forms of parkinsonism. PARK2 late adulthood, closely resembling sporadic PD. The encodes parkin, an E3 ubiquitin protein ligase. Mutations prevalence of causative LRRK2 mutations is highly in parkin appear to be the major cause of autosomal dependent on the population under study, ranging from recessive PD. Remarkably, PARK5 codes for the ubiquitin 1 to 2% of all PD cases, except in isolated pockets where MPTP, rotenone, Mitochondrial iv PINK-1 mutation DJ-1 mutation, PINK-1 mutation, dysfunction LRRK2 mutation mitochondrial DNA deletions vi Pdyasrkfuinnction Substrates Abnormal Inappropriate SECTION III Diseases of the Central Nervous SystemUCH-L1 ubiquitination phosphorylation mutation Ubiquitin Reactive oxygen species, v apoptosis, energy failure Protease Neuronal Cellular protection, vii inhibitors cell death cellular replacement Proteasome Misfolded protein Substrate accumulation iii DJ-1 mutation, proteasome inhibition, abnormal phosphorylation, oxidative stress i ii α-Synuclein Gene mutations/ multiplications Abnormal processing Monomers Protofibrils Fibrils Lewy body FIGURE 24-3 (ii); interventions to down-regulate toxic substrates or up- Pathogenesis of dopamine cell death in Parkinson’s dis- regulate parkin or proteasomal function (iii); interventions ease (PD) and possible sites for therapeutic intervention to enhance mitochondrial function with factors such as in PD. Studies on inherited forms of PD (see text) have led to CoQ10, DJ-1, or PINK-1 (iv); free radical scavengers and the identification of genes that, when mutated, lead to antioxidants (v); kinase inhibitors to block LRRK2 activity or dopaminergic cell loss. These genes are involved in cellular interventions to increase PINK-1 function (vi); and other ther- processes that include protein ubiquitination and degrada- apies using tropic factors such as GDNF (see text), survival tion via the proteasomal system, response to oxidative genes, or fetal/stem cell replacement that would protect or stress, mitochondrial function, protein phosphorylation, and replace susceptible cells (vii). MPTP, 1-methyl-1,2,4,6 protein folding. Potential points for therapeutic intervention tetrahydropyridine. (Reprinted from JM Savitt et al, with are highlighted: gene silencing therapies, to reduce synuclein permission.) levels (i); inhibition of synuclein aggregation and/or processing

the prevalence can be higher. Although the mechanism younger than 40 years, it is important to rule out Wilson 325CHAPTER 24 Parkinson’s Disease and Other Extrapyramidal Movement Disorders of action of the LRRK2 mutation is not certain, evi- disease. In younger individuals, Huntington’s disease dence suggests that abnormal kinase activity may medi- (HD) sometimes presents with prominent parkinsonian ate dopamine cell death; a similar mechanism may be features (Chap. 25). Although parkinsonian features are operative in PARK6, resulting from mutations in PINK1 often present in AD, they occur late in the course and (Fig. 24-3). Other mutations with yet-to-be-identified are greatly outweighed by cognitive and behavioral dis- genes include PARK10, a late-onset PD susceptibility turbances (Chap. 23). In DLB the parkinsonian features gene.The identification of these and other mutations are are compounded by the early appearance of hallucina- proving invaluable in refining the correlation between tions and disturbances in arousal and behavior (Chap. 23). genotypes and phenotypes, in generating animal models Parkinsonism may also develop following exposure to to study pathogenesis, and in identifying target pathways certain neurotoxins such as carbon monoxide or for possible therapeutic intervention. manganese. MRI is useful in selected cases to rule out disorders such as normal pressure hydrocephalus, vascular PATHOGENESIS disease, or mass lesions. Positron emission tomography (PET) is helpful in confirming the diagnosis but cannot In PD, nigral dopamine neurons and other cells die reliably separate PD from the most common atypical from a combination of factors, including: (1) genetic forms. As yet, genetic screening has little place in general vulnerability (e.g., abnormal processing or folding of α- practice. synuclein; Fig. 24-3, steps i, ii); (2) oxidative stress (steps iv, v); (3) proteasomal dysfunction (step iii); (4) abnormal In evaluating individuals with PD, it is also important kinase activity (step vi); and (5) environmental factors, to rule out treatable conditions that may contribute to most of which have yet to be identified. the disability, such as B12 deficiency, hypothyroidism, testosterone deficiency, and vitamin D deficiency. Oxidative stress appears to play an important role in the sporadic forms of PD. Endogenous sources of oxida- At present the frequency of misdiagnosis is still tive stress include the free radicals produced by the 10–25% even in the best of hands.The differentiation of metabolism of dopamine and melanin. Additional stress sporadic (idiopathic) PD from atypical parkinsonism (see may come from defects in mitochondrial complex I of later) is often difficult, since early in their course these the oxidative phosphorylation chain.This defect has been atypical forms may meet diagnostic criteria for PD detected in platelets and muscle and in postmortem tis- (Table 24-3). Accordingly, it is important to watch for sue from the substantia nigra. Several agents have been the development of early imbalance, falls, and character- shown to cause oxidative toxicity and dopamine cell istic abnormalities of vertical gaze that suggest progressive death in animal models of PD, further strengthening the supranuclear palsy (PSP); and early urinary incontinence, above hypothesis. The most important of these are orthostatic hypotension, and dysarthria suggestive of MPTP, a meperidine derivative, and rotenone, a com- multiple system atrophy (MSA).The early appearance of monly used insecticide. Both cause oxidative damage by drug-induced hallucinations strongly favors the diagno- inhibiting complex I. In vitro, oxidative stress can lead to sis of DLB. As a rule, the different forms of atypical PD aggregation of α-synuclein and proteasomal dysfunction. can be reliably differentiated from sporadic PD within Proteasomal system abnormalities have also been the first 3–4 years of the illness. described in the substantia nigra from sporadic cases of PD. Other contributors to the selective dopamine neu- Treatment: ron degeneration in PD are abnormal phosphorylation PARKINSON’S DISEASE of proteins, microglial activation, low-grade inflamma- tion, and apoptosis; each represents a potential target for GENERAL CONSIDERATIONS The goals of therapeutic intervention. therapy in PD are to maintain function and quality of life and to avoid drug-induced complications. Bradykinesia, DIFFERENTIAL DIAGNOSIS AND tremor, rigidity, and abnormal posture respond well to SCREENING EVALUATION symptomatic therapy early in the course of the illness. In contrast, cognitive symptoms, hypophonia, autonomic Primary and secondary causes must be considered in the dysfunction, and imbalance tend to respond poorly. differential diagnosis of parkinsonism (Table 24-2). Primary motor disability in PD is often aggravated by Essential tremor (ET) is sometimes confused with rest secondary disability resulting from physical deconditioning tremor in PD, but the absence of other signs of parkin- following a sedentary lifestyle. Prevention of secondary sonism, the bilaterality, higher frequency (8–10 Hz), and disability requires a consistent program of physical postural dependency of ET help differentiate this exercise. Multiple open-label studies of exercise in PD from the rest tremor of PD (Chap. 25). In individuals

SECTION III Diseases of the Central Nervous System326 TABLE 24-2 DIFFERENTIAL DIAGNOSIS OF PARKINSONISM Primary Parkinsonism Genetically based PD (see Table 24-1) Idiopathic (“sporadic”) PD (most common form) Phenotype may be influenced by “vulnerability” genes and environmental factors Other neurodegenerative disorders Disorders associated with α-synuclein pathology Multiple system atrophies (glial and neuronal inclusions) Striatonigral degeneration Olivopontocerebellar atrophy Shy-Drager syndrome Motor neuron disease with PD features Dementia with Lewy bodies (cortical and brainstem neuronal inclusions) Disorders associated with primary tau pathology (“tauopathies”) Progressive supranuclear palsy Corticobasal degeneration Frontotemporal dementia Disorders associated with primary amyloid pathology (“amyloidopathies”) Alzheimer’s disease with parkinsonism Genetically mediated disorders with occasional parkinsonian features Wilson’s disease Hallervorden-Spatz disease Chédiak-Hagashi syndrome SCA-3 spinocerebellar ataxia X-linked dystonia-parkinsonism (DYT3) Fragile X premutation associated ataxia-tremor-parkinsonism syndrome Huntington’s disease (Westphalt variant) Prion disease Miscellaneous acquired conditions Vascular parkinsonism Normal pressure hydrocephalus Catatonia Cerebral palsy Secondary Parkinsonism Repeated head trauma (“Dementia pugilistica” with parkinsonian features) Infectious and postinfectious diseases Postencephalitic PD Neurosyphillis Metabolic conditions Hypoparathyroidism or pseudohypoparathyroidism with basal ganglia calcifications Non-Wilsonian hepatolenticular degeneration Drugs Neuroleptics (typical antipsychotics) Selected atypical antipsychotics (see text) Antiemetics (e.g., compazine, metoclopramide) Dopamine-depleting agents (reserpine, tetrabenazine) α-Methyldopa Lithium carbonate Valproic acid Fluoxetine Toxins 1-Methyl-1,2,4,6 tetrahydropyridine (MPTP) Manganese Cyanide Methanol Carbon monoxide Carbon disulfide Hexane

TABLE 24-3 As a general principle, patients should be treated as 327 soon as symptoms begin to interfere with function in HISTORY AND EXAMINATION FEATURES SUGGESTING any way. Most specialists now have a low threshold for DIAGNOSES OTHER THAN PARKINSON’S DISEASE initiating symptomatic therapy. The concern that symp- tomatic therapy should be delayed as long as possible SYMPTOMS/SIGNS ALTERNATIVE DIAGNOSIS since the available compounds are effective for only a TO CONSIDER limited number of years is unfounded. Early initiation of therapy is often necessary to maintain an adequate level History PSP of physical and mental activity. Another common con- CHAPTER 24 Parkinson’s Disease and Other Extrapyramidal Movement Disorders Drug-induced parkinsonism cern, that dyskinesias will develop sooner if levodopa is Falls as the first symptom If PD, think genetic causes introduced “too early,” is also unfounded. Recent studies Exposure to neuroleptics Wilson’s disease (see later) have shown that the risk of “troublesome Onset prior to 40 years dyskinesias” in patients receiving levodopa therapy (up Associated unexplained Lewy body dementia to 300 mg/d) appears to be considerably lower than Vascular parkinsonism previously reported. liver disease Early hallucinations Dementia with Lewy bodies A current priority is to move beyond symptom control Sudden onset of MSA-p to neuroprotective therapies. Unfortunately, no such MSA-c therapy is yet available. High doses of coenzyme Q10, oral parkinsonian symptoms Various Parkinson’s-plus creatine supplementation, intrastriatal infusion (or deliv- Physical Exam syndromes ery via viral vectors) of neurotrophic factors, and possibly Essential tremor the use of newer monoamine oxidase B (MAO-B) Dementia as first symptom inhibitors may hold promise in this regard and are under Prominent orthostasis investigation. In animal models of PD, forced exercise Early dysarthria (e.g., treadmill running) at moderate intensities appears Lack of tremor to promote neuroprotection in dopamine neurons. High frequency (8–10 Hz) symmetric tremor support the importance of regular activity; one controlled INITIATION OF THERAPY (Fig. 24-4) From a epidemiologic study revealed a hazard ratio of observed/ practical standpoint, dopaminomimetic therapy expected deaths during the 4-year observation period of (Table 24-4) should be initiated as soon as the patient’s 1.8 in patients who did not exercise compared to those symptoms begin to interfere with quality of life. The who did. Remaining mentally active is probably equally ideal first-line agent depends on the age and cognitive important for preservation of cognition in general. Dopamine Agonist or Levodopa/Carbidopa Inadequate Inadequate control control and wearing off Add levodopa/carbidopa Inadequate control and wearing off Levodopa/carbidopa Adjunct Therapy dosed more frequently For tremor: add anticholinergic or with higher dose For drug-induced dyskinesias: add amantadine Inadequate For freezing (“off”) episodes: add apomorphine control and wearing off Failed maximal Add COMT inhibitor or medical therapy add MAO-B inhibitor Consider surgical Failed options including DBS maximal medical therapy FIGURE 24-4 Treatment approaches to newly diagnosed idiopathic PD.

328 TABLE 24-4 LEVODOPA FORMULATIONS AND DOPAMINE AGONISTS USED IN PARKINSON’S DISEASE AGENTS LD DOSE AVAILABLE INITIAL DOSING COMMENTS EQUIVALENCY STRENGTHS (MG) Carbidopa/Levodopa (Typical Initial Strength) Carbidopa/levodopa 100 mg (levodopa 10/100 25/100; Usual range = 300–800 mg/d with IR 25/100 anchor dose) 25/100 0.5–1 tab tid typical schedules being q8h 25/250 to q3h. Carbidopa/levodopa 150 mg 25/100 50/200; 1 tab Increased bioavailability with food. CR 50/200 50/200 bid to tid Splitting the tablet negates the CR properties. Usual schedule is Carbidopa/levodopa/ 120 mg 12.5/50/200 25/100/200; q8h to q4h. entacapone 100 mg 25/100/200 1 tab bid to tid Do not split tablets. May combine 25/100/200 37.5/150/200 with Sinemet IR. Usual schedule Parcopa 25/100 25/100 25/250 25/100; 1 tab tid is q8h to q4h. Can be used as regular or SECTION III Diseases of the Central Nervous System supplemental rescue doses in cases of regular dose failure. Orally dissolved without water. Dopamine Agonists Approximate Target Doses DA EQUIVALENT AVAILABLE INITIAL MONOTHERAPY AS OTHER TO ABOVE LD STRENGTHS DOSING ADJUNCTS CONSIDERATIONS ANCHOR DOSE (MG) TO LD Non-ergot alkaloids 1 mg 0.125, 0.25, 0.125 mg 1.5–4.5 mg/d 0.375–3.0 Renal metabolism; dose Pramipexole mg/d adjustments needed in 5 mg 1, 1.5 tid renal insufficiency. Ropinirole 6–16 mg/d Occasionally associated Availability 0.25, 0.5, 0.25 mg 12–24 mg/d with “sleep attacks.” Ropinirole ex- pending. Hepatic metabolism; tended release 1, 2, 3, 4, 5 tid potential drug-drug Rotigotine interactions. Occasionally Ergot alkaloids associated with “sleep Bromocriptine attacks.” Pergolide 2, 4, 6 2 mg/24 h 6 mg/d 2–6 mg/d Available as transdermal Cabergoline patch. 2 mg 2.5, 5.0 1.25 mg 7.5–15 mg/d 3.75–7.5 Rare reports of bid to mg/d pulmonary and tid retroperitoneal fibrosis. Relative incidence of sleep attacks not well studied. Removed from U.S. market in 2007. See text. Used in select cases of PD in Europe. Not approved for the treatment of PD in the U.S. Note: Equivalency doses are approximations based on clinical experience, may not be accurate in individual patients, and are not intended to correlate with the in vitro binding affinities of these compounds. DA, dopamine agonist; IR, immediate release; CR, controlled release; LD, levodopa (with carbidopa). Carbidopa/levodopa/entacapone = Stalevo. status of the patient and, to a lesser extent, the patient’s agonists is well tolerated and significantly improves clinical type and finances. The choices consist of either, a motor function and disability. Using this approach, dopamine agonist, a levodopa preparation, or one of the patients experience ~50% lower risk of dyskinesias and MAO-B inhibitors. Controlled studies support the view 25% lower risk of motor fluctuations compared to that, in early PD, monotherapy with any of the dopamine levodopa-treated patients. This difference lasts as long

as the patient remains on monotherapy. Once a Dopamine Agonists Dopamine agonists readily 329 levodopa preparation is added, dyskinesias and motor cross the blood-brain barrier and act directly on fluctuations begin to emerge, suggesting that dopamine postsynaptic dopamine receptors (primarily D2 type). CHAPTER 24 Parkinson’s Disease and Other Extrapyramidal Movement Disorders agonists delay the onset but do not prevent the Compared to levodopa, they are longer-acting and thus development of these problems. In fact, about two-thirds provide a more uniform stimulation of dopamine of patients on agonist monotherapy require levodopa receptors. They are effective as monotherapeutic agents therapy by year 5 in order to maintain motor function. and as adjuncts to carbidopa/levodopa therapy. They can also be used in combination with anticholinergics Motor fluctuations, also known as “on-off” phenom- and amantadine. Table 24-4 provides a guide to the ena, are the exaggerated ebb and flow of parkinsonian doses and uses of these agents. signs experienced by many patients between doses of antiparkinsonian medications. Dyskinesias refer to chor- Available agents for PD include three non-ergot eiform and dystonic movements that can occur as a alkaloids—pramipexole, ropinirole, and, more recently, peak dose effect or at the beginning or end of the dose rotigotine—plus the ergot alkaloids bromocriptine, (diphasic dyskinesias). More than 50% of patients with cabergoline, and lisuride (the latter two only in Europe). PD treated over 5 years with levodopa will develop Pergolide is a dopamine agonist recently removed from these complications. the U.S. market due to its association with asympto- matic valvular heart disease in 28% of patients treated Successful dopamine agonist monotherapy requires chronically. The incidence of symptomatic valvular dis- a higher dose of the agonist than is typically needed ease is far lower, perhaps as low as <1%. Nonetheless, when the agonist is used to supplement levodopa patients currently on pergolide need to be transferred (Table 24-4). In both cases, titration has to be slow and to alternative therapy, perhaps equivalent doses of non- cautious to avoid unnecessary side effects. Patients ergot dopamine agonists (Table 24-4). The dose equiva- benefit greatly from education and support during this lency of pergolide is ~1:1 with pramipexole. titration. Most patients will require the addition of levodopa or another agent within 1–3 years of initiating Subcutaneous injectable apomorphine is approved dopamine agonist monotherapy. Preclinical studies in the United States as a “rescue therapy” for dose failure suggest that the advantages of dopamine agonist (usually due to erratic gastric emptying), motor fluctua- monotherapy can be maintained with agonist- tions, and especially for the debilitating “off” spells that dominant therapy. In this case, dopamine agonists con- affect many patients with moderate to advanced dis- tinue to provide the bulk of dopaminomimetic therapy, ease. Finally, sumanirole is another potent experimental with levodopa playing a supplementary role. dopamine agonist that in a recent controlled study proved to be comparable in efficacy to ropinirole and Although dopamine agonist monotherapy is consid- better tolerated. ered the initial treatment of choice for most patients with PD, the long-term benefits noted above must be A long-acting formulation of ropinirole and a trans- balanced against a higher incidence of non-motor side dermal patch delivery system of rotigotine will soon be effects and a slightly higher level of motor disability approved for use in PD. Based on pharmacokinetic data, than with levodopa. These recommendations may need these formulations can achieve levels of continuous to be modified in patients with psychotic symptoms, dopaminergic stimulation that are closer to those behavioral disturbances, or severe daytime sleep distur- achieved with subcutaneous infusions of apomorphine bances. Older patients and those with akinetic rigid (not available in the United States). In comparison with forms of PD have a lower risk of motor complications oral dopaminomimetics, infusion therapy has proved and dyskinesias compared to the average PD patient superior at controlling motor fluctuations and reducing and may be satisfactorily treated with levodopa. dyskinesias over time. The convenience of these new formulations should overcome the major limitation of PHARMACOTHERAPY OF MOTOR SYMPTOMS infusions: cost and site reactions. Experience with the The above practices in the initiation of therapy patch delivery system thus far indicates that it is safe notwithstanding, levodopa remains the most effective and well tolerated except for occasional skin reactions treatment for PD. It significantly improves motor symptoms to the adhesive. and increases quality of life and independence.The aim of all dopaminomimetic strategies is to restore dopamine Dopamine agonists have been approved for the transmission in the striatum. This is accomplished by treatment of PD at every stage of disease and in combi- stimulating postsynaptic receptors (directly with dopamine nation with other antiparkinsonian agents; however, the agonists), increasing dopamine precursor availability use of two dopamine agonists simultaneously cannot (levodopa), blocking the metabolism of levodopa in the be recommended. Agonists are particularly effective in periphery and in the brain, and blocking the catabolism treating bradykinesia, loss of fine motor dexterity, of dopamine at the synapse. tremor, and gait disturbances. When used as monother- apy, they are less effective than levodopa-based

SECTION III Diseases of the Central Nervous System330 formulations. Accordingly, it is imperative to titrate the controlled study oral administration of etilevodopa (with carbidopa) proved no different from oral car- dose as needed to control motor function; the maxi- bidopa/levodopa with respect to mean dose require- mum dose provided in titration packs may be insuffi- ments, treatment failures, and hours of daily “off” time. cient in some patients. As the dose is escalated it is equally important to remain vigilant to potential dose- Levodopa Augmentation Strategies A number dependent side effects, particularly when combining of drugs can augment dopamine transmission by these drugs with carbidopa/levodopa and psychotropics. blocking the breakdown of dopamine at the level of the synapse. Side effects of dopamine agonists include nausea, postural hypotension, psychiatric symptoms, daytime MAO-B Inhibitors These are selective and irreversible sedation, and occasional sleep attacks. These can be inhibitors of the catabolic breakdown of dopamine; managed by decreasing the dose; by decreasing con- they work by inhibiting MAO-B at the synapse. These comitant medication with similar side effects; or, in the compounds offer a modest symptomatic motor benefit case of nausea, by the introduction of peripheral when used as monotherapy and enhance the efficacy of dopamine blockers such as domperidone (not available carbidopa/levodopa formulations when used as adjuncts. in the United States) or a short course of trimethobenza- Their potential additional role as neuroprotective agents mide or dronabinol until the patient develops tolerance remains unproven. Unlike patients taking unselective or to these symptoms. Patients should be cautioned about MAO-A inhibitors who are subject to hypertensive crises the potential for sleep attacks associated with from consumption of large doses of tyramine (the amino dopamine agonists (and to a lesser extent with car- acid precursor of norepinephrine), patients taking MAO-B bidopa/levodopa). These can occur without warning inhibitors do not require dietary tyramine restrictions. and have resulted in traffic accidents. When used as At the approved doses, rasagiline and oral zydis selegiline adjuncts to levodopa therapy, dopamine agonists can (i.e., orally disintegrating) carry little risk of a hypertensive aggravate dyskinesias if the doses of carbidopa/ complication. levodopa are not adjusted accordingly. Furthermore, dopamine agonists are more expensive than carbidopa/ Selegiline, a selective MAO-B inhibitor, was approved levodopa, which is now available in generic form. in 1989 for the treatment of PD. As monotherapy, it has a Dopamine agonist–induced impulse control disorders small symptomatic effect. As an adjunct to levodopa (pathologic gambling, etc.) are discussed earlier under therapy, it increases “on” time while reducing motor fluc- Neuropsychiatric Symptoms. tuations; the dose is 5 mg with breakfast and lunch. A significant side effect of selegiline is insomnia, probably Carbidopa/Levodopa Formulations Carbidopa/ due to an amphetamine-like metabolite. levodopa is available in regular, immediate release (IR) formulations (Sinemet, Atamet, and others; 10/100 mg, In 2006, two additional, more potent MAO-B inhibitors 25/100 mg, and 25/250 mg), controlled release (CR) with once-daily dosing were introduced for the treat- formulations (Sinemet CR 25/100 mg, 50/200 mg), or ment of PD. Rasagiline was approved for use as initial more recently as Stalevo (Table 24-4).The latter combines monotherapy and as adjunctive therapy. It is metabo- variable doses of IR-carbidopa/levodopa (12.5/50, 25/100, lized to an aminoindan metabolite that lacks the 37.5/150) with 200 mg of entacapone (see later). In most amphetamine-like properties of selegiline. As monother- individuals, at least 75 mg/d of carbidopa is necessary to apy in treatment-naïve patients it improves motor func- block the peripheral decarboxylation of levodopa to tion compared to placebo, and as an adjunct it increases dopamine, and to limit the symptoms of nausea and daily “on” time by about 1.8 h. The usual dose is 0.5–1 orthostasis associated with initiation of therapy. Initial mg/d. A recent trial suggested that rasagiline may alter target doses of these medications are summarized in the course of the disease (i.e. provide benefit other than Table 24-4. Individualized dosing and gradual dose symptomatic treatment), but this will need to be con- escalation is recommended.Initiation of dosing at mealtimes firmed as the trial demonstrated this effect for only one will reduce the incidence and severity of nausea. As of two doses tested. patients develop tolerance to nausea and other side effects, these medications can be administered on an Zydis selegiline is an orally disintegrating, freeze- empty stomach, which generally leads to a more brisk and dried tablet that is absorbed through the oral mucosa; predictable absorption. this results in higher levels of selegiline and lower levels of the plasma amphetamine-like metabolites compared Etilevodopa, the ethyl-ester pro-drug of levodopa, with the usual oral route. Its usual dose is 1.25–2.5 mg/d has greater solubility than levodopa in the stomach and in the morning. In a 2004 controlled study, Zydis selegi- a more rapid transit time to the duodenum, where it line in patients with PD and motor fluctuations is quickly absorbed after being hydrolyzed to levodopa. increased dyskinesias-free “on” time by 1–1.5 h/d in In spite of these pharmacokinetic advantages, in a comparison with placebo.

Although these compounds are generally well toler- a mechanism thought responsible for reducing drug- 331 ated, side effects include dose-dependent nausea, dys- induced dyskinesias. The side effects of amantadine are pepsia, dizziness, insomnia, dyskinesias, orthostatic nausea, headaches, edema, erythema, and livedo reticularis. hypotension, confusion, and hallucinations. They should In older patients, it may aggravate confusion and psychosis. not be used with meperidine, tramadol, methadone, or Doses need to be decreased in patients with renal propoxyphene. Rarely, a hyperserotonergic syndrome insufficiency. may result from use in combination with tricyclic antide- pressants (TCAs) and selective serotonin reuptake THERAPY OF NON-MOTOR SYMPTOMS CHAPTER 24 Parkinson’s Disease and Other Extrapyramidal Movement Disorders inhibitors (SSRIs). This syndrome is characterized by anx- Patients with frequent nighttime awakenings due to iety, tremulousness, myoclonus, and alterations in men- nocturnal akinesia or tremor can be treated with tal status. Although the risk of this complication in PD supplemental doses of carbidopa/levodopa at night. appears to be small at the approved doses, it is judicious A bedtime dose of a dopamine agonist helps restless to remain vigilant to these possible side effects until leg symptoms and urinary urgency.Treatment of bladder more Phase IV safety information is available. In the symptoms will improve sleep in many elderly patients interim, the lower dose of these compounds should be with PD. Depression typically responds to antidepressants considered in older individuals with active cardiac dis- (either TCAs or SSRIs). As discussed earlier, the combination ease, or in those who are prescribed concomitant anti- of SSRIs and selegiline carries an exceedingly low depressant drugs. risk of a hyperserotonergic syndrome (delirium with myoclonus and hyperpyrexia). Electroconvulsive therapy COMT Inhibitors The catechol-O-methyltransferase (ECT) is highly effective in drug-refractory cases or in (COMT) inhibitors entacapone and tolcapone offer yet patients intolerant of oral antidepressants. There are another strategy to augment the effects of levodopa by several reports indicating that ECT also has short-term blocking the enzymatic degradation of levodopa and benefit for parkinsonian motor symptoms. dopamine. Entacapone is preferred to tolcapone because of the low but potentially serious incidence of In patients with psychotic symptoms or confusion, hepatic and hematologic side effects of the latter. When anticholinergics and amantadine should be eliminated used in conjunction with carbidopa/levodopa, these first. Following this, MAO-B inhibitors and dopamine agents increase the plasma levodopa levels by >30% agonists should be reduced or discontinued as needed and alleviate wearing-off symptoms. Entacaprone (200 to control symptoms. This should be followed by grad- mg with each dose of carbidopa/levodopa) increases ual reductions as needed in nocturnal and then daytime “on” time by <1 h/d, whereas tolcapone (100–200 mg doses of Sinemet CR, and finally carbidopa/levodopa. If tid) increases “on” time by about 1.8 h/d. the patient improves after only a modest reduction of antiparkinsonian therapy, the overall impact on the The more common side effects are gastrointestinal parkinsonian motor symptoms may be negligible. If in and hyperdopaminergic, including sleep disturbances the process parkinsonian symptoms worsen, most spe- and increased dyskinesias that may require reductions cialists initiate treatment with an atypical antipsychotic in the dose of carbidopa/levodopa. Hyperdopaminergic that has a low incidence of extrapyramidal side effects symptoms can be managed with appropriate decreases rather than continuing to lower dopaminomimetic ther- in the dose of other dopaminomimetics. Tolcapone can apy. Clozapine (12.5–100 mg/d) is the best established be associated with a dose-dependent increase in agent for treatment of psychotic symptoms in PD. Queti- hepatic aminotransferase levels in 1–3% of cases and apine (12.5–100 mg) is sometimes used first because it rare instances of acute fulminant liver failure. ALT/AST lacks the small risk of agranulocytosis associated with levels should be monitored every 2–4 weeks for the first clozapine. Both are dosed at night to promote sleep and 6 months and periodically thereafter. Tolcapone should minimize daytime sedation and orthostasis. Their use not be used in patients with preexisting liver disease and that of all antipsychotics in PD are limited by dose- and should be discontinued if the ALT/AST levels exceed dependent sedation, orthostatic hypotension, dizziness, two times the upper limit of normal. and confusion. Other atypical antipsychotics such as risperidone, olanzapine, and, more recently, aripiprazole Other Well-Established Agents Anticholinergics are not well tolerated by most patients with PD due to a and amantadine are appropriate adjuncts to dopamino- higher incidence of drug-induced parkinsonism (DIP) mimetic therapy. Anticholinergics are particularly useful and akathisia. for controlling rest tremor and dystonia, and amantadine can reduce drug-induced dyskinesias by up to 70%. The Centrally acting acetylcholinesterase inhibitors can mechanisms of action of amantadine are unknown, improve dementia symptoms in PD, providing the although there is evidence it has both anticholinergic and same stabilization of cognitive decline noted in AD. dopaminomimetic properties. Recently amantadine has Rivastigmine is approved by the Food and Drug Admin- been shown to have weak glutamate antagonist properties, istration for the treatment of dementia in PD, and