Section V: Neurologic & Neurosurgical Disorders

OBJECTIVES

PREVALENCE & BURDEN

Cerebrovascular diseases represent a heterogeneous class of disorders affecting the central nervous system including ischemic and hemorrhagic strokes, cerebral venous thrombosis, aneurysms, and vascular malformations. These disorders are frequently associated with high morbidity and mortality. Fortunately, advances in diagnostic and therapeutic options for cerebrovascular diseases have led to improved clinical outcomes for many of these conditions.

Cerebrovascular diseases now represent the fifth leading cause of death in the United States. Approximately 3% of adults have experienced a clinical stroke; however, the incidence of subclinical or “silent” strokes is likely much higher. Nearly 795,000 strokes occur annually in the United States, of which approximately 610,000 are first-time strokes and 185,000 are recurrent attacks. It is estimated that someone has a stroke every 40 seconds. The highest incidence and mortality rates are seen in the southeastern states (termed the “Stroke Belt”) and among racial and ethnic minorities. As the population ages, it is expected that the number of incident strokes will more than double in the coming decades, especially among patients age ≥75 years. Despite the declining incidence and mortality of stroke, the global burden of stroke is increasing, particularly in low- and middle-income countries.

CEREBROVASCULAR LOCALIZATION

Clinical localization is perhaps no better demonstrated than in cerebrovascular diseases. Medical students frequently encounter their first opportunity to “localize a lesion” when evaluating a stroke patient. In addition to determining what level of the neuroaxis or which lobes of the brain are affected, symptoms of cerebrovascular disease can frequently be localized by vascular territories. For example, in a patient with right hemiparesis and hemianesthesia affecting the face and arm, coupled with aphasia, one can say that the frontal, parietal, and temporal lobes are affected in the left hemisphere. Knowledge of the homunculus will further localize the motor and sensory deficits to the lateral aspect of the hemisphere. Taken together, it becomes apparent that all of the affected areas fall within the left middle cerebral artery (MCA) territory. When a cerebrovascular disorder appears on the differential diagnosis for a patient, it is important to consider not only the anatomic localization but also the vascular localization for the symptoms.

ISCHEMIC STROKE

Among all strokes, approximately 80% to 85% are categorized as ischemic strokes. Ischemic strokes occur when a blood vessel becomes blocked, depriving a region of the brain of oxygen and glucose. Fortunately, reperfusion options are available for some ischemic stroke patients that have the potential to reverse stroke symptoms and improve functional outcomes.

Pathophysiology

Cellular Changes in Ischemia

Although the brain represents <5% of total body weight, it is responsible for 20% to 25% of energy consumption. Approximately 20% of total cardiac output is directed to the brain. Since the brain has essentially no intrinsic energy stores, even brief disruptions in cerebral blood flow (CBF) can have devastating consequences.

Normal CBF in an adult is approximately 50 mL/100 g/min. As CBF falls, protein synthesis fails and cells shift toward anaerobic glycolysis. Below 20 mL/100 g/min, neuronal electrical activity starts to fail, which usually correlates with the onset of neurologic symptoms. With further decline in CBF, cellular membranes cannot maintain their gradient and cell death ensues unless reperfusion is quickly restored. Electrical failure leads to activation of a variety of cellular cascades (eg, release of excitatory amino acids, depletion of adenosine triphosphate, activation of proteolytic processes) that ultimately result in cell death via both necrotic and apoptotic pathways. Cell survival is determined by the severity and duration of CBF reduction. Because of collateral blood flow, variable degrees of ischemia exist within an infarct. While the central core of an ischemic stroke may have irreversible cellular injury, the surrounding tissue (termed the penumbra) may have higher CBF, which is potentially salvageable if perfusion is restored.

In the days following irreversible tissue injury, infarcted tissue will become edematous with eosinophilic, pyknotic neurons (“red dead neurons”; Figure 24–1). In the ensuing days, an inflammatory response develops, initially marked by an influx of mononuclear cells that phagocytize dying cells. Subsequently, macrophages predominate after the first 24 to 48 hours, and astrocytes start to proliferate, laying down a network of glial fibers. Ultimately, liquefactive necrosis develops, and the region of the infarct is left as a cavity with a surrounding glial scar.

Cerebral Perfusion & Autoregulation

Cerebral perfusion pressure (CPP) is defined as the mean arterial pressure (MAP) minus the intracranial pressure (ICP). Because the brain is highly sensitive to fluctuations in CBF, there are mechanisms in place to protect it from variations in systemic MAP. This is principally achieved through modulation in vascular resistance, which occurs by varying the diameter of cerebral blood vessels, primarily arterioles. Because CBF is proportional to CPP but varies inversely to cerebral vascular resistance (CVR), the brain is able to maintain a fairly constant CBF despite fluctuations in perfusion pressure. This protective mechanism is known as autoregulation.

Under physiologic conditions, autoregulation allows the brain to maintain stable blood flow over a wide range of perfusion pressure (Figure 24–2). In patients who are chronically hypertensive, this curve shifts to the right. It may not be safe to acutely lower their blood pressure because they may drop below the lower threshold of autoregulation and have a drop in their CBF. Because many stroke patients have chronic hypertension, physicians have to be extremely careful about acutely lowering patients’ blood pressure and causing further ischemic damage by worsening cerebral perfusion.

Mechanisms of Ischemia

Cerebral ischemia can typically be broken down into 3 primary pathophysiologic mechanisms: thrombosis, embolism, and hypoperfusion. The goal of acute stroke evaluation is to determine this mechanism to guide appropriate long-term treatment strategies.

Thrombosis

Thrombosis refers to the occlusion of a vessel as a consequence of a local vascular process. Formation of a local thrombus may cause cerebral ischemia by reducing blood flow distal to the thrombotic plaque or fragmentation of the plaque causing an artery-to-artery embolism. Acute occlusion may also occur when platelets adhere to an ulcerated plaque, locally occluding the vessel lumen. Thrombotic mechanisms are commonly divided into large- and small-vessel subtypes.

Large-vessel disease may affect the major precerebral vessels (carotid and vertebral arteries) or the vessel comprising and emanating from the circle of Willis. The most common cause of large-vessel pathology is atherosclerosis. Atherosclerotic plaques typically develop in regions of turbulent blood flow, particularly in close proximity to vascular bifurcations, such as the origin of the internal carotid artery (Figure 24–3). Less common large-vessel pathologies include arterial dissections, vasculitides, vasospasm/vasoconstriction, and arteriopathies such as fibromuscular dysplasia or moyamoya syndrome. Patients may present with 1 or more infarcts confined within a specific vascular territory. Knowledge of clinical syndromes attributable to each vascular bed is useful to diagnose a large-vessel infarct (eg, a dominant MCA territory infarct will cause motor and sensory deficits of the contralateral arm and leg, contralateral visual field impairment, and aphasia). Depending on hemodynamic fluctuation relative to the stenosis, patients may have stroke symptoms that progress with a stuttering time course that may evolve over minutes to hours.

Small-vessel infarcts (commonly referred to as lacunar strokes or “lacunes”) are <1.5 cm in diameter and occur in the basal ganglia, thalamus, brainstem, or cerebellum. These regions of the brain are supplied by small, penetrating blood vessels that arise from large parent vessels such as the MCA. Hypertension and diabetes mellitus are particularly strong risk factors for this stroke subtype. Through a pathologic process called lipohyalinosis, these small vessels develop vascular wall thickening and endothelial dysfunction, which results in a reduction of the luminal diameter. A less common mechanism for the development of small-vessel occlusion is when a microatheroma in the parent vessel grows over the origin of the small vessel, causing proximal occlusion. Despite their small size, lacunar strokes can present with significant neurologic deficits due to the fact that they occur in regions of the brain densely populated by motor and sensory pathways. Several characteristic clinical syndromes that may assist in the diagnosis of a lacunar stroke have been described (Table 24–1). Patients typically present with symptoms that evolve over minutes to hours, and worsening of symptoms after initial presentation is not uncommon.

Embolism

Embolic strokes occur when a clot (or other material) formed in another part of the body travels to the brain and occludes a vessel. Emboli frequently arise from cardiac sources. A common embolic etiology is atrial fibrillation, which may cause clots to form in the left atrium or left atrial appendage. Valvular disease, ventricular mural thrombus following myocardial infarction, atrial myxoma, and endocarditis are additional cardiac sources of emboli. In patients with a patent foramen ovale or other cardiac wall defects, systemic emboli may shunt from the right to the left heart, bypass the lungs, and pass into the cerebral circulation. Other systemic sources of emboli include fat (long bone fractures), air (typically iatrogenic), and amniotic fluid. Clinically, embolic strokes may be small or large depending on the size of vascular bed occluded. Unlike thrombotic strokes, emboli may shower to several blood vessels, causing infarcts in multiple vascular territories simultaneously. Neurologic deficits from embolic strokes reach maximum intensity relatively abruptly, as opposed to the stuttering course that may be seen with thrombotic stroke mechanisms.

Hypoperfusion

Like other end organs, the brain is vulnerable to systemic hypoperfusion. This may occur in the setting of blood loss, systemic hypotension (eg, sepsis), or reduced cardiac output from acute heart failure or pulmonary embolism. Neurologic deficits tend to be more diffuse but preferentially affect the arterial border zone (watershed) regions of the brain, which are the boundaries between major vascular territories. Clinically, this may produce symptoms such as cortical blindness and proximal limb weakness (the arterial border zone corresponds to these areas on the homunculus). In addition to neurologic deficits, patient typically have other systemic signs of hemodynamic dysfunction.

Other Ischemic Stroke Mechanisms

Less common ischemic stroke mechanisms include hypercoagulable states and genetic conditions. Coagulation disorders more commonly cause venous thrombosis, although some conditions such as antiphospholipid syndrome may be associated with arterial events. Sickle cell disease, essential thrombocytosis, and polycythemia vera are other examples of hematologic conditions associated with ischemic stroke. Pregnancy, malignancy, and systemic inflammatory conditions such as human immunodeficiency virus (HIV) and ulcerative colitis may induce a prothrombotic state. Stroke may be seen as a late effect in genetic conditions such as Down syndrome but can also be a defining feature in genetic diseases such as CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Clinicians should consider hypercoagulable or genetic conditions in stroke patients who are under the age of 55 years, patients without vascular risk factors, and patients with a strong family history of stroke or thrombotic events.

Cryptogenic Stroke

Despite thorough diagnostic evaluations, a defined etiology is not determined in 20% to 40% of ischemic stroke patients. These patients are termed cryptogenic. This represents a heterogeneous class of patients, although many have an embolic pattern on neuroimaging. As new diagnostic tools emerge and sensitivity of existing modalities improves, it is likely that many of these patients will be able to have a stroke etiology determined. For example, the increased utilization of prolonged cardiac monitoring (>30 days) has identified paroxysmal atrial fibrillation as a common and important mechanism in cryptogenic stroke patients.

Ischemic Stroke Risk Factors

Risk factors are patient attributes and medical conditions that increase an individual’s risk of having an ischemic stroke. It is important to differentiate stroke risk factors from stroke mechanisms (described in the previous section), which are the pathophysiologic processes that result in impairment of CBF. Risk factors can be classified as modifiable and nonmodifiable.

Age is a significant nonmodifiable risk factor for stroke, with the risk of stroke doubling for each decade beyond the age of 55. As the population ages, it is expected that the proportion of stroke patients >75 years old is going to double by the year 2050. Men are at higher risk of stroke compared to women, although this difference is less pronounced in young patients. Race and ethnicity are also important nonmodifiable risk factors, with African Americans being at higher risk than whites. Finally, a family history of stroke, particularly among first-degree relatives, increases stroke risk. There are likely many additional genetic factors that shape an individual’s risk of stroke that remain poorly understood.

Numerous modifiable risk factors for stroke have been identified, although their relative contribution may differ among the ischemic stroke subtypes. Identification of these risk factors is imperative in the determination of an appropriate long-term treatment strategy for each patient. By far, hypertension is the most significant modifiable risk factor and is present in nearly 80% of ischemic stroke patients. Diabetes, dyslipidemia, cardiac disease (coronary artery disease, atrial fibrillation, congestive heart failure), and obstructive sleep apnea are also commonly encountered and contribute to stroke risk. Migraine, particularly among those who experience aura, has been shown to be associated with increased stroke risk, although the exact mechanism remains unclear. Several lifestyle risk factors, including tobacco abuse, excessive alcohol consumption, illicit drug use, diet, and physical inactivity, should also be addressed with each stroke patient and factored into their treatment plan.

Clinical Presentation of Ischemic Stroke

Ischemic stroke typically presents with the acute onset of focal neurologic deficits. Depending on the stroke subtype, symptoms may evolve over minutes to a few hours. Neurologic deficits frequently occur without warning or prodromal symptoms. Common symptoms include focal weakness, focal numbness, visual field defects, aphasia, dysarthria, and coordination deficits. Although some patients may present with 1 of these symptoms in isolation, more commonly patients have a combination of several neurologic deficits. Alterations in level of consciousness are not common with solitary infarcts within the cerebral hemispheres but may be seen with bihemispheric or brainstem strokes. Headache may also be reported but is more common with intracerebral hemorrhages than ischemic strokes.

As arterial anatomy does not vary substantially between patients, infarcts of vascular territories have characteristic constellations of symptoms that can be useful in clinical localization. Anterior cerebral artery territory infarctions cause weakness and numbness of the contralateral lower extremity and may also be accompanied by gait apraxia, mutism, reduced motivation, and urinary incontinence. MCA territory infarcts cause contralateral face and arm weakness and numbness, gaze deviation toward the side of the stroke (from impairment of the frontal eye fields), and contralateral visual field defects (from impairment of the optic radiations). Patients with dominant MCA infarcts may also have varying degrees of aphasia, whereas those with nondominant MCA infarcts may have hemineglect. Infarctions of the posterior cerebral artery (PCA) produce contralateral visual field defects. Because the thalamus also receives blood supply from perforators of the PCA, contralateral sensory deficits may be found on examination. Strokes involving the posterior circulation tend to be less stereotyped but commonly involve motor and sensory deficits as well as cranial nerve impairments. Cerebellar symptoms may also be seen with posterior circulation infarctions.

Acute Diagnosis & Management

After initial stabilization, a focused history should be performed with emphasis on determining the definitive time of symptom onset. In some cases, this time cannot be determined, and the “last known normal” time should be established. Symptom progression, presence of seizure symptoms, current medications (particularly antithrombotics), and known vascular risk factors should also be collected in the history. In many cases, it is necessary to gather information from family members or bystanders. Acutely, it is generally not possible to do a full general examination, although attention should be given to cardiovascular exam to assess for arrhythmias, bruits, or murmurs. The neurologic exam is also abbreviated acutely to allow for determination of significant neurologic deficits without causing delays in acute treatment decisions. Scales such as the National Institutes of Health Stroke Scale (NIHSS) are commonly used to guide a standardized, rapid neurologic assessment and facilitate communication of stroke severity between healthcare providers.

Given the potential for hypoglycemia to mimic a stroke, it is important to check a serum glucose level on any patient with stroke symptoms. Serum electrolytes, blood cell count, cardiac enzymes, and a coagulation profile should also be ordered. The preferred initial neuroimaging study in the acute setting is a noncontrasted computed tomography (CT) scan of the head. CT has a high sensitivity for intracerebral hemorrhage, which is necessary to exclude as the cause of the patient’s symptoms when considering acute reperfusion therapies. Radiographic evidence of ischemia may not be apparent on CT for several hours. The earliest findings may be blurring of the gray-white junction, local edema leading to sulcal effacement, and hypodensity of the infarcted brain tissue (Figure 24–4). Although cerebral blood vessels are generally not visible on a noncontrasted CT, occasionally an acutely thrombosed vessel will appear bright (hyperdense vessel sign) and signifies a large-vessel occlusion. Increasing emphasis is being placed on obtaining vascular imaging during the acute evaluation of ischemic stroke to help identify patients with large-vessel occlusion who may be amenable to endovascular thrombectomy.

Once the patient has been stabilized and the initial evaluation is complete, the patient can be evaluated for acute reperfusion therapies. Currently, intravenous (IV) tissue plasminogen activator (tPA; alteplase) is the only US Food and Drug Administration–approved medical treatment for acute ischemic stroke. This drug catalyzes the conversion of plasminogen to plasmin, which promotes fibrinolysis. It is administered as a weight-based dose with 10% given as an IV bolus followed by a slow infusion of the remainder over the course of an hour. Many inclusion and exclusion criteria must be considered, however. The primary inclusion criteria include clinical diagnosis of ischemic stroke resulting in disabling neurologic deficits. Patients with any hemorrhage on their CT scan should not receive IV-tPA. Other major contraindications include history of bleeding disorders or coagulopathy; recent surgery or trauma; uncontrolled blood pressure; active bleeding; thrombocytopenia; elevated prothrombin time (PT), partial thromboplastin time (PTT), or international normalized ratio (INR); or significant ischemic changes on the initial CT scan. IV-tPA is a time-sensitive medication and must be administered within 3 hours from onset of symptoms (up to 4.5 hours in select patients, although this is considered off-label). Patients who receive IV-tPA are significantly more likely to have minimal or no neurologic deficit at 3 months compared to patients who receive placebo, but are at a higher risk of symptomatic intracerebral hemorrhage. Unfortunately, despite increases in public awareness, many patients do not arrive at a hospital within the treatment window, and nationwide, IV-tPA treatment rates are <10%.

Recently, several randomized trials demonstrated benefit for endovascular thrombectomy in acute ischemic stroke patients with large-vessel occlusion. Although endovascular procedures have been investigated since the late 1990s, older interventional devices have not been shown to be more efficacious than IV-tPA alone. The latest classes of mechanical thrombectomy devices have been shown to produce higher recanalization rates and better clinical outcomes compared to IV-tPA alone. It should be noted that these interventions should be viewed as adjunctive therapies to IV-tPA rather than substitutes. Current guidelines recommend consideration of endovascular thrombectomy in patients with evidence of large-vessel occlusion who can be treated within symptom onset. Recently, several clinical trials have shown that multimodal imaging such as CT perfusion studies can be used to select patients up to 24 hours from last known normal. Like IV-tPA, intracerebral hemorrhage remains the biggest safety concern.

Diagnostic Studies to Determine Stroke Mechanism

After initial evaluation, stroke patients are admitted to the hospital for further diagnostic studies to determine their stroke mechanism. Each patient should be screened for vascular risk factors including testing for diabetes and lipid profiles. Each patient should then undergo brain parenchymal imaging and vascular imaging. Unless contraindicated, magnetic resonance imaging (MRI) is the preferred parenchymal imaging modality because it clearly defines the size and extent of the infarct (Figure 24–5). CT or magnetic resonance angiography provides imaging of the intra- and extracranial vessels to identify sites of occlusion or stenosis as well as other patterns of vascular irregularity such as fibromuscular dysplasia or vasculitis (Figure 24–6). Ultrasonography is another noninvasive imaging modality commonly used to assess the extracranial carotid artery. Although catheter cerebral angiography is viewed as the “gold standard” vascular imaging test, it is reserved for patients needing better definition of vascular anatomy given the potential risks of the procedure. Finally, each patient should undergo a cardiac evaluation including cardiac rhythm monitoring and cardiac enzyme assessment. Although not required for all patients, most should have an echocardiogram to assess for intracardiac thrombi, wall motion abnormalities, and valvular disease. In patients in whom an occult arrhythmia is suspected, prolonged outpatient cardiac monitoring can be pursued. Hypercoagulability assays should be considered in patients with otherwise negative evaluations, particularly young patients without vascular risk factors. Taken together, these tests will allow the clinician to develop an understanding of the likely pathophysiologic mechanism that will guide selection of secondary stroke prevention strategies.

Secondary Stroke Prevention

Long-term prevention of recurrent ischemic stroke generally consists of antithrombotic agents, statin therapy, and risk factor modification. For most pathophysiologic mechanisms of ischemic stroke, antiplatelet agents, such as aspirin or clopidogrel, are preferred over anticoagulation. The exception to this is ischemic stroke secondary to atrial fibrillation where oral anticoagulants have been demonstrated to be superior to antiplatelet therapy. Unless medically contraindicated, ischemic stroke patients should also be placed on high-dose statin therapy. The benefits of statins likely result from numerous properties beyond the lipid-lowering effects, such as plaque stabilization and anti-inflammatory properties. Effective treatment strategies should be developed to modify each individual’s vascular risk factors including promoting healthy lifestyle choices. Finally, for patients with carotid artery stenosis >50%, revascularization procedures should be considered such as endarterectomy or stenting. No benefit has been seen with revascularization of major vessels other than the extracranial carotid artery.

INTRACEREBRAL HEMORRHAGE

Intracerebral hemorrhages are the second most common type of stroke, accounting for about 15% to 20% of all strokes. They are associated with higher morbidity and mortality compared to ischemic strokes. These hemorrhages can be classified based on their location within the cranium, each with different underlying pathophysiology and treatment strategies.

Classification & Pathophysiology

Classification of Intracranial Hemorrhage

Hemorrhages within the cranium can be classified according to the anatomic space that they occupy. Epidural hemorrhages occur between the calvarium and the dura matter and most commonly result from traumatic injury to the middle meningeal artery. Subdural hemorrhages occur between the dura and arachnoid meningeal layers and are typically related to rupture of bridging veins. Hemorrhages within the subarachnoid space may be caused from trauma or aneurysmal rupture. Finally, intraparenchymal hemorrhages occur within the brain tissue itself and have a multitude of etiologies. The discussion within this chapter will focus on intraparenchymal and nontraumatic subarachnoid hemorrhages. Further details on epidural, subdural, and traumatic subarachnoid hemorrhage can be found in Chapter 33 (Neurotrauma).

Etiology & Pathophysiology of Intraparenchymal Hemorrhage

Intraparenchymal hemorrhage secondary to chronic hypertension is the most common etiology of spontaneous intraparenchymal hemorrhage. These hemorrhages occur from rupture of the same small penetrating blood vessels that are affected in lacunar ischemic stroke and are found in deep brain nuclei and the brainstem (Figure 24–7). Chronic hypertension leads to disruption in the vascular layers, which predisposes the vessel to rupture. Another common etiology is cerebral amyloid angiopathy, which leads to deposition of amyloid protein into the vessel wall, resulting in focal areas of fragility, hemorrhages, and cognitive impairment. Unlike hypertensive hemorrhage, cerebral amyloid angiopathy tends to cause more superficial (termed lobar) hemorrhage. Less common causes of intraparenchymal hemorrhage include vascular malformations (discussed in the next section), vasculitis, sympathomimetic drug abuse, and coagulopathies. Some primary intracranial tumors and metastases have a tendency to hemorrhage and may be initially mistaken as a primary intraparenchymal hemorrhage. Central nervous system infections such as herpes simplex virus and Aspergillus may cause hemorrhage and should be considered in immunocompromised patients. Finally, hemorrhages can occur within infarcted brain tissue following reperfusion injuries and infarcts secondary to venous sinus thrombosis.

Clinical Presentation

Patients with spontaneous intraparenchymal hemorrhages have onset of neurologic deficits that evolve over minutes to hours. Symptoms tend to be less abrupt at onset and evolve as the hematoma expands. Because intraparenchymal hematomas are adding volume into the intracranial compartment, symptoms of increased ICP typically accompany the focal neurologic symptoms. Early in the course, this may include headache, nausea, and diplopia. As the pressure increases, symptoms may progress to lethargy, respiratory irregularity, and ultimately coma or death if not treated. Papilledema may be an accompanying exam finding with increased ICP. A dilated, unreactive pupil is a particularly ominous finding and may suggest mass effect causing herniation of the temporal lobe uncus onto the oculomotor nerve. Seizures are more common in the early phase of intraparenchymal hemorrhage compared to ischemic stroke. In a hemorrhage patient with fluctuating levels of consciousness, there should be a high index of suspicion for nonconvulsive status epilepticus.

Diagnosis

The noncontrasted head CT is the initial radiographic study of choice for a patient presenting with the acute onset of neurologic deficits. Acutely, hemorrhage will appear bright (hyperdense) on a head CT (Figure 24–8). This scan will provide anatomic localization and hematoma volume and can show the presence of intraventricular extension and mass effect. Coagulation studies and toxicology profiles should routinely be performed on any patient with an intraparenchymal hematoma. Beyond the acute phase, neuroimaging is frequently repeated in the first 24 hours given the risk for hematoma expansion. In patients with poorly controlled hypertension and a hematoma in a location typical for hypertensive hemorrhages deep in the brain, further diagnostic workup is frequently not needed. For more peripherally located (lobar) hemorrhages, MRI is useful to identify cerebral microhemorrhages characteristic of amyloid angiopathy (Figure 24–9). An MRI may also aid in the diagnosis of underlying structural lesions such as neoplasms. Vascular imaging is necessary to investigate potential vascular malformations or vasculitis. Diagnostic catheter angiography may be necessary to fully visualize these lesions if less invasive imaging studies are inconclusive.

Management of Intraparenchymal Hemorrhage

Many patients with acute intraparenchymal hemorrhage initially present with impaired consciousness and potential respiratory collapse. As with other medical emergencies, the initial steps are focused on hemodynamic stability and securing the airway. Once the diagnosis of an intraparenchymal hemorrhage has been made, the patient should be placed with the head of bed up, and frequent blood pressure monitoring should be initiated. Whereas acute lowering of blood pressure is avoided with ischemic strokes, this has been shown to be safe in patients with intraparenchymal hemorrhage. Although current data are conflicting regarding the initial target blood pressure for these patients, lowering systolic blood pressure to at least 160 mm Hg is recommended. This is best achieved by IV antihypertensives such as labetalol or nicardipine. Invasive blood pressure monitoring techniques may be necessary to ensure appropriate titration of these medications. Antithrombotic medications should be discontinued, and if the patient is on therapeutic anticoagulation, these medications should be reversed. Hemorrhage patients are generally admitted to an intensive care setting where they can be closely monitored for neurologic deterioration and medical complications such as infections and deep venous thromboses.

If the patient has evidence of increased ICP, invasive pressure monitoring should be considered. The patient should be provided with adequate sedation and analgesia. Although steroids should be avoided, other measures to treat elevated ICP such as hyperosmolar therapies are reasonable. The role for surgery to evacuate the hematoma is limited and is typically only undertaken for lobar hemorrhages that extend to the cortex or those with cerebellar hemorrhages and evidence of brainstem compression. If there is evidence of obstructive hydrocephalus, particularly in those with intraventricular hematoma extension, an external ventricular drain may be placed to relieve the pressure within the ventricular system. Despite advances in understanding the pathophysiology and treatment options for intraparenchymal hemorrhages, prognosis is poor for many patients. Up to half of patients will die within 30 days of the hemorrhage, and only about a quarter will regain functional independence.

VASCULAR MALFORMATIONS

Cerebral Aneurysms

Cerebral aneurysms are saccular-appearing outpouchings from the vascular wall that result from a focal weakening of the layers of the blood vessel due to absence or disruption of the tunica media or internal elastic lamina. Hypertension, tobacco abuse, and alcohol abuse are major risk factors, although aneurysms are also commonly seen in some connective tissue diseases (eg, Ehlers-Danlos) and genetic conditions (eg, autosomal dominant polycystic kidney disease). It is estimated that approximately 3% of the population has a cerebral aneurysm, although rupture is relatively uncommon. Risk of rupture is directly related to the diameter of the aneurysm. Aneurysms <7 mm in diameter pose the lowest risk and can frequently just be monitored.

In patients who do have aneurysmal rupture, blood will rapidly accumulate in the subarachnoid space (aneurysmal subarachnoid hemorrhage [SAH]). Sudden, severe headache (“worst headache of my life”) is the hallmark presenting symptom. Patients will frequently also have nausea, vomiting, meningismus, and ultimately decreased level of arousal. Because of the rapid progression of symptoms, 10% of patients die before arriving at a hospital. Diagnosis can usually be made with a noncontrasted head CT scan (Figure 24–10). In rare circumstances, a lumbar puncture may be necessary to demonstrate red blood cells in the CSF in patients with a strong clinical suspicion for SAH with normal neuroimaging. After initial stabilization, vascular imaging should be undertaken to identify the location of the aneurysm. Surgical clipping and endovascular coiling are commonly used techniques to stabilize and secure the aneurysm to prevent rebleeding. Complications following SAH include hydrocephalus, ischemic injury from vasospasm, and hyponatremia from syndrome of inappropriate antidiuretic hormone (SIADH). Increased ICP is common, and an external ventricular drain may be needed to alleviate hydrocephalus. Nimodipine has been shown to improve neurologic outcomes; however, the exact mechanism of action for this effect is not well understood. Unfortunately, even with prompt treatment, the 30-day mortality for aneurysmal SAH is nearly 50%, and many who survive are left with severe neurologic deficits.

Arteriovenous Malformations

Cerebral arteriovenous malformations (AVMs) are uncommon congenital malformations within the brain parenchyma consisting of direct artery to venous connections without the normal intervening capillary bed. Intraparenchymal hemorrhage is the presenting symptom for most of these patients, although headache and seizures are also frequently reported. Unlike hypertensive hemorrhages and cerebral amyloid angiopathy, hemorrhages from AVMs tend to occur in patients younger than age 40. Although CT and MRI may confirm the diagnosis, catheter angiography is frequently employed to fully define the anatomy of the lesion and to investigate for cerebral aneurysms, which may coexist with AVMs and be the source of the hemorrhage (Figure 24–11). AVMs may be treated with open surgery, radiosurgery, and/or endovascular embolectomy, although many patients with asymptomatic, unruptured AVMs can be managed conservatively with observation.

Other Vascular Malformations

Developmental venous anomalies (DVAs), cavernous malformations, and capillary telangiectasias are other forms of cerebral vascular malformations. DVAs are compositions of small medullary veins draining into a large central vein. They are typically benign and rarely result in hemorrhage. Cavernous malformations are tufts of thin, dilated capillaries that are sometimes detected as incidental findings on MRIs obtained for other indications and occasionally cause intraparenchymal hemorrhages. In most cases, these are simply observed, although surgical treatment may be considered in those with recurrent hemorrhage, seizures, or neurologic impairment. Capillary telangiectasias are small, dilated capillaries within the brain that are benign and do not warrant treatment. They may be seen in some systemic conditions such as hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease).

VENOUS SINUS THROMBOSIS

Cerebral venous sinus thrombosis (CVST) is an uncommon cause of ischemic stroke and intracerebral hemorrhage but warrants discussion due to its pathophysiology and tendency to affect unique patient populations. These patients tend to be young adults with either genetic or acquired procoagulable states such as pregnancy, the puerperium, malignancies, inflammatory conditions, and oral contraceptive use. Thrombosis of the draining venous system of the brain can produce injury through 2 primary pathophysiologic mechanisms. If venous blood is unable to drain from a region of the brain, edema can develop which can ultimately lead to tissue infarction and/or hemorrhage. If the major venous sinuses (eg, the superior sagittal sinus) are occluded, cerebrospinal fluid cannot be reabsorbed through the arachnoid granulations, leading to hydrocephalus and increased ICP. In many cases, both of these mechanisms occur simultaneously.

Because the venous drainage of the brain is more variable than its arterial system, venous thrombosis syndromes are less well defined than those affecting the arterial tree. Headache is a nearly universal presenting complaint. Focal neurologic deficits may also be seen depending on the region of the brain affected. Signs and symptoms of increased ICP may also be seen. Seizures are more common with CVST than with arterial ischemic strokes. Although CVST may be detected on a noncontrasted head CT, the diagnosis is typically made with MRI of the parenchyma coupled with either magnetic resonance or CT venography demonstrating occlusion of a dural sinus or cortical draining vein (Figure 24–12). CVST should be considered in a patient with an ischemic stroke that does not conform to an arterial territory on imaging. Hypercoagulable studies and malignancy screens are valuable tools in patients in whom the etiology of the CVST is not clear.

Patients with CVST should be treated with therapeutic anticoagulation using either unfractionated heparin or low-molecular-weight heparin (LMWH) to prevent further propagation of the thrombus. Even in cases where there is associated intraparenchymal hemorrhage, anticoagulation can still be used because the risk of hematoma expansion is low in comparison to the benefits of preventing further venous infarction. For patients with neurologic worsening despite anticoagulation, endovascular thrombectomy may be considered. After the initial period, the patient can be transitioned to oral anticoagulation (typically with warfarin) with a total duration of anticoagulation treatment of 3 to 12 months. Because vitamin K antagonists are contraindicated in pregnancy, LMWH is typically used and continued for 6 weeks postpartum. Anticoagulation should be considered for future pregnancies, particularly in the third trimester. For patients with a known hypercoagulable disorder or those with recurrent venous thrombotic events, indefinite anticoagulation may be warranted. In general, prognosis for patients with CVST is relatively good, with the majority of patients experiencing a full recovery. Less than 15% of patients will have significant residual neurologic deficits, and <5% will experience a recurrent cerebral venous thrombosis.

SPINAL CORD VASCULAR DISEASES

Although the spinal cord can be affected by a number of vascular disorders, this discussion will focus on spinal cord infarctions and spinal dural arteriovenous fistulas because of their unique clinical presentations.

Spinal Cord Infarction

Infarction of the spinal cord most commonly involves the anterior spinal artery (ASA). The ASA territory includes the ascending spinothalamic pathway and descending corticospinal pathway, sparing the dorsal columns (Figure 24–13). This syndrome typically affects both sides of the cord and presents with weakness and sensory loss to pain and temperature below the level of the lesion as well as back pain but no loss of vibration or proprioception. Bowel and bladder symptoms may also be present in three-quarters of patients. The posterior spinal artery syndrome is less common and typically involves isolated loss of vibration and proprioception below the level of the lesion. Spinal cord ischemia most commonly affects the mid and lower thoracic cord. This region of the cord receives a significant radicular artery, the artery of Adamkiewicz, which can lead to spinal cord ischemia when occluded.

Spinal cord infarcts frequently do not have an identifiable cause. Common mechanisms that have been implicated include mechanical compression of supplying vessels, systemic embolism or hypotension, atherosclerotic disease of the aorta, and fibrocartilaginous emboli from rupture of an intervertebral disk. Iatrogenic causes are frequently reported as part of surgical or endovascular procedures involving the abdominal aorta. Diagnosis is most frequently made by MRI with diffusion-weighted imaging. Additional vascular imaging is necessary to evaluate for aortic disease and patency of the radicular arteries supplying the spinal cord.

Data on effective treatment strategies for spinal cord infarction are limited. In the majority of patients, the diagnosis of spinal cord infarction is made beyond the window for treatment with thrombolytics. In cases where infarction is secondary to aortic surgery, many authors advocate for augmenting MAP with vasopressors and lumbar drainage. Steroids have not been shown to be of benefit. Patients with high thoracic or cervical cord lesions should be monitored closely because they are at risk for spinal shock, autonomic dysreflexia, and respiratory failure. Prognosis is highly variable and is dependent on the location and severity of the spinal cord infarction.

Spinal Dural Arteriovenous Fistula

Although there are several spinal vascular malformations, dural arteriovenous fistulas are by far the most common. They most commonly come to clinical attention between the ages of 30 and 70 years and have a significant male predominance (male-to-female ratio of 9:1). They occur when a radiculomeningeal artery connects directly to a radicular vein without an intervening capillary bed. They typically occur in the thoracic or lumbar regions. Presenting symptoms include back pain, weakness, and sensory deficits that may develop acutely or more insidiously. Later in the course, bowel and bladder symptoms and gait impairment may occur.

Although MRI is frequently obtained as an initial imaging study, definitive diagnosis typically requires selective spinal catheter angiography, which can identify the full anatomy of the vascular malformation. The MRI may show cord edema in the area of the malformation (Figure 24–14). Treatment may consist of open surgical resection or endovascular embolization, although a combination of these 2 approaches may be necessary for some patients.

HYPERTENSIVE ENCEPHALOPATHY

Sudden and drastic increases in blood pressure can lead to cerebral edema and neurologic deficits. In some cases, it may be difficult to distinguish hypertensive encephalopathy from other central nervous system insults on clinical grounds alone. Most patients have headache, confusion, agitation, and, in more advanced cases, lethargy, seizures, and coma. Neuroimaging may show evidence of cerebral edema but does not show discrete ischemic lesions. The diagnosis is confirmed by the resolution of neurologic deficits after lowering of the patient’s blood pressure. Edema on neuroimaging also typically resolves.

OBJECTIVES

Nervous system tumors are a large and diverse group that can involve the brain, the meninges, the spinal cord, nerve roots, or peripheral nerves. In addition, there can be either primary nervous system tumors or metastatic spread of other primary cancers to involve the nervous system. In general, primary brain tumors and other nervous system cancers are relatively rare when compared to other cancers such as lung or breast cancer. However, despite their relative rarity, they are an important source of morbidity and mortality for patients. This chapter is not meant to be an all-inclusive review of nervous system tumors but rather will highlight key tumors and syndromes and will review common clinical presentations and basic diagnostic and treatment strategies.

PREVALENCE & BURDEN

Overall, brain tumors are uncommon, and according to the 2015 Central Brain Tumor Registry of the United States, they account for only 2% of all cancers. Meningiomas are the most common primary brain tumors (36.1%), followed by Glial cell tumors (25.8%), and pituitary tumors (15.1%) (Figure 25–1). The incidence of brain tumors varies by age, sex, and race, and there is an overall higher rate of nervous system cancers in individuals with certain predisposing genetic syndromes. Over the past 3 decades, the incidence and mortality of brain tumors have increased dramatically, especially in patients >75 years of age. Reasons for this may include improved diagnostic imaging, increased access to medical care, improved care for elderly patients, and/or changes in causal factors. Ultimately, more research is required to understand this observation.

A considerable amount of research has been devoted to identifying risk factors for nervous system cancers in order to understand why they occur and to discover better treatment options. Unfortunately, however, most brain tumors have no known cause. High-dose therapeutic ionizing radiation to the head has been associated with an increased risk for both meningiomas and glioblastomas (GBMs). In addition, there are certain hereditary genetic conditions that are established risk factors. These include, but are not limited to, Li-Fraumeni syndrome, neurofibromatosis types 1 and 2 (NF1 and NF2), and von Hippel-Lindau (VHL) syndrome. There has also been considerable interest over the question of whether cell phones cause brain tumors, and as of yet, there is no conclusive evidence of an association between cell phone use and the development of brain tumors. Other potential etiologies that have been examined are infections, head trauma, diet, tobacco, alcohol, allergies, and environmental factors. There have been some associations between these factors and the development of brain tumors, but no formal causations have been identified.

GLIOMAS

Glioma is a general term that is used to refer to all glial tumors in the central nervous system (CNS). These tumors are classified based on their histologic similarity to glial cells: astrocytes (astrocytoma), oligodendrocytes (oligodendroglioma), or ependymal cells (ependymoma). The World Health Organization (WHO) grading system is based on histologic criteria that are used to classify tumors as 1 of 4 grades, with grade I being the least malignant and grade IV being the most malignant. WHO grade I tumors are described as well circumscribed with benign cytologic features. WHO grade II tumors have some degree of cytologic atypia. WHO grade III tumors have anaplasia and increased mitotic activity, and WHO grade IV tumors demonstrate grade III features in addition to having either microvascular proliferation or necrosis. Although this is primarily a histologic classification system, molecular markers are increasingly being used to provide information on diagnosis, prognosis, and potential responsiveness to therapeutics, and their significance will likely continue to increase.

In general, low-grade glioma (LGG) refers to WHO grade I and II tumors, and high-grade glioma (HGG) refers to WHO grade III and IV tumors. LGGs tend to be more slow-growing tumors that are associated with a better prognosis, whereas HGGs tend to be more aggressive and can be rapidly fatal. We will discuss these 2 groups of tumors in the following sections.

Low-Grade Gliomas

LGGs are WHO grade I and II tumors and have a biphasic age distribution, with the first peak in childhood at around 6 to 12 years and a second peak in adulthood around 30 to 50 years. There is an increased incidence of LGGs in males as compared to females. Grade I tumors are more common in younger patients, and a common example is juvenile pilocytic astrocytoma, which is discussed further in the section on pediatric brain tumors. In adults, most LGGs are WHO grade II (diffuse infiltrating) astrocytomas but can also be WHO grade II oligodendrogliomas. We will discuss key features of oligodendrogliomas separately later in this chapter.

In terms of clinical presentation, most patients with LGGs have seizures, and in most cases, seizures are the presenting symptom of the tumor. Interestingly, most patients with LGGs do not have focal neurologic deficits such as aphasia or hemiparesis. Magnetic resonance imaging (MRI) is the preferred diagnostic imaging method, and generally, LGGs do not enhance with contrast, which can be used as a diagnostic clue (Figure 25–2). Management of these patients can be very challenging; sometimes, a “watch and wait” approach is taken with frequent imaging studies to monitor tumor growth, and at other times, the decision is made for earlier treatment with surgical intervention (biopsy vs resection, as possible). The role of chemotherapy and radiotherapy in the treatment of LGGs is a contentious area, and the intricacies of this treatment are beyond the scope of this chapter. However, it is important to consider that most LGGs will ultimately transform into higher grade gliomas, and decisions regarding up-front treatment may ultimately affect treatment choices later on and may affect patient quality of life, especially as related to the cognitive effects of radiotherapy.

High-Grade Gliomas

HGGs are malignant tumors that include the WHO grade III anaplastic astrocytomas, the WHO grade III anaplastic oligodendrogliomas, and the WHO grade IV GBMs. Of these high-grade tumors, GBMs are most common and represent about 60% of all HGGs. Most HGGs occur in the adult population, although they can occur in children. The median age at diagnosis is 64 years for GBM, 51 years for anaplastic astrocytoma, and 48 years for anaplastic oligodendroglioma, and in general, HGGs occur at slightly older ages than LGGs. There is an increased incidence of GBM in men compared to women, and they also seem to occur more frequently in whites compared to other ethnic groups.

HGGs are very aggressive, and the median overall survival with treatment is as follows: 14 to 16 months for GBM, 3 to 5 years for anaplastic astrocytoma, and 15 years for anaplastic oligodendroglioma. Clinical presentation for these tumors varies with tumor location, tumor growth rate, and associated tumor-related edema and can include focal neurologic deficits, seizures, headaches, and other symptoms of increased intracranial pressure such as nausea and vomiting. Again, MRI is the preferred imaging method and generally shows an infiltrative lesion that enhances with contrast and has associated peritumoral edema. In addition, there can be solitary or multifocal lesions. In cases of GBM, the tumors often have necrotic cores and hemorrhagic components that are seen on MRI (Figure 25–3). When a GBM crosses the corpus callosum on imaging, it may be described as a “butterfly” GBM (Figure 25–4). The histologic criteria for diagnosis were discussed earlier, but key histologic findings of GBMs are areas of pseudo-palisading necrosis where the hypercellular tumor nuclei appear to line up around areas of tumor necrosis (Figure 25–5).

There are 3 main treatment modalities for HGGs: surgical resection, radiation therapy, and chemotherapy. Standard treatment for GBM has been established by randomized, phase III clinical trials and includes maximal safe surgical resection followed by concurrent radiation therapy and chemotherapy followed by adjuvant chemotherapy. This same approach is often used for anaplastic astrocytomas. Current research is investigating the optimal treatment for anaplastic oligodendrogliomas. In general, patients who are younger, who have a complete surgical resection, and who have limited neurologic disability are thought to have a better prognosis. There are also molecular features of tumors, such as tumor methylation status and IDH gene mutation status, that are increasingly being used to prognosticate and to guide treatment decisions. When HGGs progress or recur, treatment options are limited and are often dictated by the availability of clinical trials.

Oligodendrogliomas

We have already discussed oligodendrogliomas in the sections on LGGs and HGGs, but they have some characteristic features that warrant individual discussion. Oligodendrogliomas are relatively uncommon and account for only about 5% to 6% of gliomas. As compared to astrocytomas, these tumors are more likely to occur in the cerebral hemispheres and are therefore even more likely to be associated with seizures. Histopathologically, these tumors also have some distinguishing features. Microscopically, they demonstrate calcifications; perinuclear halos, which have a “fried egg” appearance; and a delicate capillary network, which is often described as looking like “chicken wire” (Figure 25–6). The perinuclear halos are artifact and are due to fixation of the tissue specimens. Molecularly, oligodendrogliomas may have allelic losses on 1p and 19q, either separately or combined, with the combined loss being most common. The 1p/19q codeletion is a favorable prognostic sign, and these patients have improved responses to chemotherapy and longer survival.

Ependymomas

Ependymomas are another type of glial tumor. They primarily occur in children and are therefore discussed later in the section on pediatric brain tumors.

MENINGIOMAS

Meningiomas are generally benign, slow-growing neoplasms that arise from the arachnoid cap cells. They are the most common primary brain tumor in adults, accounting for >30% of all CNS tumors. The incidence of meningiomas appears to increase with age, and they occur more frequently in women, with a 2:1 female-to-male ratio. The only established environmental risk factor for meningioma is ionizing radiation, especially among those exposed in childhood. There are genetic syndromes that increase the risk of meningioma, and these will be discussed later in the chapter.

Meningiomas are classified by the WHO into 3 grades based on local invasiveness and cellular features of atypia. Grade I meningiomas are referred to as benign meningiomas and have a low mitotic rate and do not demonstrate brain invasion. Grade II meningiomas, or atypical meningiomas, demonstrate any of the following: higher mitotic rate, brain invasion, or specific histologic features. Grade III meningiomas, or anaplastic meningiomas, have a very high mitotic rate or have a specific histology, either papillary or rhabdoid meningioma. There are specific subtypes within each of the grades. Meningiomas may also be characterized microscopically by the presence of spindle cells concentrically arranged in a whorled pattern and psammoma bodies.

Meningiomas are frequently detected incidentally as part of the workup for other problems, such as headaches. However, some patients can experience focal neurologic deficits, seizures, increased intracranial pressure, and/or neurocognitive deficits, which are likely related to the anatomic location and size of the tumor. Most meningiomas can be diagnosed with imaging studies including MRI and computed tomography (CT). They are extra-axial tumors (meaning external to the brain parenchyma). They are typically contrast enhancing and often have a “dural tail,” which is a thickening of the dura mater at the periphery of the tumor (Figure 25–7). CT scans often demonstrate calcification within the tumor and can also help to identify bony involvement.

Not all meningiomas require treatment, and the decision to treat is often based on the age of the patient and whether or not the patient is experiencing side effects related to the tumor. Incidental, asymptomatic meningiomas can often be safely monitored with imaging studies. If treatment is required, surgical intervention is often first-line treatment. Factors that affect whether or not patients undergo surgery include, but are not limited to, the age of the patient, the patient’s performance status and current neurologic condition, the patient’s comorbidities, and tumor factors, such as size and location. Complete surgical removal is the goal, but in approximately 1/3 of cases, this is not possible. In those cases, radiation therapy is often given after surgery. In addition, more aggressive or recurrent tumors may require repeat surgeries, multiple rounds of radiotherapy, or even chemotherapy.

HEMANGIOBLASTOMAS

Hemangioblastomas are benign (WHO grade I) vascular tumors that can occur anywhere in the body but are especially common in the brainstem, cerebellum, and spinal cord. They predominately occur in young adults and seem to occur more frequently in men than women. Hemangioblastomas can occur sporadically (70% of cases) or in association with VHL disease (30% of cases; see separate section on VHL). Patients with hemangioblastomas in association with VHL typically present at younger ages than patients with sporadic tumors. Clinical presentation varies with tumor location, but common symptoms include headaches, hydrocephalus, or cerebellar symptoms. Pain is commonly noted with spinal hemangioblastomas. Hemangioblastomas can produce erythropoietin, which can cause secondary polycythemia in approximately 5% of patients. The characteristic MRI finding is a fluid-filled cyst with an enhancing mural nodule. Hemangioblastomas also tend to have “flow voids” present on MRI, which correspond to enlarged vasculature. Histopathologically, they demonstrate tightly packed, thin-walled vessels with neoplastic stromal cells. Treatment for hemangioblastomas can involve surgical resection or radiation therapy or both. The highly vascular nature of the tumor and the anatomic location can make surgical resection difficult or impossible. In these cases, radiation therapy would be more likely. In addition, antiangiogenic agents are being investigated as potential therapies for this type of tumor.

PEDIATRIC PRIMARY BRAIN TUMORS

Pediatric brain tumors differ from adult brain tumors and therefore require individual discussion. Although the incidence rates of brain tumors in children are less than those in adults, pediatric brain tumors are the leading cause of cancer-related morbidity and mortality in children. It is also important to recognize that one of the major differences between primary brain tumors in adults versus children is location, with most adult primary brain tumors being supratentorial and most of those in children being infratentorial in location. There are many different types of childhood primary brain tumors, and we focus on the most common in this chapter.

Pilocytic Astrocytomas

Pilocytic astrocytomas are low-grade (WHO grade I) astrocytomas that are found predominately in the pediatric age group, most commonly occurring around 9 to 10 years of age. Although they can be located throughout the brain, in children, they are most often found in the posterior fossa, specifically in the cerebellum. If these tumors occur in the adult population, they are more likely to be located in the cerebrum. In general, these tumors tend to arise from midline structures, such as the cerebellum, optic nerves/optic chiasm, hypothalamus, and brainstem.

Patients often present with signs of increased intracranial pressure and cerebellar symptoms, especially if their tumor is located in the posterior fossa. Radiographically, these tumors are well circumscribed and classically have a large cystic component with a brightly enhancing solid mural nodule (Figure 25–8).

Histologically, they are sparsely cellular without anaplasia or mitoses. These tumors often contain Rosenthal fibers, which are corkscrew-shaped, eosinophilic intracytoplasmic inclusions (Figure 25–9), and eosinophilic granular bodies, which are globular aggregates within astrocytic processes. Neither Rosenthal fibers nor eosinophilic granular bodies are specific for pilocytic astrocytomas, and both may be seen in other neoplasms and disease processes. In general, pilocytic astrocytomas are slow-growing tumors with a relatively good prognosis (5-year survival >90%), and they rarely progress to a higher grade neoplasm. Surgical resection is first-line therapy and is usually curative if a complete resection is achieved.

Medulloblastomas

Medulloblastoma is the most common malignant brain tumor of childhood, accounting for 25% of all pediatric brain tumors. These tumors occur most commonly in the first decade of life and have a bimodal peak in incidence between 3 and 4 years old and then again between 7 and 10 years old. Medulloblastomas occur in the posterior fossa, predominately in the region of the fourth ventricle. As a result of this location, they often lead to hydrocephalus, because of obstruction of cerebrospinal fluid (CSF) flow, and patients present with symptoms of increased intracranial pressure, such as headache, lethargy, and vomiting. Tumors also often involve the cerebellum and can cause cerebellar signs such as truncal or limb ataxia and nystagmus.

Medulloblastoma is an aggressive embryonal tumor and is classified as a CNS primitive neuroectodermal tumor (WHO grade IV). Histologically, these tumors are extremely cellular and are composed of small, round blue cells with hyperchromatic nuclei (Figure 25–10) and Homer-Wright rosettes. The most updated WHO classification also classifies medulloblastomas according to molecular characteristics; however, the details of this are beyond the scope of this chapter. On MRI, medulloblastomas are generally contrast enhancing and show effacement of the fourth ventricle (Figure 25–11). All patients with medulloblastoma should have entire neuraxis imaging to assess extent of disease dissemination and for spinal drop metastases and CSF cytology to assess for CSF involvement because these tumors have a high propensity for spread within the CNS. Surgery is first-line therapy for these tumors. Postsurgically, patients are divided into standard-risk and high-risk groups based on age, degree of surgical resection, and presence of metastasis. In general, the standard-risk group receives postsurgical radiotherapy alone, and the high-risk group receives postsurgical radiotherapy plus chemotherapy. Five-year survival rates for the standard-risk and high-risk groups are 70% and 40%, respectively. Long-term survivors of medulloblastoma often have neurologic disabilities, including significant learning disabilities.

Ependymomas

Ependymoma is the third most common CNS tumor of childhood and is especially prevalent among children younger than 3 years old. There is an increased incidence in males (1.7:1 male-to-female ratio). The WHO classification system includes 3 grades of ependymomas: grades I, II, and III. Ependymomas can occur anywhere throughout the CNS, but infratentorial tumors are most common. Infratentorial ependymomas are also commonly located intraventricularly, especially in the fourth ventricle. Ependymomas can also occur in the spinal cord, and patients who have only intraspinal lesions but not intracranial lesions are often found to have NF2. Patients with infratentorial lesions commonly present with signs of increased intracranial pressure due to hydrocephalus. Ependymomas may have calcifications that are visible on CT scans, and they are typically well-circumscribed masses with varying degrees of enhancement on MRI. Histologically, these tumors have characteristic perivascular pseudorosettes, which are formed when ependymal cells form rings around vessels. Ciliary basal bodies (blepharoplasts) can be demonstrated on electron microscopy. Surgical resection is first-line therapy in these tumors, and the extent of resection is the most significant prognostic factor for patients with ependymoma. In most cases, local irradiation is given after surgical resection. Chemotherapy appears to have a limited role in the treatment of these patients.

Craniopharyngiomas

Craniopharyngioma is the most common supratentorial tumor in childhood; however, it is a rare tumor overall. This tumor has a bimodal age distribution with 1 peak in children between ages 5 and 10 years and another peak in adults between ages 50 and 60 years. Craniopharyngiomas are slow-growing, benign (WHO grade I) tumors that are derived from remnants of the Rathke pouch. There are 2 subtypes of craniopharyngiomas that are histologically and molecularly distinct. The classic adamantinomatous subtype is more common and occurs more frequently in children. The papillary subtype occurs predominantly in adults. Craniopharyngiomas are usually located in the suprasellar region of the brain. Common clinical presentations for these tumors include hypopituitarism, visual changes (diplopia or bitemporal hemianopsia), and/or hydrocephalus. Craniopharyngiomas contain both solid and cystic areas. The cystic areas contain dark fluid that is composed of cholesterol crystals and necrotic debris. This cystic fluid has a dark brown or black color and is often described as “motor oil.” Calcification is common in these tumors, and they often appear as a calcified mass in the parasellar region on head CT. On MRI, these are usually intensely enhancing lesions (Figure 25–12). Craniopharyngiomas are most commonly treated with complete resection or subtotal resection followed by radiotherapy. Like the pituitary tumors, craniopharyngiomas can produce significant endocrine abnormalities, and patients should be managed by a multidisciplinary team that includes neurosurgeons, radiation oncologists, and endocrinologists.

PITUITARY TUMORS

Pituitary tumors are the third most common intracranial neoplasm. Recent studies suggest that the incidence of pituitary tumors is actually higher but is underestimated because many tumors are asymptomatic and therefore go undiagnosed. Pituitary tumors are uncommon in pediatric populations, and their incidence increases with age. Some pituitary tumors may be associated with genetic syndromes, such as multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 4 (MEN4), McCune-Albright syndrome, or Carney complex.

Before discussing pituitary tumors, it is important to review the pituitary gland, which plays a key role in regulating the body’s hormones and the hormones it secretes. The pituitary gland is divided into 2 parts: the adenohypophysis (the anterior lobe) and the neurohypophysis (the posterior lobe). The adenohypophysis, or anterior pituitary, contains 5 types of endocrine cells, which are defined by the hormones they secrete: corticotrophs (adrenocorticotropic hormone), thyrotrophs (thyroid-stimulating hormone), gonadotrophs (follicle-stimulating hormone and luteinizing hormone), somatotrophs (growth hormone), and lactotrophs (prolactin). The neurohypophysis, or posterior pituitary, is responsible for the secretion of oxytocin and vasopressin. Pituitary tumors result from hyperplasia of the previously listed endocrine cells, and most pituitary tumors arise from the anterior pituitary gland.

Pituitary adenomas are the most common pituitary tumor, and are generally benign tumors that do not spread outside the skull. For a pituitary tumor to be classified as a pituitary carcinoma, there has to be metastasis, which is rare. Pituitary adenomas are typically classified according to size: pituitary microadenomas, which are <10 mm, and pituitary macroadenomas, which are ≥10 mm. In general, pituitary macroadenomas are approximately twice as common as pituitary microadenomas. Although these tumors are considered “benign,” they can have a significant impact on health because of the symptoms they produce. Most pituitary adenomas present clinically because of inappropriate hormone secretion or because of compression of adjacent structures. The optic chiasm is most often compressed (Figure 25–13), which results in bitemporal hemianopsia. In addition, headaches and/or hydrocephalus may result from compression or disruptions in CSF flow.

Pituitary adenomas are also classified by whether or not they make excessive hormone (“functional” adenoma vs a “nonfunctional” adenoma, respectively). Most pituitary adenomas that come to clinical attention are functional, and these tumors are named for the hormones they produce. For example, a prolactin-producing adenoma is called a prolactinoma. The prolactinoma is the most common functional pituitary adenoma, and common signs and symptoms associated with it are galactorrhea, amenorrhea, hypogonadism, and sexual dysfunction. The second most common functional pituitary adenoma is a growth hormone–secreting adenoma, and affected individuals may experience acromegaly. The type of hormone secreted by the adenoma dictates the signs and symptoms the patient may experience, diagnostic testing choices, and treatment options. In most cases, neurosurgical intervention is first-line therapy for these tumors. However, some cases can be treated with medical management, such as bromocriptine, a dopamine agonist, for prolactinoma. In some cases, radiation therapy or chemotherapy may be necessary. In all cases, patients will require long-term follow-up to assess disease status and close monitoring by endocrinology for management of hormonal abnormalities.

PINEAL REGION TUMORS

Pineal tumors are rare, accounting for <1% of all primary brain tumors. They are a very heterogenous group made up of benign pineal region tumors, glial tumors, pineal parenchymal tumors, and germ cell tumors. Each of these categories of tumors has distinct histopathologic features as well as differences in disease course, treatment modalities, and prognosis. Clinical presentation among these different tumors is similar, however, and commonly includes hydrocephalus, manifested by lethargy, nausea, headache, and/or Parinaud syndrome, which is characterized by absent upgaze, lid retraction, near-light dissociation (better pupillary reaction to accommodation than to light), and convergence nystagmus and is caused by compression of the midbrain tectum. In addition, adolescent males may experience precocious puberty due to β-human chorionic gonadotropin production. Most pineal tumors require at least a biopsy for tissue diagnosis, but some can be diagnosed by detection of secreted hormones in CSF or serum. Treatment usually involves surgical resection with or without additional radiation therapy. Chemotherapy is also used in certain situations.

PRIMARY CNS LYMPHOMA

Primary CNS lymphoma (PCNSL) is rare and represents only approximately 3% of all primary brain tumors. PCNSL mainly occurs in older individuals, with a median age at diagnosis of 59 years. According to the Surveillance, Epidemiology, and End Results (SEER) database, the incidence of PCNSL appears to be increasing among patients age 65 years and older, with the highest incidence in patients age 75 years or older. PCNSL occurs in both immunocompetent and immunocompromised patients, but at a higher frequency among the latter group. The most significant risk factor for CNS involvement of lymphoma is an immunocompromised state, either acquired, such as acquired immunodeficiency syndrome (AIDS) or after transplantation, or congenital, such as Wiskott-Aldrich syndrome or severe combined or common variable immunodeficiency. PCNSL in AIDS patients and in posttransplant patients is almost exclusively associated with Epstein-Barr virus infection. PCNSLs are unique in that they are confined to the CNS, but they do not arise from neural tissue. Instead, they are extranodal, malignant non-Hodgkin lymphomas of primarily B-cell origin. PCNSL can involve the brain, the eyes, the leptomeninges, or the spinal cord.

PCNSL can present in a variety of ways, but cerebral symptoms including personality/cognitive changes, hemiparesis, aphasia, or headache are most common. MRI is the preferred imaging modality for diagnosis and typically demonstrates a highly infiltrative tumor with an intense, homogenous enhancement pattern. In patients with AIDS-related PCNSL, brain lesions are often ring enhancing and may be associated with hemorrhage or necrosis. Stereotactic brain biopsy is most commonly used for diagnosis of PCNSL. In addition, cytologic and/or flow cytometric analysis of lymphoma cells isolated from CSF or via vitreous biopsy may result in the diagnosis.

Surgical resection has a very limited role in PCNSL and is generally not associated with improved survival and may actually result in worsened neurologic status of patients. Current mainstays of treatment include steroids, chemotherapeutics primarily involving high-dose intravenous methotrexate with or without additional agents, rituximab (a monoclonal CD20 antibody), and radiotherapy. In general, whole-brain radiation therapy is delayed as long as possible, especially among elderly patients, due to associated neurotoxicity. Untreated PCNSL is rapidly fatal, and patients typically die within 1.5 months from time of diagnosis. With treatment, 5-year survival rate in immunocompetent adults is approximately 30%. Poor prognosis is associated with age >60 years old, poor functional status, elevated serum lactate dehydrogenase, elevated CSF protein concentration, and involvement of deep regions of the brain (ie, periventricular regions, basal ganglia, brainstem, and/or cerebellum). Even patients who have an initial good response to treatment will likely have disease recurrence at some point, and treatment options at recurrence include additional chemotherapy, radiation therapy, or palliative care.

PERIPHERAL NERVE TUMORS

Schwannomas

Schwannomas are the most common peripheral nerve tumor. They are benign (WHO grade I) nerve sheath tumors that arise from Schwann cells, which produce the myelin sheath around nerve fibers. Most schwannomas occur extracranially in the peripheral nerves of the skin and subcutaneous tissues. They can arise from spinal nerve roots and can cause radicular symptoms and signs of nerve root or spinal cord compression. When schwannomas occur intracranially, they have a strong predilection for cranial nerve VIII in the cerebellopontine angle and are referred to as vestibular schwannomas or acoustic neuromas. Vestibular schwannomas can cause tinnitus, hearing loss, and/or dizziness. Approximately 90% of schwannomas occur as solitary, spontaneous tumors, and approximately 4% of schwannomas arise in the setting of NF2 (see later section on NF2). MRI is the preferred diagnostic imaging modality and often shows a well-circumscribed mass with intense contrast enhancement (Figure 25–14). Schwannomas are encapsulated and do not infiltrate into the nerve fibers, but rather displace them. Pathologically, these tumors consist of alternating highly cellular regions (Antoni A regions) that have areas of nuclear palisading (Verocay bodies) and loosely arranged hypocellular regions (Antoni B regions). Most schwannomas strongly express the S100 protein (Figure 25–15). Surgical resection is most often used to treat these slow-growing tumors, and there is a low risk of recurrence or malignant transformation.

Neurofibromas

These are also benign (WHO grade I) nerve sheath tumors that typically occur as solitary and sporadic tumors. There is, however, a strong association with multiple neurofibromas and NF1. Neurofibromas are composed of Schwann cells and fibroblasts. These tumors, unlike schwannomas, are not encapsulated, and they infiltrate between nerve fascicles of the parent nerve. MRI often demonstrates fusiform lesions that enhance with contrast. Surgery is often used to treat these tumors, but unlike schwannomas, it is difficult to resect these tumors completely without sacrificing the entire nerve that is involved. In neurofibromas associated with NF1, surgery is less often used because there are typically multiple lesions. In addition, recurrence and malignant transformation are more common in neurofibromas associated with NF1.

NERVOUS SYSTEM METASTASES

Systemic cancers can metastasize to various parts of the nervous system, including the brain parenchyma, the leptomeninges, the dura, and the spinal cord and are associated with significant morbidity and mortality. Parenchymal brain metastases are the most common type of brain tumor and occur in 10% to 15% of people with cancer. The overall incidence of brain metastases appears to be increasing, and this is likely related to improved overall survival times of cancer patients, increased awareness of brain metastases, and improved diagnostic techniques. The frequency with which systemic cancers metastasize to the brain varies according to the type of primary cancer. Common cancers that spread to the brain are lung, breast, melanoma, renal, and colorectal cancers, in decreasing order of frequency. Although some cancers are more likely to metastasize to the brain, any primary cancer can spread to the brain, and therefore, metastasis should always be considered as part of the differential diagnosis in cancer patients who also have brain lesions. Brain metastases can produce a significant amount of peritumoral edema, which, in turn, can produce clinical symptoms such as headache, seizures, and/or focal neurologic deficits.

Pathologically, most brain metastases are spheroid and appear to be well demarcated from surrounding brain tissue on gross examination. In addition, the majority of brain metastases are multiple lesions, and they are often located at the junction of the gray and white matter (Figure 25–16). The cerebrum is the site of 80% to 85% of brain metastases, whereas the cerebellum is the site of 10% to 15% and the brainstem is the site of only 3% to 5%. Some brain metastases are more likely to hemorrhage, and these include melanoma, renal cell carcinoma, thyroid cancer, and choriocarcinoma. The gold standard for diagnostic imaging is MRI with contrast, which is more sensitive that CT in determining the location and number of metastases. Often, the diagnosis of brain metastasis can be assumed, especially in the setting of a known primary cancer and multiple typical-appearing lesions, and other times, tissue must be obtained for diagnosis, especially in the setting of no known primary cancer and a solitary brain lesion.

There are several treatment options for patients with brain metastases, including whole-brain radiotherapy, stereotactic radiosurgery, conventional surgical resection, and use of systemic therapies. Decisions regarding which therapy to use are made based on such factors as the number, size, and location of the lesions; the overall and neurologic condition of the patient; the status of the primary cancer; and the goal of therapy (ie, to provide palliation or symptom management or to extend survival).

PARANEOPLASTIC SYNDROMES

Paraneoplastic syndromes are a group of rare disorders that are associated with cancer but are not directly attributable to cancer cells. Instead, these syndromes are either due to substances secreted by the tumor or due to immune cross-reactivity between tumor and normal host tissues. Paraneoplastic syndromes were first recognized more than a century ago, and since that time, the understanding of paraneoplastic syndrome pathogenesis has increased significantly. It is estimated that up to 8% of patients with cancer will be affected by a paraneoplastic syndrome, and this number will likely increase as patients with cancer continue to live longer and diagnostic techniques for these syndromes continue to improve.

Paraneoplastic syndromes can represent the first manifestation of cancer, even in a patient without a known primary malignancy. Therefore, if a patient with an unknown primary cancer presents with a common paraneoplastic syndrome, then a diagnostic workup for malignancy must be done. Paraneoplastic syndromes can affect many organ systems, with the nervous system often being severely affected. Commonly associated malignancies include small-cell lung cancer, breast cancer, gynecologic tumors, and hematologic malignancies. Diagnosis of a paraneoplastic syndrome is based on clinical presentation, exclusion of other causes, performance of autoantibody and other diagnostic testing such as imaging studies, and workup for relevant cancers. Treatment of paraneoplastic disorders can involve immunotherapy and identification and treatment of the underlying malignancy.

Paraneoplastic syndromes of the peripheral nervous system can include paraneoplastic sensory neuropathy or Lambert-Eaton myasthenic syndrome (LEMS). LEMS is characterized by muscle weakness and is often associated with dry mouth, constipation, and sexual dysfunction. LEMS is clinically similar to myasthenia gravis (MG), with the main difference being that patients with LEMS get temporarily stronger with exertion unlike patients with MG, who get weaker with exertion. LEMS is seen in approximately 1% to 3% of patients with small-cell lung cancer and is caused by autoantibodies directed against the presynaptic P/Q-type voltage-gated calcium channels, which leads to a decrease in acetylcholine release. Paraneoplastic disorders that affect the CNS can include limbic encephalitis, paraneoplastic encephalomyelitis, and paraneoplastic cerebellar degeneration. See Table 25–1 for a list of common paraneoplastic disorders and their associated autoantibodies.

FAMILIAL TUMOR SYNDROMES/CANCER-PREDISPOSING SYNDROMES

Most nervous system tumors occur sporadically. However, there are some syndromes that predispose affected individuals to cancers of both the nervous and other systems. We will review some of the more well-known syndromes in this chapter.

Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen syndrome, is a relatively common syndrome, affecting approximately 1 in 3000 people. NF1 is autosomal dominant but can also occur as the result of a spontaneous mutation. NF1 is due to a germline mutation of the NF1 tumor suppressor gene (neurofibromin) on chromosome 17q11.2. Neurofibromin is a major negative regulator of Ras, which is a key protein involved in signaling for cell growth and division. NF1 affects multiple organ systems, with the central and peripheral nervous systems, the skin, the eyes, and the bones being most frequently involved. NF1 is commonly characterized by cutaneous findings of café-au-lait spots, axillary and inguinal freckling, optic gliomas, osseous lesions, and pigmented iris hamartomas (Lisch nodules) (Figure 25–17). Patients with NF1 are at increased risk of tumors including benign neurofibromas and intracranial tumors such as optic gliomas and meningiomas. The most common primary CNS tumors seen in NF1 are optic gliomas, and bilateral optic gliomas are considered to be virtually pathognomonic for NF1. Patients with NF1 are also at increased risk for other malignancies such as pheochromocytomas, malignant peripheral nerve sheath tumors, thyroid carcinomas, and leukemias. Most patients with NF1 are monitored closely with neurologic and ophthalmologic examinations, and any treatment is directed at specific complications.

Neurofibromatosis Type 2

Neurofibromatosis type 2 (NF2) is less common than NF1. It is an AD disorder, but spontaneous mutations do occur. NF2 is caused by germline mutations in the NF2 gene on chromosome 22. NF2 encodes for the tumor suppressor protein merlin (also called schwannomin) that plays an important role in the interaction of cytoskeletal components with proteins in the cell membrane. Clinically, NF2 primarily affects the nervous system, and one of the hallmark features of this disease is bilateral vestibular schwannomas, classically located at the bilateral cerebellopontine angles. Vestibular schwannomas can cause significant hearing loss, and management often involves surgical resection and/or radiation therapy. Other findings include cutaneous manifestations, such as café-au-lait spots and subcutaneous schwannomas, cataracts, gliomas, meningiomas, and spinal intramedullary ependymomas.

Tuberous Sclerosis

Tuberous sclerosis (TS) is a rare, multisystem autosomal dominant disorder that is characterized by hamartomas involving the nervous system, skin, and other organs such as the kidneys, heart, and lungs. Clinically, the nervous system is most often affected, and clinical manifestations can include seizures, developmental delay, intellectual disability, and behavioral problems. Other common clinical manifestations include cutaneous abnormalities, including facial angiofibromas, hypopigmented ash leaf spots, subungual fibromas, fibrous forehead plaques, and shagreen patches; cardiac rhabdomyomas; mitral regurgitation; and renal angiomyolipomas. Possible brain lesions include subependymal giant-cell astrocytomas (SEGAs) and cortical tubers, so called because these nodules become calcified and hard and resemble potatoes. SEGAs generally form in the ventricles of the brain and can lead to disruption in CSF flow, which can result in hydrocephalus that may clinically manifest as headaches and blurred vision. Individuals with tuberous sclerosis have germline mutations in either TSC1 (chromosome 9q34), which encodes the protein hamartin, or TSC2 (chromosome 16p13.3), which encodes the protein tuberin. Treatment of patients with tuberous sclerosis is primarily symptomatic and involves seizure control and tumor surveillance.

Von Hippel-Lindau Disease

Von Hippel-Lindau (VHL) disease is a rare, AD condition that is characterized by hemangioblastomas of the retina and the CNS (particularly involving the brainstem, cerebellum, and spine), renal cell carcinomas, pheochromocytomas, and epididymal cysts. Hemangioblastomas are slow-growing, benign tumors that are highly vascular and have hyperchromatic nuclei. Hemangioblastomas are seen in approximately 75% of patients with VHL; however, only approximately 30% of patients with hemangioblastomas will have VHL. Regardless, patients who have a hemangioblastoma should also have a thorough workup that includes a funduscopic exam, a renal ultrasound, and consideration of imaging of the entire spine in order to exclude other lesions. VHL results from germline mutations in the VHL gene on chromosome 3q25. Patient with VHL require lifelong monitoring for associated tumors, and treatment of any tumors typically involves surgical resection.

Li-Fraumeni Syndrome

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome. It is linked to germline mutations of the p53 tumor suppressor gene, which plays an important role in regulating cell cycles. Individuals with LFS are at increased risk for multiple malignancies including sarcomas, premenopausal breast cancers, leukemias, CNS neoplasms, and adrenal cortical carcinomas. Approximately 12% of the malignancies seen in LFS involve the CNS and can include astrocytomas, medulloblastomas, primitive neuroectodermal tumors, choroid plexus carcinomas, and ependymomas. As a result of the increased lifetime risk of cancer, individuals with LFS must be followed indefinitely.

Sturge-Weber Syndrome

Sturge-Weber syndrome (also known as encephalotrigeminal angiomatosis) is a congenital, noninherited disorder that is characterized by a port-wine nevus affecting the skin in the ophthalmic (V1) or maxillary (V2) distributions of the trigeminal nerve, leptomeningeal angiomas on the side of the brain ipsilateral to the port-wine stain (usually occipital), glaucoma, seizures, stroke, and intellectual disability. It is caused by a somatic activating mutation in the GNAQ gene, which plays a role in vascular development. There are several classical imaging findings associated with this syndrome, including gyral calcifications seen on head CT and “tram-track” calcifications, due to leptomeningeal vascular malformations, seen over the occipital or parietal regions on head CT or skull radiographs. Sturge-Weber syndrome is not associated with the development of either central or peripheral nervous system tumors.

CONCLUSION

Nervous system tumors are a large and varied group that can present diagnostic and treatment challenges. It is important to recognize the impact that these types of tumors can have on patients’ lives and productivity and the significant morbidity and mortality associated with them. Treatment options largely consist of surgery, radiation therapy, and chemotherapy, and management often involves a multidisciplinary team of physicians.

OBJECTIVES

PREVALENCE & BURDEN

Headache is perhaps the most common neurologic syndrome. About half the world’s population experiences headache at least once each year, and up to three-quarters of people will have a headache at some point in their lives. The most common type of headache is tension-type headache, followed by migraine. The 1-year prevalence of migraine in the United States is 12%, with a female predominance. Migraine prevalence is highest during some of the peak productive years of life (age 30 to 39 years), and 1 of every 4 migraineurs misses at least 1 day of work every 3 months. Migraine is among the top 10 causes of disability worldwide and accounts for the most years lived with disability of any neurologic disorder.

EVALUATION OF HEADACHE DISORDERS

The workup of a headache is guided by several factors in the history and exam (Figure 26–1). The more common primary headache disorders, namely migraine and tension-type headache, are diagnosed based on a thorough history and physical exam. Neuroimaging is not required unless the patient has an abnormal neurologic exam or the history is concerning. However, secondary headaches could masquerade as trigeminal autonomic cephalgias and some of the headaches classified under other primary headache disorders; therefore, further workup is often warranted. There are a number of potential “red flags” in the history that may suggest the need for further workup (Table 26–1).

PRIMARY HEADACHE SYNDROMES

Migraine

Migraine can present in childhood, but generally begins around puberty during adolescence or young adulthood. The pathophysiology of migraine is likely secondary to genetic predisposition and environmental factors leading to the phenotypic presentation of migraine. Three genetic mutations have been identified in familial hemiplegic migraine. These are the CACNA1A gene on chromosome 19, which encodes a P/Q type calcium channel subunit and increases presynaptic calcium; the SCN1A gene on chromosome 2, which encodes a sodium channel subunit and causes persistent sodium influx; and the ATP1A2 gene on chromosome 1, which encodes a subunit of the sodium-potassium ATPase and decreases potassium and glutamate clearance. Mutations in the PRRT2 gene, which is not an ion channel gene but encodes for synaptosomal-associated protein 25 (SNAP25), may also cause hemiplegic migraine. The genetics behind the more common types of migraine are likely multifactorial and still under study. It is thought that patients with migraine have cortical neuronal hyperexcitability and likely abnormal brainstem function.

The initiating mechanism of a migraine headache is thought to be secondary to cortical spreading depression (Figure 26–2). This is a wave of increased cortical neuronal activity, followed by neuronal suppression. Cortical spreading depression propagates at a velocity of 2 to 3 mm per minute. The aura spreads at a similar speed, and therefore, it has been attributed to cortical spreading depression. When the cortical spreading depression initiates in the occipital lobes, a visual aura ensues. Migraine without aura may result from cortical spreading depression in a clinically silent area of cortex. Cortical spreading depression (via an unknown mechanism) is thought to activate the trigeminal vascular system and release of substances involved in pain pathways including calcitonin gene-related peptide and glutamate. The trigeminal vascular system and neuromediators cause the headache and likely lead to neurogenic inflammation and peripheral sensitization. If the headache persists, central sensitization and allodynia can occur in a pattern similar to that which arises with chronic pain in other parts of the body (Figure 26–3).

A migraine attack can be divided into 4 phases: (1) the premonitory phase, which occurs hours to days before the onset of head pain and includes various symptoms ranging from euphoria to fatigue; (2) the aura phase, when neurologic symptoms occur just before or during the headache onset; (3) the headache phase, which includes the associated migrainous symptoms; and (4) the postdrome. Migraine is a recurrent headache disorder that is diagnosed clinically based on diagnostic criteria. Neuroimaging is not indicated unless historical warning signs (see Table 26–1) are present or the neurologic exam is abnormal, but may reveal small subcortical hyperintensities that are not periventricular or in the corpus callosum.

Migraine headache can be episodic or chronic, and chronic migraine is defined as a headache on at least 15 days per month with a minimum of 8 days meeting criteria for migraine. Migraine can be further characterized as migraine with or without aura. Based on diagnostic criteria, an untreated migraine attack lasts 4 to 72 hours in adults but can be of shorter duration in children. It has at least 2 of the following 4 characteristics: (1) unilateral location (Figure 26–4), (2) pulsating quality, (3) moderate to severe pain intensity, and (4) aggravation by or causing avoidance of routine physical activity. During the headache, the patient must have 1 of the following features: (1) nausea and/or vomiting or (2) phonophobia and photophobia.

Migraine aura has ≥1 visual, sensory, speech and/or language, motor, brainstem, or retinal symptoms that are fully reversible, with at least 2 of the following 4 characteristics: (1) aura spreads gradually over >5 minutes and/or symptoms occur in succession; (2) each individual aura symptom lasts 5 to 60 minutes; (3) at least 1 aura symptom is unilateral; or (4) the aura is accompanied or followed within 60 minutes by headache. Each individual aura can last up to 1 hour, so if a patient has multiple aura symptoms in succession, the total aura time will be longer than 60 minutes.

Migraine with aura has several different variants; these include migraine with typical aura, migraine with brainstem aura, hemiplegic migraine, and retinal migraine. In migraine with typical aura, the aura consists of visual, sensory, and/or speech and language symptoms. However, it excludes motor, brainstem, and retinal symptoms. The typical visual aura is described as a scintillating scotoma with a zig-zag “fortification spectra,” which slowly enlarges at a speed similar to that of cortical spreading depression (Figure 26–5). Migraine with brainstem aura requires at least 2 of the following brainstem symptoms: (1) dysarthria, (2) vertigo, (3) tinnitus, (4) hypoacusis (hearing impairment), (5) diplopia, (6) ataxia, and (7) decreased level of consciousness. Hemiplegic migraine is a subtype of migraine with aura in which the aura is a syndrome of fully reversible motor weakness and fully reversible visual, sensory, and/or speech or language symptoms. Retinal aura is distinguished from the typical visual aura because it is a monocular positive or negative visual phenomenon. This is confirmed by clinical visual examination during an attack or the patient’s drawing of a monocular field defect.

Migraine Treatment: Preventive

The treatment of migraine headaches hinges on both preventive and abortive therapies. All patients who suffer from migraine headaches should be counseled on lifestyle modifications, such as regular sleep and meals, healthy diet and exercise, and avoidance of triggers, as part of their preventive therapy. Common triggers for migraine headache include stress, hormonal changes, skipping meals, weather changes, sleep disturbances, strong odors (eg, perfume, gasoline, smoke), lights, alcohol, food (eg, tyramine in aged meat/cheese and ripe bananas, aspartame), and heat. Some migraine triggers cannot be avoided. Migraine patients should be offered prescription preventive migraine therapy if they have >3 migraine days without disability per month or >2 migraine days with disability per month.

For optimal prevention of migraine headaches, it is important to involve patients in their care. Consider comorbidities, and when possible, choose a single medication to treat multiple diseases. With women of childbearing age, discuss contraception and the potential risk of medication use during pregnancy. Each preventive medication should be started at a low dose and slowly titrated up. It is important to give each preventive medication an adequate trial. Generally, once at a therapeutic dose, a preventive medication should be continued for at least 6 weeks before reevaluating. The use of headache calendars before and after initiation of migraine preventive therapy can give objective data on the efficacy of the drug in that patient.

Medications with established efficacy (level A evidence) for the prevention of migraine include antiepileptic agents (divalproex sodium, topiramate) and β-blockers (metoprolol, propranolol). Divalproex sodium should be considered in someone with concomitant mood disorders and requires monitoring for weight gain, hyponatremia, and hepatitis. Topiramate might be helpful in an overweight patient, as it can cause weight loss. It is contraindicated in patients with renal calculi and glaucoma. Patients need to be monitored for cognitive complaints and should be warned about tingling and changes in taste (carbonated drinks taste “flat”), which are common side effects. Other antiepileptics that can be beneficial in the treatment of headaches include gabapentin, levetiracetam, zonisamide, and lacosamide. Propranolol should be considered in someone with concomitant hypertension or anxiety. It should be avoided in individuals with asthma or diabetes. Patients on an antihypertensive need to be monitored for signs and symptoms of hypotension and bradycardia. Other antihypertensives that can be considered in the preventive treatment of migraine are verapamil and candesartan.

Medications that are probably effective (level B evidence) for the prophylaxis of migraine headaches include antidepressants (amitriptyline, venlafaxine). Amitriptyline should be considered in someone with insomnia or mild depression. It should be used with caution in patients with cardiovascular disease because it can lead to arrhythmia, and an electrocardiogram is warranted prior to initiation in this population of patients. The main side effect is sedation, although it has the potential to cause other anticholinergic side effects including xerostomia, dizziness, blurred vision, constipation, and urinary retention (especially in the elderly). Patients should also be monitored for suicidal ideation. Alternative tricyclic antidepressants that can be used for the prevention of migraine include nortriptyline and protriptyline. Venlafaxine might be useful in a migraine patient who suffers from moderate depression. It requires routine laboratory monitoring of renal function and lipids. Patients should also be monitored for hypertension and, as with many of the antidepressants, suicidal ideation.

If medications in the anticonvulsant, antihypertensive, and antidepressant categories are ineffective or contraindicated, memantine (category B in pregnancy) should be considered in the prevention of migraine headaches. Supraorbital nerve stimulation has also been shown to be an effective preventive therapy. In addition, in a patient who meets criteria for chronic migraine, injection of botulinum toxin in the face, occiput, neck, and shoulders following the chronic migraine paradigm is effective at decreasing the intensity and frequency of migraine attacks. The calcitonin gene-related peptide (CGRP) receptor antagonists are a newer class of preventive treatments made specifically for migraine. CGRP antagonists appear to have good efficacy with a low side effect profile, though their long term effects are unknown.

These treatments can be used in conjunction with progressive relaxation techniques and cognitive behavioral therapy. There is evidence for the use of herbal supplements such coenzyme Q10, magnesium, riboflavin, and feverfew. Although Petasites hybridus extract has strong evidence in the preventive treatment of migraine, its use is currently not recommended because of safety concerns given potential liver toxicity and carcinogenic/teratogenic properties of formulations that are not free of pyrrolizine alkaloids. Trigeminal and occipital distribution nerve and sphenopalatine ganglion blocks, as well as trigger point injections using local anesthetic, may also be beneficial as adjunctive therapy for both the prophylaxis and acute treatment of migraine.

If a patient has predictable migraine headaches during menses, she may qualify for a “mini-prophylaxis.” Instead of taking a daily preventive medication, she would use therapy the week of her expected migraine headache, which can be calculated fairly accurately in someone with regular menstrual cycles. Although the traditional preventive migraine medications can be used during the week of prophylaxis, using frovatriptan has been found to be effective (level A evidence) for this purpose. Aside from this setting, medications in the triptan category are traditionally used for migraine abortive treatment, especially because of their potential to cause medication overuse headache.

Migraine Treatment: Abortive

As an adjunct strategy to preventive therapies in the treatment of migraine, patients should be offered abortive agents. Migraine-specific medications include ergot derivatives and triptans. These medications act as serotonin (5-HT) receptor agonists. Triptans are more selective 5-HT receptor agonists than ergotamine and dihydroergotamine, acting on 5-HT 1B/1D receptors. Triptans are the abortive treatment of choice in migraine headache (level A evidence). Contraindications to triptans include untreated arterial hypertension, coronary artery disease, history of ischemic stroke, administration of an ergot compound within 24 hours of triptan use, severe renal or hepatic disease, peripheral vascular disease, Raynaud disease, age >65 years, and migraine with brainstem aura or hemiplegic migraine.

Originally, migraine was thought to be a vascular disorder, and brainstem symptoms were thought to be secondary to basilar artery vasoconstriction. Because triptans induce vasoconstriction, migraine with brainstem aura was excluded from triptan clinical trials due to concerns of increasing the risk of brain infarction and is thus not a formal indication for triptan therapy. However, it is now clearer that aura is primarily a neuronal process related to cortical spreading depression, and more recent literature suggests that treating these patients with triptans may actually be beneficial without increased risk for ischemic vascular events.

A variety of triptans are approved for migraine treatment (Figure 26–6). Sumatriptan was the first triptan introduced for acute migraine treatment. It has the fastest time to peak levels but also the shortest half-life. Sumatriptan and zolmitriptan are both available in oral and nonoral formulations. Rizatriptan is available in an oral tablet, as well as an oral disintegrating tablet. Almotriptan, eletriptan, frovatriptan, and naratriptan are only available in an oral tablet formulation. Frovatriptan and naratriptan have a slower onset and lower potency but also a lower headache reoccurrence rate because they are longer lasting. Frovatriptan has the longest half-life of the triptans.

When choosing a triptan, it is important to consider how quickly the headache climaxes, as well as associated symptoms of nausea and vomiting. Gastroparesis is common during migraine. Although a patient might be able to tolerate oral medications without symptoms of nausea, vomiting, or bloating, the absorption of medications may be delayed. Therefore, nonoral triptans should be considered early, especially if gastrointestinal symptoms are present. Unlike preventive therapy where one would “start low and go slow,” symptomatic therapy should be prescribed at the dose most likely to be effective within the prescribing range. If a lower dose formulation is partially effective, the patient should be instructed to redose, and the practitioner should prescribe the equivalent higher dose formulation in the future.

In patients who cannot take triptans, longer acting nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac and naproxen can be used as abortive therapy (level A evidence). These have less of a potential for medication overuse headache. If triptans and NSAIDs cannot be used, then combination medications with isometheptene can be considered. Cyclobenzaprine has a similar chemical structure to amitriptyline and can also be used as an adjunct for symptomatic headache therapy. It is unlikely to cause medication overuse headache. Adding antiemetics, especially in the setting of gastrointestinal symptoms, may also be beneficial. In patients with migraine with aura, transcranial magnetic stimulation at the occipitalis is another option.

The patient should also be counseled on how to use symptomatic medication effectively, using migraine-specific medications when possible at headache onset. Waiting until the headache has built up in intensity may render the symptomatic medication less effective. The goal is to stop the headache, not just to decrease the intensity. The patient should limit all pain medications to 9 days or less per month to avoid medication overuse headache. Note that it is the number of days, not the total number of times during a day, that puts the patient at risk. Therefore, if within prescribing range, the patient should redose or use multiple medications from different categories in an effort to completely abort the headache.

Medication overuse headache only occurs in patients with primary headache disorders. It is defined as a headache occurring ≥15 days per month, with regular overuse for >3 months of ≥1 medication that can be taken for symptomatic relief of headache. The top 3 offenders are caffeine, butalbital, and opioids. However, any symptomatic pain medication or decongestant, whether used for headache or another condition, has the potential to cause medication overuse headache in a patient with a primary headache disorder. Therefore, patients should avoid, if possible: (1) opioids (including butorphanol nasal spray); (2) combination medications containing butalbital, tramadol, or caffeine; and (3) short-acting NSAIDs (eg, ibuprofen). In addition, because many symptomatic medications are available over the counter, it is important to ask patients about nonprescription medication use (type and number of days per week). This is especially important because in the setting of medication overuse headache, preventive and abortive medications are less efficacious.

Tension-Type Headache

The prevalence of episodic tension-type headache is high, as it is the most common primary headache disorder in the population. It affects women slightly more than men, with an onset between the second and third decades of life and the highest prevalence between the third and fourth decades of life. Much like migraine, there is a decline in the prevalence of tension-type headache later in life. Because the severity of tension-type headache remains mild to moderate, patients are less likely to seek medical attention unless the headache becomes more frequent and meets criteria for the frequent episodic or chronic tension-type headache subtypes. The pathophysiology of tension-type headache is under investigation. It is thought that peripheral pain mechanisms are involved in episodic tension-type headache, whereas central pain mechanisms are more significant in chronic tension-type headache.

Tension-type headache is further subdivided into the following subtypes: infrequent episodic (once per month; <12 days per year), frequent episodic (<15 days per month; >12 days but <180 days per year), and chronic (>15 days per month; >180 days per year). The headache can last 30 minutes to 7 days in the episodic subtype and hours to days if not unremitting in the chronic tension-type subtype. It requires 2 of the following 4 characteristics: (1) bilateral location (Figure 26–7), (2) pressing or tightening (nonpulsating) quality, (3) mild or moderate intensity, and (4) not aggravated by routine physical activity. Tension-type headache requires no more than 1 symptom of photophobia, phonophobia, or mild nausea and neither of the symptoms of moderate or severe nausea or vomiting.

Episodic infrequent tension-type headache can be treated with over-the-counter analgesics including acetaminophen, aspirin, and ibuprofen. There is always the potential for medication overuse headache, and the patient should be instructed to take symptomatic medications 9 days or less per month, or about twice per week. Episodic frequent and chronic tension-type headaches can cause moderate to severe disability and are treated with a treatment strategy similar to migraine headache. Amitriptyline has been shown to be efficacious in the preventive treatment (level I evidence) of tension-type headache; however, given the overlap between migraine and tension-type headache, other migraine prophylactic agents can also be used.

Trigeminal Autonomic Cephalgias

The trigeminal autonomic cephalgias are a group of headache disorders characterized by unilateral headache associated with ipsilateral autonomic features. These include cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks (with 2 forms: short-lasting unilateral neuralgiform headache attacks with conjunctival injection and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms), and hemicrania continua.

Cluster headaches are very severe headaches that occur in bouts, typically every 6 to 24 months. During a bout, patients have a number of cluster attacks (headaches), usually 0.5 to 8 per day when the disorder is active. Although not part of the diagnostic criteria, circadian periodicity is a hallmark of cluster headaches, and the times of attacks are often predictable, frequently occurring at night. The syndrome is relatively rare and male predominant.

Cluster headaches attacks cause unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes (Figure 26–8). These headaches are very intense and are often referred to as “suicide headaches” because they pain is so severe it can lead to suicidal ideation or attempt during an attack. Cluster headaches must have either or both of the following: (1) at least 1 ipsilateral autonomic symptom including conjunctival injection, lacrimation, eyelid edema, ptosis, miosis, nasal congestion and/or rhinorrhea, forehead and facial sweating and/or flushing, and/or a sensation of fullness in the ear (Figure 26–9), or (2) a sense of restlessness or agitation during an attack. Unlike migraine patients who prefer to be still during an attack, patients with cluster headache tend to pace and move around during a cluster episode.

Prior to diagnosis, secondary disorders that can present like cluster headache, including pituitary tumors, need to be ruled out. Therefore, this patient population needs neuroimaging with magnetic resonance imaging (MRI) of the brain at presentation. If the history is suspicious for vascular etiology, then further vascular imaging of the head and neck may be warranted to look for arterial dissection, aneurysm, or arteriovenous malformations, among other causes. Management of cluster attacks involves counseling against alcohol use during the cluster bout and discussing the use of preventive and abortive therapies.

The drug treatment of choice for a cluster attack is subcutaneous sumatriptan. When available, continuous inhalation of 100% oxygen at 7 to 12 L/min via a non-rebreathing facial mask for 15 to 20 minutes can completely abort a cluster attack. However, a quarter of patients find that oxygen only delays an attack. Preventive medications are used to speed up the time to remission and to decrease the frequency and intensity of cluster attacks during a bout. Except in patients with chronic cluster headache, there is no evidence that continuing prophylactic medications beyond the cluster bout is beneficial. Preventive treatments that can be used include lithium, verapamil, gabapentin, topiramate, valproic acid, corticosteroids, and high-dose melatonin. Greater occipital nerve and sphenopalatine ganglion blocks using local anesthetic in combination with steroid can also be effective.

Hemicrania continua is more common in women and generally presents in adulthood. It is a unilateral, mild to moderate continuous headache with exacerbations of moderate to severe intensity that often has both autonomic and migrainous associated symptoms. The diagnostic criteria require either or both of the following: (1) at least 1 ipsilateral autonomic symptom and/or (2) a sense of restlessness or agitation or aggravation of pain by movement. Hemicrania continua is an indomethacin-responsive headache. The treatment and diagnosis rest on the response to indomethacin, and the dose should be up titrated to at least 50 mg 3 times per day before efficacy is determined. If needed, it can be increased to 75 mg 3 times per day as tolerated. In patients who cannot tolerate indomethacin, Boswellia serrata extract is an herbal supplement with a similar chemical structure that may be beneficial.

Other Primary Headache Disorders

The other primary headache disorders include primary cough headache, primary exercise headache, primary headache associated with sexual activity, primary thunderclap headache, cold-stimulus headache, external-pressure headache, hypnic headache, primary stabbing headache, new daily persistent headache, and nummular headache.

Hypnic headache mainly occurs in the elderly (age >40 to 50 years) and is more common in women. It presents as frequent headaches that are only present during sleep and usually occur around the same time each night. The diagnostic criteria require that the recurrent headache attacks (1) develop only during sleep and cause awakenings; (2) occur on ≥10 days a month; (3) last from 15 minutes to 4 hours after awakening; and (4) have no autonomic symptoms or a sense of restlessness. Other causes of secondary headache that can lead to nocturnal awakenings such as sleep apnea, nocturnal hypertension, subdural hematomas, communicating hydrocephalus, vascular lesions, temporal arteritis, pheochromocytomas, subacute angle-closure glaucoma, and medication overuse or withdrawal headache need to be excluded. Scheduled bedtime caffeine, melatonin, indomethacin, and lithium have been found to be effective in the treatment of hypnic headache.

Primary stabbing headache often occurs in migraine patients and can coexist in those with other primary headache disorders. Among other descriptions, it has been referred to as “jabs and jolts syndrome” and “ice pick headache.” It is characterized by brief and localized stabs of pain that occur in the absence of pathologic damage to underlying structures or cranial nerves. The diagnostic criteria require head pain occurring spontaneously as a single stab or a series of stabs where (1) each stab lasts for up to a few seconds; (2) stabs recur with irregular frequency, from 1 to many per day; and (3) there are no cranial autonomic symptoms. Other causes for similar pain such as meningioma and pituitary tumors, cerebrovascular diseases, cranial or ocular trauma, and herpes zoster need to be ruled out prior to diagnosis. This is usually an indomethacin-responsive headache at total daily doses of 25 to 150 mg. However, if a patient is unable to tolerate indomethacin, success has been reported with high-dose melatonin or the use of gabapentin.

New daily persistent headache is described as development of a daily and unremitting headache in a patient who does not have history of major life stressor, trauma, or illness prior to the onset of headaches. There usually is no history of prior headaches; however, if such history is present, then the patient does not report a crescendo in headache frequency and/or intensity over the time preceding onset of daily headaches. If present, this pattern might suggest medication overuse headache or other types of secondary headache. A patient with new daily persistent headache is able to give a definitive date of when the headache started. The diagnostic criteria necessitate a distinct and clearly remembered onset, with pain becoming continuous and unremitting within 24 hours. Since the diagnosis of new daily persistent headache is one of exclusion, it requires normal neuroimaging, lumbar puncture, and blood work. Preventive medications used for other headache disorders are often tried in new daily persistent headache with variable efficacy.

Nummular headache has a female predominance with a mean age of onset in the fourth decade of life. The root of the word means “resembling a coin,” and the pain usually affects a small, coin-shaped area of the scalp. The character of the pain can differ from one patient to the next and has been described as pressure-like, sharp, achy, throbbing, burning, or itching. There can also be exacerbations in the intensity of pain. The diagnostic criteria require continuous or intermittent head pain felt exclusively in the scalp with the following 4 characteristics: (1) sharply contoured, (2) fixed in size and shape, (3) round or elliptical, and (4) 1 to 6 cm in diameter. Gabapentin, tricyclic antidepressants, and injections of botulinum toxin at the headache site have been found to be effective in the treatment of nummular headache.

SECONDARY HEADACHE SYNDROMES

It is important to know the warning signs that need to be worked up in order to distinguish primary from secondary headache disorders. Historical “red flags” or an abnormal neurologic exam needs to be expeditiously investigated. Despite being aware of these warning signs, some secondary headaches can be missed if the practitioner does not have a high level of suspicion, and these include medication overuse headaches and medication or caffeine withdrawal headaches. Further, the presence of these headaches can have a great impact on the efficacy of preventive and abortive headache treatments. Medication overuse headache was described earlier in the migraine section to emphasize the most common offending agents and stress the importance of limiting symptomatic migraine therapy to ≤9 days per month.

Medication withdrawal headache requires daily intake of a substance for >3 months that has been interrupted. Evidence of causation is demonstrated by both of the following: (1) the headache has developed in close temporal relation to withdrawal from the substance, and (2) the headache has resolved within 3 months after total withdrawal from the substance. Caffeine withdrawal headache requires caffeine consumption of >200 mg/d (∼2 cups of coffee) for >2 weeks, which has been interrupted or delayed. There is also evidence of causation demonstrated by development of the headache within 24 hours of last caffeine intake and either headache relief within 1 hour of taking 100 mg of caffeine or resolution within 7 days of total caffeine withdrawal.

Medication overuse and withdrawal are probably the most common causes of intractability in migraine patients. These causes can be missed by a practitioner because patients often do not include over-the-counter analgesics, decongestants, and herbal supplements in their medication list. In addition, caffeine intake is generally not part of a routine social history and can be overlooked. Some patients are also embarrassed about medication misuse, and therefore, it is essential to take a detailed medication history focusing on both prescription and over-the-counter medications, including vitamins, herbs, and natural products. Excessive use of symptomatic agents and caffeine overuse (on average more than once a day) can cause intractable migraine, and vitamin A or D overuse may lead to headaches. When stopping or tapering the offending agent, the patient may have an initial worsening of the headache before there is improvement. This worsening can be bridged with relaxation therapy and outpatient pharmacologic treatment using long-acting NSAIDs, muscle relaxers, or steroids, but may require inpatient admission for detoxification from an offending agent if the patient has daily use of potent opioids and/or barbiturates or has failed outpatient attempts.

High- and low-pressure headaches can also be tricky to diagnose. The historical warning signs (see Table 26–1) and neurologic exam can raise the clinician’s level of suspicion, but it can sometimes be difficult to distinguish between the 2 conditions.

Idiopathic Intracranial Hypertension

Idiopathic intracranial hypertension, also known as pseudotumor cerebri, most commonly occurs in obese women of childbearing age. The disease is most prevalent in the second and third decades of life. The majority of patients present with headache that is worse with lying down and Valsalva maneuvers. It is accompanied by symptoms of increased intracranial pressure including transient episodes of visual loss and visual obscurations, pulse-synchronous tinnitus, diplopia due to cranial nerve VI palsy, and papilledema (Figure 26–10), which is the hallmark of idiopathic intracranial hypertension, with associated visual loss.

Idiopathic intracranial hypertension is characterized by increased cerebrospinal fluid opening pressure (>250 mm H₂O) without evidence of ventriculomegaly. It is thought to be secondary to decreased absorption of cerebrospinal fluid, although increased production may also play a role. Neurodiagnostic studies reveal no ventricular obstruction, abnormal enhancement, or intracranial lesion to explain the increased pressure. MRI of the brain can show signs of increased intracranial pressure including flattening of the posterior sclera and a partial empty sella turcica. Potential intracranial lesions include scarring secondary to previous inflammation (eg, meningitis, subarachnoid hemorrhage) leading to decreased flow through the arachnoid granulations and venous sinus thrombosis causing obstruction of venous flow. Arteriovenous malformations and dural shunts are also associated with intracranial hypertension. Other potential secondary causes of intracranial hypertension include corticosteroid withdrawal, increased vitamin A, and the use of isotretinoin and tetracycline. The differential also includes obstructive sleep apnea and orthostatic edema (abnormal systemic retention of sodium and/or water).

Most patients with idiopathic intracranial hypertension and papilledema have visual loss, and perimetry to assess visual field defects is the main measure used to determine the course of therapy. The management of idiopathic intracranial hypertension is divided into symptomatic treatment of headaches and treatment of increased intracranial pressure. Medications used in prophylaxis of migraine can be effective in symptomatic treatment of headaches; however, agents that cause weight gain should be avoided or monitored closely. Topiramate can be used for the treatment of headache, but it is a weak carbonic anhydrase inhibitor, and therefore, it should not be used alone to decrease intracranial hypertension.

Patients should be counseled on weight loss (about 10% of the patient’s body weight) as an effective treatment of intracranial hypertension. A low-sodium diet and avoiding excessive fluid intake can also help in the management of idiopathic intracranial hypertension. Acetazolamide is effective at lowering intracranial pressure because it is a carbonic anhydrase inhibitor that reduces production of cerebrospinal fluid. It can cause changes in taste, paresthesias, and drowsiness. Furosemide is a second-line agent that is efficacious in the treatment of idiopathic intracranial hypertension either alone or in combination with acetazolamide. It is thought to work both by decreasing sodium transport to the brain and increasing urine production. However, potassium supplementation is required. If the patient is refractory to medical treatment and has progressive visual loss, optic nerve sheath fenestration is indicated. Ultimately, if other therapies have failed and vision loss continues, lumboperitoneal or ventriculoperitoneal shunting should be considered. Surgical procedures should not be used if refractory headache is the only symptom.

Spontaneous Intracranial Hypotension

The presentation of spontaneous intracranial hypotension is analogous to that caused iatrogenically in post–lumbar puncture headache. Spontaneous intracranial hypotension is often preceded by trivial trauma (eg, lifting boxes, falls, coughing, roller coaster rides, exercise). Patients who are hyperflexible or have a history of connective tissue disorders seem to be predisposed to developing spontaneous intracranial hypotension. It is thought to be caused by cryptogenic cerebrospinal fluid leaks via dural fistulas adjacent to the spinal roots. Tears in the arachnoid and dural layers can also lead to chronic cerebrospinal fluid leaks. The majority of the leaks in this condition are in the thoracic spine or near the cervicothoracic junction. Cranial nerve abnormalities are thought to be secondary to downward traction caused by decreased pressure.

Spontaneous intracranial hypotension presents as a postural headache that is worse when upright and better lying down, and it tends to be worse toward the end of the day. The character and location of headaches in spontaneous intracranial hypotension can be variable, but most often, they are either holocephalic or in the bilateral frontal, occipital, or occipitofrontal regions. Neck stiffness or pain, nausea, and tinnitus tend to be more common, and other associated symptoms of interscapular pain, upper extremity radicular pain, vomiting, auditory muffling, dizziness, diplopia, or visual blurring may also be present. In extreme cases, intracranial hypotension can cause alterations in consciousness. Physical exam can be normal, but often the patient’s headache improves or resolves after being placed in the Trendelenburg position for about 5 minutes.

Neuroimaging can show pachymeningeal gadolinium enhancement (Figure 26–11) and cerebellar tonsillar descent. Sometimes, subdural hematomas can be present, although in roughly 25% of cases, MRI of the brain with contrast is normal. On lumbar puncture, opening pressure is low or unobtainable; otherwise, cerebrospinal fluid studies are normal. Patients can improve with caffeine and hydration; however, often treatment with an epidural blood patch is warranted. In this procedure, approximately 20 mL of the patient’s blood is drawn and then injected into the epidural space, and clotting factors in the blood help seal the leak. Computed tomography and MRI myelography may be necessary to confirm and locate the leak for directed high-volume epidural blood patching or fibrin glue, among other options if initial treatments fail.

NEUROLOGIC PAIN SYNDROMES

Fibromyalgia

Fibromyalgia is often a comorbid condition in patients with chronic headaches. It is more common in women, with a prevalence of 2% to 3% worldwide that is similar across different socioeconomic classes. It manifests as chronic widespread musculoskeletal pain and tenderness. The pathophysiology is likely multifactorial, and associated genes are linked to pathways controlling pain sensitivity and the stress response. There are theories that chronic fibromyalgia can elicit the same central sensitization that is seen in chronic migraine, likely through similar neuropeptide cascades (eg, calcitonin gene-related peptide and substance P). The term fibromyalgia is something of a misnomer, and there is no evidence of inflammation or lesions of the fibrous tissues of the muscles, fascia, and aponeuroses.

The diagnosis is based on clinical symptoms of widespread pain and neuropsychological symptoms. Tenderness to palpation (4 kg of digital pressure) of predefined sites in the occiput, trapezius, supraspinatus, gluteal region, greater trochanter, low cervical region, second rib, lateral epicondyle, and knee bilaterally on exam can help with diagnosis (Figure 26–12). Management of patients with fibromyalgia revolves around counseling on improvement of quality of life rather than abolition of pain. Physical therapy, relaxation techniques, and cognitive behavioral therapies are used in conjunction with pharmacologic treatments such as antidepressants (amitriptyline, duloxetine, milnacipran) and anticonvulsants (gabapentin, pregabalin).

Complex Regional Pain Syndrome

Complex regional pain syndrome is a neurogenic pain syndrome. Complex regional pain syndrome type I develops spontaneously and was formerly known as reflex sympathetic dystrophy. Complex regional pain syndrome type II is more common and occurs after nerve injury including trauma or immobilization of a limb and was formerly known as causalgia. The pathophysiology underlying complex regional pain syndrome is under investigation. It was initially postulated that the pain was related to short-circuiting of impulses; however, it is now thought that the abnormal cross-excitation is chemical (secondary to neurotransmitters) rather than electrical. Studies are underway to define the molecular changes that occur in the nervous system with this type of chronic pain.

In both types of complex regional pain syndrome, there is persistent disabling regional neuropathic pain in the absence of recognizable pathology to adjacent nerves. There is also associated regional autonomic dysfunction, and patients can present with limb edema, skin discoloration, altered temperature/sweating, allodynia, and hyperalgesia. Medications used to treat neuropathic pain disorders that are similar to those used as preventive therapy in migraine should be used. Early mobilization of the limb also helps. Overall, current treatment options are unsatisfactory.

Postherpetic Neuralgia

Herpes zoster, commonly known as shingles, is a relatively common condition affecting older individuals and those who are immunocompromised. The herpes virus primarily lies dormant in the spinal ganglia, especially in the unilateral thoracic or lumbar segments. In a significant minority of patients, the cranial ganglia, especially the ophthalmic division of the trigeminal ganglion, can be involved (Figure 26–13). When the virus reactivates, neuralgic pain or dysesthesia is the presenting symptom. This is followed in about 4 days by cutaneous erythema and vesicular eruption in the area supplied by the affected roots. The vesicular eruption scabs over in about 10 to 14 days. Postherpetic neuralgia can persist for ≥3 months in a significant minority of patients. Diagnosis is based on history and clinical exam; however, if necessary, the vesicular fluid can be cultured for varicella-zoster virus.

The zoster vaccine is recommended as preventive treatment in all patients age 60 or older. Antiviral therapy with acyclovir is the treatment of choice for acute herpes zoster, but valacyclovir and famciclovir can also be used and may be more successful at decreasing healing time and the duration of postherpetic neuralgia. The prompt administration of antivirals within the first 72 hours of varicella-zoster virus reactivation may decrease the duration of postherpetic neuralgia. Amitriptyline and other tricyclic antidepressants, as well as antiepileptic medications including carbamazepine, gabapentin, and phenytoin, can be effective, although postherpetic neuralgia is often refractory to medical treatments.

Trigeminal Neuralgia

Trigeminal neuralgia is also known as tic douloureux and is the most common of all neuralgias. Idiopathic trigeminal neuralgia presents in middle age and later in life. It is characterized by severe, paroxysmal, sharp and stabbing facial pain without numbness or objective findings in the distribution of the fifth cranial nerve. The second and third divisions of the trigeminal nerve are more commonly affected (Figure 26–14). The cause of trigeminal neuralgia is unknown. Theories based on patients’ response to treatments suggest that it may be related to excessive firing within the fifth cranial nerve nucleus with concomitant peripheral excitation and abnormal neuronal chemical discharges. The diagnostic criteria require attacks of unilateral facial pain in 1 or more divisions of the trigeminal nerve (without radiation outside of the nerve) with at least 3 of the following 4 characteristics: (1) recurring in paroxysmal attacks lasting from a fraction of a second to 2 minutes; (2) severe intensity; (3) electric shock–like, shooting, stabbing, or sharp pain; and (4) precipitated by innocuous stimuli to the affected side of the face. Although some attacks can be spontaneous, patients report minimal stimulation provoked by chewing, facial movements, touch, or temperature (even a breeze) can trigger an attack.

Trigeminal neuralgia can be symptomatic due to underlying neurologic lesions and therefore is a diagnosis of exclusion that requires imaging of the brain and arterial vasculature to look for compression of the trigeminal nerve, basilar artery aneurysm, tumor in the cerebellopontine angle, or multiple sclerosis among the potential causes. Trigeminal neuralgia in a young female, especially if bilateral, should raise the suspicion for multiple sclerosis. The most effective treatment for trigeminal neuralgia is carbamazepine, which can cause drowsiness, dizziness, and ataxia. Blood work should be monitored for renal toxicity, hepatotoxicity, pancytopenia, and hyponatremia. Other antiepileptic medications such as phenytoin, valproic acid, gabapentin, and pregabalin can help as well. Baclofen is also effective, especially as adjunctive therapy to an anticonvulsant. If the pain is refractory, the patient may be a candidate for botulinum toxin injections to the affected trigeminal division or surgical procedures including microvascular decompression, radiofrequency ablation, chemical gangliolysis, and rhizotomy.

Phantom Limb Pain

The incidence of phantom limb pain in patients requiring amputations is high, and factors such as the site of amputation and the presence of preamputation pain are associated with the risk of developing phantom limb pain. Phantom limb pain is the sensation that pain is coming from a body part that no longer exists, although it does not necessarily need to be a limb (eg, tongue). The pain is likely generated secondary to peripheral and central mechanisms. Although the mechanism is poorly understood, symptoms are likely secondary to a combination of neuroma hypersensitivity in the periphery, spinal cord sensitization, and cortical reorganization. Tricyclic antidepressants; anticonvulsants such as carbamazepine, oxcarbazepine, gabapentin, and pregabalin; and memantine are agents used in the treatment of phantom limb pain. Transcutaneous nerve stimulation, mirror therapy, biofeedback, and cognitive-behavioral therapy can also be beneficial. Nerve blocks and surgical procedures can be considered if conservative therapies fail.

Central Pain Syndrome

Central pain syndrome is also known as thalamic pain syndrome and Dejerine-Roussy syndrome. Patients with this syndrome have continuous moderate to severe pain (with variable characterization: tingling, aching, stabbing, burning, pressure-like) secondary to a lesion in the central nervous system (brain, brainstem, and spinal cord) that can be exacerbated by trivial cold or hot stimuli, emotional disturbances, and loud noises. Despite this, the patient has a higher pain threshold to objective testing in the affected hemibody. The syndrome was first described secondary to stroke in the ventral posteromedial and ventral posterolateral nuclei of the thalamus (posterior cerebral artery–penetrating branches). Classically, there is initial hemisensory loss that is followed by hemibody pain. In this instance, the pain is thought to be secondary to partial recovery of the thalamus. Acute but incomplete lesions (eg, vascular insult, multiple sclerosis, tumors, epilepsy) affecting the central nervous system can also produce central pain syndrome. Lesions causing central pain syndrome have been reported in the thalamus, parietal lobe, medial lemniscus, and posterior columns of the spinal cord. Stress reduction in conjunction with tricyclic antidepressants or anticonvulsants, including gabapentin, can help in the treatment of central pain syndrome.

OBJECTIVES

A seizure is a transient occurrence of signs and/or symptoms due to abnormal, excessive, or synchronous neuronal activity in the brain. Seizures can be caused by a wide variety of provoking insults, including electrolyte disturbances, brain injury/insult, and fevers in children, or can occur completely unprovoked (Table 27–1). After a single unprovoked seizure, only about 30% of patients will go on to have another seizure. After 2 seizures have occurred, the recurrence risk for additional seizures is approximately 75%.

Epilepsy is a disorder of the brain characterized by a predisposition to generate recurrent unprovoked epileptic seizures. It is defined by any of the following conditions: (1) at least 2 unprovoked seizures occurring >24 hours apart; (2) 1 unprovoked seizure and a high probability of further seizures occurring over the next 10 years because of an underlying predisposing condition; or (3) diagnosis of an epilepsy syndrome.

PREVALENCE & BURDEN

Approximately 2 million Americans and >65 million people worldwide have epilepsy. The prevalence of epilepsy in the general population is about 1%. Each year, approximately 300,000 people have their first seizure and 150,000 new cases of epilepsy are diagnosed. The incidence of epilepsy is highest in young children and older adults. Risk factors for developing epilepsy include intellectual or developmental delay, family history of seizures, cerebral palsy, autism, hypoxia, stroke, head trauma, central nervous system infection, intracranial hemorrhage, dementia, brain tumors, and tubers or other brain malformations.

Risk of death is up to 3 times higher in patients with epilepsy than the general population. Causes of death in epilepsy include injury, drowning, suicide, status epilepticus, and sudden unexpected death in epilepsy (SUDEP). SUDEP is defined as a sudden, unexpected, nontraumatic, nondrowning, witnessed or unwitnessed death while in a reasonable state of health in a person who has epilepsy and no other obvious or structural cause. SUDEP is the leading cause of epilepsy-related death, with >1 out of 1000 people with epilepsy dying each year. The main risk factors for SUDEP include the presence of generalized convulsive seizures and frequent or uncontrolled seizures of any kind. Other risk factors include long duration of epilepsy, epilepsy beginning at a young age, medication nonadherence, stopping or changing medications suddenly, intellectual disability, young adult age, and diffuse generalized suppression noted on electroencephalogram (EEG) immediately following a seizure. The exact cause of SUDEP is unknown at this time.

SEIZURE CLASSIFICATION (GENERALIZED TONIC-CLONIC, PARTIAL, & ABSENCE)

Seizures are classified according to the scheme proposed by the International League Against Epilepsy (Figure 27–1). This classification scheme divides seizures into partial onset and generalized based on the origin of the seizures, with partial-onset seizures arising from 1 focal area in the brain and generalized seizures arising from epileptic networks that affect the entire brain at the same time. Partial-onset seizures can be further divided into simple partial seizures, which are focal seizures with preserved consciousness, and complex partial seizures, which are focal seizures with loss of consciousness. Partial-onset seizures can arise from any cortical region, and the clinical manifestations of the seizure correspond to that location. For example, partial-onset seizures arising from the occipital region manifest with visual phenomena. Generalized seizures can be further divided into types of seizures based on their clinical manifestations: tonic-clonic, tonic, clonic, atonic, myoclonic, and absence.

Tonic-clonic seizures have an initial tonic phase whereby there is continuous contraction of the muscles of the limbs, initially in a flexed position, followed by extension. There may also be contraction of the respiratory muscles, which can result in a vocalization called an “ictal cry.” Contraction of the masticatory muscles can lead to tongue biting and other oral trauma. The tonic phase is followed by a clonic phase where there is symmetric, rhythmic jerking of the limbs. The jerking is initially of lower amplitude and faster frequency, and as this phase progresses, the jerking becomes larger in amplitude and slower in frequency. As the seizure subsides, respiratory effort returns and can result in deep gasping and/or snoring sounds.

Tonic seizures consist only of continuous contraction of the limb, respiratory, and masticatory muscles without the subsequent clonic phase.

Clonic seizures consist only of symmetric, rhythmic jerking of the limbs, without the initial tonic phase.

Atonic seizures are also called “drop attacks” and result in a loss of muscular tone. This seizure type has a strong association with injury and is frequently seen in patients with Lennox-Gastaut syndrome.

Myoclonic seizures consist of brief, shock-like muscle contractions. They can occur in 1 or both hemispheres simultaneously and involve small or large muscle groups. Typically, they occur in the arms but can involve the legs or have a more generalized distribution. This seizure type is frequently seen in patients with juvenile myoclonic epilepsy.

Absence seizures consist primarily of staring with loss of consciousness and without a significant postictal period. Minor eye and mouth movements can be seen, but more complex automatic behaviors are uncommon.

Etiologies of epilepsy can be classified as genetic, structural/metabolic, or unknown. Genetic epilepsies are the result of a known or presumed genetic defect. Structural causes can include stroke, trauma, or tumors. When they are not genetic and no structural or metabolic cause is found, they are unknown.

EPILEPSY SYNDROMES

In addition to the descriptive terms used to classify epilepsy, there are a number of recognizable epilepsy syndromes. These are diagnosed because of the presence of a constellation of consistent clinical and electrical features (Figure 27–2). Recognizing epilepsy syndromes can help to guide treatment and predict outcome. Some of the most common seizure syndromes are listed here. For additional details, please see Chapter 35, “Pediatric Neurology.”

West syndrome is characterized by the triad of infantile spasms, hypsarrhythmia on EEG, and developmental regression. West syndrome is most often caused by tuberous sclerosis but can also be seen in patients with focal cortical dysplasias, malformations of cortical development, perinatal hypoxia, and various metabolic syndromes. Many of these patients evolve to develop Lennox-Gastaut syndrome or other generalized epilepsies.

Dravet syndrome usually begins in infancy with febrile and afebrile generalized and unilateral clonic or tonic-clonic seizures. Up to 80% of patients will have a mutation in the sodium channel α1 subunit (SCN1A) gene.

Childhood absence epilepsy (CAE) begins in children age 3 to 8 years old. Seizures consist mainly of staring off with loss of consciousness and a minimal postictal period. Typically, they occur multiple times per day and are provoked by hyperventilation. Minor eye or mouth movements can be seen, but more complex automatic behavior is uncommon. The EEG is typically normal interictally except for generalized spike and wave discharges that occur at 3 Hz. During a seizure, the EEG shows prolonged bursts of 3-Hz generalized spike and wave discharges that can last up to 10 to 20 seconds. Absence seizures resolve by the teenage years in >90% of patients, and those who continue to have seizures often evolve to have juvenile myoclonic epilepsy (Figure 27–3).

Lennox-Gastaut syndrome begins in children age 3 to 8 years old and is preceded by West syndrome in 20% of patients. Lennox-Gastaut syndrome is defined by a triad of mixed seizure types, abnormal EEG, and encephalopathy. The most common seizure type is the “drop attack” or atonic seizure, followed by tonic and atypical absence seizures. Generalized tonic-clonic and focal seizures can also occur. The EEG pattern shows diffuse background slowing as well as interictal slow spike and wave discharges at <2.5 Hz and generalized paroxysmal fast activity noted during sleep. Seizures are frequently medically refractory, and intellectual prognosis is poor.

Benign epilepsy with centrotemporal spikes is the most common form of epilepsy in childhood, with onset between 3 and 13 years of age. Seizures are mostly nocturnal and consist of focal sensory and motor seizures, particularly beginning in the face. These seizures infrequently progress to generalized tonic-clonic seizures. The interictal EEG shows single and repetitive unilateral or bilateral independent spike and wave discharges in the centrotemporal region. Rarely is medical treatment needed, and seizures generally remit within several years of onset.

Febrile seizures occur between 6 months and 6 years of age and typically affect 2% to 5% of children. They usually occur during the first 24 hours of a febrile illness. Simple febrile seizures consist of brief, generalized convulsions that lack focal features. Approximately two-thirds of children with simple febrile seizures have a single seizure, and <10% of children have >3 febrile seizures. Complex febrile seizures can be prolonged, have focal features, or occur with multiple seizures during the first 24 hours. These features increase the likelihood of subsequently developing epilepsy, which occurs in 2% to 6% of children with febrile seizures. Febrile seizures plus is an epilepsy syndrome that begins with febrile seizures in infancy or childhood. Patients then go on to develop other seizure types that are not necessarily associated with fever. This is a genetic syndrome with multiple gene mutations identified, such as those affecting SCN1A and type A γ-aminobutyric acid (GABA) receptor.

Juvenile absence epilepsy (JAE) begins at age 8 to 12 years old and consists of absence seizures and rare generalized tonic-clonic seizures. The absence seizures in JAE are less frequent than those in CAE. The interictal EEG is similar to that in CAE, consisting of 3-Hz generalized spike and wave discharges. Seizure remission occurs in >80% of patients with JAE by the end of the teenage years.

Juvenile myoclonic epilepsy is the second most common epilepsy syndrome across all age groups and accounts for approximately one-sixth of adult epilepsies. Seizures usually begin between age 12 and 18 years and may follow CAE or JAE. The hallmark of this syndrome is frequent myoclonic jerks, particularly upon awakening, in addition to generalized tonic-clonic seizures. Approximately one-third of patients also have absence seizures. The interictal EEG consists of 4- to 6-Hz generalized spike/polyspike and wave discharges. Seizures typically respond well to medication, with prolonged seizure-free intervals easily attainable, but seizures will recur upon medication withdrawal.

DIAGNOSIS

Origins of EEG

The EEG is recorded from wires placed on the surface of the head and represents electrical activity in the brain transmitted through the skull and skin. Pyramidal cells are the primary output neurons of the cerebral cortex. They are glutamatergic and compose approximately 80% of the neurons of the cortex. Their cell bodies are triangular shaped and have a single apical dendrite that is oriented toward the pial surface, multiple basal dendrites, and a single axon (Figure 27–4). Pyramidal cells are grouped closely together and organized in the same orientation. The EEG signal is derived from the summation of excitatory postsynaptic potentials and inhibitory postsynaptic potentials of the apical dendrites of pyramidal cells. The activity of a single cell is too small to detect, but when pyramidal cell activity becomes synchronized over a large number of cells, then the electrical activity can be detected (Figure 27–5). EEG is recorded from highly conductive silver or gold cup electrodes placed on the surface of the scalp. The electrodes are placed at regular intervals and labeled according to the International 10–20 System (Figure 27–6). The electrical signal must travel through many layers before reaching the recording electrode, including pia mater, subarachnoid space, arachnoid mater, dura mater, skull, subcutaneous tissues, and scalp. All of these layers degrade the electrical signal to a degree, such that there is temporal and spatial dispersion, as well as decreased amplitude. Because pyramidal cells are oriented perpendicular to the cortical surface, EEG best measures electrical activity from the gyri close to the skull and does not accurately measure electrical activity from the sulci. The paroxysmal depolarization shift (PDS) is the pathophysiologic cellular phenomenon that underlies all types of epileptic seizures and interictal epileptiform activity. The PDS occurs when rapidly repetitive action potentials are not followed by the usual refractory period, which causes a prolonged membrane depolarization. An interictal epileptiform discharge occurs when a large number of neurons generate a synchronous PDS (Figure 27–7). An epileptic seizure occurs when a large number of neurons repeatedly generate synchronous PDSs.

Importance of EEG

EEG is the main diagnostic tool used for epilepsy; however, a normal EEG does not exclude the diagnosis of epilepsy. The EEG has a sensitivity of approximately 50% to 60% and a specificity of approximately 70% to 90% in predicting seizure recurrence. Interictal epileptiform discharges are detected in approximately 30% to 55% of patients with seizures on their initial EEG and are associated with a 2-fold increased risk of seizure recurrence. Several methods can further increase the diagnostic value of the EEG. If the EEG is obtained within 24 hours of the seizure episode, the sensitivity is increased by 15%. If the EEG is obtained during sleep, the sensitivity is increased by 25%. If no abnormalities are noted on the initial EEG, then repeated testing increases the likelihood by 15% to 20% that interictal epileptiform discharges will be seen, up to 90% by the fourth EEG obtained. Different types of EEG studies can be performed based on the clinical situation and needs of the patient.

A routine EEG is performed in the EEG laboratory and records approximately 20 minutes of cerebral activity. Prolonged EEG recordings of an hour or more can be performed at the physician’s discretion. Additional time for EEG recording increases the probability that interictal epileptiform discharges will be seen during the test.

A sleep-deprived EEG is performed in the EEG laboratory after a night of voluntary sleep deprivation. Because EEG during sleep improves sensitivity, this test is ordered to improve the likelihood that the patient will fall asleep during the test.

A continuous video EEG is performed while the patient is hospitalized. It can be performed on comatose patients or those who need a definitive diagnosis or characterization of their events. The video is beneficial because it can be correlated with EEG to improve diagnostic accuracy. Subtle changes on the EEG can be mistaken for epileptic patterns where video would confirm that such changes are simply due to artifact. Continuous EEG is performed on patients while admitted to the hospital where medical staff are available for close monitoring. During the hospitalization, medications are withdrawn and other provocative measures are performed to try to induce seizures, which puts patients at high risk for status epilepticus. An epilepsy monitoring unit (EMU) is a designated area in the hospital where several patients can undergo continuous video EEG monitoring at the same time. The EMU is designed to evaluate, diagnose, and treat seizures of all kinds, as well as perform medication adjustments and evaluate for potential surgical and other therapies.

An ambulatory EEG is performed for 1 to 3 days while the patient is going about his or her daily routine, after an initial placement of electrodes in the EEG laboratory. This study allows for prolonged recording of cerebral activity and can capture clinical events. It is beneficial because the patient is allowed to remain in his or her usual environment where stress and activity levels are more typical. Unfortunately, because simultaneous EEG and video cannot usually be obtained, it is difficult to use this type of EEG to obtain a definitive diagnosis of epilepsy. In addition, because this is not performed in the hospital, medication withdrawal cannot be performed due to a high risk of status epilepticus.

DIFFERENTIAL DIAGNOSIS

The diagnosis of epilepsy is essential to initiate treatment and reduce morbidity and mortality. The principal steps toward making a proper diagnosis are obtaining a thorough history, performing a complete physical exam, and conducting appropriate testing.

A surprising number of patients referred for evaluation of epilepsy turn out to have other disorders. Events that mimic epileptic seizures typically fall into 1 of 2 categories: physiologic events or psychiatric events. Physiologic events can include syncope, migraine, transient ischemic attack, transient global amnesia, vertigo, sleep disorders, delirium, and intermittent movement disorders. Psychiatric events can include panic attack, conversion disorder, dissociative state, acute psychosis, and malingering. By far, the most common mimic for epileptic seizures is conversion disorder, which manifests as psychogenic nonepileptic spells (PNESs).

Psychogenic Nonepileptic Spells

PNESs consist of paroxysmal changes in movements, responsiveness, or behaviors that resemble epileptic seizures. These events can be distinguished from epileptic seizures by the absence of ictal EEG epileptiform abnormalities and typical clinical features. Typical clinical features of PNES include asynchronous limb movements, pelvic thrusting, side-to-side head movements, dystonic posturing including opisthotonos, out-of-phase clonic activity, and waxing and waning movements. Although these clinical features are often seen in PNES, none are pathognomonic for the disorder. Simultaneous video and EEG recordings are required to confirm the diagnosis of PNES.

PNES is common, composing 5% to 10% of outpatients in epilepsy clinics and 20% to 40% of inpatients in EMUs. It can occur at any age, but peak incidence is in young adulthood, and it is up to 3 times more common in women than men. It can also coexist in up to 5% of patients with a diagnosis of epilepsy. Predisposing factors for developing PNES include female sex; history of prior trauma including sexual abuse, physical abuse, or neglect; traumatic brain injury; and psychiatric comorbidities. These are factors that make someone susceptible to developing PNES. Precipitating factors include injury, death of a loved one, rape, surgical procedures, giving birth, natural disasters, family/relationship difficulties, and impending legal action. These factors can trigger a patient to begin having PNES. Perpetuating factors include anxiety, depression, misdiagnosis, and inappropriate treatment. These factors may worsen the severity of PNES and make it harder for patients to recover.

Treatment for PNES lies in formal psychological assessment and treatment with psychotherapy, such as cognitive-behavioral therapy. Psychopharmacology can also be helpful in certain circumstances where perpetuating factors are playing a large role. Once a diagnosis of PNES is confirmed, antiepileptic drugs (AEDs) should be tapered off because they do not treat conversion disorder. Unfortunately, even with proper psychotherapeutic treatments, many patients continue to have PNES. Factors associated with improved outcomes include younger age at onset and diagnosis, greater educational attainments, fewer somatoform complaints, and attacks with less dramatic features.

TREATMENT

Medical Management

Medications are the first-line therapy for epilepsy. Due to the potential risks of medications, it is important to carefully select patients who are likely to have further seizures if left untreated. The benefits of seizure control should outweigh the risks of the medications. Acute symptomatic seizures do not require long-term medication therapy, and not all patients presenting with their first unprovoked seizure will go on to have additional seizures. Increased risk of seizure recurrence is associated with prior brain insult, abnormal EEG with interictal epileptiform discharges, abnormal brain imaging, and history of nocturnal seizure. The main consideration in AED selection is one based on the seizure types that the patient experiences. Approximately two-thirds of patients will become seizure-free on the first or second AED used. It is also important to consider possible side effects in choosing AEDs. Adverse events occur in 10% to 30% of patients and are usually mild and reversible. Finally, drug interactions and patient comorbidities may also play a role in the decision-making process. For example, certain AEDs such as valproic acid should be avoided in patients with comorbid liver disease. Comparative effectiveness studies on initial monotherapy and adjunctive therapy for partial-onset seizures and generalized seizures have failed to demonstrate that one AED is clearly superior to any other AEDs. Therefore, practice guidelines recommend considering unique patient characteristics to guide AED selection, such as patient age, concomitant medications, and AED tolerability, safety, and efficacy. Some of the most commonly used AEDs are described in the following sections.

First-Generation AEDs

Phenytoin is indicated for the treatment of partial-onset and generalized tonic-clonic seizures and works by blocking voltage-gated sodium channels. It is highly protein bound and is metabolized in the liver. It is a strong inducer of the cytochrome P450 system. Phenytoin has a narrow therapeutic range and zero-order kinetics, such that a small change in dose can lead to a large change in the serum concentration, and thus, toxicity can easily occur. Dose-related side effects include nystagmus, ataxia, dysarthria, and encephalopathy. Common side effects related to long-term use include hirsutism, gingival hyperplasia, reduced bone density, and cerebellar degeneration. It comes in an intravenous formulation for the treatment of status epilepticus. Due to the alkaline nature of the intravenous solution, rapid infusion can lead to a complication called purple glove syndrome. Purple glove syndrome consists of edema, erythema, and blue-purple discoloration of the skin. This is a serious complication that can lead to necrosis and subsequent amputation if left unrecognized. When rapid infusion of phenytoin is necessary, it is best to use fosphenytoin, a water-soluble prodrug of phenytoin, which can be infused at a high rate more safely. Rapid infusion of phenytoin or fosphenytoin can cause severe hypotension and cardiac arrhythmias, so careful monitoring is required.

Carbamazepine is also indicated for the treatment of partial-onset and generalized tonic-clonic seizures and works by blocking voltage-gated sodium channels. It can exacerbate absence and myoclonic seizures and therefore is contraindicated in these patients. Carbamazepine is metabolized in the liver and induces the cytochrome P450 system. It also induces its own metabolism, called autoinduction, whereby increased dose may not lead to a significant increase in plasma concentration. Common dose-related side effects include hyponatremia, drowsiness, ataxia, diplopia, vertigo, and blurred vision. Serious side effects include skin rash, bone marrow suppression, and hepatic failure.

Valproic acid is indicated for the treatment of partial-onset and absence seizures that occur in isolation or in combination with other seizure types. It is a first-line treatment for juvenile myoclonic epilepsy. Valproic acid enhances GABA activity and may block voltage-gated sodium channels. It is highly protein bound and metabolized in the liver. It inhibits uridine diphosphate–glucuronosyltransferase (UGT) and the cytochrome P450 system. Common side effects include drowsiness, nausea, gastrointestinal disturbances, tremor, weight gain, and hair loss. Serious side effects include hyperammonemia, encephalopathy, hepatotoxicity, and pancreatitis. Valproic acid has a high incidence of birth defects, particularly neural tube defects, and should be used with caution in women of childbearing age.

Ethosuximide is indicated for the treatment of absence seizures and blocks low-threshold, “transient” (T-type) calcium channels in thalamic neurons. It is not effective against partial-onset or generalized seizures. It is primarily renally excreted but does undergo some hepatic metabolism. Common side effects include nausea, abdominal discomfort, drowsiness, anorexia, and headache.

Second-Generation AEDs

Topiramate is indicated for the treatment of partial-onset seizures, generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome. It blocks voltage-gated sodium channels, inhibits carbonic anhydrase, and increases the frequency at which GABA opens chloride channels. It is metabolized in the liver and is a weak inducer of the cytochrome P450 system, particularly at higher doses. Common dose-related side effects include somnolence, paresthesias, weight loss, and naming difficulties. Serious side effects include nephrolithiasis and acute open-angle glaucoma. It is also associated with hypohidrosis, which can lead to overheating.

Lamotrigine is also indicated for the treatment of partial-onset seizures, generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome. There are some reports of efficacy against absence seizures. It should be used with caution in patients with myoclonus because there are some reports of myoclonus exacerbation. Lamotrigine primarily blocks voltage-gated sodium channels and is metabolized in the liver through the UGT system. Due to UGT metabolism, lamotrigine has substantially increased clearance during pregnancy, and lamotrigine levels should be checked regularly with concomitant dose increases. Common dose-related side effects include vertigo, diplopia, blurred vision, ataxia, headache, and insomnia. Serious side effects include Stevens-Johnson syndrome and toxic epidermal necrolysis.

Levetiracetam is indicated for the treatment of partial-onset and generalized tonic-clonic seizures and binds to a synaptic vesicle protein known as SV2A, which is important in vesicle exocytosis. It is mainly excreted unchanged in urine. Common dose-related side effects include somnolence, dizziness, and headache. Uncommon side effects include behavior change, irritability, depression, and psychosis.

With the use of antiepileptic medications, approximately 70% of patients can have their seizures controlled or substantially improved. The remaining 30% of patients have medically refractory epilepsy. When trials of 2 different medications at therapeutic doses fail to achieve seizure freedom, <10% of patients will respond to a third medication. Moreover, patients who initially respond to a medication may become unresponsive after a period of time. Uncontrolled seizures have a 0.5% risk of death per year due to SUDEP. In addition, uncontrolled seizures can lead to cognitive decline over time and decreased quality of life. Therefore, it is reasonable to consider surgical interventions to treat seizures in medication-refractory patients.

Dietary Therapy

Modified diets have been proven safe and effective for treating many different intractable epilepsy syndromes and seizure types. All of these diets mimic the physiology of fasting. During periods of decreased glucose availability, fats are metabolized into ketone bodies—acetone, β-hydroxybutyrate, and acetoacetate. As ketone body levels rise and blood glucose levels fall, ketones become the primary source of fuel for the brain. At the cerebral level, ketones act to suppress seizures, but the exact mechanism is unknown. Possible mechanisms include: (1) decreased membrane excitability, (2) decreased synaptic excitation, (3) enhancement of synaptic inhibition, and (4) improved mitochondrial function. The classic ketogenic diet is the most well-known diet and uses a ratio of 4:1 grams of fat to carbohydrates plus protein. All food must be weighed on a scale and carefully monitored. This diet is typically initiated in the hospital due to potential complications, such as hypoglycemia and acidosis. Other complications include nephrolithiasis, hyperlipidemia, and gastrointestinal distress. Serious side effects such as hepatic failure, pancreatitis, and cardiomyopathy have also been reported. Approximately 50% of patients on the classic ketogenic diet achieve >50% reduction in seizures, and up to 30% of patients achieve >90% seizure reduction.

Alternative ketogenic diets are less restrictive than the classic ketogenic diet and may produce similar anticonvulsant efficacy. The main benefit for these diets is their dietary flexibility. Alternative diets include the medium-chain triglyceride (MCT) diet, modified Atkins diet, and low glycemic index treatment. The MCT diet uses MCT oils, which are very ketogenic, as the main fat source and allows a higher amount of protein and carbohydrate than the classic ketogenic diet. The modified Atkins diet uses 60% daily calories from fat and also allows more carbohydrates than the classic ketogenic diet. The low glycemic index treatment uses only carbohydrates with a low glycemic index and allows for more carbohydrates than any of the other dietary therapies for epilepsy.

Surgical Treatment

Medication remains the first-line treatment for epilepsy; however, patients with refractory epilepsy are unlikely to respond to additional medication trials. Patients with disabling complex partial seizures who have failed first-line AEDs should be considered for epilepsy surgery. A patient is considered medically refractory once there is failure of ≥2 appropriate AEDs to control seizures. When a person has a lesion causing epilepsy, a surgical resection of the lesion (and possibly surrounding tissue) is often required to improve seizure outcomes.

Resective surgery involves removing the epileptogenic area of the brain with the intent of reducing seizure frequency without injuring vital cortical functions, such as language, motor, or sensory functions. This can only be done safely after careful investigation of the seizure focus as well as the surrounding brain tissue. Investigation of the seizure focus includes ictal and interictal video EEG, magnetic resonance imaging (MRI) of the brain, positron emission tomography scan, and psychological and neuropsychological assessments. Additional testing can be performed as needed, such as magnetoencephalography, ictal single-photon emission computed tomography, functional MRI, or intracarotid amobarbital test (Wada test). If surface EEG yields inconclusive results, then further localization is required with intracranial electrodes. Subdural grid and strip electrodes and intraparenchymal depth electrodes can be placed to more accurately localize the seizure onset zone. Functional mapping can also be performed to localize eloquent cortex.

Once the seizure focus is clearly defined, then a more detailed surgical plan can be formed. Ideally, the entire epileptogenic zone will be resected without disrupting eloquent cortex. For patients with lesions causing epilepsy, often the surrounding brain tissue becomes irritated and generates seizures. In this case, it is important that this tissue does not remain since it is generating seizures and there may be little or no change to seizure frequency. For patients with temporal lobe epilepsy, there is a standard resection protocol that consists of resection of the anterior temporal lobe and mesial structures. The middle and inferior temporal gyri and the hippocampus and amygdala are removed, while the superior temporal gyrus often remains. The resection goes posteriorly from the temporal pole approximately 5.5 cm on the nondominant hemisphere and 4.5 cm on the dominant hemisphere (to reduce the likelihood of producing language deficits). In patients who have an epileptogenic lesion noted on MRI, such as a tumor, cavernoma, or hippocampal sclerosis, there is an approximately 70% chance of seizure freedom from surgery. In nonlesional epilepsy, the success rate drops to approximately 50%.

Vagus nerve stimulation (VNS) should be considered when patients are refractory to medications and resective brain surgery is not a good option. VNS therapy leads to a 50% reduction in seizure frequency in 25% to 50% of patients, and this reduction improves over time and is sustained at long-term follow-up. VNS consists of a generator, which is implanted in the subcutaneous tissues of the left chest wall, and a bipolar helical lead that is attached to the cervical portion of the left vagus nerve. The generator delivers a biphasic current in an open-loop fashion, such that the generator cycles between on and off periods at predetermined time intervals. The stimulus intensity, frequency, and duration can all be programed by the physician, and interrogation and device programming are carried out via an external programming wand connected to a handheld computer. A handheld magnet is provided to the patient for the purpose of on-demand stimulation, whereby the patient can swipe the magnet across the generator and initiate a stimulation. On-demand stimulation performed at the onset of a seizure can modulate the intensity or even abort or terminate the seizure. The precise mechanism through which VNS works is poorly understood. Previous research has shown that VNS therapy alters cerebral electrical activity and blood flow by activation of neuronal networks via the vagus nerve’s connections in the ventroposterior and intralaminar regions of the thalamus and thalamocortical pathways. Voice alteration and throat pain are the most common side effects, followed by cough, paresthesias, worsened obstructive sleep apnea, nausea, and chest pain. Transient arrhythmias have been rarely reported, and no serious cardiac dysfunction has been noted. In addition, the generator must be replaced approximately every 10 years, which requires outpatient surgery. The major benefits to VNS are that it does not interact with other medications, has no known systemic neurotoxic effects (eg, somnolence, vertigo, fatigue, cognitive impairment), does not cause bone marrow suppression, does not lead to liver or renal impairment, can improve mood, and is considered safe during pregnancy.

Responsive neurostimulation (RNS) uses implanted electrodes to record EEG activity, recognize epileptiform activity, and provide electric stimulation to suppress or disrupt seizures. This is a closed-loop system whereby the generator only delivers stimulation in response to epileptiform abnormalities recognized on the intracranial EEG. The device requires the seizure-onset zone to be in a localized area and precisely identified, since the implanted electrodes only record EEG activity and perform stimulations over a small area of cortex. Complex algorithms are used to detect possible seizure activity very early on, in order to provide a stimulation before the seizure activity has spread. The generator is placed in a partial-thickness cavity in the skull (under the scalp). The generator is interrogated and programmed by an external wand that is connected to a computer. The patient is also given a wand and computer for use at home to download recordings performed by the device. Patients are asked to perform frequent downloads initially, and these can be spaced out after longer periods of time. Prospective clinical trials have demonstrated median seizure frequency reductions of 44% at 1 year and 53% at 2 years and seizure reductions ranging from 60% to 66% 3 to 6 years after implant. The main benefit of RNS is that very precisely localized stimulation is delivered only when seizure activity is detected and that stimulation can be given in multiple locations or over eloquent cortex. In addition, there are no systemic effects of the device, and it does not interact with other medications. The main risks associated with RNS occur at the time of electrode and device implantation and include bleeding and infection. In addition, the device must be replaced every 2 to 3 years in outpatient surgery.

STATUS EPILEPTICUS

Status epilepticus is a neurologic emergency. Untreated, it is usually fatal, and even with best therapy, it has a mortality rate of approximately 20%. It is commonly defined as continuous seizure activity lasting for ≥30 minutes or repetitive seizures without returning to neurologic baseline between seizures. Continuous seizures of this duration produce irreversible brain damage, primarily through the release of excitotoxic levels of glutamate. Thus, rapid treatment is essential. Practically speaking, any seizure lasting >5 minutes is unlikely to resolve on its own and should be treated as status epilepticus.

Status epilepticus can be classified using the partial-onset or generalized dichotomy and whether or not the patient has convulsive activity present. The main types of convulsive status epilepticus include generalized convulsive, focal motor, and myoclonic, and the main types of nonconvulsive status epilepticus include subtle generalized, complex partial, and absence. Nonconvulsive status epilepticus can be difficult to detect, so continuous video EEG monitoring should be used in any patient with suspected nonconvulsive status epilepticus to confirm the diagnosis. Approximately 40% of patients with status epilepticus report a prior history of epilepsy. In fact, 15% of epilepsy patients will experience an episode of status epilepticus in their lifetime, and 12% of the time, status epilepticus is the first manifestation of epilepsy. Often, the cause for status epilepticus in patients with epilepsy is related to low levels of their antiepileptic medications or changes in their medication regimen. Additional causes of status epilepticus include acute stroke, various metabolic causes, alcohol, hypoxia, infection, tumor, and trauma. The etiology of status epilepticus is important to determine because this may affect treatment and predicts prognosis. Predictors of poor outcome after status epilepticus include hypoxia, prolonged seizure, advanced age, low initial Glasgow Coma Scale score, and other complications.

Treatment of status epilepticus is most effective when initiated early. Immediately after the diagnosis of status epilepticus, basic life support measures should be taken including evaluating airway, breathing, and circulation. Additionally, blood should be obtained to evaluate for metabolic abnormalities, toxicology screen, and AED levels. Initial pharmacotherapy is initiated with intravenous thiamine 100 mg followed by 50 mL of D50 dextrose solution. Intravenous lorazepam is given in 2-mg increments every 2 minutes as long as seizures persist up to a maximum dose of 0.1 mg/kg. If venous access has not been obtained, intramuscular midazolam and rectal diazepam are options, given at 10 mg and 20 mg, respectively. Next, intravenous fosphenytoin should be administered as a loading dose of 20 mg/kg with a rapid infusion rate of 150 mg/min. Continuous blood pressure and cardiac monitoring should be performed throughout the infusion, because fosphenytoin can cause hypotension and cardiac arrhythmias. If seizure activity persists, then continuous intravenous infusion is required, along with intubation, central venous access, and continuous blood pressure and cardiac monitoring. Midazolam, pentobarbital, and propofol are options for continuous intravenous infusion. Continuous EEG monitoring is necessary during continuous infusion because these medications are titrated to burst suppression pattern seen on the EEG. Supplemental seizure medications can be used to aid in long-term seizure control. Examples of these medications include levetiracetam, phenobarbital, valproate, and lacosamide. The goal for treatment with continuous infusions is to maintain burst suppression and seizure control for at least 24 hours. After this point, the continuous infusion can be slowly weaned. If seizures recur during the continuous infusion taper, then the continuous infusion should be increased back to achieve burst suppression, and a supplemental seizure medication should be added. After another 24 hours of seizure freedom, the weaning process can be tried again. Continuous EEG monitoring should be maintained for at least 24 hours after the continuous infusion is discontinued to monitor for seizure recurrence.

CONCLUSION

Epilepsy is diagnosed when a person has the propensity for recurrent unprovoked seizures. EEG is the primary diagnostic tool, and the presence of interictal epileptiform discharges is associated with a 2-fold increased risk of seizure recurrence. Proper diagnosis is important so that appropriate treatment can be initiated. Mortality is higher in people with epilepsy than in the general population, particularly due to SUDEP. Medical management is the primary treatment for epilepsy. There is similar efficacy between AEDs chosen for the particular seizure type, so patient factors should guide the medication choice. Up to one-third of people with seizures will be refractory to medications and should consider surgical options. Status epilepticus is a state of continuous seizure activity and is considered a neurologic emergency. It is associated with high morbidity and mortality and should be recognized early and treated aggressively for the best overall outcome.

OBJECTIVES

PREVALENCE & BURDEN

Given the breadth of pathologies responsible for the various movement disorders, there is great variation in disease prevalence. More will be discussed later for each of the diseases, but in general, movement disorders are relatively common neurologic problems. The most prevalent movement disorder is essential tremor, with a prevalence of roughly 400 per 100,000. While essential tremor is common, many of the cases are mild, and often these patients do not seek treatment. The most common movement disorder encountered in clinical practice is Parkinson disease, a serious and debilitating disorder affecting approximately 200 people per 100,000 population and >1 million people in the United State and 10 million people worldwide. Combined direct and indirect cost of care of US patients with Parkinson disease is estimated at $25 billion per year. Huntington disease is rare, with a prevalence in the 7 per 100,000 range.

LOCALIZATION

The entire motor system is quite extensive, spanning from motor cortex to muscle. For simplicity, however, disorders of the motor system are divided anatomically. Disorders involving the corticospinal tract (pyramidal) extending out to the peripheral muscle are classified as neuromuscular disorders (see Chapter 31). Disorders of the basal ganglia and cerebellum (extrapyramidal) are grouped into the field of movement disorders and will be discussed here. Pathways through the basal ganglia moderate and adjust voluntary movement (Figure 28–1). The direct pathway primarily facilitates movement (“go”), whereas the indirect pathway primarily inhibits movement (“no go”).

DISORDERS

We will discuss each of the main movement disorders, but to establish a framework, most movement disorders are classified as either predominately hypokinetic (too little movement) or hyperkinetic (too much movement). The prototypical hypokinetic movement disorder is Parkinson disease, whereas the prototypical hyperkinetic movement disorder is Huntington disease.

HYPOKINETIC MOVEMENT DISORDERS

Parkinsonism is the umbrella term for a tetrad of symptoms: rigidity, resting tremor, bradykinesia, and postural instability. Together, these are the cardinal signs of parkinsonism. Rigidity is a velocity-independent muscular stiffness. This means that with the patient’s limb relaxed, there is still resistance to passive range of motion, and the amount of resistance is the same whether the limb is moved quickly or slowly. This is often described in the context of parkinsonism as “lead pipe rigidity,” meaning that moving the limb passively feels like trying to bend a lead pipe. This is in contrast to spasticity, which is a velocity-dependent increase in muscular tone, usually with more resistance when the limb is moved quickly and less when moved slowly. Spasticity is often described as being like a “clasp knife” (like opening a pocket knife) and is seen in motor disorders where the corticospinal (pyramidal) tract has been disrupted. Resting tremor is present when the body part is at rest and diminishes with action. The presence of resting tremor can help distinguish idiopathic Parkinson disease from other forms of parkinsonism, as will be described later. Bradykinesia is a slowness of movement that can manifest as decreased facial expression, decreased blink rate, impaired fine movements of the hands, and an overall statue-like appearance. Postural instability refers specifically to a tendency to fall and is associated with the classic stooping of posture, shortening of stride length, and shuffling of gait seen in Parkinson disease.

Parkinson Disease: Pathology & Diagnosis

The most common cause of parkinsonism is idiopathic Parkinson disease (PD). PD is a degenerative disorder that results from loss of dopaminergic neurons in the substantia nigra pars compacta (Figure 28–2A). These neurons normally project to the putamen and provide dopaminergic input to both the direct and indirect pathways. Therefore, death of these cells leads to loss of stimulation in the direct pathway (less “go”) as well as loss of inhibition in the indirect pathway (increase in “no go”). These changes in output from the putamen are, at a basic level, an explanation for the bradykinesia and overall loss of movement seen in PD. Affected dopamine (DA) neurons develop intracellular protein accumulations called Lewy bodies (Figure 28–2B), and the abnormal protein that composes Lewy bodies is known as α-synuclein.

The diagnosis of PD is purely clinical and based on presence of at least 2 of the 4 cardinal parkinsonian symptoms, which were described earlier. The average age of onset of PD is 65 years, and the average time from diagnosis to severe disability or death is 15 to 20 years. At the time of diagnosis, idiopathic PD patients usually have parkinsonian symptoms that are more severe on 1 side of the body than the other. This reflects asymmetric degeneration of DA neurons in the substantia nigra, a feature that is characteristic of the disease. The classic resting tremor of PD is a 4- to 6-Hz tremor that tends to begin distally in 1 hand. Because it involves the fingers, in early stages, it often has the appearance of rolling pills between the thumb and index finger and thus is described as “pill rolling.” The bradykinesia of idiopathic PD may present as decreased facial expression (masked facies) or slowness in the fingers (causing micrographia, which is very small handwriting). The rigidity of PD is often described as cogwheeling, and this is simply tremor superimposed on rigidity in that limb, which gives a cogwheeling or ratcheting type of feel when the limb is moved passively. The postural instability of PD tends to occur later in the disease and is the least responsive of the cardinal symptoms to DA replacement therapy.

Other common motor features of PD can be grouped as follows. From a posture and gait standpoint, stooping forward and having decreased arm swing on the more affected hemibody are common early symptoms. As the gait problem progresses, patients develop shorter stride length, which leads to shuffling of the feet and difficulty with turning (described as “en bloc” turns, a French term that refers to the body turning as if it were a rigid block). Speech and swallowing problems are common and related to rigidity and bradykinesia of the oropharynx. The decrease in involuntary swallowing can lead to drooling (overflow of pooled saliva). Decreased speech volume (hypophonia) and mild dysphagia are common as well.

Nonmotor symptoms are also common in PD. Anosmia (impaired sense of smell) is an early feature. Autonomic symptoms such as constipation and orthostatic hypotension can be seen. Rapid eye movement sleep behavior disorder, depression, and dementia can all be seen, although dementia is usually not seen until later in the disease. Psychosis (usually in the form of visual hallucinations) can be seen and is often associated with dopaminergic therapy being used to treat motor symptoms.

Other Hypokinetic Movement Disorders: The Parkinson-Plus Syndromes

In addition to idiopathic PD, there are 4 other main causes of parkinsonism that are collectively called the Parkinson-plus syndromes, or atypical parkinsonism. The term Parkinson-plus syndromes is particularly helpful because all of the disorders in the group are characterized by parkinsonism plus other symptoms that are either completely atypical for idiopathic PD or in greater proportion than would be seen in PD. The 4 Parkinson-plus syndromes that will be discussed here are dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and corticobasal syndrome. In general, the parkinsonism seen in these 4 disorders is more symmetric at onset than PD, and they generally have less tremor but more rigidity and bradykinesia. None of the 4 have specific pharmacologic treatments and, in general, are treated symptomatically with antiparkinsonian medications. All 4 disorders have a much poorer response to dopaminergic therapy and thus a worse prognosis than idiopathic PD.

Dementia with Lewy bodies (DLB) is sometimes referred to simply as Lewy body disease and is characterized pathologically by the same α-synuclein inclusions and Lewy bodies as idiopathic PD. The difference between the 2 conditions is the distribution, as the pattern of Lewy body accumulation within the brain is much more diffuse in DLB but more concentrated in the basal ganglia in PD. Clinically, patients with DLB have parkinsonism and dementia within the first year of symptom onset. This differs from PD, where only 30% to 40% of patients develop dementia, and if it occurs, the onset of the dementia is usually 10 years after the onset of motor symptoms. Other common features of DLB include visual hallucinations, prominent clinical fluctuations, and neuroleptic sensitivity. Notably, the visual hallucinations occur even without exposure to dopaminergic therapy (unlike in PD, where this is primarily seen as a side effect of dopaminergic therapy). The fluctuations are in the cognitive status and can be dramatic, even within the same day, where the patient at times seems cognitively normal and at other times is completely demented. Likewise, the neuroleptic sensitivity refers to a cognitive, delirious/agitated response to neuroleptic treatment (which is usually initiated to treat the hallucinations). Recent work has emphasized that DLB and PD are likely part of a spectrum with shared pathophysiology, and patients with mixed features or who are intermediate between the 2 extremes will be encountered. See Chapter 29 for more information on the cognitive deficits in DLB.

Multiple system atrophy (MSA) is also characterized pathologically by α-synuclein inclusions, but these are found in glia (glial cytoplasmic inclusions) as opposed to the intraneuronal inclusions that are Lewy bodies. However, because the primary abnormal protein accumulation is α-synuclein, it is still organized with PD and DLB as 1 of the synucleinopathies. The prevalence of MSA is less than that of PD, at approximately 4 cases per 100,000 population. As the name alludes, MSA is a multisystem neurodegenerative disorder that is characterized by cerebellar and pyramidal tract signs and autonomic dysfunction in addition to parkinsonism. The cerebellar signs include intention tremor when reaching for objects, slurred speech, and an uncoordinated, ataxic gait. Autonomic symptoms are nonmotor features such as orthostatic hypotension, urinary retention, constipation, and abnormal heat or cold intolerance. There are 2 clinical variants distinguished based on the predominant presenting symptoms. If parkinsonism is the dominant feature, it is called MSA-P, and if cerebellar ataxia is the dominant feature, it is called MSA-C. Both variants have the preponderance of autonomic dysfunction. Although autonomic dysfunction can be seen in idiopathic PD, it occurs earlier and to a more severe degree in MSA than in PD.

Progressive supranuclear palsy (PSP) is pathologically different from the previously discussed causes of parkinsonism because there is abnormal accumulation of the protein tau instead of α-synuclein. Aggregates of tau, particularly in glial cells, are the pathologic hallmark of PSP. The prevalence of PSP in the United States is significantly less than that of PD, approximately 6 cases per 100,000 population. In addition to parkinsonism, the most striking clinical feature is the supranuclear gaze palsy referenced by the disease name. The patient has difficulty volitionally initiating gaze in a certain direction, but when performing the oculocephalic maneuver, the patient’s extraocular muscles can physically still make the appropriate movements. Therefore, the problem localizes above the level of the brainstem nuclei that control eye movements, hence the term supranuclear gaze palsy. This is most commonly seen early with vertical eye movements, which present as difficulty with reading or frequent stumbling over impediments due to inability to look down. As it progresses to a complete gaze palsy in all directions, the patient may move his or her entire head in order to look around the room. The gaze issue combined with parkinsonism leads to early gait problems and frequent falls. Speech and swallowing are significantly affected, and the speech of PSP patients can have a characteristic growling quality. As PSP progresses, patients can develop disproportionate atrophy of the dorsal midbrain, which can sometimes be seen on magnetic resonance imaging (MRI), as noted in Figure 28–3.

Corticobasal syndrome (CBS) is another Parkinson-plus syndrome that is often marked pathologically by abnormal accumulation of tau in a form called corticobasal degeneration (CBD). (CBS refers to the clinical syndrome while CBD refers to the specific neuropathological findings that are often associated.) Because both PSP and CBD have accumulation of tau isoforms containing four microtubule-binding repeats, they are considered related and sometimes referred to as “4R tauopathies.” Although there are no formal studies on the prevalence of CBS, estimates are that it is roughly half as common as PSP. Unlike PSP, however, CBS tends to present asymmetrically with parkinsonism plus prominent apraxia of 1 hand. The patient may report progressive loss of use of that hand. On testing, apraxia manifests as intact motor strength but difficulty performing complex voluntary tasks, such as brushing teeth or giving a thumbs-up signal. When the apraxia becomes severe, the patient has little voluntary control of the limb, and it may move on its own. This is known as the “alien limb phenomenon.” Ultimately, the disease progresses to involve the other side of the body, and the cortical reference in the disease name means that patients will ultimately develop dementia as well.

One additional cause of parkinsonism is drug-induced parkinsonism from medications being taken for other conditions. The clinical key is that unlike idiopathic PD, the parkinsonism is symmetric at onset and begins after introducing 1 or more agents that interfere with central nervous system (CNS) DA. Medications known to cause drug-induced parkinsonism are DA antagonists (antipsychotics, certain antiemetics such as metoclopramide), DA depleters (reserpine, tetrabenazine), and chemotherapeutic agents (fluorouracil, doxorubicin, cyclophosphamide). All of these causes are reversible, meaning that removal of the offending agent should lead to resolution of parkinsonism over weeks to months, depending on exposure. Certain toxins can poison and damage the basal ganglia, causing irreversible parkinsonism. These include the compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP; a by-product of synthetic opioid manufacturing that caused a spate of drug-induced parkinsonism in the 1980s), organophosphates (pesticides), carbon monoxide, cyanide, and methanol.

Parkinson Disease: Pharmacology & Other Treatments

Currently available treatments are mostly symptomatic and do not alter the underlying degenerative process. Symptomatic treatments are useful and can restore function and quality of life for many years, but ultimately, the progression of the disease leads to increasing difficulty in managing the symptoms.

Most of the pharmacologic interventions currently used in PD are aimed at restoring DA levels in the brain. In general, medications used in the management of PD can be divided into DA precursors, DA receptor agonists, and inhibitors of DA degradation. There is a smaller but still useful role for existing nondopaminergic therapies, such as anticholinergic agents that modify the function of striatal interneurons.

Dopamine Precursors

DA itself is not useful for therapy because it cannot cross the blood–brain barrier (BBB). However, DA’s immediate precursor, levodopa, is readily transported across the BBB, and once in the CNS, levodopa is converted to DA by the enzyme aromatic L-amino acid decarboxylase (AADC). Orally administered levodopa is readily converted into DA by AADC in the gastrointestinal tract, which both diminishes the amount of levodopa that can reach the CNS and increases the peripheral DA-related adverse effects (predominantly nausea, due to binding of this DA to receptors in the area postrema). When levodopa is administered alone, only 1% to 3% of the administered dose reaches the CNS unchanged (Figure 28–4). To boost the levels of levodopa available to the brain and reduce the adverse effects of peripheral levodopa metabolism, levodopa is almost always administered in combination with carbidopa, which inhibits peripheral AADC without affecting central AADC. Carbidopa increases the fraction of orally administered levodopa available in the CNS from 1% to 3% (without carbidopa) to 10% (with carbidopa), allowing a significant reduction in the dose of levodopa and reducing the incidence of peripheral adverse effects. The combination of carbidopa/levodopa (trade name Sinemet, from the Latin for “without emesis”) is still considered the gold standard of therapy for PD. By increasing CNS DA levels, carbidopa/levodopa effectively treats all 4 cardinal symptoms of PD, although gait instability tends to be slightly less responsive.

In later stage PD, use of high doses of carbidopa/levodopa can cause hyperkinetic choreiform movements at peak doses. This phenomenon is known as levodopa-induced dyskinesia and is thought to be due to temporary DA excess in the direct and indirect pathways causing chorea. Other adverse effects of levodopa therapy include hypotension, vivid dreams, and visual hallucinations. It is an important distinction that levodopa-related hallucinations are usually visual and not auditory, because auditory hallucinations are almost always due to a primary psychiatric disorder. The classic levodopa-related visual hallucinations are miniature-sized people or animals, sometimes referred to as “Lilliputian figures.”

DA Receptor Agonists

Another strategy for enhancing dopaminergic neurotransmission is to target the postsynaptic DA receptor directly using DA receptor agonists. The earliest therapies in this class were the ergot derivatives bromocriptine (D₂ agonist) and pergolide (D₁ and D₂), but these have been found to induce long-term side effects such as cardiac valve fibrosis and have fallen out of favor. The newer nonergot agonists are pramipexole, ropinirole, and rotigotine (all D₃ > D₂). All DA agonists are nonpeptide molecules and do not compete with levodopa for transport across the BBB. Furthermore, because they do not require enzymatic conversion by AADC, they remain effective late in the course of PD. All of the DA receptor agonists in current use have half-lives longer than that of levodopa, which allows for less frequent dosing and a more uniform response to the medications.

The major limitation on the use of the DA receptor agonists is their tendency to induce unwanted adverse effects, which may include nausea, peripheral edema, and hypotension. All of the DA agonists may also produce a variety of adverse cognitive effects, including excessive sedation, vivid dreams, and hallucinations, particularly in elderly patients. A rare but problematic side effect is DA dysregulation syndrome, in which patients develop problems with impulse control. Common manifestations include pathologic gambling, overspending, compulsive eating, and hypersexuality. These behaviors may be socially destructive and require discontinuation of the medications.

Inhibitors of DA Metabolism

Another strategy to treat PD involves the inhibition of DA breakdown. Inhibitors of both monoamine oxidase type B (MAO-B; the isoform of monoamine oxidase [MAO] that predominates in the striatum) and catechol-O-methyltransferase (COMT) have been used as adjuvants to levodopa in clinical practice. Selegiline is an MAO inhibitor that is selective for MAO-B at low doses. One potential problem with selegiline is that it has an amphetamine metabolite, which can cause sleeplessness and confusion, especially in the elderly. Rasagiline is a newer MAO-B inhibitor that does not form amphetamine metabolites and is more specific for MAO-B than selegiline. The specificity for MAO-B over MAO-A allows these drugs to avoid the tyramine effect associated with nonselective MAO blockade. Both rasagiline and selegiline improve motor function in PD when used alone, and both can augment the effectiveness of levodopa therapy.

Tolcapone and entacapone inhibit COMT and thereby inhibit the degradation of levodopa as well as DA. Tolcapone is a highly lipid-soluble agent that can cross the BBB, whereas entacapone distributes only to the periphery. Both drugs decrease the peripheral metabolism of levodopa and thereby make more levodopa available to the CNS. There have been reports of fatal hepatic toxicity associated with tolcapone, and thus in practice, entacapone is the most widely used COMT inhibitor.

Nondopaminergic Pharmacology in PD

Amantadine was developed primarily as an antiviral that reduces the length and severity of influenza A infections. In patients with PD, however, amantadine can have mild benefits on the cardinal motor symptoms but also can treat levodopa-induced dyskinesias. Although the exact mechanism of action for amantadine in PD is unknown, the mechanism for reducing dyskinesia is thought to involve blockade of excitatory N-methyl-D-aspartate receptors. Trihexyphenidyl and benztropine are muscarinic receptor antagonists that reduce cholinergic tone in the CNS. They reduce tremor more than bradykinesia and are therefore more effective in treating patients for whom tremor is the major clinical manifestation of PD. These anticholinergic drugs are thought to act by modifying the actions of striatal cholinergic interneurons, which regulate the interactions of direct and indirect pathway neurons. They also cause a range of anticholinergic adverse effects, which may include dry mouth, urinary retention, and importantly, impairment of memory and cognition.

Surgical Therapy for PD

Deep brain stimulation (DBS) therapy is approved by US Food and Drug Administration (FDA) for the treatment of medically refractory PD. DBS involves surgical placement of an electrode into the basal ganglia, either in the subthalamic nucleus or the globus pallidus internal segment. The electrode wire is tunneled under the skin and connected to a subcutaneous pacemaker-type pulse generator that controls electrical stimulation to the implanted basal ganglia site. High-frequency stimulation is applied through the electrode and has an ablative effect on cells in these nuclei and results in decreased output from the indirect pathway (less “no go”) and alleviation of PD motor symptoms. Although DBS provides powerful suppression of PD motor symptoms and can be adjusted over time to address symptom progression, on its own, it does not alter progression of the disease. Risks of the procedure are infection related to the implanted hardware and hemorrhage during intracranial placement of the electrode. Most patients receiving DBS therapy can reduce their antiparkinsonian medications, but the ability to completely replace oral medications is rarer. Candidates for DBS must have proven response (at some point in the disease course) to levodopa, because DBS only benefits symptoms that are responsive to levodopa. Thus, DBS has no effect on the nonmotor symptoms of PD. The most common PD patients to receive DBS therapy are those who have advanced disease requiring such high doses of oral medications that they frequently alternate between adverse effects and insufficient benefit when the medications wear off.

HYPERKINETIC MOVEMENT DISORDERS

Essential Tremor

As mentioned previously, the most prevalent of all movement disorders is essential tremor (ET). The exact pathologic mechanism of ET is not known, but degeneration of the cerebellum and its outflow tracts is most commonly implicated. ET is characterized by a bilateral postural and action tremor most commonly involving the arms. Head and voice tremor are also very common, whereas leg tremor is less common. ET is a pure tremor disorder because there are no other major clinical features other than the tremor. This distinguishes it from PD, but the tremor itself is also different because PD tremor is present at rest but abates with posture and action while the tremor of ET is present with posture and action but absent at rest. Patients with ET frequently have a positive family history of a similar tremor, indicating a genetic component of ET, although no single gene has been identified. ET is thought to be polygenic, not unlike hair color. Although ET is most common in the elderly, it can occur at younger ages when there is a strong family history of earlier onset tremor. The tremor itself is slowly progressive with age, but in later stages, the amplitude of the tremor can become quite large, to the extent that it impairs activities of daily living due to impaired use of the hands. Pharmacologic treatments for ET include propranolol and primidone. Propranolol is a nonselective β-blocker, can cross the BBB, and has a sedative effect on the tremor. Primidone is a prodrug for phenobarbital and thus exerts a γ-aminobutyric acid (GABA)-ergic effect to reduce the tremor. Both are symptomatic and do not prevent worsening of the tremor with time. DBS is also an FDA-approved therapy for ET. The target for electrode placement is the ventral intermediate nucleus of the thalamus. Thalamic DBS is highly effective at treating ET and is considered by most to be superior to either propranolol or primidone in suppressing tremor. As in PD, DBS remains a symptomatic therapy for ET.

Dystonia

Dystonia is defined as involuntary, sustained contraction of muscles around a joint that often results in (often painful) twisting postures and/or repetitive movements. The exact pathophysiology of dystonia is poorly understood, although the origin of the aberrant signal for the muscle contraction is central (coming from the basal ganglia) and not peripheral (ie, originating in the peripheral nerves or muscles). There are increasing numbers of genetic mutations identified that cause dystonia as 1 of the primary clinical manifestations, and the current nomenclature for these genes is DYT1, DYT2, and so on. Dystonia is most commonly categorized as being either focal or generalized based on the part of body involved. The most common focal dystonia is cervical dystonia, which involves the neck (cervical) region. Depending on the direction that the neck is twisted or pulled due to the abnormal muscle contractions, cervical dystonia is subdivided further. Torticollis is a cervical dystonia that primarily causes twisting of the neck and turning of the head (Figure 28–5). Anterocollis is when the head and neck are pulled forward, laterocollis is when they are pulled to the side, and retrocollis is when they are pulled backward. Another common focal dystonia is blepharospasm, which involves the orbicularis oculi, thus causing eye blinking or eye closure. Writer’s cramp, which is often provoked by the hand posture required to write with a pen on paper, primarily involves wrist and finger flexors. The treatment of choice for all focal dystonias is botulinum toxin injections into the affected muscles. Although botulinum toxin does not address the aberrant brain signal generating the movement, it does effectively abort the muscle contraction itself. Botulinum toxin works by preventing presynaptic release of acetylcholine into the neuromuscular junction. On average, 1 set of botulinum toxin injections can relieve a focal dystonia for up to 3 to 6 months. Oral medications such as antiparkinsonian medications (eg, carbidopa/levodopa or trihexyphenidyl) or muscle relaxants/benzodiazepines are sometimes used for generalized dystonias but are rarely effective for focal dystonias.

One unique genetic dystonia is dopa-responsive dystonia, which is usually caused by a mutation in the gene for guanosine triphosphate (GTP) cyclohydrolase 1. Both autosomal dominant and autosomal recessive mutations have been described. GTP cyclohydrolase is a critical enzyme in the pathway to synthesize tetrahydrobiopterin, which is a cofactor needed for the generation of DA. This disorder is extremely rare, with a prevalence of 1 in 2,000,000. Dopa-responsive dystonia causes childhood-onset dystonia and parkinsonism. The dystonia is worse in the legs than the arms and tends to worsen in the evenings. The dystonia and parkinsonism are highly responsive to very-low-dose levodopa, although patients require lifelong therapy. The dramatic responsiveness to treatment makes it one of the most easily treatable of all dystonias, and therefore, many advocate for an empiric trial of carbidopa/levodopa in all patients who present with a dystonia, regardless of age.

There are also secondary dystonias that are not felt to be idiopathic. Most common are symptomatic dystonia and Wilson disease (which are discussed later in this chapter). Symptomatic dystonia is due to basal ganglia damage by stroke or trauma. Treatment for the secondary dystonias is similar to that of the primary dystonias.

Chorea

Chorea is an abnormal hyperkinetic movement consisting of nonrhythmic, irregular muscle contractions appearing to flow from 1 muscle group to the next. The word chorea is derived from the Greek word for dance, describing the dance-like quality of the movement. It is felt to be on the spectrum with athetosis, which has a more writhing quality, and ballismus, which has a more thrashing, large-amplitude quality. Causes of chorea can be divided into genetic causes and acquired causes.

Huntington Disease

The most well-known genetic cause of chorea is Huntington disease (HD). HD is the prototypical pure genetic neurodegenerative disorder. The HD gene (HTT) on chromosome 4 encodes the protein huntingtin and contains a trinucleotide (CAG) repeat. HD was 1 of the first trinucleotide repeat disorders to be discovered, and the HTT gene was 1 of the first human genes to be completely sequenced. In an affected patient, the mutated allele will usually have ≥40 repeats, whereas there are normally only 15 to 20 repeats. CAG repeat expansions in the elevated range of 36 to 39 may lead to the disease, but there is reduced penetrance in this range. Expansions of >40 repeats are considered to be fully penetrant. As with all trinucleotide repeat disorders, HD can exhibit anticipation (an earlier age of onset in each generation, reflecting instability and expansion of the repeat), but interestingly, anticipation is primarily with paternal inheritance in HD. Patients who are homozygous for the mutation have been reported but are rare. There is a direct correlation between the CAG repeat length and disease onset and severity. The average age of symptom onset is 40 years, but larger repeat expansions (ie, CAG repeats >55) can have juvenile onset, whereas a CAG repeat of exactly 40 can result in symptom onset in the 70s. The exact function of the huntingtin protein is unknown, but it is thought to be a toxic gain of function. Pathologically, mutant huntingtin causes neuronal loss diffusely in the brain but most selectively in the medium spiny neurons of the striatum (caudate and putamen). Disproportionate caudate atrophy can often be seen on brain imaging in an HD patient (Figure 28–6).

Phenotypically, HD has a classic triad of motor, cognitive, and behavioral symptoms. The most common motor symptom is chorea, and 90% of patients with HD will develop chorea at some point in their disease course. Other hyperkinetic movements such as dystonia, myoclonus, and tics can be seen in HD but are less common. It should be noted that juvenile-onset HD is much different phenotypically in that it actually presents with parkinsonism instead of chorea. Cognitive symptoms can range from mild executive dysfunction to dementia. Behavioral symptoms can range from mild depression or anxiety to severe agitation or psychosis. Diagnosis is confirmed by genetic testing after clinical suspicion is raised, usually with chorea and a positive family history. Genetic testing is available for at-risk presymptomatic patients as well, although there are significant ethical considerations, and thus, genetic testing should always be done with the involvement of a genetic counselor. At present, there are no curative treatments available, although gene silencing clinical trials are underway. The only approved symptomatic treatment is tetrabenazine, which treats the chorea only. Tetrabenazine is an irreversible vesicular monoamine transmitter (VMAT) type 2 inhibitor that depletes presynaptic DA. As might be expected with this mechanism, tetrabenazine can cause the adverse effect of parkinsonism at high doses. Like its fellow DA depleter, reserpine, tetrabenazine also carries a risk of worsening depression. DA-blocking agents such as typical and atypical antipsychotics can also suppress the chorea of HD and may also treat psychosis if present.

Acquired Causes of Chorea

Other important acquired causes of chorea include cerebrovascular disease, Sydenham chorea, and tardive dyskinesia. When cerebral ischemia involves the basal ganglia, the irritation may result in chorea or ballismus. Given the focality of strokes, the clinical result is usually a hemichorea or hemiballismus contralateral to the side of the infarct or ischemia. The classic presentation of hemiballismus is the result of a lacunar infarct to the subthalamic nucleus. The treatment for hemiballismus is a short course of a DA antagonist (neuroleptic) or DA depleter.

Sydenham chorea is a complication of childhood infection with group A β-hemolytic Streptococcus. It occurs in 20% of children and adolescents with rheumatic fever, although this incidence is decreasing due to better and earlier treatment of streptococcal infection. Sydenham chorea primarily affects the face, feet, and hands. No treatment is necessary because the chorea usually remits within a few months.

Tardive dyskinesia is a chorea that develops after chronic exposure to DA-blocking agents such as antipsychotics and certain antiemetics (eg, metoclopramide). Development of tardive dyskinesia usually requires years of daily exposure to the DA-blocking agent, although it has been seen with much shorter exposure periods. It is thought that downregulation of DA receptors over time plays a role in the pathogenesis. The classic presentation of tardive dyskinesia is with repetitive lip-smacking/tongue-protruding movements, but the chorea can involve any part of the body. Treatment of tardive dyskinesia involves withdrawal of the offending agent, and 50% of patients will have resolution of the chorea within 6 months. However, if persistent, the chorea can be suppressed by DA depleters (which do not tend to cause tardive dyskinesia).

Tics

Tics are sudden, repetitive, nonrhythmic movements that tend to be stereotyped. If involving the face or body, they are classified as motor tics, but if involving an utterance or sound, they are classified as vocal tics. Tics may also be simple or complex. If the tics become persistent, it is classified as a disorder, and all tic disorders are felt to be on the spectrum with obsessive-compulsive disorder (OCD). Most patients describe a premonitory urge to make the tic prior to the initiation of the tic itself. The tic can also usually be suppressed temporarily, but the longer it is suppressed, the more uncomfortable this becomes and the larger the cluster of tics to relieve the urge.

Tourette syndrome is defined as the combination of both motor and vocal tics that have been persistent for >1 year. Average age of onset is 8 to 12 years old, and symptoms tend to improve into adulthood. Patients with Tourette syndrome may have obscene vocal tics (coprolalia) as a feature, but this occurs in only 15% of patients and tends to develop later in the course of the disease. Comorbid psychiatric symptoms such as attention-deficit/hyperactivity disorder (ADHD) and OCD are common. These should be treated aggressively because they are felt to be more debilitating than the tics themselves. Treatments to suppress the tics include clonidine, topiramate, DA depleters, and DA antagonists (antipsychotics).

Myoclonus

Myoclonus is a rapid lightning-like involuntary twitch and has numerous causes. Hiccups are an example of a myoclonic jerk of the diaphragm muscle. Physiologic (benign) myoclonus includes examples such as sleep starts or sleep myoclonus of infancy. Myoclonus can also be a feature of certain myoclonic epilepsies, all of which have epileptiform discharges on electroencephalography that correlate with myoclonus. These include myoclonic epilepsy with ragged red fibers and Lafora progressive myoclonic epilepsy. Both are genetic diseases that affect multiple organ systems and are progressive and ultimately fatal at a young age. Myoclonus is commonly seen in hospitalized patients due to severe metabolic derangements such as uremia or cerebral anoxia. Spinal cord injury can cause myoclonus, and it can also be associated with advanced neurodegenerative disorders such as Alzheimer disease, subacute sclerosing panencephalitis, and Creutzfeldt-Jakob disease. Certain drugs such as lithium, bismuth, meperidine, and cyclosporine can also cause myoclonus. Definitive treatment for myoclonus depends on the etiology. Symptomatic suppression of myoclonus can be attempted with clonazepam or a variety of other antiepileptic drugs (eg, levetiracetam, valproate).

Other Atypical Movement Disorders

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is a rare and life-threatening adverse reaction to DA antagonists. The most common drugs to precipitate NMS are the typical antipsychotics, although NMS has been reported from atypical antipsychotics, usually the ones with the highest D₂ antagonism. NMS has been reported with DA depleters such as reserpine and tetrabenazine, as well as potent DA-blocking antiemetics such as metoclopramide. NMS can also be seen with abrupt withdrawal of prodopaminergic drugs, such as carbidopa/levodopa. This is clinically relevant for PD patients who become hospitalized for other reasons and have their antiparkinsonian agents stopped during the inpatient stay, which can precipitate NMS.

NMS typically consists of parkinsonism (primarily rigidity), fever, and autonomic instability. Although encephalopathy and elevated serum creatine kinase levels are commonly seen, these are not required to make the diagnosis of NMS. Fever is thought to be due to hypothalamic DA receptor blockade. The most significant risk factor for the development of NMS is the titration schedule, because rapid titration of high-potency DA-blocking agents carries the highest risk for NMS. Other risk factors include dehydration, exhaustion, and agitation. The incidence of NMS has been reported at 1 in 500 but is decreasing due to increased physician awareness and resultant changes in management as well as increased use of atypical antipsychotics over typical antipsychotics. Treatment involves removal of the DA antagonist as a first step. Prodopaminergic agents such as the DA precursors and DA agonists can be used as treatment, although the most commonly used treatment is dantrolene. Intensive care unit care with aggressive rehydration, temperature regulation, and correction of electrolytes is also critical for survival. Finally, if the NMS was precipitated by withdrawal of prodopaminergic agents, then these should be reinitiated as soon as possible.

Wilson Disease

Another important mixed movement disorder is Wilson disease, which is an autosomal recessive disorder of copper metabolism. Mutations in the ATP7B gene lead to abnormal copper accumulation, which leads to organ dysfunction. Although prevalence of mutation carriers is 1 in 100, prevalence of the actual disease is much rarer, at 2 per 100,000. The primary sites of copper accumulation are in the liver and brain, and those with more accumulation in the liver (60%) present with hepatic dysfunction and jaundice as children or teenagers. Patients with more brain accumulation (40%) present with neuropsychiatric symptoms in their 20s or 30s. The most common neurologic symptoms of the disease are parkinsonism, an unusual postural/action tremor that is often described as “wing-beating tremor,” dysarthria, sialorrhea, dystonia, and ataxia. Psychiatric symptoms can include personality change, depression, anxiety, and psychosis. Wilson disease is treatable if caught early but can be fatal if it is missed. When neurologic or psychiatric symptoms are present, this should correlate with basal ganglia hyperintensities on brain MRI and copper deposition in the irises of the eyes, known as Kayser-Fleischer rings (Figure 28–7). Diagnosis is confirmed by lab test results, which include low ceruloplasmin levels, elevated 24-hour urine for copper, and/or high copper content on liver biopsy. Treatment of Wilson disease involves chelation therapy with agents such as penicillamine or liver transplant if disease is severe.

OBJECTIVES

PREVALENCE & BURDEN

One of the most striking demographic trends over the past century has been a dramatic extension of life expectancy, which has almost doubled from 44 years in 1890 to >80 years today. An unfortunate accompaniment of this change is an increase in age-related cognitive change, perhaps the most common and feared result of aging. Age-related cognitive change includes both “normal” cognitive aging and several neurodegenerative diseases causing dementia.

Among the neurodegenerative diseases, Alzheimer disease (AD) is the most common, affecting >5 million people in the United States. Interestingly, the incidence (rate of new cases per unit of population) of dementia seems to be declining worldwide, with improvement in control of vascular risk factors and other public health improvements. However, the prevalence (overall number of cases) of dementia is still growing at an alarming rate. The risk of developing dementia due to AD doubles every 5 years after age 65 years, and with the growth of the aged population, AD prevalence is expected to continue increasing dramatically.

NEUROANATOMY

One of the reasons it is important to define which cognitive domains are involved in a patient’s cognitive decline is the fact that each domain has a particular anatomy. Thus, identifying an impaired domain is the primary mode of localization in behavioral neurology. Episodic memory localizes to the medial temporal lobe, including the hippocampus (Chapter 20). Language is generally localized to the left hemisphere and can be more precisely localized based on the type of aphasia (Chapter 21). Visuospatial function is generally localized more to the right hemisphere and occipital, and executive function is primarily frontal.

SCREENING & DIAGNOSIS

History

The history is the most important part of the workup in diagnosing cognitive disorders. A collateral informant is usually helpful because the patient’s deficits may prohibit the patient from providing a reliable history. An important goal is to identify the initial symptoms, which enables inferring the initial cognitive domain involved and in turn defining the initial neuroanatomy, a key factor in differential diagnosis. Later in the course of neurodegenerative diseases, multiple brain regions invariably become involved, and thus multiple domains are affected. Elucidating the initial symptoms can suggest where in the brain the pathologic process might have started. It is important to remember that patients may use the term “memory” to refer to other cognitive domains. For example, “I can’t remember words” is likely to reflect language impairment, and “I forget how to get to the grocery store” is likely to reflect visuospatial impairment. Asking for anecdotes or specific examples of cognitive functions that the patient can no longer perform is most informative.

Other important details include the time course of the onset and progression of the cognitive changes (eg, acute, subacute, intermittent, or chronic). A cognitive review of systems may include asking specifically for any history of change in gait, the presence of a tremor, language dysfunction, visuospatial deficits, or sleep changes. The patient should be screened for symptoms of depression, anxiety, psychosis, or other behavior change.

Cognitive Examination

A brief bedside cognitive screening exam can be performed. The Mini Mental State Exam (MMSE) is widely used. Somewhat more challenging tests that are more sensitive for detecting milder deficits include the Montreal Cognitive Assessment (MoCA) and the Saint Louis University Mental Status (SLUMS) exam. Full neuropsychological evaluation requires up to a full day of testing, but provides standardized scores normed to age and education across a range of cognitive domains and may be helpful in subtler or atypical cases of impairment.

To assess learning and memory, the patient is typically asked to repeat and remember 3 unrelated words. Normal performance is to learn and repeat all 3 words. After generally 5 or more minutes of other mental state testing, the patient should be asked to recall the words. Remote memory can be checked by asking the patient to describe his or her medical, family, and social history; however, a knowledgeable informant must be available to confirm the information.

The evaluation should also include orientation testing. Disorientation to self occurs only in advanced dementia. Its presence in the context of mild or moderate cognitive disability suggests delirium or a primary psychiatric disturbance.

Assessment of language includes naming, sentence repetition, fluency (effortfulness of speech), comprehension, reading, and writing. This can be tested with everyday objects available to the examiner, such as a jacket, shoe, or pen. Parts of objects are more difficult to name than whole objects. Therefore, in addition to a jacket as a whole, the patient might be asked to name the collar, lapel, sleeve, pocket, and cuff.

A brief sequence of commands can further assess language comprehension, praxis, and left–right orientation. The patient should be asked to show how he or she would perform actions with each hand (eg, using a hammer to hit a nail or a key to open a lock). A subsequent 2-handed task, such as slicing bread or opening a jar, tests the patient’s ability to integrate the actions of both hemispheres in a single task. These can be followed with commands that require the patient to correctly identify right and left, both in reference to his or her own body (eg, “Touch your right thumb to your left ear”) and the examiner’s body (eg, “Point to my left hand with your left hand”).

Visuospatial or perceptual-motor function can be tested by asking the patient to copy a drawing of a cube or other simple 3-dimensional figure. Normal performance is to accurately depict 3 sides and 3 dimensions. The integration of motor behavior in space can be further tested with a drawing task. The clock drawing test assesses multiple realms of cognition, including executive function (planning), spatial relationships, and semantic knowledge. Normal performance requires placing all numbers and the hands in the correct position.

Executive functions can be evaluated in different ways. Category (also called semantic) fluency tests the patient’s ability to name as many words as possible belonging to a category set, such as animals or fruits. Patients who name <15 animals in 1 minute have a high likelihood of cognitive impairment. Attention, concentration, and working memory can be tested by asking the patient to add the value of a penny, a dime, a nickel, and a quarter. For this task, it is important that the names of the coins be used, because the working memory system is engaged throughout the process of translating the names to numerical values, performing addition, and reporting the answer in a unit different than what was provided. This pocket change addition task is useful as a cognitive screening tool because it can assess calculation simultaneously with working memory. The patient who answers “36 cents” can add numbers, but has failed to include all 4 coins. Other tests of working memory or related aspects of attention can be used if pocket change addition is inappropriate (eg, for someone unfamiliar with the common names of US coins). Alternatives include asking the patient to state the months of the year or days of the week in reverse order. Digit span is a common test of primary memory that also depends on attention. In this task, the patient is asked to repeat a string of random digits in the order that he or she heard them. Normal performance is to repeat strings of 5 or more correctly. Deficits may be more pronounced when patients are asked to repeat digits in reverse order. Normal performance in this task is to reach a span at least 2 digits less than the forward span.

Physical Examination

A general physical and neurologic examination should be completed. These are often normal in AD and other dementias. Parkinsonism can develop in several disorders and can be helpful in narrowing a differential diagnosis. Focal neurologic finding can suggest the presence of a structural or vascular lesion.

Ancillary Testing

The American Academy of Neurology evidence-based practice parameter for the diagnosis of dementia recommends blood tests to exclude systemic illnesses as the cause of dementia (Table 29–2). General metabolic and hematologic states, as well thyroid function and vitamin B₁₂ levels, should be tested. Syphilis serology tests are no longer considered part of the routine screening.

Imaging is also recommended as part of the routine assessment of patients with dementia symptoms. Computed tomography (CT) is useful to exclude structural lesions that may contribute to the dementia such as cerebral infarctions, neoplasm, extra-axial fluid collections, and hydrocephalus. However, magnetic resonance imaging (MRI) is preferred due to its greater resolution and the additional information provided. Medial temporal atrophy on MRI strongly supports the likelihood of AD when appropriate clinical features are present (Figure 29–1). Fluorodeoxyglucose (FDG) positron emission tomography (PET) scans reveal temporoparietal hypometabolism in patients with AD and frontotemporal hypometabolism in frontotemporal dementia. The presence or absence of amyloid plaques can be determined by amyloid PET.

Cerebrospinal fluid (CSF) examination by lumbar puncture is not a routine part of the dementia evaluation. Standard CSF tests (cell count, protein, glucose) have a low likelihood of influencing diagnosis in most people with dementia. CSF examination is more useful in cases with serologic evidence of past syphilis, as well as in patients with immunosuppression or atypical dementia symptom patterns, such as young age at onset or very rapid progression. CSF assays for soluble amyloid-beta (Aβ) and tau are commercially available. The finding of abnormal CSF Aβ and tau increases the probability that cognitive impairment is due to AD but is not highly specific.

Electroencephalography (EEG) is also not recommended as part of the routine evaluation of dementia. EEG findings are nonspecific. They are frequently normal in early stages and evolve toward generalized slowing.

COGNITIVE AGING

Cognitive aging is a decline in cognition that is considered to be generally inevitable with age, although the degree of cognitive change is highly variable, and some individuals age with very little cognitive decline. It is a common feature of aging across species. Declines associated with cognitive aging begin as early as the 40s. Some cognitive domains are more susceptible than others. Processing speed commonly declines with aging, and difficulty remembering names, especially proper names, is also typical. Overall, the degree of change is milder compared to the neurodegenerative diseases, although it can limit abilities to perform technical or highly demanding tasks.

Cognitive aging is not a disease, and the biological basis is still under study. Generally, neuronal death is not involved, as in the neurodegenerative dementias. Some brain “pathology,” such as development of neurofibrillary tangles in the medial temporal lobe and brain atrophy on imaging, is considered a nearly universal accompaniment of aging, but the relationship of these changes to cognitive aging is not clear.

ALZHEIMER DISEASE

AD is by far the most common cause of dementia and thus is almost always a consideration in the workup of cognitive change. Its hallmark is early change in episodic memory, although formal diagnostic criteria also require change in a second cognitive domain, such as language, visuospatial processing, or executive function. Social graces remain intact early. Noncognitive symptoms, including apathy and unawareness, are important contributors to the impact of disease. The general neurologic exam is usually normal.

Clinical Manifestations

Memory dysfunction is usually the first symptom recognized in AD. Recent memories are impaired because new information cannot be adequately stored for later recall. This leads to the characteristic rapid forgetting of people with AD. Declarative memory is most impaired in AD and is impaired early in the disease. This fact-oriented memory system allows us to store and recall specific information and experiences. Procedural memory (eg, knowing the steps to perform a task) is often better preserved, which contributes to the appearance of normalcy to a casual observer in mild AD. Emotionally charged memories are often better maintained. Orientation to time is often affected in early AD, and as the illness progresses, orientation to place becomes more disrupted. This may result in becoming lost in familiar settings.

Language impairments are prominent in AD. They usually begin as word-finding difficulty in spontaneous speech, which may later become severe enough to interrupt the flow of speech. The language of AD patients becomes progressively vaguer as semantic memories are lost. Their verbal output frequently lacks specifics. Prosody, the normal rhythm, melody, and emotional intonation of speech, is affected in many AD patients, particularly in more severe stages. Reading skills and verbal comprehension worsen as AD progresses. In late stages, global aphasia is common.

Disorders of higher visual processing and visual impairment are also common in AD. The dysfunction is evident at the level of basic visual processing, including impaired sensitivity to movement and visual contrast. Deficits in depth perception are also observed.

Executive dysfunction, including problems with judgment, problem solving, planning, and abstract thought, affects the majority of AD patients. Executive function behaviors require selecting tasks appropriately, sequencing their execution, and monitoring performance to ensure successful completion. Intact executive function also requires the suppression of inappropriate responses to the environment. Failures in this area of cognition are manifested as failure to manage more complicated tasks such as family finances or meal preparation. Socially inappropriate behavior, disinhibition, and poor task persistence may also emerge. The presence of executive dysfunction predicts the transition from more benign age-related cognitive changes to early dementia.

Noncognitive or behavioral symptoms are also important, especially as the disease evolves. Personality changes involving passivity and apathy are frequent in the early phases of the illness. Apathy is separable from depression and represents an organic loss of motivation. It occurs in 25% to 50% of AD patients. Another common noncognitive problem in AD is unawareness of illness (called anosognosia or lack of insight), which occurs in >50% of patients. Unawareness of illness is a major impediment to early diagnosis and may reduce the effective implementation of management strategies. Psychosis and agitation tend to occur later in the disease course. Delusions are often paranoid in character and may lead to accusations of theft, infidelity, and persecution. The delusion that caregivers or family members are impostors or that one’s home is not his or her real home is a common trigger for wandering or aggression. Anxiety and depression can lead to catastrophic reactions, an intense emotional outburst of short duration. They are characterized by the abrupt onset of tearfulness, aggressive verbalizations or actions, and contrary behaviors. Sundowning is commonly used to describe predictable increases in confusion and behavioral symptoms in the afternoon and evening hours. It is reported in up to 25% of AD patients.

AD follows a relentlessly progressive course, although there may be periods of relative symptom stability. Symptoms tend to progress less rapidly in both early and late disease, with more rapid losses, especially in activities of daily living, in moderate disease. It is a fatal disease, with an average survival of 8 to 12 years following diagnosis. Approximately half of AD patients die from complications of global neurologic dysfunction such as immobility and malnutrition; the other half of deaths are attributed to other factors, typically other age-related diseases such as stroke and cancer. Life expectancy is reduced by about 50%.

Diagnosis

The symptoms of AD begin insidiously and progress gradually. Most patients are initially diagnosed when their symptoms are still not functionally limiting, so the clinical diagnosis is mild cognitive impairment (MCI) due to AD. With time, as the disease progresses and activities of daily living become impaired, the diagnosis becomes dementia due to AD.

Pathologic diagnosis of AD, of course, requires autopsy. On gross examination, the AD brain is atrophic with enlarged ventricles and sulci (Figure 29–2), and on microscopic examination, there is neuronal loss and gliosis. The basis for a pathologic diagnosis of AD, though, is the presence of 2 hallmark findings on microscopic examination: amyloid plaques and neurofibrillary tangles. Amyloid plaques (Figure 29–3), also known as neuritic or senile plaques, are extracellular aggregates composed primarily of Aβ peptide, 39– to 43–amino acid fragments derived from cleavage of amyloid precursor protein (APP). Neurofibrillary tangles (Figure 29–4) are intracellular accumulations of tau, a microtubule-associated protein that is normally found in cells but becomes hyperphosphorylated and aggregates in AD.

The diagnoses of MCI and dementia, as described under “Vocabulary,” are based on the severity of cognitive impairment and do not themselves indicate etiology. MCI is diagnosed when the symptoms are more than expected with normal cognitive aging but do not have a significant impact on daily function, and dementia is diagnosed when the line of functional impairment is crossed. A patient can have MCI (or dementia) due to any of a multitude of causes. The determination that a patient’s MCI or dementia is due to AD has traditionally been based on purely clinical characteristics, especially the memory predominance of the cognitive symptoms.

More recently, biomarkers that help to identify AD pathophysiology have begun to be used in clinical diagnosis. The primary clinical biomarkers for AD are designed to detect changes related to the pathologic findings of AD, specifically Aβ, tau, and neurodegeneration, either by neuroimaging or CSF analysis. Aβ plaque deposition can be detected with a PET scan using amyloid tracers (Figure 29–5). In CSF, Aβ levels decrease in AD, which is somewhat paradoxical since overall Aβ levels are higher in brain due to accumulation in plaques; presumably the shift toward plaque deposition lowers Aβ concentrations in the interstitial fluid. Levels of both total and phosphorylated tau increase in CSF, so the ratio of CSF Aβ to tau is a sensitive measure (since the numerator decreases and denominator increases). Neurodegeneration can be detected by either structural imaging showing atrophy, particularly in the hippocampus, or by functional imaging with FDG-PET scans, which show decreased metabolic activity in areas with neurodegeneration.

The growing use of AD biomarkers has revealed that many changes begin well before symptoms emerge. For example, amyloid plaque deposition begins about 15 years before clinical symptoms develop, and typical AD changes in CSF Aβ and tau are also detected in a similar time frame. Thus, many older individuals with completely normal memory and no symptoms have evidence of AD pathophysiology on testing, which is known as preclinical AD. Although preclinical AD is a research concept, not a clinical diagnosis, the fact that people with AD pathophysiology can be identified even before they are symptomatic raises the hope of applying future AD therapies and arresting disease in a presymptomatic (ie, asymptomatic) stage.

Pathophysiology

Merely identifying certain brain changes in a disease state is not sufficient evidence that those changes play a causal role in the disease, of course. Genetics provides some of the strongest evidence for causality, and although the vast majority of AD cases are sporadic, there are rare families in which an early-onset form of AD is inherited in an autosomal dominant pattern. These families have mutations in 1 of 3 genes: APP, presenilin 1 (PSEN1), or presenilin 2 (PSEN2). All 3 genes are involved in the production of Aβ peptides, which are generated when presenilin, a component of the γ-secretase protease, cleaves APP. Aβ tends to aggregate and can form both small oligomers, which have toxic effects on synapses, and larger aggregates that form amyloid plaques. The idea that Aβ plays a central role in AD pathogenesis is based largely on this genetic evidence and is known as the amyloid hypothesis of AD.

The exact mechanism by which neuronal dysfunction and death occur in AD is unknown. APP or its normal derivatives might play a role in maintaining synaptic function and neuronal health. Aβ also is an activating trigger for microglial cells, leading them to produce several inflammatory cytokines with cytotoxic properties, including tumor necrosis factor-α. Activation of microglia may contribute to a self-propagating cycle of local inflammation and neuronal dysfunction. Although most models of AD pathophysiology place Aβ in a causative role, other approaches suggest oxidative stress or bioenergetic failure as triggering factors in the amyloid cascade. It is possible that AD is a disorder with heterogeneous origins, with different primary mechanisms resulting in similar patterns of neuronal failure and pathologic expression in different individuals.

Treatment

There are several US Food and Drug Administration (FDA)-approved drugs for AD. First-line treatment is usually a cholinesterase inhibitor, such as donepezil, rivastigmine, or galantamine. These drugs inhibit the enzyme that degrades acetylcholine in the cleft of cholinergic synapses and thus serve to boost cholinergic transmission. The rationale for using cholinesterase inhibitors in AD stems from early observations of cholinergic cell loss in AD and the known role of cholinergic transmission in memory. Because cholinesterase inhibitors do not halt the pathophysiologic processes that kill cholinergic neurons, they are considered a symptomatic, not disease-modifying, treatment. Their effect is modest; most patients do not experience actual improvement in symptoms but do benefit from slowing or arresting symptom progression for 6 to 12 months. The most common side effects are gastrointestinal, which can be avoided to some extent with the transdermal preparation of rivastigmine. Because these drugs are procholinergic, muscle cramps and bradycardia can also occur.

The other FDA-approved AD treatment is memantine, which blocks overstimulation of N-methyl-D-aspartate (NMDA)-subtype glutamate receptors. NMDA receptor activity is critical for normal learning and memory, but excessive activation results in excitotoxicity due to abnormal calcium influx. Memantine is a use-dependent blocker designed to allow physiologic NMDA receptor stimulation but prevent excitotoxicity. It is indicated for the moderate and severe dementia stages of AD and so is generally added to a cholinesterase inhibitor later in the disease. Memantine, like the cholinesterase inhibitors, provides a modest benefit by temporarily slowing progression of impairment.

Other drugs can be used to treat the behavioral and psychiatric symptoms that can occur in AD. Selective serotonin re-uptake inhibitors (SSRI) or serotonin-norepinephrine reuptake inhibitors should be considered, with side effect profiles guiding the choice of agent. Citalopram has shown efficacy in reducing agitation. Antipsychotics can be used to treat agitation or psychosis in patients with dementia, but because of the FDA Black Box warning for increased mortality when used in these patients, antipsychotics should be reserved for cases when nonpharmacologic intervention and other treatments fail. Atypical antipsychotics may be better tolerated compared with traditional agents.

Nonpharmacologic strategies are generally more effective and better tolerated approaches for treating behavioral and psychiatric symptoms in dementia. These include scheduled toileting and prompted toileting for incontinence, offering graded assistance (as little help as possible to perform activities of daily living [ADLs]), role modeling, cueing, positive reinforcement to increase independence, and avoiding adversarial debates by using redirection instead. Caregivers should be advised to maintain a calm demeanor and use the services of caregiver support groups. In addition, a systems-based approach to treatment might decrease caregiver burden. Home health services or assisted living facilities where multiple healthcare disciplines can become involved in the care of the person with dementia are likely to prevent caregiver burnout and subsequent skilled nursing facility placement. Sleep hygiene should be addressed, and if necessary, pharmacologic sleep aides with the least cognitively slowing effects can be used. Antihistaminic and anticholinergic agents are relatively contraindicated.

FRONTOTEMPORAL DEMENTIA