Epidemiology and Etiology

Cerebrovascular disease refers to disorders of the cerebral blood vessels that cause impaired cerebral circulation. Stroke is an impairment in blood flow to the brain due either to lack of blood flow (ischemia) or hemorrhage, resulting in cell injury and death, causing loss of neurologic function, including loss of motor, sensory, visual, and cognitive function, depending on the location of the injury. Ischemic stroke accounts for 85% of all strokes, while cerebral hemorrhage accounts for the remaining 15% and can be further divided into primary intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), subdural hematoma, and epidural hematoma. Transient ischemic attack (TIA) is defined as an acute, short‐duration, focal neurologic deficit, typically lasting less than 1 hour, without evidence of infarction on brain imaging.²

Stroke is the second most frequent cause of mortality world‐wide³ and the fifth most frequent in the United States,⁴ with a prevalence of 2.6% in those over 20 years of age, despite a decrease in the incidence of stroke and stroke mortality over the past 30 years.^5,6 Stroke disproportionately affects the elderly, ethnic minorities, and those of lower educational achievement.⁷ In 2013, the total estimated cost of stroke was estimated to be $75.2 billion in the United States alone and these costs will continue to increase due the aging population.⁸ Risk for stroke increases with age, with a crude age‐adjusted rate per 1000 persons of 0.5 for ages 18–44 years, 2.5 for ages 45–64 years, 6.9 for ages 65–74 years, and 12.4 for ages 75 years and older.⁹ Approximately 20% of all strokes are heralded by a TIA; the short‐term risk of stroke after TIA is 10% at 90 days, with the highest risk being in the first 24 hours;^10–12 80% of all strokes following TIA are preventable. Within 1 year of a TIA, 12% of patients die.^13,14

Impaired cerebral blood flow leading to ischemia and energy failure is the common pathogenic mechanism for stroke. A 50% decrease in blood flow to the brain for as few as 3–4 minutes can result in irreversible brain injury. Following infarction, edema and excessive neurotoxic excitation contribute to further regional tissue injury and death. Ischemic strokes occur through three mechanisms: (1) primary thrombosis of artery or vein; (2) embolism of debris to the central nervous system (CNS) from a proximal site; or (3) systemic hypoperfusion.¹⁵ Thrombotic stroke occurs due to primary occlusion of a blood vessel supplying the CNS. They can be further divided into large vessel or small vessel strokes. Large vessel stroke includes the carotid and vertebral arteries and their major branches. The major cause of primary occlusion of these vessels is atherosclerosis, but dissection, trauma, and vasculitis are other etiologies.¹⁵ Strokes are characterized by extensive downstream ischemia, usually due to a thromboembolic event along the distribution of these vessels. Small vessel or lacunar strokes result from obstruction of the small (<5 mm diameter) penetrating arterioles supplying the basal ganglia, anterior limb of the internal capsule, and (less commonly) deep cerebral white matter. Age and uncontrolled hypertension are the greatest predisposing factors.^16,17 Symptoms usually include unilateral motor or sensory deficit without visual field changes or disturbances of consciousness or language. Embolic strokes result from debris that originates from a source outside the CNS, typically the heart or aorta. Sources include atrial fibrillation, valvular heart disease, ventricular thrombus, heart failure with low cardiac function, patent foramen ovale, infectious endocarditis, hypercoagulability, and aortic atherosclerosis.¹⁸ Strokes may occur due to periods of sustained systemic hypoperfusion resulting in decreased cerebral perfusion in conditions such as cardiac arrythmias or arrest.

Approximately 15% of strokes result from hemorrhagic events leading to infarction, most often related to hypertension, trauma, substance abuse, or aneurysmal rupture.¹⁹ Primary cerebral ICH typically occurs from rupture of small arteries in the subcortical brain tissue, resulting in a hematoma that expands slowly until it is stopped by intracranial pressure. The most common cause is chronic or acute hypertension, but trauma, sympathomimetic drug abuse, amyloid angiopathy (cortical ICH), or vascular malformations are other causes.²⁰ Headache, nausea, and decreased consciousness typically accompany neurologic deficits coinciding with the location of the ICH. The major cause of SAH is rupture of arterial intracranial aneurysms, but other etiologies include trauma, vascular malformations, and amyloid angiopathy. The aneurysmal rupture releases blood into the cerebral spinal fluid surrounding the brain under arterial pressure, which results in a sudden increase in intracerebral pressure with abrupt changes in consciousness, severe headache, and focal neurologic deficits. The aneurysmal SAH may occasionally be preceded by a subtle bleeding episode with headache only, called a sentinel hemorrhage.²¹ Acute interventional treatment with catheter‐based or open surgical clipping of aneurysm is often required to prevent rebleeding of the aneurysm, which is frequently fatal.

Clinical Manifestations

The hallmark of stroke is a sudden loss of brain function. The clinical manifestations of stroke vary depending on the size and location of the affected brain region. The most common signs and symptoms include sensory and motor deficits, changes (paresis) in extraocular muscles and eye movements, visual defects, sudden headache, altered mental status, dizziness, nausea, seizures, impaired speech or hearing, and neurocognitive deficits such as impaired memory, reasoning, and concentration.^19,22,23

Diagnosis

Stroke should be considered whenever a patient experiences the clinical manifestations described above, with the additional goals of ensuring medical stability and identifying the cause of the deficits. Other nonstroke causes for these signs and symptoms, particularly when focal, may include seizures, hypoglycemia, intracranial tumors, trauma, infection, encephalitis, multiple sclerosis (MS), and prolonged migrainous aura.²² In addition to a thorough neurologic and cardiovascular examination, anatomic and functional brain imaging is central to the diagnosis of stroke. Time is of the essence for instituting treatment to manage acute stroke due the potential to employ reperfusion strategies, which are now the standard of care in ischemic stroke. Intracranial hemorrhage must be quickly excluded before life‐saving thrombolytic therapy can begin. While brain magnetic resonance imaging (MRI) provides greater anatomic detail and sensitivity for detection of early infarction, noncontrast computed tomography (CT) scan is the first line of imaging because of its speed, low cost, and availability (see Figures 23‐1 and 23‐2).^24–26 Laboratory evaluation of the stroke patient includes compete blood count, comprehensive metabolic panel, urinalysis, coagulation profile, and, when indicated, blood culture, echocardiography, and lumbar puncture.²²

Treatment

The outcome of stroke and TIAs is significantly affected by the timeliness of treatment. Early intervention is critical to prevention, treatment, and recovery. The critical issue in treatment of ischemic TIA is identification of the cause, as large number of strokes following TIAs or minor strokes are preventable. This evaluation includes laboratory work to exclude anemia, erythro/thrombocytosis, coagulopathies, and hypoglycemia that can mimic stroke; as well as cardiac evaluation with electrocardiogram (ECG), long arrhythmia monitoring, and echocardiogram to exclude atrial fibrillation and other cardiac sources of embolism. Vascular imaging of neck and head with ultrasound, CT, or magnetic resonance angiography (MRA) will identify large vessel sources of stroke such as carotid stenosis. Structural brain imaging with CT or MRI is also necessary to rule out mimics such as brain tumors. TIAs are treated by reduction in hypertension (lifestyle changes such as diet, exercise, smoking cessation, and stress reduction; medical therapy for hypertension; and anticoagulant or antiplatelet medications), or large vessel revascularization.²⁷ The reader is referred to Chapters 14 and 18 in this textbook that describe more thoroughly anticoagulant and antihypertensive therapies.

The core principle of acute stroke care is recanalization of occluded vessel (reperfusion of ischemic tissue that can be saved, known as the penumbra), optimization of collateral flow, and avoidance of secondary brain injury. Management of acute stroke includes medical therapy to reduce bleeding or thromboembolic occlusion, medical therapy to reduce brain edema and neurotoxicity/nerve injury, and surgical interventions (revascularization, hemorrhage control).^22,23,27 Once intracranial hemorrhage has been excluded as the source of acute cerebral ischemia, thrombolysis with intravenous tissue plasminogen activator (t‐PA) can improve reperfusion, minimize infarction, and reduce disability.²⁸ The American Heart Association and American Stroke Association advisory statement recommends administration of t‐PA from 3 to 4.5 hours after stroke onset.^29,30 Advance perfusion imaging techniques now enable identification of patients who may benefit from treatment of ischemic stroke up to 24 hours after, utilizing catheter‐based mechanical thrombectomies for large cerebral occlusions where brain tissue can be still be rescued.³¹ No neuroprotectant agent has been found for acute stroke, although extensive investigation continues to develop and test new neuroprotective drugs to minimize neurotoxicity, reduce edema, and correct ischemia, mostly among excitatory amino acid antagonists, free radical scavengers, and cytokine inhibitors.^23,27 Once acute stroke management is complete, etiologic evaluation of ischemic stroke follows a similar pathway to that of TIA and identification of cause is critical to preventing recurrent stroke.

Primary hemorrhagic stroke is typically managed conservatively, although SAH, subdural, and epidural hemorrhages may require surgical intervention aimed at treating the specific mechanism or lesion.

Oral Health Considerations

Following stroke, patients may experience several oral problems (see Table 23‐1). These problems can lead to impairment of food intake, poor nutrition, and weight loss due to diminished taste satisfaction, chewing capacity, and swallowing; choking; and gagging.^32–34 Diminished motor function of masticatory and facial muscles may also reduce food clearance from the mouth and teeth and, alone or combined with the presence of diminished dexterity of the arms or hands, may adversely affect oral hygiene and increase the risk for caries and periodontal disease.^34,35 Creative and effective use of adjuvant oral hygiene techniques and devices (oral antimicrobial rinse, oral irrigation, floss holders, etc.) represents an important approach to oral health promotion and disease prevention, supported by frequent recall examination and prophylaxis. Replacement of missing teeth and adequacy of removable and fixed prostheses are essential to effective chewing and diet.

Dental management of the patient with a history of TIA or stroke presents several challenges.^32–34,36 Physical limitations secondary to stroke, such as hemiplegia or paralysis, must be assessed to determine practical aspects of delivering oral healthcare. Ambulatory patients may require assistance getting into the dental operatory and transferring to the dental chair.³⁷ These patients may also require chair modifications, such as commercially available pillow and wedge support devices, to maintain an upright position and comfort during dental treatment.³⁷ If the patient is in a wheelchair, it must be determined whether transfer to the dental chair is feasible.^37,38 The dental team should be familiar with various transfer techniques to ensure the safety of all those involved in the process.³⁸ Dental treatment may need to be administered to patients in wheelchairs if they are not able to transfer, which can pose various challenges to oral healthcare providers.³⁸

Stroke prevention through routine monitoring of blood pressure is an important step in hypertension risk, detection, and reduction through referral and effective management. Identification of calcified carotid artery atheroma (CCAA) in the neck on panoramic imaging may represent findings associated with stroke risk. CCAA‐related calcifications occur in the common carotid artery at the bifurcation of the internal carotid artery and the external carotid artery, located lateral and inferior to the hyoid bone or in either branch (see Figure 23‐3).³⁹ These radiographic findings provide reasonable accuracy in the detection of vessel stenosis, but do not infer the presence of hemodynamically significant disease related to risk of stroke.³⁹ Patients with identified CCAA on panoramic imaging should be informed of the findings and referred to a medical provider for further evaluation. Prior history of TIA or stroke increases the risk of a future or second stroke, with the highest risk during the first 90 days.^13,14,40,41 A comparative retrospective study⁴² examining complications of invasive dental treatment following acute stroke found no evidence to support the historical intuitive guideline to defer elective dental treatment for 6 months following a stroke or for a patient with active TIAs. With optimal medical monitoring and poststroke care, patients can safely undergo invasive dental treatment, with appropriate consideration for stress reduction, medication interactions, adverse effects, neurologic deficit management, and control of underlying cardio/cerebrovascular risk factors.⁴²

Use of antiplatelet and anticoagulant medications is common in patients with a history of stroke and TIAs. This includes oral aspirin, oral antiplatelet drugs, such as ticlopidine and clopidogrel, subcutaneous low molecular weight heparin, and warfarin. These medications, taken in therapeutic dosages, and for warfarin with an international normalized ratio (INR) ≤3.5, rarely require dose modification before routine dental and minor oral surgical treatment.^43–47 Novel anticoagulants, such as factor Xa inhibitors—that is, apixaban (Eliquis), rivaroxaban (Xarelto), edoxaban (Savaysa)—and direct thrombin inhibitors (DTIs)—that is, dabigatran (Pradaxa)—are now commonly used in stroke prevention. Current evidence suggests that these medications should not be discontinued for basic dental treatment and minor invasive dental procedures due to risk of a thromboembolic event.⁴⁸ Bleeding complications arising in patients using these medications are typically managed with local measures, including pressure, topical hemostatic agents, and primary closure.^48,49 However, an individualized approach should be considered in all cases of patients taking these medications who undergo invasive dental procedures, accounting for type of procedure, risk of bleeding, and risk of embolism.⁵⁰ For additional information regarding management of patients taking antiplatelet and anticoagulant medications, the reader is referred to Chapter 14 in this textbook. Concomitant use of nonsteroidal anti‐inflammatory drugs (NSAIDs) may increase the risk for bleeding, and their long‐term use may reduce the protective effect of aspirin. Potential drug interactions of note include, but are not limited to, use of metronidazole, erythromycin, and tetracycline, which may alter the bioavailability of warfarin.

Stress reduction and confidence building for the patient during dental visits are important behavioral goals to make the patient comfortable and minimize anxiety‐related elevation in blood pressure. Epinephrine‐containing impression cord should not be used.^36,42 Blood pressure should be monitored at every visit and during a visit if long and stressful.

Epidemiology and Etiology

MS is a disorder of variable clinical features resulting in deficits in cognitive, sensory, motor, and bladder function. It is characterized pathologically by inflammation, axonal injury, and demyelination of the CNS.⁵¹ The typical presentation of MS is of recurrent, focal neurologic deficits that typically improve over several weeks or months, but over time these recurrent episodes evolve into progressive loss of neurologic function. In Western societies, MS is second only to trauma as a cause of neurologic disability in early to middle adulthood.⁵¹ The age at onset is typically between 20 and 31 years; rarely does MS appear clinically before the age of 10 or after age 60.^51,52 MS is more common among women than men (2.3:1 ratio); however, in patients with later onset of MS, the sex ratio tends to be more even.⁵³ The concept that the prevalence of MS increases with increasing distance from the equator has been disproved.⁵⁴ When racial differences are correlated with prevalence rates for MS worldwide, white populations are at greatest risk and both black and Asian populations have a low risk of disease.⁵²

The cause of MS is unclear, and the most widely accepted theory is that MS is an inflammatory autoimmune disorder caused by autoreactive lymphocytes resulting in demyelination of axons in the CNS.⁵⁵ Myelin is critical for the propagation of nerve impulses and when it is destroyed in MS, slowing and/or complete block of impulse propagation is manifested by abnormal muscular and neurologic signs and symptoms. While loss of myelin is a hallmark of disease, it appears that neuronal and axonal loss is also important in disease progression.^56,57 This results in brain lesions called plaques. MS lesions or “plaques” vary in size and are characterized by perivenular cuffing with inflammatory mononuclear cells, predominantly macrophages and T cells, which is generally limited to the white matter and periventricular areas of the CNS.⁵⁸ Studies have established that demyelinated lesions are also commonly found in the cortical gray matter and meningeal inflammation is prominent in early MS.⁵⁹ Plaques may be found in both the brain and the spinal cord, and within the plaques there is variable destruction of myelin and neuronal axons, with preservation of the ground structure.⁵² Uniform areas of incomplete myelination are called shadow plaques and may be evident in chronic lesions of MS.⁵¹ Although an inflammatory and autoimmune mechanism is involved in the disease, it is unclear whether this is a primary process or a reaction to an infectious agent or underlying primary neurologic degeneration.⁶⁰

Substantial evidence suggests that autoimmune mechanisms are involved in the pathogenesis of MS.⁶¹ Myelin basic protein (MBP) is an important T‐cell antigen that is critical in the development of experimental allergic encephalomyelitis (EAE) in animals. Certain forms of EAE are pathologically similar to MS and activated MBP‐reactive T cells are often found in the blood or cerebrospinal fluid (CSF) of MS patients, supporting the autoimmune theory of MS pathogenesis.⁶¹ Increased levels of immunoglobulin G (IgG) and cytokines such as tumor necrosis factor are commonly detected in the CSF of patients with MS.⁶² A genetic susceptibility to MS clearly exists, and it is thought that an initial trigger leads to autoimmune mechanisms causing demyelination. The major histocompatibility complex (MHC) on chromosome 6p21 (HLA‐DRB1 gene) has been identified as one genetic determinant for MS.⁶³ The MHC encodes the genes for the human leukocyte antigen (HLA) system, and susceptibility to MS lies with the class II alleles, particularly the class II haplotypes DR15, DQ6, and Dw2.⁵²

Epidemiologic evidence supports the role of an environmental exposure in MS, and two common infectious agents to be implicated in the pathogenesis of this disease are Epstein–Barr virus and human herpesvirus 6.⁶⁴ Other viruses that have been implicated in the pathogenesis of MS include measles, mumps, rubella, Chlamydia pneumoniae, parainfluenza, vaccinia, and human T‐lymphotropic virus 1.^52,64 There does appear to be a relationship between a lack of sun exposure and low serum vitamin D levels with the risk of MS.⁶⁵ This finding initially led to the belief that MS was more prevalent in northern latitudes, but more recent data have not supported this finding. There has been no association with vaccination and MS.⁶⁶

Clinical Manifestations

The onset of MS may be insidious or abrupt, and symptoms range from trivial to severe. The clinical course of disease generally extends for decades, but a rare few cases are fatal within a few months of onset. The clinical manifestations of MS depend on the areas of the CNS involved, and frequently affected areas include the optic chiasm, brainstem, cerebellum, and spinal cord.^52,58 The sudden onset of optic neuritis (diminished visual acuity, dimness, or decreased color perception), without any other CNS signs or symptoms, is often considered the first symptom of MS.⁶⁷ Other common visual signs in patients with MS include diplopia, blurring, nystagmus, gaze disturbances, and visual field defects.⁵⁸

Limb weakness is characteristic of MS and can manifest as loss of strength or dexterity, fatigue, or gait disturbances. Spasticity associated with painful muscle spasms is often observed in the legs of patients with MS and may interfere with a patient’s ability to ambulate. Ataxia may affect the head and neck of MS patients and may result in cerebellar dysarthria (scanning speech). Bladder dysfunction and bowel dysfunction frequently coexist and are present in >90% of MS patients. The most common complaints are urinary urgency and constipation. Sensory symptoms are the most common feature of MS, present in almost 100% of patients, and include numbness, paresthesia, and hyperesthesia in the limbs and thorax.⁶⁸ Impairments of vibratory and position sense can also exist. Paroxysmal attacks of pain and muscle spasm can occur, often triggered by specific sensory stimuli. The classic Lhermitte sign is described as sensory shock that runs up and down the spine, which is typically brought on by neck flexion. Fatigue, sleep disorders, depression, cognitive dysfunction, sexual dysfunction, vertigo, and chronic pain are frequently observed in patients with MS.^52,69 Patients with MS often experience exacerbation of neurologic symptoms in response to an elevation of the body’s core temperature. This is referred to as Uhthoff’s symptom and is generally seen in response to increased physical activity.⁵²

Diagnosis

There is no definitive diagnostic test for detection of MS and the disease remains a clinical diagnosis, although MRI demonstrates characteristic abnormalities of MS in >95% of patients.⁵² MS plaques are visible as hyperintense focal areas on T₂‐weighted images that are characteristic of chronic lesions. T₁‐weighted images reveal hypointense areas that are usually indicative of active MS lesions.⁵² Evoked potentials measure CNS electrical potentials, and abnormalities are detected in up to 90% of patients with MS. CSF is often analyzed in patients suspected of having MS and CSF‐specific oligoclonal bands are found in 95% of patients, which indicates evidence of chronic autoimmune dysfunction.⁷⁰ Recent formulations of the diagnostic criteria for MS begin with an initial clinical presentation typical for an MS attack known as the McDonald criteria.⁷¹ These are relatively complex criteria, but essentially rely on the presence of at least one distinct monophasic clinical episode lasting greater than 24 hours, which is then supported by confirmation of at least two distinct objective correlating findings, either on MRI imaging, evoked potentials, optical imaging, or the presence of CSF‐specific oligoclonal bands.⁷¹ These criteria require evidence of more than one distinct lesion occurring at different times (time and space), as the differential diagnosis of a single monophasic attack is broad and includes CNS vascular events, neoplasm, and infections.⁷¹

Treatment

Therapy for MS can be divided into three categories: (1) treatment of acute attacks; (2) disease‐modifying therapies; and (3) symptomatic therapy.^51,52 Corticosteroids are used to manage both initial attacks and acute exacerbations of MS. High‐dose corticosteroids have been shown to hasten recovery.⁷² Intravenous methylprednisolone is typically administered at a dose of between 500 and 1000 mg/d for 3–5 days to reduce the severity and length of an attack.⁵⁸ Over the last two decades, a large number of disease‐modifying agents have been approved for the treatment of MS that have shown various benefits to patients by decreasing relapse rate, clinical disease progression, and imaging‐based progression.^73–75 The choice of drugs is made based on the progression of disease, side effects, risk of complications, type of administration, patient preference, and response rate.^73–75 Disease‐modifying agents include subcutaneously injectable interferon (IFN)‐β1a, IFN‐β1b (cytokines that modulate immune responsiveness), and glatiramer acetate (mimics MBP).⁷⁶ Fingolimod (inhibits T‐cell migration), teriflunomide (inhibitor of pyrimidine synthesis), dimethyl fumarate (activates nuclear factor erythroid 2‐related factor), cladribine (purine antimetabolite agent), and siponiod (sphingosine 1‐phosphate receptor modulator) are oral agents approved for the treatment of MS. Mitoxantrone (Novantrone) is a chemotherapeutic agent administered intravenously that is effective in reducing neurologic disability and frequency of clinical relapses in patients with MS.⁷⁷ Natalizumab (binds α‐4 integrin), ocrelizumab (anti‐CD 20), and alemtuzumab (binds CD52 surface proteins) are monoclonal antibodies that are given intravenously. Common agents employed for the management of specific MS symptoms include anticonvulsants, benzodiazepines, tricyclic antidepressants, smooth muscle relaxants, anticholinergic agents, and various pain medications.^51,78

The prognosis for MS is variable. It is difficult to predict the course of MS in an individual patient; however, earlier age of onset, female sex, fewer number of baseline brain MRI lesions at time of clinical diagnosis, and less disability 5 years after onset are generally considered favorable prognostic signs.⁵² Most patients with MS experience progressive neurologic disability and gait disturbances and/or difficulty with ambulation, as these are common clinical sequelae for patients with this disease.⁷⁹ Mortality as a direct consequence of MS is uncommon, and death usually results from a complication of the disease, such as pneumonia.⁸⁰

Oral Health Considerations

Individuals may present to the oral healthcare provider with signs and symptoms of MS. Trigeminal neuralgia (TGN), which is characterized by electric shock–like pain, may be an initial manifestation of MS in up to 5% of cases.^51,81–84 MS‐related TGN is similar to idiopathic TGN, and the reader is referred to Chapter 11 in this textbook that describes idiopathic TGN more thoroughly. Features of MS‐related TGN include the possible absence of trigger zones and continuous pain with lower intensity.⁸² Glossopharyngeal neuralgia (GN) affects the sensory distribution of the glossopharyngeal or vagus nerve and clinically presents as a severe, stabbing pain in the region of the ear, base of the tongue, angle of the mandible, and/or tonsillar fossa. Prevalence of GN has been reported in 0.5% of patients with MS.⁸⁵ Several medications can be used to manage TGN and GN and the reader is referred to Chapter 11 that describes these medications and alternative therapies.

Patients with MS may also demonstrate neuropathy of the maxillary (V2) and mandibular branches (V3) of the trigeminal nerve, which may include burning, tingling, and/or reduced sensation.⁸⁵ Neuropathy of the mental nerve can cause numbness of the lower lip and chin.^83,84 Myokymia may be seen in patients with MS and consists of rapid, flickering contractions of the facial musculature secondary to MS lesions affecting the facial nerve.⁸⁶ Facial weakness and paralysis may also be evident in MS patients. Dysarthria that results in a scanning speech pattern is often seen in patients with MS. Other orofacial pain conditions that may be present at higher frequency in patients with MS compared to the general population include temporomandibular disorder and headache.^87,88 If MS is suspected, oral healthcare professionals should carefully evaluate cranial nerve function. If cranial nerve abnormalities are detected upon examination, the individual should be referred to a neurologist for further evaluation. In addition, MS patients may experience increased frequency and severity of oral disease, such as xerostomia and gingival bleeding, compared to healthy individuals.⁸⁹

It is recommended to avoid elective dental treatment in MS patients during acute exacerbations of the disease, due to limited mobility and possible airway compromise.^90,91 Emergency dental treatment may be considered in patients experiencing an acute flare of MS in consultation with the patient’s physician to ensure medical stability.³⁷ MS patients with significant dysfunction and/or who are medically unstable may require dental treatment in an operating room under general anesthesia due to the inability to undergo treatment in an outpatient setting. In addition, electric toothbrushes and oral hygiene products with larger handles may be necessary for completing oral hygiene in patients with significant motor impairment. It is critical for oral healthcare providers to maintain accurate medication inventories for patients with MS and to be aware of possible interactions of these medications with those commonly used and prescribed in dentistry, as well as oral and systemic side effects of these agents. MS patients managed with immunosuppressants may place those individuals at increased risk for opportunistic and community‐acquired infections, emphasizing the need for optimal oral hygiene (see Table 23‐2).⁹⁰

Epidemiology and Etiology

Dementia is defined as an acquired deterioration in cognitive abilities that impairs the successful performance of activities of daily living.⁹² Memory is the most common cognitive ability lost with dementia; other mental faculties affected include problem‐solving skills, judgment, visuospatial ability, and language. The global prevalence of dementia is estimated at 24 million and has been predicted to quadruple by the year 2050.^93,94 Alzheimer’s disease (AD) is a disease of older age and is rare except for those with inherited forms prior to age 65. The disease doubles in prevalence every 5 years past the age of 65. The clinical features of AD were first described in 1906 by Alois Alzheimer;⁹⁵ more than a century later, the molecular basis of AD has been greatly elucidated, and enhanced diagnostic modalities have enabled clinicians to visualize neurologic changes secondary to AD.

The neuropathology of AD is characterized by neuritic plaques (extracellular beta‐amyloid deposition) and neurofibrillary tangles (intracellular hypophosphorylated tau protein), coupled with a degeneration of neurons and synapses. In addition, cerebral amyloid angiopathy, inclusion of alpha synuclein (Lewy bodies and vascular brain injury), and loss of hippocampal pyramidal cells are commonly seen.^96–98 The most severe pathology associated with AD is atrophy, usually found in the medial temporal lobe structures and cortical areas of the brain.⁹⁹ While the exact pathogenesis of AD is unclear, an imbalance between the production and clearance of Aβ in the brain, termed the amyloid cascade hypothesis, is thought to be the disease‐initiating event that ultimately leads to neuronal degeneration and dementia.⁹⁹ Studies have suggested a more complex pathophysiology regarding Aβ processing than previously thought.^93,100 Amyloid deposited around meningeal and cerebral vessels, termed amyloid angiopathy, may lead to cerebral lobar hemorrhages. The pathogenesis also involves tau, a microtubule‐associated protein. Neurofibrillary tangles are twisted neurofilaments in neuronal cytoplasm that represent abnormally phosphorylated tau protein and appear as paired helical filaments by electron microscopy.⁹² Tau protein is thought to aid in assembly and stabilization of the microtubules that convey cell organelles and glycoproteins through the neuron. In AD, tau becomes hyperphosphorylated and leads to sequestration of normal tau and other microtubule‐associated proteins, thus impairing axonal transport and normal neuronal function. In addition, tau becomes prone to aggregation into insoluble fibrils that develop into tangles, further compromising neuronal function.⁹⁹

The genetic basis of AD has been studied extensively, and specific genetic mutations have been implicated in both the familial and sporadic forms of the disease. Familial AD is an autosomal dominant disorder with onset typically prior to age 65 years. Mutations in the APP gene on chromosome 21 were the first to be identified as the cause of familial AD; subsequent investigations have demonstrated mutations in the presenilin 1 and 2 genes (PSEN1 and PSEN2, respectively) that account for the majority of familial AD cases.^101,102 The most commonly reported gene associated with sporadic AD is apo‐lipoprotein E (APOE) on chromosome 19, which is involved in cholesterol transport.^92,99,101 The e4 allele accounts for most of the genetic risk in sporadic AD.⁹⁹ Mutations of the sortilin‐related receptor (SORL1) have been associated with both late‐onset AD and sporadic AD.^93,103

Clinical Manifestations

AD is a slowly progressive disorder represented by a continuum of clinical characteristics. It is a disease of the elderly; it is unusual to present prior to age of 60 unless a familial form is present. Updated clinical criteria recognize three stages of AD: (1) preclinical AD; (2) mild cognitive impairment due to AD; and (3) dementia due to AD.¹⁰⁴ Preclinical AD occurs before changes in cognition and everyday activities are observed and is primarily used for research purposes.¹⁰⁵ Cognitive impairment due to AD is characterized by mild changes in memory and other cognitive abilities that are noticeable to patients and families, but are not sufficient to interfere with day‐to‐day activities. Dementia due to AD is characterized by changes in two or more aspects of cognition and behavior that interfere with the ability to function in everyday life.¹⁰⁴ The initial signs of AD involve retrograde amnesia from progressive declines in episodic memory.¹⁰⁶ This may initially go unrecognized or be viewed as forgetfulness; however, as the disease progresses, memory loss begins to affect the performance of daily activities, including following instructions, driving, and normal decision‐making. As AD progresses, the individual is often unable to work, gets confused and lost easily, and may require daily supervision. Language impairment, loss of abstract reasoning skills, and visuospatial deficits begin to interfere with simple, routine tasks. Advanced AD is characterized by loss of cognitive abilities, agitation, delusions, and psychotic behavior.⁹² Patients may develop muscle rigidity associated with gait disturbances and tend to wander aimlessly. In end‐stage AD, patients frequently become rigid, mute, incontinent, and bedridden.⁹⁹ Help is needed for basic functions, such as eating and dressing, and patients may experience generalized seizure activity. Death typically results from malnutrition, heart disease, pulmonary emboli, or secondary infections.⁹²

Diagnosis

The formal diagnosis of AD requires histologic confirmation, which typical occurs post mortem, although clinical criteria exist. The clinical diagnosis should be entertained in any adult with onset of insidious and progressive memory decline and impairment of at least one other cognitive function in the absence of another confounding medical or neurologic disorder. Probable AD is defined by the decline or loss of the ability to function at work or at one’s usual activities, onset of delirium or major psychiatric disorder, and cognitive impairment on objective bedside memory tests (includes the following domains: reasoning, judgment, ability to acquire and remember new information, language function, behavior, visuo‐spatial abilities).¹⁰⁷ These bedside scales include the Mini‐Mental Status Exam, Montreal Cognitive Assessment, and the standardized neurologic exam of the American Academy of Neurology. Possible AD refers to those who meet the criteria for dementia, but have another illness that may contribute to the neurologic status, such as hypothyroidism or cerebrovascular disease.¹⁰⁷

Diagnostic analysis of CSF may show a slight increase in tau protein and a lower concentration of Aβ peptide compared with healthy individuals or those with other dementias. Electroencephalographic (EEG) studies typically demonstrate generalized slowing without focal features. Neuroimaging is important in evaluating suspected AD to exclude alternative causes of dementia, such as cerebrovascular disease, subdural hematoma, or brain tumor. MRI and CT typically reveal dilatation of the lateral ventricles and widening of the cortical sulci, particularly in the temporal regions.¹⁰¹ Volumetric MRI uniformly demonstrates shrinkage in vulnerable brain regions, especially the entorhinal cortex and hippocampus.¹⁰¹ Positron emission tomography (PET) can identify areas of hypometabolism in the temporal, parietal, and posterior cingulated cortices and has a high ability to differentiate AD from other dementias.⁹⁹ Slowly progressive decline in memory and orientation, normal results on laboratory tests, and neuroimaging showing only diffuse or posteriorly predominant cortical and hippocampal atrophy are highly suggestive of AD.⁹²

Treatment

There is no cure for AD, and therapy is aimed at slowing the progression of the disease. Cholinesterase inhibitors are approved by the US Food and Drug Administration (FDA) to treat mild to moderate cases of AD and are considered the standard of care.^108,109 They provide a proven, modest symptomatic benefit for patients with AD. The three types of cholinesterase inhibitors currently available are donepezil, rivastigmine, and galantamine; these medications decrease the hydrolysis of acetylcholine released from the presynaptic neuron into the synaptic cleft by inhibiting acetylcholinesterase, resulting in stimulation of the cholinergic receptor.¹⁰¹ Common side effects of these medications include nausea, vomiting, diarrhea, weight loss, bradycardia, and syncope.¹⁰⁸ Memantine, a noncompetitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist believed to protect neurons from glutamate‐mediated excitotoxicity, is used for treatment of moderate to severe AD.¹⁰⁸ Studies have demonstrated greater cognitive and functional improvement when memantine is used in conjunction with cholinesterase inhibitors compared to monotherapy.¹¹⁰ Antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), are commonly used to treat depression, which is often seen in the mild to moderate stages of AD.^99,111 Antipsychotic agents are used for those patients who display aggressive behavior and psychosis, especially in the later stages of the disease. Other agents that have been reported to be of clinical value in the treatment of AD include antioxidants, such as selegiline and α‐tocopherol (vitamin E).^99,108,110 Currently, disease‐modifying agents aimed at reducing Aβ production, preventing Aβ aggregation, promoting Aβ clearance, and targeting tau phosphorylation and assembly are being investigated for future clinical use in the treatment of AD.^110,112,113 Caregivers of patients with AD must be involved in the overall treatment, since they are responsible for maintaining the patient’s general health and ensuring a meaningful quality of life; it is often necessary to provide educational, emotional, and psychological support to these individuals, as the task for caring for patients with AD can be extremely challenging.

Oral Health Considerations

Oral and dental health is a major issue in patients with AD, because significant deterioration in oral health status is commonly observed with advancing disease.^114,115 Patients with AD appear to be at higher risk for developing coronal and root caries, periodontal infections, temporomandibular joint abnormalities, and orofacial pain compared to healthy subjects.^116,117 Oral healthcare providers should be able to recognize symptoms of AD and refer patients for further medical evaluation, if necessary. Patients with AD can become frustrated, irritable, and possibly combative when confronted with unfamiliar circumstances or with questions, instructions, or information that they do not understand.¹¹⁴ The presence of a caregiver may be beneficial, as they can verify patient information, interpret patient behavior, and alleviate anxiety.¹¹⁶ The oral healthcare provider must approach AD patients with empathy and explain all procedures and instructions clearly, since communication is essential in the management of dental patients with AD.^118,119 Patients with AD should be placed on an aggressive preventive dentistry program, including a 3‐month recall, oral hygiene education, and prosthesis adjustment, as poor oral health status can have a negative impact on the systemic health and wellbeing of patients with AD.^120,121 Specially adapted products, such as modified toothbrushes and foam mouth props, may be useful for oral hygiene and provision of dental care in patients with AD.¹¹⁶ It is recommended to complete restoration of oral healthcare function in the earliest stages of AD, because the patient’s ability to cooperate diminishes as cognitive function declines.¹¹⁴ Time‐consuming and complex dental treatment should be avoided in persons with severe AD.¹²²

Medications used to treat AD can cause a variety of orofacial reactions and potentially interact with drugs commonly used in dentistry. Cholinesterase inhibitors may cause sialorrhea, whereas antidepressants and antipsychotics are often associated with xerostomia. In addition, dysgeusia and stomatitis have been reported with use of antipsychotic agents.¹¹⁴ Antipsychotic medications also increase the risk of involuntary jaw movements, which can lead to oral hard and/or soft tissue injuries (see Table 23‐3).³⁷ Antimicrobials, such as clarithromycin, erythromycin, and ketoconazole, may significantly impair the metabolism of galantamine, resulting in central or peripheral cholinergic effects.¹¹⁴ Anticholinesterases may increase the possibility of gastrointestinal irritation and bleeding when used concomitantly with NSAIDs.¹¹⁴ Local anesthetics with adrenergic vasoconstrictors should be used with caution in AD patients taking tricyclic antidepressants, due to the potential risk of cardiovascular effects, such as hypertensive events or dysrhythmias.¹¹⁰

Epidemiology and Etiology

An epileptic seizure is a “transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.”¹²³ The term epilepsy is a neurologic disease characterized by either an individual who has a known epileptic syndrome, or evidence that the patient’s brain demonstrates a pathologic tendency to have recurrent seizures following the occurrence of at least one unprovoked seizure.¹²⁴ Epilepsy is considered resolved if a patient has been seizure free for more than 10 years while not using antiepileptic drugs (AED) for the last 5 years of this period.¹²⁵ The incidence of epilepsy in developed countries is approximately 50 per 100,000 people per year (approximately 1% of the US population), affecting over 75 million people.¹²⁶ Of these patients, 75% are untreated.¹²⁶

The International League Against Epilepsy (ILAE) originally developed a classification system of epilepsies and epileptic syndromes based on the clinical features of seizure activity and associated EEG changes.¹²⁷ Subsequent revisions of the classification scheme have taken into consideration several other factors in classifying epileptic syndromes, such as focal or generalized onset, genetics, age at onset, and pathophysiologic mechanisms of disease.¹²⁸ Focal, generalized, and unknown seizures are currently the three major categories of seizure activity used in clinical practice.¹²⁸

Onset of seizure activity may occur at any point throughout an individual’s life, and etiology usually varies according to patient age. The most common seizures arising in late infancy and early childhood are febrile seizures without evidence of associated CNS infection; these generally occur between 3 months and 5 years of age and have a peak incidence between 18 and 24 months.^129,130 Isolated, nonrecurrent, generalized seizures among adults are caused by multiple etiologies, including metabolic disturbances, toxins, drug effects, hypotension, hypoglycemia, hyponatremia, uremia, hepatic encephalopathy, drug overdoses, and drug withdrawal.^131,132 Cerebrovascular disease may account for approximately 50% of new cases of epilepsy in patients older than 65.¹³³ Other etiologies for epilepsy include degenerative CNS disease, developmental disabilities, and familial/genetic factors.^131,133 Epilepsy occurs more frequently in individuals who have neurologic‐based disabilities, such as cerebral palsy and autism.^134,135

Six etiologic categories now exist for seizures: (1) structural, (2) genetic, (3) infectious, (4) metabolic, (5) immune, and (6) unknown; prior terms, such as symptomatic and cryptogenic, are no longer used.¹²⁴ Structural implies a structural lesion on neuroimaging in combination with EEG data, suggesting that the lesion is the cause of the seizure. Causes include stroke, trauma, or tumor. Genetic implies the existence of known or presumed genetic mutation(s) where seizures are a known complication of the genetic disorder that is the result of the mutation(s). This etiology includes some of the well‐known genetic epilepsy syndromes, such as juvenile myoclonic epilepsy, or may include an unknown mutation but obvious familial inheritance pattern.¹²⁴ Infectious etiologies include neurocysticercosis, human immunodeficiency virus (HIV), cytomegalovirus (CMV), cerebral toxoplasmosis, and prior meningitis or encephalitis.¹²⁴