The Journal of the American Dental Association
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Am Dent Assoc, Vol 137, No 9, 1240-1251.
© 2006 American Dental Association
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Supplemental Data
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Friedlander, A. H.
Right arrow Articles by Yagiela, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Friedlander, A. H.
Right arrow Articles by Yagiela, J. A.
Related Collections
Right arrow Pharmacology

CLINICAL PRACTICE

JADA Continuing Education

Alzheimer’s disease

Psychopathology, medical management and dental implications



Arthur H. Friedlander, DMD, Dean C. Norman, MD, Michael E. Mahler, MD, Keith M. Norman and John A. Yagiela, DDS, PhD


   ABSTRACT
TOP
 ABSTRACT
STAGES OF ALZHEIMER'S DISEASE
 EPIDEMIOLOGY
 ETIOLOGY
 PATHOPHYSIOLOGY
 DIAGNOSIS
 TREATMENT
 OROFACIAL FINDINGS
 DENTAL TREATMENT
 CONCLUSION
 REFERENCES
 
Background. The authors review the clinical features, epidemiology, pathophysiology, medical management, dental findings and dental treatment of patients with Alzheimer’s disease (AD).

Studies Reviewed. The authors conducted MEDLINE searches for 2000 through 2005 using the terms "Alzheimer’s disease," "geriatric," "epidemiology," "pathophysiology," "treatment" and "dentistry." Reports selected for further review included those published in English in peer-reviewed journals. The authors gave preference to articles reporting randomized, controlled trials.

Results. AD is a progressive and fatal neurodegenerative disorder characterized by cognitive dysfunctions, particularly in learning and memory, and the emergence of behavioral abnormalities. Deficiencies in the cells responsible for storage and processing of information underlie the cognitive, functional and behavioral changes seen in patients with the disorder.

Clinical Implications. As the elderly population grows, increasing numbers of Americans with AD will require dental treatment. The prevalence of dental disease likely will be extensive, because of diminished salivary flow and patients’ inability to perform appropriate oral hygiene techniques. Preventive dental education for the caregiver and use of saliva substitutes and anticaries agents by the patient are indicated.

Key Words: Dental treatment; Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disorder characterized by the loss of intellectual functions, including memory, language, visiospatial skills, problem-solving ability and abstract reasoning, as well as by the frequent occurrence of behavioral abnormalities. The disorder is seen most commonly after age 60 years (so-called "late-onset"), and people with AD experience a decline in their ability to learn new information, perform routine tasks and remain oriented in time and space. They often undergo a personality change. The disease causes patients to lose the ability to care for themselves and, ultimately, causes loss of motor function, leading to immobility, inanition (severe weakness and wasting from lack of food) and death.1,2


   STAGES OF ALZHEIMER’S DISEASE
TOP
 ABSTRACT
 STAGES OF ALZHEIMER'S DISEASE
EPIDEMIOLOGY
 ETIOLOGY
 PATHOPHYSIOLOGY
 DIAGNOSIS
 TREATMENT
 OROFACIAL FINDINGS
 DENTAL TREATMENT
 CONCLUSION
 REFERENCES
 
Researchers have developed a number of schema to better define the progressive nature of the cognitive deterioration.3–6 Seven stages of the illness have been identified3–6; however, great variability exists among people in both presentation and speed of deterioration.

Stage 1. In stage 1 (no cognitive decline/normal), intellectual function appears intact. This initial stage of the disorder is identified retrospectively once the person begins to exhibit symptoms of cognitive decline. It is assumed that during this initial stage, various pathological processes are ongoing in the central nervous system (CNS).

Stage 2. In stage 2 (very mild cognitive decline/ forgetful), the person begins to forget the location of common objects, such as wallets, keys, eyeglasses and medicine bottles, but he or she has sufficient cognition to locate them. During this phase of the illness, the person’s ability to communicate remains relatively intact.

Stage 3. In stage 3 (mild cognitive decline/ early confusion), word choice and recollection of familiar names become difficult. The person loses valuable objects frequently and experiences a decline in the ability to plan, organize and sequence activities (disturbance in executive functioning).

Stage 4. In stage 4 (moderate cognitive decline/late confusion), the patient has significant short-term memory loss, reduced memory of personal events and social withdrawal. He or she no longer may be able to provide important personal or medical information.

Stage 5. In stage 5 (moderate-to-severe cognitive decline/early dementia), the patient experiences increasing confusion and has inconsistent ability to answer questions accurately. The inability to recognize or identify familiar objects (agnosia), such as a toothbrush, and to skillfully and purposefully manipulate them (apraxia) often occurs in this stage of the disorder. These impairments necessitate that the patient be provided with assistance in the activities of daily living (ADL), such as bathing, dressing, toileting, achieving mobility (such as transferring in and out of a bed or chair) and feeding.

Stage 6. In stage 6 (severe cognitive decline/ middle dementia), the person requires extensive assistance with ADL as communication deteriorates (aphasia). Urinary and fecal incontinence increasingly is common.

Stage 7. In stage 7 (very severe cognitive decline/late dementia), the patient no longer is able to participate in self-care. Speech may be absent or unintelligible, and swallowing may be impaired. Twenty-four–hour care is necessary.

The cognitive deterioration seen in patients with AD often (in up to 70 percent of patients) is accompanied by prominent behavioral changes and psychiatric symptoms.7 Initially, the patient may appear apathetic (socially and emotionally withdrawn and requiring the caregiver to initiate and oversee activities), depressed (sad, crying, guilt ridden) and anxious. As the disease progresses, inappropriate behaviors appear, especially at night. Soon, periods of agitation develop, manifesting as physically and verbally aggressive behaviors (noted in 20 to 50 percent of patients), pacing, wandering and continual requests for attention.8 The latter manifestations often are accompanied by psychotic symptoms (that is, visual hallucinations [sensory perceptions without an environmental stimulus], delusions [erroneous but firmly held ideas] and suspiciousness), disinhibition (for example, inappropriate sexual behavior) and sleep disturbances.9,10 As the person’s behavior worsens, it becomes more difficult for him or her to participate in meaningful social activities. These behavioral components of the disease diminish the patient’s quality of life, place an increased burden on the caregiver and increase the likelihood that the patient will be placed in a long-term care facility.11

People with AD often are elderly and have the same common medical illnesses as do their cohorts. These problems include sensory deficits (especially in vision and hearing), dental problems, hypertension, congestive heart failure, chronic obstructive pulmonary disease, diabetes, hypothyroidism, genitourinary conditions and arthritis. As AD progresses, these underlying illnesses often worsen and may be accompanied by an onset of pneumonia, nutritional disorders, fractures, decubitus ulcers (pressure sores) and septicemia; this combination eventually leads to death. The pneumonia (commonly the aspiration type) and nutritional deficiencies often are the result of the patient’s developing xerostomia and difficulty in swallowing, as well as losing interest in eating. The swallowing abnormality then gives rise to aspiration of oropharyngeal fluids containing oral pathogenic microorganisms or stomach contents, either or both of which help colonize the lower respiratory tract and precipitate a fatal course of pneumonia.12–23


   EPIDEMIOLOGY
TOP
 ABSTRACT
 STAGES OF ALZHEIMER'S DISEASE
 EPIDEMIOLOGY
ETIOLOGY
 PATHOPHYSIOLOGY
 DIAGNOSIS
 TREATMENT
 OROFACIAL FINDINGS
 DENTAL TREATMENT
 CONCLUSION
 REFERENCES
 
The prevalence of classic, so-called "late-onset" AD increases rapidly with age. The prevalence is 3 percent for people aged 65 to 74 years, 19 percent for those aged 75 to 84 years and 47 percent for those aged 85 years and older. The incidence of AD is much greater among African-Americans and Hispanics than it is among whites.24 Women appear to be at somewhat greater risk of developing the disorder than are men, irrespective of race.25 In the United States, 4.5 million people have the disorder and, given the population trend toward increasing numbers of elderly people, it is anticipated that this figure will increase threefold during the next 30 years. One-half of all people with AD require help with personal care, and one-third eventually are institutionalized.26 The average life span of people with AD is about eight to 10 years, with a range of three to 20 years.


   ETIOLOGY
TOP
 ABSTRACT
 STAGES OF ALZHEIMER'S DISEASE
 EPIDEMIOLOGY
 ETIOLOGY
PATHOPHYSIOLOGY
 DIAGNOSIS
 TREATMENT
 OROFACIAL FINDINGS
 DENTAL TREATMENT
 CONCLUSION
 REFERENCES
 
The etiology of late-onset AD is known only partially at this time. There is, however, increasing evidence that certain risk factors (that is, ethnicity; limited education; history of head trauma; consumption of a high-caloric, high-fat and low-folate diet; hypercholesterolemia; diabetes mellitus; sedentary lifestyle) influence the incidence, age at onset and clinical course of AD, but the mechanisms remain ill-defined.27–31 In about 5 percent of cases, there is a clear familial incidence, with an autosomal dominant inheritance pattern.32

Much research also has centered on the amyloid precursor protein gene located on chromosome 21. Verdile and colleagues33 noted that mutations in this gene have increased the formation of ß-amyloid, a toxic substance that accumulates in the brain of people with AD, causing neuronal dysfunction and death. Furthermore, the presence of a second gene, A{rho}o{varepsilon}4, on chromosome 19 is associated with heightened susceptibility to late-onset AD, and researchers believe that this gene accelerates the deposition of ß-amyloid, but this may have limited value in predicting who will develop the disease.34


   PATHOPHYSIOLOGY
TOP
 ABSTRACT
 STAGES OF ALZHEIMER'S DISEASE
 EPIDEMIOLOGY
 ETIOLOGY
 PATHOPHYSIOLOGY
DIAGNOSIS
 TREATMENT
 OROFACIAL FINDINGS
 DENTAL TREATMENT
 CONCLUSION
 REFERENCES
 
Histopathologic examination of the brains of humans with AD and experimental rodent models demonstrate soluble oligomers of ß-amyloid, extracellular ß-amyloid plaques and intracellular neurofibrillary tangles (formed primarily from abnormal aggregations of a protein material called tau protein) mainly in those areas (for example, entorhinal cortex, hippocampus, basal forebrain, amygdala and parietotemporal cortex) that are related to memory, learning, language and emotional behaviors.35 These deposits presumably disrupt synaptic function and eventually lead to neuronal death. Neurons that use acetylcholine as a neurotransmitter appear to be particularly affected, but neurons that use 5-hydroxytryptamine (serotonin), dopamine and norepinephrine also are affected adversely, but to a lesser degree.36

The synaptic dysfunction and death of cholinergic nerve cells responsible for the storage and processing of information may lead to the memory decline seen in AD. For example, it is known that acetylcholine is necessary for attention and learning processes, and that presynaptic cholinergic deficits correlate with the severity of AD. The synaptic dysfunction and death of nerve cells that use serotonin and dopamine are believed to be responsible for the behavioral and psychiatric symptoms seen in patients with AD, because these neurotransmitter systems are involved with mood, emotional balance and psychosis.37

Brain imaging studies provide valuable information to assist in diagnosis.38,39 Longitudinal studies using magnetic resonance imaging (MRI) have demonstrated that portions of the temporal and frontal lobes of the brain involved in learning and memory progressively atrophy over time, and that this correlates strongly with both the degree of cognitive decline and the density of ß-amyloid and neurofibrillary tangle accumulation observed at autopsy. These MRI studies also correlate with single-photon emission computed tomographic and positron emission tomographic (PET) scans, which demonstrate decreased blood flow and decreased glucose metabolism in the regions of the brain exhibiting atrophy, because metabolic demand decreases in regions experiencing neuronal loss.40,41


   DIAGNOSIS
TOP
 ABSTRACT
 STAGES OF ALZHEIMER'S DISEASE
 EPIDEMIOLOGY
 ETIOLOGY
 PATHOPHYSIOLOGY
 DIAGNOSIS
TREATMENT
 OROFACIAL FINDINGS
 DENTAL TREATMENT
 CONCLUSION
 REFERENCES
 
Physicians usually arrive at the clinical diagnosis of AD by identifying the patient’s clinical symptoms and comparing them with a set of known criteria.39 However, when presumed symptoms of the disorder arise, it is imperative that the patient undergo a complete physical, psychiatric and neurological evaluation to rule out more treatable illnesses, such as depression, drug toxicity, hypothyroidism, electrolyte imbalance, cardiovascular accident, Parkinson’s disease, vitamin B12 deficiency, neurosyphilis and HIV infection within the CNS.

A comprehensive evaluation includes a complete medical history and cognitive evaluation with tests such as the Mini Mental State Examination.42 This test evaluates the patient’s "orientation" (the clinician asks the patient to identify such facts as the date, year, day, month, season, location); "registration" (the clinician gauges the number of attempts it takes the patient to learn the names of three objects); "attention" and "calculation" (the clinician measures the patient’s ability to perform serial subtraction, such as 100 minus seven, 93 minus seven and so forth, for a total of five subtractions); and "recall" (the clinician asks the patient to recall the names of the three objects previously learned), as well as the person’s skills in language (the clinician shows the patient an object and asks him or her to name the object), reading, writing and shape-copying.42,43

Laboratory tests are conducted, which consist of a complete blood cell count, determination of levels of serum electrolytes, glucose, urea nitrogen, creatinine, liver-associated enzymes, cholesterol, serum lipids, vitamin B12 and folate, as well as thyroid function tests and a urinalysis. In addition, the patient’s physician obtains a chest radiograph and conducts electroencephalography, CNS imaging studies (for example, computed tomography, MRI and PET scans) and electrocardiography. Currently, the diagnosis can be made with certainty only at the patient’s death, when brain tissue is examined at autopsy.44


   TREATMENT
TOP
 ABSTRACT
 STAGES OF ALZHEIMER'S DISEASE
 EPIDEMIOLOGY
 ETIOLOGY
 PATHOPHYSIOLOGY
 DIAGNOSIS
 TREATMENT
OROFACIAL FINDINGS
 DENTAL TREATMENT
 CONCLUSION
 REFERENCES
 
Our review of randomized, controlled trials conducted since 2000 and published in peer-reviewed journals revealed that cholinesterase inhibitors (for example, donepezil, galantamine and rivastigmine) and memantine often are prescribed to improve cognitive performance temporarily, delay the loss of ADL and ameliorate behavioral symptoms (Table 1Go). Some clinicians add vitamin E ({alpha}-tocopherol) to this regimen. Caretakers also invoke nonpharmacological interventions to manage emerging behavioral signs of the disorder. If these interventions are inadequate, the patient’s physician prescribes anti-psychotics, mood stabilizers and antidepressants to control the behaviors (Table 1Go).


View this table:
[in this window]
[in a new window]
  		TABLE 1 Common medications for the treatment of Alzheimer’s disease.

 
Cholinesterase inhibitors. The cholinesterase inhibitors boost cholinergic neurotransmission at remaining functional synapses by inhibiting acetylcholinesterase, the key enzyme involved in the degradation of the neurotransmitter acetylcholine. Administration of these agents has resulted in transient (one to five years) cognitive improvement (especially in memory and attention) and improvement in daily function and behavior in some patients with mild-to-moderate AD.45–48 Researchers believe that these medications also enhance dopaminergic activity and that this may explain the behavioral improvement.49 The efficacy of these medications appears similar, and concurrent administration of more than one cholinesterase rarely is done. Use of these medications occasionally is associated with nausea, vomiting, diarrhea, anorexia, weight loss, muscle cramps, bradycardia, heart block, syncope and fatigue, which may necessitate discontinuation of this therapy.50

Memantine. Memantine, an antagonist of the N-methyl-D-aspartate receptor, is indicated for people with moderate-to-severe AD. The medication prevents elevated concentrations of glutamate (the principal excitatory neurotransmitter in the CNS) from destroying cholinergic neurons. Researchers51–53 believe that toxic levels of the neurotransmitter stem from ß-amyloid’s ability to facilitate glutamate release during neuronal depolarization. Researchers have shown that memantine, which often is administered in combination with a cholinesterase inhibitor, improves cognitive function, reduces the patient’s decline in ADL and reduces the frequency of new behavioral symptoms.54 Adverse effects of memantine include dizziness, headache and hypertension.

Physicians often add vitamin E to each of the above regimens. Some investigators believe that vitamin E’s antioxidant effects are neuroprotective. Sano and colleagues55 conducted a study in which it appeared to delay significantly the development of severe dementia, placement in a nursing home and death.

Minimizing behavioral and psychological symptoms. The magnitude of behavioral and psychological symptoms of AD can be minimized by structuring a predictable routine, modifying the environment, simplifying tasks and reducing excessive stimulation. Patients are encouraged to dress each day in their own clothes. Meals, exercise, recreation (including activities requiring simple thinking, such as bingo or sorting easily distinguishable objects) and prebedtime activities are provided in a routine and punctual manner. Caregivers provide calendars, clocks, graphic labels and newspapers to assist the person regarding time, and he or she places color-coded or graphic labels on closets and drawers as cues for orientation.

Caregivers break down tasks into simple elements, and they provide instructions for each component. They explain all procedures and activities to the patient in simple language.56 In addition, caregivers repeat information often, reassure the patient and, if a situation is problematic, redirect his or her attention.57 Excessive stimulation, such as exposure to crowds and noise from a television set, is reduced to avoid disorientation and agitation.

Pharmacological therapy. The patient’s physician often institutes pharmacological therapy when behavioral and environmental approaches fail to ameliorate behavioral symptoms sufficiently.58 Specific targeted symptoms dictate the choice of pharmacological agent (Table 1Go).

Atypical antipsychotic agents. The atypical antipsychotic agents (that is, olanzapine, quetiapine, risperidone, ziprasidone), which interact mainly with the serotonergic neurotransmitter system and, to a lesser extent, with the dopaminergic system, are used to treat delusions, hallucinations and agitation.59 These medications cause minor degrees of sedation, adverse cardiovascular side effects (orthostatic hypotension, hypotension, tachycardia), weight gain (possibly leading to type 2 diabetes mellitus) and anticholinergic effects (for example, xerostomia, blurred vision, constipation, urinary retention). On occasion, they cause involuntary dyskinetic movements, especially in women and the very elderly.60,61

A complication of atypical antipsychotic drug treatment in patients with AD is the increased risk (1.6 times that of placebo) of death from cardiovascular events (cardiac arrest, heart failure) or infections. The tendency for these agents to cause dysphagia may promote aspiration and pulmonary infection.

Haloperidol. Haloperidol, a high-potency neuroleptic (typical antipsychotic) agent, interacts mainly with the dopaminergic system and is used to treat symptoms of psychosis, agitation and aggression in patients who have not responded to the atypical agents. Haloperidol frequently causes more severe anticholinergic effects and commonly (in approximately 50 percent of patients) is associated with the development of movement disorders such as parkinsonian symptoms (for example, marked drowsiness and lethargy, hyper-salivation and drooling, fixed stare) and tardive dyskinesia (rhythmic involuntary movements of the tongue, face, mouth and jaw).62

Carbamazepine and divalproex sodium. The mood-stabilizing/antiseizure medications carbamazepine and divalproex sodium also may reduce agitation. Carbamazepine’s mood-stabilizing effect is believed to be derived from its ability to stabilize sodium and potassium channels and by the upregulation of GABAB receptors.63–65 Long-term use of carbamazepine rarely is associated with decreased white blood cell and platelet counts.66 Researchers believe that the actions of divalproex sodium on inhibitory and excitatory amino acid systems and on membrane-associated ion channels in the brain are responsible for its mood-stabilizing effect.63 Approximately 9 percent of patients who are treated with this drug develop leukopenia, 7 percent develop thrombocytopenia and a lesser percentage experience decreased fibrinogen concentrations with long-term use.64,65

Selective serotonin reuptake inhibitors. The selective serotonin reuptake inhibitor antidepressants, including citalopram, fluoxetine, paroxetine and sertraline, are prescribed to improve patients’ mood and reduce agitation and aggression.67 They exert their clinical effects by preventing presynaptic neurons from actively taking up serotonin from the synaptic cleft for recycling. Thus, the concentration of serotonin in the cleft is increased and synaptic transmission is enhanced. These medications frequently cause diarrhea, nausea, dizziness, insomnia, tremor, headache, dry mouth and sexual dysfunction. Rare side effects include suicidal ideation and platelet dysfunction.

Tricyclic antidepressants. The tricyclic antidepressants (TCAs), including nortriptyline and desipramine, exert their antidepressant effect by preventing presynaptic neurons from reabsorbing both serotonin and norepinephrine from the synaptic cleft. Thus, the concentrations of these two neurotransmitters are elevated, and neuronal transmission is increased. TCAs cause peripheral anticholinergic side effects such as dry mouth, urinary retention, constipation and blurred vision. These medications also can cause cardiac dysrhythmias. Many older people with pre-existing medical problems cannot tolerate the adverse side effects of TCAs, and they now are used infrequently in patients with AD.68

Venlafaxine and mirtazapine. The atypical antidepressant venlafaxine exerts its antidepressant effects mainly by inhibiting the reuptake of serotonin and norepinephrine and, to a lesser extent, that of dopamine. The use of venlafaxine has been associated with a sustained increase in diastolic blood pressure in some patients. The atypical antidepressant mirtazapine acts as an antagonist at central presynaptic {alpha}2-adrenergic autoreceptors and heteroreceptors, causing enhanced central noradrenergic and serotonergic activity and resulting in a lessening of depression. Mirtazapine also has been associated with elevations in blood pressure.


   OROFACIAL FINDINGS
TOP
 ABSTRACT
 STAGES OF ALZHEIMER'S DISEASE
 EPIDEMIOLOGY
 ETIOLOGY
 PATHOPHYSIOLOGY
 DIAGNOSIS
 TREATMENT
 OROFACIAL FINDINGS
DENTAL TREATMENT
 CONCLUSION
 REFERENCES
 
Adverse orofacial reactions. The official U.S. Food and Drug Administration’s medication package insert accompanying each of the medications used to treat AD and the current medical literature specify adverse orofacial reactions that may occur.69,70 The cholinesterase inhibitors have been shown to cause nausea and sialorrhea, and memantine may cause tinnitus and blurred vision. The atypical antipsychotic agents may cause xerostomia, dysgeusia (altered taste sensations) and stomatitis. Haloperidol, like other neuroleptic agents, produces intense xerostomia. In addition, it is associated with spasms of the muscles of mastication, with resultant dislocation of the temporomandibular joint, as well as the development of tardive dyskinesia, which can result in unceasing mandibular movements, dislodgement of complete removable prostheses and orofacial pain from mucosal ulcers. Haloperidol also may induce granulocytosis and leukopenia that can manifest in the mouth as buccal mucosal ulcerations and Candida infections.71 Carbamazepine and divalproex sodium have been shown to cause xerostomia and glossitis. A majority of the antidepressants used to treat AD can cause xerostomia and glossitis, as well as stomatitis. In addition, some have been identified as causing sialadenitis, gingivitis and edema, as well as discoloration of the tongue.

Factors leading to oral disease. People with AD also are likely to have a unique set of factors that lead to the development of advanced oral diseases. Impaired cognition, apathy and apraxia in the middle stages of the disorder are responsible for a disinterest in and an inability to perform appropriate oral hygiene techniques.72 This may result in patients’ forgetting to remove dental prostheses for days at a time and permitting food debris and plaque to remain undisturbed in the proximal and cervical areas of the residual dentition.

Concomitant hyposalivation (limited to the submandibular gland and of unproven cause) in unmedicated people with AD,73–75 as well as the hyposalivation induced by many of the medications used to treat AD and other medical problems encountered in the elderly, is marked. This paucity of saliva leads to reduced lubrication; reduced antibacterial, antiviral and antifungal activity; loss of buffering capacity; reduced flushing of plaque and bacteria from dental and oral mucosal surfaces; and interference with normal remineralization of teeth, resulting in the increased prevalence of dry and chapped lips, plaque, gingival bleeding, calculus, periodontal disease and coronal and cervical caries in this patient population.76–80

Finally, dentists must recognize that oral care often is not high on the caregiver’s priority list, given the patient’s other extensive needs and because oral hygiene practices may cause the patient to become resistive or combative.81


   DENTAL TREATMENT
TOP
 ABSTRACT
 STAGES OF ALZHEIMER'S DISEASE
 EPIDEMIOLOGY
 ETIOLOGY
 PATHOPHYSIOLOGY
 DIAGNOSIS
 TREATMENT
 OROFACIAL FINDINGS
 DENTAL TREATMENT
CONCLUSION
 REFERENCES
 
General schema. Providing safe and appropriate dental treatment requires consultation with the patient’s physician and rapport among the dentist, the patient and the patient’s care-giver. Vitally important information to be garnered from the physician includes the disease stage, the patient’s cognitive ability to provide consent for treatment, the disease prognosis, the drug regimen and the identification of any other medical conditions (for example, valvular heart disease) that may influence dental treatment. If the physician believes that the patient is incapable of providing consent, the dentist should ask the caregiver for the identity of the patient’s legal guardian and obtain written consent from him or her.

Dentists should develop realistic treatment plans for each patient. The plan must take into account the patient’s needs (for example, it should give greater weight to removing a jagged nonrestorable tooth damaging the adjacent mucosa than to treatment of early recurrent caries around a crown), the patient’s desires, if expressible, and the caregiver’s desires, if reasonable. However, paramount are the patient’s physical and mental state and the predictive benefit of treatment to the patient’s quality of life.82,83

Patients with AD can become frustrated and irritable (manifesting as threatening gestures, crying and restlessness) when confronted with unfamiliar circumstances or with questions, instructions or information that they do not understand.84 However, with the appropriate psychological set attitude on the part of the dentist and dental team, most routine care can be provided with only minor modification. The practitioner must be able to capture the patient’s wandering attention; usually, this can be accomplished by minimizing office noise (for example, shutting off the air conditioner, fans, suction and water devices, telephones and the television) and the overall level of activity. In addition, the dentist and team members need to be alert to the patient’s needs, communicating acceptance and reassurance and providing a sense that the environment is safe.

Routine procedures, such as measuring blood pressure or applying a rubber dam, may arouse intense anxiety or irrational behavior in a patient who has not been forewarned. The dentist should begin all conversations by identifying himself or herself ("I am Dr. Smith, your dentist."); explaining procedures before performing them ("I would like to examine your teeth."); using simple words, short sentences and nouns rather than pronouns; and limiting use of the face mask. Smiling, direct eye contact and gentle touching help to convey appropriate cues. In addition, it is helpful to have the caregiver sit next to the patient in the operatory to help alleviate stress and anxiety, provide a distraction and have someone with whom the patient can hold hands if needed.85–88

Dentists should complete restoration of oral health function as early as possible in the AD process, because the patient’s ability to cooperate diminishes as cognitive function declines. Scheduled appointments should be of short duration (no more than 45 minutes), and morning appointments usually are best. Before the dentist begins treatment, the caregiver should assist the patient in emptying his or her bladder.89

Adverse drug interactions. Adverse interactions may occur between the medications used in dentistry and the cholinesterase inhibitors used to treat AD. Diphenhydramine and amitriptyline (often used to treat chronic facial pain) have anti-cholinergic properties and, when prescribed for prolonged periods, may antagonize the effects of the cholinesterase inhibitors and place the patient at risk of developing worsening cognition and behavioral complications. The antimicrobial drugs erythromycin and ketoconazole may decrease the metabolism of donepezil and galantamine. Prolonged administration of these dental agents may result in central (excitation, agitation) or peripheral (for example, bradycardia, loss of consciousness, digestive disorders) hypercholinergic effects; therefore, it is prudent to consult with the patient’s physician before initiating therapy with these drugs.90,91 Numerous other adverse interactions have been reported and are identified in Table 2Go90–97 along with suggested modifications to dental treatment.


View this table:
[in this window]
[in a new window]
  		TABLE 2 Interactions between drugs used in dentistry and those used to treat Alzheimer’s disease.

 
Early stages of AD. In the early stages of AD, which lasts two to four years, most patients can discuss dental pain issues reliably as long as questions are framed in the "here and now" and can be answered by "yes" or "no." The accuracy of the information is enhanced by using suggestive questions ("Does your tooth hurt when I bang on it?") and giving the patient adequate time to respond. Dentists often need to repeat questions, and when doing so, they should use the exact same words. During this stage of the disorder, most restorative and rehabilitative dental care can be provided with minimal modification in technique; however, as the disease progresses, the focus of care changes.98

It is paramount that dentists and team members educate the patient’s caregiver about techniques that can prevent dental disease.99 He or she should receive oral and written instructions on proper toothbrushing and flossing methods and on how to apply chlorhexidine gluconate to the patient’s teeth with a toothbrush or sponge applicator. Dentists also should prescribe artificial salivary products for patients exhibiting signs of xerostomia. They should conduct a clinical examination, provide an oral prophylaxis and apply a brush-on fluoride gel (with a concentration of at least 1.0 percent fluoride) at three-month follow-up visits. Clinicians also should treat defects in the natural dentition or in prostheses at these recall visits.

Middle stages of AD. In the middle stages of AD, when the patient is relatively healthy physically but has lost cognitive skills, treatment consists of eliminating any sources of potential pain or infection, hand scaling and curettage, and caries control. It is best for dentists to avoid using ultrasonic scalers, because the noise can be frightening to the patient and elimination of the water spray minimizes the likelihood of aspiration. During this stage of the illness, patients’ perception of dental pain may be distorted and they may not be able to identify the tooth causing the pain.100,101 The patient also may be physically abusive and attempt to bite the dentist or assistant; therefore, clinicians should insert a ratchet-type mouth prop between the teeth to help the patient keep his or her mouth open.

Because of the difficulty these patients have in adapting to new appliances, it is preferable to maintain old prosthetic devices through relining and repair than to fabricate new ones.102 Prostheses should be labeled with the patient’s name for ready identification.

Short-acting benzodiazepines (for example, triazolam) may enhance dental treatment if they are administered beforehand to patients who receive only the cholinesterase inhibitors or memantine. However, if the patient already is being treated with an anxiolytic agent, the dental appointment should be synchronized with the regularly scheduled dosage interval for maximum benefit (that is, the appointment should begin 45 minutes after the patient takes the medication). Similarly, when a patient is being treated with an anxiolytic on an as-needed basis, the dentist should instruct the caregiver to administer the medication 45 minutes before the appointment.

Profound local anesthesia is mandatory to perform dental procedures adequately in these often-anxious patients. However, dentists must take precautions when administering local anesthetics containing adrenergic vasoconstrictors (levonordefrin and epinephrine) to patients receiving TCAs.103 TCAs block the reuptake of these vasoconstrictors; they also block muscarinic and {alpha}1-adrenergic receptors, which may cause their own cardiovascular effects.

Clinicians should not use anesthetic agents containing levonordefrin, because they may interact adversely with the TCAs, causing a dramatic increase in systolic blood pressure and cardiac dysrhythmias.97 Epinephrine interacts more modestly with TCAs, so it can be used, but the dose should not exceed 0.05 milligram (the equivalent of three cartridges of 1:100,000 epinephrine) per one-half hour. The dentist also should aspirate carefully to avoid intravascular administration. Dentists also must take similar precautions when administering local anesthetics containing vaso-constrictors to patients receiving venlafaxine or mirtazapine therapy, because these antidepressants also enhance noradrenergic activity.104

Late stages of AD. In the late stages of AD, the patient is unable to communicate distress resulting from recent onset of dental pain or to cooperate during most forms of treatment. Clinicians may garner clues regarding dental pain by querying the caregiver about recent behavioral changes such as increased restlessness, constant rubbing of the face and mouth or facial grimaces, vocalizations (moaning, groaning, screaming) or guarding the mouth when manipulating it with a toothbrush or when eating hard or cold foods. Dentists can best diagnose and treat these acute problems in the dental office using intravenous sedation administered by trained anesthesiologists or by having general anesthetic administered in the operating room of a surgical center or hospital.

Dentists should use extreme caution when administering intravenous sedation to elderly patients concurrently receiving other CNS depressants. Sedative agents such as midazolam may obtund protective airway reflexes; because of impaired swallowing in people with AD, the chances of aspiration are enhanced. Therefore, it is best to avoid using the air/water syringe and to position the dental chair in a more upright position so that fluids do not run into the patient’s throat. Some intravenous medications also are associated with orthostatic hypotension; thus, it is best to raise the back of the chair slowly after completing treatment and permit the patient to sit upright for five minutes before he or she exits the chair.

Optimal treatment involves the removal of all likely sources of pain and infection, such as would be achieved with a full-mouth extraction. However, the clinician must achieve primary wound closure to minimize the potential for postoperative aspiration of blood.105 He or she should administer long-acting local anesthetic toward the end of the procedure, and patients should receive postoperative medications as soon as they have recovered safely. Dentists should administer these so-called "preemptive analgesics" routinely rather than on an as-needed basis for pain, because patients with AD have difficulty in making their needs known.106

Administering some muscle relaxants during dental procedures performed under general anesthesia may result in a prolonged recovery time. Particularly worrisome is the nondepolarizing neuromuscular blocking agent mivacurium and the depolarizing neuromuscular blocker succinylcholine, both of which are inactivated by plasma esterases. On the basis of the half-life of the anti-cholinesterases for AD, it is best to discontinue donepezil therapy approximately two weeks before surgery, galantamine therapy one to two days before surgery and rivastigmine therapy three to four days before surgery to ensure restoration of plasma esterase activity.91,107,108


   CONCLUSION
TOP
 ABSTRACT
 STAGES OF ALZHEIMER'S DISEASE
 EPIDEMIOLOGY
 ETIOLOGY
 PATHOPHYSIOLOGY
 DIAGNOSIS
 TREATMENT
 OROFACIAL FINDINGS
 DENTAL TREATMENT
 CONCLUSION
REFERENCES
 
As America’s population ages, large numbers of people will develop AD. With recent advances in treatment, many of these people will remain in the community and obtain dental treatment from the private sector. This review article provides dentists with the information needed to administer safe and efficient dental treatment.


   FOOTNOTES
 

Dr. Friedlander is associate chief of staff and director of graduate medical education, VA Greater Los Angeles Healthcare System, director of quality assurance, Hospital Dental Service, University of California Los Angeles Medical Center, and professor-in-residence, Oral and Maxillofacial Surgery, University of California Los Angeles School of Dentistry. Address reprint requests to Dr. Friedlander, VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd., Los Angeles, Calif. 90073, e-mail "arthur.friedlander{at}med.va.gov".


Dr. Norman is chief of staff, VA Greater Los Angeles Healthcare System, and a professor of medicine, David Geffen School of Medicine, University of California Los Angeles.


Dr. Mahler is director of organizational improvement, VA Greater Los Angeles Healthcare System, an attending neurologist, Neurobehavior Clinic, VA Greater Los Angeles Healthcare System, and a professor of neurology, David Geffen School of Medicine, University of California Los Angeles.


Mr. Norman is a research associate, VA Greater Los Angeles Healthcare System.


Dr. Yagiela is a professor and chair, Diagnostic and Surgical Sciences, University of California Los Angeles School of Dentistry, and a professor of anesthesiology, David Geffen School of Medicine, University of California Los Angeles.


Readers interested in additional detailed information regarding adverse orofacial and other reactions to drugs used to treat Alzheimer’s disease may access it via the Supplemental Data link in the online version of this article on the JADA Web site ("http://jada.ada.org").


   REFERENCES
TOP
 ABSTRACT
 STAGES OF ALZHEIMER'S DISEASE
 EPIDEMIOLOGY
 ETIOLOGY
 PATHOPHYSIOLOGY
 DIAGNOSIS
 TREATMENT
 OROFACIAL FINDINGS
 DENTAL TREATMENT
 CONCLUSION
 REFERENCES
 

  1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-IV-TR. 4th ed., text revision. Washington: American Psychiatric Association; 2000:147–58.

  2. Cummings JL. Alzheimer’s disease. N Engl J Med 2004;35(1): 56–67.

  3. Reisberg B, Ferris SH, De Leon MJ, Crook T. The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry 1982;139(9):1136–9.[Abstract/Free Full Text]

  4. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34(7):939–44.[Abstract/Free Full Text]

  5. Reisberg B, Ferris SH, de Leon MJ, et al. The stage specific temporal course of Alzheimer’s disease: functional and behavioral concomitants based upon cross-sectional and longitudinal observation. Prog Clin Biol Res 1989;317:23–41.[Medline]

  6. Capitani E, Cazzaniga R, Francescani A, Spinnler H. Cognitive deterioration in Alzheimer’s disease: is the early course predictive of the later stages? Neurol Sci 2004;25(4):198–204.[Medline]

  7. Finkel SI, Costa e Silva J, Cohen G, Miller S, Sartorius N. Behavioral and psychological signs and symptoms of dementia: a consensus statement on current knowledge and implications for research and treatment. Int Psychogeriatr 1996;8(supplement 3):497–500.[Medline]

  8. Craig D, Hart DJ, McCool K, McIlroy SP, Passmore AP. Apolipoprotein E e4 allele influences aggressive behaviour in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2004;75(9): 1327–30.[Abstract/Free Full Text]

  9. Meehan KM, Wang H, David SR, et al. Comparison of rapidly acting intramuscular olanzapine, lorazepam, and placebo: a double-blind, randomized study in acutely agitated patients with dementia. Neuropsychopharmacology 2002;26(4):494–504.[Medline]

  10. Mega MS, Cummings JL, Fiorello T, Gornbein J. The spectrum of behavioral changes in Alzheimer’s disease. Neurology 1996;46(1):130–5.[Abstract/Free Full Text]

  11. Cohen CA, Gold DP, Shulman KI, Wortley JT, McDonald G, Wargon M. Factors determining the decision to institutionalize dementing individuals: a prospective study. Gerontologist 1993;33(6): 714–20.[Abstract]

  12. Frenkel H. Alzheimer’s disease and oral care. Dent Update 2004;31(5):273–4, 276–8.[Medline]

  13. Kalia M. Dysphagia and aspiration pneumonia in patients with Alzheimer’s disease. Metabolism 2003;52(10 supplement 2):36–8.[Medline]

  14. Horner J, Alberts MJ, Dawson DV, Cook GM. Swallowing in Alzheimer’s disease. Alzheimer Dis Assoc Disord 1994;8(3):177–89.[Medline]

  15. Chouinard J. Dysphagia in Alzheimer’s disease: a review. J Nutr Health Aging 2000;4(4):214–7.[Medline]

  16. Wada H, Nakajoh K, Satoh-Nakagawa T, et al. Risk factors of aspiration pneumonia in Alzheimer’s disease patients. Gerontology 2001;47(5):271–6.[Medline]

  17. Gillick MR. Rethinking the role of tube feeding in patients with advanced dementia. N Engl J Med 2000;342(3):206–10.[Free Full Text]

  18. Gitto CA, Moroni MJ, Terezhalmy GT, Sandu S. The patient with Alzheimer’s disease. Quintessence Int 2001;32(3):221–31.[Medline]

  19. Navazesh M, Mulligan R. Systemic dissemination as a result of oral infection in individuals 50 years of age and older. Spec Care Dentist 1995;15(1):11–9.[Medline]

  20. Chouinard J, Lavigne E, Villeneuve C. Weight loss, dysphagia, and outcome in advance dementia. Dysphagia 1998;13(3):151–5.[Medline]

  21. Priefer BA, Robbins J. Eating changes in mild-stage Alzheimer’s disease: a pilot study. Dysphagia 1997;12(4):212–21.[Medline]

  22. Limeback H. Implications of oral infections on systemic diseases in the institutionalized elderly with a special focus on pneumonia. Ann Periodontol 1998;3(1):262–75.[Medline]

  23. Scannapieco FA, Papandonatos GD, Dunford RG. Associations between oral conditions and respiratory disease in a natural sample survey population. Ann Periodontol 1998;3(1):251–6.[Medline]

  24. Tang MX, Cross P, Andrews H, et al. Incidence of AD in African-Americans, Caribbean Hispanics, and Caucasians in northern Manhattan. Neurology 2001;56(1):49–56.[Abstract/Free Full Text]

  25. Fitzpatrick AL, Kuller LH, Ives DG, et al. Incidence and prevalence of dementia in the Cardiovascular Health Study. J Am Geriatr Soc 2004;52(2):195–204.[Medline]

  26. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 2003;60(8):1119–22.[Abstract/Free Full Text]

  27. Karp A, Kareholt I, Qiu C, Bellander T, Winblad B, Fratiglioni L. Relation of education and occupation-based socioeconomic status to incident Alzheimer’s disease. Am J Epidemiol 2004;159(2):175–83.[Abstract/Free Full Text]

  28. Mayeux R. Epidemiology of neurodegeneration. Annu Rev Neurosci 2003;26:81–104.[Medline]

  29. Mattson MP. Gene-diet interactions in brain aging and neurode-generative disorders. Ann Intern Med 2003;139(5 part 2):441–4.[Abstract/Free Full Text]

  30. Puglielli L, Tanzi RE, Kovacs DM. Alzheimer’s disease: the cholesterol connection. Nat Neurosci 2003;6(4):345–51.[Medline]

  31. Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K. Midlife cardiovascular risk factors and risk of dementia in late life. Neurology 2005;64(2):277–81.[Abstract/Free Full Text]

  32. Silverman JM, Ciresi G, Smith CJ, Marin DB, Schnaider-Beeri M. Variability of familial risk of Alzheimer disease across the late life span. Arch Gen Psychiatry 2005;62(5):565–73.[Abstract/Free Full Text]

  33. Verdile G, Fuller S, Atwood CS, Laws SM, Gandy SE, Martins RN. The role of beta amyloid in Alzheimer’s disease: still a cause of everything or the only one who got caught? Pharmacol Res 2004;50(4): 397–409.[Medline]

  34. Bertram L, Tanzi RE. The current status of Alzheimer’s disease genetics: what do we tell the patients? Pharmacol Res 2004;50(4): 385–96.[Medline]

  35. Walsh DM, Selkoe DJ. Deciphering the molecular basis of memory failure in Alzheimer’s disease. Neuron 2004;44(1):181–93.[Medline]

  36. Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature 2004;430(7000):631–9.[Medline]

  37. Tanaka Y, Meguro K, Yamaguchi S, et al. Decreased striatal D2 receptor density associated with severe behavioral abnormality in Alzheimer’s disease. Ann Nucl Med 2003;17(7):567–73.[Medline]

  38. Wang H, Shu L, Xie J, Zhang H, Zhang D. Diagnostic utility of neuropsychological performance and quantitative MRI-based measurement in Alzheimer disease. Alzheimer Dis Assoc Disord 2004;18(3): 163–70.[Medline]

  39. Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56(9):1143–53.[Abstract/Free Full Text]

  40. Scarmeas N, Habeck CG, Zarahn E, et al. Covariance PET patterns in early Alzheimer’s disease and subjects with cognitive impairment but no dementia: utility in group discrimination and correlations with functional performance. Neuroimage 2004;23(1):35–45.[Medline]

  41. Hirono N, Hashimoto M, Ishii K, Kazui H, Mori E. One-year change in cerebral glucose metabolism in patients with Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 2004;16(4):488–92.[Abstract/Free Full Text]

  42. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12(3):189–98.[Medline]

  43. Wang H, Shu L, Xie J, Zhang H, Zhang D. Diagnostic utility of neuropsychological performance and quantitative MRI-based measurement in Alzheimer disease. Alzheimer Dis Assoc Disord 2004;18(3):163–70.[Medline]

  44. Braak H, Braak E. Evolution of neuronal changes in the course of Alzheimer’s disease. J Neural Transm Suppl 1998;53:127–40.[Medline]

  45. Courtney C, Farrell D, Gray R, et al.; AD2000 Collaborative Group. Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomized double-blind trial. Lancet 2004;363(9427):2105–15.[Medline]

  46. Pirttila T, Wilcock G, Truyen L, Damaraju CV. Long-term efficacy and safety of galantamine in patients with mild-to-moderate Alzheimer’s disease: multicenter trial. Eur J Neurol 2004;11(11):734–41.[Medline]

  47. Johannsen P. Long-term cholinesterase inhibitor treatment of Alzheimer’s disease. CNS Drugs 2004;18(12):757–68.[Medline]

  48. Colombres M, Sagal JP, Inestrosa NC. An overview of the current and novel drugs for Alzheimer’s disease with particular reference to anti-cholinesterase compounds. Curr Pharm Des 2004;10(25):3121–30.[Medline]

  49. Zhang L, Zhou FM, Dani JA. Cholinergic drugs for Alzheimer’s disease enhance in vitro dopamine release. Mol Pharmacol 2004;66(3):538–44.[Abstract/Free Full Text]

  50. Thompson S, Lanctot KL, Herrmann N. The benefits and risks associated with cholinesterase inhibitor therapy in Alzheimer’s disease. Expert Opin Drug Saf 2004;3(5):425–40.[Medline]

  51. Miguel-Hidalgo JJ, Alvarez XA, Cacabelos R, Quack G. Neuroprotection by memantine against neurodegeneration induced by ß-amyloid (1–40). Brain Res 2002;958(1):210–21.[Medline]

  52. Livingston G, Katona C. The place of memantine in the treatment of Alzheimer’s disease: a number needed to treat analysis. Int J Geriatr Psychiatry 2004;19(10):919–25.[Medline]

  53. Hynd MR, Scott HL, Dodd PR. Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer’s disease. Neurochem Int 2004;45(5):583–95.[Medline]

  54. Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ; Memantine Study Group. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003;348(14):1333–41.[Abstract/Free Full Text]

  55. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N Engl J Med 1997;336(17): 1216–22.[Abstract/Free Full Text]

  56. Cummings JL, Frank JC, Cherry D, et al. Guidelines for managing Alzheimer’s Disease, part II: treatment. Am Fam Physician 2002;65(12):2525–34.[Medline]

  57. Sultzer D, Cummings JL. Alzheimer’s disease. In: Rakel RE, Conn HF, eds. Current therapy, 1993: Latest approved methods of treatment for the practicing physician. Philadelphia: Saunders; 1993:838–40.

  58. Finkel SI. Managing the behavioral and psychological signs and symptoms of dementia. Int Clin Psychopharmacol 1997;12(supplement 4):S25–S28.

  59. Mintzer JE. Underlying mechanisms of psychosis and aggression in patients with Alzheimer’s disease. J Clin Psychiatry 2001;62(supplement 21):23–5.

  60. Wirshing DA, Spellberg BJ, Erhart SM, Marder SR, Wirshing WC. Novel antipsychotics and new onset diabetes. Biol Psychiatry 1998;44(8):778–83.[Medline]

  61. Wirshing WC. Movement disorders associated with neuroleptic treatment. J Clin Psychiatry 2001;62(supplement 21):15–8.

  62. Chan WC, Lam LC, Choy CN, Leung VP, Li SW, Chiu HF. A double-blind randomized comparison of risperidone and haloperidol in the treatment of behavioural and psychological symptoms in Chinese dementia patients. Int J Geriatr Psychiatry 2001;16(12):1156–62.[Medline]

  63. Johannessen CU. Mechanisms of action of valproate: a commentary. Neurochem Int 2000;37(2–3):103–10.[Medline]

  64. Muller-Oerlinghausen B, Retzow A, Henn FA, Giedke H, Walden J. Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes of mania: a prospective, randomized, double-blind placebo-controlled, multicenter study. European Valproate Mania Study. J Clin Psychopharmacol 2000;20(2):195–203.[Medline]

  65. Bowden CL, Calabrese JR, McElroy SL, et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Arch Gen Psychiatry 2000;57(5):481–9.[Abstract/Free Full Text]

  66. Post RM, Weiss SRB, Chuang DM, Ketter TA. Mechanisms of action of carbamazepine in seizure and affective disorders. In: Joffe RT, Calabrese JR, eds. Anticonvulsants in mood disorders. New York: M. Dekker; 1994:43–92.

  67. Schneider LS, Tariot PN, Lyketsos CG, et al. National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): Alzheimer disease trial methodology. Am J Geriatr Psychiatry 2001;9(4):346–60.[Abstract/Free Full Text]

  68. Lebowitz BD, Pearson JL, Schneider LS, et al. Diagnosis and treatment of depression in late life: consensus statement update. JAMA 1997;278(14):1186–90.[Abstract]

  69. Physicians’ desk reference. 59th ed. Oradell, N.J.: Medical Economics; 2005.

  70. McEvoy GK. AHFS drug information 2005. Bethesda, Md.: American Society of Health-System Pharmacists; 2005.

  71. Friedlander AH, Marder SR. The psychopathology, medical management and dental implications of schizophrenia. JADA 2002;133(5): 603–10.

  72. Arai K, Sumi Y, Uematsu H, Miura H. Association between dental health behaviors, mental/physical function and self-feeding ability among the elderly: a cross-sectional survey. Gerodontology 2003;20(2):78–83.[Medline]

  73. Ship JA, DeCarli C, Friedland RP, Baum BJ. Diminished sub-mandibular salivary flow in dementia of the Alzheimer type. J Gerontol 1990;45(2):M61–6.[Medline]

  74. Ship JA, Puckett SA. Longitudinal study on oral health in subjects with Alzheimer’s disease. J Am Geriatr Soc 1994;42(1):57–63.[Medline]

  75. Chiappelli F, Bauer J, Spackman S, et al. Dental needs of the elderly in the 21st century. Gen Dent 2002;50(4):358–63.[Medline]

  76. Ship JA. Oral health of patients with Alzheimer’s disease. JADA 1992;123(1):53–8.

  77. Jones JA, Lavallee N, Alman J, Sinclair C, Garcia RI. Caries incidence in patients with dementia. Gerodontology 1993;10(2):76–82.[Medline]

  78. Henry RG. Alzheimer’s disease and cognitively impaired elderly: providing dental care. J Calif Dent Assoc 1999;27(9):709–17.[Medline]

  79. Friedlander AH, Jarvik LF. The dental management of the patient with dementia. Oral Surg Oral Med Oral Pathol 1987;64(5): 549–53.[Medline]

  80. Kocaelli H, Yaltirik M, Yargic LI, Ozbas H. Alzheimer’s disease and dental management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;93(5):521–4.[Medline]

  81. Henry RG, Wekstein DR. Providing dental care for patients diagnosed with Alzheimer’s disease. Dent Clin North Am 1997;41(4):915–43.[Medline]

  82. Nordenram G, Ryd-Kjellén E, Ericsson K, Winblad B. Dental management of Alzheimer patients: a predictive test of dental cooperation in individualized treatment planning. Acta Odontol Scand 1997;55(3):148–54.[Medline]

  83. Niessen LC, Jones JA. Professional dental care for patients with dementia. Gerodontology 1987;6(2):67–71.[Medline]

  84. Henry R, Smith B. Treating the Alzheimer’s patient: a guide for dental professionals. J Mich Dent Assoc 2004;86(10):32–6, 38–40, 42 passim.[Medline]

  85. Ostuni E, Mohl G. Communicating more effectively with the confused or demented patient. Gen Dent 1995;43(3):264–6.[Medline]

  86. Henry RG. Neurologic disorders in dentistry: managing patients with Alzheimer’s disease. J Indiana Dent Assoc 1997–1998;76(4):51–7.

  87. McCann D. Treating patients with Alzheimer’s disease: the challenges and rewards. CDS Rev 2000;93(4):10–3.[Medline]

  88. Ocasio NA, Solomowitz BH, Sher MR. Dental management of the patient with Alzheimer’s disease. N Y State Dent J 2000;66(3):32–5.[Medline]

  89. Tips for managing patients with Alzheimer’s disease. Dent Assist 2003;72(4):14, 31.[Medline]

  90. Defilippi JL, Crismon ML. Drug interactions with cholinesterase inhibitors. Drugs Aging 2003;20(6):437–44.[Medline]

  91. Bentue-Ferrer D, Tribut O, Polard E, Allain H. Clinically significant drug interactions with cholinesterase inhibitors: a guide for neurologists. CNS Drugs 2003;17(13):947–63.[Medline]

  92. Goff DC, Baldessarini RJ. Drug interactions with antipsychotic agents. J Clin Psychopharmacol 1993;13(1):57–67.[Medline]

  93. Ketter TA, Flockhart DA, Post RM, et al. The emerging role of cytochrome P450 3A in psychopharmacology. J Clin Psychopharmacol 1995;15(6):387–98.[Medline]

  94. Haas DA.