Article Archive
May/June 2017

Differentiating Dementias: Focus on Accurate Dementia Diagnosis — Part Two in a Two-Part Series
By Susan Scanland, MSN, CRNP, GNP-BC, CDP, CSP, and Tyler Bielinski
Today's Geriatric Medicine
Vol. 10 No. 3 P. 18

Failure to identify a patient's specific type of dementia can result not only in inappropriate treatment but also in needless excessive health care costs.

With dementia affecting nearly 10% of individuals aged 65 and older, according to the Alzheimer's Association, the need for an accurate diagnosis has become more compelling than ever. As discussed in Part One of this article published in the March/April issue, dementia is an umbrella term for a number of neurocognitive disorders, encompassing not only Alzheimer's disease (AD), which was addressed in the previous issue, but also vascular dementia, Lewy body dementia, Parkinson's dementia, and frontotemporal dementia (FTD), with a similarity of symptoms existing among the disorders.

Vascular Dementia
Vascular dementia is second in prevalence following AD,1 comprising about 15% of all dementias.2 Vascular cognitive impairment and vascular dementia may result from multiple cortical vascular infarcts, subcortical small vessel disease with lacunes/extensive white matter lesions, hypoperfusion, hemorrhage, and hereditary vascular dementia. Such cerebrovascular pathology can coexist with AD, resulting in mixed dementia.2 The likelihood of having a combination of AD and vascular dementia is greater than that of having pure vascular dementia as age increases.3

Vascular dementia can be differentiated from AD by the early onset of gait disturbance, falls, and urinary changes. Idiopathic normal pressure hydrocephalus may mimic vascular dementia with its symptom triad of ataxia, urinary incontinence, and dementia.

Neuropsychiatric signs of vascular dementia include apathy, emotional liability, lack of motivation, depression, and psychomotor retardation. Memory, language, and praxis have more variability than AD.3 Vascular dementia patients have significantly more agitation (40% vs 14%) and sleep disturbance (57% vs 32%) than those with AD. Compared with the mixed dementia of vascular disease combined with AD, vascular dementia presents with higher rates of depression (48% vs 20%) and aberrant motor behaviors (31% vs 13%).4

The dementia workup should be completed for suspected vascular dementia.1 A diagnosis/problem list with multiple cardiac/cerebrovascular risk factors, including diabetes and obstructive sleep apnea, raises the risk for vascular dementia. Lifestyle factors of smoking, inhalation of secondhand smoke, obesity, and alcohol abuse also raise vascular dementia risk. CT scanning visualizes established infarcts and extensive white matter lesions. MRI is more detailed in determining the degree, location, and extent of cerebrovascular disease.3

Recent research on medication to treat vascular dementia in large trials is lacking. A meta-analysis in 2007 revealed that cholinesterase inhibitors offer small cognitive benefits of uncertain clinical significance with a significant risk of adverse effects. The available data are insufficient to recommend widespread use in vascular dementia. Memantine (Namenda) is better tolerated but evidence does not support its use in vascular dementia.5

Lewy Body Dementia
Lewy body dementia, also known as dementia with Lewy bodies (DLB), is pathologically different from AD. Lewy bodies are abnormal aggregations of the protein alpha-synuclein in neurons (also occurring in Parkinson's disease).6 Lewy body dementia differs from Parkinson's disease dementia (PD-D) by its presentation symptoms at disease onset. Parkinson's patients exhibit motor deficiencies prior to the onset of cognitive impairments; in Lewy body dementia, cognitive impairment precedes the decline in motor function. The "one year rule" refers to the minimum one-year interval between the first-occurring parkinsonian symptoms and the subsequent dementia in order to be diagnosed as PD-D.7 The Movement Disorder Society Task Force defining the clinical diagnostic criteria for PD-D recommended that a diagnosis of PD-D should be made when dementia develops within the context of established Parkinson's disease. A DLB diagnosis is appropriate when the diagnosis of dementia precedes or coincides within one year of the development of motor symptoms.8

Current criteria for probable Lewy body dementia include the central feature, dementia with progressive cognitive decline, interfering with normal function, plus at least two of three core features: fluctuating cognition with pronounced variations in attention and alertness, recurrent typically well-formed detailed visual hallucinations, and spontaneous parkinsonian features. Two core features are sufficient for diagnosis of probable DLB and one for possible DLB. Suggestive features include rapid eye movement sleep behavior disorder, severe neuroleptic sensitivity, and low dopamine transporter uptake in the basal ganglia, as demonstrated on single-photon emission CT (SPECT) or positron emission tomography (PET) imaging. If one or more suggestive features is present with one or more core features, the diagnosis of probable DLB can be made. Without a core feature, one or more suggested features are adequate for a possible DLB diagnosis. Supportive clinical features include repeated falls, syncope, transient unexplained loss of consciousness, severe autonomic dysfunction (orthostasis or urinary incontinence), depression, systematized delusions, or hallucinations in other modalities. CT/MRI scans reveal a relatively preserved medial temporal lobe. On SPECT/PET perfusion scans, there is low uptake with reduced occipital activity.7

How can a clinician differentiate DLB from AD and PD-D in the early stages? A recent study showed more amnesia and orientation deficits in AD and fewer executive and visuospatial deficits in AD than DLB. Persons with DLB experienced more sleepiness, cognitive/behavioral fluctuations, and hallucinations than AD or Parkinson's disease. Axial motor, gait, and balance disturbances were related to executive function, visuospatial, and global cognitive deficits in DLB.9

Although cholinesterase inhibitors are not FDA approved for treating DLB in the United States, several studies have explored their use. A 52-week study assessed cognitive function, behavioral, and psychiatric symptoms, finding that cognitive function/fluctuations/behavioral symptoms improved after the start of donepezil, with improvement maintained for one year.10

One study found an increased dose of 10 mg of donepezil was effective in managing the relapse of hallucinations, which occurred on donepezil 5 mg.11 A second study revealed DLB patients who experienced a relapse of neuropsychiatric symptoms on donepezil 5 mg experienced improvement in six of 10 Neuropsychiatric Inventory (NPI) behaviors (including visual hallucinations) following a donepezil dose increase to 10 mg.12

A meta-analysis of randomized, controlled DLB memantine trials evaluated impact on motor function, activities of daily living, the NPI, and the Mini-Mental State Exam (MMSE). No significant impact of memantine was found on motor function, MMSE, NPI, or activity of daily living scores.13 It is important to stress to families safety, fall prevention, and education about neuroleptic sensitivity. Patients with DLB taking typical and atypical antipsychotics are particularly sensitive to their dopaminergic affinity. There is a very high risk for extrapyramidal symptoms and the potentially fatal complication of neuroleptic sensitivity, affecting approximately 50% of DLB patients.14

As with AD, patients and families need to prepare for the course of this dementia, considering all safety, legal, financial, and power of attorney issues. Families experiencing DLB should be encouraged to explore the Lewy Body Dementia Association's website, www.lbda.org.

Parkinson's Dementia and Parkinson's Disease Psychosis
Parkinson's disease is a progressive neurodegenerative disease with motor function deficiencies. Compounding progressive declines in gait, motor function, activities of daily living, and neuropsychiatric symptoms often occur, with elders at greatest risk. Parkinson's disease psychotic symptoms of presence and visual illusions affect up to 72% of individuals with Parkinson's disease. The prevalence of visual hallucinations reaches approximately 50% over the lifetime of a Parkinson's patient.15 PD-D is estimated to occur in between 50% and 80% of people with Parkinson's disease. The average interval between onset of Parkinson's disease and PD-D is approximately 10 years.16 Parkinson's disease psychosis (PDP) precedes or occurs with PD-D.

The memory deficit in PD-D is believed to be one of information retrieval rather than encoding and storage. Verbal and visual memory are impaired in PD-D but to a lesser extent than in AD. Attention is impaired in PD-D, with more fluctuation than in AD. Visual-spatial construction (eg, clock drawing) deficits exist in PD-D, probably to a greater degree than in AD. Executive function is usually more impaired in patients with PD-D than in patients with AD. PD-D patients have less impairment in core language functions compared with AD. PD-D patients exhibit word-finding difficulties and impaired comprehension of complex sentences. Behaviors in PD-D include apathy, which is evidenced by decreased spontaneous, motivated, interested, and effortful behavior. Depressed mood and anxiety are common. Hallucinations, usually complex and visual, are often comprised of people, animals, or objects. Delusions typically are paranoid, clustering around themes of infidelity or phantom boarder (unwelcome guests living in one's home). Excessive daytime sleepiness may occur.17

Rivastigmine (Exelon), a cholinesterase inhibitor, has FDA approval for the treatment of mild to moderate Parkinson's dementia.18,19 Patients treated with rivastigmine, in a 24-week study, showed improved executive and cognitive functioning.20 Rivastigmine is associated with improvement in memory and language in both AD and PD-D. A greater response was seen for PD-D.21 A meta-analysis of six trials using memantine in PD-D and DLB revealed minimal effects on cognition in both diseases.22

An FDA black box warning exists for use of atypical and typical antipsychotics in all dementias. Until recently, all antipsychotics bonded to dopamine D2 receptors. Dopaminergic activity of atypical and typical antipsychotics negatively affects Parkinson's disease by worsening motor function. One study showed that antipsychotic use in Parkinson's disease resulted in unsteady gait, higher comorbidities, and increased number of medications.23 In Parkinson's disease and DLB, antipsychotic/D2 receptor affinity increases the risk of extrapyramidal side effects and neuroleptic malignant syndrome. Recent studies and reviews noted increased mortality rates in Parkinson's disease when antipsychotics were prescribed.24,25 VA data from 1999 to 2010 evaluated morbidity risk associated with antipsychotic use in Parkinson's patients who were in stable physical health when enrolled. Morbidity rates for 180 days were compared in patients initiating an antipsychotic vs matched nonantipsychotic users. Results revealed that any antipsychotic use, including the atypical antipsychotics, was associated with a significant increase in physical morbidity in Parkinson's patients, evidenced by increased emergency department, inpatient, and outpatient visits.26

Quetiapine (Seroquel) is commonly used off label by clinicians for PD-D and/or PDP despite the black box warning for antipsychotic use in dementia. An analysis of 241 persons with Parkinson's in seven studies showed that quetiapine failed to significantly reduce psychotic symptoms in Parkinson's disease compared with placebo, as objectively assessed with the Brief Psychotic Rating Scale in those studies.27

PDP may present prior to the onset of dementia, as well as throughout the lengthy course of Parkinson's disease. It may coexist with PD-D. PDP is diagnosed by the presence of at least one of four symptoms, including illusions, false sense of presence, hallucinations, or delusions. A patient must already meet the criteria for Parkinson's disease and have recurrent or continuous psychotic symptoms for one month. The psychosis must not be due to DLB, psychiatric disorders, or a medical condition, including delirium. Hallucinations are typically visual, vivid, and well formed, usually of people or animals. They have similar patterns and often occur in the evening when there is decreased stimulation. Minor hallucinatory signs are presence hallucinations (experiencing that someone is present when no one is there). Passage hallucinations are fleeting, vague images. Illusions may occur, which are misperceptions of real visual stimuli. Auditory hallucinations occur less frequently than visual hallucinations. A patient may hear people talking or whispering, music playing from another area, or threatening voices. Insight is usually retained initially but may eventually disappear. A proportion of PDP patients will develop delusions with disease progression. Delusions are often paranoid, with themes of spousal infidelity, abandonment, or harm. Persons with PDP are very fixed in believing their own delusions.28

Individuals with PDP visual hallucinations have increased serotonin 2A receptor binding in the brain's ventral visual pathway.29 A new selective antipsychotic, pimavanserin (Nuplazid), a selective serotonin 5-HT2A inverse agonist,30-32 was FDA approved and released in 2016 for PDP. It is not approved for PD-D in the absence of PDP. Pimavanserin safety information differs from other antipsychotic warnings for antipsychotic use in dementia because pimavanserin is not approved "for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson's disease psychosis."30 Long term care staff dealing with PDP can reassure state surveyors that an FDA-approved medication exists for PDP that does not warrant antipsychotic dose reduction. Pimavanserin has only one dose: 34 mg daily.30 This differs from other atypical and typical antipsychotics that continue to be used off-label for various dementias. Pimavanserin is the first in a new class of medications offering treatment for the hallucinations and delusions of Parkinson's disease. Unlike all previous antipsychotics, it has no D2 activity. It has "zero" dopaminergic, adrenergic, histaminergic, or muscarinic receptor affinity. In addition to negating the risk of extrapyramidal motor drug-induced side effects in the at-risk Parkinson's patient, this serotonin inverse agonist's high selectivity will not affect adrenergic and muscarinic receptors (that may play a role in orthostasis/urinary incontinence in Parkinson's disease). Trial results of pimavanserin revealed a clinically significant reduction of hallucinations and delusions in six weeks (37% reduction in the treatment group vs 14% placebo) in patients who had PDP symptoms for several years. Unlike previous atypical and typical antipsychotics with dopaminergic activity, there was no treatment-related worsening of the subjects' motor symptoms.31

Parkinson's disease caregiver support is available at www.parkinson.org/find-help. Information on PDP for patients/families is at www.nuplazid.com.

Frontotemporal Dementia
FTD, like early-onset AD, strikes at a younger age. Several FTD variations exist, including behavioral-variant FTD, nonfluent variant primary progressive aphasia, and semantic-variant primary progressive aphasia.

Behavioral-variant FTD presents with apathy, personality changes, and disinhibition (inappropriate social behaviors and/or conversations). There is increased impulsivity and carelessness with possible disregard for the law. Impaired financial decision making may have devastating consequences. Apathy mimics depression, with reduced interest in an individual's usual social, occupational, and recreational activities. A decreased awareness and concern for the feelings and needs of others strains relationships. Repetitive phrases or compulsive behaviors may occur. Hyperorality is evidenced by binging and increased consumption of sweets or alcohol. Executive dysfunction becomes evident.33

The first two years of primary progressive aphasia FTD begin with an insidious progressive decline in linguistic ability. Obvious conversational deficits include challenges with word production/arrangement in sentences, object naming, and verbal comprehension. Nonfluent variant primary progressive aphasia is characterized by slow, labored, and halted speech as well as omission or misuse of grammar. Patients may struggle with understanding complex sentences. Some may be able to communicate via writing rather than speech. Semantic variant primary progressive aphasia dementia has symptoms of semantic aphasia and associative agnosia. Anomia for people, places, and objects (usually nouns vs verbs) occurs. There are word-finding/comprehension difficulties. Farther into the disease course, irritability, withdrawal, insomnia, and selective eating habits arise.33

Considering the age/life stage of an FTD patient and the potential for legal/financial risks, a very thorough dementia workup is essential (see "Differentiating Dementias: Alzheimer's Disease and Its Management" in the March/April issue of Today's Geriatric Medicine).1 FTD must be differentiated from other neurocognitive illnesses that strike at a younger age, eg, early-onset AD and chronic traumatic encephalopathy (CTE). Like behavioral-variant FTD, CTE presents with executive dysfunction and disinhibition. CTE symptoms include memory impairment, poor impulse control, depression, apathy, irritability, and possible suicidality. Persons suffering from CTE are often younger (aged 30 to 50) than those with FTD (aged 45 to 65) and have a slower progression of symptoms than persons with FTD. Those suffering from CTE consistently have a positive history of head/brain trauma. Other CTE symptoms are being "short-fused" or "out of control." Aggression and violence may occur in CTE.34

Both behavioral-variant FTD and CTE must be differentiated from Lyme neuroborreliosis,35 which may also present with cognitive impairment and/or mood alterations. Differentiating FTD from CTE, Lyme1 central nervous system infection, early-onset AD, or brain mass, all of which can occur at a younger age, is essential. Additionally, screening for sleep apnea, heavy metals, illicit drugs, inflammatory processes, or infectious diseases such as sexually transmitted infections or HIV causes should be considered. Persons with cognitive decline at a younger age require referral to a neuropsychologist for full neuropsychiatric testing, considering the likelihood of even more significant relationship, parenting, and occupational challenges than elderly adults with memory loss. Structural MRI and CT in FTD reveal predominant frontal or temporal atrophy (especially frontoinsular region atrophy).36 Fluorodeoxyglucose PET, functional MRI, and SPECT reveal disproportionate hypoperfusion and hypometabolism in the frontal and temporal lobes.37

There are no FDA-approved medications for FTD. Most of the studies on the management of FTD have been small and case-based or have had mixed FTD types in samples. The strongest trend cited is that antidepressants (selective serotonin reuptake inhibitors) may help manage behavioral symptoms in FTD patients and are well tolerated.38 The Association for Frontotemporal Degeneration (www.theaftd.org) should be offered as a resource to patients and families; spouses and children are younger than those involved with other dementia types apart from early-onset AD. General dementia advice on safety, driving, planning legal and financial strategies, power of attorney issues, and caregiver support is essential for families facing this challenging dementia.

Part One of the Differentiating Dementias article series introduced how distinguishing Alzheimer's from other dementias through a full dementia workup is essential to optimal quality of life for a patient, family, and caregivers.1 The fact that the diagnostic category of "dementia NOS" (dementia not otherwise specified) was used in 92.9% of 21.6 million recent fee-for-service Medicare recipients strongly suggests that only 7% of elders received a full cognitive/functional/behavioral history, physical examination, and diagnostic studies to diagnose their specific types of dementia.39 This is not acceptable; there are unique safety risks that vary by dementia type (eg, fall risk in DLB and an even higher stroke risk when using an antipsychotic in vascular dementia). Ignoring these differences may result in hospitalizations for stroke, hip fracture, or mortality.

Annual costs of Medicare beneficiaries have been shown to increase by $9,500 to $14,000 when an inaccurate diagnosis of AD was made instead of the actual diagnosis of Parkinson's or vascular dementia.40 Misdiagnosing AD in those with vascular dementia resulted in substantial excess health care costs. These excess costs decreased following finalization of the correct diagnosis of vascular dementia.41

It is our ethical and fiscal responsibility as primary care, specialty, and long term care clinicians to give dementia the same diagnostic attention as any other chronic illness regardless of the age, living situation, or social support of a demented person. Hospitalizations doubled for Medicare beneficiaries aged 65 and older with AD and other dementias (538 per 1,000) compared with 266 per 1,000 for Medicare beneficiaries aged 65 and older without dementia.6,42 Our health care system cannot afford to add extra costs by incorrectly diagnosing a type of dementia or, even worse, failing to diagnose dementia at all.

— Susan Scanland, MSN, CRNP, GNP-BC, CDP, CSP, a certified speaking professional and practicing geriatric nurse practitioner, specializes in dementia behaviors and optimal pharmacotherapy. Through her firm, Dementia Connection, she's presented extensively on dementia in the United States, Canada, and Europe. She has served as an advisor or speaker for Alzheimer's pharmaceutical corporations and is a nursing faculty specialist at the University of Scranton in Pennsylvania.

— Tyler Bielinski is a junior premed neuroscience major with a minor in biochemistry at the University of Scranton. He is a telehealth technician and student supervisor for the Telehealth Intervention Program for Seniors, which provides daily vital sign monitoring through the use of wireless technology to approximately 200 older adults throughout northeastern Pennsylvania. Beyond geriatrics, his research interests include the correlation of facial structure size with cognitive abilities, political orientation, and personality traits, and the use of cockroaches as invertebrate models for pharmacological manipulations of learning and memory.

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