When Mind and Body Fail: Coping with Complex Neurologic Diseases

Educational Objectives

The goal of this program is to improve the management of Alzheimer's disease (AD) and atypical degenerative par­kinsonian syndromes. After hearing and assimilating this program, the clinician will be better able to:

1.   Distinguish dementia from normal aging.

2.   Describe effects of medications used in AD, such as cholinesterase inhibitors, memantine, and antipsychotic drugs.

3.   Counsel patients, family, and caregivers about management of behavioral complications of AD.

4.   Detail the differential diagnosis for patients presenting with parkinsonian features.

5.   Compare and contrast Parkinson disease with the atypical parkinsonian syndromes in terms of presentation, progression, and management.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose. Drs. Eslami and Boyd present information in their lectures that is related to off-label or investigative use of a therapy, product, or device.

Acknowledgements

Dr. Eslami spoke in Los Angeles, CA, at the 36th Annual UCLA Family Practice Refresher Course, presented May 26-30, 2009, by the David Geffen School of Medicine at the University of California, Los Angeles. Dr. Boyd was recorded on April 7, 2009, at the Vermont Geriatrics Conference, presented by the Vermont Area Health Education Centers (AHEC) Network, in partnership with the University of Vermont and Fletcher Allen Health Care. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Alzheimer’s Disease

Michelle S. Eslami, MD, Professor, Department of Medicine, Division of Geriatrics, David Geffen School of Medicine at the University of California, Los Angeles

Dementia: prevalence increases with age; not part of normal aging process; between ages 65 and 85, prevalence dou­bles; affects 36% to 50% of people >85 yr of age; characterized by memory loss and impaired cognitive function that affects daily life; difficult to diagnose and distinguish from other causes of memory loss

Distinguishing dementia from normal aging: normal aging  —patient complains about memory loss; some forget­fulness, but information can be retrieved quickly; dementia  —  poor recent memory for all events; substantial func­tional decline affects daily life

Natural history of dementia: pathologic changes appear to occur years before clinical effects of illness; mild cogni­tive impairment (MCI)  —  predementia phase; characterized by significant memory loss that does not significantly affect daily life; transition period between normal aging and dementia; Alzheimer’s disease (AD) responsible for two-thirds of all cases of dementia

Neuropathology of AD: b- and g-secretases liberate b-amyloid peptide, leading to accumulation of amyloid (neuro­toxin to brain cells); neuritic plaques and neurofibrillary tangles form; inflammation leads to formation of tau pro­tein; neurofibrillary tangles contribute to nerve cell death and synaptic failure (correlates with degree of dementia and disability)

Natural history of AD: chronic, gradual, progressive illness; without therapy, score on Mini-Mental State Examina­tion (MMSE) declines by 3 to 4 points per year; more behavioral or neurocognitive symptoms (eg, agitation, ag­gression; often determine level of care needed) as disease progresses

Cholinesterase inhibitors: increase availability of acetylcholine and other neurotransmitters to brain cells by pre­venting loss of acetylcholine in nerve cell synapse; tend to stabilize illness; some improvement seen in ³20% of pa­tients; may slow progression of disease; donepezil, rivastigmine, and galantamine available in United States, and approved for mild to moderate dementia (ie, MMSE scores of 10-24); efficacy similar; some trials show slight ben­efit in moderate to severe illness

Memantine: works at level of nerve cell; N-methyl-D-aspartate (NMDA) antagonist; regulates glutamate to stabilize nerve cell and prevent further damage; slows rate of functional and cognitive decline; indicated for moderate to se­vere disease (ie, MMSE scores of 0-14); in moderate to severe dementia, better outcomes seen when memantine used with cholinesterase inhibitors, compared to cholinesterase inhibitors alone

Treatment strategy: begin medication immediately after diagnosis of AD; cholinesterase inhibitors first-line ther­apy; use highest tolerable amount of cholinesterase inhibitor; as disease progresses and decline noted, add meman­tine; continue therapy if no changes seen; if patient continues to decline, consider stopping medication

Other agents: not “ready for prime time;” undergoing studies; no benefits of ginkgo biloba, estrogen, or nonsteroidal anti-inflammatory drugs (NSAIDs); vitamin E and selegiline  —found to slow deterioration in »25% of subjects; pa­tients on vitamin E had longer time before being placed in nursing homes, compared to other arms of trial; high-dose (1000 IU bid) vitamin E recommended; in patients with diabetes or vascular disease, vitamin E found associ­ated with increased risk for congestive heart failure; speaker does not use selegiline

Behavioral therapy: as AD progresses, more behavioral complications develop; patients with AD need calm, safe, predictable environment; consult patient’s caregiver; »50% of caregivers develop depression; greater understanding of management and coping with disease empowers caregivers; resources (eg, support groups) available for caregiv­ers; managing aggression and other behavioral complications  —  consider medical problems that can complicate mental status (perform laboratory studies; obtain urine culture to rule out infection; review medication list); use be­havioral therapy rather than medications; distract patients (ie, shift focus); remain calm; glasses or hearing aids may help minimize aggression or agitation; consider atypical antipsychotic agents (if not tolerated, consider anticonvul­sants [eg, valproic acid, carbamazepine])

Effectiveness of antipsychotic drugs in AD: study looked at large number of patients with broad range of behavioral problems (eg, delusions, hallucinations, aggression); £82% discontinued medications before end of study (most pa­tients discontinued medications within first 8 wk); efficacy of olanzapine (Zyprexa) and quetiapine (Seroquel) not high; £24% intolerant to olanzapine; for patients who remained in study for 12 wk, minimal improvement seen on Clinician Global Impression of Change scale, with no difference in efficacy between agents; conclusions  —  agents appeared better than placebo, but greater intolerability eliminated any overall effect; side effects of atypical and typical antipsychotics include illness, stroke, and increased mortality (written informed consent required)

Management of anxiety and aggression: behavioral therapy  —mainstay of treatment; listen and provide reassur­ance; decrease noise and distractions; pet therapy; aromatherapy; music therapy; medications  —  atypical antipsy­chotics; selective serotonin reuptake inhibitors (SSRIs; eg, citalopram [Celexa], escitalopram [Lexapro]); buspirone [BuSpar]; trazodone)

Management of suspicion or paranoia: do not argue with patients; offer simple answers; switch patient’s focus; du­plicate lost items (eg, glasses, jewelry)

Advance planning: early stages of disease  —  counsel patients, patient’s family, and caregivers about natural history and progression of disease; involve patients in long-term decision-making; discuss advance directives; appoint sur­rogate decision-maker; as disease progresses  —  most patients live 8 to 10 yr; consider financial planning and long-term care needs (eg, 24-hr care); prepare family to look for markers of progression of disease (eg, loss of ability to walk or swallow)

Potential new therapies: antibiotics  —  Chlamydia pneumoniae linked to brain in patients with AD (may increase amyloid deposition); small trial using doxycycline and rifampin in patients with AD saw slowing of disease pro­gression ( £6 mo); secretase modulators  —  promote development of a-secretase to prevent splitting of amyloid pre­cursor protein into toxic fragments; studies under way; immunization  —  1) live vaccine; injected into subjects with AD; study halted early due to development of meningoencephalitis in »6% of treatment group; at 1-yr follow-up, no difference in amount of b-amyloid peptide in blood between treatment and control groups; postmortem analyses found brains of some patients in treatment arm had no plaques and tangles; 2) passive vaccine; intravenous immu­noglobulin (IVIG) currently in phase III trials; statins  —shown to decrease incidence of AD; memory loss compli­cation of statin use; lipophilic statins (eg, atorvastatin, simva-statin) thought to cross blood-brain barrier more easily, leading to demyelination of nerve cells and memory loss; if memory decline seen in patient recently started on lipophilic statin with no other cause for memory loss, may be reasonable to stop statin (brain function often re­turns within 1 mo); pravastatin (Pravachol) hydrophilic (does not appear to cross blood-brain barrier); sex hormones  —  no improvement in dementia or AD with testosterone replacement in men; insulin  — increased insulin levels decrease amyloid metabolism; intranasal insulin undergoing studies; dimebolin (Dimebon)  —  old nonselec­tive antihistamine; randomized controlled trial in Russia showed improvement in cognition, sustained for up to 1 yr; not approved in United States; inhibitors of tau protein  —lithium and valproic acid inhibit tau aggregation

Atypical Degenerative Parkinsonian Syndromes

James Boyd, MD, Assistant Professor of Neurology, University of Vermont, College of Medicine, Burlington

Natural history of Parkinson disease (PD): stage 1  —unilateral tremor, rigidity, and/or bradykinesia; minimal func­tional impairment; stage 2  —  features bilateral; no problems with balance; stage 3  —  some functional impairment and problems with balance; stage 4  —  significant imbalance and functional impairment; stage 5  —  inability to walk; patient fully dependent; duration  —  each stage lasts 2 to ³5 yr

Natural history of atypical parkinsonian syndromes: patients generally present at later stage (eg, stage 3) and progress to end-stage disease faster (»5 yr) than those with PD; onset of nonmotor features  —  earliest in patients with progressive supranuclear palsy (PSP); PD associated with longest latency; falls  —  occur earliest in patients with PSP and multiple system atrophy; orthostatic hypotension  —  late feature of PD; early feature of atypical syn­dromes; urinary incontinence  —  red flag for atypical syndrome (especially multiple system atrophy)

History: collateral history important; facial expressions and spontaneous gestures (reduced); speech (reduced volume or clarity); activities of daily living (slower); handwriting (small or slow; not typically tremulous); change in ath­letic ability; changes in gait; falls; tremor at rest or while walking

Examination: tremor  —  4 to 5 Hz in patients with PD; enhanced when walking or performing mental tasks; bradykinesia  —  test hand and limb movements; observe general movements (eg, rising from chair); rigidity  —  check neck and limbs; perform Froment’s maneuver (check tone in one arm while patient performs tasks with op­posite hand); look for cogwheeling (independent of rigidity); postural instability  —  observe patient rising from chair unassisted; perform “pull test”; gait  —  slow and shuffling; flexed arms with reduced swing; dragging leg or scuffing foot; “freezing” (difficulty initiating step); en-bloc turning; frontal lobe function  —  distraction, inattention, or disinhibition; grasp reflex; collectionism; utilization behavior; imitation behavior; eye movement  —  check pur­suit eye movements and saccades (movements slow before amplitude decreases); check for fixation difficulty (may look like nystagmus), blepharospasm (spontaneous or reflexive), and eyelid opening apraxia; dysautonomia  —  orthostatic hypotension; urinary incontinence or urinary retention; erectile dysfunction (especially in younger men); constipation; excessive salivation or sweating

Hallucinations: ask directed questions and provide examples; visual hallucinations of people or animals common, but any type of psychosis may occur; visual hallucinations typically occur in low ambient light; important to ex­clude significant loss of vision or hearing

Dementia with Lewy bodies (DLB): 15% to 35% of all cases of dementia; underdiagnosed; central feature  —  progressive cognitive decline sufficient to cause functional impairment; other core features  —  fluctuating cogni­tion (important distinction from AD); recurrent visual hallucinations; spontaneous parkinsonian features; initial symptoms  —  dementia most common; »36% present with parkinsonism without dementia; »10% have dementia and parkinsonism at presentation; hallucinations not required for diagnosis

Distinguishing DLB from PD: early onset of cognitive impairment (relative to onset of motor features) suggests PD with dementia; latency >1 yr in patients with DLB; progression of Lewy bodies  —  in PD, first occur in olfactory bulb, then progress anteriorly; ubiquitous in brains of patients with DLB; laterality  —  unilateral symptoms in PD; often bilateral in DLB; rigidity  —  primarily affects limbs (PD) or neck (DLB); tremor  —  action tremor (DLB) vs resting tremor (PD); response to medications  —  antiparkinsonism medications (eg, levodopa) often in­duce hallucinations in patients with DLB

Cognitive impairment: problems with retrieval (vs true amnestic pattern) and complaints of executive dysfunction; attentional problems include slow reaction time and slow verbal responses; problems with visuospatial process­ing; fluctuating cognition  —  observed in £90% of cases; MMSE scores may fluctuate £50%; testing  —  visuospatial processing; attention

Psychosis: typical and most atypical antipsychotics induce neuroleptic malignant-like state with rapid decline in parkinsonian symptoms (irreversible); management  —cholinesterase inhibitors for patients with mild psychosis and cognitive impairment; clozapine and quetiapine only antipsychotics tolerated (start with quetiapine); cholin­esterase inhibitors associated with stabilization or mild improvements

Multiple system atrophy: »5% of patients who present with degenerative parkinsonism; onset during sixth decade; common pathology (dysfunction of a-synuclein) with DLB and PD; variants  —  autonomic (Shy-Drager syn­drome); cerebellar (olivopontocerebellar atrophy); parkinsonian (striatonigral degeneration); diagnosis based on presenting symptoms; as disease progresses, elements of other variants may emerge; autonomic features  —  orthostatic hypotension; urinary incontinence or incomplete emptying (less common); erectile dysfunction; cere­bellar features  —  gait and limb ataxia; nystagmus; ataxic dysarthria; parkinsonian features  —rigidity; akinesis; bi­lateral onset (typically); rest tremor in <10% of patients; severe antecollis (flexed neck); early instability and falls; 30% to 40% have transient response to levodopa; managing orthostatic hypotension  —  behavioral measures in­clude elevating head of bed, use of compression stockings, and salt loading; treat even mild anemia aggressively; fludrocortisone first-line medical therapy; other options include midodrine, desmopressin nasal spray, erythropoie­tin (for persistent anemia), and indomethacin

Progressive supranuclear palsy: presentation  —  96% have gait disorder and instability; 83% present after falls (typ­ically falling backwards); only 8% have gaze palsy at onset; oculomotor abnormalities  —  limited vertical gaze (some loss of upgaze occurs with normal aging); impaired saccades; reduced blink rate; retracted frontalis muscles, giving patient look of surprise; eyelid apraxia; blepharospasm; frontal lobe syndrome  —  cortical dementing pattern uncommon; aphasia, agnosia, and apraxia occur only in later stages; parkinsonism  —  severe neck stiffness and dis­proportionate retrocollis; bilateral bradykinesia; prominent akinesia without tremor; early dysarthria and dysphagia (hallmark); “pie on tie” sign; dopaminergic response modest or absent; rapid progression

Corticobasal degeneration: onset in sixth to eighth decades; incidence unclear; simultaneous asymmetric neuronal loss in substantia nigra and cortex; features  —  progressive asymmetric rigidity and apraxia; alien limb phenome­non; inability to process sensation at higher cortical levels; mirror movements of limbs; myoclonus; dystonia or hemidystonia; jerky, irregular tremor; lack of responsiveness to levodopa; varying cognitive features, depending on region of cortex involved; dementia usually occurs late in course

Palliative strategies: gait instability and falls  —  physical therapy; fall prevention; weighted walkers; speech problems  — speech therapy; communication device if severe; dysphagia  —  use of thickeners; endogastric tube for patients with advanced PSP; eyelid dysfunction  —  periocular injections of botulinum toxin; sialorrhea  —  sucking on hard candy; sublingual atropine or inhaled ipratropium; glycopyrrolate (but exacerbates constipa­tion); injections of botulinum toxin (but exacerbates dysphagia)

Suggested Reading

Birks J: Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev 25:CD005593, 2006; Doody RS et al: Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study. Lancet 372:207, 2008; Goetz CG et al: Parkin­son’s disease dementia: definitions, guidelines, and research perspectives in diagnosis. Ann Neurol 64(Suppl 2):S81, 2008; Hasnain M et al: Pharmacological management of psychosis in elderly patients with parkinsonism. Am J Med 122:614, 20009; Loeb MB et al: A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease. J Am Geriatr Soc 52:381, 2004; Muller J et al: Progression of Hoehn and Yahr stages in parkinsonian disorders: a clinicopathologic study. Neurology 55:888, 2000; Philibert M et al: Movement irregularities in atypical parkinsonian syndromes. Parkinsonism Relat Disord 15:542, 2009; Reisberg B et al: Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 348:1333, 2003; Schneider