MULTIPLE SCLEROSIS, ALZHEIMER’S DISEASE, AND DEMENTIA
From Seizures, Spells, and Shakes: Neurology for the Non-Neurologist, presented July 21-24, 2005 by the Medical
College of Georgia
Mary D. Hughes, MD, Assistant Professor of Neurology, Medical College of Georgia, Augusta
| Intorduction: autoimmune disorder; affects central nervous system (CNS); causes neurologic deficits over time; course
unpredictable; studies show 4 patterns of fluctuating neurologic symptoms (eg, inflammatory response, degenerative axonal
changes); demyelinating; axonal changes probably correlate with permanent disability
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| Symptoms: loss of vision in one eye (optic neuritis); 80% of patients have involvement of vision; slurred or slowed
speech; easy fatigability (unique to multiple sclerosis [MS]); physical or mental fatigue; 70% to 80% of patients have
cognitive changes; attention and concentration problems; severe cognitive impairment can occur without advanced physical
disability; balance problems; paresthesias; problems with bladder and bowel control; patients diagnosed with optic
neuritis should be referred to neurologist because of high predictive value for MS; look for subclinical evidence of previous
neurologic events (eg, arm numbness)
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| Imaging techniques: magnetic resonance imaging (MRI)—helpful; typically shows periventricular involvement
(round and ovoid lesions); shows changes in conductive coating around nerves; does not show dysfunctional tissue; patients
with advanced changes on MRI may have normal neurologic examination; areas that appear normal on MRI may
appear abnormal with magnetic transfer resonance and positron emission tomography (PET); multiple areas of white
matter changes on MRI help support diagnosis of MS
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| Cerebrospinal fluid (CSF) studies: look for evidence of hyperactivity of immune system; in MS, activation of immune
system in CSF out of proportion, compared to blood
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| Relapse: new neurologic symptoms or worsening of old neurologic symptoms that lasts ≥24 hr; pseudorelapse—
worsening of previous neurologic events due to, eg, infection (eg, bladder infection, upper respiratory infection) or heat
sensitivity; symptoms resolve
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| Relapsing-remitting MS: most common form; neurologic event followed by another; degree of improvement from relapse
unpredictable; over time, improvement from each neurologic event may decline; time of next neurologic event unpredictable
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| Secondary progressive phase: change in clinical history when patients left untreated for 15 to 20 yr; patients do not
remember having discrete neurologic events, but complain about deterioration in handwriting or changes in walking;
gradual neurologic decline; after 10 yr, 50% of patients need unilateral assistance (ie, cane)
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| Primary progressive MS: no history of discrete neurologic events; patient has progressive neurologic symptoms (eg,
progressive problems with walking, cognitive problems); patients do not respond to Food and Drug Administration
(FDA)-approved drugs for relapsing-remitting MS
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| Predicting MS: clinically isolated syndrome—first neurologic event; 10% to 20% risk of developing clinically definite
MS in patients with optic neuritis and normal MRI (80%-90% if MRI abnormal); natural history of MS—during
preclinical phase, patients who present with first neurologic event likely to have had MS for 5 to 7 yr; potential
triggers—infectious agents (eg, Epstein-Barr virus [EBV], Chlamydia); in pediatric MS, children <10 yr of age have
higher titers of EBV; environmental and genetic risk factors—living in areas farther from equator increases risk (may
be due to vitamin D deficiency from less sun exposure; certain viruses do better in cooler temperatures); risk of developing
MS in general population 1% to 2%, if 1 family member affected, 2% to 4%; risk for MS in identical twins 30% to
40%; women-to-men ratio 2:1 for relapsing-remitting MS, 1:1 for primary progressive MS; average age at diagnosis 28
to 30 yr; >90% of cases in whites, but incidence in nonwhite populations rising; risk affected by area of residence before
age 15 yr; people who lived in northern areas and moved south at age 20 yr retained higher risk of developing MS, but
people living in the south who moved north before age 15 yr maintained lower risk of developing MS (may be susceptible
to potential triggers during development)
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| Therapy: immune-modulating therapy—4 FDA-approved injected drugs for MS; shown to decrease frequency and severity
of relapses and slow progression of disability; relapse rate reduction 30% to 40%; natalizumab (Tysabri) removed
from market because of incidents of progressive multifocal leukoencephalopathy (PML); mitoxantrone (Novantrone)—
for patients who continue to progress despite use of FDA-approved agents; chemotherapeutic agent; smaller doses used
for MS than used for oncology; well tolerated
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| Side effects: interferons can cause influenza-like symptoms; start with low dose (25% of dose) and gradually increase for 1
mo to 6 wk; dose at night; premedicate with eg, acetaminophen (Tylenol) to block influenza-like symptoms; injection site
reactions—redness; 5% risk for necrotic skin lesions; autoinjectors helpful for decreasing reactions; liver function
abnormalities—common with interferons; elevation of liver function 2 to 3 times normal (not recommended to stop medications
until 5 times normal); glatiramer—systemic reaction occurs few minutes after injection; patients complain about
racing heart and difficulty breathing; self-limited; no documented correlation with cardiac or pulmonary function; occurs
with 5% of injections over time; mitoxantrone—risk for cardiotoxicity; use limited to 2 yr; perform multiple gated acquisition
(MUGA) scanning or echocardiography before each dose; white blood cell (WBC) count drops 2 wk after infusion
(monitor patients); if patient becomes neutropenic, do not give stimulants
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| Symptom management: fatigue—cooling (eg, ice around wrists or neck); exercise (eg, yoga, aquatic therapy in
cooler pools); patients need supportive counseling about energy conservation and safety when using assistive devices;
30% of patients respond to amantadine long term; 85% of patients respond to modafinil (improves alertness; not addictive;
does not lose effectiveness over time); consider comorbid conditions (eg, use activating antidepressant for patients
with depression); urinary urgency and retention—urinary urgency can affect daytime fatigue; long-term medical consequences
of urinary retention include urinary tract infection (UTI) and hydronephrosis (identify patients and implement
appropriate caffeine regimen); spasticity—increased tone in extremities; disabling; patients complain about pain and
discomfort; diurnal variation (patients may develop symptoms at night); ask about jumping or kicking at night and need
to stretch; interventions include stretching and identifying painful stimuli (eg, decubitus ulcer, UTI); oral baclofen (Lioresal)
or tizanidine cause sedation and cognitive changes; baclofen pump or intrathecal baclofen available (required intrathecal
dose 1% of oral dose); counsel patients about concerns with implant devices (eg, body image issues); pain—
90% of patients report pain; neurologic causes include trigeminal neuralgia and paroxysmal pain syndromes that respond
to carbamazepine; burning; tingling; paresthesias; in patients with hemiparesis, “good side” may have more musculoskeletal
pain related to overuse; give nonsteroidal agents and narcotics as necessary
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| Cognitive issues: affects 70% of patients; identifying problems and educating family important; contributing factors include
fatigue, medications, and side effects; anticholinesterase inhibitors used for Alzheimer’s disease (AD), but may be
helpful for MS (under study); mimic symptoms of attention deficit disorder (ADD); trial of stimulants can be helpful; encourage
wellness issues (eg, tobacco smoking cessation); address aspiration pneumonia and urosepsis
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| Vaccines: safety of influenza vaccine well documented; risk for relapse related to influenza high; influenza and pneumococcal
vaccine (Pneumovax) recommended for appropriate patient populations
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| ALZHEIMER’S DISEASE AND DEMENTIA
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| Introduction: acquired syndrome; interferes with daily occupation; warning signs include problems with learning and retaining
new information, losing items in unusual places (eg, losing keys in oven), difficulty handling complex tasks (eg, balancing
checkbook); recognize that family members often take over household tasks (thorough history important); effects on
reasoning ability, spatial ability and orientation (eg, difficulty driving), and increasing difficulty with language; behavior issues
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| Work-up: neurologic examination in Alzheimer’s dementia should be normal, but asymmetric in patients with vascular dementia;
rule out correctable causes of dementia
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| Imaging requirements: MRI for subcortical dementia related to vascular events; neuropsychologic examination for
patients with declining function; bedside testing (eg, Mini-Mental State Examination [MMSE]) may not help recognize
deterioration of higher level of function; detailed testing may be required; early identification important
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| Routine testing: ask patient, “what year is it?” clock-drawing test (draw large circle to test for visual and spatial abnormalities);
check language fluency; determine how many animals patient can name in 60 sec (16 normal, <11 indicates memory
problem); attention, spelling words backward, recall testing; MMSE score <25 abnormal, <10 indicates profound impairment
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| Differential diagnosis: 65% of dementia cases due to AD; Creutzfeldt-Jakob disease (mad cow disease)
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| Alzheimer’s disease: at 65 yr of age, risk 5% (at 80-90 yr of age, 50%); familial AD rare; risk for AD in patients with
Down syndrome nearly 100% by 30 yr of age; apolipoprotein E (apoE)—not risk factor for developing AD, but may
predict severity and rapidity of progression; frequency 25% to 50%; individuals with APOE*E4 allele have earlier onset,
more severe course, and earlier mortality; does not predict AD, but may predict course after diagnosis
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| Treatment: symptom management; preventive therapy—statins debatable; vitamin E safe and well tolerated; estrogen
replacement therapy—debatable; cardiovascular risk; discuss with family, gynecologist, and primary care physician;
nonsteroidal anti-inflammatory drug therapy—studies show patients treated for arthritis with standard doses less
likely to develop AD long term; statins—lowering of cholesterol drives cleavage of amyloid precursor protein into soluble
forms (may potentially protect against development of AD); disease-course modifiers—tacrine difficult to tolerate
and must be taken qid; donepezil (Aricept) taken once daily; rivastigmine (Exelon) and galantamine (Reminyl) taken bid;
long-lasting formulation of galantamine (Razadyne) taken once daily
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| Use of medications: studies suggest patients should be maintained on medications for as long as tolerated; when drugs
stopped, patients may not reach previous baseline after drugs restarted; in galantamine study, patients who started drug 6
mo after using placebo did not reach baseline of patients who had been using drug since beginning of study; Exelon study
suggests patients should be using highest possible tolerated dose; gastrointestinal (GI) side effects most common; switch
agents if patient cannot tolerate maximum recommended dose; memantine—for severely impaired and more advanced
AD, or patients on cholinergic agents who are deteriorating over time; well tolerated and efficacious when added to donepezil;
moderate improvement in cognitive function compared to baseline; in first 3 mo of study, cognition improved in
placebo group (suggests awareness of cognitive problem allows easier adaptation by family; identification of problem
important); challenges include high cost
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| Mild cognitive impairment: impairment in only one domain of cognition (eg, memory); ≈15% of patients develop
AD in 1 yr, ≤70% in 5 yr; identify and monitor closely
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| Vaccination for AD: patients developed encephalitis; safety issues inhibit development
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| Causes of acute mental status changes in elderly: metabolic or toxic (eg, UTI, pneumonia) 65%; focal structural
lesions (strokes most common); acute development of psychiatric problems uncommon in elderly
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| Assessment of agitation: determine whether patient has new problem, exacerbation of preexisting problem, or pain;
consider substance abuse, acute withdrawal, and environmental or psychosocial problems; address family; elder abuse;
change in environment; psychosis, depression, and anxiety; sundowning (problems in evening)
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| Behavioral changes in AD: start premorbid (up to 1 yr beforehand); depression; paranoia; delusions; hallucinations; aggression;
predict need for placement; anticholinergic agents decrease psychiatric manifestations and help patients remain in
home environment longer; mild agitation—environmental interventions with or without medication; keep patients on
schedules and do not remove from familiar environments; severe agitation—appropriate use of medication; education
and support for family and caregivers; structure, routine, reassurance, socialization, and day programs beneficial
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| Medications for agitation: use lowest possible dose; sedation increases risk for falls and other complications; risperidone;
valproic acid (Depakote) helpful; antidepressants; maintain good sleep hygiene; psychiatric manifestations fluctuate
over time; slowly wean medications; risk for Parkinsonian symptoms and falls with high-potency neuroleptics; newer
atypical antipsychotic agents helpful
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| Vascular dementia: ≈15% of dementias; criteria—≥2 strokes or 1 stroke with clear temporal relationship to onset of
dementia; unequal distribution of cortical function on focal neurologic examination; evidence of relevant stroke based on
neuroimaging; MRI shows white matter changes and microvascular ischemic changes; stroke correlated to neurologic
manifestation or stepwise progression in memory loss probably not vascular dementia; patients respond to cholinergic
agents; appropriate management of stroke risk factors important
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| Frontotemporal dementia: profound changes in behavioral or social conduct; associated with changes in expressive
language or naming and comprehension; loss of social inhibitions
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| Lewy body dementia: pattern of cognitive decline similar to AD; prominent visual hallucinations; fluctuation in cognition
can be significant; Parkinsonian symptoms; cholinergic agents worsen clinical manifestations
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| Polypharmacy: reevaluate medications; maximize one and eliminate others; recognize heightened sensitivity to medications
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Educational Objectives
| The goal of this program is to educate the listener about multiple sclerosis (MS), Alzheimer’s disease (AD), and dementia.
After hearing and assimilating this program, the participant will be better able to:
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 | 1. Use imaging studies and laboratory tests to diagnose MS.
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| 2. List potential triggers and risk factors for MS.
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| 3. Provide pharmacologic and nonpharmacologic symptom management for patients with MS.
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| 4. Choose appropriate therapy for patients with AD, based on clinical findings.
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| 5. Select appropriate medications for agitation and dementia.
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Discussed on This Program
Acetaminophen (N -acetyl-P -aminophenol; APAP) [several trade names]
Amantadine HCl [Symmetrel]
Baclofen [Lioresal, Lioresal Intrathecal]
Caffeine [several trade names]
Carbamazepine [Carbatrol, Epitol, Tegretol, Tegretol-XR]
Donepezil HCl [Aricept, Aricept ODT]
Galantamine HBr [Reminyl, Razadyne]
Glatiramer acetate [Copaxone]
Influenza virus vaccine [Fluarix, FluMist, Fluvirin, Fluzone]
Memantine HCl [Namenda]
Mitoxantrone HCl [Novantrone]
Modafinil [Provigil]
Natalizumab [Antegren, Tysabri]
Pneumococcal vaccine, polyvalent [Pneumovax 23]
Risperidone [Risperdal, Risperdal Consta, Risperdal M-TAB]
Rivastigmine tartrate [Exelon]
Tacrine HCl (tetrahydroacridinamine; THA) [Cognex]
Tizanidine HCl [Zanaflex]
Valproic acid [Depacon, Depakene, Depakote, Depakote ER]
Vitamin E [several trade names]
Suggested Reading
Bartzokis G et al: Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals: implications for
cognitive decline and dementia. Arch Gen Psychiatry 63:63, 2006; Chaudhuri A: Why we should offer routine vitamin
D supplementation in pregnancy and childhood to prevent multiple sclerosis. Med Hypotheses 64:608, 2005; Deryck O et
al: Clinical characteristics and long term prognosis in early onset multiple sclerosis. J Neurol, 2006; Fleisher AS et al:
Identification of Alzheimer disease risk by functional magnetic resonance imaging. Arch Neurol 62:1881, 2005; Forbes A
et al: Health problems and health-related quality of life in people with multiple sclerosis. Clin Rehabil 20:67, 2006; Kaduszkiewicz
H et al: Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised
clinical trials. BMJ 331:321, 2005; Merkelbach S et al: Multiple sclerosis and the autonomic nervous system. J Neurol
253 Suppl 1:i21, 2006; Mouzaki A et al: Immunotherapy for multiple sclerosis: basic insights for new clinical strategies.
Curr Neurovasc Res 1:325, 2004; Murray TJ: Diagnosis and treatment of multiple sclerosis. BMJ 332:525, 2006; Polman
CH et al: A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med
354:899, 2006; Takeda A et al: A systematic review of the clinical effectiveness of donepezil, rivastigmine and galantamine
on cognition, quality of life and adverse events in Alzheimer's disease. Int J Geriatr Psychiatry 21:17, 2006; Touchon
J et al: Response to rivastigmine or donepezil in Alzheimer's patients with symptoms suggestive of concomitant
Lewy body pathology. Curr Med Res Opin 22:49, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed:
Dr. Hughes is on the Speakers’ Bureau and/or has received grants from Berlex Laboratories, Inc., Biogen, Serono
Laboratories, Inc., and Teva Pharmaceuticals USA.
Dr. Hughes spoke in Kiawah Island, South Carolina at Seizures, Spells, and Shakes: Neurology for the Non-Neurologist,
presented July 21-24, 2005, by the Medical College of Georgia. The Audio-Digest Foundation thanks Dr. Hughes and the
Medical College of Georgia for their cooperation in the production of this program.
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