DISEASES MISTAKEN FOR PARKINSON’S
Stephen G. Reich, MD, Professor of Neurology, University of Maryland School of Medicine, and Co-Director,
Maryland Parkinson’s Disease and Movement Disorders Center, Baltimore
| MISDIAGNOSIS OF PARKINSON’S DISEASE
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| False positives: autopsy gold standard; in early Rajput study, initial diagnosis wrong one third of time, ie, patient
did not have Parkinson’s disease (PD), even though diagnosed by neurologist; when patient followed through
course of illness, final diagnosis wrong ≈24% of time; subsequent United Kingdom (UK) brain bank study showed
similar result, ie, final diagnosis wrong ≈25% of time; most patients had parkinsonian syndrome, eg, progressive
supranuclear palsy, multiple system atrophy (includes olivopontocerebellar atrophy, Shy-Drager syndrome, and
striatonigral degeneration); other diagnoses included Alzheimer’s disease, drug-induced parkinsonism, and essential
tremor (ET); diagnostic accuracy has improved over time; recent UK brain bank study indicates false-positive rate
still 10%, even when diagnosis made by specialists; Deprenyl and Tocopherpl Antioxidative Therapy of Parkinsonism
(DATATOP)—largest clinical study of PD; 8.1% of patients required revision of diagnosis, even with strict diagnostic
criteria for entry; most reliable predictors of PD—resting tremor (one third of PD patients do not have
tremor); PD begins as hemiparkinsonism (typically starts on one side, unrelated to handedness); sustained beneficial
response to levodopa
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| False negatives: speaker reviewed records of 177 of his patients with PD; at presentation to referring physician,
29% given correct diagnosis, 28% misdiagnosed, and 43% undiagnosed; common misdiagnoses—ET most common;
other tremors caused by hyperthyroidism, drugs, Wilson’s disease in young patients; ruled out by history and
thyroid function tests; PD patients can present with rheumatic symptoms and be diagnosed with musculoskeletal
problems; other misdiagnoses include stroke, stress, depression, and medication side effects
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Pitfalls in Diagnosis of PD
| Overdiagnosis: patients do not have PD; confusion with ET, lower-half parkinsonism, drug-induced parkinsonism,
parkinsonian syndrome, Alzheimer’s or Lewy body dementia presenting as PD, parkinsonism of “normal aging”
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| Underdiagnosis: patient has PD, but diagnosis not considered because of atypical presentation, eg, young age at
onset, sensory symptoms (musculoskeletal misdiagnosis common), unilateral lower extremity presentation (PD
usually associated with upper limb), atremulous PD
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| Confusion with ET: distinction made based on good history and physical examination
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 | History: age—onset of PD fairly uncommon after 55 yr of age, relatively uncommon after 65 yr of age; age alone
not helpful; presentation—PD patients usually present with tremor within 6 mo of onset; patients with ET have
history of tremor for years or decades; family history—usually negative in PD; 5% have autosomal-dominant
PD; up to 15% have first-degree relative with PD; ET autosomal dominant 50% to 60% of time; response to
alcohol—in 60% of ET patients, small amount of alcohol temporarily attenuates tremor (rarely occurs in PD)
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| Physical examination: tremor—resting tremor in PD attenuates with movement and maintenance of posture; ET
not present when limbs at rest, maximally activated with limbs in front, fingers in front of nose, and with movement;
frequency of tremor not helpful; morphology helpful (pill-rolling or “watch-winding” movement, ie, abduction
and adduction of thumb with flexion and extension of fingers); most helpful differential diagnostic
point—strictly unilateral tremor probably PD; ET almost always bilateral but may be asymmetric; both PD and
ET involve upper limb; PD often spreads from upper limb to ipsilateral lower extremity before contralateral
movement; can also begin in foot; tremor of head or voice (eg, Katherine Hepburn) is ET; handwriting—in PD,
small and atremulous, even when tremor begins on dominant side; in ET, handwriting normal size, but shakes;
associated features—in PD patients, include cogwheel rigidity, masked facies, shuffling gait, and trouble arising
from chair; ET patients do not have those associated features; progression—PD noticeably progressive from
year to year, eg, patients have increasing problems with activities of daily living, additional signs added; ET so
insidiously progressive that difficult for physician to see; more on tremor—in ET, tremor postural and almost always
kinetic (intention) tremor
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| Lower-half parkinsonism: parkinsonian signs and symptoms predominantly from waist down; disproportionately
good from waist up; patient does not have micrographia or resting tremor; arms fine; shuffling broad-based gait;
usually presents after 70 or 75 yr of age; normal-pressure hydrocephalus—patient has broad base and swings arms
well; no response to levodopa; speaker likes to see how many steps patient takes to turn 360º (videotapes patient);
improves after shunt placement; uncommon but important problem; difficult to diagnose; not unilateral at onset
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| Drug-induced parkinsonism: look at medication history, as symptoms may take up to 1 yr to resolve; antipsychotics
(eg, haloperidol, thioridazine) can cause symptoms; newer antipsychotics (eg, resperidone, olanzapine)
more antidopaminergic; amitriptyline and metoclopramide can cause tardive dyskinesia and tardive dystonia; amiodarone
by itself rarely causes significant parkinsonism but when coadministered in PD patient, can make things
worse; valproic acid causes postural tremor
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| Parkinsonian syndrome red flags: little or no response to levodopa (300 to 1000 mg daily); early dementia—
(preceding or at presentation); if hallucinations and delusions present, think of dementia with Lewy bodies; early
falls—probably progressive supranuclear palsy; in PD, falls do not occur until ≈5 yr into disease; early dysphagia—
probably not PD; early and prominent dysautonomia—eg, erectile dysfunction, bladder problems, orthostatic hypotension;
occur in middle to latter stages of PD; think multiple system atrophy (Shy-Drager syndrome); other red
flags—rapid progression (“wheelchair sign”); symmetric onset; not uncommon for normal elderly and PD patients
to have impaired upward gaze, but with impaired downward gaze and parkinsonism, think progressive supranuclear
palsy; pyramidal signs; cerebellar signs; parietal signs; if tremor not seen, think syndrome; red flags may not
appear at first visit; reevaluate diagnosis at every visit
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| Alzheimer’s disease or dementia with Lewy bodies presenting as parkinsonism: “any elderly person referred
to as being ‘sharp as a tack’ is demented until proven otherwise”; dementia common in PD (40% of time) but
occurs late; in early dementia with parkinsonism, consider Alzheimer’s, Lewy body dementia, or frontotemporal
dementia with parkinsonism
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| Parkinsonism of “normal aging”: at certain point, incidence of PD does not increase but decreases; PD peaks at
60 to 65 yr of age; be cautious about diagnosing PD after age 75 yr; prevalence of PD and parkinsonism in community
increases significantly until about one half of population has parkinsonism; not clear what causes this; loss of
nigral neurons, perhaps multi-infarct state, involutional changes in brain
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| Sensory and pain symptoms as presentation of PD: patient presents to orthopedic surgeon with frozen shoulder;
resolves, but has problems manipulating hand or with handwriting; not uncommon presentation; patients may
have fibromyalgia or some form of arthritis; foot pain in young-onset PD, with or without inverted foot; proximal
limb pain; tingling or numbness; vague sensory symptoms; restless leg syndrome common problem in PD; internal
tremor; do not discount PD just because symptoms sensory
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| Young-onset PD: often not recognized; can be too old for PD, but not too young; 5% of PD patients present at <45
yr of age; important for internists and family practitioners to be aware of this
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| Unilateral lower extremity presentation: foot tremor, stiffness or dragging of leg; might think radiculopathy or
peroneal neuropathy; patients complain of “weakness”; actually, strength normal, but patient uncoordinated and
slow; sometimes dystonia or pain; think PD with symptoms in one lower extremity
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| Atremulous PD: when patients do not have tremor, diagnosis of PD may not be considered; known as pseudohemiplegic
form of PD; patient appears to have hemiparesis or hemiplegia; many patients considered to have stroke, but
weakness, and hyperreflexia absent; unilateral onset important tipoff
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| Remember that PD often misdiagnosed: most reliable signs—resting tremor, unilateral or asymmetric onset,
sustained beneficial response to levodopa
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Questions and Answers
| 83-yr-old woman with moderate Alzheimer’s: living in nursing home (previously in assisted living); slowing
down over last 6 mo; looking parkinsonian; no tremor; mask-like facies, shuffling walk; admitted to hospital; neurologist
diagnosed PD and prescribed carbidopa-levodopa (Sinemet) at mild dose, increasing to 25/250 tid; several
weeks later, patient appears well; smiling, no trouble walking, no mask-like facies; answer—could be parkinsonism
of Alzheimer’s disease without unilateral resting tremor; if response to levodopa good and sustained for 1 yr, could
have both diseases; stay away from dopamine agonist (not well tolerated)
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| Woman in late 20’s diagnosed with PD; which imaging, testing, and genetic studies appropriate? no
need to image patients with typical signs; appropriate to image young patients; screen for Wilson’s disease; careful
family history; other genetic diseases can mimic PD (eg, spinocerebellar degeneration); 50% of patients with
young-onset (<30 yr of age) have recessive Parkin gene
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| What is the treatment for PD and dementia? greater cholinergic loss than in Alzheimer’s disease; cholinesterase
inhibitor might be more helpful, especially in subgroup of dementia with Lewy bodies
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| Case of pseudohemiplegic PD: initially called “stroke” with left-sided progressive weakness; however, onset not
sudden; no hemiparesis; cogwheel rigidity, slowness, mask facies; acid test improvement with levodopa
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| What is treatment for patient with ET? refer to practice parameters from American Academy of Neurology
(www.aan.com); not everyone with ET requires treatment; treat when physical impairment or embarrassment occurs;
propranolol and primidone 2 most effective drugs; both equally efficacious; can use maximally tolerated
dose; provide patients with realistic expectations, ie, medications will not stop shaking; goal is improved function;
focus on 2 to 4 activities of daily living to determine if medication working; patients with disabling, medically recalcitrant
ET should be referred for deep brain stimulation
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| What are treatment options for patients with lower-half PD not caused by hydrocephalus? no good
treatment options; important to recognize it is not PD; try levodopa, but do not have high expectations; do not continue
if improvement not meaningful; normal-pressure hydrocephalus only treatable cause of lower-half PD; often
result of multiple infarcts or cause not known; result of aging process
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| Is there benefit in immediately sending patients with atypical findings to PD expert, or should referral
wait until patient truly symptomatic? important to first establish proper diagnosis; refer if unsure of diagnosis;
no neuroprotective therapies; treatment for PD started when patient’s symptoms become problematic; do
not use levodopa as diagnostic trial; delay in diagnosis does not alter course of disease
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| How do you initiate levodopa therapy? use generic drug (less expensive); start with 25/100 to minimize nausea;
in older patients, administer one-half tablet at meals (to reduce nausea), starting with breakfast only, then gradually
adding it at other meals; might take 2 to 4 wk to see improvement; once tolerated at meals, take one-half
tablet half hour before meals to increase absorption; increase to 1 tablet if initial dose not effective; tell patients to
take during waking part of day, except if taking long-lasting dopamine agonist
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Educational Objectives
| The purpose of this program is to provide the listener with information on the pitfalls of diagnosing Parkinson’s disease
(PD). After hearing and assimilating this program, the clinician will be better able to:
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| 1. List the most reliable predictors for PD.
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| 2. Describe the diseases that are incorrectly diagnosed as PD.
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| 3. Review the atypical symptoms of PD that frequently lead to underdiagnosis of the disease.
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| 4. Distinguish PD from essential tremor.
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| 5. Discuss the treatments for PD.
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Discussed on This Program
Amiodarone HCl [Cordarone, Pacerone]
Amitriptyline HCl [Elavil]
Haloperidol [Haldol, Haldol Decanoate 50, Haldol Decanoate 100]
Levodopa and carbidopa [Parcopa, Sinemet-10/100, Sinemet-25/100, Sinemet-25/250, Sinemet CR]
Metoclopramide [Maxolon, Metoclopramide Intensol, Octamide PFS, Reclamide, Reglan]
Olanzapine [Zyprexa, Zyprexa Intramuscular, Zyprexa Zydis]
Primidone [Mysoline]
Propranolol [Inderal, Inderal LA, InnoPran XL]
Risperidone [Risperdal, Risperdal Consta, Risperdal M-TAB]
Thioridazine HCl [Mellaril]
Valproic acid [Depacon, Depakene, Depakote, Depakote ER]
Suggested Reading
Angwin AJ et al: The influence of dopamine on semantic activation in Parkinson's disease: evidence from a multipriming
task. Neuropsychology 20:299, 2006; Brandt-Christensen, M et al: Treatment with antidepressants
and lithium is associated with increased risk of treatment with antiparkinson drugs: a pharmacoepidemiological
study. J Neurol Neurosurg Psychiatry 77:781, 2006; deLau LM, Breteler MM: Epidemiology of Parkinson's disease.
Lancet Neurol 5:525, 2006; Elble RJ et al: Gait initiation by patients with lower-half parkinsonism. Brain
119:1705, 1996; Goetz CG: Safety of rasagiline in elderly patients with Parkinson disease. Neurology 66:1427,
2006; Hughes, AJ et al: A clinicopathologic study of 100 cases of Parkinson's disease. Arch Neurol 50:140, 1993;
Huse DM et al: Patterns of initial pharmacotherapy for Parkinson's disease in the United States. J Geriatr Psychiatry
Neurol 19:91, 2006; Jankovic, J et al: The evolution of diagnosis in early Parkinson disease. Parkinson Study
Group. Arch Neurol 57:369, 2000; Josephs KA et al: Benign tremulous parkinsonism. Arch Neurol 63:354, 2006;
McNamara P, Durso R: Neuropharmacological treatment of mental dysfunction in Parkinson's disease. Behav
Neurol 17:43, 2006; Mohan K et al: A patient with tremors and breathlessness. Prim Care Respir J 14:47 2005;
Nicoletti, G et al: MR imaging of middle cerebellar peduncle width: differentiation of multiple system atrophy
from Parkinson disease. Radiology 239:825, 2006; Obering CD: Update on apomorphine for the rapid treatment of
hypomobility ("off") episodes in Parkinson's disease. Pharmacotherapy 26:840, 2006; Ondo WG: Essential tremor:
treatment options. Curr Treat Options Neurol 8:256, 2006; Padovani A et al: Parkinson's disease and dementia.
Neurol Sci 27:S40, 2006; Rajput AH et al: Accuracy of clinical diagnosis in parkinsonism-a prospective study.
Can J Neurol Sci 18:275, 1991; Reich, SG: Errors and delays in diagnosing Parkinson’s disease. Ann. Neurol 52:
S84, 2002; Schapira AH: Etiology of Parkinson's disease. Neurology 66:S10, 2006; Taylor Toure J et al: Impact
of second-generation antipsychotics on the use of antiparkinson agents in nursing homes and assisted-living facilities.
Am J Geriatr Pharmacother 4:25, 2006; Temel Y et al: Targets for deep brain stimulation in Parkinson's
disease. Expert Opin Ther Targets 10:355, 2006; Voelker R: Parkinson disease guidelines aid diagnosis, management.
JAMA 295:2126, 2006; Whittington CJ et al: Memory deficits in Parkinson's disease. J Clin Exp Neuropsychol
28:738, 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. For this issue,
Dr. Reich reported nothing to disclose.
Dr. Reich addressed the Current Topics in Geriatrics, held February 9-11, 2006, in Baltimore, MD, and sponsored by
the American Geriatrics Society and the Johns Hopkins University Geriatrics Education Center. The Audio-Digest
Foundation thanks the sponsors and Dr. Reich for their cooperation in the production of this program.
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