Transcript Treatment of Moderate and Advanced Parkinson’s Disease An

Differential Diagnosis of
Parkinsonism
Katie Kompoliti, M.D.
Associate Professor
Movement Disorders Section
Department of Neurological Sciences
Rush University Medical Center
Parkinson’s Disease, Motor Abnormalities
Tremor
Bradykinesia/akinesia
Cogwheel rigidity
Postural instability
Parkinson’s Disease
UKPDS Brain Bank Diagnostic Criteria
 Inclusion criteria parkinsonism
– Bradykinesia
– One of the following
• Muscular rigidity
• Rest tremor
• Postural instability
 Supportive criteria for Parkinson’s
Disease
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Begins on one side
Remains asymmetric
Rest tremor present
Progressive disorder
Responds to levodopa
No atypical features
Balance or falls in first year
Early memory loss
Early hallucinations
Early problems with blood pressure, potency
or urinary symptoms
Pathology of Parkinson’s Disease
DAT Scan to Differentiate Parkinson’s Disease from Essential Tremor
Early Parkinson’s disease
• Early features
– Unilateral rest tremor
– Reduced spontaneous arm swing
– Loss of dexterity in one hand
– Loss of facial expression
– Unilateral foot dystonia (young onset)
– Pain in one shoulder
Advancing Parkinson disease
• Progression of PD
– Increased severity of motor symptoms
– Postural reflex impairment
– Loss of drug effect
– Freezing gait
– Drug side effects
• Motor fluctuations
• Dyskinesias
Parkinsonism, Differential Diagnosis
Primary parkinsonism
Secondary parkinsonism
Parkinsonism plus syndromes
Heredofamiliar diseases
Parkinsonism, Differential Diagnosis
Primary parkinsonism
Secondary parkinsonism
Parkinsonism plus syndromes
Heredofamiliar diseases
Primary Parkinsonism
Dopa-responsive dystonia
Idiopathic Parkinson’s disease
Juvenile parkinsonism
Juvenile Parkinsonism
Onset before 21
Heterogeneous disorder
In most cases distinct from IPD
Dystonia
Sporadic or autosomal recessive
Autosomal recessive
chromosome 6q, Parkin (Park 2)
no Lewy bodies
Dopa-Responsive Dystonia
Not a degenerative disease
GTP-cyclohydrolase I gene
Clinical features
abnormal gait
focal limb dystonia
scoliosis
rest or postural tremor
bradykinesia
rigidity
diurnal fluctuation
Normal PET or SPECT scans
Levodopa responsive
Parkinsonism, Differential Diagnosis
Primary parkinsonism
Secondary parkinsonism
Parkinsonism plus syndromes
Heredofamiliar diseases
Secondary Parkinsonism
Drugs
antipsychotics, anti-emetics, tetrabenazine, reserpine, alpha-methyl-dopa,
calcium channel blockers
Hemiparkinsonism-hemiatrophy syndrome
Hydrocephalus
Infectious
encephalitis lethargica, HIV, fungal, syphilis, SSPE, prion disease
Metabolic
symptomatic basal ganglia calcification/parathyroid abnormalities, acquired
hepatolenticular degeneration
Neoplastic
Psychogenic
Toxins
MPTP, CO, Mn, cyanide, carbon disulfide, Hg, methanol
Traumatic
Vascular
Vascular Parkinsonism
• Parkinsonism
• Acute onset, stepwise
progression
• Early gait/balance
– “lower body”
• Cognitive impairment
• Urinary incontinence
• Corticospinal or
pseudobulbar signs
Zijlmans JC et al. (2004), Mov Disord 19(6):630-640
Vascular Parkinsonism
Drug-Induced Parkinsonism
Drugs
neuroleptics, anti-emetics, tetrabenazine, reserpine, alphamethyl-dopa, calcium channel blockers, lithium, depakote
Reversible
Varies with:
drug class, potency, dosage, length of treatment
Treatment:
discontinuation of offending agent
switching to atypical neuroleptics
anticholinergics, amantadine, sinemet?
Infectious Parkinsonism
Encephalitis lethargica
HIV
Fungal
Syphilis
SSPE
Prion disease
Subacute Sclerosing PanencephalitisSSPE
Progressive disorder 2-10 years after measles
Cognitive, behavioral abnormalities, myoclonus,
parkinsonism, coma, death (1-3 yrs)
EEG periodic complexes
High Ab titers in serum and CSF
Atrophy, neuronal loss, lymphocytic infiltration,
demyelination, gliosis, NFTs
Nuclear oligodendroglial inclusions, staining for viral
Ag (NP and HA proteins)
Periodic bursts of high-amplitude, slow-wave complexes with normal background rhythm
Transmissible Spongiform
Encephalopathy
Sporadic CJD, % of cases with MD
Cerebellar 70%
Myoclonus 80%
Extrapyramidal 56%
Other (including tremor) 36%
Brown P. Ann Neurol 1994
Transmissible Spongiform
Encephalopathy
Psychogenic Parkinsonism
Not as frequent
Maximal disability at onset
Rigidity: voluntary resistance, no cogwheeling, distractible
Bradykinesia: no fatiguing component
Gait: atypical, arm held tightly to the trunk, exaggerated
response to pull test
Tremor: same at rest, posture action, variability, distractibility,
entrainment
CAUTION: Psychogenic parkinsonism has a high incidence
of underlying Parkinson’s disease
Carbon Monoxide-Induced Parkinsonism
Long-term exposure or severe acute exposure
Parkinsonism days to weeks later
Two thirds complete recovery
Other neurological manifestations
memory impairment, confabulations
emotional lability
apraxia, agnosia
stupor, coma
hyperreflexia
homonymous hemianopia
vestibular dysfunction
Carbon Monoxide-Induced Parkinsonism
Parkinsonism, Differential Diagnosis
Primary parkinsonism
Secondary parkinsonism
Parkinsonism plus syndromes
Heredofamiliar diseases
Parkinsonism plus syndromes
Cortico-basal degeneration
Dementia syndromes
AD, DLB, fronto-temporal degeneration
Multiple system atrophy
OPCA
Shy-Drager
striato-nigral degeneration
Parkinsonism-dementia-ALS complex
Progressive pallidal, pallidonigral and pallidoluysionigral degeneration
Progressive supranuclear palsy
Parkinsonism
• Synucleinopathy
– Parkinson’s Disease
– MSA
– Dementia with Lewy bodies
• Tauopathy
– PSP
– CBD
– Frontotemporal dementia
Multiple System Atrophy
Core Features
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Autonomic dysfunction
– Orthostatic hypotension
– Urinary incontinence
– Erectile dysfunction
Parkinsonism
– Poor levodopa response
Cerebellar dysfunction
– Gait ataxia/limb ataxia
– Dysarthria
– Gaze evoked nystagmus
Corticospinal abnormalities
– Hyperreflexia
– extensor plantar responses
Litvan I (2003), Mov Disord 18(5):467-486; Weiner WJ (2005), Rev Neurol Dis 2(3):124-131
Dementia with Lewy Bodies
Core features
• Parkinsonism
• Dementia
– Within 1 year of onset
• Fluctuating cognition
• pronounced variation
in attention and
alertness
Cortical Lewy Bodies
• Recurrent visual
hallucinations
Litvan, Mov Disord 2003;5:467-486
Ubiquitin
Immunocytochemistry
Progressive Supranuclear Palsy
Core Findings
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Progressive disorder
Age onset > 40
Often symmetric at onset
Falls in the first year
Vertical supranuclear gaze palsy
Dysarthria
Minimal levodopa response
Cognitive and behavioral problems
Litvan, Mov Disord 2003;5:467-486
Progressive Supranuclear Palsy
Gradually progressive parkinsonism, ≥ 40 yrs plus:
Possible:
vertical supranuclear palsy or slow vertical saccades
+ falls < 1 yr of disease onset
Probable:
vertical supranuclear palsy and
falls < 1 yr of disease onset
Definite:
All criteria for possible or probable plus
histopathological confirmation
NINDS diagnostic criteria for PSP
Corticobasal Degeneration
• Asymmetric Parkinsonism
• Other movement disorders
– Dystonia
– Stimulus sensitive myoclonus
– Action-postural tremor
• Higher cortical dysfunction
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Dementia
Aphasia
Apraxia
Cortical sensory loss
Alien limb syndrome
Parkinsonism, Heredofamiliar diseases
Ceroid lipofuscinosis
Familial basal ganglia calcification (Fahr’s disease)
GM1 gangliosidosis
Gaucher’s disease
Hallervorden Spatz disease
Huntington’s disease
Mitochondrial encephalopathies
Chorea acanthocytosis
Spinocerebellar ataxia
Wilson’s disease
X-linked dystonia-parkinsonism (Lubag)
Premutation carriers of fragile X chromosome
Fragile X Premutation
Carriers of premutation alleles (55-200
CGG)
Mild cognitive/behavioral deficits
Premature ovarian failure
Progressive tremor, ataxia, parkinsonism,
autonomic dysfunction ± peripheral
neuropathy, memory, executive impairment
Wilson’s Disease
Children:
tremor, dystonia, rigidity, postural
instability, dysarthria, ataxia,
mental/behavioral changes,
seizures, sardonic smile
Adults:
parkinsonism, dystonia, tremor,
psychiatric symptoms (1/3)
X-linked Dystonia-Parkinsonism (Lubag)
Men from the island of Panay
th th
4 -5 decade (as early as adolescence)
Parkinsonism, action tremor, dystonia
Poor response to levodopa
Neuronal loss in caudate, putamen, no LBs
DYT3, Xq13.1
Juvenile Huntington’s
Very high repeat length, paternal transmission
Westphal variant
bradykinesia
rigidity
tremor
dystonic posturing
ataxia
seizures
myoclonus
mental regression
Summary
• Parkinsonism is a clinically defined
syndrome.
• Parkinson’s disease is the most frequent
cause of parkinsonism
– In life, defined by clinical findings
– No diagnostic laboratory/imaging tests
• Parkinsonism can occur as a part of many
other disorders