1. Differential Diagnosis of Parkinsonism
Katie Kompoliti, M.D.
Associate Professor
Movement Disorders Section
Department of Neurological Sciences
Rush University Medical Center

2. Parkinson’s Disease, Motor Abnormalities
Tremor
Bradykinesia/akinesia
Cogwheel rigidity
Postural instability
Parkinson disease is the most recognized of the movement disorders. Typically occurring in older indviduals, it is diagnosed clinically. The cardinal manifestations of Parkinson disease include the rest tremor, bradykinesia or slowness of movement and akinesia or lack of movement, muscle rigidity with a ratchety component, called cogwheeling and in advanced Parkinson disease, postural reflex impairment which causes difficulties with balance and falling. The gentleman shown in this slide has the typical posture of a patient with Parkinson disease. His posture is stooped, his elbows slightly flexed. He has a masked face and is walking slowly with a shuffle.

3. 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
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

5. Pathology of Parkinson’s Disease
On the left top is a picture of a normal midbrain with abundant pigmentation of the substantia nigra. Below that is the midbrain from a Parkinson’s disease patient with the substantia nigra depigmented. The second set at the top is the microscopic section of normal substantia nigra. Below that is the section from substantia nigra of a Parkinson’s patient. It shows profound loss of pigmented neurons and gliosis. On the extreme right is a pigmented neuron containing a Lewy body inclusion. The Lewy body is characterized by dense pink center and light pink periphery. Together, the loss of substantia nigra dopaminergic neurons and the presence of Lewy body inclusions are regarded as the hallmark of idiopathic Parkinson’s disease pathology.

6. DAT Scan to Differentiate Parkinson’s Disease from Essential Tremor

7. 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

8. 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

9. Parkinsonism, Differential Diagnosis
Primary parkinsonism
Secondary parkinsonism
Parkinsonism plus syndromes
Heredofamiliar diseases

10. Parkinsonism, Differential Diagnosis
Primary parkinsonism
Secondary parkinsonism
Parkinsonism plus syndromes
Heredofamiliar diseases

11. Primary Parkinsonism Dopa-responsive dystonia
Idiopathic Parkinson’s disease
Juvenile parkinsonism

12. 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

13. 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
GTP cyclohydrolase is the enzyme that is responsible for the synthesis of tetrahydrobiopterin, an important cofactor of TH

14. Parkinsonism, Differential Diagnosis
Primary parkinsonism
Secondary parkinsonism
Parkinsonism plus syndromes
Heredofamiliar diseases

15. 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

16. Vascular 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):

17. Vascular Parkinsonism
GTP cyclohydrolase is the enzyme that is responsible for the synthesis of tetrahydrobiopterin, an important cofactor of TH

18. Drug-Induced Parkinsonism
Drugs
neuroleptics, anti-emetics, tetrabenazine, reserpine, alpha-
methyl-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?

19. Infectious Parkinsonism
Encephalitis lethargica
HIV
Fungal
Syphilis
SSPE
Prion disease

20. Subacute Sclerosing Panencephalitis-SSPE
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)
Post-infectious encephalomyelitis (2 wks post acute infection)
Subacute neasles encephalitis (1-9 months after acute infection), immunosuppressed patients
Nuclear inclusions formed in oligodendroglia (in acute encephalitis also seen in neurons and astrocytes)
Ultrastructurally the nucleus is filled with rod- or spiral-shaped tube-like structures representing the nucleocapsid of measles virus

21. Periodic bursts of high-amplitude, slow-wave complexes with normal background rhythm
Electroencephalogram (EEG) at the time of presentation in the neurology clinic (A) and 3 months later
(B). The initial EEG (A) reveals periodic bursts of high-amplitude, slow-wave complexes. (Onset of the complexes
is indicated by solid arrows; offset, by open arrows.) The background rhythm is normal, except for bifrontal
slowing. This “burst-suppression” pattern is highly characteristic of subacute sclerosing panencephalitis

22. Transmissible Spongiform Encephalopathy
Sporadic CJD, % of cases with MD
Cerebellar 70%
Myoclonus 80%
Extrapyramidal 56%
Other (including tremor) 36%
Brown P. Ann Neurol 1994
Proposed conversion of normal to pathological isoform of prion protein. Strings denote unstructured regions, coils denote alpha-helical structure, ribbons denote beta-sheet structure. Note reduction of alpha helical structure and conversion to beta-sheet structure
With the exception of cerebellar, the others are rare early in the disease

23. Transmissible Spongiform Encephalopathy

24. 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
GTP cyclohydrolase is the enzyme that is responsible for the synthesis of tetrahydrobiopterin, an important cofactor of TH

25. 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

26. Carbon Monoxide-Induced Parkinsonism
Carbon monoxide poisoning: Acute CO poisoning causes a cherry red discoloration of the brain and can also cause necrosis of the globus pallidus, as seen in this slide.

27. Mov Disord Sep;9(5):550-8.
Neurological sequelae following carbon monoxide poisoning clinical course and outcome according to the clinical types and brain computed tomography scan findings.
Lee MS, Marsden CD.
Department of Neurology, Yongdong Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
Abstract
The prognosis for patients who survive carbon monoxide (CO) poisoning is uncertain, particularly in those who develop persistent neurological complications after recovery from the initial coma. Thirty-one patients with the sequelae of CO poisoning, followed for a year, are described. Eight had a progressive course, and 23 had a delayed relapse after an initial recovery period of approximately 20 days (range, 1-36 days). Those with a progressive course developed a persistent akinetic-mute state, and four of the eight died. Those with the delayed relapsing course either developed a parkinsonian state with behavioral and cognitive impairment but could walk (nine cases), or progressed further to an akinetic-mute state, and were bed-bound (14 cases); the deterioration to either condition occurred rapidly over a few days to a week. Fourteen of the patients with the delayed relapses (61%) subsequently improved, but three (13%) died. Those with a progressive course without initial recovery were younger (mean age, 37.0 years) than those with a delayed relapsing course (55.2 years; p < 0.01). The mean duration of their initial coma (9.8 days) was longer than that in delayed relapsing cases (2.0 days; p < 0.01). The mean initial CO hemoglobin level was not different in the two groups. Brain computed tomography (CT) scans were obtained at the onset of sequelae in both groups. Ten patients had a normal CT scan, 13 had white matter low-density lesions, and four had globus pallidus low-density lesions.
Yonsei Med J Jun 30;45(3):363-6.
Chorea following acute carbon monoxide poisoning.
Park S, Choi IS.
Department of Neurology, Yonsei University College of Medicine, 134, Shinchon- dong, Seodaemoon-gu, Seoul , Korea.
The clinical cases of 6 patients suffering with chorea after acute carbon monoxide (CO) poisoning were reviewed. There were 2 men and 4 women, and the age at onset ranged from 11 to 60 (mean 33.0) years. All the patients except one were associated with mild delayed CO encephalopathy. The latency period between CO poisoning and the onset of chorea was 10 to 30 (mean 21.7) days. The duration of chorea after CO poisoning was 14 to 90 (mean 39.8) days. The brain CT findings were bilateral low- density lesions in the basal ganglia and/or in the white matter of the cerebral cortex, and there was no correlation between the lesion sites on the imagings and the development of chorea. Neuroleptic agents alleviated the chorea and the patients did not relapse after neuroleptic agents were halted.

29. Parkinsonism, Differential Diagnosis
Primary parkinsonism
Secondary parkinsonism
Parkinsonism plus syndromes
Heredofamiliar diseases

30. 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 pallidoluysio-
nigral degeneration
Progressive supranuclear palsy

31. Parkinsonism Synucleinopathy Parkinson’s Disease MSA
Dementia with Lewy bodies
Tauopathy
PSP
CBD
Frontotemporal dementia

32. Multiple System Atrophy Core Features
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): ; Weiner WJ (2005), Rev Neurol Dis 2(3):

34. Dementia with Lewy Bodies Core features
Parkinsonism
Dementia
Within 1 year of onset
Fluctuating cognition
pronounced variation in attention and alertness
Recurrent visual hallucinations
Cortical Lewy Bodies
Ubiquitin Immunocytochemistry
Litvan, Mov Disord 2003;5:

35. Progressive Supranuclear Palsy Core Findings
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:

36. 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

38. Corticobasal Degeneration
Asymmetric Parkinsonism
Other movement disorders
Dystonia
Stimulus sensitive myoclonus
Action-postural tremor
Higher cortical dysfunction
Dementia
Aphasia
Apraxia
Cortical sensory loss
Alien limb syndrome

40. 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

41. Carriers of premutation alleles (55-200 CGG)
Fragile X Premutation
Carriers of premutation alleles ( CGG)
Mild cognitive/behavioral deficits
Premature ovarian failure
Progressive tremor, ataxia, parkinsonism, autonomic dysfunction ± peripheral neuropathy, memory, executive impairment
Fragile X chromosomes are characterizied by satellite regions visible at the ends of metaphase chromosomes. These are due to a long series of CGG triplet repeats, as seen in Giemsa-stained (left) and scanning electron micrograph (right) material. Fragile X is associated with Martin-Bell Syndrome, the most common form of inherited mental retardation
eosinophilic intranuclear inclusions
Symmetric T2 hyperintensities in MCP
1/3 of male carriers over 50
Protection due to random X inactivation of the premutation allele

42. Children: Adults: Wilson’s Disease
tremor, dystonia, rigidity, postural instability, dysarthria, ataxia, mental/behavioral changes, seizures, sardonic smile
Adults:
parkinsonism, dystonia, tremor, psychiatric symptoms (1/3)

43. X-linked Dystonia-Parkinsonism (Lubag)
Men from the island of Panay
4th-5th decade (as early as adolescence)
Parkinsonism, action tremor, dystonia
Poor response to levodopa
Neuronal loss in caudate, putamen, no LBs
DYT3, Xq13.1

44. Juvenile Huntington’s
Very high repeat length, paternal transmission
Westphal variant
bradykinesia
rigidity
tremor
dystonic posturing
ataxia
seizures
myoclonus
mental regression

45. 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