Approach to parkinsonism

APPROACH TO
PARKINSONISM
Dr. Shubham Garg
SR Neurology
GMC Kota

INTRODUCTION
• Term Parkinsonism is used to describe a syndrome manifested
by a combination of the following six cardinal features:
(1) tremor at rest,
(2) bradykinesia,
(3) rigidity,
(4) loss of postural reflexes,
(5) flexed posture, and
(6) freezing (motor blocks).
• Idiopathic Parkinson’s disease (IPD) is the most common cause
of parkinsonism.
Bradley's Neurology in Clinical
Practice.2021.8th ed.

PARKINSONISM
ACUTE/SUBACUTE
USUALLY SECONDARY
PARKINSON
DRUGS
TRAUMA
TOXINS
TUMOR
INFECTION
AUTOIMMUNE
PARANEOPLASTIC
CHRONIC
DEGENERATIVE
ATYPICAL
PARKINSON(CBD,
PSP,MSA)
PD
SECONDARY
NPH
VASCULAR
GENETIC
HD
WD
NBIA
YOUNG ONSET

Any approach begins with . . .
1. A good history
2. A good physical exam
3. Keen sense of observation
4. A systematic differential diagnosis

Evaluation of Parkinsonism: History
• Direct motor manifestations of parkinsonism: Bradykinesia,
rest tremor, and rigidity especially if asymmetric with a
postural imbalance in the absence of other neurologic
complaints may suggest a diagnosis of IPD .
• Association of hypokinesia/ bradykinesia with other
neurologic symptoms usually suggests a condition other than
IPD.
• Another useful historical fact in differentiating IPD from other
forms of parkinsonism is the sequence in which otherwise
typical parkinsonian symptoms appear.

BRADYKINESIA
ASYMMETRICAL
UNILATERAL
PD
CBD
BILATERAL
MSA
PSP-P
SYMMETRIC
DRUG INDUCED
PARKINSON
LOWER BODY
PREDOMINANT
VASCULAR
PARKINSONISM
AXIAL>APPENDICULAR
PSP

Causes of hypokinesia (slowness of movement)
Nonneurological
1. Poor eyesight
2. Joint problems
3. Depression, catatonia
4. Chronic diseases (cardiac, respiratory)
Neurological
1. Spasticity
2. Cerebellar disorders
3. Peripheral neuropathy
4. Neuromuscular disorders
5. Muscle diseases
Basal ganglia
1. Parkinson’s disease
2. Parkinson mimics

TREMOR
UNILATERAL
REST
PD
PSP-P
INTENTION
MSA-C
POSTURAL/KINETIC
MSA-P
CBD
BILATERAL
POSTURAL+ FAMILY
HISTORY
ET
REST+ INTENTION
ENHANCED
PHYSIOLOGICAL
TREMOR
MISCELLANEOUS
PILL ROLLING-PD
JERKY-MSA,CBD
WING BEATING-WD
RUBRAL-VP

Rigidity
ASYMMETRIC
APPENDICULAR
PD
AXIAL
PSP
WITH
SPASTICITY
MSA
WITH DYSTONIA
CBD
SYMMETRIC
LOWER BODY
PREDOMINANT
VASCULAR
PARKINSONISM
ABRUPT ONSET
DRUG INDUCED

Postural instability
EARLY
BACKWARD FALL
PSP
MULTIDIRECTIONAL
DLB
LATE
PD
MSA(within 5 yrs)
CBD

Gait in parkinsonism: phenomenology
PD: stooped posture, flexed adducted arms, and loss of arm
swing. Reduced arm swing during gait is often the first
presenting feature of PD. Decreased height and length of step
with a shuffling gait .
MSA: Gait affected throughout the disease course , may be
parkinson or cerebellar type.
PSP: classic phenotype ambulate with an erect posture and
abducted arms .en bloc turning (minimal trunk rotation while
turning around).
VP: characterized by start- and turn hesitation, short steps, a
widened base, and imbalance with an inappropriate postural
response may resemble the abnormal gait of NPH

POSTURAL
ABNORMALITIES
FLEXED POSTURE
CAMPTOCORMIA
STRIATAL HAND
AND TOE
PD
ANTECOLLIS
MSA
ERECT POSTURE
PSP
WITH DYSTONIC
POSTURING
WILSON DISEASE
LATERAL
DEVIATION
PISA SIGN
MSA
WITH DYSTONIC
POSTURING
CBD

FACIES
HYPOMIMIA. REDUCED
BLINK RATE, DROOLING
SALIVA
PD
DIP
ATYPICAL SPONTANEOUS
OR LEVODOPA-INDUCED
DYSTONIA OR DYSKINESIA,
WHICH MAINLY AFFECTS
THE OROFACIAL MUSCLES
MSA
SEVERLY REDUCED BLINK
RATE, PROCERUS SIGN,
MONA LISA FIXITY OF
GAZE,
PSP

SPEECH
HYPOKINETIC
DYSARTHIA
HYPOPHONIC,
MONOTONOUS
PD
quivery, croaky,
strained, high-
pitched speech
MSA
slurred, lower
pitched, growling
quality of speech
PSP
MIXED
DYSARTHIA
hypophonic and
spastic
CBD

OCULOMOTAR
ABNORMALITIES
IMPAIRMENT IN VERTICAL SACCADIC
MOVEMENT. IMPAIRED DOWNWARD
OPTICOKINETIC NYSTAGMUS . SQUARE WAVE
JERKS, CONVERGENCE INSUFFICIENCY,
REDUCED BLINK RATE, EYELID OPENING
APRAXIA AND BLEPHAROSPASM.
PSP
SQUARE WAVE JERKS , OCULAR DYSMETRIA , WITH
NORMAL VELOCITY AND LATENCY, AS WELL AS
NYSTAGMUS
MSA
NYSTAGMUS, CONJUGATE OCULAR PALSY,
SACCADIC ALTERATIONS, AND OCULOGYRIC
CRISES . THE KAYSER–FLEISCHER RING
WILSON DISEASE

Non-motor manifestation
HYPOSMIA May be earliest sign in PD.
Absent in others.
RBD MSA>PD
Autonomic dysfunction Early then MSA
Constipation PD, MSA
Dermatitis, eczema PD
Sensory abnormalities (Pain,
paresthesia, RLS)
PD
Cortical sensory loss-CBD
Mantri S , Morley JF , Siderowf AD. The importance of preclinical diagnostics in Parkinson disease. Parkinsonism Relat
Disord 2019;64:20–8

Cognitive and behavioral disorders
Anxiety and depression PD
Changes in insight,
disinhibition and apathy
PSP
Profound cognitive difficulties PSP, CBD
Executive dysfunction PSP,MSA
Early cognitive decline DLB
Fluctuating cognition and
attention, visual hallucination
DLB
Mantri S , Morley JF , Siderowf AD. The importance of preclinical diagnostics in Parkinson disease. Parkinsonism Relat
Disord 2019;64:20–8

HISTORY
• Response to medications: Absence of benefit from adequate
dosages of dopaminergic drugs, suggests a diagnosis of
secondary causes of parkinsonism or one of the Parkinson-
plus syndromes.
• In IPD, psychiatric and autonomic side effects from
dopaminergic drugs are not uncommon but usually appear
when the illness is at least moderately advanced.
• If dopaminergic drugs produced psychiatric side effects in
early illness such as hallucinations or autonomic symptoms
then it suggest the possibility of DLB, and the latter indicate
MSA.

HISTORY
• Medication usage. Patients must be asked if they are
currently taking or have recently received antidopaminergic
drugs such as neuroleptics, reserpine, or metoclopramide.
• Toxic exposure. Exposure to toxins such as manganese or
carbon monoxide must be ascertained because both can
result in parkinsonism. Less common causes include mercury,
carbon disulfide, methanol, and cyanide.

• Family history. Patients with Mendelian pattern of inheritance
constitute a small minority of the overall Parkinson’s disease
(PD) population.
• Heritable disorders that can mimic PD include Wilson’s
disease (autosomal recessive [AR]), juvenile Huntington’s
disease (HD; autosomal dominant [AD]), and essential tremor
(ET; AD with variable penetrance).

MDS-Unified Parkinson Disease Rating
Scale (MDS-UPDRS)
Parkinsonism — Motor parkinsonism is an essential criterion of PD and requires both
of the following :
• Bradykinesia
• Rest tremor or rigidity
Supportive criteria — Supportive criteria are features that increase confidence in the
diagnosis of PD :
• A clear benefit from treatment with dopaminergic drugs, especially if the response
is dramatic. (Note that tremor may not respond to levodopa in some patients,
though bradykinesia and rigidity should improve.) In the absence of clear
documentation of initial response, a dramatic response can be classified as one of
the following:
Unequivocal and marked on-off fluctuations, which must have at some point
included predictable end-of-dose wearing off.
• The presence of levodopa-induced dyskinesia.
• Rest tremor of a limb (usually unilateral at onset), documented on previous or
current clinical examination.
• The presence of either olfactory loss or cardiac sympathetic denervation on
metaiodobenzylguanidine (MIBG, iobenguane I-123) scintigraphy.

Red flags — Red flags are potential signs of alternate
pathology, though with a low or uncertain specificity:
1. Rapid progression of gait impairment requiring the regular use of a wheelchair within five
years of onset.
2. A complete absence of progression of motor symptoms or signs over five or more years
unless stability is related to treatment.
3. Early bulbar dysfunction: severe dysphonia or dysarthria or severe dysphagia within the first
five years.
4. Inspiratory respiratory dysfunction: either diurnal or nocturnal inspiratory stridor or frequent
inspiratory sighs.
5. Severe autonomic failure in the first five years of disease.
6. Recurrent (more than once a year) falls because of impaired balance within three years of
onset.
7. Disproportionate anterocollis (involuntary flexion of the neck) or contractures of hand or feet
within the first 10 years.
8. Absence of any of the common nonmotor features of PD despite five years disease duration.
9. Otherwise-unexplained pyramidal tract signs, defined as pyramidal weakness or clear
pathologic hyperreflexia (excluding mild reflex asymmetry and isolated extensor plantar
response).
10. Bilateral symmetric parkinsonism. The patient or caregiver reports bilateral symptom onset
with no side predominance, and no side predominance is observed on objective examination.

Absolute exclusion criteria
1. Unequivocal cerebellar abnormalities, such as cerebellar gait, limb
ataxia, or cerebellar oculomotor abnormalities.
2. Downward vertical supranuclear gaze palsy, or selective slowing of
downward vertical saccades.
3. Diagnosis of probable behavioral variant frontotemporal dementia or
primary progressive aphasia within the first five years of disease.
4. Parkinsonian features restricted to the lower limbs for more than three
years.
5. Treatment (currently or within the past year) with a dopamine receptor
blocker or a dopamine-depleting agent in a dose and time course
consistent with drug-induced parkinsonism.
6. Absence of observable response to high-dose levodopa despite at least
moderate severity of disease.
7. Unequivocal cortical sensory loss, clear limb ideomotor apraxia, or
progressive aphasia.
8. Normal functional neuroimaging of the presynaptic dopaminergic
system.

PSP
Basic features for the diagnosis of PSP of any phenotype
and at any stage include mandatory inclusion criteria,
mandatory exclusion criteria, and context-dependent
exclusion criteria .
Mandatory inclusion criteria:
• Sporadic occurrence
• Age 40 years or older at onset of first PSP-related
symptom
• Consider any new-onset neurologic, cognitive, or
behavioral deficit that subsequently progresses during
the clinical course in absence of other identifiable cause
as a PSP-related symptom.

Mandatory clinical exclusion criteria:
1. Predominant, otherwise unexplained impairment of episodic memory, suggestive
of Alzheimer disease.
2. Predominant, otherwise unexplained autonomic failure (eg, orthostatic
hypotension suggestive of multiple system atrophy or Lewy body disease.
3. Predominant, otherwise unexplained visual hallucinations or fluctuations in
alertness, suggestive of dementia with Lewy bodies.
4. Predominant, otherwise unexplained multisegmental upper and lower motor
neuron signs, suggestive of motor neuron disease (pure upper motor neuron signs
are not an exclusion criterion).
5. Sudden onset or step-wise or rapid progression of symptoms, in conjunction with
corresponding imaging or laboratory findings, suggestive of vascular etiology,
autoimmune encephalitis, metabolic encephalopathies, or prion disease.
6. History of encephalitis.
7. Prominent appendicular ataxia.
8. Identifiable cause of postural instability (eg, primary sensory deficit, vestibular
dysfunction, severe spasticity, or lower motor neuron syndrome).

Mandatory imaging exclusion criteria:
• Severe cerebral leukoencephalopathy
• Relevant structural abnormality (eg, normal pressure or obstructive
hydrocephalus; basal ganglia, diencephalic, mesencephalic, pontine
or medullary infarctions, hemorrhages, hypoxic-ischemic lesions,
tumors, or malformations)
Context-dependent imaging exclusion criteria:
• In syndromes with sudden onset or step-wise progression, exclude
stroke, cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL) or severe cerebral
amyloid angiopathy, evidenced by diffusion-weighted imaging
(DWI), fluid attenuated inversion recovery, or T2* MRI
• In cases with very rapid progression, exclude cortical and subcortical
hyperintensities on DWI-MRI suggestive of prion disease

Context-dependent laboratory exclusion criteria:
In patients with PSP-CBS, exclude primary Alzheimer disease pathology (typical
cerebrospinal fluid constellation [ie, both elevated total tau and phospho-tau
protein and reduced beta-amyloid 42] or pathological beta-amyloid PET imaging)
In patients <45 years of age, exclude:
• Wilson disease
• Niemann-Pick disease, type C
• Hypoparathyroidism
• Neuroacanthocytosis
• Neurosyphilis
In rapidly progressive patients, exclude:
• Prion disease
• Paraneoplastic encephalitis (anti-ma2, iglon-5)
In patients with suggestive features (ie, gastrointestinal symptoms, arthralgias, fever,
younger age, and atypical neurologic features such as myorhythmia), exclude
Whipple disease

LABORATORY TEST
CBC/PBF
HEMOLYTIC ANAEMIA WD
ACANTHOCYTES NEUROACANTHOCYTOSIS
BLOOD CHEMISTRY
ABNORMAL LFT WD
HYPOCALCEMIA
LOW PARATHORMONE
HYPOPARATHYROIDSM
ELEVATED CREATINE
KINASE
NEUROACANTHOCYTOSIS
ELEVATED LACTATE AND
LACTIC ACIDOSIS
MITOCHONDRIAL
CYTOPATHIES

INVESTIGATIONS
1. Plain X-rays. Spine X-rays may reveal ankylosing spondylitis or osteoarthritis
as the cause of mechanical limitation of movement.
2. CT or MRI of the brain. CT may demonstrate a neoplasm, stroke,
hydrocephalus, basal ganglia calcification, atrophy, or sequelae of trauma.
3. MRI of the brain is more desirable. Several characteristic MRI patterns that
are suggestive of specific hypokinetic disorders are listed below:
a. Many lacunar strokes. vascular parkinsonism
b. Large ventricles, out of proportion to cerebral atrophy; transependymal
flow: NPH
c. Caudate atrophy. HD
d. Decreased T2 signal in striatum. MSA
e. Homogeneous decreased T2 signal or decreased T2 signal with a central
hyperintensity (Tiger’s eye) in the globus pallidus: NBIA
f. Striatal necrosis. Wilson’s disease, Leigh’s disease, and CO intoxication
g. Midbrain atrophy. PSP
h. Asymmetric frontoparietal atrophy. CBGD

INVESTIGATIONS
PET or SPECT. With modern analysis techniques,
fluorodeoxyglucose PET, by characterizing the regional
cerebral metabolism pattern, can distinguish PD, MSA,
and PSP from one another with >90% accuracy.
• In IPD, either of these two modalities demonstrates a
loss of dopaminergic nigral cells.
• The major clinical usefulness of Ioflupane SPECT is that it
is very accurate in distinguishing IPD from mimicking
conditions that do not involve dopamine-producing cells
such as ET, dystonic tremor, or drug-induced
parkinsonism.

INVESTIGATIONS
1. ECG. Heart block may be present in mitochondrial
cytopathy.
2. EEG. Epileptic activity or focal slowing may appear with
focal lesions (stroke and tumor). Slow background
activity is seen in some primary dementias. Periodic
triphasic complexes may be present in CJD .
3. EMG/nerve conduction studies. Mild nerve conduction
slowing suggestive of axonal polyneuropathy is seen in
neuroacanthocytosis. Myopathic findings on EMG may be
present in cases of mitochondrial cytopathies.

INVESTIGATIONS
CSF analysis. Elevated protein and pleocytosis can be detected in
CNS infections. The presence of high levels of the 14-3-3
protein in CSF is highly suggestive of CJD.
Special diagnostic tests.
1. Wilson’s disease. Low ceruloplasmin, low serum copper,
increased 24-hour urinary copper excretion, and Kayser–
Fleischer ring on slit lamp examination of the cornea are all
suggestive of Wilson’s disease.
2. NPH- Tap test.

INVESTIGATIONS
Genetic testing. Monogenic PD is found in approximately 3% of IPD
patients and mutations in these PD genes are most common in
those with an early age of onset or those belonging to certain
ethnic groups.
• In patients with onset before age 51, almost 20% have a mutation
in one of these genes, most commonly parkin, followed by LRRK2.
• In individuals developing PD under the age of 20, as many as 77%
have a mutation of the Parkin gene. Common AD PD subtypes
include PARK1 (SCNA missense mutation), PARK4 (SCNA
duplications/triplications), and PARK8 (LRRK2 mutation).
• Common AR PD syndromes are PARK2 (parkin), PARK6 (PINK1), and
PARK7 (DJ-1).

Normal Visualization of dopamine
transporters at 123I ioflupane SPECT
and FDG PET
IPD

TAKE HOME MESSAGE
• Careful history taking is essential.
• Past medical and psychiatric history, family history, and occupational or
environmental exposure to toxins will reveal most causes of secondary
parkinsonism.
• Disease onset at a young age, a strong family history, lack of resting
tremor, absent response to levodopa and early appearance of postural
instability, gait disorder, dysautonomia, aphasia, apraxia, supranuclear
gaze palsy, cortical sensory loss, alien limb phenomenon, pyramidal signs
or dementia should be considered red flags in the history suggesting a
diagnosis other than IPD.
• General physical examination is important because it may reveal signs of a
systemic disease that is contributing to secondary parkinsonism.

REFERENCES
1. Bradley's Neurology in Clinical Practice.2021.8th ed.
2. Goldman SM, Tanner C. Etiology of Parkinson's's disease. In: Jankovic J, Tolosa E, editors.
Parkinson's's disease and movement disorders, 6rd ed. Baltimore, MD: Lippincott-Williams
and Wilkins; 2017. p. 133-58
3. Marsden’s book of movemeny disorder.2016
4. Saeed, U., Compagnone, J., Aviv, R.I. et al. Imaging biomarkers in Parkinson’s disease and
Parkinsonian syndromes: current and emerging concepts. Transl Neurodegener 8 (2017).
5. Obeso JA , Stamelou M , Goetz CG , et al Past, present, and future of Parkinson's disease: a
special essay on the 200th anniversary of the shaking palsy. Mov Disord 2017;:1264–310
6. Armstrong MJ , Okun MS . Diagnosis and treatment of Parkinson
disease. JAMA 2020;323:548–60
7. Mantri S , Morley JF , Siderowf AD. The importance of preclinical diagnostics in Parkinson
disease. Parkinsonism Relat Disord 2019;64:20–8
8. Kalia LV . Diagnostic biomarkers for Parkinson's disease: focus on α-synuclein in cerebrospinal
fluid. Parkinsonism Relat Disord 2019;:21–5
9. Niemann N , Jankovic J . Juvenile parkinsonism: differential diagnosis, genetics, and
treatment. Parkinsonism Relat Disord 2019;67:74–89
10. Mehanna R , Jankovic J . Young-Onset Parkinson's disease: its unique features and their
impact on quality of life. Parkinsonism Relat Disord 2019;65:39–48

Features Suggestive of Atypical PD

LABORATORY STUDIES
• IPD. In classical IPD where the diagnosis is strongly suggested
by the history and physical examination, neuroimaging is not
necessary.
• IPD is commonly asymmetric, but if symptoms or signs of
parkinsonism are remarkably asymmetric resulting in severe
involvement on one side , MRI is indicated to evaluate for the
possibility of unilateral structural basal ganglia pathology.

• CT of the brain are usually unremarkable in IPD.
• MRI s/o absent swallow tail” sign.
• A positron-emission tomography (PET) scan shows decreased
fluorodopa uptake in the striatum but no striatal abnormality
in fluorodeoxyglucose scans.

• SPECT can be used to differentiate diseases with striatal
dopaminergic degeneration, namely, IPD and PD-plus
syndromes, from ET, drug-induced parkinsonism, dystonic
tremor, psychogenic parkinsonism, and vascular parkinsonism
without striatal dopaminergic degeneration.
• Transcranial sonography (TCS) is a cost-effective, widely
available technique to visualize cerebral echogenic changes
with high spatial resolution. The finding of substantia nigra
heterogeneity (>20 mm) through the preauricular window is
90% specific for IPD.

CLINICAL FEATURES TAUPATHY SYNUCLEOPATHY
Age of onset 7th 6th
Initial symptoms Postural &gait disorder Tremor & bradykinesia
Family history - +/-
Multi infarct state +/- -
Dementia +/- +/-
Downgaze ophthalmoparesis + -
Eyelid abnormalities + +/-
Pseudobulbar palsy + +/-
Gait Wide,stiff,unsteady Slow
shuffling,narrow,festinating
Rigidity Axial(neck) Generalised

Corticobulbar signs +/- -
Symmetry of findings + -
Weight loss - +
Improvement with DA drugs _ +
Levodopa induced dyskinesias _ +

PD: hypokinetic dysarthria. Patients develop a soft voice with accompanying
slurring
MSA: hypokinetic speech, patients may develop ataxic and, more rarely,
spastic qualities in the voice, resulting in quivery, croaky, strained, high-
pitched speech
PSP: hypokinetic dysarthria, which is commonly associated with spastic
elements, causing a slurred, lower pitched, growling quality of speech.
CBD: dysarthria of a mixed character (hypophonic and spastic). Later stages of
CBD, the peculiar characteristics of apraxic speech (slow speaking rate,
SPEECH
Armstrong MJ , Okun MS . Diagnosis and treatment of Parkinson disease. JAMA 2020;323:548–60

Akinesia/Bradykinesia in parkinsonism:
phenomenology
PD: almost always asymmetrical
MSA: more often asymmetrical than symmetrical, but always
bilateral
PSP: marked axial, minimal appendicular (in classical
Richardson’s syndrome)
CBD: severe and markedly asymmetrical
Vascular: in the classical “lower body” form predominantly
affecting lower limbs, stepwise progression

Tremor in parkinsonism: phenomenology
PD: unilateral or asymmetric pill-rolling rest tremor. A postural/kinetic
component (re-emergent tremor) may also be present
MSA: postural/kinetic tremor frequent (~2/3 of the cases). Often
incorporating myoclonus, that gives it an irregular quality (“jerky postural
tremor”)
PSP: uncommon, only in the PSP-P phenotype
CBD: the common myoclonic jerks of the involved limb(s) can clinically
resemble tremor
DIP: onset is abrupt, both resting and postural tremor, arms>leg, symmetrical.
Subside after ofending drug removed.

IMAGING
Posterior putaminal atrophy with
marginal hyperintensity on T2.
Pontine atrophy with cross like
hperintensity, MCP atrophy and
atrophy of superior vermis.
FDG PET demonstrate
hypometabolism of putamen and
cerebellum
MSA
Atophy of midbrain and superior
cerebellar peduncle and dilation of
third ventricle. Mid-sagittal plane s/o
hummingbird sign and axial images
s/o morning glory sign.
FDG PET images show
hypometabolism in the posterior
frontal lobes and basal ganglia, worse
on the right side .
PSP
Asymmetric frontoparietal atrophy.
Hyperintensity in the subcortical
white matter in the rolandic region on
FLAIR images with asymmetric
atrophy in the cerebral peduncle, and
atrophy in the midbrain tegmentuM
PET scans show reduced
[18F]fluorodopa uptake in the
caudate and putamen and markedly
asymmetrical cortical
hypometabolism, especially in the
superior temporal and inferior
parietal lobe
CBD
h typical PD is usually normal;
but a high-field-strength (1.5 T)
heavily T2-weighted MRI may
show a wider area of lucency in
the SN
FDG PET image shows parietal
and strital hypometabolism
IPD

Approach to parkinsonism

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