AKINETIC RIGID SYNDROMES

& IPD
Prof Dr.B.P.SHELLEY, MBBS,MD,DM,FRCP Edin

PEOPLE WITH PD

Michael J Fox

Michael J Fox Foundation

for Parkinsons Research
USA

Muhammad Ali

Pope John Paul II

Muhammad Ali Parkinson

Research Center, USA

HISTORICAL PERSPECTIVES

Home of Parkinson,
Hoxton Square, London

STAY HUNGRY [curiosity; critical thinking, self directed learning]

STAY FOOLISH [ thirst for knowledge]
'One thing I only know, & that is, I know nothing' Socrates

AN ESSAY ON THE SHAKING PALSY

"Involuntary tremulous motion, with lessened muscular

power, in parts not in action and even when supported;
with a propensity to bend the trunk forwards, and to pass
from a walking to a running pace: the senses and intellect
being uninjured."

la maladie de Parkinson ;Jean Martin Charcot

recognised the significance of James Parkinsons
work, almost 60 years later

HISTORICAL MILESTONES

1817: An essay on the shaking palsy

Paralysis agitans
19th century: maladie de Parkinson Charcot
1919: discovery of SN pathology
1957: Carlsson et al (Lund, Sweden) discovered dopamine
1960: Ehringer & Hornykiewicz: discovered that striatal dopamine
concentrations are markedly reduced
1961:Birkmayer & Hornykiewicz: First trials in PD; the L-3,4
dihyroxyphenylalanine (DOPA) effect in Parkinson akinesia
1968-1969: Oral LD in Parkinson disease
2000: Carlsson; Nobel Prize in Medicine

WORLD PARKINSONS DAY

11th APRIL

1990 American drama film based on the

British neurologist Oliver Sacks true story of
the beneficial effects of the then-new drug LDopa when given to catatonic patients who
survived the 1917-1928 epidemic of
encephalitis lethargica.
The film was nominated for three Academy
Awards including the Academy Award for
Best Picture, The Academy Award for Best
Adapted Screenplay, and the Academy
Award for Best Actor (Robert De Niro).
Robin Williams was also nominated at the
48Th Golden Globe Awards for Best Actor in a
Motion Picture Drama.

WHAT IS PARKINSONS DISEASE

Progressive neurodegenerative disorder Hypokinetic movement disorder

Initially described by Dr.James Parkinson in 1817

Degeneration and progressive loss of dopamine producing neurons in the mid brain
and substantia nigra pars compacta

Loss of pigmented cells in the substantia nigra (neuromelanin)

For clinical PD to manifest, at least 60 to 80% % of neuronal loss must be evident

dopamine levels decrease ; Ach / Glutamate levels imbalance

Pathological marker Brain stem eosinophilic intracytoplasmic inclusions called

Lewy Bodies (Proteinopathy-Synucleinopathy/Aggregopathy)

Parkinson's disease affects mainly the elderly - >50 yrs; peaks after 60yrs

M:F 3:2 ;1% population > 50 years old ; 14.9% at age 65-74; 52.4% at age > 85

Internationally: Overall incidence of PD is about 10- 20 cases per 100,000 population

per year. Prevalence: 190 per 100,000

PARKINSONIAN DISORDERS
Classificatory Approaches
Common denominator TRAP
Akinetic Rigid Syndromes: Collective umbrella term-denoting diverse
heterogeneous etiologies that produce parkinsonism
Idiopathic parkinsonism (IPD, Primary PD; Typical
Parkinsonian
Syndrome)
Non idiopathic parkinsonism (Atypical Parkinsonian
Syndromes)
Symmetrical neurodegenerative disorders (MSA; PSP)
Asymmetrical neurodegenerative disorders (CBS/CBD)
PD Plus Syndromes: PD features (TRAP) + Additional Neurological
System Involvement (MSA-MSA -P; MSA -C; MSA -A)
Secondary parkinsonism (Drugs, Toxins, Metabolic, Infectious, Post
Infectious, Autoimmune, BG lesions/tumours; Trauma; Psychogenic)
Genetic PD Familial Parkinsonism
Cortical & Subcortical Parkinsonism

PARKINSONISM

Parkinsonism = Parkinsonian syndrome = Akinetic-rigid

syndrome
Parkinsons Disease = Idiopathic Parkinsons disease [80%]
Neurodegenerative
Progressive Supranuclear Palsy (PSP)
Multiple System Atrophy (MSA)
Cortical Basal Ganglionic Degeneration (CBGD/CBS)
AD with PD, DLBD, FTD-PD,CJD
Hereditary Wilsons disease, Huntingtons disease
Post-Encephalitic Parkinsonism
NPH
Vascular PD
Post head trauma - boxers
Drugs and Toxins CO, MPTP, Mn
Metabolic Hypoparathyroidism, BGC
Tumours

PARKINSONS DISEASE SUBTYPES

Idiopathic Parkinsons disease Primary (unknown origin)
Parkinsonism Secondary (known origin) drugs, stroke, trauma
Familial /Genetic/Mendelian (15-20%) (genetic origin)
PARK 1 PARK 10 (AR) / Alpha Synuclein gene (SNCA
gene:1997)
LRRK2 gene (AD)
PINK1 gene (AR)
Early onset/Young onset PD (age: 21-40 yrs)
Juvenile PD (age < 20 yrs)
Premotor Parkinson Disease

DOPAMINE DEFICIENCY

Subclinical hypodopaminergic
state
Loss of 80-90% of DA neurons before symptoms present
(roughly 20 years) Concept of Premotor Parkinsons
Disease

DA neuronal loss
Loss of dopaminergic input to Striatum
Neuronal death observed in Substantia Nigra (Pars
Compacta) and the Nigrostriatal pathway
DA content decrease in extra pyramidal motor areas of basal
ganglia Caudate and putamen

CONCEPT OF PREMOTOR PD

Clinical, neuroimaging, and pathologic studies have provided

data suggesting that a variety of nonmotor symptoms can
precede the classic motor features of PD by years and,
perhaps, even decades
Braak et al. Hypothesis: Synuclein pathology (Lewy bodies
and neurites) in PD starts in the lower brainstem and
progresses following a predictable caudal-rostral pattern, only
reaching the SN in the mesencephalon only after extensive
involvement of the brainstem
prenigral stage
PreMotor PD: can antedate the classic motor features
of PD.
Early presymptomatic diagnosis; role of neuroprotective therapy
/disease modifying agents is possible if premotor PD is
recognized

SURROGATE MARKERS: DIAGNOSIS OF

INCIPIENT/PRODROMAL/PRECLINICAL NEURODEGENRATIVE
DISORDERS

PD at Risk Syndrome (PARS)

Lower brainstem synucleinopathy (medulla; DMN) Mesencephalic

synucleinopathy SN pathology and clinical parkinsonism [caudal-to-rostral
progression]
Braak 1 & 2 Presymptomatic ( Medulla, pontine tegmentum, olfactory bulb) ; Braak 3
& 4-SN & BFB stage; Braak 5 & 6-Neocortex involvement
Braak and colleagues, 2003

At the top of the pyramid is Clinical PD,

including individuals who meet
formal research criteria for PD. At the second
level, is the Prediagnostic category, in which
patients have classic PD symptoms and
clinical features but do not fulfill PD
diagnostic criteria at the next level. Patients
with Premotor PD have nonmotor symptoms
such as decreased sense of smell,
depression, and various gastrointestinal and
other systemic features, which have been
shown to predate PD. Preclinical PD refers
to characteristic neuroimaging abnormalities
involving the dopamine pathways as
visualized on SPECT and [18F]-fluorodopa
PET in the absence of motor and nonmotor
clinical features. Prephysiologic patients
have no evidence suggestive of PD but
possess traits, such as a genetic mutation,
which confer a high risk of developing PD in
the future.

AETIOLOGY - PD
Genetic hypothesis
Environmental
Hypothesis
MPTP Hypothesis Mt
damage
Genes Parkin, Alpha
Synuclein
Free radicals
Inflammatory
Oxidative stress
Apoptosis

Are you sure about this? It seems odd that a pointy head and
long beak is what makes birds fly.

Environment
vs. Genetics

THE CAUSE OF PARKINSONS DISEASE

UNKNOWN
Post encephalitic 1914-1918
Age age related changes in the nigrostriatal DA pathways
Genes Parkin gene / Alpha Synuclein gene mutations
(YOPD / EOPD)/Other candidate genes;Twin studies
Environmental factors toxins (MPTP),
herbicides, pesticides, solvents,
Non genetic factors - smoking, coffee, milk (Neurology 2005
Mar 22;64(6):1047-51).
Gene-Environmental interaction
Genetic susceptibility to environmental factors
Metabolic dysfunction mitochondrial oxidative stress & free
radical injury

NEUROANATMICAL SUBSTRATE
FOR PARKINSONS DISEASE
THE BASAL GANGLIA
&
SUBCORTICAL MOTOR CIRCUITS

Basal Ganglia
1. Neostriatum
Caudate nucleus
Putamen
Ventral striatum (nucleus accumbens)

2. Paleostriatum
Globus pallidus external segment (GPe)
Globus pallidus internal segment (GPi)

3. Substantia Nigra

Pars compacta (SNc)

Pars reticulata (SNr)

4. Subthalamic nucleus (STN)

What do the basal ganglia do?

Basal ganglia are involved in generation of
goal-directed voluntary movements:
Motor learning
Motor pattern selection

COMPONENTS OF BASAL GANGLIA

STRIATUM
Caudate Nucleus, Putamen, Nucleus Accumbens
SUBSTANTIA NIGRA
Pars compacta, Pars reticulata
SUBTHALAMIC NUCLEUS
GLOBUS PALLIDUS

Neural structures involved in the control of movement

MID BRAIN
C

Gp

ACh

St

DA
MB

SNpc

Midbrain
DA

Pigmented neuron SN pc
Lewy Body

MOTOR LOOPS

Cortico-Striato-Pallido-Thalamo-Cortical loop
Striato-Nigral & Nigro-Striatal loop
Striato-Pallido-Thalamo-Striatal loop

BG CIRCUITS DIRECT & INDIRECT PATHWAY

FUNCTIONAL ORGANISATION

NORMAL BG
DA,Glutamate,GABA

BG in Parkinsons Disease
overactive indirect pathway -
excitatory outflow to thalamus
cortex inhibited (A I R)

NEUROPATHOLOGY OF PARKINSONS
DISEASE

PD NEUROPATHOLOGY

SNpc pigmented DA neuronal drop out

NEUROPATHOLOGY HALL MARK

Intracytoplasmic Eosinophilic inclusions in SNpc neurones

Spherical bodies
8-30m,eosinophilic hyaline core
Pale staining peripheral halo

Normal number of
SN pc pigmented
neurones

Loss of pigmented
neurones in PD

PD NEUROPATHOLOGY
LEWY BODY (Frederic Lewy; 1912)

Alpha synuclein stain (Brown)

Lewy bodies are absent in some genetic PD; Parkin, LRRK2 gene mutations; alpha
synuclein pathology-Lewy bodies/neurites involve LC NE system; 5HT raphe nucleus;
Ach substantia innominata & peripheral nervous system (extra-nigral pathology)

[F-18]-fluorodopa (FD)-PET study in a normal individual (left panel) and a patient

with PD (right panel).
In PD, there is a marked reduction in striatal FD uptake, which tends to be asymmetric
and most prominent in the posterior putamen

CLINICAL FEATURES
A CLINICAL SYNDROME

CARDINAL SYMPTOMS
TRAP

Bradykinesia
Slowness and poverty of movement; planning, initiation, sequencing,
execution of movements; cortical and subcortical systems regulating the
kinematic/ballistic parameters of movement are impaired (putamen/GP);
results in reduction of muscle force at initiation of movement; EMGmultiple agonist bursts are needed to energize the appropriate muscles to
accomplish large fast movements

Cogwheel rigidity
Resting tremor
Involves hands, lips, chin, jaw, legs; head/neck, voice not involved Abates
during voluntary movement [ 30% - no tremor]

Postural instability
Impairment of postural balance, righting/postural reflexes; gait
disturbances shuffling gait (PGID)

PARKINSONS DISEASE S/S

Bradykinesia: problems with planning, initiation, and executing

motor movements [finger taps, hand grips, hand pronationsupination, heel taps]
Rest tremors: unilateral [increases at rest and on walking]
Rigidity: passive flexion, extension, rotation around a joint;
Proximal (neck, shoulders, hips); Distal (wrists, ankles)
Reinforcing maneuvers: Froments maneuver
Postural instability; axial rigidity, striatal hand, striatal toe,
pseudorheumatoid hand, dropped head (extreme neck flexion),
bent spine (camptocormia-truncal flexion of thoracolumbar spine),
Pisa syndrome (tilting of the trunk while sitting or standing)
Freezing: start hesitation, turn hesitation, hesitation in tight
quarters, destination hesitation, open space hesitation
Primitive release reflexes: Mayersons reflex: breakdown of frontal
lobe inhibitory mechanisms

BRADYKINESIA
Bradykinesia : akinesia, hypokinesia
Bradykinesia describes the slowness of a performed movement
Akinesia refers to a poverty of spontaneous movement (e.g. in
facial expression) or associated movement (e.g. arm swing
during walking).
Akinesia: freezing and the prolonged time it takes to initiate a
movement.
Hypokinesia refers to being slow and the movements are also
smaller than desired, as in the micrographia of patients'
handwriting.

PD SECONDARY SYMPTOMS

Hypomimia, decreased facial expression

Micrographia, difficulty in handwriting
Decreased blink rate
Hypophonia, Monotonous speech, dysarthric
Festination, Shuffling gait, Stooped posture, decreased arm
swing
Unilateral weakness rigidity,stiffness in an extremity
Drooling of saliva (Sialorrhea)
Decreased sense of smell
Neuropsychiatric symptoms depression [30-60%; approx
58%], PD dementia [PDD:20-30%] , apathy (54%), anxiety
(49%) , hallucinations (44%), psychosis (Aarsland D, 2007)

NON MOTOR SYMPTOMS (NMSs)

Extra nigral pathologic involvement in PD

Cognitive deficiencies: Bradyphrenia, Dementia [PDD]

Behavioural and Neuropsychiatric disorders
Depression, Psychosis, Anhedonia, Apathy, Anxiety,
Hallucinations; OCB, Impulsive behaviour, Compulsive
shopping, pathological gambling, hypersexuality
Olfactory dysfunction (smell and taste)
Sleep disturbance excessive daytime sleepiness [EDS]; sleep
onset REM [SOREM]; syndrome of sudden sleep [SOS]; RBD
Restless Leg Syndrome [RLS]
Fatigue
Sensory abnormalities: Pain, paraesthesia
Bowel and bladder problems; autonomic dysfunction
Sexual dysfunction; ERD

Hedonistic homeostatic
dysregulation
Obsessivecompulsive and impulsive behaviour:
craving (especially for sweets), binge eating,
compulsive foraging, hypersexuality, pathological
gambling, compulsive shopping and punding,
characterised by intense fascination with
repetitive handling, examining, sorting and
arranging of objects (Miyasaki JM, 2007)

SLEEP DISORDERS

RBD: yelling, swearing, grabbing, punching, kicking,

jumping and other dramatic, violent and potentially
injurious motor activity which may involve the bed partner
Sleep fragmentation; excessive sleepiness, fatigue, sleep
attacks
Related to a 50%loss of hypocretin (orexin) neurons

SENSORY ABNORMALITIES

Olfactory dysfunction, pain, paresthesia, akathisia, oral

pain and genital pain
Early marker of PD: olfactory dysfunction (hyposmia); it
correlated with a 10% increased risk for the disease 2 years
later compared with other asymptomatic relatives
Olfactory dysfunction: neuronal loss in the corticomedial
amygdala and/or decreased dopaminergic neurons in the
olfactory bulb
Pennsylvania Smell Test

AKINETIC RIGID SYNDROMES

Multisystem atrophies

Striatonigral degeneration

Olivopontocerebellar atrophy

Shy-Drager syndrome

Hereditary disorders

Wilson's disease
Huntington's disease (rigid variant)

Hallervorden-Spatz disease

Spinocerebellarnigral degeneration

Other degenerative diseases

Progressive supranuclear palsy

Senile parkinsonism

Alzheimer's disease

Primary pallidal atrophy of Hunt

Corticobasal ganglionic degeneration

PD-ALS-dementia complex of the
Western Pacific

Pick's disease

Rett syndrome
Hemiatrophy-hemiparkinsonism

Disorders with a definable cause

CNS disorders
Hydrocephalus
Binswanger's disease
Brain tumors
Arteriovenous malformations
Posttraumatic encephalopathy
Anoxic encephalopathy
Multiple cerebral infarctions
Infectious disorders
Postencephalitis lethargica
Postviral encephalitis
Metabolic disorders
Hypoparathyroidism
Recurrent hepatic coma
Disorders due to exposure to toxins or
medication
Toxins: Manganese, Carbon monoxide, Cyanide
Carbon disulfide,Methanol, MPTP
Medications: Neuroleptics, Metoclopramide
Reserpine,Methyldopa,Lithium Amiodarone

PD FACIES
Hypomimia Expressionless, Mask face,
lips parted
Vacant fixed stare (Stellwag sign)
Decreased eye blink (Normal:15-20;
PD:5-10 blinks per minute)
Mayersons sign
EOM - Hypometric saccades, Impaired
smooth pursuit
Seborrhoea
Neck flexion
Sialorrhea
Hypophonic, monotonous, hypokinetic
speech

BRADYKINESIA
Pronation & Supination

Rapid alternating
movements of hands.
Speed (slowing),
Amplitude (reduction in
amplitude ; fatiguing),
Initiation (hesitation)

Finger tap Test (FT) patient taps thumb with index finger in rapid
succession
Hand movements patient opens and closes hands in rapid succession
Leg agility patient taps heel on the ground in rapid succession picking up
entire leg 3 inches from the floor
Arising from chair patient attempts to rise from a straight backed chair,
with arms folded across chest

CLASSIC STOOPED POSTURE

En bloc turning; Festination;

Propulsion gait

FREEZING

Motor Blocks: a form of akinesia, very disabling, sudden and

transient (<10 sec) to move
Start hesitation (beginning to walk)
Turn hesitation (while turning)
Hesitation in tight quarters (walking through a narrow
passage)
Destination hesitation (while approaching a destination)
Open space hesitation (crossing busy streets)
Risk factors: presence of rigidity, bradykinesia, postural
instability, longer disease duration
To overcome freezing: sensory tricks: marching to command,
stepping over objects (walking stick), walking to music, and
shifting body weight
Extreme bradykinesia: kinesia paradoxica = emotion
triggered activation of intact motor programmes in response
to external trigger (loud noise, marching music, visual cue)

CAMPTOCORMIA
Bent spine syndrome

Camptocormia was first described by the English physiologist and

surgeon Brodie in 1818. It was described for the first time in
idiopathic Parkinson's disease in 1999. CC is a motor disorder of
heterogeneous aetiology. "Not all stoops are due to osteoporosis".
The diagnosis of camptocormia was made if the patients exhibited
marked (>45) flexion of their thoracolumbar spine that increased
during walking and markedly abated or disappeared in the
recumbent position.
Heterogeneous etiology
Parkinsonian camptocormia could be the consequence of axial
rigidity of the flexion muscles, with a weakness of the erector
spinal muscles; possibly due to dysfunction of the basal ganglia
controlling the reticulospinal pathway. The main projections of the
reticulospinal pathway are located in the axial muscles, and they
control the dynamic and static posture. Camptocormia could be
due to an imbalance between excessive central motor drive to the
ventral and dorsal trunk musculatures (leading to excessive
activation of the abdominal wall muscles) and reduced motor drive
to the paraspinal muscles (which would favour secondary muscle
atrophy and injury). The camptocormia, Pisa syndrome and
antecollis may represent the continuum of the same motor
phenomenon and most of the authors refer them to unusual form
of axial dystonia.

CAMPTOCORMIA
Heterogeneous aetiology
"Not all stoops are due to osteoporosis".

Psychogenic CC; Hysterical

kyphosis (World War I/II
neurosis)
Myopathic CC
Dystonic CC; abdominal
segmental dystonia
Associated with MND, ALS
Drug induced CC
Paraneoplastic CC: NHL
Vertebral/Intradural pathology
related
Alzheimer disease; Graves
disease
BG disorders: PD, MSA, LD
responsive CC/LD responsive
dystonic CC

Focal spinal myopathy/myositis

Nemaline, Amyloid myopathy;
Polymyositis, Inclusion body
myositis,Dermatomyositis,
LGMD IIB/Dysferlinopathy,
Myotonic dystrophy
Mitochondrial myopathy
Drugs: Antipsychotics, VP,
Olanzapine
IVDP, infective
spondyloarthritides, spinal canal
stenosis, spinal cord tumours
BG lesions: striatum, putaminal
lesions
Post encephalitic dystonic CC

Camptocormia
Striatal hand/foot

PISA syndrome

Pisa syndrome is another (but clinically similar) form of rapidly

evolving and severe axial dystonia with forward, but also laterally
orientated trunk flexion.

totally or partially reducible

MSA

REST TREMORS

Early sign rest tremor

Unilateral
4-6Hz slow tremor

Difficulty performing
simple manual tasks
may be initial symptom
Bradykinesia

Tremor often improves OR

Appears with purposeful
function

Rest tremor in patients with PD can also

involve the lips, chin, jaw and legs but, unlike
essential tremor, rarely involves the neck/head or
voice.

TREMOR

PD- Re-emergent tremor: the appearance of

tremor is often delayed after the patient
assumes an outstretched horizontal position

PD HAND SIGNS

Unilateral tremors

Bradykinesia

Micrographia
Archimedes Spiral
Drawing

MICROGRAPHIA

Small handwriting in a series of

signatures; bradykinesia causes a
decrease in amplitude of the letters
and width of the name when a patient
repeatedly signs the name vertically
down unlined paper

CHAIR TIPPING TEST

The chair of the seated patient is

tipped backwards without
warning.The PD patient tips
backwards with the chair,whereas
the normal person corrects and
maintains an upright position

Loss of Postural/Righting reflexes

ARM SWINGING TEST / PULL BACK TEST

The examiner moves the

shoulders of the passive,standing
patient so that his arms swing
with him. In PD, the arm swing is
dampened by rigidity

The examiner pulls back the

shoulder without warning, the PD
patient staggers backwards
without a foot stop; taking more
than TWO STEPS backwards
indicates an abnormal postural
response.

STAGES OF PD
Stage I

Stage II

Stage III

Stage I unilateral involvement;

affected arm-flexed
posture,reduced arm
swing,unilateral rest
tremor,leaning to the unaffected
side
Stage II bilateral involvement
with early postural changes, slow
dragging gait with decreased
excursion of legs
Stage III pronounced gait
disturbance,moderate generalised
immobility,postural instability;and
tendency to fall
Stage IV significant immobility,
limited ambulation with
assistance

Stage IV

Stage V

Stage IV complete
immobility,confined to bed or
chair,cannot stand or walk even
with assistance

MANAGEMENT
Is it Primary PD or Secondary Parkinsonism?

Diagnosis

Early management DA agonist monotherapy vs. Early

combination therapy

Late management Advanced PD [ Motor complications]

Late combination therapy with DA agonists or COMT Inhibitors

Management of complications Motor complications of LD,

Drug side effects, Behavioural & Neuropsychiatric problems

DIAGNOSIS
Parkinsons
Disease
PD Mimics

DIAGNOSIS: no definite test

Pure extrapyramidal syndrome
Tremor Rigidity Bradykinesia Response to dopaminergic therapy

Unilateral onset
Persistent asymmetry affecting side of onset
Rest tremor
Slow progressive disorder
Clinical course of 10 year or more
Excellent response to levodopa
Levodopa response for 5 years or more
Severe levodopa-induced chorea

Exclude other neurodegenerative disease and secondary

parkinsonism ( drugs, toxins, trauma, tumor, hydrocephalus,
stroke, etc.)

STAGES OF PD
Hoehn and Yahr Staging of Parkinson's Disease
Stage Descriptions

Stage 1 Signs and symptoms on one side only Symptoms mild Symptoms
inconvenient but not disabling Usually presents with tremor of one limb
Friends have noticed changes in posture, locomotion & facial expression

Stage 2 Symptoms are bilateral Minimal disability Posture and gait affected

Stage 3 Significant slowing of body movements Early impairment of

equilibrium on walking or standing Generalized dysfunction that is
moderately severe

Stage 4 Severe symptoms Can still walk to a limited extent Rigidity and
bradykinesia No longer able to live alone Tremor may be less than earlier
stages

Stage 5 Cachetic stage Invalidism complete Cannot stand or walk

Requires constant nursing care

PD SCALES

UPDRS
Unified Parkinsons Disease Rating Scale
Mentation,Behaviour & Mood Score (Cognitive)
ADL Score
Motor Score
Therapy complication Score (Dyskinesia & Fluctuations)
Hoehn & Yahr Stage

HRQOL-PD
PDQL [Parkinsons Disease Quality of Life questionnaire]
PDQ-39 [39 item Parkinsons Disease Questionnaire]

THE UK PARKINSONS DISEASE SOCIETY

BRAIN BANK CRITERIA

Bradykinesia
PLUS at least one of following
Rigidity
4-6 Hz Rest tremor
Postural instability
Supportive Criteria (At least three)
Unilateral onset, Rest tremors
present
Progressive disorder
Persistent asymmetry affecting
side of onset most
Excellent response to levodopa
Levodopa induced dyskinesia
Levodopa response for 5 years
or more
Clinical course of 10 years or
more

Exclusion criteria for PD

H/o repeated strokes with step
wise progression of parkinsonian
features
H/o repeated head injury
H/o definite encephalitis
Strictly unilateral features after 3
years
Early severe autonomic
involvement
Early severe dementia
Cerebellar signs
Babinski sign
Presence of cerebral tumour /
NPH
Negative response to large doses
of LD

ATYPICAL / RED FLAGS -PD

Early gait instability

Falls within the first year
Rapid progression over months to 1 year
Wheel chair dependence within 5 years (Wheel chair Sign)
Poor response to levodopa
Absent LD induced motor fluctuations/dyskinesias
Symmetrical signs
Lower body parkinsonism
Gaze abnormalities
Disproportionate antecollis
Apraxia, Alien limb, Cortical sensory loss
Obstructive sleep apnea, stridor, gasping respirations
Upper motor neuron signs
Early ,prominent dementia, Early hallucinations & delusions
Prominent early autonomic signs or symptoms
Cerebellar signs
Severe bulbar symptoms dysphagia,dysphonia, dysarthria
Peripheral neuropathy

D/D PD vs. PD PLUS SYNDROME

Typical PD

PD Plus Syndrome

Pattern of Onset

Asymmetrical

Symmetrical (CBGD)

Rigidity

Peripheral>Axial

Axial>Peripheral

Rest Tremor

Present

Absent or Atypical

Associated features [early

dementia,vertical gaze
palsy,pyramidal signs,cerebellar
signs,early dysautonomia,cortical
sensory signs,myoclonus]

Absent

Present

LD response

Excellent

Mild to moderate response

initially;then gradually wanes
after 1 year

Progress of Disease

Slow

Usually rapid

PSP
Facies: Staring expression, astonished worried , reptilian appearance, frontalis
overactivity, and retrocollis. She is wearing a neck sling for a fractured wrist,
sustained in a fall.

Figure. (Top) Upper facial muscles anatomy: procerus muscle originates in the nasal bone
and inserts in the skin in the center of the forehead between the eyebrows.

Romano S , Colosimo C Neurology 2001;57:1928-1928

2001 by Lippincott Williams & Wilkins

Differential diagnosis of PD

INVESTIGATIONS

Lab tests: CBC, Chemistries, LFT's, and thyroid function tests. If

patient is under 50 yrs: serum ceruloplasmin, 24 hr urine copper,
and a slit-lamp exam for Kayser-Fleisher rings to rule out
Wilson's disease. MRI of the head if there is any atypical feature
MRI: To differentiate PD Plus Syndromes PSP, MSA, CBGD, Multiinfarct state, NPH, Wilsons Disease, Age<55 yrs, Atypical Red
flags

MEDICAL TREATMENT

GOALS OF TREATMENT

Decreased parkinsonian disability

Tailor made to each individual patient
Decreased complications of Levodopa therapy
Prevent deterioration of disease
Restore dopamine biosynthetic capacity

Medical Treatment
Surgical Approaches
Thalamotomy, Pallidotomy, Subthalamotomy
Deep Brain Stimulation
Fetal transplantation
Gene Therapy
Stem cell research

MEDICAL TREATMENT
Anticholinergic
Trihexyphenidyl, Benzotropine
Levodopa
Sinemet, Sinemet CR, Madopar
Dopamine Agonists
D1: Apomorphine
D2: Bromocriptine, Pergolide, Pramipexole, Ropinirole,
Cabergoline
D3: Pramipexole, Ropinirole
D3/D2/D1: Trans dermal delivery (patch)
MAO-B Inhibitor
Selegiline / Rasagiline
COMT Inhibitors
Tolcapone, Entacapone
Anti- NMDA / Glutamate
Amantadine, Remacemide
[anti-tremor; anti-dyskinetic agent; neuroprotective]

COMT AND MAO-B INHIBITORS

Carbidopa
DD
Levodopa

Dopamine
MAO-B

Entacapone

COMT

6 OH Dopamine

Selegiline
Rasagiline

DOPA/DOPAC
3 OH Methyl Dopa

Mt Oxidative stress
Complex I deficiency

Free radical induced SN

neurodegeneration

Initial MONOTHERAPY with DOPAMINE AGONISTS in early PD

MONOTHERAPY WITH DA AGONISTS

Early PD delay the use of LD; can control PD symptoms > 3 yrs
Longer t than LD (2 hrs) sustained DA stimulation vs. pulsatile
DA stimulation No motor fluctuations
Stimulate post synaptic DA receptors
Neuroprotective Delays progression of PD; No toxic metabolites
Early combination therapy LD sparing effect; permits reduction in
LD dose
Useful in prevention of motor complications of LD
Do not require decarboxylase enzymes for conversion into active
NTs
Ergot derivative:

Cabergoline [D2]
t1/2-65 hrs
Bromocriptine [D2] t1/2-1-7 hrs
Pergolide [D1/D2]
t1/2-1-7 hrs
Non Ergot derivative: Pramipexole [D3>D2]
Ropinirole [D3>D2]

EARLY LD ?

Initial LD monotherapy reserved for the elderly > 70-80 years

ELLDOPA trial (Fahn S, NEJM 2004) disproved LD toxicity

Requip as Early Therapy vs L-dopa- PET (REAL-PET) & Comparison of the Agonist
Pramipexole vs. Levodopa on Motor Complications of Parkinson Disease (CALM-PD):
SPECT striatal -CIT uptake; Patients randomized to initial treatment with the dopamine
agonist ropinirole or pramipexole had a reduced rate of decline in the imaging biomarker
compared with those started on levodopa. Dopamine agonistinduced protective effect
or to a levodopa induced toxic effect (no control group)

Current approach to symptomatic therapy

(Ref: Neurology; May 2008)
1)
2)
3)

A low threshold for initiation of treatment- patients should not be

tolerating disability for the sake of delaying treatment
Initiating treatment with levodopa in older patients (generally
over the age of 60)
Initiating treatment with a dopamine agonist in patients under
age 60 and maintaining a very low threshold for switching to or
adding levodopa if the treatment response is suboptimal or if
problematic adverse effects develop (this includes a thorough
and regular evaluation for dopamine agonist-related
complications)

STEP WISE APPROACH FOR MANAGING

PARKINSONS DISEASE

Ensure that correct diagnosis is made

Consider neuroprotective therapy (eg, selegiline) as soon as
diagnosis is made
Initiate symptomatic therapy with a dopamine agonist as
appropriate; Start with low doses and titrate slow. Maintain a
motor diary with UPDRS ADL / Motor score
Supplement with levodopa when dopamine agonist
monotherapy no longer
Consider introducing supplemental levodopa therapy in
combination with a COMT inhibitor to extend its elimination halflife
Consider surgical intervention when parkinsonism cannot be
satisfactorily controlled with medical therapies
OLANOW CW , NEUROLOGY 2001

EARLY TREATMENT

Should initial treatment be with a dopamine agonist or L

dopa?
Is L dopa toxic?
Does early treatment shorten the time that the patient will
respond to therapy?
Are some therapies neuro protective?
Important to emphasise that treatment is symptomatic only!
Treat if symptoms are a problem.
Most neurologists would favour L dopa as the initial
therapy (Controversial seat of hot debate)
Equally dopamine agonists can be used although the effect
may not be as marked, but prevents the speed of
progression of neurodegeneration

SYMPTOMATIC PHARMACOLOGICAL
TREATMENT

Dopamine agonists monotherapy (disease modifying /

neuroprotective)
Amantadine NMDA antagonist
MAOI Selegeline (DATATOP trial) , Rasagiline (TEMPO,
ADAGIO, PRESTO, LARGO, PROUD trials)
Levodopa Early vs. Late Therapy
Levodopa + DA agonists (Pramipexole, Cabergoline)
Levodopa + COMTI (Entacapone)
Pramipexole Advanced PD, tremorlytic action,
antidepressant action

LEVODOPA THERAPY

Start with very low doses; Titrate slowly

Administer LD 1 hour before meals
Use LD formulations with highest ratio of DD inhibitor to LD
1:4 combination [25/100] than 1:10 combination [10/100 ;
25/250]
Supplemental Carbidopa
Manipulation of dietary protein/ Low protein diets avoid Large,
neurtal amino acids (LNAAs L Tryptophan, Phenylalanine,
Tyrosine, Leucine, Isoleucine, Valine)
Avoid Pyridoxine
Other formulations: Controlled release preparations
Liquid Levodopa
Late PD add COMTI / MAOBI (reduce metabolism,increase
bioavailability,smooth drug effect,sustained striatal stimulation)

PROBLEMS WITH LEVODOPA

Short t - Pulsatile striatal DA stimulation genesis of motor

complications
Erratic drug GI absorption, role of dietary proteins
Peripheral decarboxylase inhibitors increase brain levels;
prevent peripheral LD side effects
Neurotoxicity of LD 6 OH Dopamine [toxic metabolite]
Oxidative stress hypothesis
Long term use Motor complications
Dopamine dysregulation syndrome
LD insensitive non-motor symptoms
Advanced, Late PD decreased capacity to store LD
presynaptically as there is severe striatal neuronal cell loss;
reduced storage capacity; Need DA agonists or COMT inhibitors
Levodopa-induced hyperhomocysteinemia folate, cobalamin
supplementation;COMTI

Dopamine agonists: Advantages and

disadvantages
Levodopa: Advantages and
disadvantages

Punding is human activity characterized by compulsive fascination with

and performance of repetitive, mechanical tasks, such as assembling
and disassembling, collecting, or sorting household objects.

LEVODOPA: DDS

Dopamine induced stereotypies: pleasurable, intense

fascination, purposeless, irrational, unproductive, repetitive,
stereotypical, impulsive, compulsive motor behaviour: punding,
pathological gambling, compulsive sexual behaviour,
compulsive buying, binge eating; neuroanatomical substrate:
mesolimbic dopaminergic projections, nucleus accumbens,
orbitofrontal cortex
Impulse control disorders (ICD)
Hedonic homeostatic dysregulation: addiction-like state
More common with dopamine replacement therapy
(pramipexole, ropinirole, pergolide) than LD
Management: reduce; switch; discontinue the DA agent;
behavioural treatment (CBT); increase LD dose

DDS: REWARD & REINFORCEMENT BEHAVIOUR:

Brain regions, neurotransmitter systems & neural circuitry

BRAIN REWARD CIRCUITRY

Brain Reward Circuitry : network of four circuits involved in drug abuse

and addiction
Reward circuit _Nucleus Accumbens DA-regulated reward circuit
Motivation circuit _Orbitofrontal cortex, Subcallosal cortex
Memory circuit _Amygdala (Conditioned-learned associations ) and
Hippocampus (memory of expected reward)
Cognitive Control circuit _Prefrontal cortex and Cingulate gyrus
OFC-Amygdala-NA reward circuit
Without the inhibitory frontal cognitive control, a positive-feedback loop
is set forth that result in compulsive drug intake. The prefrontal cortex is
involved in self-monitoring, decision-making processes, and in inhibitory
control. The disruption of the prefrontal cortex leads to loss of selfdirected/willed behaviour in favour of automatic sensory-driven
behaviour (high reward dependence).

BRAIN REWARD CIRCUITRY

LEVODOPA TREATMENT COMPLICATIONS

LATE COMPLICATIONS
75% of PD patients who have been treated with L-dopa for a
prolonged period (after 5-10 years) develop motor complications

On-Off phenomenon
Wearing-off effect

Delaying the introduction of LD can delay the onset of motor

complications
Younger and milder PD should probably be treated with DA
agonists [Bromocriptine, Ropinirole, Cabergoline, Pramipexole]
Functional imaging with 18 F PET [REAL-PET) and -CIT SPECT
[CALM-PD] measures nigrostriatal dopaminergic neurons
greater reduction of uptake in LD group than DA agonist group
Treatment with DA agonist slows down the progression of
Parkinsons disease relative to treatment with LD

MOTOR COMPLICATIONS OF LD
1. Response fluctuations on & off phenomena
2. Hyperkinetic phenomena dyskinesia & dystonia

FLUORO-DOPA PET SCAN

In PD there is a decreased level of Dopamine in the Striatum

SURGERY
MEDICALLY REFRACTORY DISEASE

Stereotactic surgery Atlas Target localisation

SURGERY

Stereotactic surgery / Leskel gamma knife radiosurgery

Pallidotomy for tremors and drug induced dyskinesias

Thalamotomy rest tremor & rigidity

Deep Brain Stimulation (DBS) High frequency stimulation (100180 Hz) of bilateral GPi [pallidal DBS],STN [subthalamic DBS]

Moderate to advanced disease with poor quality of life due to

fluctuating medication response,troublesome dyskinesia,or LD
unresponsive symptoms

SURGERY

MRI Brain post surgery Pallidotomy

Rt sided lesion at GPi

NEUROSTIMULATION

NEUROSTIMULATION
Deep brain stimulation DBS
Activa Brain pacemaker

STN
( Tremor-80%;Rigidity-65%;
Bradykinesia-50%)

GPi
VIM nucleus (Tremors)
Ventral intermediate nucleus

Bilateral DBS: Quadripolar

electrodes implanted in STN

NEWER HORIZONS
o

Neuroprotective trials - Slowing progression of underlying

pathophysiological processes in PD. No existing agent is clearly
neuroprotective

Possible candidates
Dopamine agonists (pramipexole and ropinirole)
Neurotrophic factors neurotrophins (BDNF,GDNF)
Anti-inflammatory drugs (COX pathways)
Anti - apoptotic agent
Glutamate antagonists, Caspase inhibitors (Minocycline)
Free radical scavengers/antioxidants, Adenosine A2R antagonists,
Curcumin
Mitochondrial bio energisers 1200mg/day coenzyme Q10 ,creatine
Citicoline and neuroimmuniphilines
o Surgery
o Gene Transfer ; Stem cell implants

Candidate approaches to
neuroprotection

NEUROTRANSPLANTATION

Adrenal medullary transplants

Human fetal SN nigral transplants into putamen
Intracerebral administration of GDNF

Stem cell transplant (Cell therapy)

ES cell-derived DA neurogenesis
Embroyonic DA neuroblasts (Neural stem cells)
Adult human embryonic haemopoietic stem cell transplantation

Sir William Osler

In what may be called the natural method of teaching, the

student begins with the patient, continues with the patient, and
ends his studies with the patient, using books and lectures as
tools, as means to an end

Educating the mind without educating the heart is no education

at all.

CRITICAL THINKING & SELF DIRECTED LEARNING

'One thing I only know, & that

is, I know nothing'
Socrates

WORLD PARKINSON'S DISEASE DAY

APRIL 11TH