Movement Disorders

Paul Tuite, MD
Director of Movement Disorders
University of Minnesota

Disease is of an
antiquity that does not
change; it is we that
change and recognize
that which was
previously
imperceptible
Jean-Martin Charcot

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 Basal Ganglia Neuroanatomy
• Substantia nigra: pars c & r
• Striatum = Caudate + Putamen
• Globus pallidus: internus & externus
• Subthalamic nucleus (STN)
• Intralaminar n of thalamus

Basal Ganglia Neurochemistry

Dopamine
GABA
Glutamate (GLU)
Substance P
Endorphins/Enkephalins
Adenosine A2A
Acetylcholine

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 Important Enzymes
• Tyrosine Hydroxylase (TH)
• Dopa decarboxylase (DDC)
• Monoamine oxidase: A & B (MAOa/b)
• Catechol-O-Methyl Transferase (COMT)
• Glutamic acid decarboxylase (GAD)

Substantia Nigra

SN

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 Substantia Nigra

Brain MRI Scan

Parkinson’s disease Normal brain

Substantia Nigra

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Substantia
Nigra
Lewy Body

Striatum

Brain MRI Scan

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 Dopamine release
Striatum

Substantia
Nigra

Striatum

http://www.phuk.com/179.htm

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Dopamine
Release
onto
Striatal
Neurons

Dopamine Production
Phenylalanine

Tyrosine
TH

Levodopa (L-dopa)
DDC
Dopamine

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 PET Scanning

Striatal Uptake

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Dopamine binds to a Dopamine Receptor

Dopamine (yellow dots)

Striatal
Nerve Cell

Substantia Nigra Pallidal

Dopamine Nerve Cell Nerve Cell

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 Basal Ganglia Structures

Caudate
Putamen

GPe
GPi*

Basal
BasalGanglia
GangliaStructures
Structures

Putamen
Putamen

STN*
STN*

SN
SN

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Subthalamic nucleus (STN)

STN
STN

STN

Cortex
Striatum
D2 D1
GABA Dopamine GLU
Enk
SNigra GABA
GPe SP
VL
GABA GLU

GLU
STN GPi/SNpr
Dyn

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 Parkinson’s disease (PD)
• Described by James Parkinson in 1817
• Parkinsonian: adjective
– Features of PD
• Parkinsonism: noun
– PD & other conditions that resemble it

Parkinsonism
Tremor = rhythmical movement
Rigidity = resistance to movement
Akinesia = slowness/absence of
movement

Postural changes

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Resting Tremor

Rigidity

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Akinesia/Bradykinesia

Postural Changes

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Some Causes of Parkinsonism

VP
PPFG
DLBD
PSP
AD PD
CBD
MSA
Meds

MPTP Parkinsonism

MAOB
MPTP MPP+

MPP+ Kills Dopamine Neurons

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 Parkinsonism DDx
• Parkinson’s disease (PD)
• Multiple System Atrophy (MSA)
• Progressive Supranuclear Palsy (PSP)
• Medication-induced parkinsonism
• Parkinsonism with Alzheimer’s Disease (AD)
• Diffuse Lewy Body Disease (DLBD)
• Vascular parkinsonism (VP)
• Toxins: Manganese, MPTP, CO, rotenone?, others

PSP
• Supranuclear palsy
• Falls early in course
• Dysarthria
• Cogntive impairment
• Emotional
incontinence
• Abducted arms when
ambulating: “gun-
slinger’s gait”
Dudley Moore

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 PSP

Parkinsonism DDx II
• Wilson’s disease (AR; chromosome 13)
• Corticobasal Degeneration (CBD)
• Normal Pressure Hydrocephalus (NPH)
• Primary Progressive Freezing Gait Disorder
(PPFG)
• Gait disorder of the elderly
• Toxins: CO, CN, Manganese, MPTP, CS2

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 Kayser-Fleischer Ring

Faces of Parkinson’s disease

Pope John Paul II

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 Faces of Parkinson’s disease

Janet Reno Michael J Fox

Muhammad Ali vs Ken Norton

"There are many men that are affected by the

times in which they live but there are
very few that actually shape them."

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 Faces of PD

Adolph Hitler

Subtypes of PD
• Genetic
– alpha-synuclein: AD
– Parkin/PARK 2: AR: juvenile PD
– Park 3: AD
– Park 4: AD
– Park 5: mitochondrial?
• Environmental Toxins: ?

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 PD: A Clinical Diagnosis
• History
• Examination
• Response to levodopa
• Development of fluctuations in mobility and
dyskinesias over time
• MRI: R/Os other diagnosis
• PET/SPECT scanning – research tool

Initial Parkinsonian Features

• Difficulty turning in bed

• Frozen, painful shoulder
• Stiffness, numbness or pain in a limb
• Altered handwriting

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 Initial Parkinsonian Features

• Difficulty with fine finger movements

• Tremor of hand, jaw or foot
• Decreased facial expression
• Decreased arm swing, dragging a leg

Chronic PD Symptoms
• Motor Fluctuations
• Dyskinesias
• Gait Disturbances: falls, freezing, etc.
• Neuropsychiatric
• Autonomic dysfunction
– Orthostatic hypotension
– Swallowing disturbances

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 Motor Fluctuations &
Dyskinesias

Treatment Strategies
• Symptomatic: improves symptoms

• Neuroprotective: slows nerve cell loss

• Restorative: restores cell function or

increases the number of cells

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 Symptomatic Therapies
• Definition: Do not alter the course of the
PD, which progresses slowly over years.

• Examples:
– L-dopa (L-dopa/carbidopa; Sinemet®)
• L-dopa is converted into dopamine
• Dopamine agonists
– These resemble dopamine and generate a
similar response

Dopamine Parkinson’s disease

Dopamine Dopamine Agonist

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 Surgical Therapies
Symptomatic
Pallidotomy/Pallidal stimulation
Thalamotomy/Thalamic stimulation
Subthalamic nucleus (STN) stimulation
Restorative
Transplantation

MR-guided STN DBS Implantation

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 Tremor
• Definition: Rhythmical oscillation of a body
part
• Determine the distribution: head, voice,
jaw, limb, etc.
• Determine when it occurs: rest, action,
posture, etc.

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 Essential Tremor
• Cause(s): multiple different genes?
• Features:
– Variable voice, head & limb involvement
– Usually postural and action limb tremor
– Often tremor improves with alcohol
• Rx:
– Beta-blockers: propranolol (Inderal), etc.
– primidone (Mysoline)
– clonazepam (Klonopin)
– Surgery: thalamotomy, thalamic DBS

ET: Postural & Action Tremor

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 Ataxia
• Definition: disturbance in smooth
performance of voluntary motor acts
• Features:
• Asynergia Dysarthria
• DysdiadochokinesiaDysmetria
• Gait disturbance
Hypotonia/Rebound
• Nystagmus

Cerebellar Disorder

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 Cerebellar Atrophy

Huntington’s disease (HD)

• Cause: >38 CAG repeats in IT-15 gene
• Autosomal dominant transmission
• Anticipation
• Features: chorea, cognitive/behavioral
disturbances, dystonia, parkinsonism
• Clinical course: fatal after 10-20 yrs
• Pathophysiology: polyglutamine ---> ??

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 HD

HD Neuropathology
• Cortical and striatal atrophy
• Loss of medium spiny striatal neurons with
accompanying gliosis
• Polyglutamine ubiquitously expressed
though!

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HD: Cortical & Caudate Atrophy

HD: Striatal Gliosis & Neuronal Loss

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 Case #1: 69 yo Man
• R hand tremor
• Slowing down
• Rigidity
• Altered gait and arm swing
• Rx: carbidopa/levodopa 25/100 po TID
• Symptoms improved

Case #2: 50 yo Woman

• Progressive “incoordination”
• Impairment in ADLs due to tremor
• No slowing in movements per se
• Rx: propranolol
• Diminished symptoms

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 Case #3: 34 yo Woman
• Nervousness, gait dysfunction &
incoordination
• Chorea seen on exam
• FHx

Case #4: 50 yo Man

• Progressive decline in gait & speech
• Exam: ataxia limbs, dysarthria
• FHx?
• Autonomic dysfunction?

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 Tardive Dyskinesia
• Association with chronic neuroleptic
exposure (>3 - 6 months)
• Nature of movements: chorea + …
• Orobuccal involvement: bon-bon sign

Levodopa-induced dyskinesias
• Variable types of movements: chorea,
dystonia, etc.
• Movements brought out by Levodopa, the
symptomatic movement for PD

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 Generalized Dystonia
• Def: Abnormal Posture
• Distribution: focal, segmental & generalized
• Cause: AD 9q DYT1 gene
• Ethnicity: AJ and non-AJ

Segmental Dystonia
• Example: Cervical dystonia (torticollis)
• Geste Antagoniste: sensory trick to reduce
the dystonia

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Cervical Dystonia

Before After
BOTOX BOTOX

Focal Dystonia
• Meige’s syndrome: cranio-facial dystonia --
accompanying blepharospasm
• Writer’s cramp: a type of action dystonia --
meaning the dystonia is brought out by the
performance of a specific action

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 Two Different Focal
Dystonia Cases

Tourette’s Syndrome
Tics: involuntary stereotypic movements
TS:
Vocal and motor tics
Onset before age 18/21
Suppressibility/inner tension
Coprolalia: only ~17% have this

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 Hemiballismus
• Commonly associated with
• Subthalamic nucleus (STN)
• pathology, e.g., ischemia,
• hemorrhage, etc.

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