Parkinson’s disease and other

Movement Disorders
Hypokinetic movements

• Parkinsonism
• Hypothyroid stiffness
• Stiff muscles
• Catatonia
• Psychomotor depression
• Blocking tics
Hyperkinetic movements

• Chorea • Myokymia
• Dystonia • Stereotypy
• Myoclonus • Tics
• Hemifacial spasm • Restless legs
• Ballism • Paroxysmal dyskinesias
• Athetosis
• Tremors
Parkinsonism
Etiologies
Idiopathic Parkinson’s disease
Secondary Drug induced (neuroleptics, antiemetics, reserpine,
tetrabenazine, lithium, flunarizine, cinnarizine, diltiazem)
Hydrocephalus
Hypoxia
Toxins
Infections
Metabolic
Paraneplastic parkinsonism
Psychogenic
Trauma
Tumor
Vascular
Parkinson-plus syndromes MSA
Progressive supranuclear palsy
Corticobasal ganglionic degeneration
Progressive pallidal atrophy
Lytico-Bodig
Heredodegenerative Disease AD
DLB
Pick’s disease
Huntington’s disease
Machado Joseph disease
Hallervorden Spatz disease
Lubag
Parkinson’s disease

• Second common neurodegenerative disease

• Affects all men and women of all races, all occupations
and all countries
• Mean age of onset: 60 years
• Frequency of PD increases with aging, but cases can be
seen in patients in their 20s and even younger
Parkinson’s Disease

• Cardinal features
• Resting tremor
• Rigidity
• Bradykinesia (slowing)
• Gait impairment
 Clinical Features of PD
Cardinal Motor Features Other Motor Features Nonmotor Features
Bradykinesia Micrographia Anosmia
Rest tremor Masked facies Sensory disturbances (e.g.
Rigidity (hypomimia) Pain)
Gait disturbance/ Reduced eye blinking Mood disorders (e.g.
postural instability Soft voice (hypophonia) depression)
Dysphagia Sleep disturbance
Freezing Autonomic disturbances
Orthostatic hypotension
GI disturbances
GUT disturbances
Sexual dysfunction
Cognitive impairment (MCI/
dementia)
Parkinson’s disease
Parkinson’s disease
Pathogenesis
Pathology

• Hallmark features:

Degeneration of
dopaminergic neurons in
the substantia nigra pars
compacta (SNc)
Pathology

• Hallmark features:
• reduced striatal dopamine
• intracytoplasmic proteinaceous inclusions known as Lewy bodies that primarily
contain the protein alpha synuclein
Pathology

• While interest has primarily focused on the dopamine system,

neuronal degeneration with inclusion body formation can also affect:
• cholinergic neurons of the nucleus basalis of Meynert (NBM)
• norepinephrine neurons of the locus coeruleus (LC)
• serotonin neurons in the raphe nuclei of the brainstem
• neurons of the olfactory system, cerebral hemispheres, spinal
cord, and peripheral autonomic nervous system
• This “nondopaminergic” pathology is likely responsible for the
development of nondopaminergic clinical features characterized by
their lack of satisfactory response to dopaminergic replacement
therapy
 Diagnosis

• No definitive tests for PD

• PET scans shows reduced uptake of striatal
dopaminergic markers, particularly in the
posterior putamen with relative sparing of
the caudate nucleus
• Medical history and neurological tests are
conducted to diagnose
• Usually, if two of the cardinal
symptoms are present
Treatment

⦿ No cure for PD
⦿ Treatment can be divided into two stages
● Early and Later stages

⦿ Early stage
● Onset of symptoms, treated with physical therapy and
medications (Levodopa, dopamine agonists, etc)
Treatment

⦿ Later stage
● Usually after having received 5+ years of levodopa
treatment
● “Wearing-off” and “On/Off” effect develops, other
medication in conjunction levodopa is commenced
● MAO-B and COMT inhibitors
Drug treatment

• Levodopa
• COMT
• Dopamine Agonist
• MAOB inhibitor
• Amantadine
• Anticholinergics
 Levodopa

• Mainstay of therapy for PD

• L dopa is converted to dopamine by
dopa decarboxylase
• Combined with decarboxylase inhibitor
to prevent peripheral conversion to
dopamine
• Levodopa + carbidopa (Sinemet)
• Levodopa + benserazide (Madopar)
 Levodopa

• Used with Carbidopa,

which blocks the early
conversion of L-DOPA
into dopamine
Levodopa

• remains the most effective symptomatic treatment for PD

• gold standard against which new therapies are compared
• No current medical or surgical treatment provides antiparkinsonian
benefits superior to what can be achieved with levodopa
• benefits the classic motor features of PD
• prolongs independence and employability
• improves quality of life
• increases life span
• Almost all PD patients experience improvement, and failure to respond
to an adequate trial should cause the diagnosis to be questioned
 Levodopa

• Limitations
• No effect on disease course
• No effect on non dopaminergic
symptoms such as dysautonomia,
cognitive disturbances and
postural instability
• Motor complications
Levodopa

⦿ Acute adverse effects

● Confusion, psychosis, dizziness
● Nausea and vomiting
● Orthostatic hypotension
Levodopa

⦿ Levodopa induced motor complications consists of fluctuations

in motor response ( “on” episodes when the drug is working and
“off” episodes when parkinsonian features return) and
involuntary movements known as dyskinesias
⦿ With continued treatment, the duration of benefit following an
individual dose becomes progressively shorter until it
approaches the half-life of the drug. This loss of benefit is
known as the wearing off effect.
 Levodopa

• Motor fluctuations and dyskinesia

develop over time
• Likely to occur in:
• Females
• Younger patients
• More severe disease
• Requiring higher doses of
levodopa
Catechol O-Methyl Transferase (COMT)
inhibitors

• Inhibits levodopa catabolism to 3-O methyldopa

increasing levodopa bioavailability and transport into
brain
• Entacapone
• Tolcapone
• Levodopa + carbidopa + entacapone (Stalev)
Catechol O-Methyl Transferase (COMT)
inhibitors

• Extend duration of levodopa effect

• Indicated for treatment of patients with PD experiencing
end of dose wearing off with levodopa
• No role as monotherapy
• Used in combination with levodopa
• Side effects:
• Dyskinesia, diarrhea, nausea
Dopamine agonist

• Acts directly on the dopamine receptors

• Unlike levodopa, they do not require metabolism to an active
product and do not undergo oxidative metabolism
• They were initially introduced as adjuncts to levodopa to enhance
motor function and reduce “off” time in fluctuating patients
• Today, sometimes prescribed before L-DOPA, to delay “wearing-off”
effect and other motor complications brought on by prolonged use
of L-DOPA
• Effective against key motor symptoms --- tremor, bradykinesia and
rigidity
DOPA agonists

• Triggers dopamine receptors in place of depleted

dopamine neurotransmitters
Dopamine agonist

• Early use shows reduced risk of dyskinesia compared with levodopa

• Adverse effects:
• Nausea/vomiting
• Sedation
• Orthostatic hypotension
• Hallucinations
• Leg edema
• Impulse control disorders
Monoamine Oxidase B (MAOB) Inhibitor

• Inhibitors of monoamine oxidase type B (MAO-B) block

central dopamine metabolism and increase synaptic
concentrations of the neurotransmitter
• Used as monotherapy or in conjunction with L-DOPA
• It can reduce the dosage of L-DOPA by 15%
MAO-B Inhibitors

• MAO-B is an enzyme that metabolizes dopamine

• From the breakdown of dopamine, hydrogen peroxide is
produced, which the oxidative stress can damage
dopaminergic neurons in the substantia nigra
• MAO-B inhibitor delays or reduces the metabolism of
dopamine
Other Drugs for PD

• Amantadine
• Antiviral agent
• Provides mild to moderate benefit by decreasing
tremor, rigidity and akinesia
• Rarely effective as monotherapy for > 1-2 years
• Maybe continued as adjunctive therapy
• Effective for levodopa induced dyskinesia
• Antiparkinsonian effect: NMDA receptor antagonism
Anticholinergics

• Option for young patients (<60 years old) whose

predominant symptoms are resting tremor and
hypersalivation
• Improve tremors and stiffness
• Cause memory impairment and confusion
• Trihexyphenidyl and benztropine
Surgery

• Deep Brain Stimulation

• Surgery of globus pallidus internus or subthalamic
nucleus
• Brain pacemaker, sends electrical impulses to brain to
stimulate the subthalamic nucleus
• Improves motor functions and reduce motor
complications
Surgery

• Deep Brain Stimulation

• Complications include:
• brain hemorrhage
• Seizures
• death
Surgery

• Ideal surgical candidate

• Clear PD diagnosis with unequivocal and
sustained levodopa response
• Relatively young
• Nondemented
• Nonanxious
• Nondepressed
• Emotionally and physically stable
Non Pharmacologic Treatment
Physical Therapy

• Regular exercise
• Recommended throughout the life of disorder
• Helps maintain and improve mobility and strength
• Physical exercise aids in rigidity relief, muscle strength
and flexibility, balance, etc.
• Caution is advised to avoid sudden movements or
strenuous activities – fall could result in serious injury
Parkinson plus syndrome
 Multiple System Atrophy
Striatonigral Familial Olivoponto Sporadic Olivoponto Shy-Drager Syndrome
degeneration cerebellar degeneration cerebellar degeneration

Age of onset 4th -7th decade (56.6yrs) 28 yrs old 50 yrs old
Sex preference None Male to female ratio = 1.8:1.0 Male to female ratio = 1:1

Clinical Akinetic rigid syndrome Cerebellar disturbances Cerebellar disturbances Prominent autonomic
manifestation Rigidity Dementia – 60% of patients Dementia – 35% of patients dysfunction
Hypokinesia Orthostatic hypotension
Repeated falling Erectile dysfunction
Bladder and bowel
disturbance
Course Progressive Progressive Progressive
2-10 years (mean: 4.5-6 16 years 6 years
years)
Treatment Do not respond to OHT: fludrocortisone;
levodopa midodrine

Pathology Cell loss and gliosis in the Neuronal loss with gross Neuronal loss with gross Intermediolateral cell
striatum and substantia atrophy in pons, medullary atrophy in pons, medullary columns of the spinal
nigra olives & cerebellum olives & cerebellum cord are affected
Progressive supranuclear palsy

• Steele-Richardson-Olszewski syndrome
• Clinical manifestation:
• Supranuclear ophthalmoparesis (especially downgaze) and
falls within the 1st year of onset of parkinsonism
• 60-80% with subcortical form of dementia
• Pathology:
• Widespread diencephalic and mesencephalic, brainstem
and cerebellar neuronal loss
• Falls and aspiration cause the frequent complications
Corticobasal ganglionic degeneration

• Asymmetric form of Parkinsonism

• Clinical manifestation
• Unilateral dystonia
• Myoclonus
• Alien limb phenomenon
• Parkinsonism
• Dementia is common
Hyperkinetic movement
Tremor

• Tremor consists of alternating contractions of agonist and

antagonist muscles in an oscillating, rhythmic manner.

• It can be most prominent at rest (rest tremor) –-PD,

on assuming a posture (postural tremor) –- essential
tremor, or on actively reaching for a target (kinetic
tremor) --- cerebellar disease
Tremor

• Normal individuals can have a physiologic tremor that typically

manifests as a mild, high-frequency (10–12 Hz), postural or
action tremor that is usually of no clinical consequence
• Enhanced physiologic tremor (EPT)
• can be seen in up to 10% of the population
• often in association with anxiety, fatigue, a metabolic
disturbance (e.g., hyperthyroidism, electrolyte
abnormalities), drugs (e.g., valproate, lithium), or toxins
(e.g., alcohol)
Essential Tremor

• commonest movement disorder

• characterized by a high-frequency tremor (6–10 Hz)
• predominantly affects the upper extremities
• most often manifest as a postural or action (kinetic) tremor
and, in severe cases, can interfere with functions such as
eating and drinking
• typically bilateral and symmetric but may begin on one side
and remain asymmetric
Essential Tremor

• Tremor involvement
• head - ~30% of cases
• voice - ~20%
• tongue - ~20%
• face/jaw - ~10%
• lower limbs -~10%
• The tremor is characteristically improved by alcohol and
worsened by stress
Essential Tremor

• The etiology and pathophysiology of ET are not known.

• Approximately 50% of cases have a positive family history
with an autosomal dominant pattern of inheritance
• Treatment
• Mild cases require no treatment
• Severe cases – propranolol or primidone
Chorea
Chorea

• Chorea
• Involuntary, irregular, purposeless, nonrhythmic,
abrupt, rapid, unsustained movements that seem to
flow from one body part to another
Etiology
 Huntington’s disease

• Autosomal dominant
carried on chromosome 4
• caused by an increase in
the number of
polyglutamine (CAG)
repeats (>40) in the coding
sequence of the huntingtin
gene
• The larger the number of
repeats, the earlier the
disease is manifest
Huntington’s disease

• Clinical features:
• Cognitive (subcortical dementia)
• Movement disorder (chorea, dystonia, motor
impersistence, incoordination, gait instability)
• Psychiatric disorders (depression, anxiety, impulsivity,
apathy, obsessive-compulsive disorder)
• Commonly manifest by 20-40 years old
• Progresses to death in 10-15 years
Huntington’s disease

• Pathology
• Brain is atrophic
• Striking atrophy of the
caudate nucleus
 Huntington’s disease

• Brain imaging
• Atrophy of the caudate
nucleus
• Compensatory
hydrocephalus maybe
seen
 Huntington’s disease

• Genetics
• The probability of each
offspring inheriting an
affected gene is 50%
Huntington’s disease

Treatment
• No disease-modifying therapy for this disorder
• Current treatment involves a multidisciplinary approach, with medical,
neuropsychiatric, social, and genetic counseling for patients and their
families.
• Chorea
• Dopamine receptor blocking agents
• Haloperidol
• Resperidone
• Reserpine
• Clonazepam
• Amantadine
Huntington’s disease

• Treatment
• Gait instability
• Physical and occupational therapy
• Depression and anxiety
• Selective serotonin reuptake inhibitors
• Speech and swallowing therapy
• Genetic counseling
• Family counseling
Dystonia
Dystonia

• Twisting movements that tend to be sustained at the

peak of the movement, frequently repetitive and often
progress to prolonged abnormal postures.

• Dystonia can be classified according to:

• age of onset (childhood vs adult)
• distribution (focal, multifocal, segmental, or
generalized)
• etiology (primary or secondary)
Dystonia

• Distribution
• Focal – writer’s cramp, blepharospasm, torticollis

• Multifocal
• Early onset – starts in the leg or arm then progress
to other limbs
• Late onset – starts in the neck, cranial muscles or
arms and tend to remain localized
 Causes of dystonia
Primary (idiopathic) torsional dystonia
Secondary dystonia Acquired
Dystonia plus disorders Trauma
Dopa responsive dystonia Encephalitis
Myoclonus dystonia Peripheral nerve injury
Rapid onset dystonia-parkinsonism Stroke
AD Tumor
Huntington’s disease
SCA type 3 (Machado-Joseph disease)
Dentatorubropallidoluysian atrophy
Familial basal ganglia calcifications
SCA type 1
AR
Juvenile parkinsonism
Wilson’s disease
Neuroacanthocytosis
Glutaric aciduria
Hallevorden Spatz syndrome
Ataxia telangiectasia
X-linked
Lubag
Lesch Nyhan Syndrome
Primary dystonia

• At least 16 gene mutations are associated with dystonia and

classified as DYT1–DYT16
• Idiopathic torsion dystonia (DYT1) or Oppenheim’s dystonia
• predominantly a childhood-onset form of dystonia
• autosomal dominant pattern of inheritance that primarily
affects Ashkenazi Jewish families
• majority of patients have an age of onset younger than 26
years (mean 14 years)
• in young-onset patients, dystonia typically begins in the foot
or the arm and in 60–70% progresses to involve other limbs as
well as the head and neck
Focal dystonia

• most common forms of dystonia

• typically present in the fourth to sixth decades
• affect women more than men
Treatment

• Symptomatic
• Oral baclofen
• High dose anticholinergics
• Botulinum toxin injection
Reading assignment

• Tics
• Myoclonus
• Restless Leg Syndrome