Movement Disorders

Prof. Dr TAHA KAMEL ALLOUSH MD NEUROLOGY

Outline
Anatomy and physiology Types of movement disorders parkinsons disease
Clinical features Drug Therapy Other lines of treatment

zOverview of movement execution

Parts of the Motor System

z Premotor areas (PMA, SMA) plan the motor activity z Primary motor cortex (M1) initiates motor activity:
y Basal ganglia loop (near thalamus) gives the go signal y Cerebellar loop tells the motor cortex how to carry out the planned activity
x Controls direction, timing and force by activating motor neurons in learned programs. x Cerebellum compares what was intended with what happened, then modifies circuits to compensate.

Basal Ganglia Anatomy ; Nuclei and Nomenclature

Corpus striatum Caudate (= with a tail) Striatum or Neostriatum Putamen (= shell) Lenticular nucleus Globus pallidus (= pale sphere) Subthalamus Substantia nigra (= black substance)

Neurotransmitters
z Dopamine (-): substantia nigra to caudate nucleus z ACh (+): from cortex to putamen and caudate z GABA (-): from caudate and putamen to globus pallidus and substantia nigra

Neurotransmitters
z Norepinephrine, serotonin, enkephalin [ - ] glutamate also serve as transmitters.

Basal Ganglia
So what is the basal ganglia circuit doing? The Brake hypothesis B.G. essentially acts like a brake to prevent unwanted movement. Excitation of STN via motor input
leads to diffuse increase in inhibition. Excitation of the striatum in one motor circuit decreasing this inhibition focally thus releasing the brake for the selected movement.

M1, PM SMA

Cortex

Striatum
Indirect pathway

SNc

Direct pathway

GPe

Thalamus

STN
excitatory inhibitory

GPi/SNr

Basal Ganglia Circuit

M1, PM SMA

Cortex

Striatum
Indirect pathway Hyperdirect pathway

SNc

Direct pathway

GPe

Thalamus

D2(-) D1 (+) Indirect Direct

STN
excitatory inhibitory GPi/SNr

(bias is to maintain thalamic channels opened and info flowing to cortex)

Parkinsons Disease (Hypokinetic Movement)

M1, PM SMA
Decreased output of SNc dopaminergic projections Decrease excitation in direct pathway Increase inhibition in indirect pathway Net effect: more inhibition of thalamus and therefore less excitatory input to motor cortex
Direct pathway

Cortex

Striatum
Indirect pathway

SNc

GPe

Thalamus

STN
excitatory inhibitory GPi/SNr D2(-) D1 (+) Indirect Direct

Huntingtons Disease (Hyperkinetic Movement)

M1, PM SMA Cortex Cell loss in the striatum that seems to affect the indirect pathway disproportionately Net effect: less inhibition of the thalamus and therefore excessive excitation of motor cortex

Striatum
Indirect pathway

SNc

Direct pathway

GPe

Thalamus

STN
excitatory inhibitory GPi/SNr

Movement Disorders
z Functions ;
y Planning and modulation of voluntary movement [Role in initiation of the movements , also they assist in the pattern , velocity and rhythm ; gross movements and automatic and associated movements. ] Suppression of involuntary movements Regulation of muscle tone . Postural reflexes Regulation of autonomic nervous system . Involved in a variety of cognitive and emotion processes

y y y y y

z Hyperkinesia: any involuntary movements ; tremors , chorea z Dyskinesia: any involuntary movement (although often used to refer to druginduced choreas and dytonias).

Historical and Examination Features

1] Rhythmic vs arrhythmic [ relation to time ] 2] Patterned vs nonpatterned [ regular or not ] 3] Sustained vs nonsustained 4] Amplitude [ fine vs coarse ] 5] Force [ slight vs powerful ] 6] Speed [slow , rapid vs jerky ]

Historical and Examination Features

7] Distribution ; Unilateral , bilateral, focal ,multifocal & segmental . 8] At rest vs with action or postural. 9] Suppressible 10] Distractible 11] Influenced by sensory stimuli 12] Effect of sleep , emotion

Movement Disorders ; types

Tremors : Rhythmic & regular nonpurposeful oscillatory movements produced by regular contraction of

agonist and antagonist muscles.

x Postural Tremor
During sustained posture

x Intention Tremor

During movement; absent at rest

At rest

x Resting Tremor

Causes : z Parkinsonian tremors ; rest 4-6 / sec coarse. z Essential tremors ; rest and postural 8-10 / sec coarse. z Cerebellar tremors ; kinetic irregular and in horizontal plane. z Rubral tremors ; proximal. z Physiological tremors ; 8-12 / sec fine. z Drug induced ; 10-20 / sec fine.

Movement Disorders ; types

Chorea:
Rapid jerky , non-regular , non-rhythmic , quasipurposive & more proximal involuntary movements
Forceful movements of limbs, head, facial grimacing, & tongue movements Characterized by: Clumsiness of voluntary movements. Due to Caudate lesion.

Causes : z Acute infections ; sydenhams chorea z Vascular ; SLE z Endocrine ; chorea gravidarum z Metabolic ; Wilson disease z Degenerative ; Huntington disease z Drug induced ; oral contraceptive AEDs.

SMA

Putamen

Huntingtons Disease

VLo

GPe GPi

Subthalamus

Movement Disorders ; types

Hemiballismus :
Unilateral violent flailing movements x Involves the proximal muscles x Vascular disease of contralateral subth subalamic nucleus

SMA

Striatum

hemiballism

VLo

GPe GPi

X-

Subthalamus

Movement Disorders ; types

Athetosis :
x Continued slow, twisting & writhing movements. Mainly distal ; hyperextension of fingers and toes. x Wide spread lesion [ midbrain tegmentum, subthalamus and thalamus. ]

Movement Disorders ; types

Dystonia:

Slow, Sustained, patterned Agonists and Antagonists muscle contractions. Affecting axial and appendicular muscles. Due to putamen lesion.
[ Repetitive Twisting or Squeezing Movement with Fixed Postures ]

Movement Disorders ; types

Dystonia:

Localization
1-Focal
Face (Blepharospasm ) Neck (Cervical Dystonia) Limbs (Task Specific Dystonias)

2-Segmental 3-Generalized

Focal Limb Dystonia Blephrospasm Oculogyric Crisis

Movement Disorders ; types

Myoclonus :
z Sudden, shock-like contractions of muscle or group of muscles
x Generalized: widespread Physiological Essential Epileptic Symptomatic Segmental: more localized

Asterixis x negative myoclonus (brief lapses of posture) seen in metabolic encephalopathy

Movement Disorders ; types

Myoclonus : Etiology: any lesion to the central/peripheral nervous system y Benign: sleep jerk, hiccups y myoclonic seizures y Dementing illnesses (alzheimers disease, Jacob-creutzfeld disease,) y Other etiologies: metabolic insult, toxins/drugs, anoxic/traumatic brain injury, CNS infections,

Movement Disorders ; types

Tics :

z
z z z

Semi-voluntary (e.g. suppressible), rapid,nonrythmic movements or sounds Background of normal activity Associated Compulsions May be associated with OCD

Movement Disorders ; types

Tics :
Types ; Transient Simple: common in children, resolve

w/I 1 yr

Chronic: any age, no tx Persistent Simple or Multiple: onset before 15

yoa, resolve in adults Chronic Multiple: Tourettes Sydrome

Movement Disorders ; types

Restless Leg syndrome : z Urge to move legs at night z Improves during movement z Worsens with inactivity z Worse in evening/night z Prevents sleep

Movement Disorders ; types

Drug-Induced Acute Dyskinesia :
y Occurs in 2-3% of patients exposed to DRB agents, especially young adults (<30 years). Prophylaxis? y Abrupt onset: y 50% occur within the first 48 hours y 90% occur within the first 5 days y Often mistaken for a conversion disorder y Limb/trunk dystonia, cervical dystonia, blepharospasm, oromandibular dystonia, oculogyric crisis, even respiratory stridor !

Movement Disorders ; types

z Drug-induced Parkinsonism
More common in elderly and women Symmetric onset of bradykinesia, tremor, and/or rigidity Onset within a few days to 3 months in 90% of affected patients Stop drug, try anticholingeric therapy
New and Old Antipsychotics Risperdal Haldol Phenothiazines Compazine Phenergan Others causing mainly postural tremors: Lithium Amiodarone Depakote

Movement Disorders ; types

Akathisia : Motor restlessness with a desire to mov Often very disabling Cause: MEDICATIONS antipsychotics and Metoclopromide

Movement Disorders ; types

Tardive Dyskinesia (TD) : Prevelance: Risk Factors:

0.5-65% of patients exposed to DRB agents Old age (unlike the cases of acute and tardive dystonia) Female gender (probably) Type of DRB used (traditional vs atypical DRB) Dose and duration of DRB exposure

Movement Disorders
Hypokinetic Movement Disorders
Parkinsons Disease

Hyperkinetic Movement Disorders

Huntingtons Disease , others Wilsons Disease Tourettes Syndrome Restless Leg Syndrome Ballism

Parkinsons disease
Described byJames Parkinson,1817 Most common disorder of movement Affects 3% of the population overthe age of 65 years .

Parkinsons Disease
Degenerative disease in which the dopaminergic, neuro-melanin containing neurons in Substantia nigra pars compacta die.
Normal Parkinsons

Pathophysiology of PD Disease
Cortex

Caudate nucleus
Corpus striatum

Putamen Globus pallidus

Thalamus

Loss of dopaminergic input to striatum

Midbrain

Degeneration of neurons in substantia nigra pars compacta

Disrupted signaling between basal ganglia, cortex, and thalamus

Cardinal Features of Parkinsons Disease

Tremor Rigidity Bradykinesia , hypokinesia Postural Instability Autonomic nervous system dysfunction Mental changes. Secondary manifestations

Clinical features of PD
Resting tremor: Most common first symptom, usually asymmetric and most evident in one hand with the arm at rest. [ pill rolling ]. Bradykinesia: Reduction or loss of initiation , implementation and facility of execution of volitional and automatic movements. Difficulty with daily activities such as writing, shaving, and opening buttons; decreased blinking, masked facies, slowed chewing and swallowing.

When to suspect Parkinsons disease?

Bradykinesia (slowness of movement) & Hypokinesia (poverty of movement) Rigidity Resting tremor Postural instability

Motor Features of Parkinsons disease

1. Bradykinesia
Slower in all movements Movements may be restricted in range Gait
shuffling Turning en bloc Freezing festinant

Clinical features of PD

Rigidity: Muscle tone increased in both flexor and extensor muscles providing a constant resistance to passive movements of the joints; stooped posture, anteroflexed head, and flexed knees and elbows.

Postural instability: Due to loss of postural reflexes. Shuffling gait, decreased stride , Cant start cant stop , Freezing, Speeding up, flexion attitude ,Altered center of gravity, Tendency to retropulsion , Decreased arm swing ,Compass turn

Clinical features of PD
Dysfunction of the autonomic nervous system: Impaired gastrointestinal motility, bladder dysfunction, sialorrhea, excessive head and neck sweating, and orthostatic hypotension. Depression: Mild to moderate depression in 50 % of patients. Cognitive impairment: Mild cognitive decline including impaired visual-spatial perception and attention, slowness in execution of motor tasks, and impaired concentration in most patients; at least 1/3 become demented during the course of the disease.

Posture disturbance in Parkinsons disease

Non-motor Problems in PD
Autonomic Dysfunction Neuropsychiatric Symptoms Cognitive Impairment Sleep Disturbances Sensory Phenomena

Drug-induced Parkinsonism
More common in elderly and women Symmetric onset of bradykinesia, tremor, and/or rigidity Onset within a few days to 3 months in 90% of affected patients Stop drug, try anticholingeric therapy
New and Old Antipsychotics Risperdal Haldol Benzamides Reglan Phenothiazines Compazine Phenergan Others causing mainly postural tremors: Lithium Amiodarone Depakote

Sites of Action of Parkinsons Disease Drugs

SINEMET (CARBIDOPA-LEVODOPA) DESCRIPTION SINEMET* (Carbidopa-Levodopa) is a combination of carbidopa and levodopa for the treatment of Parkinson's disease and syndrome.

Inhibitor of MAOB

Selegiline (l-deprenyl, Eldepryl or Anipryl veterinary) is a drug used for the treatment of early-stage Parkinson's disease and senile dementia. Rasagiline (Azilect) .

Inhibitors of COMT

Entacapone

Tolcapone

Inhibitors of COMT

Entacapone is marketed by Novartis as Comtan in the US Stalevo is a combination of Levodopa, Carbidopa, and Entacapone

Dopamine Agonists
Act directly at postsynaptic DA receptors Longer half life -less wearing off Older Agents:
bromocriptine -d2 agonist, partial d1antagonist pergolide -d1 and d2 agonist

Newer Agents -d2/d3 agonists

pramipexole (Sifrol) ropinirole (Requip)

Amantadine
Amantadine HCL (Symmetrel)
Inhibits dopamine recapture Blocks acetylcholine and glutamate receptors Dose 100mg BID to TID Currently used to reduce choreic movements. Unpleasant side effects such as nausea, dizziness, confusion, hallucinations, nightmares, dry mouth peripheral edema, and livedo reticularis

Anticholinergics
Trihexyphenidyl HCL (Artane) Biperdine ( Akinton ) Benztropine Mesylate (Cogentin)
Monotherapy or adjunct Predopaminergic therapy Long touted as most effective for reducing tremor Use Limited by side effects especially in the elderly.

Pharmacotherapy of PD
Levodopa preparations:
Carbidopa/levodopa Sinemet Sinemet CR Parcopa Stalevo

Dopamine agonists
Apomorphine (Apokyn) Pramipexole (Sifrol) Ropinirole (Requip) Rotigitine (Neupro) Parlodel (Bromocriptine)* Pergolide (Permax)*
*no longer used d/t cardiac valve complications; pergolide no longer on US market

Pharmacotherapy of PD
NMDA Antagonists
Amantadine (Symmetryl)

Anticholinergic agents
Benztropine (Cogentin) Trihexyphenidyl (Artane)

MAO-B Inhibitors
Selegeline (Eldepryl or Deprenyl) Zydis Selegeline (Zelapar) Rasagiline (Azilect) Carbidopa

COMT Inhibitors
Entacapone (Comtan) Tolcapone (Tasmar)

Pallidotomy

Surgical lesion of the globus pallidus Effect can be long-lasting (>3 years), butunderlying disease continues to progress

Deep Brain Stimulation

Recently FDA-approved Implanted into subthalamic nucleus, to control all symptoms of PD Require periodic adjustment ,battery changes, carry risk of infection ,surgical complications