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
