EXTRAPYRAMIDAL DISEASE
I NVOLUNTRY MOVEMENT DR ZAKI NOAH HASAN Professor of neurologyThe Basal Ganglia Consists of Five Large Subcortical Nuclei That Participate in Control of Movement: Caudate Nucleus Putamen Globus Pallidus Subthalamic Nucleus Substantia Nigra
Within the basal ganglia are complex inhibitory and excitatory connections
Function of BG
precise control over initiation Fine control of movements.input from the cerebral cortex through the thalamus and output to the thalamus/ cerebral cortex and pyramidal system.
movement disorders
either an excess or a hyperkinetic movement disorder paucity of movement [ hypokinetic movement disorders]Hypokinetic movement disorders
characterized by rigidity bradykinesia or akinesia. Postural instability gait disorder. Parkinson disease is the most common hypokinetic disorderl Substantia Nigra
DEPIGMENTATIONParkinson's Disease (Idiopathic Parkinson's Disease, ParalysisAgitans)
chronic progressive neurodegenerative disease of basal ganglia characterized by loss of substantia nigra [SN] dopaminergic neuron. 150 – 200 per 100000 prevalence�� 1% prevalence > age 65 years�� 2% prevalence > age 85 years�� Females = Males It is less common in cigarette smokers.
:pathological findings : Depigmentation of substantia nigra Neuronal loss of substantia nigra Lewy bodies : eosinophilic cytoplasmic inclusions
Imbalance of dopamine and acetylcholine Loss of 80 to 90% of dopaminergic production in the substantia nigra depletion of neurons in the locus coeruleus
Causes of parkinsonism• Idiopathic PD• Familial (hereditary) PD• Parkinsonian syndromes:• PSP• MSA• Corticobasal degeneration (CBD)4- Secondary parkinsonism:• Postencephalitic• HydrocephalusDrug-induced Parkinsonism (esp. anti-psychotic, anti-emetics)Vascular ParkinsonismToxins (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP], CO, manganese, cyanide, methanol)Trauma “ pugilistic encephalopathy [punchen drunken disease]Neoplastic,Hydrocephalus Infections (fungal, acquired immunodeficiency syndrome,subacute sclerosing panencephalitis, Creutzfeldt-Jakob disease 5- • Degenerative disorders with associated parkinsonism:• Alzheimer disease (AD)• Parkinson—dementia—motor neuron disease complex6• Genetic disorders with associated parkinsonism:• Wilson disease (consider in all cases <50 years)• Huntington disease (HD)(akinetic rigid [Westphal] variant)• Dopa-responsive dystonia
Familial PD• Rare (often one family per mutation); multiple genotypes impacting different proteins (or unknown products) with widely different function resulting in similar phenotypes• 20 or more mutations identified (e.g., PARK 1–20) on 5 or more chromosomes• Autosomal dominant and recessive forms
Non-motor symptoms, although commonly seen alongside the motor symptoms of PD, might in many cases arise earlier
MOTOR DISTURBANCES
NON-MOTOR DISTURBANCEShypophonia
mild cognitive impairment, dementia
hypomimia
depression, anxiety
dysphagia
sialorrhea
hand incoordination
orthostatic hypotension
hand incoordination
orthostatic hypotension
dystonia
gastrointestinal dysmotility, constipation
generalized slowing
bladder dysfunction
gait impairment
sexual dysfunction
imbalance and falls
hyposmia
freezing (gait, speech uncommon)
sleep disorders: RBD; RLS; sleep fragmentation`
micrographia
visual impairment: impaired contrast discrimination
R-A-T-PRigidity (cogwheel; lead pipe)Akinesia Tremor (at rest) Postural Instability• Rigidity: increased tone; cogwheeling (a “catching” or ratcheting felt by examiner when joints passively manipulated)
The core features of Parkinson’s disease are bradykinesia and rigidity. Bradykinesia is slowness of initiation of voluntary movement with progressive reduction in speed and amplitude with repetition and lack of spontaneous movements (often most noticeable as reduced blinking, lack of facial expressionand reduced arm swing when walking), a slowing of movements, especially fine repetitive ones.
Hypokinesia means reduced amplitude of movement Akinesia means inability to move leads to masking of the face [hypomamia], loss of blinking , absence of arm swing , small cramped hand writing soft slow monotonous speech
Absence of blinking Dribbling of saliva Expressionless Monotonous, soft speech Sweatiness, sialorrhea Weakness of upward gaze Glabellar tap [ myerson sign]
FACE
Micrographia-small handwriting
excessive salivation and drooling of saliva
Excessive greasiness of the skin and seborrhic dermatitis ,characteristically seen over the forehead, eyebrows, and malar area
TremorResting4 – 6 Hz, disappears with voluntary movementInitially appears intermittently – disappears while sleepingAccentuated by anxiety or emotional stressPill rolling• May be the first symptom in 75% of cases of PD.• Twenty percent of patients never develop tremor.• Some patients may in addition have a postural element
Gait
Slow to start walking Shortened stride Rapid, small steps, tendency to run (festination) Reduced arm swing Impaired balance on turningmental disturbances :depression 35% dementia 20% personality disorder slow memories retrieval Akathesia [urge to move]
autonomic system features occurs in 20-25 %
DIFFERENTIAL DIAGNOSIS OF PARKINSON DISEASE
ESSENTIAL TREMOR – OCCASIONALLY CONFUSED WITH PARKINSON DISEASE. HOWEVER, 20% OF ET PATIENTS DEVELOP PDSECONDARY PARKINSONISM, i.e. DRUGS, NPH, INFECTIONS, etc.“PARKINSON – PLUS” SYNDROMES, i.e. CBD, LBD, AD, MSA, PSPHEREDODEGENERATIVE – HD, WILSON, HALLERVORDEN-SPATZ"Red flags" in the diagnosis of Parkinson's disease Early or prominent dementia Symmetrical signs Bulbar dysfunction Early gait disorder Falls within the first year Wheelchair dependence within 5 years Early autonomic failure Sleep apnea Gasping respirations Apraxia Gaze palsy lower limb only involvement Cortical sensory loss
Oculogyric crises, which are sudden episodes of involuntary ocular deviation (most often up and to the side) in the absence of neuroleptic drug exposure, are virtually pathognomonic of parkinsonism after encephalitis lethargica,
Parkinsonism diagnostic criteria: 1. Tremor at rest 2. Bradykinesia 3. Rigidity 4. Loss of postural reflexes 5. Flexed posture 6. Freezing (motor blocks) Definitive: at least 2/3 of these features,
Diagnosis
Diagnosis
Parkinson disease is a clinical diagnosis. No laboratory biomarkers exist for the condition, and findings on routine magnetic resonance imaging and computed tomography scans are unremarkable.FP-CIT SPECT (DaTscan) is now available for clinical use in many countries,Approaches focused upon specific protein measures in CSF (e.g. -synuclein, DJ-1, tau, Aβ1-42), genomic, proteomic, transcriptomic and metabolomic analyses, markers of oxidative stress, inflammatory markers and others are not yet close to clinical applicationTREATMENT OF PARKINSON DISEASE
MEDICAL DOPAMINERGIC AGENTS ANTI-CHOLINERGICS; etc. SURGICAL ABLATIVE RESTORATIVE D.B.S.PHYSICAL THERAPIES P.T. O.T. SPEECH OMT, BIOFEEDBACK EXERCISE Rx, TAI-CHI PSYCHOTHERAPIES COUNSELLING SOCIAL WORK MEDS., etc.
Drugs that increase brain levels of dopamine Levodopa Drugs that mimic dopamine (dopamine agonists) Apomorphine Bromocriptine Pramipexole Ropinirole Drugs that inhibit dopamine breakdown (MAO-B inhibitors) Selegiline (deprenyl) Drugs that inhibit dopamine breakdown (COMT inhibitors) Entacapone Tolcapone Drugs that decrease the action of acetylcholine anticholinergics) Trihexyphenidyl Benztropine Ethopropazine Drugs with an unknown mechanism of action for PD Amantadine
Levodopa Dopamine agonists COMT inhibitors Amantadine Anticholinergics Selegiline
L dopa
more than 90% is decarboxylated to dopamine peripherally in the gastrointestinal tract and blood vessels, and only a small proportion reaches the brain. This peripheral conversion of levodopa is responsible for the high incidence of side-effects if used alone. The problem is largely overcome by giving a decarboxylase inhibitor that does not cross the blood-brain barrier along with the levodopa. Two peripheral decarboxylase inhibitors, carbidopa and benserazide, are available as combination preparations with levodopa, as Sinemet and Madopar. Actual dopamine can’t be used because it is unable to cross the cell walls into the brain.Carbidopa is used in conjuction with Levodopa to increase the amount of Levodopa to enter the brain.Most effective against bradykinesia and rigidityis absorbed from the gut, crosses the blood–brain barrier converted into dopamine by the enzyme dopa-decarboxylase.It is given with a dopa-decarboxylase inhibitor which does not cross into the brain. This prevents the levodopa from being converted into dopamine in the body (where it would cause nausea and vomiting)
L-Dopa Crosses the blood-brain barrier Levodopa has been the mainstay of PD treatment since the 1960’s. It is highly efficacious in symptomatic treatmentAdverse effects such as nausea, vomiting, postural hypotension, involuntary movements, restlessness, and cardiac arrhythmias
Long term complication of L dopa
Wearing off: the response becomes shorter and less marked.• Dyskinesia: each dose produces involuntary chorea movements.• On–off effect: the transition between lack of response (off) and response (on) becomes rapid.Bromocriptine Mesylate (Parlodel) Pergolide Mesylate (Permax) Pramipexol (Mirapex) Ropinirole HCL (Requip)
Dopamine Agonists
The oral dopamine agonists are not as potent as levodopa in alleviating parkinsonism, less prone to cause dyskinesia and fluctuation. Young and mildly affected patients are sometimes started therefore on a dopamine agonist initially, in the hope of postponing levodopa therapy and its complications for a while. Alternatively the agonist drugs can be introduced later, to reduce the patient’s reliance on levodopa after these complications have begun.
Pramipexole (Mirapex) Monotherapy or Adjunct Initial dose of 0.125 mg TID and increased every 5 to 7 days as tolerated up to 3 to 4.5mg/d Higher doses are not more effective than 1.5mg/d and are associated with more side effects Mean 27% reduction of L-Dopa Decrease dose with renal function impairment Drugs that are secreted by the cationic transport system may decrease the clearance of pramipexole by 20%. These include cimetidine, diltiazem, quinidine, quinine, ranitidine, triamterene, and verapamil.
Entacapone (Comtan) Adjunct therapy Initial dose of 200mg with each dose of levodopa up to 8 times daily Decrease of L-dopa may be necessary Exacerbation of L-dopa side effects , diarrhea, urine discoloration, abdominal pain
Anticholinergic drugs are useful for treating tremor, but have much less effect on the other aspects of parkinsonism, and often seriously aggravate memory problems and hallucinations. Conversely, memory problems and hallucinations often respond to cholinergic therapy with drugs like donepezil and rivastigmine. These inhibit the cholinesterase enzyme that beaks down acetylcholine
Amantadine
• Previously used in early PD to delay the use of levodopa; with the advent of DA drugs there is little use for this indication.• New role in the management of drug-related dyskinesias due to glutamate antagonistic properties.• Dose 100–300 mg/day.• Side effects: confusion, hallucinations, ankle edema, livedo reticularis, insomnia (second dose at midday)Pallidotomy and Pallidal Stimulation Thalamotomy and Thalamic Stimulation
Multiple systems atrophy (MSA)Degeneration is more widespread than in idiopathic Parkinson's disease, and the disappointing response to levodopa and other anti-parkinsonian drugs Features of parkinsonism, often without tremor, are combined with varying degrees of autonomic failure, cerebellar involvement and pyramidal tract dysfunction. The combination of parkinsonism with autonomic failure was called the Shy-Drager syndrome