PARKINSON’S DISEASE

Dr. SHOBHIT SHAH

GENERAL ASPECTSComponents of basal ganglia:• Striatum (caudate nucleus and putamen )• Globus pallidus• Substantia nigra• Nucleus accumbens• Subthalamic nucleus• Affernts : 1) from cerebral cortex to striatum• 2)from centromedian nucleus of thalamus to striatum• Efferents : 1) mainly from internal segment of globus pallidus to CM nucleus of

thalamus• 2)from substantia nigra to thalamus• Intrastriatal pathways are cholinergic• Striatonigral pathways are GABAergic• Nigrostriatal pathways are dopaminergic• In Parkinson disease, all pathways are effected but nigrostriatal pathway is effected

the most

FUNCTION OF BASAL GANGLIA

• Planning and programming of movement ( skilled movements)

• Role in cognitive process ( esp. that of caudate )

• Parkinson disease is a chronic progressive disease of nervous system characterised by cardinal features of tremors , rigidity , bradykinesia and postural instability.

• UK brain bank criteria ( resting tremors, asymmetry and good response to levodopa). Diagnosis of PD is confirmed in 99% cases by this criteria.

TREMORS

• Resting tremor: causes "pill rolling" between thumb and index fingers and illegible writing

• Parkinsonian tremor is characteristically slow, of medium to coarse amplitude (3-7 Hz); present at rest; increased by emotion, fatigue, stress, and anxiety; absent in sleep; and decreased by volitional activity.

• It typically affects the distal appendicular muscles, leading to: • Flexion-extension movements of the metacarpophalangeal

and interphalangeal joints of the fingers and thumb • Adduction-abduction movements of the thumbs (pill rolling) • Pronation-supination movements of the wrists. • It often begins unilaterally in the hand and may be present

initially only in the thumb or a single finger.

TREMORS

• The tremor then typically spreads to the ipsilateral lower extremity (hemiparkinsonism) before involving the opposite half of the body.

BRADYKINESIA

• Bradykinesia (decreased movements). • Bradykinesia is the most disabling manifestation of

parkinsonism • It’s characterized by delay in the initiation and execution of

willed movements and a general reduction of associated automatic movements.

• Bradykinesia explains (at least partially) the facial hypomimia, reduced blinking, impaired ocular convergence, monotonous and low-volume speech (bradylalia, eventually leading to anarthria), drooling of saliva, micrographia, and slow shuffling gait with reduced associated movements that occur in parkinsonism.

RIGIDITY

• Muscle rigidity: causes slowness of voluntary muscle movement (bradykinesia) and cogwheel rigidity

• Rigidity is characterized by a plastic resistance to passive movements that affects both agonist and antagonist muscles (e.g., flexors and extensors, pronators, and supinators) to a similar extent and that is constant throughout the entire range of movement.

• Rigidity affects more axial and proximal limb muscles

OHTER ASSOCIATED FEATURES(MOTOR FEATURES)

MicrographiaMasked facies (hypomimia)Reduced eye blink Soft voice (hypophonia)DysphagiaFreezing

ASSOCIATED NON MOTOR FEATURES

Anosmia Sensory disturbances (eg. Pain)Mood disorders ( eg. Depression)Sleep disturbancesAutonomic disturbances( orthostatic hypotension,

GI disturbances, GU disturbances, sexual dysfunction )

Cognitive impairment / dementia

PATHOLOGY

Degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), reduced striatal dopamine and intracytoplasmic proteinous inclusions k\a lewy bodies

Neuronic degeneration can also affect cholinergic neurons of nucleus basalis of meynert (NBM), serotonin neurons in raphe nuclei of brainstem and neurons of olfactory system, cerebral hemispheres, spinal cord, and peripheral autonomic nervous system

PATHOLOGY

• Symptom reflecting nondopaminergic degeneration such as constipation, anosmia, rapid eye movement(REM) behavior sleep disorder and cardiac depervation precede the onset of the classic motor features of the illness

PATHOGENESIS

Nigral dopamine neurons and other cell dies because of following facters :

Genetic vulnerability ( abnormal processing or folding of alfa-synuclein leds to lewy body formation )

Oxidative stress ( due to mitochondrial dysfunction)

Proteasomal dysfunction ( protease inhibition substrate accumulation)

PATHOGENESIS

• Abnormal kinase activity inappropiate phosphorylation

• Enviromental facters• Oxidative stress plays major role in sporadic form

of PD. Free radicals produced by metabolism of dopamine and melanin Defect in mitochondrial complex 1 of oxidative phosphorylation chain.

• MPTP, a meperidine derivative ; rotenone inhibits complex 1.

• Genetic factors: • Autosomal dominant (AD) and autosomal recessive (AR)

patterns of inheritance have been identified. chromosome 4q21-23: • Alanine-53-threonine mutation in the α-synuclein gene. • Autosomal dominant (AD). • Earlier disease onset (mean, age 45 years).• Faster progression. • Some with fluent aphasia.

• chromososme 6q25.2-27:• The parkin gene. • Autosomal recessive (AR).• Relatively young-onset parkinsonism. • Early dystonia. • Symmetric involvement.• Good levodopa response. • Absence of Lewy bodies at autopsy.

• chromosome 2p13: • Autosomal dominant (AD) but with 40% penetrance. • All from northern Germany and southern Denmark. • Nigral degeneration and Lewy bodies at autopsy. • Dementia may be more common

• chromosome 4p14-16.3: • Autosomal dominant (AD). • From a family known as the Iowa kindred. • Also younger age of onset (mean, 34 years).• Rapid clinical course. • Early-onset dementia. • Equivocal response to levodopa. • Some family members with only postural tremor

resembling essential tremor. • Autopsy shows Lewy bodies in the nigra and hippocampus.

mutation in ubiquitin carboxy-terminal hydrolase L1 on chromosome 4:

• Autosomal dominant (AD). • Young-onset progressive parkinsonism. chromosome 1p35-36: • Autosomal recessive (AR). • Early-onset parkinsonism. • Slow progression. • Marked response to levodopa. • Gene not yet identified.

chromosome 1p3: • Early Autosomal recessive (AR) parkinsonism. • Slow progression. • With levodopa responsiveness.

D/D

• Differential Diagnosis: • There are other disorders that may cause parkinsonism

besides Parkinson disease (sometimes called “Parkinson plus”).

• These disorders may be difficult to separate clinically from Parkinson disease.

• A lack of response to medication for Parkinson, early dementia, and other neurologic signs may all suggest such conditions.

• Up to 30% of patients with parkinsonism ultimately have a cause other than Parkinson disease.

D/D

• Medications may cause secondary parkinsonism by blocking the D2 receptor in the basal ganglia.

• Common agents responsible for this effect include typical neuroleptics such as haloperidol and the anti-emetic metoclopramide.

• Up to 5% of patients on long-term valproic acid will develop parkinsonism with a cognitive decline that may be reversible.

D/D

• Progressive supranuclear palsy (PSP) is a degenerative disorder in which patients have a toppling gait, impaired voluntary up-and-down eye movements, and pseudobulbar palsy.

• PSP should be considered in a parkinsonian patient who presents with falling as an early symptom.

D/D

• Multiple system atrophy (MSA) refers to a group of degenerative disorders in which there are abnormalities in multiple neurologic systems, including the basal ganglia, corticospinal tract, autonomic nervous system, and cerebellum.

• The Shy-Drager syndrome is a subtype of MSA with impotence, postural hypotension, and parkinsonism.

• Early urinary incontinence, orthostatic hypotension, and dysarthia are suggestive of multiple system atrophy.

• (MSAc – cerebellar) has intentional tremors, dysarthia• (MSAp – parkinson ) has resting tremors.

D/D

• Diffuse Lewy body disease may cause parkinsonism, accompanied by an early cognitive decline, prominent visual hallucinations, a fluctuating course, and sensitivity to major antipsychotics.

• Pathologically, Lewy bodies are seen in cortical areas in addition to the pigmented nuclei.

D/D

• Normal pressure hydrocephalus (NPH) involves the triad of gait disorder, cognitive decline, and incontinence.

• Patients may appear parkinsonian but the gait is usually apraxic rather than parkinsonian (patients seem unable to “figure out” how to walk but can still bicycle with their legs effectively when lying in bed on their back).

• NPH may be a delayed manifestation following a head injury, subarachnoid hemorrhage, meningitis, or may occur spontaneously.

• On computed tomography (CT) or magnetic resonance imaging, large ventricles are seen without significant atrophy.

• Gait is “magnetic,” with difficulty picking up the feet despite good strength (gait apraxia).

D/D

• Parkinsonism may be secondary to toxins such as chronic manganese or carbon monoxide intoxication.

TREATMENT OUTLINE

• PD pharmacological interventions neuroprotection - ? Resagiline functional disability if present then levodopa/ dopamine agonists combination therapy with LEVODOPA/ DOPAMINE AGONISTS/ COMT INHIBITERS/ MAO INHIBITERS SURGERY/CDS

• Non pharmacological measures : physiotherapy, counselling, life style modifications.

TREATMENT

• Levodopa is the most effective anti-parkinsonian medication, and is the cornerstone of therapy for most patients.

• Despite this, many physicians delay the use of levodopa until later in the course with the hope that the long-term side effects of this medication can be reduced or delayed.

• The effect may be dramatic when administered early in disease. Used alone, large doses are needed for effect, and the peripheral effect causes nausea and orthostatic hypotension.

• When combined with a dopa-decarboxylase inhibitor (carbidopa), the peripheral effects are minimized, and the dose may be reduced as more of the dopa reaches the brain to be converted to dopamine

TREATMENT

• Combination medication is available as a short-acting or long-acting preparation.

• The short-acting medication is available as 10/100, 25/100, and 25/250, with the first number referring to the milligrams of carbidopa and the second number referring to the milligrams of levodopa.

• A long-acting (CR) form is available as 25/100 or 50/200 mg, but does not confer a significant added benefit.

• Carbidopa/ Levodopa 25/100, 3 to 4 times a day is the usual starting dose. The most common side effect of levodopa therapy is nausea.

TREATMENT

• Early motor fluctuations, dyskinesia, and on-off phenomena are common problems encountered with levodopa/carbidopa as parkinsonism progresses.

• Dystonia, agitation, hallucinations, and sleep disorders also may occur, particularly in patients with dementia.

• Providing levodopa/carbidopa 30 minutes before meals and limiting protein intake during the day may improve absorption and efficacy of levodopa/carbidopa.

TREATMENT

• Dopamine replacement might excessively inhibit the pallidal output system , there by leading to increased thalamo-cortical activity dyskinesia

• Levodopa induced alternation in Gpi neuronal firing pattern.This leds to transmission of misinformation from pallidum to thalamus/cortex leding to dyskinesia. Pallidotomy thus ameliorate dyskinesia

TREATMENT

• Advantages of Levodopa: • Most efficacious antiparkinsonian drug • Immediate therapeutic benefits (within 1 week) • Easily titrated • Reduces mortality • Lower cost

• Disadvantages of Levodopa:• No effect on disease course, • No effect on nondopaminergic symptoms, such as dysautonomia,

cognitive disturbances, and postural instability, motor fluctuations and dyskinesia develop over time (especially in younger patients, those with more severe disease and those requiring higher doses).

TREATMENT• Dopamine agonists are advocated by some authorities as early

monotherapy in an attempt to spare the use of levodopa early in the disease.

• Pergolide, bromocryptine, ropinerole, pramipexole, and rasagiline are available dopamine agonists.

• Because pergolide, pramipexole, and ropinerole are longer-acting agents, they may help smooth out motor fluctuations seen with levodopa therapy, and have fewer choreiform-like dyskinesias than levodopa.

• However, they may cause nausea, hypotension, hallucinations, and confusion, as well as excessive somnolence.

• Gradual titration to the desired dose is the most effective strategy.

TREATMENT

• They may be used as monotherapy or in combination with other anti- parkinsonian medications.

• Ergot derived dopamine agonists (pergolide, bromocryptine, cabergoline) have recently been shown to cause valvular heart disease in up to 5% of treated patients.

• In addition, dopamine agonists may cause impulsive behaviors, such as gambling and hypersexuality, particularly at higher doses.

• Patients taking dopamine agonists should be warned not to drive if excessive somnolence is a significant complaint. It is not known if lowering the dose of dopamine agonist will help this.

TREATMENT

• Catecholamine-O-methyltransferase (COMT) inhibitors (entacapone and tolcopone)

• Extend the pharmacologic half-life of levodopa

• May decrease the amount of “off” time.

TREATMENT

• Selegiline is a selective monoamine-B oxidase inhibitor that increases the availability of dopamine at the synaptic terminal.

• Rasagiline, a selective monoamine-B oxidase inhibitor, was recently approved for use in Parkinson disease.

• This can be used both as an initial agent early in Parkinson disease, or as an add-on agent for “on-off” problems later in the disease.

• In the usual dosing of 0.5 to 1.0 mg per day, there do not appear to be problems with reactions to tyramine-containing foods.

TREATMENT

• Anticholinergic medications were used in the past, but are no longer commonly prescribed due to their side effect profile.

• option for young patients (<60 y/o) whose predominant symptoms are resting tremor and hypersalivation

• available agents—trihexyphenidyl and benztropine;

• adverse effects often limit use—memory impairment, confusion, hallucinations

TREATMENT

• Amantidine, an NMDA antagonist, was initially demonstrated to have a modest anti-parkinsonian effect.

• This agent is now used to reduce dyskinesias when that side effect of treatment occurs.

TREATMENT

• Treatment (Late Stage):• After approximately 5 years of treatment with levodopa,

probably because of loss of buffering action by remaining dopaminergic neurons, patients develop a variety of difficult-to-treat side effects of levodopa.

• Such problems include the following: • Wearing-off of levodopa may be improved by giving the

levodopa more frequently, using longer-acting dopa preparations, adding dopamine agonists to levodopa, adding COMT inhibitors such as tolcapone or entacapone, or adding rasagiline (grade A).

• Fatal hepatotoxicity has occasionally occurred with tolcapone.

TREATMENT

Peak-dose dyskinesias • Use smaller and more frequent levodopa

doses, or lower the levodopa dose and add dopamine agonists.

• Amantidine may also be helpful in this setting

TREATMENT

• “On-off” fluctuations refer to dramatic, unpredictable shifts from under-treated to over-treated states.

• These are difficult to treat. • Adding dopamine agonists, using COMT

inhibitors, using rasagiline, and occasionally using injectable apomorphine may be helpful.

TREATMENT

• Confusion, sleep disorder, and psychosis may be helped by decreasing the medication, particularly limiting anticholinergics, amantidine, and other medications with sedating or anticholinergic effects.

TREATMENT

Impulse control disorders have recently been identified in patients with Parkinson disease (gambling, hypersexuality, excessive shopping, etc.).

• These may be associated with the use of dopamine agonists or be related to the disease entity.

SURGICAL MANAGEMENT

Lesion surgery • Thalamotomy— most effective for parkinsonian and

essential tremor • Pallidotomy—improves bradykinesia, tremor, rigidity,

dyskinesia in PDINDICATIONS : 1) INTRACTABLE TREMORS• 2) DRUG INDUCED DYSKINESIA• Deep brain stimulaters : most preferred site for

implantation is subthalamic nucleus but in parkinson with depresion,the most preffered site is GPi

THANK YOU