Parkinson’s Disease

Introduction 

-Parkinson’s disease is a neurodegenerative disorder due to dopamine depletion in the substantia nigra and in the nigrostriatal pathway to the caudate and putamen. 

-the second most common age-related neurodegenerative disease, exceeded only by Alzheimer’s disease (AD)

-The mean age of onset of PD is about 60 years

-The cause remains largely unknown 

-The only known cause of PD: Genetic mutations 

-Occurs in all ethnic groups with equal sex distribution 

-Prior use of ibuprofen is associated with a decreased risk of developing Parkinson disease 

Symptoms & Signs 

rest tremor, rigidity (stiffness), bradykinesia (slowing), and gait dysfunction with postural instability. freezing of gait, speech difficulty, swallowing impairment, autonomic disturbances,

MOTOR FEATURES 

Cardinal features: Tremor (most conspicuous at rest, enhanced by stress)Rigidity, Bradykinesia(the most disabling symptom; a slowness of voluntary movement) 

Craniofacial: Masked facial expression (hypomimia), hypophonia, Dysphagia, Repetition of a phrase or word with increasing rapidity (palilalia), speech impairment 

Visual: blurred vision, Eyelid opening apraxia, hypometric saccades, impaired vestibuloocular reflex 

Musculoskeletal: Stooped posture, micrographia, dystonia, myoclonus, difficulty turning in bed

Gait: A loss of the normal automatic arm swinging, Shuffling, Short-stepped gait, freezing, festination  

NONMOTOR FEATURES 

Psychosis: Visual, auditory, olfactory, and tactile hallucinations 

Fatigue

Olfactory dysfunction: loss of smell 

Sensory disturbances: Pain 

Mood disorders: Depression (most common psychiatric disturbance seen in PD), anxiety, loss of motivation, 

Sleep disturbances: Rapid eye movement sleep behavior disorder (RBD), sleep fragmentation, early morning awakening, restless legs syndrome 

Autonomic disturbances

 Orthostatic hypotension

 Gastrointestinal disturbances Constipation, Dysphagia 

 Genitourinal disturbances Urinary difficulties 

 Sexual dysfunction: underactivity, hypersexuality 

Cognitive impairment/Dementia

Dermatologic: Seborrhea 

Diagnosis 

There are no diagnostic tests for PD 

Primarily a clinical diagnosis based on symptoms and signs 

Myerson Sign: Repetitive tapping (about twice per second) over the bridge of the nose producing a sustained blink response

Treatment 

PHARMACOLOGIC TREATMENT 

Dopamine Replacement Therapy 

Dopamine: Given the deficiency of dopamine, it would be nice if we could just give dopamine itself. However, dopamine does not cross the blood-brain barrier. 

Levodopa: 

Logic behind Levodopa-Carbidopa combination: 

Levodopa can cross the blood-brain barrier, but large doses are required because much of the drug is decarboxylated to dopamine in the periphery causing side-effects like nausea, vomiting, and orthostatic hypotension. 

Carbidopa is a dopamine decarboxylase inhibitor that does not cross the blood–brain barrier. It reduces the peripheral metabolism of levodopa, thereby increasing the amount of levodopa that reaches the brain.

-It is the most effective symptomatic treatment for PD 

-It controls classic motor features of PD, improves quality of life, and increases the lifespan

MAO-B inhibitors 

Selegiline, Rasagiline, Safinamide 

At lower doses, Selegiline and rasagiline are not associated with a cheese effect (hypertensive crisis), usually seen when MAO-B inhibitors are taken with tyramine-rich containing foods 

Side-effects: nausea, headache, confusion, hallucinations 

COMT Inhibitors 

-Tolcapone, Entacapone, Opicapone  

-Inhibitors of COMT prolong the elimination half-life of levodopa and enhance its brain availability.

Side-effects of Tolcapone: Severe diarrhea, Fatal hepatic toxicity; periodic monitoring of liver function required

Amantadine

-Antiviral drug effective in the treatment of influenza 

-it ameliorates dyskinesias resulting from prolonged levodopa therapy

-Side-effects: Livedo reticularis, weight gain; should always be discontinued gradually to prevent withdrawal-like symptoms 

Dopamine Agonists (DAs) 

Ergot DAs: Bromocriptine 

Nonergot DAs: Pramipexole, Ropinirole, Rotigotine, Apomorphine 

Due to their serious side-effects, the first generation dopamine agonists (bromocriptine, pergolide, cabergoline) were replaced by second generation agonists such as pramipexole, ropinirole, rotigotine. 

-Side-effects: Sedation with sudden unintended episodes of falling asleep, impulse-control disorders (compulsive eating, shopping, hypersexuality, pathologic gambling) 

Anticholinergics 

Trihexyphenidyl(most widely prescribed anticholinergic), benztropine, biperiden 

-Contraindicated in patients with prostatic hypertrophy, narrow-angle glaucoma, or obstructive intestinal disease 

Side-effects: Dryness of the mouth, constipation, urinary retention, cardiac arrhythmias, palpitations, mydriasis, agitation, restlessness. 

Antipsychotics

Olanzapine, Quetiapine, Risperidone, Clozapine 

-Clozapine can cause marrow suppression, necessitating weekly cell counts 

Antidepressants: selective serotonin-norepinephrine reuptake inhibitor (SNRI) or a selective serotonin reuptake inhibitor (SSRI), cognitive behavioral therapy 

Stimulants: Modafinil, methylphenidate 

Nonpharmacologic management: 

Exercise and physical therapy 

Speech therapy

Occupational therapy

Nutrition 

Cognitive behavioral therapy 

Deep Brain Stimulation 

Palliative care 

Prognosis 

The serum urate level may be a prognostic indicator in men—the rate of progression declines as the urate level increases.

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