Parkinson’s Disease

Overview

Definition

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder affecting the CNS with cardinal features of resting tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies, rigidity Rigidity Continuous involuntary sustained muscle contraction which is often a manifestation of basal ganglia diseases. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity. Megacolon, bradykinesia, and postural instability.

Epidemiology

• One of the most common neurodegenerative disorders
• Annual incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 4.5–21 cases per 100,000 population
• Mean Mean Mean is the sum of all measurements in a data set divided by the number of measurements in that data set. Measures of Central Tendency and Dispersion age at onset: approximately 60 years
• Lifetime risk: approximately 2% for men and 1.3% for women

Etiology

The etiology of PD is unclear but depends on various genetic and environmental factors. 

Risk factors

• Environmental and nongenetic risk factors: 
  • Exposure to pesticides
  • Exposure to nitrogen Nitrogen An element with the atomic symbol n, atomic number 7, and atomic weight [14. 00643; 14. 00728]. Nitrogen exists as a diatomic gas and makes up about 78% of the earth’s atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. Urea Cycle dioxide
  • History of traumatic brain injury Traumatic brain injury A form of acquired brain injury which occurs when a sudden trauma causes damage to the brain. Le Fort Fractures
  • Exposure to hydrocarbon solvents
  • Living in a rural environment
  • Living in proximity to industrial plants Plants Cell Types: Eukaryotic versus Prokaryotic or quarries
  • Drinking well water
  • Use of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to cause irreversible parkinsonism Parkinsonism West Nile Virus.
  • Excess body weight
  • Type 2 Type 2 Spinal Muscular Atrophy diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
• Gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations associated with PD:
  • Alpha-synuclein (SNCA) gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
  • Leucine-rich repeat kinase 2 (LRRK2) gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics loci
  • Parkin (PARK2) gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations
  • Phosphatase and tensin homolog Phosphatase and TENsin homolog A lipid phosphatase that contains a C2 domain and acts on phosphatidylinositol-3, 4, 5-trisphosphate to regulate various signal transduction pathways. It modulates cell growth processes; cell migration; and apoptosis. Mutations in pten are associated with cowden disease and proteus syndrome as well as neoplastic cell transformation. Cowden Syndrome (PTEN)–induced putative kinase 1 (PINK1) gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics loci

Pathophysiology

Compensatory mechanisms in the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification may temporarily decrease the effects of dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS depletion until these mechanisms are overpowered by the progression of PD.

• Depletion of dopaminergic neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology in the substantia nigra Substantia nigra The black substance in the ventral midbrain or the nucleus of cells containing the black substance. These cells produce dopamine, an important neurotransmitter in regulation of the sensorimotor system and mood. The dark colored melanin is a by-product of dopamine synthesis. Basal Ganglia: Anatomy pars compacta → depletion of dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS in the nigrostriatal pathway Nigrostriatal pathway Basal Ganglia: Anatomy → development of motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology symptoms
• Overactivity of the indirect pathway Indirect Pathway Huntington Disease functionally disables functioning of the substantia nigra Substantia nigra The black substance in the ventral midbrain or the nucleus of cells containing the black substance. These cells produce dopamine, an important neurotransmitter in regulation of the sensorimotor system and mood. The dark colored melanin is a by-product of dopamine synthesis. Basal Ganglia: Anatomy. 
• Lewy bodies (the pathologic hallmark of PD):
  • Round, eosinophilic, intracytoplasmic neuronal inclusions
  • Contain abnormal alpha-synuclein proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis 
  • Seen in:
    • Substantia nigra Substantia nigra The black substance in the ventral midbrain or the nucleus of cells containing the black substance. These cells produce dopamine, an important neurotransmitter in regulation of the sensorimotor system and mood. The dark colored melanin is a by-product of dopamine synthesis. Basal Ganglia: Anatomy
    • Locus Locus Specific regions that are mapped within a genome. Genetic loci are usually identified with a shorthand notation that indicates the chromosome number and the position of a specific band along the P or Q arm of the chromosome where they are found. For example the locus 6p21 is found within band 21 of the P-arm of chromosome 6. Many well known genetic loci are also known by common names that are associated with a genetic function or hereditary disease. Basic Terms of Genetics coeruleus
    • Cerebral cortex Cerebral cortex The cerebral cortex is the largest and most developed part of the human brain and CNS. Occupying the upper part of the cranial cavity, the cerebral cortex has 4 lobes and is divided into 2 hemispheres that are joined centrally by the corpus callosum. Cerebral Cortex: Anatomy
    • Sympathetic ganglia
• The pathologic changes in PD start in the olfactory bulb Olfactory bulb Ovoid body resting on the cribriform plate of the ethmoid bone where the olfactory nerve terminates. The olfactory bulb contains several types of nerve cells including the mitral cells, on whose dendrites the olfactory nerve synapses, forming the olfactory glomeruli. The accessory olfactory bulb, which receives the projection from the vomeronasal organ via the vomeronasal nerve, is also included here. Olfaction: Anatomy → progress over many years to the cerebral cortex Cerebral cortex The cerebral cortex is the largest and most developed part of the human brain and CNS. Occupying the upper part of the cranial cavity, the cerebral cortex has 4 lobes and is divided into 2 hemispheres that are joined centrally by the corpus callosum. Cerebral Cortex: Anatomy in 6 stages, called Braak staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis:
  • Presymptomatic stages 1 and 2: pathologic changes are found in:
    • Olfactory bulb Olfactory bulb Ovoid body resting on the cribriform plate of the ethmoid bone where the olfactory nerve terminates. The olfactory bulb contains several types of nerve cells including the mitral cells, on whose dendrites the olfactory nerve synapses, forming the olfactory glomeruli. The accessory olfactory bulb, which receives the projection from the vomeronasal organ via the vomeronasal nerve, is also included here. Olfaction: Anatomy
    • Medulla oblongata Medulla Oblongata The lower portion of the brain stem. It is inferior to the pons and anterior to the cerebellum. Medulla oblongata serves as a relay station between the brain and the spinal cord, and contains centers for regulating respiratory, vasomotor, cardiac, and reflex activities. Brain Stem: Anatomy 
  • Stages 3 and 4: symptoms start appearing as the pathology migrates to:
    • Substantia nigra Substantia nigra The black substance in the ventral midbrain or the nucleus of cells containing the black substance. These cells produce dopamine, an important neurotransmitter in regulation of the sensorimotor system and mood. The dark colored melanin is a by-product of dopamine synthesis. Basal Ganglia: Anatomy pars compacta 
    • Structures of the midbrain Midbrain The middle of the three primitive cerebral vesicles of the embryonic brain. Without further subdivision, midbrain develops into a short, constricted portion connecting the pons and the diencephalon. Midbrain contains two major parts, the dorsal tectum mesencephali and the ventral tegmentum mesencephali, housing components of auditory, visual, and other sensorimotor systems. Brain Stem: Anatomy
  • Stages 5 and 6: pathologic process reaches:
    • Temporal lobe Temporal lobe Lower lateral part of the cerebral hemisphere responsible for auditory, olfactory, and semantic processing. It is located inferior to the lateral fissure and anterior to the occipital lobe. Cerebral Cortex: Anatomy
    • Frontal lobe Frontal lobe The part of the cerebral hemisphere anterior to the central sulcus, and anterior and superior to the lateral sulcus. Cerebral Cortex: Anatomy

Clinical Presentation

The signs of PD are progressive and gradually appear over a long period of years to decades.

Cardinal motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology manifestations

• Bradykinesia = slowness of movements:
  • Seen in about 80% of individuals with PD
  • Decreased manual dexterity of the fingers 
  • Progresses proximally
  • Difficulty in completing simple tasks such as tying shoelaces, buttoning clothes, and picking up small objects. 
  • Short shuffling gait Shuffling Gait Normal Pressure Hydrocephalus 
  • Loss of coordination Coordination Cerebellar Disorders of movements as the disease progresses
  • Advanced stages: Freezing of movements may occur.
• Tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies: 
  • Resting tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies described as a “pill-rolling” tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies
  • Intermittent in the early stages
  • Decreases with voluntary action
  • Can involve the hands, legs, lips Lips The lips are the soft and movable most external parts of the oral cavity. The blood supply of the lips originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy, jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint: Anatomy, and tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy
  • Exacerbated by anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder, emotional excitement, and stressful situations
  • Initially unilateral involvement → progresses to bilateral
• Rigidity Rigidity Continuous involuntary sustained muscle contraction which is often a manifestation of basal ganglia diseases. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity. Megacolon:
  • Seen in 70%–90% of individuals with PD
  • Described as increased resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing to passive movement
  • Begins unilaterally → progresses to the contralateral side; remains asymmetrical throughout the course of the disease.
  • Cogwheel rigidity Rigidity Continuous involuntary sustained muscle contraction which is often a manifestation of basal ganglia diseases. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity. Megacolon = a pattern of resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing and relaxation in passive movement
  • “Lead pipe” rigidity Rigidity Continuous involuntary sustained muscle contraction which is often a manifestation of basal ganglia diseases. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity. Megacolon may also be seen in a few individuals = tonic resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing that is smooth in passive movement 
• Rigidity Rigidity Continuous involuntary sustained muscle contraction which is often a manifestation of basal ganglia diseases. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity. Megacolon affecting the face: characteristic “masked” expression
• Postural instability = impairment of postural reflexes resulting in a feeling of imbalance and a tendency to fall: 
  • Usually occurs in advanced stages of PD 
  • In the “pull test,” the examiner stands behind the individual and pulls the individual by their shoulders; those with PD are likely to take a few steps back or fall.

Other motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology manifestations

• Speech impairment
• Laryngeal dysfunction and dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia
• Blurred vision Blurred Vision Retinal Detachment
• Micrographia
• Stooped posture
• Myoclonus Myoclonus Involuntary shock-like contractions, irregular in rhythm and amplitude, followed by relaxation, of a muscle or a group of muscles. This condition may be a feature of some central nervous system diseases; (e.g., epilepsy-myoclonic). Nocturnal myoclonus is the principal feature of the nocturnal myoclonus syndrome. Neurological Examination
• Gait Gait Manner or style of walking. Neurological Examination abnormalities:
  • Shuffling, short-stepped gait Gait Manner or style of walking. Neurological Examination
  • Freezing in gait Gait Manner or style of walking. Neurological Examination
  • Festinating gait Gait Manner or style of walking. Neurological Examination = pattern described as small, increasingly quick steps

Nonmotor symptoms

• Autonomic dysfunction Autonomic Dysfunction Anterior Cord Syndrome presenting as:
  • Orthostasis
  • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
  • Diaphoresis
  • Urinary difficulties
  • Sexual dysfunction Sexual dysfunction Physiological disturbances in normal sexual performance in either the male or the female. Sexual Physiology
• Olfactory dysfunction: anosmia Anosmia Complete or severe loss of the subjective sense of smell. Loss of smell may be caused by many factors such as a cold, allergy, olfactory nerve diseases, viral respiratory tract infections (e.g., COVID-19), aging and various neurological disorders (e.g., Alzheimer disease). Cranial Nerve Palsies
• Mood disorders, including depression and anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder
• Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways and sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology disturbances
• Cognitive dysfunction and dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders
  • Psychosis 
  • Hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia
• Sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep disturbances:
  • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
  • Daytime sleepiness Daytime sleepiness Narcolepsy
  • REM sleep REM sleep A stage of sleep characterized by rapid movements of the eye and low voltage fast pattern eeg. It is usually associated with dreaming. Physiology of Sleep behavior disorder (RBD)

Diagnosis

The diagnosis of PD is made by clinical history and neurologic examination.

Diagnosis requires 4 things:

1. Motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology parkinsonism Parkinsonism West Nile Virus
2. No absolute exclusion criteria
3. At least 2 supportive criteria
4. No red flags

Motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology parkinsonism Parkinsonism West Nile Virus, an essential criterion of PD, requires bradykinesia and at least 1 of the following:

• Resting tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies
• Rigidity Rigidity Continuous involuntary sustained muscle contraction which is often a manifestation of basal ganglia diseases. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity. Megacolon
• Postural instability

Absolute exclusion criteria (incompatible with a diagnosis of PD):

• Cerebellar abnormalities such as cerebellar gait Gait Manner or style of walking. Neurological Examination or limb ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia
• Downward vertical supranuclear gaze palsy Palsy paralysis of an area of the body, thus incapable of voluntary movement Cranial Nerve Palsies or selective slowing of downward vertical saccades
• Diagnosis of frontotemporal dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders within the 1st 5 years after disease onset
• Parkinsonian features restricted to the lower limbs for > 3 years
• Treatment in the past year with a dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors blocker that may be associated with drug-induced parkinsonism Parkinsonism West Nile Virus
• Lack of response to high-dose levodopa Levodopa The naturally occurring form of dihydroxyphenylalanine and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonian disorders and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. Parkinson’s Disease Drugs in (at least) moderate disease
• Cortical sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology loss (e.g., agraphesthesia, astereognosis), ideomotor apraxia Apraxia A group of cognitive disorders characterized by the inability to perform previously learned skills that cannot be attributed to deficits of motor or sensory function. The two major subtypes of this condition are ideomotor and ideational apraxia, which refers to loss of the ability to mentally formulate the processes involved with performing an action. For example, dressing apraxia may result from an inability to mentally formulate the act of placing clothes on the body. Apraxias are generally associated with lesions of the dominant parietal lobe and supramarginal gyrus. Cranial Nerve Palsies, and/or progressive aphasia Aphasia A cognitive disorder marked by an impaired ability to comprehend or express language in its written or spoken form. This condition is caused by diseases which affect the language areas of the dominant hemisphere. Clinical features are used to classify the various subtypes of this condition. General categories include receptive, expressive, and mixed forms of aphasia. Ischemic Stroke
• Functional neuroimaging Neuroimaging Non-invasive methods of visualizing the central nervous system, especially the brain, by various imaging modalities. Febrile Infant of the presynaptic dopaminergic system is normal.

Supportive criteria:

• Dramatic improvement of symptoms with dopaminergic drugs
• Levodopa-induced dyskinesia
• Resting tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies of a limb (unilateral or bilateral)
• Either olfactory loss or cardiac sympathetic denervation on nuclear medicine Nuclear medicine A specialty field of radiology concerned with diagnostic, therapeutic, and investigative use of radioactive compounds. Nuclear Imaging imaging

Red flags (signs of alternative pathology that point toward another diagnosis):

• Rapid progression of gait Gait Manner or style of walking. Neurological Examination impairment requiring the use of a wheelchair
• Absence of progression of motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology symptoms or signs > 5 years
• Early bulbar dysfunction within the 1st 5 years after onset:
  • Severe dysphonia Dysphonia Difficulty and/or pain in phonation or speaking. Epiglottitis
  • Severe dysarthria Dysarthria Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from cranial nerve diseases; neuromuscular diseases; cerebellar diseases; basal ganglia diseases; brain stem diseases; or diseases of the corticobulbar tracts. The cortical language centers are intact in this condition. Wilson Disease
  • Severe dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia
• Inspiratory stridor Stridor Laryngomalacia and Tracheomalacia or dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
• Severe autonomic failure in the 1st 5 years after disease onset:
  • Orthostatic dysfunction
  • Severe urinary retention Urinary retention Inability to empty the urinary bladder with voiding (urination). Delirium
• Recurrent falls due to impaired balance within 3 years after onset
• Involuntary flexion Flexion Examination of the Upper Limbs of the neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess or contractures Contractures Prolonged shortening of the muscle or other soft tissue around a joint, preventing movement of the joint. Wound Healing of hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand: Anatomy or feet 
• Absence of the common nonmotor symptoms in the 1st 5 years after disease onset
• Unexplained pyramidal tract signs:
  • Pyramidal weakness
  • Clear pathologic hyperreflexia
• Bilateral symmetric parkinsonism Parkinsonism West Nile Virus

There are no physiologic, radiologic, or blood tests to confirm the clinical diagnosis of PD:

• Imaging may be needed to rule out other causes of parkinsonism Parkinsonism West Nile Virus (e.g., stroke):
  • MRI
  • DaTscan: a type of SPECT SPECT An imaging technique using a device which combines tomography, emission-computed, single-photon and tomography, x-ray computed in the same session. Nuclear Imaging that can visualize brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS transporter levels
• Olfactory and nuclear medicine Nuclear medicine A specialty field of radiology concerned with diagnostic, therapeutic, and investigative use of radioactive compounds. Nuclear Imaging tests for autonomic testing for cardiac sympathetic denervation are helpful in distinguishing PD from other causes of parkinsonism Parkinsonism West Nile Virus (supportive criteria as above).

Parkinson disease is confirmed with the finding of Lewy bodies on postmortem analysis.

Management

The goal of management is to treat the symptomatic motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology and nonmotor features of the disorder to improve quality Quality Activities and programs intended to assure or improve the quality of care in either a defined medical setting or a program. The concept includes the assessment or evaluation of the quality of care; identification of problems or shortcomings in the delivery of care; designing activities to overcome these deficiencies; and follow-up monitoring to ensure effectiveness of corrective steps. Quality Measurement and Improvement of life.

Treatment

General measures:

• Physical therapy Physical Therapy Becker Muscular Dystrophy
• Occupational therapy Occupational Therapy Skilled treatment that helps individuals achieve independence in all facets of their lives. It assists in the development of skills needed for independent living. Fetal Alcohol Spectrum Disorder 
• Emotional support

Medical therapy:

• Levodopa Levodopa The naturally occurring form of dihydroxyphenylalanine and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonian disorders and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. Parkinson’s Disease Drugs is the drug of choice in individuals of any age with moderate or severe symptoms:
  • A dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS precursor converted into dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS after crossing the blood–brain barrier Blood–Brain Barrier Meningitis in Children 
  • Normally combined with carbidopa, which enhances CNS bioavailability Bioavailability Pharmacokinetics and Pharmacodynamics 
• Monoamine oxidase Oxidase Neisseria type B (MAO-B) inhibitors ( selegiline Selegiline A selective, irreversible inhibitor of type B monoamine oxidase that is used for the treatment of newly diagnosed patients with parkinson disease, and for the treatment of depressive disorders. Monoamine Oxidase Inhibitors, rasagiline Rasagiline Monoamine Oxidase Inhibitors, safinamide Safinamide Parkinson’s Disease Drugs): 
  • Inhibit the enzyme MAO from breaking down dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS, serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS, norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS, and tyramine in the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification 
  • Effective as an early symptomatic treatment for PD
  • Monotherapy or in combination with levodopa Levodopa The naturally occurring form of dihydroxyphenylalanine and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonian disorders and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. Parkinson’s Disease Drugs/carbidopa
• Non-ergot dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS agonists ( pramipexole Pramipexole A benzothiazole derivative and dopamine agonist with antioxidant properties that is used in the treatment of parkinson disease and restless legs syndrome. Parkinson’s Disease Drugs, ropinirole Ropinirole Parkinson’s Disease Drugs, apomorphine Apomorphine A derivative of morphine that is a dopamine D2 agonist. It is a powerful emetic and has been used for that effect in acute poisoning. It has also been used in the diagnosis and treatment of parkinsonism, but its adverse effects limit its use. Parkinson’s Disease Drugs):
  • Indicated in younger individuals to postpone use of levodopa Levodopa The naturally occurring form of dihydroxyphenylalanine and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonian disorders and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. Parkinson’s Disease Drugs/carbidopa and avoid long-term side effects 
  • Monotherapy or in conjunction with levodopa Levodopa The naturally occurring form of dihydroxyphenylalanine and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonian disorders and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. Parkinson’s Disease Drugs/carbidopa
  • Should not be stopped abruptly

Deep brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification stimulation:

• Neurosurgical implantation Implantation Endometrial implantation of embryo, mammalian at the blastocyst stage. Fertilization and First Week of stimulating electrodes Electrodes Electric conductors through which electric currents enter or leave a medium, whether it be an electrolytic solution, solid, molten mass, gas, or vacuum. Electrocardiogram (ECG) in the substantia nigra Substantia nigra The black substance in the ventral midbrain or the nucleus of cells containing the black substance. These cells produce dopamine, an important neurotransmitter in regulation of the sensorimotor system and mood. The dark colored melanin is a by-product of dopamine synthesis. Basal Ganglia: Anatomy
• Exact mechanism of action is unknown. 
• Best candidates are individuals who:
  • Are younger
  • Have a short course of illness
  • Have a good response to levodopa Levodopa The naturally occurring form of dihydroxyphenylalanine and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonian disorders and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. Parkinson’s Disease Drugs 
• Not recommended for those with atypical parkinsonism Parkinsonism West Nile Virus

Side effects of dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS therapy

• Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics
• Orthostasis: worsened by dopaminergic therapy 
  • May need to stop antihypertensive medication 
  • May need to taper dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS agonists and MAO-B inhibitors 
• Drug-induced dyskinesia (abnormal involuntary movements can occur with long-term use of levodopa Levodopa The naturally occurring form of dihydroxyphenylalanine and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonian disorders and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. Parkinson’s Disease Drugs)
• Confusion and hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia
• Impulse control disorders → dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS agonist therapy must be reduced
• Dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS dysregulation syndrome: 
  • Cyclical mood disorder characterized by hypomania Hypomania Bipolar Disorder or manic psychosis 
  • Prevention of the excessive use of dopaminergic drugs is imperative.

Differential Diagnosis

• Essential tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies: most common neurologic cause of action tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies. Essential tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies usually affects both hands and arms and is apparent when the arms are held outstretched or when they are engaged in activities. Essential tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies is most often symmetrical Symmetrical Dermatologic Examination.
• Dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders with Lewy bodies: characterized clinically by dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders with visual hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia, fluctuating cognition, RBD, and parkinsonism Parkinsonism West Nile Virus. Dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders occurs before the development of signs of parkinsonism Parkinsonism West Nile Virus. Cholinesterase Cholinesterase Liver Function Tests inhibitors, atypical antipsychotics Atypical Antipsychotics Antiemetics, and regular Regular Insulin exercise are used for treatment. 
• Corticobasal degeneration Corticobasal Degeneration Atypical Parkinsonian Syndromes: distinctive form of parkinsonism Parkinsonism West Nile Virus that is a progressive asymmetric movement disorder. Cognitive features of corticobasal degeneration Corticobasal Degeneration Atypical Parkinsonian Syndromes include aphasia Aphasia A cognitive disorder marked by an impaired ability to comprehend or express language in its written or spoken form. This condition is caused by diseases which affect the language areas of the dominant hemisphere. Clinical features are used to classify the various subtypes of this condition. General categories include receptive, expressive, and mixed forms of aphasia. Ischemic Stroke, apraxia Apraxia A group of cognitive disorders characterized by the inability to perform previously learned skills that cannot be attributed to deficits of motor or sensory function. The two major subtypes of this condition are ideomotor and ideational apraxia, which refers to loss of the ability to mentally formulate the processes involved with performing an action. For example, dressing apraxia may result from an inability to mentally formulate the act of placing clothes on the body. Apraxias are generally associated with lesions of the dominant parietal lobe and supramarginal gyrus. Cranial Nerve Palsies, behavioral changes, loss of executive function, and visuospatial dysfunction. Asymmetrical cortical atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation is seen on imaging. 
• Progressive supranuclear palsy Palsy paralysis of an area of the body, thus incapable of voluntary movement Cranial Nerve Palsies: clinically presents as postural instability with a history of multiple falls. Progressive supranuclear palsy Palsy paralysis of an area of the body, thus incapable of voluntary movement Cranial Nerve Palsies is the most common degenerative form of parkinsonism Parkinsonism West Nile Virus. The disorder includes dysarthria Dysarthria Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from cranial nerve diseases; neuromuscular diseases; cerebellar diseases; basal ganglia diseases; brain stem diseases; or diseases of the corticobulbar tracts. The cortical language centers are intact in this condition. Wilson Disease, dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia, rigidity Rigidity Continuous involuntary sustained muscle contraction which is often a manifestation of basal ganglia diseases. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity. Megacolon, and cognitive symptoms. MRI shows the “ hummingbird sign Hummingbird Sign Atypical Parkinsonian Syndromes” or prominent midbrain Midbrain The middle of the three primitive cerebral vesicles of the embryonic brain. Without further subdivision, midbrain develops into a short, constricted portion connecting the pons and the diencephalon. Midbrain contains two major parts, the dorsal tectum mesencephali and the ventral tegmentum mesencephali, housing components of auditory, visual, and other sensorimotor systems. Brain Stem: Anatomy atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation without pontine atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation. Management is supportive, with both pharmacologic and nonpharmacologic measures.
• Multiple system atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation ( MSA MSA A syndrome complex composed of three conditions which represent clinical variants of the same disease process: striatonigral degeneration; shy-drager syndrome; and the sporadic form of olivopontocerebellar atrophies. Clinical features include autonomic, cerebellar, and basal ganglia dysfunction. Pathologic examination reveals atrophy of the basal ganglia, cerebellum, pons, and medulla, with prominent loss of autonomic neurons in the brain stem and spinal cord. Atypical Parkinsonian Syndromes): group of rare, fatal neurodegenerative symptoms. Multiple system atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation presents with akinetic rigid parkinsonism Parkinsonism West Nile Virus, autonomic and urogenital dysfunction, cerebellar ataxia Cerebellar ataxia Incoordination of voluntary movements that occur as a manifestation of cerebellar diseases. Characteristic features include a tendency for limb movements to overshoot or undershoot a target (dysmetria), a tremor that occurs during attempted movements (intention tremor), impaired force and rhythm of diadochokinesis (rapidly alternating movements), and gait ataxia. Cerebellar Disorders, and pyramidal signs. Lack of response to levodopa Levodopa The naturally occurring form of dihydroxyphenylalanine and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonian disorders and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. Parkinson’s Disease Drugs can help distinguish MSA MSA A syndrome complex composed of three conditions which represent clinical variants of the same disease process: striatonigral degeneration; shy-drager syndrome; and the sporadic form of olivopontocerebellar atrophies. Clinical features include autonomic, cerebellar, and basal ganglia dysfunction. Pathologic examination reveals atrophy of the basal ganglia, cerebellum, pons, and medulla, with prominent loss of autonomic neurons in the brain stem and spinal cord. Atypical Parkinsonian Syndromes from PD, and MSA MSA A syndrome complex composed of three conditions which represent clinical variants of the same disease process: striatonigral degeneration; shy-drager syndrome; and the sporadic form of olivopontocerebellar atrophies. Clinical features include autonomic, cerebellar, and basal ganglia dysfunction. Pathologic examination reveals atrophy of the basal ganglia, cerebellum, pons, and medulla, with prominent loss of autonomic neurons in the brain stem and spinal cord. Atypical Parkinsonian Syndromes progresses more rapidly than PD. Diagnosis is clinical and management is symptomatic, as there are no disease-modifying treatments available.