![CORTICOBASAL DEGENERATION
The dystonia, which may be painful, develops gradually but often becomes
severe and fixed, leading to contractures.
Speech is hesitant and dysarthric, and aphasia and apraxia of speech occur.
Other cortical signs may include apraxia (difficulty performing motor activities
despite normal understanding and normal sensory/motor systems); cortical
sensory loss (eg, two-point discrimination)
Agraphesthesia [difficulty recognizing letters/numbers written on the skin with
eyes closed] and astereognosis [difficulty recognizing objects by touch alone).
Cortical myoclonus (spontaneous or reflex, or both), which can be diagnosed
accurately only with electrophysiology but usually consists of multifocal, very
rapid shock like jerks; alien limb phenomenon .](https://image.slidesharecdn.com/presentation1-221025131319-8e398f64/85/Presentation1-pptx-30-320.jpg)
![MULTIPLE SYSTEM ATROPHY
Patients starting with bradykinesia and rigidity (called MSA with predominant
parkinsonism [MSA-P]) usually do not have resting tremor and do not improve
with levodopa.
Patients starting with ataxia and other cerebellar features (eg, scanning speech,
hypometric saccades, square-wave jerks) would be consistent with MSA with
predominant cerebellar ataxia (MSA-C).](https://image.slidesharecdn.com/presentation1-221025131319-8e398f64/85/Presentation1-pptx-32-320.jpg)
Presentation1.pptx
- 1. PARKINSON DISEASE Dr. Khairi Faleh Al-Zirei
- 2. PARKINSON DISEASE a chronic, progressive, and disabling disorder that is characterized by both motor and nonmotor symptoms. The disease affects millions of people worldwide and is the second most prevalent neurodegenerative condition next to Alzheimer disease. Despite its progressive nature, it remains one of the few neurodegenerative diseases whose symptoms can be readily treated with dopamine replacement therapy.
- 3. BRIEF HISTORY OF PARKINSON DISEASE The English physician, James Parkinson, first characterized Parkinson disease in his 1817 monograph “An Essay on the Shaking Palsy.” Parkinson described several people who presented with resting tremor, shuffling gait, stooped posture, sleep problems, and constipation. He noted the progressive nature of the disease and the great disability it incurred and called it paralysis agitans. Charcot later expounded on the disease, adding bradykinesia and rigidity to the constellation of symptoms, and renamed the condition Parkinson disease.
- 4. EPIDEMIOLOGY OF PARKINSON DISEASE Parkinson disease affects millions of people worldwide, and the number of affected patients may double by 2030. The incidence of Parkinson disease prior to age 50 is low but increases with advanced age. The lifetime risk of Parkinson disease is 2% in men and 1.3% in woman aged 40 years and older. Men carry a greater chance of having Parkinson disease than women.
- 5. CLINICAL SYMPTOMS OF PARKINSON DISEASE
- 6. CLINICAL PROGRESSION OF PARKINSON DISEASE Parkinson disease is a neurodegenerative progressive disease. The Movement Disorder Task Force recently recognized three stages in early Parkinson disease: (1) the preclinical phase, in which neurodegeneration begins but patients lack clinical symptoms (2) the prodromal phase, in which symptoms are present but are insufficient to make a diagnosis of Parkinson disease (3) the clinical phase, in which parkinsonian symptoms are manifest and recognizable.
- 7. CLINICAL PROGRESSION OF PARKINSON DISEASE While it is difficult to accurately predict the general disease progression, motor fluctuations usually affect patients within 5 to 10 years after diagnosis, while postural instability occurs after about 10 years. Patients usually have a “good” period early on after diagnosis, in which they benefit from dopaminergic therapy. Patients with younger-onset disease are more prone to levodopa-induced dyskinesia and motor fluctuations, while patients with older-onset disease have more cognitive issues and dysautonomia.
- 9. ETIOLOGY OF PARKINSON DISEASE Parkinson disease is characterized by the loss of dopaminergic neurons in the nigrostriatal system and by the presence of Lewy bodies in the brainstem. Motor symptoms become evident when 60% to 80% of dopaminergic neurons are lost in the pars compacta of the substantia nigra. Genetic Causes of Parkinson Disease : 1) It is estimated that 5% to 10% of patients have a genetic etiology for the disease. Monogenic forms of Parkinson disease include PARK-SNCA, PARK- LRRK2, and PARK-VPS35 2) GBA1 directs the production of the glucocerebrosidase protein, which is involved in lysosomal activity. A genetic defect in GBA1 causes a reduction in glucocerebrosidase activity, an increase in glucosylceramide, and promotion of α-synuclein accumulation, leading to a a greater chance of developing Parkinson disease
- 10. Environmental Causes of Parkinson Disease : Some of the environmental factors and toxic exposures that may be associated with Parkinson disease include: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), pesticides (rotenone and paraquat); heavy metals (manganese, lead, and copper); well water; woodworking; head injury; other substances including polychlorinated biphenyls, and rural living. Exposure to toxins, including carbon monoxide, trace metals, organic solvents, and cyanide have also been implicated as environmental risk factors. Smoking and caffeine intake are thought to reduce disease risk.
- 11. NEUROIMAGING OF PARKINSON DISEASE In 2011, the US Food and Drug Administration approved dopamine transporter SPECT using ioflupane I-123 injection.39 Dopamine transporter SPECT has a high sensitivity (87% to 98%) and specificity (80% to 100%) when differentiating Parkinson disease from essential tremor and is considered an adjunct to diagnostic assessments. However, dopamine transporter SPECT is not a confirmatory test for Parkinson disease, nor is it intended to differentiate between Parkinson disease and other degenerative forms of parkinsonism .
- 12. PHARMACOLOGIC AGENTS FOR PARKINSON DISEASE Levodopa is the gold standard for dopamine replacement therapy in Parkinson disease. It is administered with a dopa decarboxylase inhibitor (carbidopa) to reduce its peripheral breakdown and lessen nausea. Levodopa is particularly effective in treating akinesia and rigidity, with more variable effects on tremor. Carbidopa/levodopa is available as immediate-release, extended- release, and orally disintegrating tablets. A newer formulation of extended-release carbidopa/levodopa (IPX066) was designed for rapid absorption, ease of administration, and longer duration of clinical benefit.
- 13. levodopa inhalation powder has also been FDA-approved for intermittent treatment of off episodes in patients with Parkinson disease who take carbidopa/levodopa. Levodopa/carbidopa intestinal gel may be recommended for patients with Parkinson disease who experience motor fluctuations and dyskinesia who cannot be optimally treated with oral medication. Patients with advanced Parkinson disease who are not candidates for surgical management may also benefit from levodopa/carbidopa intestinal gel.
- 14. Dopamine agonists directly stimulate dopamine receptors, thereby bypassing degenerating dopaminergic neurons in the brain. Non–ergot dopamine agonists are used as both monotherapy and adjunctive therapy in the treatment of Parkinson disease. a) They have longer half-lives (greater than 6 hours) than levodopa, but also have a higher incidence of psychiatric side effects, including hallucinations and impulse control disorders as well as potential “sleep attacks” (i.e., episodes of sudden onset of sleep). b) Dopamine agonists include pramipexole, ropinirole (available in immediate- release and extended-release formulations), rotigotine (transdermal formulation), and apomorphine for subcutaneous use as a rescue medication for acute off periods.
- 15. COMT inhibitors reduce the breakdown of levodopa to 3-O-methyldopa and increase the plasma half-life of levodopa and its area under the curve. COMT inhibitors are used in conjunction with levodopa to improve end-of-dose wearing-off time, although they may increase dyskinesia. Currently available COMT inhibitors include entacapone and tolcapone
- 16. MAO-B inhibitors prevent levodopa degradation in the brain and limit its reuptake. 1. Selegiline is a selective and irreversible MAO-B inhibitor approved as adjunctive medication to levodopa in patients with motor fluctuations. 2. Rasagiline, a second-generation MAO-B inhibitor, lacks the amphetamine metabolites of selegiline and may be used as monotherapy and adjunct therapy. 3. Safinamide is another potent, reversible MAO-B inhibitor that has been recently approved as adjunct therapy in patients with Parkinson disease with motor fluctuations.
- 17. An N-methyl-D-aspartate (NMDA) receptor antagonist, amantadine, was originally used as an antiviral medication in the 1960s and has anti dyskinetic properties. A newer preparation of amantadine, ADS-5102, is an extended- release form of amantadine that may be used to treat levodopa-induced dyskinesia in patients with Parkinson disease.
- 18. Anticholinergic medications such as trihexyphenidyl and benztropine were the original drugs used to treat Parkinson disease. They are used to treat tremor in younger patients with Parkinson disease as their side effects include confusion, dry mouth, urinary retention, and constipation.
- 19. TREATMENT OF PARKINSON DISEASE Early Parkinson Disease : When a patient is newly diagnosed with Parkinson disease, it is important to determine whether symptoms are bothersome enough to the patient to warrant treatment while also keeping nonmotor symptoms in mind. Factors to be taken into consideration are the patient’s age, comorbid conditions, employment status, and other quality-of-life issues. Younger patients may need more effective control of their symptoms with levodopa if they need to remain employed or have other responsibilities including childcare or eldercare. Several studies suggest that starting treatment with levodopa leads to better long- term motor outcomes and better functioning long-term. Exercise should be encouraged for all patients with Parkinson disease as long as it is performed safely. Some evidence suggests that long-term aerobic exercise may slow Parkinson disease progression . Exercise modalities include core strength training exercises, tai chi, yoga, boxing, and dance and music therapy.
- 20. Advanced Parkinson Disease : As Parkinson disease advances, the reduced storage and release capacity of endogenous dopamine can lead to the shortened duration of levodopa benefit. Patients will experience a decline in medication efficacy in which symptoms return prior to the next dose, referred to as predictable wearing off. The aim of Parkinson disease treatment is to optimize on time and reduce off time while minimizing troublesome levodopa-induced dyskinesia. Off time may be treated by taking Parkinson disease medications more frequently , using an extended-release form of levodopa, adding a COMT inhibitor or MAO-B inhibitor, or by the addition of a dopamine agonist to provide a more stable response. Treatment of levodopa-induced dyskinesia requires identifying its occurrence in relation to levodopa dosing . Redistribution of medication doses, as well as changing forms of medication from immediate-release to extended-release formulations . Amantadine has been shown to treat levodopa-induced dyskinesia and is now available as an extended-release formation, which has been shown to reduce levodopa-induced dyskinesia and off time.
- 21. Surgical Treatment of Parkinson Disease Surgical treatment of Parkinson disease was developed for patients who despite medication optimization, experience motor symptoms that cannot be satisfactorily ameliorated by medication. A common surgical treatment is DBS, which targets the subthalamic nucleus, globus pallidus internus, or ventral intermediate nucleus of the thalamus for tremor-predominant Parkinson disease with otherwise minimal symptoms. It has been demonstrated to improve tremor, dyskinesia, and motor fluctuations. Most DBS procedures are performed about 10 years after diagnosis, but the EARLYSTIM (Controlled Trial of Deep Brain Stimulation in Early Patients with Parkinson’s Disease) trial suggests that DBS may be used earlier in the course of the disease.
- 22. Surgical Treatment of Parkinson Disease Exclusionary criteria for DBS include the presence of an atypical parkinsonism, unstable psychiatric disease, advanced disease with significant dementia, comorbidities that preclude surgical candidacy, and advanced age Possible complications of DBS include medical issues such as myocardial infarction, pneumonia, deep vein thrombosis, and pulmonary embolism and surgical issues such as cerebral hematoma, stroke, seizures, infections, and hardware dysfunction, all reported in a small percentage of patients. Side effects may include paresthesia, dysarthria, ataxia, and mood dysregulation, which are typically reversible and ameliorated by changing the stimulation parameters.
- 23. Atypical parkinsonian syndromes Patients who have parkinsonian features, especially without tremor, that are not responsive to levodopa, usually have one of these three major neurodegenerative disorders rather than Parkinson disease: progressive supranuclear palsy (PSP), multiple system atrophy (MSA), or cortico basal degeneration (CBD). Each of these disorders eventually develops signs and symptoms that distinguish it from idiopathic Parkinson disease, but these may not be present at disease onset. Although these conditions are not generally treatable, it is still important to correctly diagnose the condition as soon as possible.
- 24. Atypical parkinsonian syndromes In recent years, it has been increasingly recognized that the symptoms of these diseases do not accurately predict the pathology, and the pathology does not accurately predict the clinical syndrome. Despite this , interest has grown in treating these diseases by targeting misfolded tau (in the case of PSP and CBD) and misfolded α-synuclein (in the case of MSA). After the introduction of levodopa to treat Parkinson disease (PD) in the late 1960s, the pathologies and clinical pictures of dopamine deficiency syndromes broadened dramatically. Unfortunately, no definitive diagnostic tests are easily available to distinguish these diseases from each other during life. The gold standard diagnostic test is autopsy, but autopsies are highly selected and may lead to conclusions that do not represent the entire population of a disease.
- 25. PROGRESSIVE SUPRANUCLEAR PALSY The pathology of progressive supranuclear palsy is characterized by deposits of 4-repeat tau in astrocytes and oligodendroglia in multiple regions of the basal ganglia and cortex of the brain. Patients with the classic presentation, also called Richardson syndrome, develop a symmetric akinetic rigid syndrome with axial greater than limb rigidity, lack of resting tremor (although they may have an action tremor), early development of a supranuclear gaze palsy, and lack of response to levodopa. Supranuclear gaze palsy is the inability to look up or down on command, but up gaze is present when the neck is passively flexed, and downgaze is present when the neck is passively extended (i.e., the doll’s eyes maneuver).
- 26. Patients may have continuous square-wave jerks and other oculomotor disturbances, early loss of postural reflexes leading to falls, and progressive dementia. Square-wave jerks are involuntary horizontal saccades that go alternately to the right and then to the left with brief pauses before changing direction. Patients with PSP often have an unusual facial expression, labeled dystonia, with deep nasolabial folds and furrowed brow, giving them an angry or puzzled expression. Patients may have hypophonia, often have growling speech, and frequently become aphonic. Patients with PSP develop dysphagia early in the course of the disease, and aspiration pneumonia is common. They often have a broad-based, slightly ataxic gait and often walk with their arms abducted and elbows flexed (a “gunslinger” gait).
- 27. Some patients with the pathology of PSP present with what looks like levodopa responsive, asymmetric PD with resting tremor. These patients go on to lose levodopa responsiveness and develop imbalance, eye movement abnormalities, and the other signs and symptoms of classic PSP , which is referred to as PSP with predominant parkinsonism (PSP-P) . Some patients’ symptoms begin with gait freezing, micrographia, and imbalance, which is referred to as pure akinesia or PSP with progressive gait freezing (PSP-PGF). PSP with cerebellar ataxia (PSP-C), which begins with ataxia PSP with primary lateral sclerosis (PSP-PLS), which starts with a generalized spasticity syndrome similar to primary lateral sclerosis
- 28. PSP with predominant frontal presentation (PSP-F), which begins with a frontal syndrome including behavioral changes such as irritability and other personality changes, lack of insight, inappropriate behavior, impulsivity, and stereotyped behaviors. PSP with predominant ocular motor dysfunction (PSP-OM), which begins with oculomotor signs/symptoms Some patients present with non-fluent primary progressive aphasia or progressive apraxia of speech, referred to as PSP with predominant speech/language disorder (PSP-SL).
- 29. CORTICOBASAL DEGENERATION The pathology of corticobasal degeneration also involves widespread deposition of 4-repeat tau but also includes asymmetric cortical atrophy and neuronal, oligodendroglial, and astrocytic deposits distinct from the deposits in progressive supranuclear palsy. The parkinsonism is usually without tremor, does not respond to dopamine replacement therapy, and loss of balance usually occurs early in the course.
- 30. CORTICOBASAL DEGENERATION The dystonia, which may be painful, develops gradually but often becomes severe and fixed, leading to contractures. Speech is hesitant and dysarthric, and aphasia and apraxia of speech occur. Other cortical signs may include apraxia (difficulty performing motor activities despite normal understanding and normal sensory/motor systems); cortical sensory loss (eg, two-point discrimination) Agraphesthesia [difficulty recognizing letters/numbers written on the skin with eyes closed] and astereognosis [difficulty recognizing objects by touch alone). Cortical myoclonus (spontaneous or reflex, or both), which can be diagnosed accurately only with electrophysiology but usually consists of multifocal, very rapid shock like jerks; alien limb phenomenon .
- 31. MULTIPLE SYSTEM ATROPHY There are widespread pathologic abnormalities in multiple system atrophy, but the characteristic inclusions contain α-synuclein, not tau. The first identified abnormality was a glial cytoplasmic inclusion containing α- synuclein, but neuronal inclusions have also been identified. Rarely, Lewy bodies are found in multiple system atrophy. When middle-aged patients have sporadic disease with parkinsonism (usually including bradykinesia and rigidity), autonomic insufficiency (usually including urinary incontinence or retention, orthostatic hypotension sometimes alternating with hypertension, anhidrosis, and impotence in men), and cerebellar abnormalities (including ataxia, dysmetria, and nystagmus), MSA is the most likely diagnosis
- 32. MULTIPLE SYSTEM ATROPHY Patients starting with bradykinesia and rigidity (called MSA with predominant parkinsonism [MSA-P]) usually do not have resting tremor and do not improve with levodopa. Patients starting with ataxia and other cerebellar features (eg, scanning speech, hypometric saccades, square-wave jerks) would be consistent with MSA with predominant cerebellar ataxia (MSA-C).
- 33. EPIDEMIOLOGY AND GENETICS OF PSP, CBD, and MSA The reported prevalence of each syndrome is probably underestimated in clinical studies and overestimated in pathologic studies since unusual cases are more likely to come to autopsy. Among the three disorders discussed here, PSP is most commonly reported in clinical studies. A recent study reported estimates of the prevalence of clinically defined PSP as about 1.4/100,000 to 6.4/100,000 and the prevalence of clinically defined MSA as about 1.9/100,000 to 4.4/100,000 in people older than 50 years of age. The prevalence of CBS based on clinical criteria was about 2/100,000 in a population
- 35. Midbrain atrophy in PSP may give a characteristic sign on brain MRI (sometimes called the hummingbird sign on sagittal MRI or morning glory sign on axial MRI) and these may be specific but are not sensitive.
- 36. Brain MRI in patients with MSA may show hyperintensity in the dorsolateral margin of the putamen (putaminal slit sign) and cruciform increased signal in the pons (hot cross bun sign), but the sensitivity of these tests, while unknown, is probably low
- 37. TREATMENT OF SYMPTOMS IN PSP , MSA, and CBD Since none of these diseases are curable, treatment is directed to specific symptoms, many of which can occur in any of the conditions. Treating patients with MSA with dopaminergic agents often worsens orthostasis Botulinum toxin injections can treat apraxia of eyelid opening, blepharospasm, painful dystonia or rigidity, and sialorrhea. Botulinum toxin type B is more potent at reducing sialorrhea but is more painful to inject than botulinum toxin type A Desmopressin at bedtime may help avoid nocturnal incontinence (and also help orthostasis). Mild constipation may be successfully managed with high-fiber diets or laxatives such as bisacodyl or senna. Liquifying stool with agents such as polyethylene glycol or lactulose may help more severe cases.