Pathophysiology Test 1 - Dementia PDF

Pathophysiology test 1 DEMENTIA Definition, etiology and pathogenesis Dementia - syndrome of acquired cognitive deficits which interfere with daily function and are not due to other conditions such as delirium or severe depression. - Causes...

Pathophysiology test 1 DEMENTIA Definition, etiology and pathogenesis Dementia - syndrome of acquired cognitive deficits which interfere with daily function and are not due to other conditions such as delirium or severe depression. - Causes of dementia: Neurodegenerative conditions (e.g. Alzheimer disease) cerebrovascular disease, trauma, infections, etc - In order to destigmatize the label of dementia the DSM-5 replaces dementia with major neurocognitive disorder - The DSM-5 is the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders The formal definition of dementia: - Cognitive or behavioral symptoms that represent a decline from previous levels of function; interfere with daily function; are not explained by delirium or psychiatric illness; could be detected by history and cognitive testing; and include 2 or more of the following → amnesia, agnosia, aphasia, executive dysfunction, and behavior change (eg, apathy, disinhibition). - Agnosia (brain can't recognize something) - Aphasia (brain cannot comprehend or formulate language) Pathologic subtypes: - AD is the most common pathology that causes dementia - Nearly 50% of cases of dementia are due to AD - ⅓ of cases of dementia are due to a combination of pathologies, most commonly AD with cerebrovascular disease - The other principal neurodegenerative diseases are frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB). FTD - Limbic-predominant age-related TDP-43 encephalopathy (LATE), is a newly discovered FTD pathology associated with a similar amnestic presentation as AD. - Genetic influences account for 50% of FTD cases. DLB - DLB is related to Parkinson disease (PD), and a family history of PD may be present. - Primary PD is also associated with high risk of developing dementia. Mild cognitive impairment (MCI) = refers to the period of asymptomatic disease that happens just before the onset of symptoms of dementia and is associated with preserved daily function. - E.g. In people with AD, a period of mild memory deficits, which do not compromise daily function occurs before the onset of dementia → This is known as amnestic MCI and in the DSM-5 definition is termed minor neurocognitive disorder. Risk factors: - Many risk factors of dementia are similar to the risk factors of cardiovascular and cerebrovascular disease (eg, diabetes mellitus, hypertension, smoking, prior stroke, physical inactivity) - Risk factors unique to dementia include: repeated or severe head trauma, exposure to pesticides, fewer years of education, and use of anticholinergic drugs. - The greatest risk factor of dementia is age - Increasing prevalence of dementia is due to the increasing life expectancy of humans Genetic factors: Genetic influences are important in early-onset Alzheimer disease (EOAD) - autosomal dominant transmission may occur in EOAD - 2% of dementia cases are EOAD - EOAD means it occurs before the age of 65 - If you have a single gene mutation in the amyloid precursor protein gene (APP) and in the presenilin gene (PS1, PS2) → you will 100% develop EOAD  - Patients with down syndrome have nearly a 100% chance of developing EOAD → The APP gene, which produces APP, is on chromosome 21 → In Down syndrome (trisomy 21), the extra chromosome leads to overexpression of APP, increasing the production of beta-amyloid plaques—a hallmark of Alzheimer's disease. - Very rarely spontaneous mutations may occur Late-onset Alzheimer disease (LOAD) is MORE COMMON: - Less dependent on Genetic factors - E.g. In the APO E gene system on chromosome 19 there are three alleles: ε2, ε3, and ε4. - The presence of ε2 lowers the risk for AD - ε3 is neutral - Having 1 or (worse) 2 copies of ε4 increases the risk of LOAD. Clinical features and natural history 1. AD: AD is a neurodegenerative condition characterized by neuronal death and accumulation of the toxic protein aggregates beta-amyloid and tau. First symptom: memory impairment (affects recent or episodic memory so the patient may not notice it, but family members and close friends will e.g. repeating questions or stories) ONSET IS INSIDIOUS AND PROGRESSION IS GRADUAL → so the date of onset is hard to determine Over time, other cognitive functions are affected: - Language (i.e. patients are not able to find appropriate words) - Executive function (the ability to plan and sequence complex tasks → patient cannot use a remote control) - Visuospatial function (the ability to orient oneself in one’s environment → patient is lost in a familiar environment) - Praxis (the ability to perform learned motor skills). - As these deficits increase, patients experience difficulty performing familiar tasks (eg, the electrician can no longer change a light bulb, the cook can no longer prepare a meal). - As the disease progresses further, behavior problems such as apathy, irritability, and aggression may supervene. In the final stages of the disease, motor function may be affected. - Swallowing difficulty, rigidity, and contractures The average duration from first symptoms to death is generally within 7 to 10 years In the Canadian Study of Health and Aging, the average life expectancy was only 3.4 years (but only because their participants had an average age of onset was 81 years → 10 years later than the usual onset). At age 81, the usual life expectancy is ~5 years Apart from the typical amnestic presentation of AD, there are different clinical phenotypes: 1. Language variant: progressive nonfluent aphasia (affects forming sentences, speaking and finding the right words) 2. Visuospatial variant: posterior cortical atrophy (affects vision and spatial awareness) 3. Frontal executive variant: frontal atrophy (affects planning and decision making) DIAGNOSTIC CRITERIA FOR AD: 1. Insidious onset 2. Clear-cut history of worsening 3. Initial and prominent cognitive deficits on history and examination with either amnestic or nonamnestic presentation 2. Frontotemporal dementia: In contrast to AD, the prominent early symptoms of FTD do not involve memory, but feature behavioral and/or language changes. FTD can be as common as AD between the ages of 45 and 64 years, with an annual incidence of 15/100,000 in some studies. There are 3 principal variants of FTD: - Initially you can see behavioral or language changes in each FTD variant, but as the disease progresses, combinations of both symptoms develop 1. behavioral variant FTD (bvFTD) - Presents an early onset of behavioral changes such as a. Behavioral disinhibition → i.e. socially inappropriate behavior like insulting strangers or being sexually inappropriate, stealing and being impulsive → this reaches the medical and legal systems rapidly. b. Loss of sympathy or empathy or personal warmth  c. Obsessive/perseverative behaviors d. hyperorality (binge eating, oral exploration of inedible objects) e. Patients have difficulty executing tasks (impaired executive function) but have intact episodic memory. f. Apathy can be present → if it is very prominent, it can be hard to differentiate from depression 2. semantic dementia (SD) (language variant) - Presents with progressive aphasia - SD patients have no issue with speech production (motor and grammar) - They have difficulties with confrontational naming, single-word comprehension, and objective knowledge. - E.g. When you ask an SD patient if they can pass you the scissors, they may reply with ‘what are scissors?’ - SD patients may call objects by incorrect names - SD patients lose the meaning of words and symbols - Living with SD: A short film 3. progressive nonfluent aphasia (PNFA) (another language variant) - Presents with progressive aphasia - PNFA involves effortful halting speech, with spared single-word comprehension and object knowledge → patients can become MUTE over time - Living with PNFA: A short film In aphasic variants of FTD (SD and PNFA) - Language deficits impair daily activities at disease onset. - Patients with aphasic variants may evolve to resemble bvFTD in the course of their disease and occasionally develop movement disorders, including progressive supranuclear palsy and corticobasal syndrome. FTD shares the underlying pathology with movement disorders The evolution of a clinical phenotype means that a patient may start out with one disorder and progress to look like a different disorder over time: - E.g. a patient with behavioral disinhibition and apathy, resembling a case of bvFTD, may evolve over time to develop rigidity and tremor, apraxia, and dystonia, and be better classified as with frontal features - E.g. a person with PNFA may present with language difficulties, and then develop traits consistent with progressive supranuclear palsy. - There is clinical and pathophysiologic overlap among bvFTD, SD, PNFA, corticobasal syndrome, and progressive supranuclear palsy. Diagnostic criteria for frontotemporal dementia - Early and progressive changes in personality an language 1. Personality: Difficulty modulating behavior, inappropriate responses and activity (eg, disinhibition, apathy, poor insight and judgment, self-neglect) 2. Language: Expression, severe naming difficulty or meaning (progressive expressive aphasia) contraction of language 3. Dementia with Lewy bodies: Patients with PD have aggregations of alpha synuclein called lewy bodies within their basal ganglia, cerebral cortex and other parts of the brain. Individuals with DLB exhibit: - Hallucinations or delusions - Fluctuations in the severity of symptoms - spontaneous or drug-induced parkinsonism - History of repeated investigations for the causes of delirium (because their symptoms are mistaken for delirium) - Disturbances in visuospatial performance e.g. difficulties with clock drawing or completing the interlocking pentagons on the Mini-Mental State Examination (MMSE) - REM sleep behavior disorders (RBD) are a VERY early symptom of DLB → RDB involves physically acting out dreams, sometimes violently. - People with DLB have adverse reactions to neuroleptic agents e.g. rigidity, bradykinesia and other extrapyramidal adverse effects  The hallucinations and fluctuating attention can also occur in delirium → so its important to differentiate the two Diagnostic criteria for dementia with Levy bodies 1. Core features: - in Fluctuating cognitionChanges person's mentalability - Well-formed visual hallucinations - Spontaneous parkinsonism 2. Suggestive features: - REM sleep behavior disorder - Severe neuroleptic sensitivity 4. Vascular dementia (vascular cognitive impairment [VCI]): Most dementias previously considered to be of vascular origin are actually due to the presence of cerebral vascular disease superimposed upon neurodegenerative conditions, such as AD. So AD+ vascular disease = dementia Individuals even with prominent pathologic changes of AD (neurofibrillary tangles and amyloid plaques) may appear cognitively normal in life, but the presence of even a single white matter stroke greatly increases the risk of that individual having dementia. 5. Limbic-predominant age-related TDP-43 encephalopathy (LATE): LATE can cause dementia Symptoms of LATE: - Amnesia (especially over 80) - Hippocampal sclerosis. Patients with LATE are clinically indistinguishable from those with Alzheimer disease. Causes of LATE: - Build up of TDP-43 protein in the brain - Can co exist with the build up of amyloid plaque (as seen in AD) but it is classified as FTD because of the TDP-43 pathology Diagnosis of LATE: - LATE can be suspected in individuals with Alzheimer disease but with negative amyloid PET scans or no amyloid detected in the cerebral spinal fluid. - LATE occurs in 20% to 50% of people over 80 years of age Treatment - Cholinesterase inhibitors are not expected to benefit patients with LATE. 6. Rapidly progressive dementia (RPD): RPD develops within 1 year from the individual being cognitively normal. Causes of RPD: - tumors, paraneoplastic syndromes, infections (eg, HIV) - metabolic, autoimmune, psychiatric, toxic, and vascular events. - Neurodegenerative diseases can cause RPD e.g. AD. - Creutzfeldt-Jakob disease - Anti-NMDA (N-methyl-D-aspartate-type) receptor encephalitis Diagnosis The type of dementia can be determined by history taking and examining the patient Insidious onset with progressive memory decline = AD. Onset of progressive aphasia = FTD or a language variant of AD. Prominent apathy = FTD or frontal variant AD but it requires exclusion of depression as a potential diagnosis. Abrupt onset in the absence of a new medication or intercurrent infection = vascular or mixed etiology. Simple neuroimaging studies may be added if indications are present. 1. History: The most important diagnostic tool → includes data from family and others You should collect data regarding a. The timing and onset of symptoms, type of symptoms b. precipitating events c. risk factors d. The prescription of a new medication  e. onset of systemic disease (eg, heart failure, pulmonary, renal or hepatic failure, hypothyroidism, infection) f. psychiatric, family, educational, and occupational history g. You should consult other health-care professionals for background history → Findings such as “poor historians,” missing appointments, or poor adherence to prescribed medications are clues that should not be ignored. 2. Objective cognitive testing: Once the suspicion of a cognitive disorder is raised, physical examination, neurologic examination and brief cognitive tests are the next step. There are many brief cognitive tests in common use a. Mini Mental State Examination: - Was originally designed to distinguish dementia from depression - Is used in clinical practice, epidemiologic surveys, and pharmacologic studies - MMSE assesses orientation, short-term recall, basic language, and visuospatial construction. - The MMSE detects severe cognitive impairment disorders that impact one's daily life → so it does not detect Mild cognitive impairments (MCl) - If you have MCI, have progressive AD and do the MMSE → the results will decline at a predictable rate b. Montreal Cognitive Assessment (MoCA) - Used to detect mild cognitive impairment and other cognitive disorders - It tests: a. delayed recall b. Orientation c. Language (has a more comprehensive section than the MMSE) d. executive function (by clock drawing) e. Attention (measured by digit span forward and backward as well as a finger-tapping exercise) f. Abstract thinking Simple bedside cognitive tests allow for measurement of decline or response to treatment of dementia. Who is the testing for? Extensive neurocognitive testing is reserved for younger patients who may need to apply for disability pensions or to determine whether an occupation is still feasible. Testing is used for older patients who are still working, especially in medical, academic, and legal occupations. Neurocognitive testing is used for unusual presentations of dementia → to determine if MCI will progress to dementia 3. Laboratory tests: In all suspected cases of dementia or MCI → 6 basic laboratory tests need to be performed: - complete blood count (CBC) - blood glucose level or glycated hemoglobin (HbA1c) - serum calcium - serum thyroid-stimulating hormone - electrolytes and serum B12 levels 4. Neuroimaging: Neuroimaging is good for people who have signs of dementia or who are at risk of dementia (e.g. head injuries) Specific findings on imaging may help refine diagnosis In the scan: - Medial temporal and hippocampal atrophy = AD - frontotemporal atrophy = FTD - Occipital and posterior parietal lobe atrophy = visuospatial presentation of AD. When performing a CT, or MRI for suspected dementia → make sure you get 3 views (axial, coronal, sagittal) to obtain maximum information. Radionuclide scans can differentiate FTD from AD A PET scan with fluorodeoxyglucose (FDG) is optimal but rarely available → so a SPECT scan is a reasonable alternative. PET amyloid scanning is emerging as an accurate method of diagnosing AD but is not yet widely available. Indication for neuroimaging - Above 65 years of age - Relatively short clinical history  - Focal neurologic symptoms - Focal neurologic signs - History of head trauma - Anticoagulants or bleeding condition - Malignancy that might metastasize to brain - Atypical features (not suggesting Alzheimer disease) - In cases where finding of cerebrovascular disease would significantly influence management 5. Cerebral spinal fluid (CSF) analysis: A CSF analysis of a patient with AD (even before dementia) includes an elevated level of tau and depressed level of beta-amyloid. 6. Screening: Routine screening for cognitive impairment or dementia in any age group is not supported → it shows few benefits Management of dementia 1. Education and support: - Education and support for patients, caregivers, and family is the foundation of management. - Establishing the degree of risk to the individual and others is an important first step. - Several items require urgent attention e.g. the stove must be disabled and guns must be removed from the house. - Support and advocacy organizations such as the Alzheimer’s Society of Canada (ASC) are extremely helpful to patients, relatives, and caregivers. - Newly diagnosed individuals are referred to a local office (branch) of the ASC 2. Driving: - If you have a condition that threatens your driving safety, physicians report you to the ministry of transport - If the condition is early e.g. MCL or early dementia → on-road assessments or computer tests are carried out - If the patients has severe dementia → driving is completely prohibited - In patients with mild to moderate dementia → the decision to report is made on an individual basis. 3. Future planning: - Make a will - Arrange powers of attorney for property and personal care - Arrange therapeutic and social day programs, individually tailored recreational therapies, and other activities to improve the quality of life of the patient 4. Coexisting conditions: - Poorly controlled pre-existing endocrine and metabolic disorders can aggravate the cognitive deficits at present in an individual with dementia. - E.g. Heart failure worsens cognitive deficits → so managing heart failure can improve cognitive defects - Medications can also aggravate cognitive symptoms → i.e. sedatives, hypnotics, anxiolytics, and anticholinergic drugs have adverse effects - Anticholinergic drugs include → tricyclic antidepressants, antispasmodics, older antihistamines, and medications used for overactive bladder. - Most narcotics also affect cognition Pharmacologic therapy Medications play a minor role in the management for dementia 1. Cholinesterase inhibitors (ChEI) ARE COGNITIVE ENHANCERS - Cognitive enhancers have mild efficacy → so they may improve or stabilize symptoms over many months - So, patients with AD, mixed dementia, DLB, or PD should be offered a trial of a ChEI for 3 to 6 months. - If decline continues during the trial, patients are given an alternative ChEI - If Nothing improves → the ChEI should be gradually lessened before discontinuation - CHeI drugs have modest benefits in cognition, daily activities, and possibly behavior but they're expensive and can have significant adverse effects. - Adverse effects include:  Wonderland Alice in a. GIT disturbance → occurs in 10% of patients (i.e. nausea, anorexia, abdominal cramps, and loose bowel movements, vomiting or severe diarrhea) b. Bradycardia and heart blocks can develop → resulting in falls and syncope. - Contraindications/cautions of CHeI: a. CONTRAINDICATION: ChEIs are not given to people with Bifascicular and trifascicular blocks b. CAUTION: Giving ChEI to patients who take beta-blockers or nondihydropyridine calcium channel blockers (eg, diltiazem, verapamil), can cause bradycardia c. CAUTION: Right bundle branch or left anterior fascicular blocks are not considered contraindications as long as there is no atrioventricular delay. d. CAUTION: CHeIs can cause bronchospasm so they should be used with caution in individuals with reversible airway diseases e. CAUTION: before prescribing ChEIs → carry out an ECG and collect history regarding any previous peptic ulceration, gastroesophageal reflux disease, or asthma. The 3 ChEIs are donepezil, galantamine and rivastigmine 2. Memantine - It is an NMDA receptor partial agonist with modest efficacy in moderate to severe degrees of AD. - Memantine + ChEI are prescribed together → the have complimentary actions - - Bid means BI-DAILY → twice daily 3. Aducanumab - It is a monoclonal antibody directed against amyloid beta, which acts to reduce amyloid plaques in the early stages of AD. - Aducanumab was CONDITIONALLY approved by the FDA in the United States in 2021, which was controversial → it was conditional because a secondary analysis revealed reduction in amyloid beta → but this is a surrogate outcome→ it does not necessarily correlate with clinical improvement. - A postapproval trial is required to show clinical benefit. - The European Medicines Agency did not approve the drug  - Randomized trials suggest aducanumab has no significant cognitive function improvement - Side effects → 35% of patients developed cerebral edema associated with amyloid-related imaging abnormalities (ARIA-E), which requires frequent MRI monitoring. Neuropsychiatric Symptoms in dementia Depression, apathy, anxiety, and agitation are the most prevalent features. Management should start with nonpharmacologic strategies Pre-existing depression should be treated as it can make irritability and apathy WORSE Caregiver education and counseling are also crucial. A patient's agitation can be due to an underlying condition and not due to dementia → infection, organ failure, dehydration, constipation, pain, inappropriate medications, or insomnia → so these should be identified and treated If symptoms continue despite nonpharmacologic means → antidepressants are considered e.g. citalopram Atypical antipsychotics should be considered only when serious psychotic symptoms are present, as they are associated with an increased risk of stroke and death End-of-Life Care in Dementia Decisions must be made as the condition worsens → - E.g. if it's worth continuing or stopping medications for other conditions e.g. statins - E.g. if it's worth doing surgery and causing discomfort if the patient has a very advanced stage of dementia or if it's better to focus on palliative treatment to make them more comfortable for the short time they have left - E.g. if it's worth initiating invasive care for acute infections (eg, ventilation for respiratory failure) - Decisions must be individualized and must consider the prognosis in advanced dementia. In nursing home residents with advanced dementia, pneumonia or a febrile episode cause a 50% chance of mortality within 6 months. Eating problems in nursing home residents with advanced dementia causes a 40% chance of mortality in 6 months. One approach to weighing up the risks and benefits of planned treatments in frail individuals has been well described in the process entitled Palliative and Therapeutic Harmonization (PATH), which sets out a framework to approach decision-making in this context. Specialist Clinic Management Specialist clinics are used by patients or caregivers when diagnosis is unclear or if they need help with management They offer advice on: Future planning, home and driving safety, community outreach, pharmacotherapy and end-of-life care. They help the caregiver through: Counseling, education (e.g. via research studies), and support → reducing caregiver burnout and reducing the amount of people who put their loved ones in care homes How to prevent dementia The SYST-EUR study showed that: - The reduction of vascular risk factors prevents dementia e.g. if you delay or prevent strokes, you may be able to delay or prevent mixed or vascular dementias. - Treating moderately severe systolic hypertension reduced the risk of dementia by 50% over 5 years. Epidemiologic studies showed that: - Increased physical activity decreases dementia risk → but evidence is lacking Restriction of heavy (but not moderate) alcohol use decreases dementia risk More education decreases dementia risk. Adhering to a Mediterranean diet (rich in fruits, vegetables, healthy oils, and low in red meat) can slow cognitive decline with age, but the quality of the data supporting it is low. The prevalence of dementia is beginning to decline in North America and Europe, which is thought to be due to more aggressive management of vascular risk factors. Neuropsychiatric symptoms of dementia Definition Dementia = syndrome characterized with progressive cognitive decline and impairment in 1 or more cognitive domains sufficient to cause decline in daily function. DSM-5 = american Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders  In 2013 the DSM -5 renamed ‘dementia’ as a ‘major neurocognitive disorder’ The DSM-5 made the term ‘Mild neurocognitive disorder’ to categorize a less severe level of cognitive impairment (also referred to as mild cognitive impairment [MCI]) MCI is a risk factor for the development of Alzheimer disease or other neurodegenerative forms of dementia. The introduction of ‘neurocognitive disorder’ does not mean that “dementia” is no longer used People with MCI or dementia have neuropsychiatric symptoms (NPSs) (a.k.a behavioral and psychological symptoms of dementia [BPSD]): - Agitation, depression, apathy, delusions, hallucinations, and sleep impairment,Elevated mood, Irritability, Mood lability (instability), Anxiety, Disruptive vocalization, Aggression, Sundowning, Wandering, Pacing, Hoarding, Inappropriate sexualized behavior - In some cases they present as clusters, causing syndromes such as dementia-associated psychotic or mood disturbances. - These symptoms can seriously affect patients and caregivers → greater impairment in activities of daily living, more rapid cognitive decline, worse quality of life, earlier institutionalization, and greater caregiver depression. - Therefore, the NPSs of dementia are serious conditions that are increasingly becoming a focus of attention. Epidemiology NPSs can occur in over 90% of patients with dementia NPSs can occur as an isolated symptom or as symptom clusters Having NPSs → means more rapid disease progression of dementia, worse outcomes, and significant distress to the patient and caregivers. The NPSs in patients with dementia can be due to: - neurobiologically related disease factors - patient’s unmet needs (eg, too hot, too cold, hunger, incontinence, need to go to the bathroom → increases agitation) - caregiver factors - environmental triggers - Interactions of the patient, caregiver, and environmental factors. - regional brain degeneration - Changes in the brain structure e.g. neuronal and neurotransmitter changes → altering the brains biology - NPSs can also be due to experiencing challenges with communication and environment. NPSs are common to all late stages of dementia The NPSs are usually termed ‘challenging’ but now it is being termed as ‘responsive behaviors’ → this is because the behaviors are how the brain attempts to communicate distress or unmet needs and should motivate caregivers to determine potential triggers. Clinical features NPSs may impact the safety and care of patients with MCI or dementia. The most common NPSs in dementia → Agitation, depression, apathy, delusions, hallucinations, sleep impairment, Elevated mood, Irritability, Mood lability (instability), Anxiety, Disruptive vocalization, Aggression, Sundowning, Wandering, Pacing, Hoarding, Inappropriate sexualized behavior 1. Agitation - MOST COMMON SYMPTOMS - Can occur as a primary symptom - Can accompany other NPSs e.g. anxiety, depression, or psychosis → as a secondary symptom - Agitation can manifest itself verbally or motorly - Verbal agitation = repetitive vocalizations, shouting - Motor agitation = pacing, physical aggression, resistance to care - Agitation can lead to injury and can impact the safety of the patient and others. - Sundowning is a pattern of agitation → where agitation worsens in the late afternoon or early evening. - sundowning can be associated with decreased light exposure, timing of medications, and dysfunctional sleep-wake cycles. 2. Apathy - Apathy can manifest as: deficits in thinking, diminished ability to initiate action, cognitive and emotional blunting, diminished self care, and increased isolation - It is important to distinguish apathy from depression - Depression causes great suffering and distress to the patient → apathy doesn't - Apathy causes more distress to the caregiver than the patient  3. Psychotic symptoms → hallucinations and delusions - Hallucination and delusions occur in delirium as well → so you need to distinguish delirium from dementia - Visual hallucinations suggest delirium, Parkinson disease, dementia with Lewy bodies, progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration syndrome - Paranoid delusions are the most common → they cause the patient to be suspicious and create false beliefs e.g accusing their partners of cheating on them, accusing others of theft etc - Psychotic symptoms can vary in intensity and severity → if they're not causing harm or distress to the patient or others → pharmacotherapy is not required 4. Depression - Occurs in 15%-18% of patients with dementia - Patients with dementia who have a past history or family history of depression and/or stroke are at greater risk for a major depressive episode - Irritability and mood lability become more prominent with the progression of dementia. - Those who carry the apo-E ε4 allele → have a higher risk of developing Alzheimer disease, depression and anxiety. 5. Disinhibition - Occurs in ⅓ of patients and is more common with frontal lobe involvement (FTD) - Sexually disinhibited or inappropriate behavior causes distress to caregivers - The cause of disinhibited behavior = dementia, neurologic disorders, adverse effects of medication (eg, dopamine agonists for Parkinson's disease, benzodiazepines), undiagnosed bipolar disorder with mania - It's important to distinguish dementia from mania/ hypomania as they both present disinhibited behaviors - People with a past personal or family history of bipolar or depressive disorder, are given a trial of a mood stabilizer, if helpful, it may provide diagnostic information, but this should not be done routinely and should prompt referral to a geriatric psychiatrist for diagnostic clarification and management. 6. Sleep-wake cycle disturbances: - Worsen caregiver burden. - Patients with dementia experience more sleep-wake cycle arousals and awakenings → spending less time in REM sleep → taking more daytime naps → exacerbating the problem. Diagnosis The diagnosis of NPSs includes a thorough evaluation of the following items: 1. Taking patient history It can determine the cause of the NPSs Take details from the patient and the caregiver It requires skills, patience, and flexibility to obtain accurate data. Face the patient directly and pay particular attention to eye contact, use unambiguous language, and speak in a calm, non threatening tone. Assessing frustration or agitation of the patient is critical, as is recognizing when to switch topics or allow a break. The most important differential diagnosis is to exclude delirium as a cause for the behavioral change. Important elements of the history include: - Chronology and onset of the emergence of NPSs. - Sudden decline in the ability to perform every activity suggests delirium or acute cerebrovascular events (i.e. stroke) - Presence of a pre-existing illness → e.g. signs and symptoms of delirium, vascular disease (risk factor for depression and agitation), infection, pain, and constipation. - Presence of past psychiatric episodes (eg, mood, psychosis, anxiety), which may represent a recurrence or relapse of underlying psychiatric disorder. - Presence of a pre-existing substance use disorder or withdrawal - Medication adherence, changes, and withdrawal. 2. Physical examination and neurologic examination - Physical and neurological examinations allow us to rule out infections, pain, constipation, cerebrovascular or cardiovascular diseases being the cause of the NPSs. - A neurologic examination is important to exclude focal neurologic signs that suggest stroke or subdural hematoma. - Focal neurologic sign = an effect confined to one area  3. Regular mental status examinations - Patients with NPSs should undergo regular mental status examinations that involve cognitive assessments - The most important tasks are to: a. Distinguish NPSs (of dementia) from delirium b. Distinguish depression as an NPS from a primary depressive disorder or a depressive episode of bipolar disorder. → in both cases the severity, the degree of distress and the impairment of function determine the treatment. - Sadness, weepiness, agitation, suspiciousness or paranoia, disinhibition, or apathy should be documented. - The Cognitive assessment involves the Mini-Mental State Examination (MMSE) → which detects cortical deficits - The MMSE should be supplemented by the Clock Drawing Test and the Montreal Cognitive Assessment (MoCA), - The MoCA → evaluates the frontal-subcortical executive function - MoCA is free for clinical use, but it requires clinicians to undergo the MoCA training and certification program to ensure validity and reliability of the test. - In advanced stages of the illness → patients are unable to complete formal cognitive tests → in this case, you have to rely on observations of behavior, speech, and response to stimuli to determine the level of cognitive impairment, noting that a change from baseline is more significant than the absolute test scores. 4. Neuropsychological assessment - When NPSs occur in someone with cognitive impairment but don't match the typical progression of dementia, a neuropsychological assessment can help measure the extent of the impairment and monitor how it changes over time - Neuropsychological assessments are intensive, expensive, and not recommended on a routine basis. - The NPI-Clinician (NPI-C) version scale measures 14 domains and includes aberrant vocalization. - The most commonly used scale for detection of NPSs of dementia is the Neuropsychiatric Inventory (NPI), which assesses NPSs in 12 domains: 1. Delusions 2. Hallucinations 3. Agitation 4. Dysphoria 5. Anxiety 6. Apathy 7. Irritability 8. Euphoria 9. Disinhibition 10. Aberrant motor behavior 11. Night-time behavior disturbances 12. Appetite and eating abnormalities Diagnostic Tests Diagnostic tests are used when 1. patients exhibit NPSs EARLY in the course of dementia 2. Diagnostic clarification will impact the management of a patient with dementia 3. We want to exclude other contributing or reversible factors First you carry out basic screening tests: - Complete blood count - TSH levels - Serum electrolytes - GFR - Serum calcium - Serum glucose - Screen for depression → using the geriatric depression scale Then, if justified, you carry out specific examinations:  - Heavy metal screens - VDRL test (venereal disease research laboratory.) - Routine genetic marker tests are not recommended (e.g. apoE) You can also carry out an ECG to screen for vascular risk factors A lumbar puncture test is carried out if: - You have specific concerns (e.g. infection, demyelinating diseases) - You want to check for the presence of the CSF 14-3-3 protein (if present it means the patient has creutzfeldt-jakob disease) - If you want to check for CSF biomarkers of alzheimer’s disease (CSF Abeta 1-42 and tau) → even though they have no clinical utility, they are part of the research protocol Carry out an EEG - To identity creutzfeldt-jakob disease - And to identify dementia with seizures Structural brain imaging (CT or MRI) can be carried out: - Neuroimaging is not required in all patients with cognitive impairment - Although MRI is more expensive, it is preferred as opposed to CT - CT or MRI is carried out in the assessment of cognitive impairment, IF the doctor suspects that there's an underlying cerebrovascular disease and IF its identification would alter the treatment plan Functional brain imaging - FDG-PET or PET amyloid imaging is used in patients with atypical dementias 18 - F-florbetaben FDG-PET is used for differential diagnosis purposes if the underlying pathologic process remains unclear after a baseline evaluation, preventing adequate clinical management. - If FDG-PET is unavailable, a SPECT study can be used instead - Tau-PET with 18F-flortaucipir is used for analyzing the aggregated tau neurofibrillary tangles in patients’ brains with cognitive impairment who are being evaluated for Alzheimer disease. - Flortaucipir was the first tau-PET tracer to be introduced - SPECT with 123I-ioflupane (DaTscan) differentiates Alzheimer disease from Lewy body disease Differential Diagnosis Differential diagnosis is the process of differentiating between two or more conditions which share similar signs or symptoms. The differential diagnoses to be considered in a patient with cognitive impairment exhibiting NPSs include delirium, neurologic diseases, infections, metabolic abnormalities, depression, psychotic disorders, and drug-related mood or psychotic syndromes. Treatment The treatment of NPSs can have a significant impact on the quality of life of the patient, their families, and caregivers. Patients should refer to a geriatric psychiatrist, a psychiatrist, or a geriatrician in instances of uncontrollable symptoms that cause marked distress How to approach NPSs and take into consideration their causes. 1. Nonpharmacologic treatment: The first line of treatment should always be to identify and address the underlying cause of the NPS whenever possible (eg, pain, infection, constipation). Few risks are associated with these treatments, so they should always be considered first  Nonpharmacologic treatment is tailored to the individual patient and their impact should be monitored through the use of standardized behavioral assessment tools such as the Cohen-Mansfield Agitation Inventory. Non-pharmacologic interventions should be used in combination with medication Family and caregivers are key collaborators and need to be educated and involved in treatment planning. By making dementia education more accessible, online toolkits and material can help manage issues at home before a crisis occurs. E.g. iGeriCare is a free online dementia education program developed by experts in psychiatry, geriatrics, and online learning at McMaster University Nonpharmacologic intervention for symptomatic treatment includes: - Sensory enhancement/relaxation: massages, music, white noise, controlled multisensory stimulation (snoezelen), art therapy, aromatherapy - Social contact: pet therapy, 1:1 social interaction, stimulated interactions/family videos - Behavior therapy: differential reinforcement, stimulus control - Structured activities: recreational activities, outdoor walks, physical activities - Environmental modifications: wandering areas, natural environments, reduced stimulation, light therapy - Training and development: staff education, staff support, training programmes for family caregivers 2. Pharmacologic treatment of NPSs: General prescribing principles: - Before prescribing, inform the patient and the caregiver of the risks and the benefits of taking the medication and document CONSENT - Consider the age related changes in pharmacodynamics and pharmacokinetics of psychotropic medications (eg, longer time to reach steady state, longer half-life, and longer elimination time) - Lower doses, cautious dose adjustments, and regular reassessment of the need for continuing the treatment in the geriatric patients should be considered. - Geriatric patients with dementia are more vulnerable to adverse effects - Adverse effects: sedation, anticholinergic adverse effects, cognitive decline, extrapyramidal symptoms, and drug-drug interactions. - Agitation (which is the main characteristic for mood, anxiety and psychotic disorders) is the most common NPS requiring specific pharmacologic treatment after other treatments have failed. a. Antidepressants: Antidepressants have little effect on NPSs of dementia patients BUT if there is a high suspicion for depression causing distress, you give the patient an ANTIDEPRESSANT TRIAL WHILE monitoring for adverse effects. Adverse events of antidepressants: - Headache, nausea, diarrhea, sweating, insomnia, hyponatremia, GI bleeding, risk of falls, fractures, and osteoporosis, prolonged QT interval (citalopram) At HIGH doses → selective serotonin reuptake inhibitors (SSRIs) can cause reduced expression and worsen apathy. In patients partially responsive to SSRIs, have prominent apathy, and are medically ill → use low-dose psychostimulants (eg, methylphenidate, atomoxetine, modafinil) Psychostimulants increase blood pressure and heart rate, irritability, agitation, and psychosis → so you should not use them in patients with severe cardiovascular disease If a patient has had depression or cerebrovascular disease before, there is less hesitation to prescribe antidepressants again. Starting antidepressants earlier in such patients can help prevent the worsening of depression or reduce risks associated with cerebrovascular conditions SSRIs are the preferred antidepressants in treating depression in patients with dementia and are generally well tolerated. What determines the selection of an antidepressant → adverse-effects (particularly anticholinergic), drug-drug interactions, medical comorbidities, and cost. What do SSRIs treat: - Depression in dementia patients - Citalopram treats Agitation in dementia patients (sertraline can also moderately treat dementia) - psychosis in alzheimer's disease  Citalopram has been shown to be as effective as risperidone, a second-generation antipsychotic (SGA), in the treatment of agitation due to dementia. Citalopram is most effective in patients with moderate agitation and low levels of cognitive impairment. Citalopram prolongs the QTc interval, so it is contraindicated in patients with increased risk for arrhythmias Citalopram should be discontinued in the case of a persistent QTc above 500 ms. Health Canada and the FDA recommend: - A maximum daily dose of 20 mg of citalopram for patients aged 60 and above Sertraline at daily doses 25 to 100 mg can have a modest benefit on agitation. If you use SSRIs for a NPSs other than depression → constant assessments of benefits vs risks are required → discontinuation of the SSRI should be done gradually. Evidence shows that → NPSs in frontotemporal dementia can be due to deficits in the serotonergic system, in particular the repetitive behaviors. There is limited evidence of benefit for serotonergic antidepressant agents in these patients (Table 5). Given the absence of evidence for using any other pharmacologic agents in this illness, a trial of an SSRI in these patients is warranted if the NPSs are causing distress. b. Cholinesterase inhibitors: - Cholinesterase inhibitors improve the NPSs by a small amount - What NPSs do they treat: apathy, anxiety, depression, disinhibition and aberrant motor symptoms - What diseases do they treat: Alzheimer disease, dementia with Lewy bodies, - Side effects: worsen agitation in (FTD) dementia patients - Contraindication: DO NOT USE ChEIs in FTD c. Anticonvulsant mood stabilizers:  Anticonvulsant mood stabilizers include → carbamazepine, valproic acid, gabapentin Anticonvulsants are not routinely used in the treatment of NPSs, unless the patient has a pre-existing diagnosis of bipolar disorder Carbamazepine can have significant adverse effects (particularly in geriatric patients): - Sedation, ataxia, falls, neutropenia, hyponatremia, increased liver function tests, skin rashes - Cardiac toxicity - Carbamazepine is a strong enzymatic inducer → it induces drug-drug interactions → making the risk of use too high to be considered on a routine basis. Valproic acid is less recommended due to very limited efficacy on these symptoms. d. Antipsychotics: Antipsychotics treat: Psychosis and aggression in dementia E.g. risperidone, olanzapine, and aripiprazole Haloperidol should only be used for treating agitation or psychosis in delirium because it is the most likely antipsychotic to cause EPS SEVERE Side effects: - Sedation - Postural hypotension - Increased risk of falls and fractures - Increased risk of cerebrovascular events - Increased risk of Mortality - Extrapyramidal symptoms (EPS) = parkinsonism, dystonias, and akathisia (particularly with antipsychotics with high D2 blockade, such as haloperidol, risperidone, and aripiprazole) - metabolic adverse effects = weight gain and dyslipidemia (higher risk in female patients, with olanzapine and quetiapine). - Longer-term use of FGAs (and some SGAs and TGAs) can cause → tardive dyskinesia, particularly in older female patients with dementia and comorbid depressive or bipolar disorders. - There is no single most effective and safe treatment option → so, physicians prescribing antipsychotics to patients with dementia should trade off between the effectiveness and safety of these medications in the treatment of NPSs. Antipsychotics are the last resort for treating NPSs of dementia because of their adverse effects → they are only used if non drug therapies have failed and if the patients behaviors are a risk to themselves or others. Antipsychotics DO NOT TREAT: wandering, social withdrawal, vocalizing, pacing, touching, or incontinence There are 3 types of antipsychotics → first generation (FGA), second generation (SGA), and third generation (TGA) SGA - RISPERIDONE → should be used for short term treatment of aggression or psychotic symptoms in patients with severe dementia of the Alzheimer type → only used if nondrug therapies ave failed and if the patients behaviors are a risk to themselves or others TGA - ARIPIPRAZOLE and BREXPIPRAZOLE → are partial agonists at dopamine D2 and serotonin 5-HT1A receptors and antagonists at serotonergic 5-HT2A receptors. - Brexpiprazole treats: agitation in patients with dementia due to Alzheimer disease. - Brexpiprazole is not recommended as an as-needed treatment for agitation because it takes 6 to 8 weeks to see results Behavioral symptoms of dementia do not usually persist for more than 3 months → so you should try regularly to discontinue the medication Even long term use of antipsychotics in a patient with dementia does not cause problems so discontinuation is safe The only time discontinuation should be done carefully is when a short term use of antipsychotics worsens behavioral symptoms  Successful discontinuation of antipsychotics = lower daily doses of antipsychotics and decreased behavioral symptoms. Patients with more severe NPSs might not be able to discontinue antipsychotics → so long term treatment is required It remains uncertain whether discontinuation of antipsychotics leads to a decrease in mortality. e. Benzodiazepines (sedative/hypnotics): Despite widespread use, we DON'T KNOW if its safe to prescribe benzodiazepines to older adults The risks clearly outweigh the benefits  Studies show that you DOUBLE your chances of worsening cognition, falls, and hip fractures leading to hospitalization and death if you take benzodiazepines as an older adult According to Choosing Wisely Canada → benzodiazepines should only be used to treat: - Alcohol withdrawal symptoms in delirium tremens - severe generalized anxiety disorder unresponsive to other therapies - neuroleptic malignant syndrome - catatonia Outside of these specific indications, benzodiazepines should not be used as a first-line agent in treating agitation or other behavioral disturbances in patients with NPSs of dementia. Benzodiazepines are highly addictive → so initiating (risk of dependence) or discontinuing (risk of withdrawal) sedative-hypnotics in hospitals can have substantial impact on their long-term use. Short-term use and on-demand use of shorter-acting benzodiazepines (e.g. lorazepam), can be used to treat severe agitation or aggression. Many older adults who present with NPSs have been on benzodiazepines for decades are addicted → so the goal is to gradually decrease and use the lowest doses of short-acting or intermediate-acting agents (lorazepam, clonazepam) that are effective. Ultra-short-acting agents (e.g. alprazolam), are not recommended because they cause dependency and amnesia. f. Disease-modifying agents (anti-amyloid monoclonal antibodies): - Monoclonal antibodies, lecanemab and aducanumab, slow the progression of Alzheimer disease by modifying the disease - The disease modifying agents work in mild cognitive impairment where amyloid beta plaques are present and in mild stage dementia - Lecanemab is under review by health canada - Donanemab, another monoclonal antibody, has shown some positive effects in patients with prodromal to moderate dementia due to Alzheimer disease - There is little evidence proving that disease-modifying agents work to treat Alzheimer disease patients - A surveillance program for the disease modifying agents is used to weigh the modest benefits (ie, moderately lower decline on measures of cognition and function at 18 months) against safety concerns (eg, infusion-related reactions, cerebral edema, intracerebral hemorrhage). - So, monoclonal antibodies are not yet used and it is not confirmed if they can improve NPSs The heterogeneity of the disease can require a personalized approach and sometimes combination therapy → to maximize therapeutic efficacy How to treat and how not to treat NPSs in dementia NPSs in dementia Pharmacologic option “Better not to use” pharmacologic option Agitation/ Serotonergic antidepressants (eg, citalopram, Do not use TGAs/SGAs/FGAs as first choice aggression sertraline, trazodone) Avoid highly anticholinergic FGAs/SGAs (eg, chlorpromazine, perphenazine, clozapine) Shorter-acting BZPs (eg, lorazepam, oxazepam) Avoid highly dopamine-blocking FGAs and SGAs in parkinsonism-related dementias (eg, haloperidol, risperidone → because they cause EPS, worsening symptoms) Anticonvulsants (eg, carbamazepine, valproic acid) if comorbid bipolar disorder Limit use of anticonvulsants (eg, carbamazepine, valproic acid) if no comorbid bipolar disorder – SGAs/TGAs (eg, risperidone, olanzapine, quetiapine, aripiprazole, brexpiprazole) ChEIs may worsen agitation; do not use in FTD FGAs (eg, haloperidol) (LAST RESORT) Avoid BZDs/sedative-hypnotics as first choice Apathy ChEI (donepezil, rivastigmine, galantamine) FGA/SGA worsen apathy Antidepressants High doses of antidepressants worsen apathy Spsychostimulants (methylphenidate, modafinil) Psychosis ChEIs (donepezil, rivastigmine, galantamine) Limit use of FGAs and most of TGAs and SGAs (except quetiapine) in dementia with Lewy bodies and Parkinson disease dementia due to worsening of EPSs in TGA dose-dependent fashion SGA FGA Limit use of FGAs/SGAs/TGAs in prolonged QTc syndrome (except aripiprazole) Depression Antidepressants eg, citalopram, escitalopram, Avoid highly anticholinergic antidepressants sertraline, venlafaxine, bupropion, mirtazapine) Disinhibition Antidepressants (citalopram, trazodone) BZPs may worsen disinhibition Antiandrogens (medroxyprogesterone acetate) – Dopamine agonists may worsen disinhibition GnRH analogues (leuprolide) SGA/FGA (quetiapine and haloperidol) sleep disturbance Antidepressants (eg, mirtazapine, trazodone) Avoid BZDs/sedative-hypnotics as first choice Shorter-acting BZPs/sedative-hypnotics, if Do not use long-acting BZPs (eg, diazepam, chlordiazepoxide, flurazepam) due to drug necessary, for a brief period of time (eg, accumulation, active metabolites lorazepam, oxazepam, temazepam, zopiclone PARKINSON DISEASE Definition Parkinson disease (PD) involves : - Degeneration of cerebral structures - Atrophy (decrease in size) of dopaminergic neurons in the substantia nigra → decreasing the dopamine levels in the striatum - Apart from in the substantia nigra, degeneration can also occur in the locus coeruleus, amygdala, medial temporal lobes, and the Peripheral NS. - Loss of proliferation of glial cells - degeneration of other neurotransmitter systems - The presence of lewy bodies in affected regions of the brain (although they can also be found in other neurodegenerative diseases e,.g. Dementia with lewy bodies) - Lewy bodies are intraneuronal cytoplasmic inclusions containing alpha-synuclein and ubiquitin. - Absence of inclusion bodies in oligodendroglial cells CARDINAL Motor features of PD: movement control - bradykinesia (slowness of movement) - muscular rigidity (stiffness) - resting tremor  - gait dysfunction - postural instability - autonomic or neuropsychiatric disturbances. 120 out of 100,000 people have PD Per year 5 - 24 people out 100,000 are diagnosed with PD PD occurs more frequently in men than in women → 3:2 The onset of PD begins in people over 50 → with an average of 60 years. If you have an onset of PD under 40 years of age → it suggests a genetic cause. People over 70 with Parkinson's disease are 10 times more likely to experience serious health problems (morbidity) compared to the general population Etiology (causes): - Not been clearly identified. - Can be due to genetic and environmental factors (e.g. polymorphic variants and mutations in selected genes) - 4% of patients with PD have a single-gene mutation (single-gene hereditary autosomal dominant or recessive PD). - Most mutant genes in PD encode proteins associated with mitochondrial function. Currently PD is defined as a systemic synucleinopathy with motor (parkinsonian syndrome) and nonmotor manifestations (olfactory, neuropsychiatric, autonomic, sensory, and sleep disturbances). Types of PD: 1. Akinetic-rigid PD 2. Tremor-dominant PD 3. Mixed PD Signs and symptoms 1. Deficits in primary motor automaticity: - Hypokinesia or even akinesia (inability to move) - development of synkinesis (voluntary muscle movement causing simultaneous involuntary contraction of other muscles) - Propulsion and retropulsion (tendency to fall forward or backward). 2. Increased muscle tone. 3. Resting tremor. 4. Other somatic symptoms: - Micrographia (abnormally small handwriting) - hypophonic speech (weak voice) - olfactory disturbances, - dysphagia, - limb pain, - fatigue, - autonomic disturbances (constipation, drooling, facial and scalp seborrhea, episodes of diaphoresis or excessive cold, orthostatic hypotension, erectile dysfunction, urinary dysfunction). 5. Neuropsychiatric disorders: - Depression, anxiety, apathy, cognitive impairment, psychosis. 6. Sleep disturbance: - Rapid eye movement (REM) sleep behavior disorder, excessive daytime sleepiness. Natural history PD is progressive, with increasing motor and nonmotor disturbances over the course of ~15 to 20 years. In advanced PD the combination of movement difficulties—with high risk of falls—and neuropsychiatric symptoms leads to severe disability and complete dependence of the patient on caregivers. Diagnosis Diagnosis of PD can be challenging, especially in early stage PD Nonmotor manifestations e.g. mood symptoms, constipation, and REM sleep behavior disorder, can come before motor manifestations. There are currently no established diagnostic criteria for PD. Clinical diagnosis of PD is based on identifying cardinal motor symptoms linked to dopamine deficiency in the nigrostriatal system. Diagnostic criteria for idiopathic Parkinson disease developed by the United Kingdom Parkinson’s Disease Society Brain Bank Step 1. Diagnosis of a parkinsonian syndrome - If patient has bradykinesia and 1 or more of → Muscular rigidity, 4-6 Hz rest tremor, Postural instability not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction → then they have parkinsonian syndrome Step 2. Exclusion of signs and symptoms not favoring the diagnosis of idiopathic PD - So if the patient has one of the following, the clinician should strongly consider alternative diagnoses other than idiopathic parkinson disease 1. History of repeated strokes with stepwise progression of parkinsonian features 2. History of repeated head injury 3. History of definite encephalitis 4. Oculogyric crises (episodes of involuntary gazing, caused by tonic spasms of extraocular muscles) 5. Neuroleptic treatment at onset of symptoms 6. 1 or more affected relative 7. Sustained remission 8. Strictly unilateral features after 3 years 9. Supranuclear gaze palsy 10. Cerebellar signs 11. Early severe autonomic involvement 12. Early severe dementia with disturbances of memory, language, or praxis (ability to perform complex intentional movements) 13. Babinski sign 14. Presence of a cerebral tumor or communicating hydrocephalus on computed tomography 15. Negative response to high doses of levodopa (if malabsorption excluded) 16. Exposure to MPTP Step 3. demonstration of typical signs and symptoms of PD. - 3 or more of the following must be present to diagnose definite parkinson disease 1. Unilateral onset Only 2. Resting tremor present one side 3. Progressive disorder 4. Persistent asymmetry affecting the side of onset most 5. Excellent response to levodopa (>70%) 6. Severe levodopa-induced chorea 7. Levodopa response for ≥5 years 8. Clinical course of ≥10 years (typical course of Parkinson disease) Based on these criteria, bradykinesia (typically asymmetric) is a requirement for the diagnosis of PD and an excellent response to levodopa is a supportive feature. So how can you diagnose PD? - Identify cardinal motor symptoms - Use the diagnostic criteria for idiopathic parkinson disease - Make a definitive diagnosis by identifying the characteristic neuropathologic features in a postmortem study (loss of neurons in the substantia nigra, presence of Lewy bodies in the substantia nigra, absence of inclusion bodies in oligodendroglial cells). - olfactory testing and transcranial ultrasonography, are very rarely (if ever) done → they are reserved for patients with atypical features (magnetic resonance imaging [MRI]). - Drug challenge clinical tests are not recommended. - Genetic testing is indicated only in selected patients with a positive family history, early age of onset, or both. Differential diagnoses This is when you are differentiating between 2 or more conditions which share similar signs or symptoms You can be uncertain between PD and:  1. Other parkinsonian syndromes 2. Essential tremor 3. Normal-pressure hydrocephalus 4. vascular parkinsonism: Akinesia and muscular rigidity in patients with a history of vascular incidents, frequently with other coexisting neurologic manifestations. 5. Drug-induced parkinsonism 6. Depression 7. Dementia 8. Hemiparesis 9. Hemisensory syndrome In diagnostic uncertainty e.g. you are trying to differentiate between PD and essential tremor, you can use: - Single-photon emission computed tomography (SPECT) with DaTscan (radiolabeled ioflupane with high affinity for dopamine transporters in the presynaptic membrane) - PD patients have a lack of presynaptic dopamine transporters in the striatum → so they have a weaker signal in this area of the brain in SPECT images - Cardiac scintigraphy with 123I-metaiodobenzylguanidine (123I-MIBG) may also be useful → Cardiac autonomic denervation and reduced MIBG uptake occur in Lewy body diseases. Cardiac scintigraphy facilitates differentiation between PD and other causes of parkinsonism. Different parkinsonian syndromes include: Treatment of PD There is no disease-modifying treatment available to alter the biological course of PD → there is only treatment to manage symptoms of the disease and manage adverse effects of pharmacologic treatments. These include nonpharmacologic techniques, pharmacotherapy, and surgical treatment. Nonpharmacologic Approach Patient education physical therapy and exercise adequate nutrition and hydration Participation in mutual support groups for patients with PD. Pharmacotherapy Pharmacotherapy is needed when the patient has functional impairments, and when their symptoms begin impacting their quality of life Symptoms are improved with dopaminergic treatment → levodopa (precursor of dopamine) or a dopamine agonist Using Dopamine agonists monotherapy, BEFORE starting levodopa treatment, can delay dyskinesia (involuntary, unpredictable movements) If the response to monotherapy with a dopamine agonist is no longer satisfactory despite using increasing doses, add levodopa. Dopamine agonists cause more side effects in elderly patients Dopamine agonists may not delay levodopa induced dyskinesia in elderly patients This is why levodopa is given to elderly patients from the get go  Drug dosage must be adjusted over time in PD patients as it is a progressive disease Motor complications, including motor fluctuations and dyskinesia are reported 3-5 years after the disease - The fluctuations are between “on” time, when symptoms are reasonably controlled - “off” time, when symptoms recur In patients treated with levodopa who are experiencing the return of “off” symptoms before each dose is due (ie, “wearing off”), it may be beneficial to add a COMT inhibitors, MAO-B inhibitors, or other medications that block the degradation of neurotransmitters, including dopamine. Dopamine agonists, COMT inhibitors, and MAO-B inhibitors are given alongside levodopa to improve motor symptoms → They also allow for lower levodopa doses → so they can reduce the risk of dyskinesia, motor fluctuations, and other adverse effects of long-term levodopa treatment. In patients with prominent tremor, the use of a non dopaminergic medication, such as a nonselective beta-blocker, or of an anticholinergic medication may be reasonable early in the disease course to postpone the use of the above-mentioned agents. If the patient does not improve after a treatment is added, the dose or timing of the medication can be slowly increased. If the effect remains minimal despite adjustments, including titration of levodopa up to ~1 g/d, consider alternate diagnoses. 1. Levodopa - What it treats: muscular rigidity, bradykinesia, resting tremor - Levodopa can treat resting tremor but not remove it completely - Levodopa is always used in combination with an aromatic L-amino acid peripheral decarboxylase inhibitor (carbidopa or benserazide) to increase dopamine availability in the brain and reduce peripheral adverse effects. - Dose of Levodopa: starts at 50 mg per day, then it is increased by 50 mg/d every few days, until it reaches 300 to 450 mg/d initially in 3 divided doses → depending on the severity of the symptoms, the dose can be increased further to 1200-1500 mg per day (in some cases even higher) in divided doses. - - Adverse effects of levodopa: a. nausea, orthostatic hypotension, constipation b. Long term effect: DYSKINESIA (these are involuntary movements that appear in 80%-90% of patients after 5-10 years of levodopa treatment) c. Long term effect: Motor fluctuations (reported after 3-5 years of levodopa treatment) - “Off” periods = when the patient experiences both motor (bradykinesia, rigidity, tremor) and nonmotor symptoms (inability to move at all a.k.a ‘freezing’) - “On” periods = when the symptoms of the patient are relatively diminished - Using levodopa for a long time causes motor fluctuations because: a. The levels of endogenous dopamine are decreased b. The effect of levodopa is weaker c. The duration of levodopa is shorter - To manage motor fluctuations: a. increase the dose of levodopa b. shorten the time interval between doses of levodopa c. Add other drugs : Dopamine agonists, COMT inhibitors, and MAO-B inhibitors d. Add an extended release formulation of levodopa - In advanced PD (specifically in patients with prominent motor fluctuations despite optimized oral medications) a levodopa/carbidopa gel may be administered continuously (~16 h/d), directly into the jejunum, using a percutaneous endoscopic gastrostomy tube. 2. Dopamine agonists - What they treat: bradykinesia and rigidity, but they do not significantly improve tremor. - Administration: mostly orally - ONLY rotigotine is administered through a transdermal patch. - Apomorphine can be provided through a sublingual film or through infusion - Apomorphine is a dopamine agonist with the shortest half-life of 0.55 hours, meaning it produces a rapid effect → It can help treat the delayed onset of levodopa's effects. - People taking levodopa may experience delays in its effectiveness, such as between doses, after dose failures, or upon waking - Dopamine agonists are less effective than levodopa - Dopamine agonists can be used alone early on to delay the need for levodopa, helping to postpone the development of dyskinesia in younger patients with PD.  - Adverse effects of dopamine agonists: a. orthostatic hypotension, hallucinations → cause the drugs to be withdrawn in elderly patients b. impulse control disorders (eg, excessive eating, gambling, sexual behaviors, shopping) c. hypersomnolence (hyper sleepiness) with or without sleep attacks d. lower limb edema e. Ergot-derived dopamine agonists (bromocriptine, pergolide, cabergoline) also carry a high risk of fibrosis, especially cardiac valvular fibrosis. 3. COMT inhibitors → entacapone, tolcapone - What it does: inhibit the enzymatic breakdown of levodopa → increasing its plasma concentration. - COMT inhibitors are only used in combination with levodopa - Dose of Entacapone: 200 mg with each dose of levodopa, up to a maximum of 2000 mg/d. - Side effects of entacapone: it increases the levodopa levels, so it can aggravate the adverse effects of levodopa (e.g. dyskinesia and orthostatic hypotension) it can also cause diarrhea - Dose of tolcapone: 300 mg per day in 3 divided doses → This is a peripheral and central inhibitor - Side effects of tolcapone: Hepatotoxicity. 4. MAO-B inhibitors: selegiline and rasagiline - What they do: Similarly to entacapone, MAO-B inhibitors inhibit the breakdown of levodopa and increase its levels in the brain. - When used ALONE (in monotherapy) → MAO-B inhibitors have minor beneficial effects in early PD and delay the need for dopaminergic treatment. - In moderate PD, MAO-B inhibitors added to levodopa reduce motor fluctuations associated with levodopa treatment. - Dose of Selegiline: 5 mg once daily or bi-daily - Dose of Rasagiline: 1 mg per day. - Side effects: a. Slegiline taken in the evening can cause sleep disturbances b. MAO-B inhibitors taken in combination with antidepressants can increase the risk of serotonin syndrome → so low doses of citalopram and sertraline are preferred 5. Amantadine - What it does: increases the release of endogenous dopamine in dopaminergic neurons and blocks the glutaminergic NMDA receptors - Has minor effects on the symptoms of PD - What does it treat: levodopa-induced dyskinesia - Dose: 100 - 400 mg per day and is available as capsules and liquid formulations. - Adverse effects: livedo reticularis, anxiety, lower limb edema, and psychotic disturbances.  6. Anticholinergic agents: Trihexyphenidyl and biperiden - Dose = 2 - 12 mg per day in divided doses - Who does it treat = patients with EARLY PD→ under 60 years of age with tremor as the dominant clinical feature. - Down sides: many adverse effects and contraindications, and drug-drug interaction Surgical Management Surgical management of PD can treat: - severe tremors that are not responsive to oral medications - significant motor fluctuations - Debilitating dyskinesia How? - Deep brain stimulation: where electrodes are placed in targeted brain areas (thalamus, globus pallidus, or substantia nigra) and connected to an implantable pulse generator under the skin of the chest. - New and advanced treatment methods are under investigation e.g. MRI-guided focused ultrasonography, stem cells, and gene therapy Treatment of Nonmotor Disturbances Symptoms of PD can be motor (bradykinesia, dyskinesia, motor fluctuations and tremor) and non motor (depression, anxiety, dementia, sleep disturbances, autonomic disturbances, sensory symptoms) Non motor symptoms of PD can worsen the quality of life of a patient to a greater extent than motor disturbances, especially given that they frequently remain undiagnosed and untreated. 1. Erectile dysfunction - Can be an early sign of PD in men - Treated with Phosphodiesterase inhibitors (e.g. sildenafil) 2. Orthostatic hypotension - Can be managed by increasing fluid intake , adding salt to foods, sleeping with an elevated head (10-15 cm), and reducing or eliminating hypotensive agents (including antihypertensive agents and dopamine agonists). - levodopa-induced orthostatic hypotension is treated with domperidone - In general it can be treated with: mineralocorticoids and alpha-adrenergic agents - If a patient has orthostatic hypotension and supine hypotension ALREADY → you should carefully consider the risk of falls, cognitive impairment (associated with orthostatic hypotension), stroke, and myocardial infarction (associated with supine hypertension). 3. Constipation: - How to manage: A fiber-rich diet, increased intake of fluids, and physical activity - How to treat: stop using anticholinergic agents, start using laxatives (e.g. macrogol or lactulose (10-20 g/d)) 4. Urinary incontinence: - How to treat: a. Anticholinergic agents → oxybutynin, tolterodine, and solifenacin (remember they are contraindicated in patients with cognitive impairment due to the risk of confusion and hallucinations b. Mirabegron 5. Drooling - How to treat: a. Anticholinergic medication e.g. atropine drops, ipratropium bromide spray, and glycopyrrolate tablets (but they are contraindicated in patients with dementia/ hallucinations) b. Botox injections to the salivary glands (parotid and submandibular glands) may be effective. 6. Sleep disturbances: - Quality of sleep is treated with drugs ensuring prolonged activation of dopamine receptors throughout the night, such as extended-release levodopa or dopamine agonists. 7. Somnolence (sleepiness): - How to treat: modafinil. - Downside: modafinil is expensive 8. Chronic fatigue: - How to treat: Methylphenidate and amantadine. 9. Pain: - Pain can occur alongside muscle stiffness during “off” periods and may therefore respond to alterations in the dose and timing of dopaminergic medications. - How to treat: a. Over-the-counter analgesic agents  b. muscle relaxants c. Opioids d. anticonvulsant medications - Painful dystonia, often of the toes and feet, may also be effectively managed by botulinum toxin injections. 10. Mood symptoms: - E.g depression and anxiety - Non Pharmacological treatment: cognitive behavioral therapy - Pharmacological treatment: serotonin, norepinephrine 11. Psychosis: - Hallucinations and delusions are treated with quetiapine and clozapine - Other antipsychotic medications are contraindicated due to the risk of worsening parkinsonism. 12. Dementia: - How to treat: Improvements in cognitive function, behavioral symptoms, and motor function may result from treatment with cholinesterase inhibitors. - Memantine may possibly also have a positive effect. Complications 1. Most PD patients die of pneumonia - PD can cause rigidity of respiratory muscles, it can impair the cough reflex, it can increase risk of infections, and it can impair the muscles for swallowing causing → dysphagia - Dysphagia can lead to food aspiration and aspiration pneumonia. 2. Urinary tract infection due to dysfunction of the urinary bladder and urinary retention. 3. Recurrent falls Special considerations: Akinetic Crisis (a.k.a Neuroleptic Malignant-Like Syndrome; Parkinsonism-Hyperpyrexia Syndrome) What is it: Akinetic crisis is a life-threatening deterioration of the patient’s condition What is it caused by: e.g. sudden discontinuation of antiparkinsonian agents a.k.a dopaminergic treatment How to treat it: - Aggressive treatment with antiparkinsonian agents - Cooling of the body - Systemic treatment tailored to the patient’s condition ( i.e. adequate fluid volume, correction of electrolyte disturbances, thromboembolism prophylaxis, antibiotics where appropriate). Prognosis 7 to 10 years after onset → patients with PD experience disability related to imbalance and increased risk of falls 10 years after onset → 50% of PD patients have dementia. The clinical course of PD lasts 15 to 20 years If you are diagnosed with PD at a younger age → you can have a more prolonged course If you are diagnosed with PD at an elderly age → the course may be shorter and progress more rapidly Other adverse prognostic factors (faster deterioration of motor function and shorter survival) include significant comorbidities and muscular rigidity and bradykinesia as presenting symptoms of PD. STROKE What is a stroke? An abrupt onset of focal brain, spinal cord, or retinal injury caused by abnormalities of cerebral blood flow - clinical symptoms or signs last over 24 hours - Radiologic abnormalities of infarction or hemorrhage are shown in imaging studies. - Subarachnoid hemorrhage (SAH) is also considered in the category of stroke although cerebral dysfunction is usually generalized. Transient ischemic attack (TIA): focal neurologic signs and symptoms that resolve spontaneously within 24 hours and without radiologic abnormalities Stroke can be classified as:  1. Ischemic stroke 80% of stroke cases are ischemic strokes Causes of ischemic stroke: usually an occlusion of an artery resulting in decreased blood flow to the brain a. Atherosclerotic plaques - Can be either in situ plaque rupture with occlusion or an artery-to-artery embolism in the major arteries supplying the brain (aortic arch, carotid and vertebral arteries) or in large- and medium-size intracranial arteries (large artery atherosclerosis). - In situ plaque rupture → the plaque (fatty build up) breaks the artery open, and the plaque itself or blood clots block the artery → disrupting blood flow to the brain. - artery-to - artery embolism → where clot or debris formed in one artery breaks off and travels to a smaller artery in the brain, where it gets lodged, causing a blockage. This is called an embolism → and it reduces blood flow (ischemia), causing a stroke. b. Degenerative lesions/micro atherothrombosis (in situ occlusion): - Occurs in small penetrating arteries of the brain (lacunar stroke [LACI]). c. Cardiac embolism (a blood clot formed in the heart, and when it travels it becomes an emboli) - Can be due to atrial fibrillation, ischemic heart disease, mitral or aortic valvular heart disease d. Less common causes: - Patent foramen ovale (PFO) (paradoxical embolism) - Arterial dissection - Coagulopathies. e. 17% of ischemic strokes are cryptogenic (embolic stroke of undetermined source) 2. Hemorrhagic stroke - 15%-20% of stroke cases are hemorrhagic strokes - Hemorrhagic infarction is often asymptomatic - If Hemorrhagic stroke is more severe → it can impair neurologic function - It can be caused by 2 types of bleeding a. Intracerebral hemorrhage (ICH): bleeding inside the brain due to ruptured blood vessels - Ruptured Blood vessels can be due to High blood pressure leading to a weakened blood vessel (due to aging or small aneurysms), - Amyloid buildup in the brain, weakening vessels, especially in older adults. - Arteriovenous malformations (AVMs), where abnormal blood vessels rupture. b. Subarachnoid hemorrhage (SAH) : bleeding around the brian - 5% of stroke cases - usually occurs when a saccular aneurysm (a weak spot in a blood vessel) at the brain's base ruptures, causing symptoms like headache and a decreased level of consciousness (LOC) Hemorrhagic transformation occurs when an ischemic stroke (caused by a blocked artery) turns into a hemorrhagic stroke (bleeding in the brain). This can happen due to the breakdown of a clot (thrombus degeneration) after treatment, but it can also occur spontaneously in cardioembolic strokes or large infarctions. 3. Cerebral venous thrombosis - Less than 1% of stroke cases are cerebral venous thrombosis - Thrombosis is when a blood clot blocks a vein or artery - Cause: thrombosis of the intracranial venous sinuses, deep venous system, and cortical veins, causing cerebral ischemia, infarction, and hemorrhage. - Characteristics: headache, seizures, focal signs, and decreased LOC. - Focal signs refer to neurological symptoms that are localized to a specific area of the body or brain. Risk factors causing stroke: - Hypertension, - diabetes mellitus, - dyslipidemia, - tobacco smoking, - physical inactivity, - cardiac diseases, - alcohol abuse,  - oral contraceptives, - hormonal replacement therapy, - pregnancy, - migraine. SYMPTOMS OF STROKE Symptoms of ischemic stroke a.k.a cerebral infarction → They depend on the location of the lesion. 1. Total anterior circulation infarct (TACI) - Lesion affects the anterior and middle cerebral arteries → causing total anterior circulation syndrome (TACS) - Symptoms of TACS → hemiparesis (weakness on one side of the body in the face, arms or legs), aphasia, and homonymous hemianopsia blindness ontheysamesideofthe visualfieldinboth eyes - 2. Partial anterior circulation infarct (PACI) - Lesions affect a part of the anterior cerebral circulation → causing partial anterior circulation syndrome (PACS): - Symptoms of PACS → motor or sensory symptoms in face, arms or legs and isolated aphasia. 3. Lacunar Cerebral infarct → LACI - Lesions affect the deep penetrating arteries → affecting the blood supply to deep brain structures i.e. basal ganglia, internal capsule, thalamus, or brainstem → causing lacunar stroke syndrome (LACS) partialweakness - LACS symptoms → paresis or sensory disturbances in (face, arms , or legs), isolated weakness (in the face, arm and leg) - Isolated weakness in the face, arm, and leg (pure motor stroke) is characteristic to LACS 4. Posterior circulation infarct (POCI) - Lesion affects the vertebrobasilar system → affecting the cerebellum, brainstem, occipital lobe - posterior circulation syndrome (POCS) symptoms → ataxia, nystagmus, cranial nerve palsies, or isolated homonymous hemianopia. clumsy poor muscle control i Intgiedments Symptoms of hemorrhagic stroke → they depend on the location of bleeding: 1. ICH - Sympt