Pathophysiology of Neurologic Disorders By: Amir Ashkan Ashrafian, MD.

Goal: Learning 1. Alzheimer’s disease 2. Parkinson’s disease 3. Seizure and epilepsy

Alzheimer’s disease Definition ● The most prevalent form of dementia ● progressive, but some are static and unchanging ● Most patients with Alzheimer's disease (AD), begin with memory impairment. ● Dementia is defined as an acquired deterioration in cognitive abilities that impairs the successful performance of activities of daily living.

Definition ● Memory is the most common cognitive ability lost with dementia; 10% of persons >70 and 20–40% of individuals >85 have clinically identifiable memory loss. ● In addition to memory, other mental faculties may be affected; these include language, visuospatial ability, calculation, judgment, and problem solving. Alzheimer’s disease

● Dementia syndromes result from the disruption of specific large- scale neuronal networks; the location and severity of synaptic and neuronal loss combine to produce the clinical features. ● Behavior and mood are modulated by noradrenergic, serotonergic, and dopaminergic pathways, whereas cholinergic signaling is critical for attention and memory functions. ● AD begins in the transentorhinal region, spreads to the hippocampus, and then moves to lateral and posterior temporal and parietal neocortex, eventually causing a more widespread degeneration. Pathophysiology Alzheimer’s disease

● The single strongest risk factor for dementia is increasing age. ● The prevalence of disabling memory loss increases with each decade over age 50 and is usually associated with the microscopic changes of AD at autopsy. ● Yet some centenarians have intact memory function and no evidence of clinically significant dementia. Whether dementia is an inevitable consequence of normal human aging remains controversial. Etiology Alzheimer’s disease

● Common causes of dementia : Alzheimer disease (AD) Vascular dementia (Multi-infarct) Alcoholism Parkinson's disease Drug/medication intoxicationa Etiology

Alzheimer’s disease ● Other less common causes: Vitamin deficiencies (Thiamine (B1): Wernicke's encephalopathy, B12, Nicotinic acid (pellagra)) Endocrine and other organ failure Hypothyroidism Adrenal insufficiency and Cushing's syndrome Hypo- and hyperparathyroidism Renal failure Liver failure Pulmonary failure Chronic infections Etiology

Alzheimer’s disease ● The primary focus is on long-term amelioration of associated behavioral and neurologic problems, as well as providing caregiver support. ● Building rapport with the patient, family members, and other caregivers is essential to successful management. ● In the early stages of AD, memory aids such as notebooks and posted daily reminders can be helpful. ● Kitchens, bathrooms, stairways, and bedrooms need to be made safe, and eventually patients must stop driving. Treatment

Alzheimer’s disease ● Donepezil, rivastigmine, galantamine, memantine, and tacrine are the drugs presently approved by the Food and Drug Administration (FDA) for treatment of AD. ● the use of estrogen replacement therapy appeared to protect— by about 50%—against development of AD in women. ● NonSteroidal Anti-Inflammatory Drugs and 3-hydroxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) may have a protective effect on dementia. Treatment

Definition ● Clinically, PD is characterized by rest tremor, rigidity, bradykinesia, and gait impairment, known as the "cardinal features" of the disease. ● Additional features can include freezing of gait, postural instability, speech difficulty, autonomic disturbances, sensory alterations, mood disorders, sleep dysfunction, cognitive impairment, and dementia. Parkinson’s disease

Epidemiology ● Parkinson's disease (PD) is the second commonest neurodegenerative disease, exceeded only by Alzheimer's disease (AD). ● PD affects men and women of all races, all occupations, and all countries. ● The mean age of onset is about 60 years, but cases can be seen in patients in their 20s, and even younger.

● Pathologically, the hallmark features of PD are degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Pathophysiology Parkinson’s disease

● Levodopa ● Dopamine Agonists (e.g., bromocriptine) ● Surgical Treatment Treatment Parkinson’s disease

Seizure and epilepsy ● A seizure is a paroxysmal event due to abnormal excessive or synchronous neuronal activity in the brain. ● Depending on the distribution of discharges, this abnormal brain activity can have various manifestations, ranging from dramatic convulsive activity to experiential phenomena not readily discernible by an observer. ● 5–10% of the population will have at least one seizure, with the highest incidence occurring in early childhood and late adulthood. Definition

Seizure and epilepsy ● Epilepsy describes a condition in which a person has recurrent seizures due to a chronic, underlying process. This definition implies that a person with a single seizure, or recurrent seizures due to correctable or avoidable circumstances, does not necessarily have epilepsy. ● Epilepsy refers to a clinical phenomenon rather than a single disease entity, since there are many forms and causes of epilepsy. ● Using the definition of epilepsy as two or more unprovoked seizures, the incidence of epilepsy is 0.3–0.5% in different populations throughout the world, and the prevalence of epilepsy has been estimated at 5–10 persons per Definition

Seizure and epilepsy 1. Focal seizures 2. Generalized seizures A. Absence a. Typical b. Atypical B. Tonic clonic C. Clonic D. Tonic E. Atonic F. Myoclonic 3. May be focal, generalized, or unclear A. Epileptic spasms Classification

Seizure and epilepsy ● Seizures are a result of a shift in the normal balance of excitation and inhibition within the CNS. ● There are many different ways to perturb this normal balance, and therefore many different causes of both seizures and epilepsy. ● high fevers in children ● Penetrating head trauma ● brain tumors ● infections ● medications ● idiopathic Pathophysiology

Seizure and epilepsy ● Therapy for a patient with a seizure disorder is almost always multimodal and includes: 1) treatment of underlying conditions that cause or contribute to the seizures (treatment of tumor, infection, or avoidance of the medications); 2) avoidance of precipitating factors (sleep deprivation, alcohol intake, music, or an individual's voice ("reflex epilepsy"), stress); 3) suppression of recurrent seizures by prophylactic therapy with antiepileptic medications or surgery. Treatment