Patho Exam 3 Guide PDF

The technical term for the transmission of neuronal electric current from node of Ranvier to node of Ranvier is known as \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_. - Saltatory Conduction What are some pathophysiologic causes of demyelination? \[ONLY KNOW THE FOLLOWIN...

The technical term for the transmission of neuronal electric current from node of Ranvier to node of Ranvier is known as \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_. - Saltatory Conduction What are some pathophysiologic causes of demyelination? \[ONLY KNOW THE FOLLOWING\] - JC virus polyomavirus which normally lies dormant; in response to immunosuppression secondary to **[monoclonal antibodies,]**the JC virus can become reactivated results in **[PML (progressive multifocal leukoencephalopathy),]** which is largely fatal - Cytomegalovirus think **[HIV/AIDS, especially AIDS patients with a CD4 \< 50.]** Results in **[retinitis and subsequent blindness ]** - Epstein-Barr Virus think "**[association with multiple sclerosis" ]** - Guillain-Barre Syndrome **[anti-ganglioside autoantibodies; ascending inflammatory demyelinating polyneuropathy]** (loss of reflexes +muscle weakness/paralysis) - Multiple Sclerosis **[Type IV HS-like syndrome]** - Vitamin B12 Deficiency associate with **[pernicious anemia, veganism]** - Diabetes mellitus **[diabetic neuropathy, diabetic retinopathy ]** What are the 3 parts of a synapse? - Presynaptic neuron neuron which produces and releases neurotransmitter - Synaptic Cleft space which contains modulatory enzymes which help to regulate downstream neurotransmitter activity - E.g., acetylcholinesterase (breaks down acetylcholine), monoamine oxidase (can break down norepinephrine, dopamine, serotonin) - Postsynaptic neuron neuron which contains receptors for neurotransmitter binding; post-synaptic effects vary depending on the neurotransmitter to which it binds What is the role of calcium in the presynaptic neuron? - Calcium promotes vesicular docking to the presynaptic terminal via voltage-gated calcium channels promotes release of neurotransmitter! What is the basal ganglia? - The basal ganglia is an important subcortical (within the brain) area which is responsible for the **[integration]** **[and fine-tuning]** of nerve fibers which project to MULTIPLE locations; "grand central station" of the brain - Parts of the Basal Ganglia: - Globus Pallidus, external component (GPe) - Globus Pallidus, internal component (GPi) - Substantia Nigra, pars compacta - Substantia Nigra, pars reticulata - Striatum (caudate, putamen) - Subthalamic nuclei - From a motor perspective, the thalamus is ultimately affected by the basal ganglia, resulting in modulations in output to supplemental areas of the motor cortex (located in the frontal cortex) and, therefore, "fine-tuning" of movement - IMPORTANT NOTE: The basal ganglia does not ELICIT conscious movement! Therefore: PARKINSON'S DISEASE AND HUNTINGTON'S DISEASE DO NOT RESULT IN COMPLETE PARALYSIS! What is the Indirect Pathway of the Striatum? - WITHOUT DOPAMINE, THE STEPS ARE BELOW: - The striatum releases GABA onto the GPe. - GABA from the striatum is inhibitory; this results in decreased GPe-mediated release of GABA onto the subthalamic nuclei. - The subthalamic nuclei, because they receive less GABA from the GPe, are capable of releasing high amounts of glutamate (which is excitatory) onto the GPi. - The GPi, because it is highly stimulated by glutamate from the subthalamic nuclei, releases large amounts of GABA onto the thalamus. - The thalamus, now inhibited by the GABA from the GPi, decreases its output to the motor cortex, resulting in DECREASED motor coordination. - WITH DOPAMINE BINDING TO D2 RECEPTORS: - D2 binding of dopamine leads to INHIBITION OF THE STRIATUM. This means that the striatum releases LESS GABA onto the GPe, resulting in decreased inhibition of the GPe. - The GPe, now less inhibited, releases MORE GABA onto the subthalamic nuclei. - The subthalamic nuclei, now more inhibited, DECREASES glutamate release onto the GPi. - Given that it receives less glutamate from the subthalamic nuclei, the GPi's release of GABA onto the thalamus is now decreased. This renders the thalamus MORE ACTIVE. - Given the decreased release of GABA from the GPi, the thalamus is now more highly activated, resulting in INCREASED output from the thalamus to the motor cortex, resulting in INCREASED motor coordination and fluidity of movement. What is the Direct Pathway of the Striatum? - WITH DOPAMINE BINDING TO D1 RECEPTORS: - The striatum releases GABA onto the GPi directly, resulting in increased inhibition of the GPi. - Increased inhibition of the GPi results in DECREASED GABA released from the GPi onto the thalamus. - Decreased GABA release onto the thalamus results in INCREASED activation of the motor cortex, resulting in INCREASED motor coordination and fluidity of movement. - WITHOUT DOPAMINE BINDING TO D1 RECEPTORS: - The striatum does not release as much GABA onto the GPi. - As a result, the GPi is capable of releasing MORE GABA onto the thalamus, resulting in INCREASED INHIBITION OF THE THALAMUS. - Increased inhibition of the thalamus results in decreased excitatory output to the motor cortex, resulting in DECREASED motor coordination. Which portion of the substantia nigra is most highly affected by Parkinson's Disease, resulting in decreased dopamine release? - Pars Compacta What are some of the clinical phenotypes associated with Parkinson's Disease? - Bradykinesia (slow movements) - Tremors (initially with voluntary movement; with advanced disease, at rest too) - Gait abnormalities (shuffling gait) - Cognitive difficulties -- late stage findings (amnesia, depression, emotional instability) What are some pharmacologic management choices for Parkinson's Disease? - **[Levodopa + Carbidopa]** - Levodopa precursor of dopamine which is capable of crossing the blood-brain barrier and being converted to dopamine in the brain via **[dopa decarboxylase]**. - Carbidopa Peripheral dopa-decarboxylase inhibitor; PREVENTS the breakdown of levodopa in the peripheral tissues, reducing the adverse reactions associated with excessive dopamine AND increasing bioavailability of levodopa in the brain - **[Dopaminergic Agonists]** can sometimes aid in the restoration of balance within the indirect and direct pathways - **[Pramipexole, Ropinirole]** non-ergot based - **[Bromocriptine]** ergot-based; significantly more concerning side effect profile! Rarely used except as last resort! - **[MAOI (Monoamine oxidase inhibitors), specifically MAO-B inhibitors\_]** downregulation of MAO-B mediated dopamine breakdown, promoting increased dopamine levels - **[Selegiline, Rasagiline ]** What is the classic mutation associated with Huntington's Disease? - CAG trinucleotide repeats (on chromosome 4) accumulation of Huntingtin protein - encodes the amino acid **[glutamine]** Where in the basal ganglia is most highly affected by Huntington's Disease? - The **[striatum (caudate, putamen nuclei) ]** What is the classic neuroimaging finding associated with Huntington's Disease? - On imaging **[enlargement of the lateral ventricles is seen;]** due to gradual degeneration of subcortical tissue secondary to Huntingtin protein accumulation, which increases neuronal death secondary to oxidative stress What are the clinical findings associated with Huntington's Disease, and why do they occur from a pathophysiologic perspective? - Early Stages **[hyperkinetic phenotypes (chorea, athetosis)]** - destruction of the striatum decreased release of GABA onto GPe Increased release of GABA from the GPe onto the subthalamic nuclei INCREASED inhibition of subthalamic nuclei, resulting in decreased glutamate release from subthalamic nuclei onto the GPi Decreased GABA release from the GPI onto the thalamus decreased inhibition of thalamus, which leads to hyperkinetic phenotypes (chorea, athetosis) - Chorea dance-like flailing motions - Athetosis writing, worm-like movements with the limbs (usually the upper extremities) or trunk - Late stages **[BRADYKINESIA, RIGIDITY!]** - Eventually, Huntingtin protein accumulation affects the **[substantia nigra, resulting in destruction and]** **[decreased dopamine release. ]** - The Direct Pathways is most adversely affected resulting in **[bradykinesia, increased rigidity, tremors]** (similar phenotype to Parkinson's Disease) Which non-motor symptoms are more prominent with Huntington's Disease? - Disruption of striatal neurons projecting to the frontal cortex **[lack of behavioral/social inhibitions ]** - E.g., urinating in public - Disruption of striatal neurons projecting to the occipital cortex **[visuospatial deficits (knowing where objects/people are in space, inability to discriminate the size/depth of a room/area) ]** - Disruption of striatal neurons projecting to limbic cortex, hippocampus **[neuropsychiatric deficits, dementia ]** What are pharmacologic options for the management of Huntington's Disease? - Early-Stage: - **[Tetrabenazine TWO-HEADED MECHANISM which ultimately DECREASES the effect of dopamine at the D2 receptor:]** - preventing dopamine packaging into pre-synaptic vesicles (meaning that it can't be released from the neuron) - competitive antagonism of dopamine receptors on the post-synaptic neuron (D2 receptors in the striatum), resulting in decreased responsivity to dopamine decreased inhibition of the striatum (remember, D2 = inhibitory; blocking it with Tetrabenazine reverses this inhibitory effect!), resulting in **[increased thalamic and cortical inhibition and, therefore, decreased hyperkinetic features associated with Huntington's Disease! ]** - **[DO NOT USE IN LATE-STAGE HUNTINGTON'S DISEASE!]** - Late-Stage: - Similar treatment options as Parkinson's disease How does glutamate toxicity occur in ALS? - Glutamate binding to the NMDA receptor increased calcium entry into the neuron increased calcium binding to the mitochondrion, resulting in mitochondrial damage and increased oxidative stress - Over time the mitochondrion is destroyed; when this occurs, the neuron shifts to anaerobic metabolism, resulting in lactic acid accumulation and, therefore, subsequent neuronal destruction What are some prominent physical exam findings associated with ALS? - Upper Motor neuronal symptoms **[Hyperreflexia, increased spasticity (stiffness/tightness of muscles), Uncontrollable laughing/crying]** - Lower Motor neuronal symptoms **[Muscle atrophy (due to gradual denervation secondary to neuronal death), muscle twitches due to abnormal discharges from damaged neurons, muscle weakness which evolves to complete muscle paralysis, gradual loss of reflexes (areflexia) ]** - Other symptoms (usually seen in late stages) **[slurred speech which evolves to a complete loss of vocalization, difficulty swallowing, tongue atrophy with fasciculations, various cognitive difficulties ]** What is the most common cause of death in patients with ALS? - Respiratory Failure due to paralysis of the diaphragm and other respiratory muscles What are some pharmacologic options for the management of ALS? - **[Riluzole]** blocks glutamate transmission via two mechanisms: [ ] - Stabilizes the voltage-gated sodium channels on glutamatergic neurons, preventing depolarization of these neurons and, therefore, release of glutamate onto NMDA receptors; - "Stabilization" in this context = preventing the neuron from reaching threshold potential (REMEMBER, ONLY NEURONS THAT REACH THRESHOLD POTENTIAL CAN SUCCESSFULLY FIRE ACTION POTENTIALS!) - Serves as a NON-competitive antagonist of the NMDA receptor post-synaptically - **[Decreased release of glutamate + decreased binding of glutamate to NMDA receptors]** = decreased free radical formation, decreased mitochondrial damage, promotes neuronal survival - ONLY INTERVENTION WITH PROVEN SURVIVAL BENEFIT! - **[Edaravone]** exact mechanism is unknown, but **[known to be a fantastic free-radical scavenger]** - By destabilizing free radicals and ROS, reduces oxidative damage to neurons - **[EXCELLENT adjunctive therapy with riluzole! Should never be used alone]** - What are the steps involved with the nerve action potential? - Stimulation leads to an influx of sodium ions, resulting in the neuron becoming more positively charged. - If the neuron does NOT become positive enough to surpass the threshold potential NOTHING HAPPENS - If the neuron DOES surpass threshold potential ACTION POTENTIAL IS FIRED! - Once the neuron surpasses threshold potential voltage-gated sodium channels open, allowing for a HUGE influx of sodium ions (depolarization). This will render the cell very positively charged. - The Peak phase electric current is propagated down the axon. Once the peak phase is achieved, the neuron must become negatively charged once again. - Repolarization voltage-gated potassium channels open, resulting in potassium efflux. This renders the cell more negative once again. Keep in mind, there is a lag time between the closing of the voltage-gated channels and re-opening of sodium channels; this results in the membrane potential becoming slightly more negative than the resting membrane potential (absolute refractory period); during this period, no further action potentials can be fired. - What is the numerical value for the resting membrane potential of most neurons in the CNS? - -70 millivolts - Which two receptors within the CNS bind glutamate? - AMPA allows for sodium entry into the post-synaptic neuron - Highly associated with focal seizures - NMDA allows for calcium \>\>\> sodium entry into the post-synaptic neuron - Magnesium blocks NMDA receptor under normal resting conditions; block is removed upon glutamate binding + post-synaptic neuronal depolarization - Highly associated with generalized seizures - Which two receptors within the CNS bind GABA? - GABA~A~ only post-synaptic; binds GABA, resulting in the opening of chloride channels. Chloride moves intracellularly, resulting in hyperpolarization. Ionotropic - Common target for benzodiazepines (agonists) - GABA~B~ presynaptic AND postsynaptic; metabotropic, meaning that it utilizes GPCR (G-protein coupled receptor based signal transduction) mechanisms to have its effects. Slightly smaller role with seizures. - Presynaptic inhibition of voltage-gated ion channels, resulting in decreased synaptic vesicle docking + neurotransmitter release - Post-synaptic opening of potassium efflux channels, resulting in potassium efflux and, therefore, hyperpolarization - What are the general pathophysiologic etiologies of seizure? - Excessive Activation by Glutamate increased glutamatergic release, increased AMPA/NMDA receptor expression post-synaptically - Decreased Inhibition due to decreased GABAergic effect decreased GABA release, decreased GABA~A~ expression - Synchronization of Neuronal Firing Neurons firing together significantly increase the likelihood that other nerve networks within the brain are depolarized simultaneously, resulting in seizure-like activity - Metabolic/Electrolyte Abnormality most notably, hyponatremia - Hypoxia +/- mitochondrial dysfunction - What are the two general types of seizures? - Focal Seizures abnormal hyperexcitability begins in one location; can either remain localized or spread to other areas over time, and may cause motor +/- nonmotor symptoms. Don't always result in loss of consciousness/awareness of seizure activity - Clinical findings usually reflect the lobes which are affected: - Frontal Lobe primary motor cortex, supplemental motor areas; focal motor findings - Parietal Lobe Primary somatosensory cortex - Occipital Lobe Primary Visual Cortex; may result in visual auras - Temporal Lobe most common epileptiform focus! - Deep to the temporal lobe the hippocampus is the most highly affected subcortical area involved with seizures! - Subcortical areas Thalamus, Amygdala (subcortical area primarily responsible for induction of fear, aggression) - Brainstem primarily responsible for the loss of consciousness that many experience in severe, generalized seizures - Can be involved in both focal and generalized seizures - Generalized Seizures often involve both hemispheres, without one specific focus of epileptiform activity; usually affects subcortical areas (thalamus, neuronal projections from the thalamus/basal ganglia to cerebral lobes of the brain, brainstem) result in loss of consciousness. Often followed by a post-ictal state (post-seizure state where patient feels fatigued and confused) - Generalized tonic-clonic seizures initially, patients are tonic (muscles become stiff), and patient falls to the ground with complete loss of consciousness; after approximately 45 -60 seconds, the patient's muscles become clonic (jerking, uncontrollable movements). Usually last 2-5 minutes, after which the patient has no recollection of what transpired during the seizure. - Absence Seizures Generalized, but rarely presents with significant clonus/tonic movements; rather, patients appear to be staring into space. No post-ictal state present. - More common in childhood - What is status epilepticus, and how is it managed? - Status Epilepticus pathophysiologic state where continuous seizure activity is seen for longer than 5 minutes OR there are recurrent seizures without recovery of consciousness between them. - MEDICAL EMERGENCY - Three Primary Subtypes: - Generalized Convulsive Status Epilepticus MOST COMMON; presents as persistent tonic-clonic seizure, hyperthermia, hypertension, tachycardia - Non-Convulsive Status Epilepticus no motor manifestations, but EEG (electro-encephalogram) proven epileptiform activity; prominent staring into space, unresponsiveness can be seen - Focal Status Epilepticus Predictable focal motor/sensory/visual symptoms, depending on which lobe is affected; CAN progress to generalized seizure - Management of Status Epilepticus ABC's (airway, breathing, circulation) + TIERED PHARMACOLOGIC MANAGEMENT: - IV Benzodiazepines (Ativan, Midazolam, Diazepam) FIRST LINE - Long-Acting Anticonvulsant (Phenytoin, Valproic Acid, Levitiracetam) - Phenobarbitol/Other barbiturates of Pheno isn't on hand - General Anesthesia (propofol) - How do hemorrhagic strokes increase the risk of seizure? - Due to the direct leakage of pro-inflammatory cytokines onto neurons, resulting in oxidative stress and increased neuronal excitability - Though ischemic strokes can lead to seizure too, hemorrhagic strokes carry significantly more risk! - What are some important infectious causes of seizure? KNOW THESE ASSOCIATIONS! - Meningitis - Streptococcus Pneumoniae think COPD patients - Neisseria Meningitidis college-age students, military barracks, prisons - Cryptococcal Meningitis most common cause of meningitis in HIV/AIDS patients - Encephalitis - Borrelia Burgdorferi Lyme Disease (Ixodes Deer Tick) - Herpesviruses (mostly HSV-1, HSV-2) bitemporal encephalitis - Mosquito-borne infections (Zika, West Nile) - Widespread Demyelination - JC Virus progressive multifocal leukoencephalopathy (PML) - What is the mechanism as to how hyponatremia leads to seizures? - Hyponatremia results in decreased extracellular sodium concentration outside of the neuron. This facilitates the movement of water to the inside of the neuron (higher tonicity), resulting in neuronal swelling/edema. - Neuronal edema alters the electrochemical gradients of sodium and potassium and, therefore, promotes increased neuronal excitability and, thus, seizure activity - COMMON in athletes/marathon runners/boxers/MMA athletes who consume exorbitant amounts of water---\> primary polydipsia - Also common in patients who take Lithium (which, remember, causes nephrogenic diabetes insipidus) - What illicit drugs increase the risk of seizures? - Amphetamines, Cocaine, MDMA (ecstasy, Molly) increase glutamate release, resulting in hyperexcitability - Ketamine unique because it results in seizures in an NMDA-independent manner! - Ketamine is NORMALLY an NMDA receptor ANTAGONIST; however, ketamine ALSO potentiates (promotes) increased norepinephrine and dopamine release from subcortical areas, especially the thalamus, resulting in hyperexcitability of cortical neurons SEIZURES! - IMPORTANT TO KNOW The excitation produced by ketamine is NOT due to glutamate, but rather NE + dopamine! - What are some commonly prescribed drugs which can lower seizure threshold and, therefore, promote seizure development? - Bupropion (MOST COMMON) Commonly used in smoking cessation, but also a decent antidepressant - BupropionDNRI (dopamine-norepinephrine reuptake inhibitor) also has sodium blockade effects, which increases membrane permeability for sodium and, therefore, lower seizure threshold. ALSO, increased dopamine results in increased neuronal excitability - Flumazenil benzodiazepine reversal agent; GABA~A~ antagonist - competitive GABA~A~ antagonist decreased inhibitory effect on neurons, which increases the risk of seizures! - Isoniazid commonly used in TB antibiotic regimens, but seizures occur secondary to pyridoxine deficiency - Isoniazid-induced pyridoxine deficiency decreased GABA production, increased glutamate accumulation glutamate toxicity, resulting in hyperexcitation of neurons and seizure - Clozapine, other antipsychotics D2 antagonist which is utilized in the management of schizophrenia; can increase glutamatergic transmission, resulting in seizures. CLASSICALLY causes agranulocytosis (decreased WBC count which specifically affects granulocyte-based WBC's) and seizures! - How does benzodiazepine withdrawal result in seizures? - in patients who have abused benzodiazepines chronically, acute cessation of benzodiazepines results in decreased GABA transmission CNS hyper-excitability due to relative increase in glutamatergic activity**[,]** increased sympathetic NS activity - Short-acting benzodiazepines (Alprazolam, Lorazepam) more rapid onset of symptoms - Long-acting benzodiazepines (Chlordiazepoxide, Diazepam) symptoms can last for WEEKS - Early symptoms Anxiety, Insomnia, Sweating, Tremors, Heart palpitations/tachycardia - Late symptoms (CAN BE LETHAL) Seizures (usually generalized tonic-clonic, hallucinations (visual more common than auditory; may have tactile hallucinations too); Paranoia which may evolve into frank aggression; severe autonomic instability featuring hypertension, tachycardia which may evolve to cardiac arrest, hyperthermia - Management Use SHORT-ACTING BENZODIAZEPINES such as Lorazepam, Midazolam, or Diazepam; Manage ABC's, autonomic instability; some seizures may require general anesthesia. - How does alcohol withdrawal result in seizures? - Alcohol commonly potentiates GABA~A~ transmission, promoting hyperpolarization. Over time, chronic alcohol use leads to downregulation of available GABA~A~ receptors, resulting in desensitization. - Alcohol withdrawal which is sudden acute loss of GABA transmission through decreased receptor sensitivity significantly decreased inhibition, relative increase in glutamatergic activity, CNS hyper-reactivity! - Initially anxiety, tremors, insomnia, heart palpitations; in chronic alcoholics, severe nausea and abdominal pain (due to underlying chronic pancreatitis) present - Delirium Tremens life-threatening manifestations of alcohol withdrawal (seizure, autonomic instability, paranoia + aggression); occurs 48-96 hours after last drink - SEVERE agitation (worse than BZ withdrawal), AGGRESSION, Hallucinations (visual and tactile most common), life threatening autonomic instability with high risk for cardiac arrest - Management IV Lorazepam for acute agitation, long-acting benzodiazepines (Chlordiazepoxide) to help restore GABA sensitivity, physiologic response; general anesthesia in severe cases