Disorders of CNS Flashcards
What is a generalized epileptic seizure? Status epilepticus? Grand mal?
Affects BOTH sides of the brain
- MOST DANGEROUS form with tonic-clonic seizure lasting 30min+ without recovery of consciousness between attacks
- synchronous activation of large populations of neurons –> universal motor manifestations
What are partial epileptic seizures?
Focal, affecting ONLY small regions
- Focal nature results in focal impairment (i.e. small motor manifestations)
What is Rasmussen’s Encephalitis?
Overactivity of glutamate pathway due to developed excitatory antibodies that bind glutamate receptors (AGONISTS)
- trauma allows for the antibodies to cross the blood brain barrier; seizure then causes more BBB leak and more antibody crosses, etc.
Consequences of Rasmussen’s Encephalitis?
Cerebral damage, lactic acidosis, hypoglycemia, hyperpyrexia
What is the main reason for epileptogenesis in the limbic structures (hippocampus)?
The rhythmic bursting activity of that region
- GABA/Glutamate balance is KEY because imbalance between excitation/inhibition is classic sign of epileptic seizure
- Hippocampal and limbic region show a lack of GABA
Diagnosis of epilepsy?
EEG or MRI!
List some general treatments of epilepsy.
- Medication - Antiepileptic drugs (AEDs)
- Surgery
- Vagus nerve stimulation (those not surgical candidates and pharmacological resistance, low success rate)
- Ketogenic diet (2 out of 3 may prevent seizure, 1 out of 3 prevent completely, mechanism unclear (switch from glucose to ketone bodies))
List some classes of AEDs:
- Sodium channel blockers - prevent repetitive axon firing
- T-type Calcium channel blockers - inhibit rhythmic thalamocortical spike/waves bursts
- AED’s acting on GABA - agonists, reuptake inhibitors, GAD enhancers (enhance synthesis), inhibiting GABA-transaminase
- Glutamate blocker - (AMPA, NMDA, glycine, metabotropic)
When/how is epileptic surgery done?
- Used when epilepsy is pharmacologically resistant, most commonly in the form of temporal lobe resection, rates of success are 30-80%
- MRI, PET, single-photon emission CT (SPECT) of ictal-interictal cerebral blood flow –> Identify epileptic focus
- Magneto-encephalography with fMRI, EEG can map location of interictal epileptic dischargers
List some anxiety disorders (7):
- Generalized Anxiety Disorder (GAD)
- Phobia
- OCD
- Acute stress disorder
- PTSD
- Agoraphobia
- Panic disorder
What is GAD?
Causes motor (trembling, twitching), autonomic (shortness of breath, palpitations), psychological symptoms
MAIN SX: unrealistic or excessive worry for 6mo+
What are some theories for causes of GAD?
- Deficiency in GABA within the amygdala strongly implicated, other substances also involved
- Hypothesis that uncoupling of anterior cingulate-amygdala circuit occurs
- Genetic link between short allele for 5’ promoter of serotonin uptake leads to increased anxiety
Treatment for GAD?
- Benzodiazepines (Valium) – GABA agonist (depressing neurons within the amygdala)
- Enhancing serotonin – via SSRIs and MAOI’s as well as buspirone
What is Major Depressive Disorder?
One or more major depressive episodes lasting 2wk+, seen in unipolar and bipolar depression
What is Unipolar Depression?
Occurs 2-3x more women, average onset at 30yo
Endogenous depression with no precipitating cause (40-60% of those hospitalized for depression) as opposed to reactive depression (from loss of loved one)
Describe a proposed mechanism for depression.
In severe depression, hypersecretion of CRH –> increased ACTH –> increased cortisol; NE can stimulate CRH release
Suggestion that hypercortisolemia damage to hippocampus mood changes
Treatment for unipolar depression?
- SSRIs
- Serotonin and NE reuptake inhibitors (SNRIs)
- NE and dopamine reuptake inhibitors (NDRIs)
- Tricyclic antidepressants
- MAOI
What is Bipolar Disorder (Manic-Depressive Illness)?
Distinguished from Unipolar Depression based on depression with punctuated episodes of elevated, expansive, irritable mood
- Thinking is fluid, speech and physical activity excessive, inflated self-image (MANIA) occurring every 2-4yr but can occur annually or more frequently
Possible link to inositol-1-phosphatase overactivity in neurons of those with manic depressive illness
Treatment for Bipolar Disorder?
- Lithium carbonate – block inositol-1-phosphatase from the PIP2 second messenger system, blocking results in buildup of IP3 and subsequent reduced neuron response to those neurotransmitters associated with this cascade
- Antidepressants – used during the depressive phase
Positive symptoms of schizophrenia?
Delusions, hallucinations (visual/auditory), disorganized speech or thought, purposeless behavior
Negative symptoms of schizophrenia?
Reduced range and intensity of emotional expression, lessening speech fluency/productivity, laconic, empty replies, inability to initiate/persist in goal-directed behavior
Who is affected by schizophrenia?
- Affects 0.5-1% of the population, leading to social withdrawal (homelessness), however the threshold for schizophrenia is not very precise
- SX show in 20s earlier in men (18-25), 1/5 recover, 1/10 commit suicide
What is the Diathesis-stress model?
Strong genetic component which conveys a genetic vulnerability, which in combination with an environmental or psychosocial stressor, causes the disease
Some proposals for cause of schizophrenia:
- PFC volume reduced from DECREASED SYNAPTIC CONNECTIVITY (not from loss of neurons), which causes a disorder of working memory (attention) –> inattention, poor associations, etc.
- Altered activation of dopamine receptors diminished cortical dopamine function (NOT the whole answer)
Things that cause schizophrenia-like symptoms?
- PCP causes schizophrenia like symptoms coupled with dopamine hypofunction
- Seen in NMDA receptor blockers (phencyclidine/ketamine)
Limitations of drugs in treating schizophrenia?
Drugs not useful to help cognitive impairment; treat the positive symptoms BUT NOT THE NEGATIVE SX (lack of motivation, emotion prevent normal social relationships)
Drugs used to treat schizophrenia (the positive symptoms):
Antipsychotics block D2 receptors
- Also acts on the basal ganglia –> tardive dyskinesia, rigidity, akinesia (extrapyramidal side effects)
Clozapine – “atypical drug” high affinity for D4 dopamine receptors and low affinity for D2 receptors prevents some of the extrapyramidal side effects; however other actions probably exist for this drug
Characteristics of Alzheimer’s:
Symptoms onset after age 60 but early onset forms exist; symptoms are decline in thinking ability, memory, movement, language, judgment, behavior, abstract thinking, nearly all brain functions are eventually affected
Typical cause of death is pneumonia (aspiration)
- Suggested cause is gene for amyloid beta-protein precursor (betaAPP)
Anatomy particularly affected:
Anatomy particularly spared:
- Association cortex, nucleus basalis of Meynert and hippocampus/parahippocampal structures, locus ceruleus, & dorsal tegmental nuclei –> narrow gyri and widened sulci
- Primary somatosensory/visual/auditory cortex, motor cortex, cerebellum, basal ganglia, brain stem, thalamus
3 categories of Alzheimer’s:
- Early onset familial (65yr)
- Sporadic late onset (>65yr) = 75% (leading cause of dementia and death in those over 65yr)
Some histological characteristics of Alzheimer’s:
- Neurofibrillary tangles (composed of hyperphosphorylated Tau protein)
- Neuritic plaques (composed of amyloid beta-protein)
Amyloid beta protein has three enzymes (secretases) for processing (therapeutic targets) – What are they?
ABP is glycosylated transmembrane protein – processing important for the formation of the plaques
- Beta-secretase – amyloidogenic pathway IN COMBINATION with gamma-secretase
- Gamma-secretase – intramembrane protease, amyloidogenic IN COMBINATION with beta-secretase
- Alpha-secretase – amyloid beta fragment forming (non-amyloidogenic) = SOLUBLE
How are amyloid plaques formed?
Amyloidogenic secretases form an amyoid beta-protein oligomer –> polymerize to INSOLUBLE amyloid –> INFLAMMATORY RESPONSE
How are neurofibrillary tangles formed?
Tau protein is hyperphosphorylated from activation of kinases
Treatments for Alzheimer’s?
- Anticholinesterase drugs – modest improvement from initial loss of nucleus baslis of Meynert for improving cognition; ONLY effective for 6-12 months
- Drugs acting on glutamate – Memantine – NMDA antagonist –> reduce excitotoxic effects showing slowing of the declined behavioral and intellectual functioning but doesn’t modify pathology
Future approaches to treatment of Alzheimer’s?
- Vaccine to Amyloid beta
- Antibodies to A-beta
- Brain cell apoptosis inhibitor
- Neuroprotection
- Fibrilization of amyloid-beta prevention
