- Nucleus: Large, spherical, euchromatic nucleus with very prominent nucleolus

- Cell body: Nissl bodies

- Dendrites --> Carry signal from post-synaptic membrane to cell body

- Dendritic spines: Specialized evaginations of the dendritic surface --> Largely in excitatory neurons

- Axon: Myelinated or unmyelinated

- Microfilaments (5-7 nm) --> Neuronal cytoskeleton and actin based --> Found in regions of the neuron where processes change to form terminal boutons and dendritic spines

- Neurofilaments: Intermediate filaments (10 nm) diameter

1. Retrograde: From cell body to distal processes

- Dynein

- Fast 100-200 mm/day

- Returns used/degraded substances to soma for processing

- Relays signals from the terminals back

2. Anterograde: From distal to proximal -->Towards the cell body

- Kinesin

- Fast 200-400 mm/day --> For organelles, vesicles, and NT precursors

- Slow 1-2 mm/day --> Cytoskeletal components and some enzymes

- Classified based on the projection pattern of the axon

- Bipolar: Olfactory bulb and retina --> Input and output processes, with the cell body interposed between

- Pseudounipolar: Sensory neurons --> Single process that bifurcates at a short distance from the cell body and divides into central and peripheral processes

- Multipolar: Two or more dendritic arbots with various degrees of complexity --> One axon that branches throughout its course --> Axonal tuft at the end

- Principal excitatory neurotransmitter of the CNS

- Synthesized from glutamine via glutaminase

- Taken up by perisynaptic astrocytes --> Converted back to glutamine

- Glutamine is then transported back to the terminal and serves as new substrate for glutaminase

- NT of choice for almost all relay neurons and some interneurons

- Glutamatergic neurons of cerebral cortex --> Layer 4 granular layer excitatory interneurons, and layer 5 and 6 pyramidal cells

- Principal inhibitory neurotransmitter

- Hyperpolarizes the post-synaptic membrane

- Most commonly used by interneurons

- Synthesized from glutamate via glutamic acid decarboxylase

- Each interneuron axon is wrapped around another dendrite to inhibit synapse and signal transmission

- Examples: Purkinje cells of the cerebellum --> GABAergic inhibitory relay neurons

- Formed from choline and acetyl CoA via choline acetyl transferase (CHAT)

- Synthesized at synpatic boutons

- Degraded by acetylcholinesterase

- NT of voluntary neuromuscular systems and autonomic nervous system

- Pre-ganglionic neurons of both sympathetic and parasympathetic pathways

- Post-ganglionic parasympathetic neurons

- Post-ganglionic sympathetic neurons innervating eccrine sweat glands

- Role in CNS: Involved in wakefullness, arousal, learning, and memory --> Neurons project through cerebral cortex, hippocampus, and amygdala --> Distribute ACh to thalamus, brainstem, cerebellum, and medulla

- Group of neurotransmitters that all have a catechol ring

- All degraded by monoamine oxidase --> Also breaks down serotonin too

- Involved in a long-range neurotransmitter system

- Neurons are concentrated in substantia nigra and the ventral tegmental area (VTA)

- Made from L-dopa via L-dopa decarboxylase

- Mesostriatal pathway --> Regulation of movement via excitability of extrapyramidal regions of the basal ganglia (caudate and putamen)

- Mesolimbic pathway --> Projects to medial temporal lobe, cingulate cortex, nucleus accumbens, and amygdala --> Mediates affect, reward and emotions

- Mesocortical pathway --> Distributes to the neocortex (pre-frontal) --> Involved in cognition and working memory

- Synthesized from dopamine via dopamine beta-hydroxylase

- PNS: Sympathetic post-ganglionic neurons

- CNS: Locus coereleus in rostral pons --> Projects throughout the CNS --> Involved in attention and maintaining wakefullness

- Derived from tryptophan --> Two step process via tryptophan hydroxylase and then hydroxytraptophan decarboxylase

- Serotonin neurons most commonly found in the raphe nuclei

- Rostral raphe nuclei --> Projects to forebrain to modulate mood and emotion

- Caudal raphe nuclei --> Project to cerebellum, medulla, and spinal cord --> Modulate pain and perception

- Found within the posterior hypothalamus --> Tubulomamillary nucleus

- Long range projections to forebrain as well as cerebellum and pons

- Maintains the alert state

- Several neurotransmitters involved --> ACh, NE, 5-HT, histamine and DA

- Extensive axons that reach large portions of the nervous system

- Axons have both junctional and non-junctional contacts

- Neurons don't have true post-synaptic membranes

- Neurons secrete basal levels of neurotransmitters, which is then taken up by neuropil of the brain

- Modulation of entire populations of neurons and neuropil via 2nd messanger systems

- These long-range systems are extremely sensitive to pathological changes --> Changes in these systems well before symptoms of Alzheimer's present

- Packaged in the cell body and relayed to the axon terminal --> Cleaved into active form and released

- Have their effect via receptors

- Opioid-producing cells --> Periaqueductal gray and posterior horn of the spinal cord

- Composed of endothelial cells, basement membrane, pericytes, and astrocyte end-feet

- Endothelial cells --> Joined by extremely tight tight junctions

- Pericytes --> Exist within the BM that contribute to the structural integrity of the barrier

- Astrocytic end-feet --> Looser tight junctions and helps to regulate the tightness of the endothelial cell barrier

- Made up of 1-5 layers of squamous perineurial cells

- Cells connected by tight junctions to create tight barrier

- Composition of extracellular fluid is tightly regulated

- 90% of cells are Schwann cells but the others are fibroblasts, macrophages, and mast cells

- Connective tissue is present --> Basal lamina and endoneurial collagen fibers

1. Retrograde Degeneration --> Response of the neuronal real estate proximal to the cut

- Axonal disintegration occurs in the proximal segment of the axon

- Morphological changes in the cell --> Peripheral movement of the nucleus, dissolution of Nissl bodies, and stripping of synapses from dendrites and cell body

2. Anterograade Degeneration (Wallerian) --> Response of the axon distal to the cut

- Occurs within the first 24 hours

- Myelin becomes pinched off from the Schwann cells and phagocytosed by macrophages

- Blood-nerve barrier is disrupted --> Allowing the influx of additional macrophages

- Loss of neural input leads to atrophy of muscle fibers

3. Injury recovery

- After the distal axon and myelin are phagocytosed by macrophages, hollow tube exists, lined by Schwann cells and leads to muscle target

- Cell body begins heightened production and proximal axon sprouts

4. Regeneration

- Tips of the neuritic sprouts love laminin --> BM of Schwann cell tube

- Schwann cells secrete chemical factors that attract and encourage axonal sprout growth

- Neurites travel down to the target

- Schwann cells re-myelinate

- Muscle regains signal and is restored to normal size

5. Failure of Regeneration

- If distance is >1 cm from proximal nerve --> Will not regrow

- Disruption of Schwann cell tube leading to muscle

- Depends on the preservation of connective tissue

- Full regeneration very uncommon

- Not nerve regrowth but nerve re-routing

- Extracellular matrix and external lamina doesn't exist --> Nothing to guid axon sprouts to target

- CNS myelin is a potent inhibitor of growth

- Microglial cells do not clear myelin to the degree that macrophages do in the PNS

- Response to injury --> Astrocytes proliferate and wall off the injured area

- Physical separation isolates effects of damage --> Results in a physical barrier to regeneration and fibrotic scar

- Macroencephaly --> Too much brain

- Hydrocephaly --> Too much CSF

- Sickle cell disease --> Too much bone due to extramedullary hematopoeisis

- Subdural hematoma --> Too much fluid

- Big tongue/macroglossia --> Congenital hypothyroidism

- Kernicterus --> Auditory nuclei and basal ganglia are easily effected

- Bulbar ALS --> Lower CN abnormalities

- No words by 18-24 months or no phrases by 3 years

- Psychosocial causes --> Second child, multiple child family, twins, lower socio-economic class and institutionalized kids

- Children born to deaf/mute parents

- Bilingualism with delayed introduction of 2nd language

- Hearing loss --> Child who is inattentive or looks at you very intentively, trying to lip read --> Conductive (low frequency) and sensorineural (high frequency)

- Pathological left-handedness at an early age --> Should have a dominant hand until 3 years --> Abnormality in left cerebral hemisphere which displaces speech to the right hemisphere and causes delayed speech

- Acquired verbal agnosia --> Type of seizure

- Acquired epileptic aphasia

- Autism --> Pt will go through a regression where child will lose previously acquired capabilities

- Develops before the age of 5

- More common in girls than boys

- 90% caused by school phobia

- Separation anxiety

- Attention-seeking

- Poor hearing

- Poor attention

- Poor motivation

- Poor affect

- Poor intelligence

- Poor vision

- Poor coordination of movements

- Perceptual motor handicap

- Abnormalities of speech apparatus

- Moderate/severe mental retardation --> IQ >80, will speak

- Selective mutism

- State of the individual's awareness of self and environment

- Considered in terms of arousal and attention

- Level of arousal --> Assessing the level of wakefulness and the stimulus required to elicit a response

- Attentional disorders --> Inability to maintain concentration and unable to attend fully to the examiner's questions

- Arousal and attention depends on the integrity of physiologic mechanisms --> Reticular formation, other structures in the upper brain stem which extend from the middle pons to hypothalamus

- Diagnosis: Labs to rule out toxins and infectious disorders, electroencephalogram, CSF analysis, and CT or MRI scans

- Associated with executive function --> Reasoning, abstraction, planning and initiation of movements, activity, prioritizing and sequencing actions, problem solving, and coordinating functions necessary to produce coherent, appropriate, and goal-directed behavior

1. Dorsolateral convexity and medial frontal lobe damage --> Indifference, abulia, and apathy

- Akinetic mutism in the most severe form

2. Orbitofrontal area damage --> Disinhibition, irritability, and lability

- Patients are inattentive, distractible, socially inappropriate and have impaired judgment --> Phineas Gage case

- Reflects disinhibition and are a sign of diffuse cerebral disturbances

- All reflexes are normal in infancy but will reappear when frontal lobe is damaged

1. Grasp reflex --> Forced grasp that the patient can't inhibit --> Grasping the hand even when told not to do so

2. Snout reflex --> Tapping on the mouth produces puckering of the lips

3. Rooting reflex --> Elicited by lightly scratching the mouth --> Infants do this while searching for the nipple to breast feed

4. Glabellar reflex --> Tapping the forehead normally elicits blinking, but blinking will stop after a short time --> Blinking won't stop with frontal lobe damage

5. Palmomental reflex --> Twitching of ipsilateral lower jaw when hand briskly scraped on the thenar eminence

- Acquired disorder of language

- Different types depend on the deficits in reading, writing, speech and comprehension

- Spontaneous speech?

- Comprehension --> Reading and verbal

- Repetition

- Confrontation naming --> Naming objects when asked

- Reading

- Writing

- Non-fluent speech output

- Poor repetition

- Relatively preserved comprehension --> Written and verbal

- Speech is slow, effortful, agrammatic, and limited to a few words

- Writing is comparable to speech output --> Poor

- Causes --> Stroke of middle cerebral artery

- Fluent speech output --> Well articulated with normal phrase length and melody --> Word salad though

- Poor comprehension

- Poor repitition

- Rarely have a prominent hemiparesis

- "Pie in the sky" visual field cut --> Deficits in the contralateral superior visual field

- Causes --> Embolic stroke

- Prominent deficit in repetition

- Relatively preserved spontaneous speech and comprehension

- Speech is contaminated by paraphasic substitutions and word-finding difficulty

- Comprehension is fairly good but may break down

- Writing is comparable to level of speech

- Reading aloud parallels repitition --> Poor

- Causes --> Arcuate fasciculus (white matter surrounding temporal-parietal junction) --> Disconnects Wernicke's and Broca's areas

- Significant hemiparesis is rare

- Hemisensory syndrome is pretty common

- Damage to the watershed areas of the brain --> Cortex surroudning Wernicke's and/or Broca's area

- Intact repitition

- Speech may be fluent or non-fluent depending on if Broca's area is involved

- Comprehension may or may not be involved as well

1. Transcortical motor aphasia

- Marked reduction in the amount and complexity of spontaneous speech

- Retained ability to repeat sentences, read aloud and name objects

- Reading and auditory comprehension normal

- Repetition ability differentiates from simply Broca's aphasia

2. Transcortical sensory aphasia

- Impaired auditory comprehension

- Preserved repetition and fluent speech output

- Speech fluent but disrupted by word-finding pauses and occasional paraphasic errors

- Reading aloud is possible

- Reading comprehension is poor

- Writing is usually worse than spontaneous speech

- Inabilty to generate names in confrontation tasks and spontaneous speech

- Auditory and reading comprehension normal

- Reading aloud possible

- Repetition normal

- Spontaneous speech is fluent

- Severe word-finding difficulty

- Causes --> Toxic and metabolic encephalopathies

1. Aphasic alexia: Impaired reading associated with aphasia

2. Alexia with agraphia: Alexia without aphasia

- Lesions in the temporal-parietal region --> Angular gyrus

- Mixed reading and writing problems

3. Alexia without agraphia

- Damage to the left (dominant) visual cortex and splenium of the corpus callosum

- Infarction of the left posterior cerebral artery

- Right-homonymous heminopsia --> Inability to read and interpret written language in one visual field

- Writing on both sides is normal

- Amensia: Disorder of memory

- Episodic memory: Anterograde or retrograde memories and depends on the hippocampal-diencephalic system

- Semantic memory: Body of knowledge and facts independent of a particular episode of learning --> Depends on anterior temporal lobe

- Working memory: Very limited capacity that allows us to retain information for a few seconds --> Dorsolateral prefrontal cortex

- Confabulation: Production of a fabricated statement

- Momentary confabulation --> Placing of a past event in the wrong temporal or spatial context

- Fantastic confabulations --> Spontaneous production of false memories that the patient believes to be true

- Associated with closed head trauma --> Concussion and other causes of transient altered mental status

- Retrograde and aterograde memory loss

- Anterograde > Retrograde

- Serious injuries --> Retorgrade component doesn't allow the patient to recall events immediately preceding the trauma

- Anterograde amnesia

- Patchy retrograde amnesia

- Confabulation

- Can't learn new information

- Lack of insight and deny difficulties

- Flat affect and lack of motivation

- Lesions --> Diencephalon and frontal lobe, often bilateral with mamillary body atrophy

- Causes --> Metabolic or nutritional defects (B vitamins), exogenous toxins, CNS infections, trauma, vascular lesions, and post-surgery

- Often alcohol-related

- Causes --> Thiamine (Vitamin B1) deficiency

- Most common in alcoholics

- Can be triggered by IV glucose given to a thiamine deficient patient

- Triad: Confusional state, oculomotor dysfunction, and ataxia

- Peripheral neuropathy commonly associated

- Treatment: Parenteral thiamine and metabolic correction

- Mental status may evolve into Korsakoff's confabulatory state

- Inability to perform a movement despite intact sensory and motor function

- Limited localizing value

- May be associated with both left parietal or frontal lobe defects

- Corticobasal degeneration --> Progressive, isolated limb apraxia

- Failure to recognize or identify a stimulus

- Asterognosis --> Failure of tactile recognition --> Contralateral parietal lesions

- Visual agnosia --> Inability to recognize things by sight --> Parieto-occipital or splenium lesions

- Prosopagnosia --> Inability to recognize faces --> Temporal or occipital lobes (often bilateral)

- Unilateral neglect --> Patient fails to respond to stimuli in one half a space --> Contralateral to lesion

- Agraphia: Inability to write

- Acalculia: Inability to perform simple math tasks like counting fingers

- Finger agnosia: Inability to distinguish, name and recognize fingers

- Left-right disorientation --> Can't tell left from right

- Lesions in the dominant hemisphere --> Angular or supramarginal gyri

- Causes --> Stroke or parietal lobe damage

- 5 main types

- Somatosensory defects --> Posterior insular stroke

- Gustatory disorders --> Left posterior infarct

- Vestibular-like syndrome --> Dizziness, gait instability, and tendency to fall without nystagmus --> Posterior insula

- Cardiovascular disorders --> Hypertensive episodes --> Right posterior insula

- Neuropsychological disorders --> Aphasia (left post), dysarthria, and transient somatoparaphrenia (out of body experience, right post.)

- Isolated lesions --> Post-stroke hyperglycemia and loss of interest in smoking (even in previously heavy smokers)

- Alien Hand syndrome

- Involuntary uncontrolled movement of an arm with a sense of estrangment from the limb

- "Limb not mine"

- Parietal infarcts or corticobasal degeneration

- Often associated with limb apraxia

- Ventrally located in the brainstem

- Crosses in the low medulla --> Pyramidal decussation

- Lesion above decussation --> Contralateral paralysis

- Lesions below decussation --> Ipsilateral paralysis

- Responsible for joint positional sense and light touch

- Fibers are located axially in the brainstem

- Crosses in the medulla --> After synapsing

- Lesions above decussation --> Contralateral loss

- Responsible for pain and temperature sensation

- Fibers cross very quickly once they enter the spinal cord

- Fibers are located laterally in the brainstem

- Lesions --> Contralateral loss of pain and temp

- Located in the midbrain, medulla, and pons

- All are ipsilateral, except for IV

- IV is also the only CN that enters the brainstem rostrally

- Lesion often accompanied by contralateral hemiparesis

1. Midbrain CNs: CN III and IV --> CN IV is the only one that crosses

- Alternating hemiplegia

- Unilateral lesion --> Only CN affected --> No hemiplegia

- Ipsilateral III + IV affects --> Lesion outside brainstem

2. Pons CNs: V, VI, VII

- CN V: Exits in midpons --> Motor and main sensory nuclei

- CN VI: Exits in the lower pons --> Exits ventrally

- CN VII: Fibers exit and loop around CN VI nucleus

3. Medullary CNs: VIII through XII

- Ventral medulla lesion causes ipsilateral tongue paralysis and contralteral hemiparesis

- Wallenberg's syndrome

- Ipsilateral loss of pain and temperature sensation in the face

- Ipsilateral facial pain

- Ipsilateral ataxia of the arm and leg

- Ipsilateral gait ataxia

- Ipsilateral nystagmus

- Nausea and vomiting, vertigo, horseness, dysphagia, and horner's syndrome

- Contralateral loss of pain and temperature sensation in the arms and legs

- Hiccups and other fasciculations --> Aggravation of the vagus nerve

- CN VI on one side and the CN III of the other side communicate to move both eyes together via the medial longitudinal fasciculus (MLF)
- MLF lesions lead to inability of the eyes to move together

- Leads to diplopia

- LR6SO4 --> Lateral rectus CN VI, Superior oblique CN IV 

- Cerebral: Cortex informs cerebellum of intended movement --> Cerebellum in turn controls the rate, range, and force of movement

- Spinal: Spinal cord notifies the cerebellum about movement as it happens

- Vestibular: Vestibular nuclei inform the cerebellum about body position in space

- Lesions --> Ipsilateral ataxia --> Cerebello-cortical tract crosses twice

- Supraoptic and Paraventricular Nuclei: Synthesize ADH, oxytocin, and CRH --> Regulates water balance via ADH

- Paraventricular nucleus also modulates stress too

- Anterior Nucleus: Temperature regulation --> Decreases temp by stimulating parasympathetic nervous system

- Preoptic Nucleus: Released gonadotropin releasing hormone --> Lesions lead to impotence and amenorrhea

- Suprachiasmatic Nucleus: Regulates circadian rhythms

- Dorsomedial Nucleus: Regulates hunger and feeding --> Stimulate leads to obesity and disinhibition

- Posterior Nucleus: Increases temperature by stimulating the sympathetic nervous system

- Lateral nucleus: Feeding center --> Increases hunger

- Mamillary body: Important in memory --> Lesions lead to confabulation and amnesia

- Ventromedial nucleus: Satiety center

- Arcuate Nucleus: Inhibits prolactin

- Results in increased water absorption in the distal tubules and collecting ducts

- Results in hyponatremia

- Diagnosis: Serum and urine electrolyte measurement

- Treatment: Water restriction and hypertonic saline if hyponatremia is really bad

- Inappropriately dilute urine

- Presents with excessive urination and thirst

- Leads to hypernatremia and hyperosmolarity

- Diagnosis: Serum and urine electrolytes

- Treatment: Vasopressin

- Bony structures surrounding the pituitary become enlarged

- Symptoms: Headache and occasionally endocrine dysfunction

- Treatment: Reversing any endocrine dysfunction

- Pituitary apoplexy/hemorrhage

- Often occurs post-partum

- Causes: Hypovolemic shock and ischemic necrosis of pituitary

- Loss of ACTH secretion, then FSH, LH, and TSH

- Visual changes

- Diagnosis: head CT for bleed and MRI to define region of lesion

- Lesion with cystic and solid components

- Slow growing tumor derived from Rathke's pouch

- One of the most common brain tumors in children

- Pituitary abnormalities are common

- Headaches

- Vision and balance issues

- VPL: Sensory info from the arms, legs, and trunk

- VPM: Sensory info from the face

- VL: Motor info from the cerebellum and basal ganglia --> Relays to motor cortex

- VA: Motor info from the frontal cortex --> Relays to premotor cortex

- Anterior: Obtains info from the mamillary bodies --> Relays to cingulate gyrus

- Medial dorsal: Relays info from the amygdala, substantia nigra, and the temporal cortex --> Relays to prefrontal cortex

- LGN: Visual input from the eyes --> Relay to primary visual cortex

- MGN: Auditory input from inferior colliculus --> Relays to primary auditory cortex

- Primary Sensory Nuclei: Relay priimary sensory info to the cerebral cortex

- Lesion produces contralateral sensory deficits

- VPL and VPM both involved --> Entire side of the body affected

- 

- Mamillary bodies, anterior nucleus of the thalamus, cingulate gyrus, hippocampal formation, and amygdala

- Helps create memory

- Memory is amplified by emotion

- Triangle of Mollaret --> Inferior olive to dentate nucleus, to red nucleus and back to inferior olive

1. Middle Peduncle --> Only afferent input

- Afferent input from the pons --> HUGE input

2. Superior CBL peduncle

- Afferent: Anterior/ventral spinocerebellar tract

- Efferent: All except for the bulbar tract

3. Inferior CBL preduncle

- Afferent: All except pontine and anterior/ventral spinocerebellar tract

- Efferent: Cerebello-bulbar tract --> Input to lateral and medial vestibular nuclei

1. Molecular layer

- Stellate and basket cells --> Inhibitory interneurons that modulate the visual and somatosensory pathways

- Axons of granule cells run parallel in this layer

2. Purkinje cell layer

- Output of CBL

- Inhibitory neurons --> GABA

- Complex spikes evoked by climbing fibers

- Simple spikes evoked by mossy fibers

3. Granular cell layer

- Densely packed  granule cells

- Mossy fibers --> Major CBL input

4. Mossy fibers

- Originate from nuclei in the spinal cord and brainstem

- Carry peripheral and central sensory info

5. Climbing fibers

- Fibers wrap around Purkinje cell bodies like a vine

- Originate from the inferior olive

- Convey somatosensory, visual, and cerebral cortex information

- Responsible for balance and eye movement

- Receives input from the semicircular canals and otolith organs

- Output: Lateral and medial vestibular nuclei

- Lateral: Controls axial muscles and limb extensors

- Medial: Eye movements and head/eye coordiantion via MLF

- Input: Ventral and dorsal spinocerebellar tracts via Clarke's nucleus

- Output: Descending motor systems for motor execution --> Interposed to red nucleus and VL thalamic nucleus

- Involved with muscle memory and the mental rehearsal of movements

- Output via the dentate to the motor and pre-motor cortices

- Prehension: Shaping of the hand to the object to be grasped

- Decomposition of movement: Loss of prehension by disruption of timing due to lateral cerebellar lesions

- Lesions lead to increased reaction time

- Lateral lesions --> Pure cognitive impairements --> Difficulty juding time of tones and speed of objects

- Right lesions --> Broca-like aphasia

- Lack of coordination of movement

- Errors in rate and regularity of movement --> Dysdiadochokinesia

- Delay in intitiating a response with affected limb

- Decomposition

- Dysmetria: Errors in range and force of movement --> Hypo or hypermetria

- 

- Explosive syllables and incorrect points of emphasis

- Nasal in character

- Ataxic: Interference of articulation, respiration, and phonation

- Adiadocokinesis: Slowness of speech

- Explosive-hesitant speech

- Scanning speech: Stretching of syllables --> Sharply cut off from one another

- Concurrent disease in brainstem

- Gaze-evoked --> Occurs at the very end of gaze

- Rebound

- Downbeat --> Occurs when pt looks down

- Positional --> Only when patient looks a certain direction

- Named for the direction of the fast movements

- Skew: One eye is slightly vertically displaced based on the other

- Saccadic dysmetria: Choppy point to point motion of eyes

- Impairment in smooth pursuit of an object

- Fixation abnormalities

- Postsaccadic drift --> Glissades

- Wide-based and staggering gait

- May be stiff-legged due to loss of postural reflexes

- Wiggling of midline structures

- Increases with fatigue

- Limb oscillates as it returns to it's initital position

- Metabolic: Hypoglycemia, hyponatremia, and hyperammonemia

- Infections: Bacterial and viral meningitis and encephalitis

- Toxins

- Hydrocephalus

- Cerebellar lesions

- Neuroblastoma

- Guillain-Barre syndrome

- Tick paralysis

- Labryrinthisis

- Multiple sclerosis

- Channelopathies

- Familial hemiplegic migraine

- Basilar artery migraine

- Benign paroxysmal vertigo of childhood

- Epilepsy --> Post-ictal

- Toxin --> Alcohol

- Metabolic --> Similar to acute causes

- Dominant paroxysmal ataxia

- Autosomal Dominant --> Spinocerebellar ataxia (SCA) and DRPLA

- X-linked SCA

- Autosomal recessive --> Friedreich's, vitamin E deficiency, late onset, ataxia-telengiectasia, Wilson's disease, Refsum's disease, and Bassen-Kornsweig

- Acquired disorders: Hypothryoidism, drugs/toxins, multiple sclerosis, neoplasms/paraneoplastic, hamartomas, autoimmune, and CJD

- Fixed Deficit: Cerebral palsy and malformations

- Spingolipidosis

- Ceroid-lipofuscinosis

- Neurodegenerative disease

- Multiple forms: AD, AR, and X-linked

- Typically AD though

- Trinucleotide repeat or channelopathies

- Friedreich's ataxia is the most common

- presents with gait abnormalities and eye movement problems with or without spasticity and neuropathy

- Striatum: Caudate and putamen

- Globus pallidus: Pars interna and externa

- Subthalamic nucleus

- Substantia nigra: Pars compacta and reticulata

- Internuclear Connections: Striatal outflow to entire GP --> Nigrostriatal fibers terminate in SNr

- Afferent pathways: Cortex to basal ganglia --> Smaller contributions from intralaminar nuclei and brainstem

- Efferent pathways: GPm and SNr --> Thalamus and PPN

- Somatotopic organization

- Dopamine --> Nigrostriatal pathway

- GABA --> Inhibitory imput via striatopallidal, striatonigral, pallidothalamic, pallidosubthalamic, and nigrothalamic

- Glutamate --> Excitatory input via corticostriatal, corticosubthalamic, thalamocortical, and subthalamopallidal --> Damaged in Huntington's

- Cholinergic --> Thalamostriate fibers --> Damaged in cognitive disorders

- Chorea --> Damage to the striatum, especially the caudate

- Ballism --> Subthalmic nucleus --> Usually unilateral and really fling limb with slight intiation of movement

- Dystonia --> Striatum, especially putamen --> Functional issue but structures are anatomically normal

- Tremor --> Variable but most types require disease outside of the basal ganglia

- Tics --> Unknown lesion

- Myoclonus --> Not limited to the BG and lesions in a wide variety of sites --> Hiccups is myoclonus of the diaphragm

- Hemiballism --> Intiated with movement of the limb --> Extreme lack of modulation --> Really fling their arm with slight initiation of movement --> Increased thalamo-cortical flow

- Enteroviral disease --> 3 different serotypes of poliovirus

- Fecal-oral spread

- Only about 1% of infected persons develops lower motor neuron disease

- Onset: Fever and diarrhea

- Clinically affects lower motor neurons --> Painless weakness and atrophy, asymmetric, limb and bulbar weakness, trouble swallowing and breathing, and no sensory symptoms

- Motor neurons are more widely affected than the exam initially shows

- Vaccine: Injected killed virus (Salk) or oral live attenuated vaccine (Sabin)

- Disease of sensory nerves

- Pain and numbness in a dermatomal distribution --> Varicella zoster

- Incoordination and off balance symptomes --> Tabes dorsalis, late manifestation of syphilis

- Exam: Decreased sensation in a dermatomal distribution and trouble with balance and coordination

- 

- Sensory complaints of pain or paresthesia

- Weakness

- All in a spinal root distribution

- Exam: Sensory loss, weakness, with or without muscle atrophy

- Structural causes: Infiltrative (neoplastic) and traumatic

- Autoimmune causes: Parsonage-Turner Syndrome and Post-vaccinial --> Doesn't need to present in the same arm as the vaccine

- Post-radiation

- Vascular causes: Diabetes --> Radiculoplexoneuropathy

- Peripheral neuropathy

- Axonal and typically acquired --> Diabetic neuropathy

- Dysmyelinative --> Typically inhertied --> Charcot Marie Tooth disease --> Abnormal myelin

- Demyelinating --> Always acquired --> Guillain-Barre

- Symmetrical, length-dependent, and dying back neuropathies

- Symptoms start in both feet at the same time

- Symptoms move up the legs --> Once symptoms get to the knees, symptoms in hands begin

- Most commonly cuased by diabetes, alcohol, or inherited defects in the US

- Most common caused by leprosy worldwide

- Sensory nerves --> Electrical response is recorded

- Motor nerves --> Electrical membrane potential measured

- Size and response and the velocity of the conduction along the nerve is also measured

- Damaged axons --> Response size decreases but conduction velocity normal

- Myelin damage --> Conduction velocity slows

- Acute, rapidly progressive, symmetric inflammatory polyneuropathy

- Manifested by weakness and areflexia

- Follows flu-like or diarrheal illness

- Respiratory muscles may be involved

- Autonomic problems possible to

- Painless, proximal muscular weakness --> Symptoms fluctuate

1. Post-synaptic --> Myasthenia gravis

- Associated with some antibiotics

- Problem is with the receptor on muscle --> Antibodies block the ACh receptor --> Get worse with exercise

2. Pre-synaptic

- Lambert-Eaton Myasthenic syndrome -->Paraneoplastic syndrome

- Botulism

- Problem with production or release of ACh

- Autoimmune disease where antibodies are produced to the ACh receptor on the post-synaptic membrane

- Onset: Women in the 20s, men in their 60s or 70s, and juvenile (10%) --> More common in females

- Ocular and generalized forms

- 80% of people with generalized form will have antibody and <25% of the occular form will have antibody

- Edrophonium test --> Inhibits AChE and increases the amount of ACh in the synapse --> Improvement

- U-shaped decremental response and reduced safety factor in MG

- Symptoms get worse with exercise --> Fewer ACh molecules can be released with every successive action potential --> Less post-synaptic stimulation

- Treatment: Plasma exchange, IVIG, oral immunosuppression, and acetylcholinesterase inhibitors (Pyridostigmine)

- Autoimmune paraneoplastic syndrome

- Most commonly associated with small cell lung cancer

- Antibodies against voltage gated calcium channels on the pre-synaptic membrane

- Muscle weakness that improves with repetition --> Calcium builds up in the pre-synaptic axon because there isn't enough time to re-sequester --> Allows for more ACh release

- Autonomic symptoms too --> Decrease ACh release from post-ganglionic parasympathetic neurons

- Diagnosis: Antibody tests or fast repetitive nerve stimulation test

- Inherited disease of muscle

- Due to trinucleotide repeat (CTG) --> Exhibits anticipation

- Protein kinase mutation --> Abnormal muscle membrane

- Symptoms: Frontal balding, glucose intolerance, endocrine abnormalities, multiple miscarriages, testicular atrophy, cataracts, cardiac conduction defect, cardiomyopathy, cholecystitis/constipation, and intellectual dysfunction

- Distal muscle disease

- Diagnosis: Clinical, genetic testing, EMG, and prenatal

- Treatment: Supportive

- Arises indirectly from the aorta

- Supplies the lower two thirds of the spinal cord via the anterior spinal artery

- Obstruction leads to anterior spinal artery syndrome

- Damage to the corticospinal tract --> Weakness/areflexia

- Damage to spinothalamic tract --> Loss of pain and temperature sensation

- Dorsal column is spared --> Intact joint positional and vibrational sense

1. Sympathetic system --> Short pre and long post

- Presynaptic cell bodies --> Intermediolateral cell column of spinal cord between T1 and L2

- Exit spinal cord via ventral roots --> White ramis communicantes

- Gray rami communicantes (unmyelinated) --> Exit at every level of the spinal cord and carry post-ganglionic fibers to their destination

- Neurotransmitters: ACh (pre) and NE (post), ACh (post to sweat glands and adrenal medulla)

- Horner's syndrome: Occurs if superior cervical ganglion of symp. tract is damaged --> Ptosis, miosis, and anhidrosis

2. Parasympathetic system --> Long pre and short post

- Pre-synaptic cell bodies in intermediolateral cell column between S2 and S4 and in CN nuclei

- Exit spinal cord via ventral roots --> Make pelvic splanchnic nerves

- Neurotransmitter: ACh (pre and post)

- Ipsilateral ptosis (drooping of eyelid)

- Ipsilateral miosis (small pupil)

- Ipsilateral anhidrosis (lack of sweating)

- Biceps: C5-C6

- Brachioradialis: C6

- Triceps: C7

- Patellar: L4

- Achilles: S1

- Cutaneous distribution of a single spinal root

- High degree of overlap

- C1: Hairline

- T4: Nipple line

- T10: Umbilicus

- L1: Inguinal ligament

- S4/5: Perianal

- All the muscle innervated by a single spinal root

- Most muscle receive innervation from more than one root

- Poor correlation with dermatomes

- Muscle tone --> Resistance felt on passive movement

1. Upper motor neuron --> Cortical motor neurons that synapse on LMNs

- Function by inhibiting the contant firing of LMNs

- Lesion --> Increased reflexes, no atrophy, weakness in UMN distribution, muscle spasms, and trouble walking due to stiff muscle

- UMN muscle distribution: UE extensors and LE flexor weakness

- Acute lesion --> Flaccid weakness that progresses to spastic weakness over time

2. Lower motor neurons --> Alpha motor neurons of the anterior horn of the spinal cord

- Will constantly fire without inhibitory input from UMNs

- Lesion: Flaccid weakness, reduced relexes, muscle atrophy, trouble walking due to muscle weakness, and fasciculations

- Most common between L4/L5 and L5/S1

- Can compress nerve and spinal cord

- Nerve compression --> Radiating pain down the limb in a distribution of the specific nerve root impinged

- Cord compression: Loss of function below the level of impingement --> Loss of function of legs possible

- Upper motor neuron defects below the lesion --> Hyper-reflexia, etc

- Lower motor neuron defects at the level of the lesion --> Weakness and atrophy

- Complete hemisection of the spinal cord

- Ipsilateral muscle weakness

- Ipsilateral loss of joint and positional sense

- Contralateral loss of pain and temperature

- Causes: Trauma --> Gun shot or knife wound

- Occurs with vitamin B12 (cobalamin) deficiency

- Causes: Pernicious anemia, gastritis, ulcer disease, gastric surgery, dietary (alcoholism), and nitrous oxide abuse

- Dorsal column and lateral corticospinal tracts affected --> Loss of light touch and muscle weakness

- Spontaneous firing of a single motor unit

- Represents a "sick" motor neuron or axon

- Can occur in any muscle in the body

- Evidence of LMN lesion

- Lou Gehrig's Disease

- Acquired or inherited degenerative disease of UMN and LMNs

- Unknown etiology

- Incidence: 2/100,000 --> 5,000 new cases a year in the US

- Prevalence: 5/100,000

- More common in women than men

- 90% are sporadic and 10% are inherited

- Up to 50% develop frontal lobe dysfunction

1. Classical: Limb and bulbar onset

2. Progressive bulbar palsy

3. Primary Lateral Sclerosis

4. Progressive muscular atrophy

- Theories: Oxidative stress, glutamate toxicity, and decline in growth factors

- Pathology: Degeneration of cortico-spinal tracts, nerve roots become thin, loss of large neurons from the cortex, cerebellum, brainstem and spinal cord, and bunina bodies (eosinophilic inclusions in LMNs)

- Diagnosis: Signs of LMN and UMN lesions, progressive spread of signs within a region to other regions, EMGs, and neuroimaging

- Temporary loss of motor and sensory function

- Blockage of nerve dunction

- Due to focal demyelination

- Disruption of axon with little disruption of surrounding CT

- Nerve stretching

- Disruption of axon and CT

- Compression: Carpal tunnel syndrome and amyloidosis

- Stretch: Deceleration, birth injuries, and operative

- Sever: Bone fracture and penetrating trauma

- Ischemic

- Recovery depends on the mechanism of injury and how the CT is damaged by the injury

- Rapid recovery with compression

- Slower and non-complete regrowth with axonal breakage

- Compression of the median nerve by the transverse carpal ligament

- More common in women over 50

- Often seen in pregnancy, diabetes, hypothyroidism, musicians and other people with jobs that require repetitive movements

- Characteristics: Weakness of the abductor pollicis brevis, no weakness in flexor pollicis longus, numbness of the palmar thumb and pain when tapping on the wrist

- Both muscles are innervated by the median nerve and C8

- Treatment: Cock-up wrist splint, steroid injection, and surgical loosening of the retinaculum

- AKA Erb's palsy --> Waiter's tip

- Stretching of the upper portion of the brachial plexus during birth

- Due to macrosomia

- Damage to muscle innervated by C5 and C6 --> Median and radial nerves --> Deltoid, biceps, brachioradialis, rhomboid, and serratus anterior

- Patient is unable to abduct arm

- Sensory loss: C5 and C6 --> Lateral arm, forearm and hand

- Sympathetic damage possible --> Horner's syndrome

- Lesion of the lower trunk of the brachial plexus

- Hand weakness --> Can no longer hold things --> Fingers permanently flexed

- Weakness of C8 innervated muscles and no response to pinprick in C8 dermatome

- Cisatracurium

- Mechanism: Competitively inhibits ACh binding to nicotinic receptor at muscle end plate

- 70% bound prevents ACh from evoking muscle contraction

- Results in flaccid paralysis

- Elimination: Spontaneous degradation by plasma esterases

- Onset of action: 2-8 min

- Duration of action: 20 min-1 hr 

- Succinylcholine

- Mechanisms: Non-competitively binds nicotinic ACh receptor --> Receptor desensitization and voltage-gated channel inactivation

- Ion channel closes and is refractory to further activation

- Receptor will gradually reset

- Fasciculation: Initial excitation and disorganized muscle contractions

- Phase I block: Prolonged depolarization due to persistent ACh receptor activation --> Flaccid paralysis

- Phase II block: Receptor desensitization and receptor-operated channels close --> Muscle repolarizes --> Flaccid paralysis and ACh receptors are non-responsive

- Elimination: Degradation by plasma esterases

- Onset of action: ~1 minute

- Duration of action: 6-12 minutes --> Increased in people with atypical plasma esterase

1. Nondepolarizing: Histamine release with tubocurarine and related agents

2. Depolarizing

- Malignant hyperthermia --> Genetic skeletal muscle disorder --> Treat with dantrolene

- Prolonged action with atypical plasma cholinesterase

- Hyperkalemia --> Associated with burns and prolonged immobilization

- Cardiac dysrhythmias --> Stimulation of cardiac muscarinic receptors

- Postoperative muscle pain

- Binds to pre-synpatic cholinergic nerve terminals

- Internalized into cytoplasm

- Enzymatically degrades the protein factor required for vesicle fusion and transmitter release

- Functional nerve degeneration

- Prolonged action --> Months

- Uses: Cosmetics, cervical dystonia, spasticity, strabismus, blepharospasm, severe primary axillary hyperhydrosis, urinary incontinence, and chronic migraine

- Adverse effects: Muscle weakness, difficulty eating/swallowing, and respiratory failure

- Treatment: Antitoxin --> Doesn't reverse toxicity once toxin has entered the nerve

- Increase in muscle tone --> Initial resistance to passive displacement of the limb followed by sudden relaxation

- Disinhibition of spinal reflexes due to loss of descending inputs to inhibitory interneurons

- Pharmaceutical strategy: Reduce the activity of excitatory 1a afferents from muscle spindles or enhance inhibitory interneuron activity

- Benzodiazapine

- Mechanism: Potentiates GABAa receptors and enhances inhibition of muscle afferents

- Uses: Spasiticity

- Adverse effects: Sedation, synergistic effect with alcohol, dependence, and increased seizure risk with withdrawl

- Mechanism: Agonist of pre-synpatic GABAb receptors and inhibition of excitatory transmitter release

- Administration: Oral (highly bioavailable) and intrathecal for higher CNS concentrations attainable

- Adverse effects: Sedation, hallucinations, and seizures with abrupt withdrawal

- Mechanism: A2-adrenergic agonist --> Enhances pre and post-synaptic inhibition in the spinal cord

- Adverse effect: Sedation, orthostatic hypotension, dry mouth, hepatotoxicity, and 3% had hallucinations

- Mechanism: Inhibits Ca release by the ryanodine receptor of sarcoplasmic reticulum

- Uses: Spasticity and the only drug effective for malignant hyperthermia

- Adverse effects: Sedation, hepatotoxicity, weakness, and diarrhea

1. Metaxalone (Skelaxin)

- Unknown mechanisms --> CNS depression

- Adverse effects: Sedation, dizziness, and nausea

2. Carisoprodol (Soma)

- Biotransformed to GABAa receptor modulator --> Meprobamate

- Adverse effects: Sedation and synergistic with alcohol

- Right carotid --> Branch of the brachiocephalic trunk

- Left --> Directly from the aortic arch

- ICA originates at the bifurcation of the common carotid at the level of the thyroid --> Ascends intracranially without branches

- ECA supplies the neck and face --> Lots of branches and multiple anastamoses with the ICA via opthalmic artery

- Arise from the subclavian arteries

- Enters the bony canal of the spinal cord at C6 --> Ascends within the transverse foramina of cervical vertebrae

- Leaves the canals and curves around the lateral mass of the atlas dorsally and medially at C1 --> Travels on the upper surface of the posterior arch of C1

- Runs ventrally between the occiput and the atlas and passes through the atlanto-occipital membrane

- Penetrates the dura at the level of the foramen magnum

- Within the subarachnoid space --> Vertebrals curve ventrally and join to form the basilar artery --> Join in front of the caudal pons

- Opthalamic artery

- Posterior communicating artery

- Anterior choroidal artery

- Terminal bifurcations --> Anterior and middle cerebral artery

- Anterior spinal artery --> Supplies anterior 2/3 of cord

- Posterior Inferior Cerebellar Artery (PICA)

- Basilar artery

- Branches of the basilar --> AICA, superior cerebellar artery (SCA), and bifurcates to form both posterior cerebellar arteries (PCAs)

- Medial, basal and lateral occipital lobe

- Medial and basal temporal lobe

- Communication between the anterior and posterior circulation

- Allows for continued blood flow if one of the vessels becomes occluded

- Consists of two anterior cerebral, middle cerebral, and posterior cerebral arteries

- Communicating arteries: Two posterior communicating and one anterior communicating

- External to internal carotid via the facial or STA to the angular to the ophthalmic artery

- ECA to VA via the occipital artery

- Callosal anastamoses

- leptomeningeal anastamoses

- Superior and deep veins

- Dural sinuses

- Bridging veins travel from the sinuses into the parenchyma --> Stretch with aging and commonly cause subdural hematomas

- Bleeding into the brain parenchyma

- Putamen and internal capsule (50%)

- Lobar

- Thalamic

- Cerebellum

- Pons

- Higher prevalence in blacks and Japanese

- Prognosis is worse than ischemic strokes

- Presentation: Increasing symptoms in min-hours, focal neurologic signs, and general symptoms related to ICP --> Headach, vomiting and decreased level of consciousness

- Etiology: Hypertension, amyloid angiopathy, vascular malformations, trauma, underlying mass, vasculitis, venous outflow obstruction, coagulopathy, and drugs

- Diagnosis: Head CT and angiography

- Treatment: ABCs, treat hypertension, correct coagulopathy, and surgery to remove hematoma if needed

- Blood collection between the dura and the periosteum

- Blood cannot cross sutures

- Due to rupture of the middle meningeal artery and skull fracture

- Altered mental status --> Period of lucidity --> Loss of consciousness

- Diagnosis: Head CT --> Convex on CT

- Treatment: Surgical evacuation of hemorrhage

- Watch carefully because large lesions can lead to brain herniation and death

- Blood collection between the dura and arachnoid

- Large lesions will increase intracranial pressure --> Herniation and death

- Diagnosis: Head CT --> Concave and poorly demarcated

- Treatment: Observation and imaging with small hematomas and surgical evacuation with larger lesions

- Most commonly occurs from rupture of an intracranial aneurysm (Berry aneurysm) --> 2-5% of all strokes

- Most commonly in middle aged women --> Most common in blacks

- Mortality is high --> ~12% die before ever reaching the hospital and ~25% die during hospitalization

- Presentation: "Thunderclap" headache, nuchal rigidity, photophobia, N/V, loss of consciousness, seizures, and  sub-hyaloid hemorrhages of the retina

- Exam: Meningismus (neck stiffness) and CN III palsy

- Classic headach occurs in 1/3 of patients days to weeks before hemorrhage occurs

- Etiology: Ruptured aneurysms --> Most common in anterior circulation and patients with underlying CT disorders

- Diagnosis: Head CT or CSF analysis (gross blood or xanthochromia)

- Treatment: ABCs, ICU admission, prevent re-rupture by lowering BP, prevent vasospasm with Ca channel blockers (15-25% of pts), anti-seizure meds to prevent seizures, and antifibrinolytics (tranexamic acid)

- Surgical intervention: Secure aneurysm with coils or clips --> Within 18 hours of presentation

- Ischemic (85%)

- Hemorrhagic (15%)

- ~800,000 new cases every year in the US

- 3rd leading cause of death in the US

- 15-30% become permanently disabled

- 20% of patients require institutionalized care 3 months after

- DDx: Ischemic stroke, intracerebral hemorrhage, and post-ictal paresis (Todd's paralysis)

- Diagnosis: History and exam --> Large deficit means ischemic stroke, decreased arousal/vomiting means ICH or posterior stroke, and delirium, dizziness, and visual problems means posterior stroke

- Imaging: head CT and CTA of head and neck

- Labs: Serum glucose, CBC, aPTT, PT/INR, and hCG

- Goal: Maximize perfusion to limit infarction

- Allow hypertension, give IV saline, and lay head in bed <30 degrees --> Facilitiates brain perfusion

- Do not treat hypertension unless BP >220/110 or organ dysfunction present

- IV tPA --> Within 4.5 hours of onset

- Endovascular therapy: Thrombectomy or intra-arterial tPA --> Within 4 hours of anterior circulation or within 12 hours of posterior circulation lesion

- Goal: Prevent hematoma expansion --> Occurs in 70% of patients

- 10% volume increase --> 5% increased mortality

- Treat hypertension --> Goal of 140-160 systolic

- Quickly correct any coagulopathy --> INR <1.4 --> Treat warfarin toxicity with prothrombin complex concentrate (PCC)

- PCC: Concentrated solution of factors II, VII, IX, and X

- Most severe form of status epilepticus

- Common in patients who are non-compliant with meds

- Status epilepticus: Any seizure lasting >5 minutes or >2 seizures without clearing of mental status in between

- DDx: Underlying epilepsy not taking meds, drug intoxication, hypoglycemia, vascular disease, electrolyte imbalance, CNS infection, tumor, and psychogenic

- Signs of ongoing seizure: Periorbital/periorbital clonus, forced horizontal conjugate eye deviation, and hippus

- Hippus: Conjugate contractin and dilation of pupils

- Imaging: CT scan

- Labs: Glucose, electrolytes, urine and serum tox screen, hCG, and CBC

- CSF: Must rule out infection

- Seizures beget seizures

- Excitotoxic neuronal death

- Complications: Lactic and respiratory acidosis, cardiac arrhythmias, rhabdomyolysis, myoglobulinuria, aspiration pneumonia, pulmonary edema, should dislocation, and rib fracture

- Treatment: Meds to abort seizure (lorazepam IV or midazolam IM) acutely and seizure prevention with phenytoin or fosphenytoin

1. Blood culture

2. Dexamethasone 10 mg IV --> Helps prevent complications

3. Antibiotics --> Vancomycin 1.5 mg/kg, ceftriaxone 2g, and ampicillin 2g if pt >50 years or immunocompromised --> All IV

4. CT

5. LP --> High WBCs, high protein, and low glucose

- Presentation: Gait unsteadiness, distal limb parasthesias, proximal muscle weakness, cramping, back pain, and diffuse hyporeflexia/areflexia

- Imaging: MRI of cervical spine in CNs impaired

- CSF: High protein but no cells and normal glucose

- Treatment: Control breathing with mechanical ventilation if needed --> IVIG and plasma exchange

1. Medical

- Hypertension and cardiac disease

- Atrial fibrillation

- Hyperlipidemia

- Diabetes mellitus

- Carotid stenosis

- Hx of TIA or stroke

- Elevated homocysteine

2. Behaviors

- Cigarette smoking

- Alcohol abuse

- Physical inactivity

- Illicit drug use

1. Ischemic (85%)

- Thrombotic (45%) --> Large vessel (30%) and lacunar (15%) --> More common in the anterior circulation but vessels are more distal in posterior circulation

- Embolic (25%)

- Cryptogenic (15%) --> Can't determine which category

2. Hemorrhagic (15%)

- Intracerebral hemorrhage (10%)

- Subarachnoid hemorrhage (5%) --> Most common at bifurcation between anterior cerebrals and anterior communicating artery

- Focal ischemia --> "Stroke warning"

- Duration <24 hours --> Usually 5-20 minutes

- May occur with any cause of ischemic stroke

- 10x risk of full stroke occuring --> Highest risk in first 3 months and 35% stroke risk 3-5 years after

1. Carotid System

- Unilateral weakness, sensory and visual loss

- Aphasia

- Unilateral visual loss ("amaurosis fugax") --> Carotids supply the opthalmic artery --> Due to carotid stenosis and retinal ischemia

2. Vertebro-basilar System

- Bilateral weakness, sensory, and visual loss

- Diplopia

- Vertigo

- Ataxia

- Dysarthria and dysphagia

- Larger effect on the cerebellum and occipital lobes

- Pure motor --> 68%

- Pure sensory --> 12%

- Ataxic hemiparesis --> 10%

- Dysarthria-clumsy hand --> 10%

- Risk factors: Hypertension > diabetes

- Better functional outcomes and lower mortality than other strokes

- Tend to recur

1. Major risk

- Atrial fibrillation

- Mitral stenosis

- Prosthetic heart valve

- Recent MI

- LV thrombus

- Atrial myxoma

- Infective endocarditis

- Dilated cardiomyopathy

- Marantic endocarditis

- Ascending aortic atheroma

2. Minor risk

- Mitral valve prolapse

- Mitral annulus calcification

- Patent foramen ovale

- Atrial septal aneurysm

- Calcific aortic stenosis

- LV hypokinesis

- Supplies the medial frontal and parietal lobes

- Lesion results in contralateral leg weakness

- Supplies frontal, parietal, and temporal convexities

- Widespread contralateral weakness --> Arm > leg

- Global aphasia also results

- Contralateral visual field defect

- Upper territory: Contralateral weakness of face and upper limb, and tongue weakness and motor aphasia, but without visual field defects

- Lower territory: Minimal or no contralateral weakness, snesory aphasia if dominant hemisphere involved, and visual defect involved

- Occipital cortex and thalamus 

- Presentation: Contralateral homonymous hemianopia, sensory loss without contralateral hemiparesis

- Also can affect midbrain depending on extent of lesion

- Corticospinal symptoms: Bilateral limb weakness, limb hyperreflexia, and extensor plantar response

- Corticobulbar symptoms: Facial weakness, dysarthria, dysphagia, and increased gag reflex

- Oculomotor symptoms: Diplopia, gaze palsies, nystagmus, and internuclear ophthalmoplegia

- Reticular activating system symptoms: Reduced consciousness

- Locked-in syndrome possible --> All symptoms except oculomotor or reticular activating systems

- Contralateral weakness of the upper and lower extremities

- Contralateral loss of vibration and proprioception

- Ipsilateral tongue weakness with or without atrophy

- No effect on pain, temp or light touch because these tracts don't run medially

- Ipsilateral ataxia of the limbs

- Ataxia of gain

- No limb weakness

- Only cerebellum is affected in this infarct

- Common problem

- Sleep deprivation has behavioral and physiological consequences

- Self-assessment may not be realiable

- Sleep deprivation is cumulative

- Patiens with sleep apnea and narcolepsy have severe daytime sleepiness

- Insomniacs aren't usually sleepy during the day

1. Behavioral/Mood

- Sleepiness

- Psychomotor impairment

- Accidents

- Decreased work productivity

- Reduced quality of life

- Deficits in learning/memory

- Alcohol interactions --> Makes symptoms worse

- Mood effects

- Lack of awareness

- Risk taking

2. Physiologic changes

- Insulin resistance

- Blunted arousal response

- Blunted immune response

- Increased risk for cardiovascular disease, stroke, and death

- Altered pain sensitivity

- Increased risk of Alzheimer's --> Normal clearance of products from the brain during sleep, but lack of clearance can lead to Alzheimer's

- REM Sleep --> Restorative sleep that involves rapid eye movements and muscle paralysis --> Increasing amounts of REM sleep during the night

- NREM Sleep --> 3 different stages with decreasing tonicity of musculature

- Slow wave sleep --> Decreased amounts during the night 

- Created via the suprachiasmatic nucleus (SCN) of the hypothalamus

- Input from the retina too

- Periods of drowsiness around 2-3 pm and then once the sun goes down

- Taking any sedating meds

- Drinking even small amounts of alcohol

- Having a sleep disorder --> Sleep apnea

- Driving long distances without breaks

- Driving alone or on a boring road

- Sleep disorder characterized by excessive sleepiness

- Cataplexy: Loss of muscle tone due to an emotional trigger --> Excitement or sadness

- Associated with other REM-related problems --> Sleep paralysis and hypnagogic/hypnopmopic hallucinations

- Sleep paralysis: Paralysis that persists for a minute or so after waking (10-15% of normal people)

- Fragmented sleep is common

- Prevalence: 1 in 2,000, men and women affected equally, and HLA-DQB1*0602

- Presentation: Any age but usually between 15-30 years and 6% <10 years old

- Associated systems: Hypocretin/orexin system --> Localized in the dorsolateral hypothalamus

- Diagnosis: Multiple sleep latency test (MSLT), nighttime polysomnography (PSG), epworth sleepiness scale (ESS), and maintenance of wakefulness test

- Treatment: Stimulants (amphetamine and non-amphetamines) for excessive daytime sleepiness, and tricyclic antidepressants for cataplexy

- Sodium oxybate can be used for excessive daytime sleepiness and cataplexy

- Willis-Ekbon Syndrome

- Urge to move legs that is triggered or accompanied by unpleasant sensations

- Presents during rest or inactivity

- Relieved by movement, stretching, or walking

- Symptoms are generally worse at night

- Prevalence: ~10% of adults --> Slightly more prevalent in women

- Onset: Any age and >40 years of age

- 50% is considered familial

- Periodic limb movement of sleep (PLMS) --> 80%

- Periodic movements of wakefulness --> 15%

- Low serum feritin levels

- Pathophysiology: Brain dopamine dysfunction which may involve circadian mechanisms and deficiencies in iron metabolism

- RLS is a biomarker of disease --> Associated with cardiovascular disease, diabetes, hypertension, obesity, insomnia, and lower physical function

- Treatment: Dopaminergic agents (Sinemet, requip, etc), Ca channel alpha 2-delta ligands (gabapentin and pregabelin), opioids (oxycodone, methadone, and tramadol), and benzodiazepines

- Accounts for 80% of all RLS

- Highly stereotpyes movements --> Triple flexion

- Short burst of movement --> 0.5-5 second burst

- Needs 4 consecutive movements

- Usually occurs in a 20-40 second interval

- May be associated with arousal

- Unpleasant sensory and emotional experience

- Associated with actual or potential tissue damage

- Involves nociception --> Process by which noxious stimuli are transmitted to the nervous system

- Local tissue destruction produces local inflammatory response --> Release of prostaglandins, leukotrienes, substance P, and other nociceptive substances

- Nociceptive specifc neurons are activation

- Thermoreceptive and pressure sensitive neurons are activated by heat and stretching respectively

- Input modulated at the cord level by local circuits --> Pain reflex arcs

- Signal projected to the thalamus and cortex

- Projected to the hypothalamus too --> Autonomic reflexes are activated

- C fiber linked nerve endings continue to fire due to the release of local inflammatory substances --> Local inflammation causes plasma leakage, which may prolong nociceptor firing

- Local nociception is involved but the exact mechanism is unknown

- Result of central rewiring of modulating neurons, neuronal death mediated by NMDA receptors, or failure of descending inhibitory pathways

- Usually multifactorial

- Strong physiological component is often present

- Incoming nociceptive fibers synapse on wide dynamic range (WDR) neurons

- WDRs first at different rates based on the intensity of the stimulus

- This allows for modulation and coding for pain intensity

- WDR is modulated by other inputs

- Descending NE, 5-HT, and opioid pathways decreased WDR firing

- The final signal is transmitted to the thalamus and ultimately the cortex

- Incoming pain signals trigger glutamate release from nociceptive neurons

- Glutamate then stimulates AMPA receptors on the dorsal horn WDR neurons

- Prolonged stimulation leads to polarization changes in the WDR membrane

- This polarization causes Mg and Ca displacement from NMDA receptors --> Priming them for activation

- Leads to protein kinase C activation and NO synthase activation and NO release

- NO closes K and guanyl synthase channels --> Key for endogenous opioid analgesia

- NO also causes substance P release --> NK-1 stimulation and incrased c-fos expression

- C-fos expression leads to neuronal remodeling

1. Somatic

- Well localized

- Mechanically reproducible

- Due to injury to the structures of the body wall

2. Visceral

- Poorly localized

- Described as bloating or cramping

3. Referred --> Shoulder pain for diaphragmatic pain, etc

4. Neuropathic

- Damage to the nervous system

- Described as burning or shooting

- Opiate resistant

- Sensory alteration is present at site

- Sensitivity to mechanical stimulation

- Sensitivity to cold --> Amyloid receptors develop that are extremely sensitive to cold

- Sensory abnormalities in the site of affected nerves

- Allodynia: Pain evoked by a non-noxious stimulus, like clothes

- Hyperalgesia: Increased pain evoded by noxious stimuls

- Hyperpathia: Delayed and exaggerated pain response to a noxious stimulus

- Paraesthesias: Spontaneous or evoked painless abnormal sensations

- Dysesthesias: Spontaneous or evoked unpleasant sensations

- EMG/NCV

- Quantitative sensory testing

- Autonomic testing

- Bone scans

- Alot of the time patients get diagnosed with diabetes when they come in with burning feet and pain

- Due to systemic illness --> Diabetic neuropathy, paraneoplastic and amyloid

- Due to toxic/metabolic causes --> B12/folate deficiencies, alcoholic, renal, and hepatic causes

- Ischemic

- Compressive/traumatic --> CTS, ulnar, radiculopathies, and complex regional pain syndrome

- Infections/immune --> Post-herpetic neuralgia and post-viral

- Idiopathic --> Trigeminal neuralgia

- Peripheral neuropathy

- Compressive radiopathies --> Carpal tunnel

- Radiculopathies --> Dermatomal changes, pain radiating to distal limb, and may be reproducible by mechanical stressor

- Post-herpetic neuralgia --> Reactivation of chickenpox virus

- AKA Reflex sympathetic dystrophy

- Type I: No clear nerve lesion

- Type II: Local nerve injury

- Severe form of neuropathic pain with autonomic features

- Should have changes in skin, temperature, hair growth, nail growth, and sweating

- Skin changes --> Shiny and extremely sensitive to touch

- Inexorably progressive without treatment

1. Pharmacotherapy

2. Interventional therapy --> Local blocks, sympathetic blocks, and electrical stimulation

3. Physical therapy

4. Psychological techniques

5. Medications --> Opioids, NSAIDs, tricyclics, anticonvulsants, oral anesthetics, muscle relaxants, and benzodiazepines

- Tricyclics: Increased efficacy of endogenous antinociceptive pathways --> Side effects are sedation, dry mouth, urinary retention, visual changes, and orthostatic hypotension

- Anticonvulsants: Most effective in lancinating neuropathic pain (gabapentin and pregabalin)

6. Neurostimulation

7. Stress reduction

8. Biofeedback

9. Acupuncture

- Best for unilateral limb pain of the neuropathic type

- Occassionally helpful in bilateral limb pain

- May be helpful in sympathetically maintained pain

- Bilateral or diffuse nociceptive pain

- Clear psychological profile --> Cancer patients with less than a year to live

- Effective trial period

- Previous response to opioids

- Type of disequilibrium described as a subjective sensation of moving/spinning

- May be associated with observable nystagmus, nausea, and vomiting

- Patient often uses one finger and shows a spinning motion when asked to describe symptoms

- Hearing loss that occurs with aging

- Impaired in function or loss of the inner ear hair cells

- Perception of sound seeming to come from inside the ear or inside the head

- In the absence of corresponding external sound

- Accompanied by acquired or congenital sensorineural hearing loss

- Commonly bilateral --> If unilateral, must rule out acoustic neuroma, especially in middle aged patients and with unilateral hearing loss

- About 20% of people between 55 and 65 year olds and 11.8% on a more detailed tinnitus-specific questionnaire

- Moderate to mild hearing loss --> 20% repetition of words

- Direction of nystagmus is defined by the direction of its quick phase

- Oscillations may occur in the vertical, horizontal or torsional planes

- Gross description of movement

- Central --> Result of either normal or abnormal processes not related to vestibular system

- Peripheral --> Normal or diseased functional states of the vestibular sytem

- Gaze induced: Result of changing one's gaze causes nystagmus

- Postitional: Occurs when patient is in a specific position

- Post-rotational nystagmus: Imbalance is created between a normal side and diseased side

- Spontaneous nystagmus: Occurs randomly

- Requires the proper functioning of four physiologic systems:

1. Vision

2. Vestibular input

3. Proprioception --> Lower extremity proprioception

4. Cerebellar function

- Ringing in the ears --> tinnitus

- Loss of hearing --> Neuritis, can last months

- Nausea and vomiting --> Labrynthitis

- Headache and photophobia --> Vestibular migraine

1. Weber test: Place the tuning fork on the center of the skull --> Ask patient where they hear the sound

- Lateralizes toward the ear with conductive hearing loss

- Lateralizes away from the ear with a sensorineural hearing loss

2. Rinne test: Place tuning fork on the mastoid bone, ask patient to tell you when they stop hearing sound and then see whether the sound is louder on the bone or infront of the ear canal

- Air conduction > bone conduction --> Normal/positive

- Bone conduction is louder than air conduction in an ear with conductive hearing loss

- Start in sitting position

- Remind patient to keep eyes open

- Extend neck, turn head right or left

- Rapidly lie patient down until the head is hanging at a 45 degree position

- Look for rotary nystagmus and ask patient if they feel dizzy

- Sensation of the room spinning (vertigo)

- Unsteady when walking preceded by a change in head and/or body positions

- May have nausea or vomiting

- No change in hearing present and no tinnitus

- Due to displaced otoconia within the semicircular canals

- May last minutes to hours

- Diagnostic: Dix-Hallpike positional test

- Treatment: Epley practice repositioning maneuver

- Endolymphatic hydrops

- Onset: 35-50 year old

- Triad of vertigo, fluctuating low frequency sensorineural hearing loss and tinnitus

- Diagnosis: Audiogram and electrocochleography (ECOG)

- Treatment: Salt restriction, diuretics, endolymphatic sac surgery and quick gentamycin administration in the hopes of vestibular nerve loss without damaging hearing

- Often due to bacterial infection

- Sudden onset of violent spinning to the point where patient can't get out of bed

- Significant and sudden hearing loss

- Nystagmus, nausea, vomiting, and tinnitus possible

- Can last for days

- Diagnosis: Audiogram and electronystagmography

- Treatment: Antibiotics

- Onset: Approximately 45 years old

- Precipitated by loud noises, cough, sneeze, and lifting a heavy weight

- May perceive that objects are moving in time with their pulse --> Pulsatile oscillopsia --> Can bring on sensation of motion

- Causes their eyes to move by pressing on the tragus

- Experience a feeling of constant disequilibrium and imbalance

- Diagnosis: CT scan to see dehiscence

- Treatment: Middle fossa approach to the superior semicircular canal to repair bony defect

- Migraine associated vertigo

- Presentation: Dizziness and imbalance with or without vertigo and with or without severe throbbing headache

- Extreme sensitivity to light, nausea and vomiting, and fullness of the ear with muffled hearing

- Symptoms worse during menstruation in women

- Diagnosis: No specific test

- Treatment: Medications

- Neuritis

- Presentation: Vertigo, dizzy, feeling off balance, no change in hearing, and usually no tinnitus

- Lasts for weeks to months

- Diagnostic test: No specific test

- Treatment: No specific treatment but must rule out acoustic tumor

- Vestibular schwannoma

- Arises from the abnormal growth of the Schwann cell sheath investing vestibular or cochlear nerve

- Not malignant

- Presentation: hearing loss and/or tinnitus worse in one ear

- Diagnosis: Audiogram, MRI scan of the brain or brainstem with or without contrast

- Treatment: Observation, gamma knife or cyberknife radiation therapy, or middle cranial fossa or sub-occipital surgery

- Illusion of movement felt as an aftereffect of travel on a ship or plane

- Sensation of bobbing, rocking, swaying, swinging, floating, or tumbling

- Diagnosis: Careful history, audiogram, and vestibular function tests

- Treatment: Vestibular rehabilitation therapy and meclizine (motion sickness meds)

- Common in weight lifters

- Onset of dizziness and vertigo after a pop in the ear

- Due to barotrauma such as scuba diving, plane flights, or straining

- Diagnosis: Ear fistula test

- Treatment: Await spontaneous recovery or middle ear surgery to repair fistula

- Proegressive impairment of balance that occurs with aging

- Chronic sensation of imbalance

- Tendency to fall

- Factors: Diabetes, failing vision, cataracts, and hypertension meds

- Treatment: Use a cane to ambulate, vestibular rehab and counseling

- Causes: Inflammation from otitis media, complication of cholesteatoma, CVA, facial nerve neuroma, parotid tumor, and lyme disease

- Bell's palsy --> Usually idiopathic

- Central: Paralysis or paresis of the lower half of one side of the face --> Damage to upper motor neurons of the facial nerve

- Peripheral: Paralysis of the lower motor neurons of the facial nerve --> Bell's palsy

- Rare form of cancer involving the nose and skull base

- Arise from the olfactory epithelium

- Nasal obstruction, loss of smell, taste and vision

- Diagnosis: MRI

- Treatment: Cranio-facial surgical excision and radiation therapy

- Most common movement disorder

- Present during action and absent at rest

- Correlated to activity in the sensorimotor area and the cerebellum

- Family history present in 1/2 of patients (AD inheritance)

- Usually bilateral and symmetric

- No rigidity and bradykinesia seen

- Usually involves the upper extremities, head, and voice

- No significant response to anti-Parkinson meds

- Head tremor is invariable mild

- Commonly worsens with age

1. Medical

- Primidone (older anti-epileptic) dosed at night

- Propranolol (B-blocker) during the day

- Combined primidone and propranolol pills

- Phenobarbital, gabapentin, topiramate, and benzos (Anti-epileptics) can be used

- Botulinum toxin: Used to reduce tumor severity but usually limited to dystonic tremors

2. Surgical

- Deep brain stimulation (DBS) of the ventro-intermediate nucleus (VIM) of the thalamus

- Bilateral surgery less common --> Secondary side effects of cognitive and gait disturbances --> Also troubles swallowing

- Non-specific term used to describe a constellation of signs similar to Parkinson's disease --> Tremor, bradykinesia, rigidity, postural instability and gait abnormality

- Medication related --> Old epileptic and reglan (old anti-nausea med)

- Vascular

- Post traumatic

- Normal pressure hydrocephalus (NPH)

- Other toxins --> Magnetic gait and heave metal toxicity (mercury and mangenese)

- More specific definition

- No known cause

- 4 cardinal features --> Tremor, bradykinesia, rigidity, and postural/gait instability

- Non-cardinal features --> fatigue, dementia, insomnia, constipation, bladder symptoms, sexual dysfunction, restless leg syndrome, periodic limb movement disorder, hypophina, dysarthria, dysphagia, drooling, and reduced facial expression

- Incidence: 20/100,000 in the US

- Mean survival: + 20 years after onset --> Longer in non-demented patients

- Cause of death: Pulmonary infection/aspiration and complications of falls

- CT/MRI are normal and SPET/PET scans show asymmetrical decreased dopamine levels --> 70-80% of dopamine cells lost before symptoms arise

- Pathology: Decrease in dopaminergic cells in the substantia nigra pars compacta and Lewy bodies

- Serotonin reduction as well --> Mood difficulties

- Age --> Increases with age

- Genetics: Parkin, alpa-synuclein, DJ-1, PINK-1, UCHL-1, and LRRK2 gene mutations

- Environmental: Herbicides, pesticides, mercury, manganese, jet fuel, agent orange, dry cleaning products, well water, and repeated head injury

- Parkinson plus syndrome

- Asymmetric onset

- Apraxia can transition into Alien hand syndrome --> Then dystonia

- Alien limb --> Difficulty manipulating and grabbing objects --> Literally can move on its own

- Limb gets stiff and stonic then switches to another limb --> Disease progresses until pt can't move

- Myoclonus may also be present

- More rapid progression (5-10 years)

- No good response to Parkinson's disease

- CT and MRI may reveal contralateral atrophy

- PET scan: Decreased contralateral fluorodopa uptake in the basal ganglia

- Pathology: Ballooned neurons and tau protein in cortex, basal ganglia, and substantia nigra

- Parkinsons plus syndrome

- Gait distrubance very common leading to falls

- Non-specific changes in personality

- Gaze palsy, dysarthria, and dysphagia

- Rapid progression and poor response to PD meds

- Pathology: Globose neurofibrillary tangles unpaired --> Excessive phosphorylation of tau protein

- Parkinson plus syndrome

- MSA-A: Autonomic predominance --> No prominent tremors

- MSA-P: Parkinsonism predominance

- MSA-C: Cerebellar

- Rapid progression and poor response to PD meds

- MRI: Brainstem degeneration

- Pathology: Synucleinopathy

- Parkinson's dementia

- Progressive Parkinsonism and dementia

- Functioning fluctuates throughout the day

- Can "freeze solid" for many hours (up to 24 hours) after being given haldol after recent hospitalization

- Minimal or no resting tremor

- Early cognitive, psychiatric features, and depression usually noted --> Patients can be out of control and need behavioral management

- Hallucinations: Exacerbated even by small doses of Parkinson's meds

- Cognitive function may improve with central cholinesterase inhibitors

- "Wing beating" tremor --> Only real proximal tremor of movement disorders

- Defect in copper metabolism --> Chr 13 autosomal recessive disease

- Usually presents in adolescents or young adults

- Copper builds up in the liver, brain, and eye

- Presentation: Cognitive, psychiatric, and movement disorder

- Neurologic manifestations: Tremor (wing beating), dystonia, ataxia, and dysarthria

- Liver abnormalities: Low ceruloplasmin and high urinary copper levels

- Slit lamp exam: Kayser-Fleischer rings

- MRI: Abnormal T2 basal ganglia signal

- Treatment: Reducing copper in diet, zinc, penicillamine, and trientene --> Zinc reduces copper absorption and penicillamine and trientene chelate chopper

- Presentation: Movement disorder and cognitive decline

- Onset: 3rd and 4th decade

- Inheritance: Autosomal dominant chr. 4 CAG trinucleotide repeat mutation --> Anticipation

- Diagnosis: Clinical presentation, imaging, and genetic testing

- Imaging: Atrophy of caudate and putamen (striatum)

- Juvenile form: Akinetic and rigid with seizures

- Medical treatment: Dopamine antagonist (haloperidol, risperidone, or olanzapine), benzodiazepines, and tetrabenazine (new med)

- Focal, task specific, and generalized dystonia --> Generalized dystonia is the most severe

- Often worsened by stress

- Dystonia-Parkinsonian syndrome --> Trial of L-dopa

- Treatment: Anti-cholinergic agents, benzodiazepines, muscle relaxants, anticonvulsants, clozapine, botox, and DBS in the globus pallidus interna

- Lack of coordination while performing voluntary movements --> Inability to walk in a straight line and unable to touch finger to nose

- Damage to the cerebellum and it's inputs/outputs

- Hereditary, degenerative, malformation, cancer, drug, infection, toxin, or trauma related

- Treatment: Supportive care

- Friedrich's Ataxia: Autosomal recessive --> Neurodegeneration related to frataxin with poorly functioning mitochondria --> Often become wheelchair bound after 1st or 2nd decade of life

- Endogenous precusor of dopamine

- Can cross the BBB while dopmaine cannot

- Remains the most commonly used therapy for PD

- Pathology of PD: Loss of the ability to make dopamine due to depletion of precursor --> Enzymes and mechanisms are still present though

- Decreased morbidity and mortality

- L-dopa trial --> Clinical tool for diagnosis

- Response intensity --> Amount of axon terminals still present in the striatum (projections from the nigra)

- Higher risk of side effects with higher doses

- Steady L-dopa dosage for 24 hours --> Leads to reduced response and faster wearing off

- Need to give brains time without excessive dopamine stimulation to reduce the risk of wearing off

1. Motor fluctations: Loss of stable response to L-dopa

- ~50% of patients after 5 years of therapy

- ~70% of patients after 15 years of treatment

- End-of-dose "wearing off"

- Unpredictable "on-off" fluctuations --> Unique to Parkinson's

- Falling response due to continuous loss of nigra cells not tolerance to L-dopa

- 20% of original cells can store dopamine and make enough for normal functioning --> Need SUBSTANTIAL cell loss

2. Dyskinesias: Abnormal involuntary movements

- Peak dose and diphasic

- Threshold decreases over time --> Could get dyskinesia before therapeutic response

3. Neuropsychiatric disturbances

- Hallucinations

- Confusion

- Psychosis

- Act directly on dopamine receptors --> Only D2 family of receptors (D2, D3, and D4)

- Pramipexole and ropinirole

- Slows disease progression --> Cells stay alive longer and less oxidative damage

- Viewed as dopamine by the body --> Reduces endogenous dopamine production and reduces the levels of dopamine mediated side effects

- Advantages vs. L-dopa: Don't require metabolic conversion, don't compete with circulating amino acids for transport across BBB, longer half-life, and less dyskinesia

- Disadvantages: Higher rate od behavioral side effects (addiction, hallucinations, etc), higher risk of hypotension (peripheral D receptor effect), and less motor response

- MAO-B's used in PD

- Selegiline or rasagiline

- Irreversible inhibitors of MAO-B

- Increases striatal dopamine concentrations by blocking catabolism

- Enhances the benefit of L-dopa

- May slow disease progression

- Side effect: Hypertensive crisis --> Risk is minimal if recommended doses used

- Patients <70 years old --> Dopamine agonist

- Patients >70 years old --> Carbidopa/L-dopa therapy

- Increases geometrically with age

- 5-10% of individuals >65

- 50% of individuals >85

- Alzheimer's disease is the most common --> 80%

- Insidious onset over months - years

- Memory difficulties

- Decline from prior level of function

- Progressive cognitive impairment --> Word finding difficulty, getting lost, impaired facial recognition and problem solving

- 2 or more cognitive domains: Memory, reasoning, judgment, visuospatial ability, language, personality, behavior, and comportment

- Must rule out other forms of dementia

- MRI/CT: Atrophy of medial temporal, anterior temporal and parietal lobes --> Global atrophy and symmetric

- CSF Analysis: Reduced amyloid B and increased p-Tau concentration --> Useful in clearly demented young patients where AD is unclear

- FDG-PET: Amyloid imaging with florbetapir -->Decreased metabolism seen in the temporal and parietal cortices --> Not yet paid for by alot of insurance companies

- Donepezil and galantamine --> Rivastigmine (Fewer GI side effects) availabe as QD patch and huperzine A (nutritional supplement)

- Improves cognition, participation in daily activities, global function, and behavior

- GI side effects: Anorexia, nausea/vomiting, and diarrhea

- Vivid dreams --> Take in AM to avoid

- Cholinergic symptoms --> Increased salivation and rhinorrhea, muscle cramps, and rarely slows HR

- Check EKG ~1 month after initiation of treatment to be sure bradycardia isn't present

- Improves symptoms but doesn't slow disease progression

- Recommendations are to continue cholinesterase inhibitors for as long as there is quality of life to preserve

- Small but noticeable improvements --> Less time looking for things, less repetition, less dwelling on the past, easier to keep track of conversation, and more engaged and outgoing

- Idea is the turn back the clock on symptoms

- ~25-30% show 1 year reversal of symptoms

- ~50-60% show 6 month reversal of symptoms

- ~10-15% show <6 month reversal of symptoms

- AKA namenda --> Derivative of amantadine --> Dopamine agonist

- Uses: Moderate to severe AD treatment --> Monotherapy or in conjunction with CIs 

- Mechanism: Uncompetitive NMDA-receptor antagonist

- Response: Enhances dopamine activity and doesn't alter AChE activity --> Improvement or less decline in cognition

- Therapeutic Expectations: More alert, talkative, engaged and outgoing, brighter overall, and less agitated

- No improvement in memory

- Side effects: Dizziness, drowsiness, and confusion

- Trouble remembering schedule, content of meetings, and other mild memory complaints --> Worsening over the last 2 years

- Rule out vascular, traumatic, and medical causes

- Prognosis: 70% progress to AD at a rate of 15% a year and 30% stable or improve

- Treatment: Try AChE inhibitor if patient wants to improve their memory and overall functionality

- Causes: Reptitive head trauma and multiple concussions --> Common in boxers and football players

- Presentation: Depression, irritability, impulsiveness, suicide, Parkinsonism, and generalized dementia

- Symptoms develop and progress years to decades after head trauma

- Slower progression than other dementias

- Pathology: Tau ONLY disorder --> No amyloid present

- CT scan: Cavum septum pallucidum

- Dementia with Lewy Bodies within the substantia nigra and striatum but also throughout the entire rest of the brain

- Presentation: Memory problems, Parkinsonism, visual hallucinations, and visual perceptual defects

- FDG-PET scan: Occipital lesions seen --> Only dementia with occipital lesions

- Treatment: Rivastigmine

- History of small TIAs --> Fluctuating cognitive impairments but symptoms never return to normal --> Not true TIAs

- Trouble recalling specific things

- Generally oriented to time, place and situation

- Poor walking

- Early incontinence

- Pathology: Multiple thalamic strokes seen on MRI

- Treatment: Galantamine

- Poor cognition over 6-12 months

- Very poor attention

- Urinary incontinence

- "Magnetic" gait disorder --> "Feels like my feet are stuck to the floor"

- Diagnosis: LP, serial LPs, or lumbar drain

- Treatment: Ventriculo-peritoneal shunt --> Improvement in gait and incontinence without change in cognition, AChE inhibitors, and memantine

- Memory and behavioral problems

- Uncharacteristic behaviors --> Depressed, apathetic, uncontrolled temper, etc

- Good metabolism in all lobes but the frontal lobe seen on imagine

- Semantic dementia

- Language problems --> Difficulty naming, impaired comprehension, and impaired knowledge about the world

- Memory is very impaired for words and borderline imapired for shapes

- Successfull found 10 personal items hidden around the room 20 minutes later

- Progressive atrophy of the left temporal lobe than the right

- Determine underlying cause of agitation

- Anxiety --> Treat with SSRIs

- Manage sleep cycle disturbances --> Limit naps, ritalin or provigil in AM if necessary

- Daytime agitation --> Risperidone/risperdal

- Nighttime agitation --> Trazodone and quetiapine/seroquel

- Patients with very mild AD have accident rates similar to 16-19 year olds

- Have family member ride as a passenger monthly --> If they are comfortable then patient is probably OK

- Driving evaluation at rehab hospital possible

- Aerobic exercise

- Social activities --> Staying involved and engaged

- Crying or laughing for little or no reason

- Very common in AD, Vascular dementia and other dementias

- New med --> 20 mg Dextrmethorphan/10 mg Quinidine 1 capsule daily x7 days then 1 capsule every 12 hours

- Side effects for new med: Diarrhea, dizziness, cough, vomiting, asthenia, peripheral edema, UTI, influenza, increased GGT and flatulence

- CN II

- Not a peripheral nerve

- Tract of the brain

- Retina and optic nerves are the only parts of the brain that can be directly visualized

- On fundoscopic exam, arteries are brighter than veins

- Striations on fundoscopic exam are axons

- 6 million cones and 2 million rods are present in the retina

- Disc swelling as a result of increased intracranial pressure

- Increased pressure pushes the macula out into the vitrious cavity

- Associated with headaches and projectile vomiting

- Boarder of the disc is much less distinct than normal

- Almost always a bilateral process --> Can't get unilateral increased intracranial pressure

- Signs: Good visual acuity until late, disc elevation and loss of venous pulsations

- Hemorrhages and cotton wool spots will be present if papilledema is acute

- Emergent indications for imaging to rule out tumor, hydrocephalus or intracranial bleed

- Most common cause is pseudotumor cerebri (hydrocephalus)

- Any signs of advanced visual loss should be admitted to lower intracranial pressure --> Even with normal imaging

- Unilateral in adults but can be bilateral in children

- Disc swelling as a result of inflammation

- Most commonly caused by demyelination (MS)

- Anterior form of optic neuritis

- Pain with eye movement

- Other causes: Acute disseminated encephalomyelitis, acute necrotizing hemorrhagic encephalomyelitis, and Schilder diffuse cerebral sclerosis

- Visual loss due to inflammation of the optic nerve

- Normal fundoscopic exam

- Accounts for 2/3 of optic neuritis

- Often unilateral

- Posterior form of optic neuritis

- Bright shining macula

- Issue behind the eye

- Not as bright as primary

- Due to swelling

- Chronic papilledema

- Optic cupping 

- One side of the disc gets bright and forms a "cup" shape

- Disorder of aqueous humor dynamics 

- Features optic atrophy with loss of disc substance (cupping)

- Increased intraocular pressure

- Visual field loss

- Corneal edema --> Halos around lights but needs really high pressure

- CN III

- Characterized by inability to constrict the pupil and move the inferior rectus, superior rectus, inferior oblique, medial rectus and levator papebrae muscles

- Leaves the medulla right at the level of the circle of willis

- Easily damaged by ruptured aneurysm

- No pupillary involvement --> Diabetic cause --> Parasympathetic nerves are less sensitive to the microvascualr ischemia associated with diabetes

- Causes: Aneurysm (IC/PCA), vascular/diabetic, trauma, tumor, and idiopathic

- Mimics: Myasthenia gravis (no pupil), thyroid related, ischemic myopathy in giant cell arteritis, and internuclear opthalmoplegia (MLF lesion)

- CN IV

- Innervates the superior oblique --> Moves eye inferior and abducts slightly too

- Affected eye is higher than the other --> Pt tilts head to compensate

- Causes: Head trauma (bilateral), vascular/diabetic, congenital, idiopathic

- Severe head trauma can cause tearing of the optic chiasm --> Bilateral hemiplegia

- CN IV

- Innervates the lateral rectus

- Cannot abduct the affected eye

- Causes: Trauma, neoplasm, microvascular, aneurysm, idiopathic

- Excessive production

- Obstructed egress --> Non-communicating (cerebral aqueductal stenosis)

- Insufficient absorption --> Meningitis --> Communicating

- Production > Absorption

- Congenital causes: Aqueductal stenosis, neural tube defect, arachnoid cysts, Dandy-Walker syndrome, and Chiari malformation

- Acquired causes: Intraventricular hemorrhage, meningitis, head injury, and brain tumor

- Uncal hernation --> Drags CN III, which is directly tethered to it, bump against brainstem, and pulls adjacent vessels

- Vessels commonly rupture and ischemia occurs

- Results in hemorrhage of the midbrain

- Midbrain compression --> Ipsilateral blown pupil (anisecoria), respiratory problems, loss of consciousness, etc

- Treatment: Osmotic agents (mannitol), ventricular drainage, decompression craniectomy, and brain resection

- Cerebral blood flow tends to increase with blood pressure --> Total flow to the brain remains relatively constant between 60 and 200 mmHg though

- Cerebral blood flow tightly controlled

- 30 cc's is the average ventricular CSF volume in an adult

- 1,000-1,5000 cc is fatal

- Not fatal in children because the skull is softer and can expand

- Would result in expansion of the skull and the head in children

- Large amounts of CSF aren't fatal like they would be in adults

- Treatment: Ventriculoperitoneal (VP) shunt --> Shunt from the ventricle to the peritoneal cavity to drain fluid --> Hooks up to a valve that limits drainage so CSF fluid doesn't get too low

- Can be caused by congenital stenosis of ventircular connections or by a tumor compressing the communications

- Treatment: Put an endoscope into ventirlces and poke a hole into the base of the 3rd ventricle --> Creates a communication between the ventricles and basal cisterns to drain excess fluid

- Uncal --> CN III and midbrain injury

- Tonsillary --> Medulla and PICA injury

- Cingulate --> Anterior cerebral artery injury

- Vermal --> Upward, PCA, and basilar apex perfusion injury

- Displacement drags, distorts and compresses attached and neighboring structures

- Vessels in surrounding tissue --> Infarction --> Only 10 minutes before brain tissue is irreversibly damaged

- CNs III --> Anisocoria (blown pupil)

- Brainstem --> Unconsciousness

- Treatment: Osmotic agents (mannitol), ventricular drainage, decompressive craniectomy, and brain resection

- Headache lasting 30 minutes to 7 days

- At least two of the following characteristics:

1. Bilateral

2. Pressing/tightening (not throbbing) quality

3. Mild or moderate intensity

4. Not aggravated by routine physical activity

- Not associated with nausea or vomiting

- May be associated with photophobia or phonophobia but never both

- Over 18 million outpatient visits a year

- 1.5-2% of emergency room visits

- 1/20 ER visits will have a serious disorder

- Primary headache: Migraine, tension-type, and cluster headache

- Secondary headache: Tumor, meningitis, and giant cell arteritis

- Head trauma

- Subarachnoid hemorrhage/stroke --> Thunderclap headache that comes on within 1 minute

- Meningoencephalitis

- Malignant hypertension

- Temporal arteritis --> Doesn't occur in patients >50 years old

- Raised intracranial pressure

- Systemic illness --> Common cold or flue

- Acute glaucoma

- Ilicit drugs and side effect of meds

- Must always look in the eyes and take BP to properly evaluate headache

- First/worse severe headache

- Headache worse in the morning --> Raised ICP

- Abrupt onset headache

- Progressive or changing headache pattern

- Headache with neurological symptoms > 1 hour --> Excludes TIAs

- Abnormal neurological exam

- New headache in children <5 years or adults >50 years

- New headaches in patients with cancer, immunosuppression or pregnancy --> These co-morbidities put them at higher risk

1. Vascular

- Dural venous sinus thrombosis

- Arterial dissection

- CNS vasculitis

- Temporal arteritis

2. Infectious

- Encephalitis/meningitis

- Sinusitis (sphenoid)

3. Tumor

- Posterior fossa lesion

- Infiltrative CNS glioma

- Pituitary tumor/apoplexy

- Leptomeningeal cancer

5. Other

- Idiopathic intracranial hypertension

- Low-pressure headache

- Isodense subdural hematomas

- Stimulation of the brain parenchyma did not cause pain

- Stimulation of meninges and blood vessels causes pain

- Causes severe unilateral headache

- Often genetic --> Family history common

- Lasts for 4-72 hours

- Unilateral or bilateral headache --> ~50% unilateral

- Pulsating quality

- Not associated with fever

- Moderate to severe pain quality

- Aggravation by routine physical activity

- Can be associated with an aura

- Gets worse with menstruation

- Associated symptoms: Nausea, vomiting, photophobia,  phonophobia, motion sickness, difficulty initiating and terminating sleep, difficulty adjusting to altitude or time zones, and sensitivity to alcohol

- Usually gets better with age but can't predict at what age they will get better

- Pathogenesis: Vasodilation, neuropeptide release, and trigeminal sensory activation

- Co-morbidities: Epilepsy, bipolar disorder, panic disorder, and anxiety

- Behavioral

- Acute medications: Triptans, ergotamines, butalbital products, opioids, ibuprofen/naprosyn, and antiemetics (prochlorperazine)

- Preventative medications: B-blockers (propranolol, timolol, and atenolol) and tricyclic antidepressants (amitriptyline) 

- 15% of migraines associated with aura

- Scintillating lights in the vision, black spots or void in the vision, and numbness and tingling in the hands and face

- Aura should resolve entirely within an hour of the migraine starting

- Simple light flashes and shimmering lights

- May be accompanied by a scotoma

- May be complicated with sensory disturbance on face/hand, weakness or aphasia

- Primary headache syndrome

- Strictly unilateral and short lived headache

- Generally without nausea, vomiting or photophobia

- Often associated with agitation and pacing

- More common in men than women

- Abortive treatment: Sumatriptan sc and oxygen

- Prophylactic treatment: Verapamil, lithium, topiramate, gabapentin, and melatonin

- Best inhaled anesthetics are high lipophilicity and extremely low aqueous solubility

- Newer were created to solve the problems of past anesthetics

- Ether and cyclopropane --> Flammable

- Chloroform --> Cardiac arrest

- Trichloroethylene --> Phosgene and CO poisoning

- Methoxyflurane --> Renal failure

- Advantages: Rapid induction and recovery, easty titration, measurable concentrations during administration, inhalation route of administration, and respiration can be controlled while delivering gases

- Exact mechanisms still unclear

1. Lipid Theory

- Dissolving in the membrane lipid, anesthetics affect its physical state altering membrane function

- Volume expansion --> Anesthesia occurs when the intrusion of anesthetic molecules expand the lipid phase --> Distorts membrane to alter nerve conductivity

- The longer the hydrocarbon chain, higher lipid solubility to a point --> After this point potency drops dramatically --> Argues against theory

2. Protein Theory: Interaction of anesthetic molecules with membrane proteins to affect function

- Doesn't completely explain mechanism either --> Linear response, should be sigmoid response

- Fluorinated hydrocarbons

- Developed in the 1940s and 1950s

- Inhalation anesthetics enter and leave the body via the lungs

- Metabolic degradation of anesthetics may be important in relation to their toxicity

- Only desflurane needs a special vaporizer, other halogen anesthetics boil around room temp --> Spontaneously vaporize

- Blood/gas Partition Coefficients: Want the lowest value possible --> Desflurane has the lowest value, followed by nitrous oxide, and sevoflurane

- Want most of the drug to enter the vessel rich group --> Brain, liver, kidneys, and heart

- Vessel rich group only accounts for 9% of body mass

- Accounts for 75% of cardiac input though

- In order to get most of the anesthetic into this group, drug must have low solubility in blood and high lipid solubility

- Drug must also be able to cross the BBB

- Uptake: (Blood/gas coefficient)x(CO)x (A-v partial pressure difference)

- Minimum alveolar concentration of the anesthetic that prevents movement in 50% of subjects in response to standard surgical incision (standard central laparotomy)

- Idea was to normalize the values for all of these drugs internationally

- MAC increases at higher altitudes too

- Higher BMI --> Matters how long you give the drug not how much you give --> Longer exposure leads to more time for drug to diffuse into fat --> Higher stores of fat means higher stores of drug within the body --> Takes longer to wear off and for patient to wake up

- Factors increasing MAC: MAO inhibitors, cocaine, amphetamines, chronic alcoholism/drug abuse, hyperthermia, and ephedrine --> Increases the amout needed to anesthatize 50%

- Factors decreasing MAC: Opioids, barbiturates, benzodiazepines, hyponatremia, hypothermia, and hypoxia --> Decrease the amount needed to anesthatize 50%

- Thalamus --> Trafficking of sensory information to cortex --> So you don't feel surgery

- Hypothalmus --> Memory formation --> So you don't remember the surgery

- Reticular formation --> Consciousness

- Stage 1: Analgesia --> Pt is conscious but drowsy and reduced response to painful stimuli

- Stage 2: Excitement --> Subject loses consciousness and response only to painful stimuli

- Stage 3: Surgical anesthesia --> Spontaneous movements cease and respirations become regular

- Stage 4: Medullary paralysis --> Respiration and vasomotor control ceases --> Leads to cardiovascular collapse and death --> Try to prevent entering into stage 4

- Therapeutic Index: LD50/ED50 --> Very narrow window

1. Cardiovascular

- Decreased heart contractility --> Exacerbates heart issues

- Hypotension

- Variable hemodynamic response

- Causes profound release of catecholamines

2. Respiratory

- Fast, shallow, and regular breathing pattern

- Increased oxygen gradient

- Inhibition of pulmonary hypoxic vasoconstriction --> Normally shunts blood away from unventilated areas

- Pleasant and rapid induction

- Non-flammable and chemically stable

- Non-toxic 

- No biotransformation

- Good amnesia, analgesia and relaxation

- Sufficiently potent

- No adverse cardiac or pulmonary effets

- No adrenergic stimulation

- Inexpensive

- Odorless gas

- Stored as a liquid

- Low potency --> High MAC --> >1 atm (would need to inhale more than you normally breathe into the lungs)

- Commonly used as adjuvant and effective analgesic

- Cannot produce stage III anesthesia

- Low blood/gas partition coefficient --> Fast onset and termination of action

- Mechanism: Inhibits methionine synthetase --> Does not potentiate NMBA

- Side effects: Abortion, bone marrow depression, megaloblastic anemia, leukopenia, neuropathy, may distend air filled cavities within the body, and nausea/vomiting

- May increase blood pressure and cardiac output but minimal effects on respiration

- Widely used

- Non-irritating to the airway

- Depresses cardiac output and sensitizes the heart to catecholamines

- Side effects: Halothane hepatitis

- Widely used in the USA
- Not hepatotoxic

- Commonly used in patients with CAD and maintains CO --> Safer

- Rapid induction

- Inhibits pulmonary hypoxic vasoconstriction

- EEG slows progressively --> Very good for brain surgery because you can suppress the metabolic demand during surgery

- Least soluble but quite irritating

- Not commonly used

- Can triger coughing and breath holding

- circulatory actions are similar to isoflurane --> Stable CAD

- Minimal biotransformation

- Expensive

- Latest halogen introduced

- Low solubility in blood

- Smooth inhalation induction

- Undergoes significant biotransformation

- Must be cautious when using in patients with renal insufficiency

- Elemental xenon

- Very expensive due to its rarity in the environment

- Very low solubility in blood

- Excellent cardiovascular stability

- MAC 70% can be used with FiO2 of 30%

- Some clinical use in Europe but general acceptance would require adoption of complicated scavenging systems

- Esters: Procaine and tetracaine

- Amides: Lidocaine and bupivacaine --> If their is an i in the prefix --> Amide

- Short acting: Procaine

- Intermediate: Lidocaine

- Long acting: Tetracaine and bupivacaine

- Hydrophilic property --> Aqueous solubility via tertiary amino group

- Lipophilic property --> Aromatic ring

1. Esters

- De-esterification

- Pseudocholine-esterase in plasma and tissues

- Doesn't distribute into CSF

2. Amides

- N-dealkylation

- CYP450 metabolism in the liver

- ClT affected by hepatic blood flow and hepatic disease --> Dosage should be altered with hepatic disease

- Selective inhibition of sodium channels --> Specifically the activated or inactivated state over the resting state

- Channels located along the axonal membrane of unmyelinated fibers and at the nodes of Ranvier in myelinated fibers

- Binds the alpha subunit of Na channel --> Intracellular AAs 64 and 71

- Increased by lipophilicity --> More potent

- Increased by lower pKa --> Faster onset of time

- Decreased with inflammation-induced drop in tissue pH --> Drug is more protonated and becomes less effective

- Higher sensitivity for the smaller diameter fibers --> Sensory over motor fibers

- Higher sensitivity for nerve fibers around the edge of a nerve bundle

- Anesthetic affects more proximal nerves before the more distal ones --> Infiltration begins proximally to injection and spreads distally

- Myelinated fibers --> 3 nodes must be blocked to inhibit impulse propagation

- More sensitivity for the nerves with higher firing rates --> Sensory and sympathetic nerves have higher firing rates

1. CNS Effects

- Tremor

- Restlessness

- Convulsions

- Seizures --> Can be caused by any anesthetic at high enough doses

2. Cardiac effects

- Decreased automaticity

- Myocardial depression

3. Vascular effects

- Arterior relaxation and vasodilation

4. Only cocaine blocks presynaptic transporters for NE and DA --> Causes sympathomimetic effects and euphoria

5. Antidote: 20% lipid emulsion IV --> Acts as a reservoir to suck up excess drug and pull the drug out of the sites cuasing toxicity

- Risk with ester-type agents --> Cross-reactivity and affect of para-aminobenzoic acid metabolite (PABA)

- PABA is readily allergenic

- No risk with amide-type agents for hypersensitivity reactions --> Cannot be converted to PABA

- Any allergenic responses to amide types aren't due to PABA but due to preservatives

- Epidurals affect the sympathetic nerves leaving the spinal cord

- Can result in hypotension

- must commonly monitor BP 

- Skeletal muscle paralysis also possible

- Epinephrine 1:100,000

- Alpha 1 receptor activation to decrease blood flow at injection site --> Causes increased levels at local sites to enhance duration

- Reduces absorption rate into systemic circulation

- Vasoconstrictor side effects

- Topical: Solutions, ointments, creams, and gels

- Injection: Infiltration, peripheral nerve block, IV injection with tourniquet, and central (intrathecal or epidural)

- Mild effect: Sedation and anti-anxiety effect without impairment of cognitive function

- Strong effect: Strong sedative effect with hypnotic effects, impaired cognition, and anterograde amnesia

- Fine line between hypnosis, stupor, and death

- Potentiation of GABA-A receptor --> Increased Cl influx leading to hyperpolarization

- Enhances the GABA-A receptor mediated response of spinal cord neurons --> Increases amplitude and decreases decay rate

- Flumazenil --> Directly inhibits benzo effect but NOT GABA binding

- Allosteric binding to GABA-A receptors --> Has no effect on the receptor unless 2 molecules of GABA bind receptor --> Increase affinity of GABA binding

- Pentamer of alpha, beta, and gamma subunits --> >14 subunit subtypes

- Subunit subtypes expression are genetically modified

- BZDs specifically bind gamma subunits --> Binds at the interface between a and b subunits

- Majority of GABA-A receptors are a1b2g2 --> Can be modulated by BZDs because of the gamma subunit

- Superfamily of ligand-gated ion channels --> 3 kinds of subunits

- Each subunit contains 4 hydrophobic transmembrane regions, large extracellular amino terminus, and intracellular carboxy terminus

1. Phasic GABA receptors --> Located at synaptic cleft and need gamma subunits for BZDs to be effective

2. Tonic GABA receptors --> Extrasynaptic receptors without gamma subunits

3. Tonic GABA autoreceptors --> Pre-synaptic channels that feed back and stop the release of GABA

- Alpha-5: Cognitive enhancing effects

- Alpha-3: Anxiolytic and anticonvulsant effects

- Alpha-2: Anxiolytic and anticonvulsant effects

- Alpha-1: Amnesic/sedative and muscle relaxant effects

- Different affinity  for GABA receptor subtypes

- Half-lives differ as well

- Shorter acting drugs --> Less effect on cognitive function when taken chronically

- Acute awake anxiety

- Generalized anxiety disorder

- Muscle relaxation

- Panic attacks

- Agoraphobia

- Insomnia

- Convulsive disorders

- Alcohol and cocaine withdrawal

- Pre-anesthetic medications

1. Risk of excessive CNS depression

- Exacerbated by alcohol use and COPD

2. Decreased clearance in the elder --> Renally impaired

3. Sleep apnea --> Can exacerbate sleep apnea

4. Motor incoordiation

5. Drowsiness

6. Amnestic effects

- Must readily cross the blood-brain barrier to be effective

- PO --> High sefety, lipophilic, high bioavailability and rapid CNS effect onset

- IV --> Rapid distribution into the CNS and immediate onset of effect --> Much higher risk of overdose

- Elimination: Biotransformation via P450 enzymes or glucuronidation

- Some compounds will produce active metabolites --> Increases half life

- Interactions: Alcohol and P450 inhibitors (ketoconazole)

1. Zolpidem

- Very short acting

- Selective for alpha-1 subunit

- No active metabolites

- Great for sleep induction but not maintenance

- Non desensitizing --> Doesn't affect the genetic expression of the receptors with chronic administration

2. Diazepam

- Very long acting

- Non-selective

- Produces 2 active metabolites --> Prolonges half-life

- Chornic anxiolytic effect --> Good for generalized anxiety disorder

- Sleep induction and maintenance

- Tolerance develops due to changes in receptor transcription and expression with chronic administration

- Chronic use --> Psychological and physical dependence

- Signs of withdrawal are typically mild but are generally more severe with the short-acting meds

- Withdrawal seizures may occur in patients with underlying convulsive disorder --> Flumazenil may also cause

- Severe withdrawal is seen in benzo-dependent patients

- GABA-A receptor modulators --> Higher efficacy than BZDs

- Large direct activation of GABA-A receptors at high doses

- Can actually have agonistic properties at very high doses

- Low therapeutic index --> Dangerous drugs

- Risk of fatal respiratory depression --> Synergistic with alcohol

- Limited clinical use: IV administration (thipental) and PO (phenobarbital)

- GABA-A receptor positive modulator --> Agonist effects at much lower doses than BZDs

- Most commonly used IV anesthetic

- Useful for both induction and maintenance of anesthesia

- Rapid onset and offset

- Rapid clearance to inactive glucuronid metabolite

- Need to dose adjust for patients with hepatic injury

- Ketamine: NMDA receptor inhibitor --> Dissociative anesthesia

- Scopolamine: mACh receptor inhibitor --> Motion sickness

- Midazolam: GABA-A receptor enhancer --> Sedation and anxiety

- Ethanol: GABA-A/NMDA receptor modulators

- Tendency to have recurrent unprovoked seizures

- One must have >2 unprovoked seizures before the diagnosis can be made

- Seizure is a manifestation of an underlying brain irritation

- Seizure is a brief, excessive discharge of brain electrical activity that alters behavior

- Hyponatremia

- Hyperglycemia

- Drug reactions

- Drug withdrawal

- 1 out of 100 individuals have epilepsy

- 1 out of 11 individuals will experience a seizure sometime in their lifetime

- Peak ages --> <10 years (highest in first year) and >65 years old

- 68,000 new cases per year

- Not gender specific --> Higher prevalence in pregnant women and lots of the drugs cause teratogenicity

1. Focal seizures --> Starts in a particular region of the brain -->  May remain focal or can progress to secondarily generalized

- Parietal --> Sensory symptoms

- Temporal --> Alteration of awareness, taste hallucinations, olfactory hallucinations, visual hallucinsations, and psychic symptoms (deja vu or jamais vu)

- Secondary generalized seizures --> Tonic clonic seizures

2. Generalized --> Involves the entire brain

- Absence (petit mal) --> 15 second day dream state, no aura and no aftermath

- Tonic: Rigid

- Clonic: Jerks

- Myoclonic: Brief muscle contraction of limb or trunk

- Atonic: Drop attack, head and trunk --> Abrupt transition into seizure --> Can break bones

- Tonic clonic (grand mal) --> Convulsive activity

3. Simple Partial --> Consists of total awareness and may be the aura to a complex or generalized seizure

- Jacksonian March --> Characteristic of simple partial seizures but patient is fully aware

- Epigastric aura --> Rising feeling up the esophagus, is characteristic

- Autonomic involvement --> Sweating, flushing, and bad taste

- Right temporal seizure --> Impending doom

4. Complex Partial --> Alteration of awareness, accompanied by automatisms (lasts about 5-15 minutes), followed by postictal state of drowsiness, confusion or headache, and even nausea and vomiting

- Psychomotor or temporal lobe seizures --> May originate from other regions of the brain though

- Defined by seizure types, EEG findings, nerological status, age of seizure onset, family history, and prognosis

- Occurs between ages 3-5

- 10% will go on to develop a seizure disorder

- Risk factors: Abnormal development before seizure onset, complex febrile seizure (>15 min), more than 1 seizure in 24 hours, focal in origin, and family history

- Unsure as to whether the fever triggers the underlying disorder or if it represents a reactive clinical symptom

- Infantile spasms consisting of flexion of the trunk, extension of the arms, and drawing up on the legs --> Salaam posture

- Other forms: Nodding of the head only, extension of the arms, legs, trunk or shock like contraction of the body --> Lightning attack

- Crying, laughing, giggling, flushing, pallor and cyanosis may accompany

- EEG pattern: Hypsarrhythmia --> No two lines are the same

- Can progress to Lennox Gastaut Syndrome

- Often progresses from West Syndrome

- Intractable seizures, mental retardation, and developmental delay

- EEG pattern: Slow spike and wave --> 2-2.5 spike and waves per second

- Tonic clonic, atypical absence, myoclonic and atonic seizures

- Onset between ages 1-6

- Behavioral problems are common afterwards

- Must be sure to transition care to adulthood

- Inherited condition

- Myoclonic seizures with or without tonic clonic or absence

- Beings at puberty and again in late teens

- Seizures occur in early am upon awaking

- EEG pattern: Spike and wave, polyspike and wave --> Spike, spike and wave

- Normal imaging

- Normal intelligence

- Treatment is lifelong --> Easily treated but must take meds for their entire life

- Triggers: Sleep deprivation and alcohol intake

- 75% unknown etiology

- Only 25% have known causes

1. Structural lesions

- Intracranial tumor, abscess or granuloma, vascular malformations, scarring, and malformations

2. Metabolic lesions --> Generally considered provoked seizures but can lead to epileptic focus if they become repetitive

- Hypoglycemia

- Hypoxia

- Hyponatremia/hypercalcemia

- Uremia

- Hepatic failure

- Drug toxicity

- Pyridoxine deficiency (B6) in newborns

3. Genetic: Tuberous sclerosis, Struge Weber and Neurofibromatosis

- Precise diagnosis

- Evaluate underlying cause

- Study EEG, CT, MRI, and labs

- Choice of AED based on seizure type

- Discuss diagnosis

- Instruct on restrictions --> No driving until 6 months seizure free

- Vagal nerve stimulation

- Lobectomy --> Temporal with 70-80% chance of seizure freedom

- 50-60% chance of seizure freedom

- Corpus callostomy --> Split brain surgery

- Hemispherectomy

- Subcortical transections

- Ketogenic diet in children --> High in fat and can help prevent seizures

- Neuropace: Generator implanted in the skull --> Electrodes go into the brain for people who have multiple seizure foci

- Continuous seizure activity or recurrent seizures without regaining consciousness in between seizures --> Initiate treatment when seizure >5 minutes --> True definition is > 30 minutes

- Tonic clonic seizures --> 60,000-160,000 cases/year

- Mortality is very high

- EEG monitoring is crucial

- Treatment: Examine pupils, respirations, and airway, draw labs to determine etiology and treat, and stop seizures with diazepam (.2 mg/kg at 5mg/min) or lorazepam (.1mg/kg at 8mg/min)

- Move on to phenytoin and phenobarbital if the seizures don't stop

1. Hormonal influence

- Estrogen --> Proconvulsant

- Progesterone --> Anticonvulsant

- Menstural and menopausal impact

2. Pregnancy and epilepsy

- Risk of maternal and fetal complications

- Risk of teratogenicity --> 90% have normal healthy outcomes though

- Over the age of 65 --> 68,000 new cases per year

- Seizures pattern differs with EEG pattern

- Most commonly caused by ischemia

- Often misdiagnosed

- Requires lower doses of AEDs and has a higher responsive rate

- Lower doses --> Renally impaired and on concomitant meds

1. Complications

- Hormonal influences on seizures

- Interaction with OCPs

- Bone health --> Lots of meds affect vitamin D metabolism

- Reproductive health issues

- Mood disorders

- Weight issues

- Social issues --> Driving

- Work and education issues

2. Comorbidities

- Depression

- Anxiety

- ADHD

- Autism

- Cognitive dysfunction

- 5-18% of all epilepsy deaths --> ~50% of refractory epilepsy deaths

- Most commonly in 20-40 year olds

- Death of a person with epilepsy unrelated to status epliepticus

- Without any discernable structural or toxicological cause

- Male and young adults with frequent uncontrolled generalized tonic clonic seizures with poypharmacy

- Uncontrolled seizures are life threatening

- Death occurs unexpectedly and occurs over minutes

- Occurs in benign circumstances while engaging in normal activities

- No obvious cause of death and often unwitnessed

- High mortality --> 2-3x greater than the general population and 24x greater than young healthy adults

- Physiologic or psychogenic --> Mistaken for seizures

- Physiologic --> Cardio-vascular, syncope, TIAs, migraines, movement disorders, and sleep disorders

- Psychogenic: Altered movement, emotion, sensation or experience, similar to those due to epilepsy, but purely emotional

- Evaluation: EEG monitoring, prolactin levels within 20 min of onset, ictal heart rate, neuropsych/psych evaluation, and sexual abuse history

- Increase GABA transmission

- GABA is the main inhibitory transmitter

- GABA-A receptors mediate most fast-synaptic inhibition

- Modulation of GABAergic transmission

- Class I antiepileptic

- Inhibits catalysis/breakdown of GABA

- Irreversible inhibitor of GABA transaminase

- Elimination half-life is 5-8 hours --> Activity half life is MUCH longer because drug is an irreversible inhibitor --> Activity half life depends on how long it takes the body to remake enzyme

- Doesn't induce P450 enzymes 

1. Reversible inhibitor of GABA-T

2. Inhibits histone deacetylase too --> Mechanism for schizophrenia treatment

3. Inhibits T-type calcium channel

- Both Class I and III anti-epileptic med

- Indications: Myoclonic seizures (juvenile), schizophrenia, and second choice for absence seizures

- Metabolism: 30-50% glucuronide conjugation

- Side effects: Hepatotoxicity

- Teratogenicity too --> Spina bifida

- Selective GABA reuptake inhibitor