NEUROSCIENCE

TERMINOLOGY

 Gliosis: collection of reactive changes to glial cells

(hypertrophy, proliferation) in response to CNS
damage
 Aphasia: inability to perceive and use language
(say incorrect words)
 Dysarthria: inability to pronounce words properly,
facial or mouth weakness (say words incorrectly)
 Agnosia: inability to interpret sensory information
to recognize objects
 Apraxia: inability to perform learned tasks
 Ataxia: loss of full control of movement

HUMAN BRAIN DEVELOPMENT

 First few years of life, more than 1 million new

neural connections every second
 Afterwards connections are reduced via pruning so
brain circuits become more efficient
o Early = genes
o Later = environment
 Connections proliferate and prune in prescribed
order, with later, more complex brain circuits built
upon earlier, simpler circuits
 Sensory pathways develop first  language 
higher cognitive function
 Brain is most plastic early in life to accommodate
wide range of environments and interactions (easy
to influence architecture)
 Maturing brain becomes more specialized to
assume more complex functions (harder to rewire)
 Myelination happens the most week 28 – 1st year

REFLEX GRADING

NEURODEVELOPMENTAL MILESTONES

 0, 4, asymmetry always abnormal

Skeletal Cardiac Smooth

Location MSK system Heart Hollow organs

Relative size (d) Very big: 100 20 um 8 um

um
Morphology Striated, Striated, 1-2 No striations,
multinucleated nuclei, single nucleus,
 branched spindle-shaped  Muscle action potential propagates along
Gap junctions No Yes(intercalated Yes sarcolemma and into T tubules  voltage-gated
disks) Ca2+ channels arranged in tetrads at sarcolemma
Autorhythmicity No Yes Yes membrane undergoes conformational change 
Speed of Fast Moderate Slow Ca2+ release channels in terminal cisternal
contraction membrane opens  release of Ca2+ into
sarcoplasm
Regulation Somatic ANS, Cardiac +  Ca2+-ATPase pumps constantly transports Ca2+
pacemaker stretching from sarcoplasm into reticulum. Inside has
cells, hormones calsequestrin which binds to Ca2+ and allows
MUSCLE PROTEINS more to be stored
 After last action potential  Ca2+ release channels
 Myofibrils made of contractile, regulatory, and close  uptake overpowers release
structural proteins
 Two contractile proteins are myosin (thick
filaments) and actin (thin filaments)
o Myosin has two heads, each with actin-
binding and ATP-binding site, and a tail
pointing away from M-line
o Actin each has myosin-binding site
 Two regulatory proteins tropomyosin and
troponin (both thin filaments)
o Tropomyosin normally covers myosin
binding sites on actin
o Troponin holds tropomyosin in place
 Around a dozen structural proteins
o Titin, each large, flexible molecule
connects Z disc to M line of sarcomere
o A-actinin in Z discs bind to actin
o Myomesin in M line binds to titin and
connect adjacent thick filaments
o Nebulin is nonelastic protein wrapped
around entire length of each thin filament
o Dystrophin links thin filaments to integral
membrane proteins of the sarcolemma,
which are attached to proteins in ECM

MUSCULAR CONTRACTION

Sliding filament model: myosin head attach to and

‘walk’ along thin filaments of both ends of
sarcomere
 1. Sarcoplasmic reticulum releases Ca2+ into
sarcoplasm
 2. Ca2+ binds to troponin
 3. Troponin moves tropomyosin away from NEUROMUSCULAR JUNCTION
myosin-binding sites
 4. Contraction cycle consists of four steps
 I. ATP hydrolysis and energy stored in myosin head
‘cocked’ position, perpendicular relative to thick
and thin filaments
o ADP and phosphate still attached
 II. Cross-bridge, one of energized myosin heads
attaches to actin
o Phosphate released
 III. Power stroke, myosin head pivots from 90 to 45  NMJ is synapse (junction btw neurons or a target
degrees, pulling thin filament cell) btw somatic motor neuron/skeletal muscle cell
o ADP released  Axon ends in synaptic end bulbs, neural part
 IV. Detachment of myosin from actin, only when o Synaptic vesicles with ACh
ATP binds does cross-bridge dissolve  Synaptic cleft between two cells
EXCITATION-CONTRACTION COUPLING  Motor end plate muscular part
 Normally Ca2+ in sarcoplasm very low o Integral transmembrane ligand-gated ion
channels opened by ACh
 o Abundant in junctional folds contract slowly but are more fatigue resistant; fast
 Nerve action potential  voltage-gated Ca2+ opens generate more power but fatigue rapidly
 influx of Ca2+ stimulates exocytosis of vesicles  Oxidative fibers: generally for slow, primarily use
 diffuse across synaptic cleft  two ACh binds to O2 for ATP production (aerobic)  type 1
one receptor on end plate  small cations, most  Glycolytic fibers: generally for fast, high capacity
importantly Na+, flow across  muscle action for ATP production without O2 (anaerobic)  type
potential  ACh broken down rapidly by 2
acetylcholinesterase so effect only lasts briefly  Slow oxidative -> fast oxidative-glycolytic -> fast
glycolytic: diameter small -> intermediate -> large
FORCE PRODUCTION | blood supply rich -> rich -> few capillaries |
 AP -> latent period -> myosin starts binding respiration aerobic -> both -> anaerobic | use
 Single AP = twitch contractions (uncommon) posture and endurance -> walking and sprinting ->
 Multiple AP = normal contraction power movements (e.g. face)
FACTORS REGULATING FORCE PRODUCTION MOTOR UNIT RECRUITMENT
 Motor unit: one motor neuron and all muscle fibers  All three types of fibres present in typical skeletal
it innervates (# varies) muscle, forming mosaic pattern
FACTOR 1. MUSCLE LENGTH  Size principle: motor units always recruited
 Forcefulness of muscle contraction depends on (activated) from small to biggest, or from fatigue
length of sarcomeres within muscle before resistant fibers always first
contraction begins o # recruited depends on force required
 Stretched long (less overlap) or short (thick  Once use fast glycolytic, can’t sustain force long
filaments compressed by Z discs)  less tension
 Resting muscle length (100%, 90 deg.)  optimal CELLS OF THE NERVOUS SYSTEM
overlap  maximum isometric tetanic tension
 Neurons: dendrites, cell body (soma), axon,
presynaptic terminals
 Glial cell types much outnumber neurons
 Astrocytes supply metabolic fuel as lactic acid to
neurons; synthesize neurotransmitters; secrete
trophic factors that promote neuronal survival;
modulate cerebral blood flow; maintain brain’s
extracellular K+ concentration
 Oligodendrocytes synthesize myelin in CNS;
Schwann cells in PNS
 Microglial cells proliferate following neuronal
FACTOR 2. AP FREQUENCY injury and scavengers to remove cellular debris
 Summating AP = summating Ca2+ = summate force STRUCTURE OF NEURON
 Unfused tetanus: myogram valleys because Ca2+  Cell body: surrounds nucleus of neuron and
going back in but release by AP (20-30 Hz) contains organelles
o Many = synchronized motion (common)  Dendrites: tapering processes that contain receptors
 Fused tetanus: tetanic contraction; all troponins for neurotransmitters from adjacent neurons
bound, all cross-bridges activated (60 Hz) o Multiple and short
o ~3-5x greater than max twitch force  Axons: projection from axon hillock (part of cell
body) which adjoints spike initiation zone (initial
segment) where APs generated
o Up to 1m in length
o Cytoplasm contains dense, parallel arrays
of microtubules and microfilament that
rapidly move materials between cell body
and axon terminus
o Can be insulated in myelin breaks in which
are called nodes of Ranvier
FACTOR 3: # OF FIBRES PER MOTOR UNIT
 Three types of motor units exist, based on muscle
fiber types (differ in size and ease of activation)
 Mild contraction  activate some motor units 
connective tissues pulls muscle fibers that aren’t
contracting
SKELETAL MUSCLE FIBER TYPES
 Predisposed distribution: made for running
 Slow and fast fibers (speed of contraction):
dependent on rate of myosin ATPase action; slow
 Presynaptic terminals: axon terminates on target  Integral membrane protein, consisting of large a
cells in multiple terminals subunit and two B subunits
GROUPS OF NEURONS  A subunit has four domains, each of which with six
 Nucleus – collection of cell bodies in CNS transmembrane a-helices
 Ganglion – collection of cell bodies in PNS  Repeats of transmembrane a-helices surround
central pore
NEUROPHYSIOLOGY

RESTING MEMBRANE POTENTIAL

 Potential difference across membrane of excitable
cells at rest. Conventional from intra-extracellular
 RMP established by diffusion potentials
o From concentration differences for various
ions by primary/secondary active transport
o Each permeant ion attempts to drive
membrane potential toward its own
equilibrium potential – highest
permeabilities or conductance = highest
contribution
o K+ and Cl- most, Na+ and Ca2+ less
 RMP falls in range of -70-80 mV
NA-K ATPASE
 Small direct electrogenic contribution based on
stoichiometry of three Na out, two K in
 Greater indirect is maintaining concentration
gradient for K+ across cell membrane  diffusion
potential
ACTION POTENTIALS
 Rapid depolarization followed by repolarization of
membrane potential
 Depolarization: less negative
 Hyperpolarization: more negative
 Inward current: flow of positive charge into cell, REFRACTORY PERIODS
thus depolarize  Absolute: no matter how great stimulus, another AP
 Outward current: hyperpolarizes cannot be elicited due to closure of inactivation
gates
 Threshold potential: membrane potential at which
occurrence of AP is inevitable  Relative: overlaps primarily with hyperpolarizing
afterpotential. Higher K+ conductance so require
 Overshoot: portion of AP where membrane higher Na+ inward but inactivation gates open
potential is positive
 Accommodation: when nerve or muscle depolarized
 Undershoot: portion of AP following repolarization slowly or held at depolarized level, closes
where more negative than rest inactivation gates, Na channels remain closed
 Refractory period: period in which normal AP PROPAGATION OF ACTION POTENTIALS
cannot be elicited  Spread of local currents from active to adjacent
CHARACTERISTICS inactive regions
 Each normal AP for any given cell identical  Active segment of nerve has reversed polarity 
 AP at one site causes depolarization brings adjacent flow of positive charge from active to adjacent
sites to threshold nondecremental inactive region  depolarize to threshold while
 All-or-none phenomenon original has returned to RMP
BASIS OF AP  Conduction velocity increased by:
 1. At RMP, K+ channels almost fully open, Na+ o Increasing nerve diameter: internal
inactivation gates open, activation gates closed resistance inversely proportional to cross-
 2. Inward current  threshold -60mV  rapid sectional area
opening activation gates of Na+ channels o Myelination: lipid insulation of axons that
 3. Inward Na+ current further depolarized increases membrane resistance (current
 4. Repolarization leads to outward K+ current flows along interior, least resistance, rather
o Depolarization  slower closing of membrane, high resistance) and decreases
inactivation gates on Na+ channels membrane capacitance (low-resistance
o Depolarization  opens K+ channels to breaks in sheath that cause membrane to
higher proportion than at rest depolarize faster in response to inward
 5. Hyperpolarization afterpotential because K+ current)
conductance higher than at rest  Nodes of Ranvier every 1-2 mm
THE NERVE NA+ CHANNEL
  Temporal (increased frequency from one o Parasympathetic – conserve energy,
presynaptic neurons) and spatial summation regulate growth
(several synapses to cell body)  PNS somatic – conscious sensation (e.g. cold and
 Excitatory and inhibitory postsynaptic potentials sharp) + voluntary control of muscles
OVERVIEW OF CNS
GENERAL FEATURES OF SENSORY AND MOTOR  Brain composed of cerebrum, brainstem,
 Synaptic relays cerebellum
o Relay nuclei relays nerve impulses from  Cerebrum
one tract to another within CNS o Outer layer cortex, gray matter cell bodies
o Contain several types of neurons including o Inner layers white matter, axons
local interneurons and projection neurons o Divided into two hemispheres
o Prominent in thalamus o Ridges are gyri
 Topographic organization o Valleys are sulci
o Information is encoded in neural maps o Central sulcus – primary motor cortex
o Array of neurons that receive information anterior, primary sensory cortex posterior
from and send information to specific  Cerebral lobes
locations on body, preserved at each level o Sylvian fissure divides frontal and
of CNS, even as high as cerebral cortex temporal
 Decussations o Central sulcus divides frontal and parietal
o Almost all sensory and motor pathways o Parietal, temporal, occipital no clear
bilaterally symmetric borders
o Information crosses from one side to the o Frontal – thinking, planning, motor control
other (contralateral) of brain or spinal o Parietal – integrates all sensory
o Crossings are decussations; some in spinal information
cord and some in brain stem o Temporal – creates and stores new
o Areas in brain that only have decussating memory, involved in emotional regulation,
axons are commissures, e.g. corpus language
callosum o Occipital – visual processing centre
o Some systems such as optic chiasm has  Brainstem
both crossed and uncrossed pathways o Midbrain, pons, medulla
 Types of nerve fibers o Regulates all life preserving functions and
o Classified according to conduction velocity, controls consciousness
depends on largeness and myelination  Cerebellum
o Coordinating smooth, voluntary movement
OVERVIEW OF SPINAL CORD
 31 paired spinal nerves
 8 cervical, 12 thoracic, 5 lumbar, 5 sacral,
coccygeal nerve
 Cell body of motor neuron in anterior horn
 Cell body of sensory neuron in dorsal root
ganglion
 Anterior and posterior nerve root  rami
 Leg and log spinal nerves enter brachial or
lumbosacral plexus  individual peripheral
nerves
LONG TRACTS
 Named because run throughout entirety of CNS
 Motor pathway
o UMN  corticospinal tract  decussates
in medulla  synapse at anterior horn 
LMN  part of peripheral nerve
 Sensory pathway
o 1st to 4th order neurons
o Peripheral nerve  dorsal root ganglion
synapse  decussates in medulla (DC) or
spinal cord (ST)  thalamic synapse 
DIVISIONS OF THE NERVOUS SYSTEM cerebral cortex synapse
 CNS – brain and spinal cord o Spinothalamic tract: pain and temperature
 PNS – cranial nerves (head), spinal nerves (body) o Dorsal columns: vibration and
 PNS autonomic – unconscious sensation (e.g. BP) proprioception
+ involuntary control of functions needed to sustain  After synapsing with 2nd order
life neuron becomes medial lemniscus
o Sympathetic – prepare for conflict
SOMATOTOPY OF CNS
 Point mapping of body part to neuroanatomical area
that continues down entirety of CNS
 Homunculus is pictorial representation of which
area controls which part of body
 Proportional – more precise control = more
neuroanatomical area dedicated

REGIONAL BLOOD SUPPLY

ARTERIAL SUPPLY OF CNS

 Anterior circulation from internal carotid arteries
o Common carotid artery  external carotid
(face) and internal carotid (brain)
o Internal carotid  base of brain 
anterior (medial) and middle cerebral
artery (lateral) THE MENINGES
 Posterior circulation from vertebral arteries – 1/3  Pia mater directly covers brain and spinal cord
of brain, brainstem and cerebellum  Subarachnoid space and arachnoid mater
o Vertebral artery  posterior inferior o SAS contains Circle of Willis vessels and
cerebellar artery  unite in skull to form also CSF
basilar artery  anterior inferior  Dura mater outermost layer
cerebellar artery + superior cerebellar artery o Meningeal dura mater lies on arachnoid 
+ posterior cerebral artery subdural space
 Communicating arteries join Circle of Willis o Periosteal dura mater abuts skull bone 
o Anterior communicating artery joins left epidural space
and right circulation o Potential spaces because may be
o Posterior communicating arteries join pathologically filled
anterior and posterior circulation  CSF produced by choroid plexus in ventricles 
absorbed by arachnoid granulations at subarachnoid
 Venous sinuses between meningeal and periosteal
dura
OVERVIEW OF AUTONOMIC NS
 Preganglionic neuron in CNS, postganglionic
neuron in PNS
 Parasympathetic
o Nuclei of preganglionic arises from
brainstem (III, VII, IX, X) and sacral (S2-
S4)
o Synapse at peripheral ganglia with
postganglionic to allow finer control
  Sympathetic
o Nuclei of preganglionic arises from T2-L3
o Synapse with ganglia in sympathetic chain
or various locations throughout body

THE CORTEX
SPECIALIZED AREAS
 Anterior to motor cortex
o Supplementary motor area and
premotor cortex planning of complex
movements (e.g. writing) before initiated
by motor cortex
o Frontal eye fields controls voluntary eye
movement in horizontal plane, driving
movement in contralateral direction
o Broca’s area produces language both
written and verbal, in front of motor cortex
that controls lips, tongue, larynx
 Posterior to sensory cortex
o Sensory association cortex integrates
various sensory information to make sense
of object
o Wernicke’s area responsible for language
comprehension, proximity to primary
auditory cortex LIMBIC SYSTEM
 Connected by arcuate fasciculus   Regulating emotions and motivations, particularly
damaged = conduction aphasia those related to survival (fear, anger, hunger, sexual
 Cingulate gyrus memory and behavior behavior)
 Learning and memory
 Olfaction and ANS function
COMPONENTS
 Amygdala – relays emotional reactions, esp. to
fear, aggression, anxiety; involved in decision-
making; regulates activity of autonomic nervous
and endocrine systems
 Hippocampus – forming and storing memories,
particularly short- to long-term consolidation
 Fornix – sends projections into hypothalamus
 Hypothalamus – endocrine regulation, autonomic
regulation, sleep/wake
 Cingulate gyrus – regulate pain and emotion,
particularly conscious response to unpleasant
experiences  avoidance of negative consequences
PAPEZ CIRCUIT
 Starts and ends in hippocampus
 Pyramidal cells of hippocampus  fornix 
mamillary bodies (hypothalamus) 
mammillothalamic tract  anterior thalamic
nucleus  anterior limb of internal capsule 
cingulate gyrus  cingulum  entorhinal cortex 
hippocampus
 Commonly affected in Alzheimer and Korsakoff
syndrome
BASAL GANGLIA
 Group of gray matter structures near base of
cerebrum (should be called nuclei)
 Caudate, lentiform nucleus (putamen and globus
pallidus), amygdala, subthalamic nuclei,
substantia nigra
 Framed by genu (rostral) and splenium (caudal) of
corpus callosum
 Dorsal striatum consists of caudate and putamen
 o Separated by internal capsule but gray  Outputs from both pathways are carefully balanced
matter connections give striped appearance  balance in wanted movements and unwanted
 Ventral striatum consists of nucleus accumbens movements  upsetting will lead to parkinsonism
(medial and inferior to head head) and olfactory
tubercles (medial and inferior to nucleus
accumbens)
 Insula grey matter of cortex beside putamen

THALAMUS
 Large relay centre comprising many nuclei
BASAL GANGLIA PATHWAYS  Anatomical classification
 “Gatekeepers” modulate motor and sensory signals o Internal medullary lamina is Y-shaped
back and forth between rest of cerebrum and white matter tract with intralaminar nuclei
brainstem and spinal cord o Separates into anterior, medial, and
o Aid in planning and execution of smooth lateral
movements  Functional classification
o Contribute to affective and cognitive o Specific nuclei project to single, precise
functions neuroanatomical area, all located in lateral
 Almost all areas of cerebral cortex project onto o Nonspecific nuclei project to many areas,
striatum  thalamus  cortex in anterior/medial for emotion and memory
 Indirect pathway: striatum inhibitory to external  Specific nuclei
segment of globus pallidus  inhibitory to o Ventral lateral and ventral anterior
subthalamic nuclei  excitatory to internal segment nuclei receives motor input basal ganglia
of globus pallidus and pars reticula of substantia and cerebellum  premotor cortex
nigra  inhibitory to thalamus  excitatory to o Ventral posterior lateral nucleus receives
motor cortex sensory input from medial lemniscus and
o Overall inhibitory spinothalamic  primary sensory cortex
 Direct pathway: striatum inhibitory to internal o Ventral posterior medial nucleus receives
segment of globus pallidus and pars reticulata of sensory from trigeminal nucleus  primary
substantia nigra  inhibitory to thalamus  sensory cortex
excitatory to motor cortex o Lateral geniculate nucleus receives visual
o Overall excitatory input from retina  occipital cortex
o For both pathways o Medial geniculate nucleus receives
 Inhibitory GABA auditory input from ear  auditory cortex
 Excitatory glutamate o Intralaminar nuclei regulating sleep-wake
 Additional connection: striatum and pars compacta cycle and critical role in consciousness (can
of substantia nigra result in coma if lesions on both sides)
o Dopamine is main transmitter, inhibitory
(D2 receptors) in indirect and excitatory (D1
receptors) in direct pathway
 anterior corticospinal decussates at spinal cord 
cranial nucleus brainstem (face) or anterior horn
spinal (rest of body)  CN or SN is LMN
 F-A-L lateral to medial in cortex  twist to become
anterior to posterior in internal capsule  twist to
medial to lateral
o When decussate, also for sensory, remains
medial to lateral on other side

EXTRAPYRAMIDAL TRACTS
 Do not travel through pyramids of medulla
 Involuntary control and modulation (tone, balance)
THE INTERNAL CAPSULE and originate in brainstem
 Extreme density of neuroanatomical real estate   Rubrospinal tract
devastating if stroke o Red nucleus
 Anterior limb o Fine motor control
o Thalamocortical fibers and corticothalamic o Contralateral innervation
fibers  Reticulospinal tract
 Genu “knee, bend” o Medial – pontine reticular formation
o Motor neurons for face through  Facilitates contraction, increases
corticobulbar tract, facial equivalent of tone
corticospinal tract (motor cortex to CN that  Ipsilateral
innervate face) o Lateral – medullary reticular formation
 Posterior limb  Inhibits contraction, decreases tone,
o First part is corticospinal tract for arms/legs automatic breathing
o Second part is sensory neurons from VPM  Ipsilateral and contralateral
and VPL nuclei of thalamus  Vestibulospinal tract
o Vestibular nuclei
o Balance and posture
o Ipsilateral innervation
 Tectospinal/colliculospinal tract
o Superior colliculus
o Head and eye movement coordination
o Contralateral innervation
SENSORY PATHWAYS
 Spine  adds medially in ST but laterally in medial
lemniscus  decussate at spine (ST) or medulla
(medial lemniscus)  VPM (face) and VPL (arm
and leg)  sensory cortex
 F-A-L medial to lateral (ST) and lateral to medial
(ML) in spine  twist to anterior to posterior in
internal capsule  twist to lateral to medial in
sensory cortex
MOTOR PATHWAYS
PYRAMIDAL TRACTS
 Travel through pyramids of medulla
 Voluntary muscle control
 Cortex  internal capsule  corticobulbar and
lateral corticospinal decussates in brainstem,
 o Changes in light
o For vision
 Chemoreceptors
o Chemical stimuli
o Olfactory receptors in olfactory mucosa,
taste buds in tongue, detection of oxygen
and carbon dioxide in carotid and aortic
bodies, pH of CSF in ventrolateral medulla
 Thermoreceptors
o Changes in temperature
o Cold and warm receptors in skin
 Nociceptors
o Extremes of pressure, noxious chemicals,
SENSORY SYSTEMS or temperature
o Thermal and polymodal nociceptors in skin
SENSORY PATHWAYS SENSORY TRANSDUCTION
 1. Sensory receptors  Stimulus causes change in properties (movement of
o Specialized epithelial for visual, taste, mechanoreceptor, photons cause
auditory, first-order or primary afferent photoisomerization of rhodopsin, chemical
neuron for somatosensory and olfactory stimulants active G proteins)
o Sensory transduction of stimulus into  Ion channels open or close  either net ionic
electrochemical energy current flow inward or outward 
receptor/general potential that if threshold will
o Then series of sensory afferent neurons cause AP
designated named by proximity to receptor RECEPTIVE FIELDS
 2. First-order sensory afferent neurons  Area of body that when stimulated results in change
o Usually has cell body on dorsal root or in firing rate (increase or decrease) of sensory
spinal cord ganglion neuron
 3. Second-order sensory afferent neurons  Receptive fields apply to each order sensory
o Many first synapse with second-order in neurons
relay nuclei (in spinal cord or brain stem) o First-order have simplest receptive fields
 Interneurons in the relay nuclei  Lateral inhibition demonstrated in second-order
may be excitatory or inhibitory neuron helps precise localization of stimulus
o Axonal decussation either at spinal cord or
in brain stem
o Many second synapses with third-order in
relay nuclei in thalamus
 4. Third-order sensory afferent neurons  relay
nuclei in cerebral cortex  fourth-order in sensory
area of cerebral cortex

SENSORY CODING
 Intensity encoded by number of receptors
activated, firing rates of each neuron, different
types of receptors activated

VISION
SENSORY RECEPTORS
TYPES OF RECEPTORS  Visible light 400-750 nm
 Mechanoreceptors STRUCTURES
o Changes in pressure  Three layers
o Pacinian corpuscles in subcutaneous,  Outer: cornea, conjunctiva, sclera
Meissner corpuscles in nonhairy skin (both  Middle: iris and choroid (vascular)
touch), baroreceptors in carotid sinus (BP),  Inner: retina (neural)
hair cells in organ of Corti (audition), and  Also contains lens (focuses light), pigments (absorb
in semicircular canals (vestibular system) light and reduce scatter), and aqueous humor
 Photoreceptors (anterior) and vitreous humor (posterior chamber)
RETINA o Tentacle-like processes that extend into
 Blind spot at optic disc photoreceptor layer to prevent scatter of
 VA highest at central point, macula, light focussed light between photoreceptors
on depression here fovea o Convert all-trans-retinal to 11-cis-retinal
 Rods and cones have cell body, outer segment, and and delivers 11-cis to photoreceptors
inner segment  2. Photoreceptor layer
 3. Outer nuclear layer
o Contains nuclei of photoreceptors
 4. Outer plexiform layer
o Photoreceptors synapse with interneurons,
interneurons synapse as well
 5. Inner nuclear layer
o Contains nuclei of interneurons, including
bipolar cells, horizontal cells, amacrine
cells
 6. Inner plexiform layer
 Rod photoreceptors have low thresholds  higher o Interneurons synapse with ganglion cells,
sensitivity to light interneuron synapse as well
o Night vision and no color vision  7. Ganglion cell layer
o Low acuity and not present on fovea o Nuclei of ganglion cells
o Adapt late to dark  8. Optic nerve layer
o Many rods synapse on single bipolar cell, o Axons of retinal ganglion cells pass through
explaining lower acuity but higher retina and enter optic disc
sensitivity
 Cone photoreceptors have higher thresholds 
lower sensitivity to light
o Day vision and color vision
o Higher acuity and present on fovea
o Adapt early to dark
o Only a few cones synapse on single bipolar
cell, which synapses on single ganglion,
explaining higher acuity but lower
sensitivity

OPTIC PATHWAYS
 Axons from retinal ganglion cells  optic nerve 
optic chiasm  optic tract  lateral geniculate
body (thalamus)  geniculocalcarine tract 
visual cortex
 Nasal hemiretina cross at the optic chiasm and
ascend contralaterally; temporal hemiretina does
not cross and ascends ipsilaterally
 Hemianopia: loss of vision in half of visual field
o Optic nerve: ipsilateral blindness
PHOTORECEPTION o Optic chiasm: bitemporal hemianopia
LAYERS OF RETINA o Optic tract: homonymous contralateral
 Specialized sensory epithelium hemianopia
 Synapses at outer plexiform and inner plexiform o Geniculocalcarine tract: homonymous
layer contralateral hemianopia with macular
 1. Pigment cell layer sparing
o Just inside choroid
o Pigment epithelial cells absorb stray light
AUDITION AUDITORY TRANSDUCTION
 Sound waves  tympanic membrane  chain of
 Sound is produced by waves of compression and ossicles  footplate of stapes into oval window 
decompression related to pressure displaces fluid in inner ear  vibrates off of round
 Sound pressure by decibels (dB) window (closed system)
o dB = 20logP/P0  Amplification to match increased impedance of
 Sound frequency by hertz (Hz) sound waves from air to fluid
 Human hearing between 20-20,000Hz o Lever action of ossicles
 Sound intensity of human speech ~65Hz, >100dB o Concentration of sound waves from large
can damage apparatus, >120dB can cause pain tympanic membrane to small oval window
STRUCTURES OF EAR  Vibration of organ of Corti  bending of cilia on
 External ear: pinna, external auditory meatus hair cells  change in K+ conductance on hair cell
(auditory canal) membrane (increased conductance causes
o Air-filled depolarization because endolymph flips K+
 Middle ear: tympanic membrane (oval and round concentration gradient) because of tip links like a
window), ossicles (malleus, incus, stapes) lever that acts as gate  oscillating receptor
potential (cochlear microphonic potential) 
o Air-filled depolarization opens voltage-gated Ca channels in
 Inner ear: bony labyrinth, membranous labyrinth, presynaptic terminals while hyperpolarization
horizontal, posterior, superior perpendicular closes  intermittent glutamate release (excitatory)
semicircular canals, vestibule, utricle, saccule,  intermittent firing of afferent cochlear nerves
cochlea, scala vestibuli, scala tympani, scala media, ENCODING OF SOUND
o Scala vestibuli and tympani perilymph,  Different frequencies activate different hair cells
similar to ECF  The base of basilar membrane nearest stapes and is
o Scala media endolymph, high K and low narrow and stiff  high frequencies
Na, similar to ICF  The apex is farthest from stapes and wide and
ORGAN OF CORTI compliant  low frequencies
 Mechanoreceptors in basilar membrane
o Inner hair cells: single rows, less
o Outer hair cells: parallel rows, more
 Cilia from receptors embedded in tectorial
membrane
 Cell bodies of CN VIII located in spiral ganglia,
axons synapse at base of hair cells

AUDITORY PATHWAYS
 Cochlear nerves synapse on neurons of dorsal and
ventral cochlear nuclei in medulla
 Some axons cross to contralateral side and ascend
in lateral lemniscus (primary auditory tract) to
inferior colliculus, other axons ipsilateral 
medial geniculate nucleus of thalamus  auditory
cortex
  Because some fibers crossed and uncrossed, both  Detects linear acceleration (gravitational)
ears represented at all levels of CNS  Otolith slides across vestibular hair cells 
o Cochlear lesion: ipsilateral deafness movement of stereocilia toward (depolarization) or
o Central unilateral lesion: hearing loss in away (hyperpolarization) from kinocilium
both ears but not complete deafness  In utricle, tilting head forward or laterally causes
because some fibers have already crossed excitation of ipsilateral utricle; tilting head
backward or medially causes inhibition of
VESTIBULAR SYSTEM ipsilateral
 In saccule, excited by both forward and backward
 Stable visual image and make adjustments in (pitch) and lateral and medial (roll) movements
posture for balance by detecting linear and angular  For every position of head, unique pattern of
accelerations of the head activity from otolith organs that encodes position in
 Semicircular canals and otolith organs filled with space
endolymph and surrounded by perilymph VESTIBULAR PATHWAYS
 At one end of each canal, enlargement ampulla  Vestibular nerves synapse in vestibular nuclei of
containing vestibular hair cells covered by medulla: superior, medial, lateral, and inferior
gelatinous cupula which covers entire cross-section nuclei
 Otolith organs utricle and saccule has otolith  Medial and superior nuclei from semicircular and
(mucopolysaccharides and calcium carbonate project to nerves of extraocular muscles via MLF
crystals) overlying vestibular hair cells  Inferior vestibular nuclei input from otoliths and
VESTIBULAR TRANSDUCTION canals, project to brain stem and cerebellum via
SEMICIRCULAR CANALS MLF
 Detects angular acceleration  Lateral vestibular nucleus from utricles and
 Vestibular hair cells differ from auditory in that project to spinal cord neurons via lateral
have large kinocilium and cluster of stereocilia vestibulospinal tract
 1. If left rotation, horizontal canals and anchored  Vestibular nuclei
cupula also rotate left but endolymph right o Receive input from vision, vestibular, limb
 2. If stereocilia bent toward kinocilia, depolarizes proprioception/skin sensation
and increased firing of afferent vestibular nerves. If VESTIBULAR REFLEX
away, hyperpolarizes and decreased firing  Nystagmus is reflex in response to angular or
o Left rotation = left canal excited and right rotational acceleration of head
canal inhibited o Rotate head  eyes move slowly in
 3. Endolymph eventually ‘catches up’ and cilia opposite direction to maintain constant gaze
return to original neutral positions (‘slow component’)
 4. When stop rotating, events occur in reverse as o Stop rotating  rapid eye movement in
endolymph continues to move same direction as rotation to fix on new
o Stopping left rotation = left canal inhibited position in space (‘rapid component)
and right canal excited o Defined by direction of head’s rotation
 Postrotatory nystagmus is if rotation stopped
abruptly, eyes move in direction opposite that of
original rotation
o Tends to fall in direction of original
rotation (stimulation of contralateral
extensor muscles) because thinks spinning
in opposite direction

CEREBELLUM

 Coordinates movement and smooth actions, fine

motor movement, posture and balance, some motor
learning
o Synergy: rate, range, force, and direction of
movements
 Connected to brain via three cerebellar peduncles
 Three parts
o Vermis (central) controls trunk
o Two hemispheres control ipsilateral limbs
 Three main divisions
o Vestibulocerebellum: vestibular input and
controls balance and eye movements
o Spinocerebellum: spinal cord input and
controls synergy
OTOLITH ORGANS
 o Pontocerebellum: cerebral input and o Trace out a path: ‘finger to nose’, ‘heel to
controls planning and initiation of shin”
movements o Gait: wide based to lower center of gravity
 Three main layers of cerebellar cortex to prevent falls on ipsilateral side
o Granular layer: innermost. Axons of
mossy fibers from spinocerebellar and LEARNING AND MEMORY
pontocerebellar tracts synapse on dendrites
of granule and Golgi type II cells  Learning: ability to acquire new information or
o Purkinje cell layer: contains Purkinje cells skills
o Molecular layer: outermost layer, axons of  Associative learning: connection between two
granule cells form parallel fibers, synapse stimuli
on dendrites of Purkinje cells, basket cells,  Nonassociative learning: repeated exposure to
outer stellate cells, and Golgi type II cells single stimulus causes change in behavior
INPUT TO CEREBELLUM o Habituation: irrelevant stimulus 
 Climbing fiber and mossy fiber systems provide decreased behavioral response
excitatory input to cortex and deep nuclei o Sensitization: noxious stimulus 
 Projections from cortex activate secondary circuits increased behavioral response
 modulate output of cerebellar nuclei  Memory: process by which information acquired
 Climbing fibers originate in inferior olive of through learning is stored and retrieved for recall
medulla and project directly onto Purkinje cells  Declarative (explicit): experiences that can be
(each cell only one fiber). Produces complex verbalized (e.g. facts, objects)
spikes, multiple excitatory bursts. “Condition” o Requires conscious recall
Purkinje cells and modulate responses to mossy o Stored in association areas of cerebral
fiber input cortex
 Mossy fibers majority. From vestibulocerebellar,  Procedural (implicit): motor skills, procedures,
spinocerebellar, pontocerebellar afferents. Project to rules
granule cells in glomeruli, collections of synapses
(each cell up to 250,000 parallel fibers). Produce o No conscious recall
simple spikes. Parallel fibers also cerebellar o Stored in basal nuclei, cerebellum,
interneurons (basket, stellate, Golgi II). Only premotor area
granule is excitatory; basket and stellate inhibit  Short-term: seconds to minutes
Purkinje; Golgi II inhibits granule cells and  Long-term: days to years
indirectly Purkinje  Memory consolidation: process by which short-
OUTPUT OF CEREBELLAR CORTEX term transformed to long-term
 Only output through Purkinje cell, always o Hippocampus crucial in consolidation of
inhibitory because GABA, to deep cerebellar and declarative memories  temporary storage
lateral vestibular nuclei of new long-term memories and transfers to
 Inhibitory output regulates synergy areas of cerebral cortex
 Long-term potentiation
o High frequency of stimulation at synapse
 increased strength of synapse
o Short-term: magnesium ion block removed
 calcium influx  culminate in increased
AMPA trafficking, more sensitive to
glutamate
o Long-term: genetic modification  more
presynaptic terminals, enlargement of
synaptic end bulbs, more dendrites
o Spaced repetition is key
 Plasticity: capability for change associated with
learning

LESIONS LANGUAGE
 In cerebellar ataxia, simultaneous coordination of
muscle movement is impaired  only one muscle  System of vocal sounds and symbols to convey
movement at once information
 Vermis  Wernicke’s and Broca’s only in left hemisphere
o Truncal ataxia  Wernicke’s: temporal lobe, input from primary
o Involuntarily rock body back and forth as visual area (written) and primary auditory (spoken),
try to stabilize themselves interprets written or spoken into thoughts
 Cerebellar hemisphere  Broca’s: frontal lobe, input from Wernicke’s area,
o Ataxia of ipsilateral limb translate thoughts into speech (motor pattern for a
activation of muscles at primary motor area)
BRAINSTEM

 Midbrain, pons, and medulla

 Two white matter connections
o Cerebral peduncle connects brain to spinal
cord and runs throughout entire brainstem
o Cerebellar peduncle (sometimes superior,
middle, inferior) connects spinal cord and
brainstem to cerebellum
CRANIAL NERVES
 Cranial nerves have motor function, sensory
function, and parasympathetic function
 All cranial nerves exit brainstem anteriorly except
CN IV, which leaves posteriorly and wraps around
 CN II, III, VI, XII insert more medially
 Nuclei for neurons of cranial nerves lie in brainstem PROGRESSIVE MUSCULAR DYSTROPHIES
 One nucleus for every neuron type in each CN
(motor, sensory, parasympathetic) RISK FACTORS
o But nuclei can be shared between nerves  Only males in Duchenne (DMD) and Becker
 Functions (BMD)
 CN I: olfaction  DMD: 2-5 years
 CN II: vision  BMD: adolescence or early adult, usually >15 years
 CN III: lift eyelid, all eye movements except those ETIOLOGY
of CN IV and CN VI, pupil constriction  DMD and BMD are X-linked recessive
 CN IV: inferior eye movement  Chromosomal mutations affecting dystrophin gene,
 CN V: mastication, facial sensation, corneal reflex, largest known protein-coding gene, on short arm of
jaw jerk reflex X chromosome (Xp21)
 CN VI: eye abduction o DMD: frameshift deletion or nonsense
 CN VII: facial expression, taste from anterior 2/3 mutation  shortened or absent dystrophin
tongue, tear and saliva production, corneal reflex protein
 CN VIII: balance and hearing o BMD: in-frame deletion  partially
functional dystrophin protein
 CN IX: talking and swallowing, taste from posterior PATHOPHYSIOLOGY
1/3 of tongue, saliva production (parotid)
 Dystrophin protein:
 CN X: talking and swallowing, throat sensation,
internal organ parasympathetic o Connecting cytoskeletal actin filaments to
membrane-bound a- and B-dystroglycan,
 CN XI: shoulder shrug and head turn which are connected to extracellular
 CN XII: tongue movement laminin
 Dystrophin gene:
o Due to size at increased risk of mutation
o Alterations of protein structure  partial
(BMD) or almost complete (DMD)
impairment of function  disturbs
numerous cellular signaling pathways 
necrosis of affected muscle cells 
replacement with connective and fatty
tissue  affected muscles are weak even
though appear larger
CLINICAL PRESENTATION
 Progressive muscle paresis and atrophy
o Starts in proximal lower limbs, pelvic
girdle
o Extends to upper body and distal limbs
 Weak reflexes
 Waddling gait
 Gower maneuver
o From prone to standing position by
supporting themselves on thighs then using
hands to ‘walk up’ body until upright
 Calf pseudohypertrophy
 Delayed motor milestones  inability to walk by
~12 years of age
BMD  Ocular myasthenia: only in extraocular and/or
 Similar symptoms but less severe eyelid muscles
 Slower progression (remain ambulatory into adult  Generalized myasthenia: all skeletal muscles may
life) be involved, esp. ocular, bulbar, limb, respiratory
 Heart involvement more common compared to RISK FACTORS
DMD  3:2 females to males
DIFFERENTIAL  Males peak incidence 40-70
 Facioscapulohumeral muscular dystrophy  Females peak incidence 20-40
o Face, scapula, upper arms ETIOLOGY
 Limb-girdle muscular dystrophy  Autoreactive antibodies against postsynaptic ACh
o Pelvic and shoulder girdle muscles receptors or receptor-associated proteins
DIAGNOSIS  Association with other autoimmune:
 Bloodwork o Hashimoto thyroiditis, RA, sarcoidosis,
o Increased creatine kinase in almost all SLE
affected individuals, in >50% of carriers  Association with other conditions:
o Increased serum aldolase o Thymoma in 10-15% of patients
 Genetic analysis confirmatory o Thymic hyperplasia in 65% of patients
o Dystrophin gene mutation o Graft-versus-host reaction after allogeneic
 Muscle biopsy stem cell transplantation
o If genetic analysis inconclusive PATHOPHYSIOLOGY
o Muscle fiber diameter changes  Muscle-like (myoid) cells in thymus express AChR
o Absent dystrophin DMD  autoreactive targeting by T cells  production
o Reduced dystrophin BMD of antibodies against postsynaptic AChRs of NMJ
o Later: necrosis of muscle tissue and o Only affects skeletal because nicotinic
replacement with connective and adipose o Muscarinic (parasympathetic) and
TREATMENT adrenergic (sympathetic) cholinergic in
 Medical therapy both cardiac and smooth muscle
o DMD: glucocorticoids (prednisone,  Competitive inhibition of ACh AND AChR decay
deflazacort) through receptor internalization (decreased receptor
o BMD: glucocorticoids less effective density at postsynaptic membrane) AND activation
 Supportive therapy of complement (muscle cell lysis)  impaired NMJ
o Physiotherapy to reinforce preserved signal transduction  skeletal muscle weakness
muscles, including respiratory, and prevent and fatigue
contractures CLINICAL PRESENTATION
o Orthopedic assistive devices such as  Fatigable weakness of skeletal muscles
wheelchair, walkers (need to do with o First small muscles for fine movements
physiotherapy, compression stockings, limb o Larger muscles later
movement to prevent immobility  Eye muscle weakness (often initial)
consequences DVT, flexure contraction) o Ptosis, diplopia, blurred vision
o Psychological support  Bulbar muscle
o Ventilation support o Slurred speech
COMPLICATIONS o Difficulty chewing and/or swallowing
 Cardiac and respiratory muscle involvement  Proximal limb weakness
o Dilated cardiomyopathy o Rising from chair, climbing stairs, brushing
o Cardiac arrhythmias hair
o Respiratory insufficiency o Deep tendon reflexes not affected
 Cardiac and respiratory failure common cause of  Respiratory muscle weakness
death (more cardiac in BMD) CLINICAL COURSE
 Neurologic or behavioral issues because dystrophin  Worsen with increased muscle use throughout day
also found in brain and improves with rest
 Late stage  Potential exacerbating factors:
o Nocturnal hypoventilation o Medications (muscle relaxants, beta
o Dysphagia blockers, benzodiazepines)
o Vomit o Pregnancy
o Constipation (decreased BM) DIAGNOSIS
o Diarrhea (feces stuck but fluid can get  General approach
around it) o Suspected cases of MG generally
confirmed via EMG and AChR antibodies
MYASTHENIA GRAVIS o Chest CT to rule out thymoma
 Labwork
 Autoimmune neuromuscular disease characterized o AChR antibody test
by generalized muscle weakness
  80-90% of patients with Treatment
generalized MG have antibodies o IVIg (B cells have receptor for Fc portion
 100% of patients with thymoma of Ig, inhibits antibody production)
have antibodies o Plasmapheresis, early endotracheal
o Seropositive MG: positive assays for intubation
antibodies against AChR-Ab  Mimics cholinergic crisis, can help differentiate
o Seronegative MG: negative for AChR with history (toxidrome vs. progressive)
antibodies, may be positive for muscle- NEWBORNS
specific tyrosine kinase antibodies  Autoantibodies can cross maternal placenta 
 Electrodiagnostics cause MG in newborn that lasts as long as the
o Decremental response following repetitive antibodies do in blood
nerve stimulation
o With prolonged muscle use, post-synaptic LAMBERT-EATON MYASTHENIC SYNDROME
receptor destruction. With rest, opportunity
to build up membrane again PATHOPHYSIOLOGY
 Imaging  Paraneoplastic, associated with SCLC in 2/3 of
o Every newly diagnosed MG patient to rule cases
out thymoma  Associated with autoimmune diseases
 Other tests  Autoantibodies against presynaptic voltage-gated
o Edrophonium test (Tensilon test) Ca channels  decreased Ca influx  decreased
 Before AChR antibody test ACh release into NMJ
available CLINICAL FEATURES
 Symptoms rapidly improve after  Starts with proximal muscle weakness
administration of short-acting  Reduced or absent reflexes
acetylcholinesterase inhibitor  Autonomic symptoms
o Simpson test o Dry mouth
 Positive if looking upward for >1 o Constipation
minute without lifting head
provokes eyelid fatigue o Erectile and ejaculatory dysfunction
DIAGNOSIS
o Ice test
 Main distinguishing from MG:
 Ice pack placed on one eye for 5
minutes  temporary improvement o Lambert sign: patient’s muscle strength
of eyelid fatigue improves with repetitive or ongoing use
DIFFERENTIAL DIAGNOSIS (e.g. squeeze examiner’s hand)
 Lambert-Eaton myasthenic syndrome o EMG: repetitive nerve stimulation results
 Cavernous sinus thrombosis in incremental responses
 Brainstem gliomas  Reflexes improve with active muscle contraction or
repeated muscle tapping
 Multiple sclerosis
 Serologic detection of anti-VGCC antibodies
 Botulism (botox can cause temporary ptosis) TREATMENT
 PM and DM  Treatment of underlying therapy
 Dystrophy  First-line amifampridine
TREATMENT
PHARMACOTHERAPY o Blocks presynaptic K channels  increased
AP durations  increased presynaptic
 First-line cholinesterase inhibitors calcium concentrations
o Pyridostigmine drug of choice
o Only improve symptoms (no causal
treatment) APPROACH TO MYOPATHIES
 Supplemental immunosuppressants if symptoms
persist despite anticholinesterase treatment (mostly
reduce autoab production, also reduce complement)
o Glucocorticoids
o Azathioprine, cyclosporine, mycophenolate
SURGERY
 Thymectomy, can be beneficial even if thymoma is
not present, but not for seronegative
COMPLICATIONS
MYASTHENIC CRISIS
 Acute, life-threatening exacerbation of myasthenic
symptoms leading to respiratory failure
 Most commonly 8-12 months after onset
 Etiology
o Infection, surgery, anesthesia, pregnancy,
medications
 of distal segment cytoskeleton with
dissolution of axonal membrane,
degradation of residual myelin sheath,
ultimately cell body sprouts regenerative
nerve fibers that ideally reinnervate distal
tissues
 Regeneration more efficient in PNS
than CNS
o Good chance of at least partial recovery
 Neurotmesis
o Complete nerve transection
o Chances of recovery poor without surgical
repair
DIAGNOSIS
 Imaging
o X-ray: compression or transection due to
dislocated bone or fracture
o CT/MRI: nerve tumors, focal soft tissue
pathologies
 Electrodiagnostics
o Detect and grade nerve injury, identify
early stages of recovery
o Muscle’s electrical activity in response to
stimulation of supplying nerve
TREATMENT
 Expectant management
 Statins are common for toxic  Activity modification (avoid activities that increase
likelihood of further nerve injury), physiotherapy
PERIPHERAL NERVE INJURIES  Splinting
 Drugs
MECHANISM OF INJURY o Chronic neuropathic pain with gabapentin
 Stretch-related (most common), lacerations, or other analgesics
compressions  Surgical repair indications
 From systemic diseases (DM, autoimmune) or o Open, non-contaminated sharp injuries and
localized damage (trauma, tumors) concomitant vascular injuries  immediate
 Isolated neurological conditions or in association exploration and repair
with soft tissue, vascular, and/or skeletal damage o Open, contaminated injuries and
CLASSIFICATION postreduction palsy  early surgical
 Useful for determining prognosis and choosing exploration and repair (3 weeks)
treatment strategy o Without clinical or electromyographic signs
 Neuropraxia of spontaneous recovery  delayed
o Local myelin damage causing disruption of surgical exploration and repair (3 months)
conduction mostly secondary to  Procedures
compression o Nerve repair (neurorrhaphy) for continuity
o Whole nerve remains structurally intact o Nerve transfer
o Good prognosis with complete recovery of
nerve function CARPAL TUNNEL SYNDROME
 Axonotmesis
o Damage to axon and potentially  Most common entrapment neuropathy in upper
perineurium but epineurium remains intact extremity
o Central chromatolysis: reaction of RISK FACTORS
neuronal cell body to axonal injury   Previous fracture of distal radius (most important)
increase in protein synthesis to help restore  Traumatic dislocation of lunate
integrity of axon  swelling of neuronal  Manual work  vibrating tools or prolonged,
body, dispersion of Nissl bodies (RER of forceful, repetitive flexion/extension of wrist
neurons), and displacement of nucleus to  RA and other chronic inflammation of tendon
periphery sheaths
o Wallerian degeneration: reactive neuronal  Pregnancy and puerperium: hormone-mediated
degeneration process to axonal injury  weight gain and edema of wrist
clears axonal debris and prevent scarring,  OA
facilitate targeted reinnervation and  Systemic amyloidosis
functional recovery of tissues innervated  Renal failure due to dialysis-associated deposition
before injury  progressive degeneration of amyloid
  Diabetes o Potential NSAIDs for pain
PATHOPHYSIOLOGY o Steroid injection
 Carpal tunnel is narrow fibro-osseous structure at o Short-term oral glucocorticoid therapy
palmar aspect of wrist  More severe or refractory
o Delimited by carpal bones and transverse o Open or endoscopic release of transverse
carpal ligament carpal ligament
o Contain flexor tendons and median nerve
 Pressure increase within tunnel  compression of GUILLAIN-BARRE SYNDROME
contained structures (mechanical can directly lead
to injury)  impaired blood flow and altered  Acute postinfectious polyneuropathy characterized
microvascular structure of median nerve (indirect by symmetric and ascending flaccid paralysis
mechanism)  inflammatory reaction  edema RISK FACTORS
and hypoxia  axonal degeneration  Adults > children
CLINICAL PRESENTATION  1.5 times more likely in men
 Mild to moderate ETIOLOGY
o Paresthesia (burning, tingling), loss of  2/3 experience symptoms of upper respiratory or GI
sensation/numbness, pain tract infection 1-4 weeks prior
 Palmar surface of thumb, index and  Associated pathogens
middle fingers, radial ring finger
o Campylobacter enteritis most common
o Symptoms worsen at night (hand goes into overall
position that flexes wrist)
o Cytomegalovirus most common virus
o Usually no loss of sensation to palmar
surface of thenar eminence because o Zika virus, Epstein-barr, HIV, influenza
innervated by superficial branch which  Vaccines may cause
arises 5-7cm proximal to carpal tunnel PATHOPHYSIOLOGY
 Moderate to severe  Autoimmune reaction that generates cross-reactive
o Weakened pinch and grip  dropping antibodies due to molecular mimicry
objects o Antigenic resemblance between pathogens
o Thenar atrophy and impaired thumb and normal cells
opposition  Autoantibodies against gangliosides or other
DIAGNOSIS unknown antigens of peripheral Schwann cells 
 Combine two or more provocative tests to improve immune-mediated segmental demyelination 
specificity of diagnosis AND may have axonal degeneration of motor and
sensory fibers in peripheral and CNIII-XIII
 Provocative tests, reproduce/worsen symptoms if:
 Schwann cells then remyelinate peripheral nerve
o Hand elevation test: hold hand above head axons
for ~2 minutes. Highest sens/spec CLINICAL PRESENTATION
 Driving good question to ask
 Initial
o Carpal compression test: moderate
compression with finger over proximal o Back and limb pain
edge of carpal tunnel o Symmetric paresthesia affecting distal
o Phalen test: patient’s wrist in full flexion extremities
for 1 minute. Highly specific  Moderate
o Tinel sign: percussion over carpal tunnel o Ascending paralysis
leads to shooting pain and/or tingling in  Bilateral flaccid paralysis (no
areas voluntary movement + muscle
o Flick test: in response to symptoms, flick weakness)
to ‘open up’ the carpal tunnel  From lower to upper limbs in
stocking-glove distribution
 Electrophysiological tests:
o Reduced or absent muscle reflexes starting
o Nerve conduction studies: prolongation of in lower limbs
distal motor and sensory latency.
Confirmatory o Neuropathic pain
o Electromyogram: decreased activity,  Advanced
potentials with large amplitude o Landry paralysis
 Do TSH in people esp. if people have bilateral  Respiratory muscles  failure
carpal tunnel syndrome, most of time elevated due o Autonomic dysfunction
to non-central hypothyroidism  Arrhythmia or BP dysregulation
TREATMENT  Voiding or intestinal dysfunction
 Conservative o CN involvement
o Immobilization of wrist with splint during  Facial diplegia due to frequent
night bilateral facial nerve involvement
 Course
o Ergonomics – if workplace injury, WSIB
not OHIP o Disease progression peaks 2-4 weeks after
onset of symptoms
 Drugs
 o Then recede in reverse order of Pathology often proximal (disc or osteophyte).
development See table
DIAGNOSIS  Mononeuropathy: damage to single nerve or nerve
 CSF group by trauma, injury, local compression,
o Albuminocytologic dissociation: elevated prolonged pressure, or inflammation. Asymmetric
protein levels (impaired CSF resorption) and localized weakness, loss of sensation, or
and normal WBC paresthesia to area that nerve innervates.
o CSF cell counts higher than 50 cells/uL Pathology often distal. But does not affect entire
indicate that GBS is unlikely myotome/dermatome like in radiculopathy; only
 Serological screen areas distal to injury is affected
o Potential pathogens o Carpal tunnel syndrome (most common)
o Antibodies against gangliosides o Axillary nerve dysfunction (loss of
 Electroneurography movement or sensation in shoulder)
o Demyelinated o Common peroneal nerve dysfunction (loss
 Muscle strength unaffected of movement or sensation in foot and leg)
 Slower conduction o Cranial mononeuropathy III (eyelid droop,
o Axonal pupil widened and may not narrow in
 Less muscle strength because less response to light), IV (paresis of vertical
fibres can be recruited gaze, mainly in adduction), VI (double
 Speed unaffected vision), VII (facial paralysis)
o Can help to separate from botulinum toxin, o Femoral nerve dysfunction (loss of
NMJ pathology, hypokalemia movement or sensation in part of leg)
 Electromyography o Radial nerve dysfunction (problems with
o Signs of denervation movement in arm and wrist and sensation
o Pathologic spontaneous activity is in back of arm or hand)
unfavorable prognostic sign o Sciatic nerve dysfunction (paresis and loss
TREATMENT of sensation along myotome/dermatome)
 Supportive management o Ulnar nerve dysfunction (cubital tunnel
o Monitor cardiac and respiratory function, in syndrome – numbness, tingling, weakness
some cases ICU and intubation of outer and underside of arm)
 Intravenous immunoglobulins  Polyneuropathy: damage to multiple peripheral
o Fc fragments of IgG presumably interact nerve fibers not belonging to same nerve group.
with immune cells to normalize reaction Symmetric symptoms: distal sensory loss (glove
through unknown mechanism and stocking pattern) with or without
neuropathic pain, paresthesia (including pins-
 Plasmapheresis and-needles or insect crawling sensation), and
o In adults, equivalent outcome as IVIg motor weakness. Uniquely sensory ataxia
o In children, only recommended with rapidly (drunk-like) caused by loss of sensation,
progressing or severe disease particularly proprioception, that affects afferent
COMPLICATIONS limb of postural reflexes. Decreased deep tendon
 Respiratory paralysis, pulmonary reflexes. Pathology is systemic. See table
infection/embolism, cardiac dysfunction
AXONAL VARIANT MULTIPLE SCLEROSIS
 Acute motor and sensory axonal neuropathy, acute
motor axonal neuropathy, and pharyngeal-cervical-
brachial weakness  Chronic degenerative CNS disease caused by
 Molecular mimicry of human gangliosides by immune-mediated inflammatory process
pathogen’s lipooligosaccharides for Campylobacter ETIOLOGY
jejuni-associated GBS  Genetic predisposition
 More rapid progression of weakness  prolonged o HLA-DRB1*15 allele increases risk
paralysis and respiratory failure over few days o HLA-A*02 allele protects
 Autoantibody classification and serial o 3-4% concordance among first-degree
electrophysiology cardinal approaches to relatives
differentiate axonal GBS from prototypical AIDP  Environmental risk factors
o Low vitamin D levels
MONO VS. POLY VS. RADICULONEUROPATHIES o Smoking
o Pathogens: EBV, HHV 6
 Radiculopathy: usually involves one spinal nerve RISK FACTORS
root distribution following ‘myotomal’ and  Females:males 3:1
‘dermatomal’ distribution patterns. May have back  20-40 years
pain. Paresthesia or pain along affected  Increased prevalence among white population
dermatome; muscle weakness or atrophy along PATHOPHYSIOLOGY
affected myotome. Loss of deep tendon reflexes. INITIATION
  Initiation of immune responses by reactivity o Disconjugate, lateral gaze nystagmus in
between microbial antigens and autoantigens, or contralateral eye
priming autoimmune response by strong  Patchy sensation loss from cortex lesions (instead
inflammatory stimulus  ultimately unknown of peripheral nerve distribution)
mechanism  Demyelination of spinal cord tracts
o Initial event in CNS  release of CNS o Shooting electric sensation travelling down
antigens to periphery (drainage to lymph spin upon flexion of neck (Lhermitte sign)
nodes or active carriage by APCs)  o Pyramidal tract lesion  UMN lesion
autoimmune response generated in context symptoms
of proinflammatory environment o Dorsal spinal column first sensory tract to
o Initial event outside CNS  aberrant be affected  loss of vibration and fine-
immune response against CNS touch, numbness and paraesthesia, sensory
 Tissue damage  release of antigens to periphery ataxia involving trunk or one or more limbs
 new immune responses in lymphoid tissue  o Neuropathic pain
more invasion into CNS o Absent abdominal reflex
PROGRESSION  Cerebellar involvement
 Contribution of peripheral immune system o Charcot neurological triad: scanning
decreases and confined to CNS speech, nystagmus, intention tremors
 Focal to diffuse white matter injury caused by  Cranial nerve palsies, sparing of caudal cranial
lymphocytic and monocytic infiltrates, microglia nerves (9-11)
activation, damage or dysfunction of astrocytes  o Diplopia
demyelination with partial preservation of axons o Trigeminal sensory neuralgia
(acute plaques), axonal loss (chronic plaques),
and astrocytic gliosis o Facial palsy
 Mechanisms of axonal loss: mitochondrial  Changes in mental state (late)
dysfunction, loss of myelin trophic support o Depression, emotional changes
 Axonal loss main mechanism of permanent  Exacerbation of neurological symptoms with
disability body temp because decreases impulse conduction
BRAIN ATROPHY in demyelinated nerves
 Brain atrophy starts as early as after first o Reversible exacerbation of neurological
demyelinating event and progresses slowly in symptoms following increase in body temp,
relapsing-remitting course e.g. exertion, bath, fever (Uhthoff
o Accelerates in progressive phenotype phenomenon)
STAGES
o Aggressive phenotype also characterized by
chronic inflammation that occurs with  RR-MS
intact blood-brain barrier driven by immune o Exacerbations occur
cells compartmentalized in leptomeninges o Symptoms remit almost completely
and perivascular spaces between exacerbations
PATHOLOGY TO CLINICAL FEATURES o 90% of patients
 Location and extent of acute inflammatory  Secondary progressive
demyelinating lesion o Exacerbations occur
 Clinical deficits may be reversed by: o Continuous worsening of symptoms in
 Restored nerve conduction: more continuous than between exacerbations
saltatory because demyelinated axonal membrane o Arises from RR-MS
several changes such as increase in Na channels   Primary progressive
thinner and shorter myelinated internodes upon o Exacerbations occur
remyelination o Continuous worsening of symptoms from
 Cortical plasticity: reorganization of functional very onset of disease
activation of cortical regions to maintain clinical o 10%
function DIAGNOSIS
CLINICAL PRESENTATION  Plain MRI
 Constitutional  Multiple sclerotic plaques most commonly
o Fatigue, headache periventricular white matter with finger-like radial
 Optic neuritis extensions from demyelination and reactive gliosis
o Most often earliest manifestation o T1: hypo/isointense; severe demyelination
o Unilateral, can be painful and axonal destruction  black hole
o Impaired vision, color blindness, RAPD lesions
(Marcus Gunn pupil) o T2 and FLAIR: hyperintense
 Internuclear ophthalmoplegia due to lesion in  Contrast MRI
medial longitudinal fasciculus o Enhancement of active lesion up to 6 weeks
o More frequently bilateral after exacerbation
o Ipsilateral medial rectus weakness but  CSF examination
intact convergence reflex o Lymphocytic pleocytosis
 o Increased myelin basic protein o RR-MS: low- and intermediate efficacy
o OGC bands from extra production of IgG (glatiramer acetate, IFN-B), high efficacy
subfractions with absence in blood (natalizumab, ocrelizumab, alemtuzumab)
PROGNOSTIC FACTORS FOR PROGRESSION o SP-MS: IFN-B, siponimod, ocrelizumab
 Male, age > 40, multiple symptoms with early o PP-MS: ocrelizumab, supportive therapy
motor and cerebellar involvement, black hole DISEASE-MODIFYING MS THERAPY
lesions and OGC bands in early stages of disease,  IFN-B (SC): suppresses T cell activity  decreased
incomplete recovery after relapses, high relapse in cytokines and lymphocyte invasion of CNS
first two years after MS onset  Glatiramer acetate (SC): decoy for T cells instead of
REVISED MCDONALD CRITERIA neuronal myelin, decreases activity of Th1
 Based on dissemination in time (DIT, new lesions lymphocytes
over time) and space (DIS, lesions in different  Siponimod (PO): selective agonist of subtypes 1
regions) and 5 of sphingosine-1-phosphate receptors that
 DIT cause sequestration of lymphocytes in lymph nodes
o >=2 exacerbations at least 30 days apart  Alemtuzumab (SC/IV): ab against superficial
o If not only one exacerbation: antigen CD52, found on T, B, NKT, and monocytes
o MRI demonstrates both enhancing and  B and T cells decrease drastically
nonenhancing lesions at any time OR new  Natalizumab (IV): ab against a4-integrin 
hyperintense T2 or enhancing lesion on FU decreases lymphocyte invasion of CNS
o Alternatively positive CSF OGC bands  Ocrelizumab (IV): ab against Cd20 that depletes
with no serum OGC bands premature and mature B cells
 DIS INDICATIONS
o >=2 lesions with objective clinical evidence  IFN-B: all forms
(i.e. correlation with symptoms, e.g. T2  Ocrelizumab: RR-MS, SP-MS, PP-MS
hyperintensities in regions corresponding to  Glatiramer, alemtuzumab, natalizumab,
somatosensory tracts or abnormal ofatumumab, mitoxantrone, dimethyl fumarate,
somatosensory evoked potentials in patient fingolimod: RR-MS
who reports sensory loss)  Siponimod, ozanimod: CIS, RR-MS, active SP-
o If only 1 lesion with objective evidence: MS
o Need clear history of previous exacerbation SUPPORTIVE THERAPY
with lesion in distinct CNS location, OR  Spasticity: dantrolene, baclofen, tizanidine,
o One or more hyperintense lesions on MRI physiotherapy
in T2 sequence in at least 2 of following  Tremors: carbamazepine, primidone
regions: periventricular, juxtacortical,  Painful paresthesia: anticonvulsants (e.g.
infratentorial, spinal carbamazepine), tricyclic antidepressants (e.g.
amitriptyline)
 Urinary retention: intermittent catheterization and
parasympthomimetic drugs
 Urinary incontinence: parasympatholytic agents

UMN VS. LMN LESION


UMN typically above anterior horn cell of spinal
cord or motor nuclei of cranial nerves
o No atrophy, fasciculations
 Spastic paresis: inability of voluntary movement
AND increased tone/clonus, decreased power in
muscle groups, hyperreflexia
o Detrusor hyperreflexia
TREATMENT o Upgoing Babinski (positive): big toes point
 Begin treatment as early as possible to treat primary upward while others fan out and downward
exacerbation, prevent further exacerbations, slow  LMN between anterior horn of spinal cord and
down disease process relevant muscle tissue
 Treatment of acute exacerbations o Atrophy and fasciculations
o High-dose IV methylprednisolone 3-5  Peripheral paresis: inability of voluntary
days movement AND decreased tone, decreased power
 Prophylaxis against side effects: in single muscle fibers, hyporeflexia
PPIs to prevent gastritis and LMW o Overflow incontinence
heparin for thromboprophylaxis o Downgoing (negative): all toes neutral or
o Second-line plasmapheresis point downward
 Prevention of exacerbations CAUSES
o Clinically isolated syndrome: interferon  UMN: MS, tumor, stroke, B12 deficiency
therapy (IFN-B), glatiramer acetate  LMN: peripheral neuropathy, poliomyelitis
  ALS has both UMN and LMN signs o Spine MRI – gadolinium-enhancing signal
abnormality usually extending over one or
TRANSVERSE MYELITIS more cord segments
 Often swollen at affected levels
 Acquired neuro-immune spinal cord disorder either o CSF analysis – pleocytosis and/or elevated
independent or continuum of neuroinflammatory IgG index
disorders: acute disseminated encephalomyelitis,  In total order cell count and
MS, MOGAD, neuromyelitis optica spectrum differential, protein, glucose,
disorder, and acute flaccid myelitis VDRL, OGC, IgG index, cytology
ETIOLOGY  Differentiate between idiopathic vs. secondary
 CNS autoimmune conditions: MS, NMOSD, o CNS inflammatory demyelinating
ADEM, MOGAD disorders, systemic inflammatory disorders,
 Systemic autoimmune conditions: sarcoidosis, infectious causes, paraneoplastic
Sjogren syndrome, SLE syndromes, deficiency syndromes
 Less common: ankylosing spondylitis, APS, mixed DIFFERENTIAL DIAGNOSIS
CTD, Behcet, RA, systemic sclerosis  Non-inflammatory
 Idiopathic TM o Vascular myelopathies (anterior spinal
o 30-60% cases, associated with respiratory, artery infarction, spinal-dural AVF,
GI, or systemic illness (e.g. viral infection, fibrocartilaginous embolism)
paraneoplastic) o Metabolic and nutritional myelopathies
o In infectious may be due to molecular (B12, E, copper deficiency, NO toxicity)
mimicry and super antigen o Neoplasms (intramedullary primary spinal
RISK FACTORS cord tumor, primary CNS lymphoma,
 Bimodal peak 10-19 and 30-39 intravascular lymphoma)
 No gender predisposition  Acute flaccid myelitis
PATHOPHYSIOLOGY  GBS
 Autoantibodies  perivascular infiltration of TREATMENT
monocytes and lymphocytes  damage to myelin,  Acute idiopathic: high-dose IV glucocorticoid as
axons, and oligodendrocytes soon as possible without waiting for workup
CLINICAL FEATURES  Plasma exchange if patient also has motor
 Localized pathology = muscle groups innervated impairment and in CNS demyelinating diseases that
below corresponding spinal cord level but normal fail to respond to steroids
above o Five treatments, 1.1-1.5 plasma volumes,
 Motor every other day for 10 days
o Rapidly progressing paraparesis (partial  Recurrent idiopathic TM: chronic
paralysis of lower limbs) that may affect immunomodulatory therapy, e.g. with
upper limbs (depending on location) with mycophenolate
initial flaccidity by spasticity if caused by  Acute and recurrent secondary: attacks treated
white matter damage, flaccid if grey matter with high-dose IV glucocorticoids. Treat underlying
 Sensory PROGNOSIS
o Pain, dysesthesia, and paresthesia  If gets better within first 12 weeks, more likely to
 Autonomic symptoms get complete recovery
o Urinary retention, bladder and bowel  Most idiopathic at least partial recovery beginning
incontinence, inability to void or bowel 1-3 months, continues with exercise and
constipation, sexual dysfunction rehabilitation therapy, and monophasic disease
 Suspect TM when acute or subacute signs and  Recurrence more likely if associated with another
symptoms of motor, sensory, and/or autonomic disease, especially autoimmune
dysfunction localizing to one or more contiguous
spinal cord segments with no evidence of PARKINSON’S DISEASE
compressive cord lesion
DIAGNOSIS  Neurodegenerative movement disorder
 Most important: sensory, motor, or autonomic  Parkinsonism: syndrome of bradykinesia and either
dysfunction related to spinal cord; T2 hyperintense resting tremor or rigidity (or both)
signal change on MRI; no evidence of compressive o Caused by PD, other neurodegenerative
cord lesion diseases, secondary causes
 Research purposes: bilateral signs/symptoms, ETIOLOGY
clearly defined sensory level, inflammation defined  Parkinson’s is idiopathic with genetic factors
by CSF pleocytosis, elevated IgG index, or MRI o Glucocerebrosidase (GBA mutation): most
enhancement, progression to nadir in 4 hours to 21 common genetic risk factor for all PD cases
days  altered autophagy and lysosomal
 Determining if myelopathy is inflammatory function  potentially impairment of a-
synuclein clearance
 o Dardarin (LRRK2 mutation): most common  Sleep disorders
cause of dominantly inherited PD o Acting out dreams during REM phase of
o Parkin (PARK2 mutation): most common sleep
cause of recessively inherited PD o Restless leg syndrome, excessive daytime
o a-Synuclein (SNCA mutation) sleepiness
 Secondary parkinsonism  Mood disorders
o Medication (drug-induced parkinsonism) o Depression, apathy, anxiety
with antidopaminergic effects or MPTP CLINICAL STAGE (MOTOR SIGNS)
(damages substantia nigra)  Parkinsonism
 Most frequent cause o Bradykinesia: reduction in speed and
 Typical antipsychotics amplitude of voluntary movement
(haloperidol), some antiemetics o Resting tremor: 4-6 Hz, pill-rolling tremor
(metoclopramide), some Ca subsides with voluntary movements but
channel blockers (flunarizine), increases with stress
amiodarone, valproate, lithium  Commonly hands, may involve
o Metabolic legs, jaws, lips, tongue
 Wilson disease, hemochromatosis o Rigidity: increase in muscle tone
o Toxins throughout range of movement
 Manganese, CO, CS2  Smooth and consistent – lead pipe
o CNS infections  Ratchet-like – cogwheeling
 Viruses (herpes simplex, HIV), (thought to be due to overlay of
bacteria (t. pallidum), protozoa (t. increased tone and resting tremor)
gondii), prion agents (Creutzfeldt-  Subclinical may be elicited if
Jakob disease) perform repetitive movements in
ATYPICAL PARKINSONISM other extremity (Froment
 Parkinson plus: neurodegenerative diseases that maneuver)
present with parkinsonism and a variety of  Postural instability
additional features o Imbalance and tendency to fall
 Consider if does not respond to levodopa treatment, o Pull test: moderately pulls shoulders back
dementia progresses rapidly, or gait instability and forth behind patient to see stability
occurs early in course  Gait abnormality
 E.g. multiple system atrophy, corticobasal o Parkinsonian gait: shuffling gait with
degeneration, progressive supranuclear palsy quickened and shortened steps, requiring 5-
RISK FACTORS 8 steps to turn around
 Second most common neurodegenerative disorder o Freezing: sudden inability to start or
following Alzheimer’s continue movements
 ~60 years of age in sporadic cases, genetic (10- o Festination: small, increasingly quick steps
15%) are earlier o Propulsion: forward-leaning gait with risk
 Environmental (e.g. manganese), diet/metabolism of falling forward
(low vitamin D, high iron intake, obesity), history  Other
of TBI o Micrographia: size of handwriting reduced
PATHOPHYSIOLOGY o Hypomimia: low degree of facial
 Misfolded proteins (e.g. mutations)  misfolded expression
protein response  progressive dopaminergic o Unhabituated glabellar reflex (Myerson
neuron degeneration (>50%) in the substantia nigra sign if causes repeated blinking when tap
and locus coeruleus  dopamine deficiency at area between eyebrows)
respective receptors of striatum with interrupted o Associated with seborrheic dermatitis
transmission to thalamus and motor cortex  NONMOTOR SIGNS
imbalance between direct and indirect  increased
unwanted movement, decreased wanted movement  Autonomic
 (Serotonin and NA depletion in raphe nuclei  o Orthostatic hypotension, urinary urgency,
likely causes depressive symptoms impaired sexual function
 ACh surplus in nucleus basalis of Meynert  likely  Neuropsychiatric
cause of dyskinesia) o Cognitive problems (concentration,
CLINICAL PRESENTATION executive dysfunction, impaired memory)
COURSE in advanced disease
 Long delay (avg. 10 years) separating person’s first o Behavioral: irritability, impulsivity
noticeable symptom from timing of diagnosis  Disordered sleep (sleep fragmentation)
 Motor signs are unilateral at onset (may progress to DIAGNOSIS
other side) and asymmetric  Definitive only be post-mortem identification of
PRECLINICAL STAGE (NO MOTOR) neuropathological changes in brain
 Constipation o Lewy bodies: aggregates of misfolded a-
 Hyposmia synuclein and other proteins such as
 ubiquitin within neural cell bodies in  Younger patients <65 might benefit from initial
brainstem, substantia nigra, and cortex treatment with dopamine agonists
 Appear as intracellular hyaline  Supportive therapy
eosinophilic globules o Physiotherapy, occupational therapy,
o Loss of dopaminergic neurons in substantia speech and language therapy
nigra, causing depigmentation on gross and <65 WITH NO SIGNIFICANT COMORBIDITES
microscopic examination  First-line, may be in combination with levodopa
 Additional tests such as imaging (CT/MRI) not o Nonergot dopamine agonists (pramipexole,
routinely required but considered in atypical ropinirole)
presentations to rule out other disorders o MAO-B inhibitors (selegiline)
CLINICAL DIAGNOSTIC CRITERIA o COMT inhibitors (entacapone)
 Parkinsonism  different diagnostic certainty  Alternative
o Clinically probable: two or more supportive o Levodopa
criteria + maximum of two red flags + no  Usually with peripheral
absolute exclusion criteria decarboxylase inhibitor, carbidopa
o Clinically established: two or more o NMDA antagonists (amantadine) to reduce
supportive criteria + no red flags + no levodopa-induced dyskinesias
absolute exclusion criteria o Anticholinergics/muscarinic antagonists
 Supportive (biperiden) indicated in patients <65 years
o Clear response to dopaminergic therapy with tremor as chief concern and no
 Levodopa challenge test significant bradykinesia/gain disturbance,
o Levodopa-induced dyskinesia (involuntary and advanced disease and persistent tremor
muscle movement) despite levodopa
o Resting tremor of a limb >65 YEARS OR MULTIMORBID PATIENTS
o Presence of either olfactory loss or cardiac  First-line levodopa with DOPA decarboxylase
sympathetic denervation of MIBG inhibitor (does not cross BBB so decreases
scintigraphy peripheral conversion of L-DOPA to dopamine
 Absolute exclusion and increases dopamine in CNS)
o Cerebellar abnormalities including  Others to control motor fluctuations and
oculomotor dyskinesias
o Diagnosis of probable frontotemporal SEVERE MOTOR FLUCTUATIONS
dementia in first 5 years of disease  Duodenal levodopa infusion pump
o Downward vertical supranuclear gaze palsy  Deep brain stimulation
or selective slowing of downward vertical o Targets subthalamic nucleus or internal
saccades globus pallidus
o Absence of observable response to high- o Adverse effects: infections, hemorrhages,
dose levodopa despite at least moderate breakage of electrodes
severity ASSOCIATED SYMPTOMS
o Unequivocal cortical sensory loss or  Depressive moods: SSRIs (citalopram), SNRIs
progressive aphasia (venlafaxine)
 Red flags  Dementia: cholinesterase inhibitors (donepezil)
o Rapid progression of gait impairment  Psychotic episodes: atypical neuroleptics (clozapine
o Stability of motor symptoms or signs >=5 or quetiapine)
years  Dyskinesias: anticholinergics with CNS effects
o Inspiratory dysfunction (trihexyphenidyl, benztropine)
o Early severe autonomic dysfunction or
bulbar dysfunction (dysphonia, dysarthria,
dysphagia) in first five years
o Absence of common nonmotor symptoms
in first 5 years of disease
o Otherwise unexplained pyramidal tract
signs
o Bilateral symmetric parkinsonism
TREATMENT
APPROACH
 Levodopa most effective drug for motor symptoms
but associated with unavoidable motor
complications
o Dramatic effect in early phase “honeymoon ALS
period”
o All patients eventually develop drug-related  Tends to progress slower
motor fluctuations o Diagnosis before or around age 40
o Limb-onset ALS
  Bulbar-onset ALS progresses faster o Rinne test: bone conduction > air
conduction (vibrations bypass blockage to
HEARING LOSS cochlea)
o Speech audiometry: no discrimination loss
 Conductive o Audiogram: difference between air and
o Dysfunction of outer or middle ear, bone conduction
prevents conduction of sound to inner ear o Impedance audiometry: elevated acoustic
 Sensorineural reflex threshold (stapedius muscle dampens
o Dysfunction of inner ear or auditory nerve, transmission of loud noises to inner ear)
prevents neuronal transmission to brain  Sensorineural
 Can be mixed o Weber test: lateralization to unimpaired
ETIOLOGY ear (sound not transmitted by impaired ear)
 Conductive o Rinne test: air conduction > bone
o Otosclerosis: overgrowth of footplate of conduction (cannot transmit sound
stapes bone into middle ear  fixation  information well regardless of how
decreased sound conduction vibrations reach cochlea)
o Otitis media: most commonly caused by S. o Speech audiometry: discrimination loss
pneumoniae o Audiogram: hearing loss for higher
 Cholesteatoma: chronic otitis frequency
media causes keratinizing o Impedance audiometry: normal acoustic
squamous epithelium to grow from reflex threshold
tympanic membrane into middle DIAGNOSIS
ear mucosa  Physical exam
o Ear barotrauma: injury to inner and/or  Whispered voice/finger rub test: screening
middle due to inability to equalize pressure  Weber test: vibrating tuning fork in middle of
between ambient and middle ear (e.g. forehead  normal symmetrical,
diving) abnormal/negative lateralization
o Cerumen impaction: buildup of earwax  Rinne test: tuning fork over mastoid process, then
from apocrine glands in external ear over outer ipsilateral ear  normal or sensorineural
o External auditory canal atresia (both air and bone conduction diminished) hear
 Sensorineural again; negative/abnormal or conductive cannot hear
o Meniere disease: distortion of membranous again
labyrinth resulting from overaccumulation  Otoscopy: visual assessment of external ear and
of endolymph tympanic membrane
o Otitis interna  Pneumatic otoscopy: mobility of tympanic
o Acoustic neuroma: brain tumor of membrane
Schwann cells of vestibulocochlear nerve  Further
(most common of the schwannomas)  Lab test: blood glucose, CBC with differential,
o Noise-induced hearing loss: loud sound TSH, syphilis depending on suspected etiology
damages stereocilia of cochlear hair cells  MRI or CT scan of posterior fossa: unilateral,
o Presbycusis: age-related due to progressive gradual sensorineural hearing loss to indicated to
irreversible damage of organ of Corti exclude acoustic neuroma
CLINICAL FEATURES  Audiometry: without any obvious cause of hearing
 Conductive loss
o Childhood or young adulthood SUBJECTIVE AUDIOMETRY
o Hearing improves in noisy environments  Audiogram: auditory threshold is dB level at which
o Normal voice volume identification of when sound is heard is 50% correct
o Sound is not distorted o Conductive: auditory threshold increased
o Not associated with tinnitis in air and normal in bone conduction
 Sensorineural o Sensorineural: auditory threshold
o Middle or late age increased proportionally in both air and
bone
o Hearing worsens in noisy environments
 Speech audiometry: speech reception threshold dB
o Louder voice volume level at which patient correctly repeats 50% of
o Sound is distorted because tend to lose words
higher frequencies preferentially o Conduction: increasing loudness leads to
o Often associated with tinnitus speech comprehension of 100%
DIAGNOSTIC FINDINGS o Sensorineural: increasing loudness does
 Conductive not lead to speech comprehension, instead
o Weber test: lateralization to impaired ear showing discrimination loss
(detection of vibration greater because OBJECTIVE AUDIOMETRY
cannot hear ambient noise well)
  Impedance audiometry: changes in acoustic
impedance of middle ear in response to changes in
air pressure
 Tympanometry: reflected sound from tympanic
membrane measured by applying various pressures
to external auditory canal  estimate mobility of
tympanic membrane and pressure in middle ear
TREATMENT
 Underlying etiology
 Irreversible causes = hearing aids and cochlear
implants
 Hearing aids
o Amplify sound
o Both conductive and sensorineural
o Children should be fitted as soon as
possible to avoid developmental delay in
speech
 Cochlear implant
o Electrically stimulate auditory nerve (so
must be intact)
o Moderate to severe sensorineural with
unsuccessful treatment with hearing aids
CONDUCTIVE HEARING LOSS

CLASSIFICATION OF TUMOURS

SENSORINEURAL HEARING LOSS

 oGBM (malignant): cerebral hemispheres
(supratentorial)
o Meningioma (benign): extra-parenchymal
in supratentorial or infratentorial
o Hemangioblastoma: cerebellum
(infratentorial)
o Schwannoma: cerebellopontine angle
(infratentorial)
o Oligodendroglioma: frontal lobes
(supratentorial)
o Adenoma: sella turcica (supratentorial)
 Children
o Most are primary
o Second most common cause of pediatric
cancer after leukemia
o Pilocytic astrocytoma (benign): posterior
cranial fossa (infratentorial)
o Medulloblastoma (malignant): cerebellar
vermis )infratentorial)
o Ependymoma: 4th ventricle (infratentorial)
o Craniopharyngioma: suprasellar region
(supratentorial)
o Pinealoma: dorsal midbrain (infratentorial)
PROGNOSTIC FACTORS
 Tumor histology grade (higher = worse)
 Age (younger = better)
 Symptoms (longer = better)
 Extent of tumor residual (less = better)
 Functional neurologic status (higher = better)
o Karnofsky performance score
BRAIN TUMOR o 0 = death; 100 = perfectly functional
o Alternative ECOG score
BENIGN o 0 = fully active; 5 = dead
 Meningioma (arachnoid cap cells), most common  Course (metastatic, recurrent = worse)
benign
 Growth (fast-growing easier to treat with
 Schwannoma (Schwan cells) also common chemotherapy)
 Pituitary adenoma (pituitary adenotrophic cells) o Hard to get chemotherapy past BBB
most common
o One way to get around is intrathecal
 Pineocytoma (pineal cells) injections
 Gangliocytoma (mixed neuronal-glial tumor of  Location (supratentorial and cerebellar more
neoplastic ganglion cells within stroma of non- amenable to surgery than brainstem and
neoplastic glial elements) diencephalon)
 Craniopharyngioma (Rathke pouch from ectoderm)  Molecular features
 Chordoma (notochord), most commonly tailbone  Treatment (aggressive = better)
(sacral) and base of skull (clival)
MALIGNANT
 Glioma (most prevalent arising from glia) most NEUROFIBROMATOSIS TYPE 2
common malignant
o Astrocytoma (astrocytes) most common  Inherited autosomal dominant trait
o Ependymoma (ependymal cells)  NF2 gene encodes merlin, which acts as tumor
o Medulloblastoma (granule cell precursors suppressor gene in Schwann cells
in developing cerebellum)  Hallmark is bilateral vestibular schwannoma in
o Oligodendroglioma (oligodendrocytes) internal acoustic meatus (opening of internal
 Hemangioblastoma (blood vessels) most commonly auditory canal)  splaying and displacement of
in cerebellum nerve fibers
 Rhabdoid tumors  Increased risk of other tumors: schwannomas of
other nerves, meningiomas, gliomas (e.g.
ependymomas)
PEDIATRIC VS ADULT BRAIN TUMORS  Audition: tinnitus, sensorineural hearing loss,
balance problems
 Adults  Cutaneous: elevated plaque-like lesion,
o Most are metastases subcutaneous nodules representing swelling of
o Account for ~2% of cancer cases in adults nerves and cutaneous tumors
  Other: headache, seizures, focal neurological  Neurofibrillary tangles
symptoms o Intracellular
 Diagnosis with skin findings (non-specific), o Hyperphosphorylated tau protein main
auditory testing, MRI of brain and contrast to detect component
neurofibromas, meningiomas o Hyperphosphorylation of tau  formation
 Asymptomatic followed up with consecutive MRI; of insoluble intracellular fibrils 
surgery preferred and radiation options for neurotoxic
symptomatic  Culminate in degeneration of cholinergic neurons
 role in declining cognitive abilities
ALZHEIMER o Hippocampus usually first  memory
CLINICAL FEATURES
 Chronic neurodegenerative disease  Common symptoms of cognitive impairment
ETIOLOGY o Short-term memory impairment
 Amyloid precursor protein (APP) gene  Insidious onset
o 10-15% of early-onset familial AD  Slow progression
o Since APP gene located on chromosome  Episodic memory affected first
21, trisomy 21 increases risk of early-onset o Language impairment
APP  Impaired naming, then
o Onset usually resembles parental age (~49 comprehension, then fluency
years) o Temporal and spatial disorientation
 Apo E (person, place, time, events)
o Late-onset increases risk with increased o Impairment of executive functions and
number of Apo E4 alleles judgement
o Apo E2 alleles may be protective  Less common symptoms
 Presenilin-1 o Primary progressive aphasia
o Early onset compared to AD due to o Apraxia (inability coordinated, learned
mutations of other genes (median 43 years) movements)
 Presenilin-2 o Acalculia (inability mathematical tasks)
o Later onset (average 54 years) o Alexia (inability to read)
RISK FACTORS o Agnosia (inability to process sensory
 Females over males information  cannot identify persons,
 Age is strongest predisposing for regular AD sounds, objects, etc.)
 Family history of dementia strongest for early-onset  Noncognitive symptoms
 African American or Hispanic descent o Behavioral changes
 Diabetes, obesity, dyslipidemia  Apathy
 HTN, peripheral atherosclerosis, cerebrovascular dx  Irritability, aggression
 Low SES and/or educational status o Mood disorders (e.g. depression)
DIFFERENTIAL DIAGNOSIS o Urinary incontinence
 Early-onset (<65) familial AD ~10% all cases o Hyposmia
 Alzheimer’s and vascular > 90% of cases DIAGNOSIS
 AD: slow and progressive, episodic impairment of  Use neuropsychological testing (MMSE, MOCA) to
memory diagnose dementia in patients with memory loss,
 VD: stepwise deterioration due to vascular cognitive, and/or functional decline
events/infarction, sudden onset  Rule out reversible causes
 Dementia with Lewy bodies (protein misfolds): o 1. Review medications, substance use
visual hallucinations, features of parkinsonism o 2. Sensory loss (presbycusis, presbyopia)
 Frontotemporal dementia: early changes in o 3. Depression (generalized depression
personality, inappropriate social behavior scale, diagnosis with PHQ-9)
 Normal pressure hydrocephalus: triad of gait o 4. Metabolic (TSH, Ca, vitamin B12)
disorder, dementia, urinary incontinence o 5. Neuroimaging (vascular, hydrocephalus,
 Wernicke encephalopathy: triad of confusion, tumors, signs of Alzheimer)
ataxia, ophthalmoplegia  AD can only be confirmed via
 Late neurosyphilis neurohistopathological examination post-mortem
PATHOPHYSIOLOGY CLINICAL DIAGNOSIS
 Senile/neuritic plaques  Symptoms
o Extracellular in grey matter o Insidious onset (relatives)
o AB protein main component o Objectively confirmed progressive loss of
o Enzymatic cleavage of transmembranous function in 2 or more cognitive domains
APP by B-secretase and y-secretase  AB (usually including memory)
peptide aggregation  formation of  Neuropsychological testing
insoluble plaques with tau protein and o Cognitive testing: MMSE, MoCa, Mini-
microglia  neurotoxic effect cog
 o Functional testing: FAQ, PSMS o Differences noticed in driving skills
o Global testing: GDS o Unsafe or abnormal driving behavior
 Neuroimaging o Instances where you’ve been lost
o CT/MRI o How comfortable you and family members
 Generalized or focal cerebral feel about driving abilities
atrophy: enlarged ventricles,  Behaviors that higher risk for driving behaviors
narrowing of gyri, prominent o Slow response times
cerebral sulci o Too slow or too fast
 Disproportionate atrophy of o Driving through red, stopping at green
hippocampus and/or medial o Difficulty merging with traffic
temporal lobe o Too much time to reach destination
o PET
 Temporoparietal hypometabolism FRAGILE X SYNDROME
 Increased amyloid uptake signal
 EEG
o Slower basic rhythm, long evoked potential  X-linked dominant disease
latency  CGC trinucleotide repeat expansion in FMR1
 CSF (fragile X mental retardation 1) gene during
oogenesis  hypermethylation  silences gene
o Increased phosphor-tau protein, decreased and no product
B-amyloid proteins AB1-42
HISTOPATHOLOGY  Second most common genetic cause of intellectual
disability
 Macroscopic
 Clinical features
o Cerebral atrophy
o 50-200 repeats (premutation): ataxia,
o Damage to hippocampus and primary ovarian insufficiency, tremor
parahippocampal cortex (medial temporal
lobe) is earliest change o >200 (full mutation): intellectual disability,
delayed language development, behavioral
o Diffuse cortical atrophy as disease (autistic behavior, hyperactivity, anxiety),
progresses facial anomalies (long and narrow face,
o Axonal and neuronal loss prominent jaw, large everted ears,
 Microscopic macrocephaly), mitral valve prolapse
o Amyloid beta: stains with Congo red under  Diagnosis: molecular genetic detection (PCR,
polarization Southern blot)
o Tau protein: intracellular neurofibrillary  Treatment: symptomatic
tangles that stain with Gallyas silver
o Hirano bodies: intracellular rod-shaped DEVELOPMENTAL DELAY
eosinophilic aggregates of actin and actin-
associated proteins in neurons, especially
hippocampus  Cognitive delays
TREATMENT o Intellectual functioning, learning
 Cholinesterase inhibitors difficulties, communicating and playing
o First-line for Alzheimer and vascular with others
o Donepezil, rivastigmine, galantamine  Motor delays
o Increased ACh concentration and can o Gross motor: difficulty rolling over or
improve some symptoms crawling, trouble walking up and down
o Adverse: nausea, dizziness, insomnia stairs
o Contraindications: cardiac conditions o Fine motor: holding objects, tying shoes,
brushing teeth
 **anticholinergics, e.g. tricyclic antidepressants,
should be avoided  Social, emotional, behavioral delays
 Memantine o Difficulty understanding social cues,
initiating communication, carrying two-way
o Moderate to advanced cases of Alzheimer conversations, dealing with frustration,
and vascular coping with change
o NMDA-receptor antagonism  decreased  Speech delays
glutamate-induced calcium-mediated
excitotoxicity o Receptive language disorders: difficulty
understanding words or concepts  can’t
o Adverse: headaches and dizziness, identify objects
confusion, hallucinations
o Expressive language disorders: reduced
 Memory training vocabulary of words and complex
sentences
DRIVING WITH DEMENTIA  Global developmental delay
 Doctors cannot determine, must forward medical
opinion to Ministry of Transportation CLASSIFICATION OF MOVEMENT DISORDERS
 Refer to driving assessment
o Driving patterns (when/where)
  Based on how movement affected o Atheroemboli (ICA, esp. carotid
 Hypokinesias bifurcation)
o Akinesia/bradykinesia (parkinsonism) o Infectious emboli (bacterial endocarditis)
o Apraxia  Thrombotic (40%)
o Blocking (holding) tics o Large vessel atherosclerosis (rupture of
o Cataplexy and drop attacks atherosclerotic plaque  exposure of
o Catatonia, psychomotor depression, subendothelial collagen  thrombus
obsessional slowness formation esp. at branch points in arteries)
o Freezing phenomenon o Small vessel occlusion (e.g. stenosis due to
o Hesitant gaits chronic hypertension)
o Hypothyroid slowness  Global cerebral ischemia
o Rigidity o Systemic hypoperfusion (e.g. shock)
o Stiff muscles o Hypoglycemia
 Hyperkinesias o Severe and/or chronic hypoxia
o Abdominal dyskinesias  Other
o Akathitic movements o Hypercoagulable states (thrombophilia,
o Ataxia/asynergia/dysmetria polycythemia, hormonal contraceptive use)
o Athetosis o Vasculitis
o Ballism o Arterial dissection
o Chorea DIFFERENTIAL DIAGNOSIS
o Dystonia  Tumors (gliomas, meningiomas, adenomas)
o Hemifacial spasm  Toxic or metabolic disorders (hypoglycemia,
o Hyperekplexia hypercalcemia, hyponatremia, uremia, hepatic
encephalopathy, hyperthyroidism)
o Hypnogenic dyskinesias
 Infectious disorders (meningoencephalitis)
o Jumping disorders
 Psychological disorders and migraines
o Jumpy stumps
 Seizures
o Moving toes and fingers
 Demyelization disorders
o Myoclonus PATHOPHYSIOLOGY OF BRAIN ISCHEMIA
o Myokymia and synkinesis  Arterial blockage  adjacent neurons lose oxygen
o Myorhythmia and nutrients  no aerobic metabolism to produce
o Paroxysmal dyskinesias ATP  Na/K ATPase pumps fail  accumulation
o Periodic movements in sleep of Na inside and K outside  cell depolarization 
o REM sleep behavior disorder glutamate release  opens NMDA and AMPA
o Restless legs receptors  calcium influx  continuous neuronal
o Stereotypy firing  cell death via excitotoxicity
o Tics  Intraneuronal swelling  cytotoxic edema
o Tremor  Disruption of BBB  vasogenic edema
o Both  swelling of infarcted area and
TYPES OF TREMORS increases in intracranial pressure
 Followed by invasion of phagocytic cells which try
 Parkinsonian: resting, small, 3Hz, to clear away dead cells  softening and
pronation/supination (pill rolling), asymmetric liquefaction of affected brain tissues
 Essential: postural/kinetic, 4-11Hz, mostly SYMPTOMS BASED ON CEREBRAL ARTERIES
symmetric, hands + head + voice  MCA most commonly affected
 Nystagmus o Contralateral weakness and sensory loss
o When head in one position get it and more marked in upper limbs and lower half
simpler, then more likely peripheral of face tan in lower limbs
o When moving eyes get it and more chaotic, o Gaze deviates toward side of infarction
then more likely central o Contralateral homonymous hemianopia
without macular sparing OR
STROKE superior/inferior quadrantanopia
DEFINITIONS o Aphasia if in dominant (left) hemisphere:
 Stroke: acute neurologic injury/infarction caused by Broca, Wernicke (can be associated with R
decrease in cerebral perfusion due to ischemia (clot) superior quadrant VFD)
or hemorrhage (cerebral or subarachnoid) o Hemineglect if in non-dominant (right)
 TIA: temporary, focal cerebral ischemia without hemisphere: unawareness and
acute infarction or permanent loss of function unresponsiveness to contralateral stimuli
ETIOLOGY OF ISCHEMIC (motor and sensory/perceptual neglect, esp.
 Embolic (20%) vision)
o Cardiac emboli (AF)  ACA
 o Contralateral weakness and sensory loss in Internal carotid
lower limbs more marked than in upper o Ipsilateral amaurosis fugax (transient
limbs monocular or binocular loss of vision)
o Abulia (akinetic mutism, disinterest and o Numerous contralateral symptoms
slowed mental state) (hemiparesis, hemisensory loss,
o Urinary incontinence homonymous hemianopsia)
o Dysarthria  Common carotid
o Transcortical motor aphasia o Horner syndrome
o Limb apraxia o Signs of middle cerebral artery infarction
 PCA  Vertebral artery
o Contralateral homonymous hemianopia o Lateral and medial medullary syndrome
with macular sparing due to occipital lobe o Signs of posterior cerebral artery infarction
involvement  Anterior spinal artery
o Contralateral sensory loss due to lateral o Medial medullary syndrome
thalamic involvement (including position) CLINICAL FEATURES OF TIA
o Memory deficits  Acute and transient focal neurologic symptoms (e.g.
o Vertigo, nausea amaurosis fugax)
o Alexia, agnosia if left hemisphere o Typically last <1 hour, majority resolve
o Prosopagnosia if right hemisphere <15min
 PICA  Non-focal symptoms if posterior circulation
o Lateral medullary (Wallenberg) o Vertigo, dizziness, diplopia, ataxia
syndrome DIAGNOSIS
o Nucleus ambiguus  ipsilateral bulbar  1. Immediate
palsy (dysphagia, decreased gag reflex) o Bloodwork (glucose, CBC, coagulation
o Vestibular nuclei  ipsilateral nystagmus panel, serum troponin)
and vertigo o ECG (AF, MI)
o Lateral spinothalamic  contralateral  2. Neuroimaging
decrease in pain and temperature o A. noncontrast head CT to evaluate for
o Spinal trigeminal nucleus  ipsilateral acute hemorrhage (determines whether or
decrease in pain and temperature in face not to give thrombolytic therapy) and
o Inferior cerebellar peduncle  ipsilateral ischemic changes after 6-24 hours
limb ataxia and dysmetria o B. Diffusion-weighted MRI to detect
o Sympathetic fibers  ipsilateral Horner ischemia within 3-30 minutes
syndrome  Reversible ischemia in TIA
 AICA o C. Further neuroimaging (CT angiography,
o Lateral pontine syndrome carotid duplex sonography)
o Lateral spinothalamic  contralateral loss TREATMENT
of pain and temperature  No specific treatment
o Middle and inferior cerebellar peduncles   Prevent subsequent stroke and treatment of
ipsilateral limb and gait ataxia underlying conditions
o Spinal trigeminal nerve nucleus   1. Antithrombotic therapy
ipsilateral loss of facial sensation to pain  2. Long-term stroke prevention based on suspected
and temperature etiology
o Facial nerve nuclei  ipsilateral facial o Embolic
muscle weakness, decreased lacrimation  Anticoagulation
and salivation, ipsilateral loss of taste o Lacunar/small vessel
sensation from anterior 2/3 of tongue  Antiplatelet therapy
o Vestibulocochlear nerve nuclei   HTN and statin therapy
ipsilateral vertigo, nystagmus, hearing loss o Large vessel disease
 Basilar artery  Treatment of carotid artery stenosis
o Consciousness preserved if reticular  HTN and statin therapy
activating system not affected  3. Management of modifiable risk factors
o Vertebrobasilar insufficiency o Obesity screening and lifestyle counselling
 Vertigo, drop attacks, tinnitus o Nutritionist consultation or assessment
 Ipsilateral CN deficits o Smoking and alcohol limitation
 Gait ataxia
o Pontine syndromes
 Ventral, lateral, inferior medial
pontine syndrome
 Locked-in syndrome
o Cerebellar syndromes
SYMPTOMS BASED ON EXTRACRANIAL
ARTERIES
 o Older adults (>35): alcohol withdrawal,
stroke or TIA, metabolic disorders, vascular
encephalopathies
 Epilepsy
o General increase in neuronal
hyperexcitability
o Genetic mutations of ion channels or
transmitter receptors
o Cryptogenic (idiopathic)
o Structural/metabolic: preexisting chronic
cerebral lesion of CNS abnormality
(hypoxic-ischemic injury, PKU, tuberous
sclerosis)
o Triggers: excessive physical exertion,
sleep deprivation, strobe light flashing, loud
music
CLASSIFICATION
 Anatomical origin
 Focal: one area
o Aura: neurological symptoms that precede
migraine or seizure
o Clonic, involuntary, repetitive movements
of contralateral limbs
SEIZURE o Visual (hallucinations), somatic
(paraesthesia), position (vertigo), hearing
 Seizure: abnormal, unregulated electrical activity of (complex sounds), olfactory (unusual or
cortical neurons that results in transient changes in intense smells)
behavior o With or without impaired consciousness
o Provoked = non-epileptic  Generalized: both hemispheres
o Unprovoked = epileptic o Classic tonic-clonic/grand-mal: LOC,
 Epilepsy: chronic neurologic disorder with tonic phase (generalized muscle
following: contractions), clonic phase (rhythmic
o 2 or more unprovoked seizures separated by muscle twitching)
more than 24 hours o Clonic seizures: LOC, rhythmic jerking
o One unprovoked seizure with underlying motor movements
predisposition to seizures (recurrence risk o Tonic seizures: LOC, muscle contractions
over 10 years similar to after 2 unprovoked) o Myoclonic: brief LOC, sudden jerky
ETIOLOGY muscle twitching of muscles or group of
 Provoked seizure muscles
o Metabolic/electrolyte: hypo and o Atonic seizures: brief LOC, sudden loss of
hyperglycemia, hypo and hypernatremia, muscle tone (~2 seconds)
hypocalcemia, uremia, thyroid storm, o Absence (non-motor seizure): common in
hyperthermia childhood. Brief LOC; blank stare,
o Mass: brain tumors and metastases unresponsiveness can happen several
o Withdrawal: ABBA (alcohol most common hundred times in day but 5-20 seconds
adults, barbiturates, antiseizure drugs)  Status epilepticus: continuous seizure lasting ≥ 5
o Intoxication: min, or ≥ 2 repetitive, separate seizures with
 Cocaine, ecstasy, CO poisoning consciousness not fully regained in the interictal
 Amitriptyline, penicillin, lithium, period
antipsychotics CLINICAL FEATURES
o Infections: encephalitis, meningitis, abscess  Ictal phase: sudden onset, rapid progression of
o Ischemia: stroke, perinatal injuries, TBI symptoms, 1-3 minutes
o Increased ICP and cerebral edema:  Postictal phase: residual neurologic symptoms,
eclampsia, hypertensive encephalopathy varying degree of confusion and impaired alertness,
o Fever in infants and children minutes to hours
 Causes of provoked by age group DIAGNOSIS
o TBI in all  1. Confirm seizure
o Neonates: congenital, perinatal injury  History identifies aura or provocative factors
o Infants and children: fever, idiopathic,  EEG
infections, metabolic o Ictal (during)
o Adolescents: illicit substance abuse  Epileptiform discharges (spikes,
o Younger adults: alcohol withdrawal, illicit sharp waves, spike waves,
substance abuse hypsarrhythmia)
  If no discharges, consider o Ethosuximide: inhibits voltage-gated Ca
pseudoseizures channels (T-type) in thalamic neurons
o Interictal (between) o Phenytoin: inactivates Na channels
 Normal findings, possibly show o Phenobarbital: GABA agonist  increased
epileptiform activity GABA inhibitory action
 2. Exclude underlying condition o Benzodiazepine: indirect GABA agonist 
 ECG in ever patient with LOC to exclude increased GABA inhibitory action
cardiogenic causes (e.g. arrhythmia  cerebral  Second-generation
hypoxia) o Lamotrigine: inhibition of voltage-gated Na
 CT/MRI (with and without contrast) to rule out channels  decreased glutamate release
structural lesions after first seizure o Levetiracetam: blockage of SV2A receptor
o Always for focal, less concerned for  GABA and/or glutamate release
general tonic-clonic modulation and inhibition of voltage-gated
o Don’t have to do for absence Ca channels
 Lab tests o Gabapentin, pregabalin: inhibition of
o Glucose, electrolytes, toxicology screen, presynaptic Ca channels  decreased
renal and liver function tests, antiepileptic intracellular Ca flow
drug levels o Topiramate: blockage of voltage-gated Na
 Lumbar puncture: if CNS infection suspected channels, increased GABA
TREATMENT  Preventing seizures
 Acute o Na channel inactivators
o Cardiopulmonary resuscitation (ABC)  Phenytoin, carbamazepine,
 Airway management lamotrigine, valproic acid
 Prevention of aspiration o GABA activators
o Avoid hazards  Phenobarbital, tiagabine,
 Remove sharp objects within vigabatrin, valproic acid
patient’s reach o Other mechanisms
 First seizure  Gabapentin, topiramate,
o Long-term not required unless status ethosuximide
epilepticus or abnormalities on EEG or TREATMENT OF STATUS EPILEPTICUS
MRI  First-line: benzodiazepines (lorazepam)
o Remove cause or provoking factors o Bind to GABA-receptor (chloride channel
 Recurrent seizures with cause that cannot be  hyperpolarization  less firing)
eliminated OR neuroimaging or EEG shows o Enhances inhibitory effect of GABA by
findings after first seizure increasing frequency of opening of channel
o Antiepileptic drugs raising lowered  Second-line: phenytoin
threshold  decreased neuronal excitability o Inactivates Na channels
o Focal first line: lamotrigine, levetiracetam, o Many side effects: gingival hyperplasia,
phenytoin, phenobarbital (children) hair growth, rash
o Tonic/clonic first line: lamotrigine,  Third-line: phenobarbital (barbituates)
valproate, phenobarbital o Binds to GABA-receptor (chloride channel)
o Typical absence: ethosuximide (blocks o Enhances inhibitory effect of GABA by
thalamic T-type Ca2+ channels), valproate increasing duration channel is open
o Atypical absence, myoclonic, atonic:  Then general anesthesia and intubate
valproate, lamotrigine, topiramate
 Combination therapy MENINGITIS
o Monotherapy should be maintained and
increased dosage before initiating ETIOLOGY
combination  Bacterial: Group B streptococcus most common
o Combination should be different classes cause <1 month, E. coli, Listeria monocytogenes.
and/or different modes of action Most common from 1 month onwards is
 Nonpharmacologic if pharmacoresistance streptococcus pneumoniae and Neisseria
o Surgery: resection of pathological lesion, meningitidis
disconnection of neuronal circuits o Less common: Borrelia (lyme), treponema
o Stimulation techniques: vagus nerve pallidum (syphilis), mycobacterium
stimulation, deep brain stimulation tuberculosis
ANTICONVULSANT DRUGS  Viral: often associated with encephalitis too
 First-generation o Enteroviruses (esp. coxakievirus and
o Valproate: inhibits GABA transaminase  echovirus) most common in all patient
increased GABA  decreased neuronal groups
excitability o Herpesviruses
o Carbamezapine: Inactivates Na channels o Lymphocytic choriomeningitis virus
  Fungal (coccidioides), parasitic (helminths, o Arboviruses: motor symptoms such as
protozoa) choreoathetosis and parkinsonian
 Noninfectious: sarcoidosis, tumor metastases, movements
medications such as NSAIDs COMPLICATIONS DUE TO HERPES
PATHOPHYSIOLOGY ENCEPHALITIS
 Hematogenous seeding: colonize nasopharynx and  1/3
enter bloodstream after mucosal invasion 
subarachnoid space  cross BBB
 Contiguous spread: infections in nose, eyes, ears
CLINICAL FEATURES
 Incubation period bacterial 3-7 days, viral 2-14 days
 Neonates
o Nonspecific symptoms without triad
o Lethargy, muscle hypotonia, irritability,
poor appetite, vomiting, hyper or
hypothermia
o Later: fontanelle bulging, seizures
 Children and adults
o Triad of fever, headache, neck stiffness  Horizontal gaze deviation = think of seizure
o Altered mental status, photophobia, nausea,
vomiting, seizures, possible cranial nerve EXTRA
palsies
o Prodrome viral: low-grade fever, malaise,
fatigue, myalgia, upper respiratory  Diabetes  weakness, sensory loss, decreased
symptoms ankle jerk reflexes, abnormal sensory signals in feet
 Physical exam bilaterally
o Neck stiffness o Chronic hyperglycemia:
o Brudzinski sign (flexion of neck flexes o Increased flux of the polyol pathway 
knees and hips) sorbital accumulation in peripheral nerve
tissue  osmotic damage and cell lysis
o Kernig sign (flexed thigh at hip then
extends knee causes pain) o Deposition of advanced glycating end-
products in axoplasm and endoneurial
 Meningoencephalitis vessels  direct toxicity
o Focal neurological signs  Diabetic neuropathy ~50% of patients with DM
o Seizures  Variety of patterns of neuropathy
o Sensory, motor, autonomic, mix
ENCEPHALITIS o Small and/or large-fiber
o Axonal and/or demyelinating
ETIOLOGY o Focal, multifocal, radicular, polyneuropathy
 Can be any infectious cause, but viruses most  Multiple peripheral nerve (median + ulnar = plexus)
prevalent ~70%
 Polyneuropathy (length-dependent; glove-stocking
 HSV, West Nile, enteroviruses distribution)
 Some other: varicella-zoster, EBV, CMV, measles, o Length-dependent neuropathy = symmetric,
rubella, eastern equine, dengue, rabies symptoms begin in the longest nerves at
PATHOPHYSIOLOGY their terminals
 Most reach spinal cord and brain hematogenously o Negative or positive sensory symptoms
 HSV, rabies, HZV important exceptions usually precede motor weakness
o Travel to CNS from nerve endings in o Symptoms ascend insidiously up leg, with
retrograde manner hand symptoms often evidence around time
 Virus and host’s inflammatory response disrupt leg symptoms approach knee
neural cell function  Wallerian degeneration
 Usually cerebral edema, vascular congestion, and o Active process of retrograde degeneration
hemorrhage of distal end of axon as a result of nerve
CLINICAL PRESENTATION lesion
 Most commonly fever, headache, seizures, altered o Occurs between 7-21 days after lesion
mental status occurs
 Neuropsychiatric: behavioral changes, o Separation of proximal and distal nerve 
hallucinations, and/or cognitive decline macrophages signalled by Schwann cells to
 Exam findings specific to virus clean up axonal and myelin debris (slower
o HZ encephalitis: rash and skin vesicles in CNS due to clearance rate of myelin,
o EBV: lymphadenopathy and splenomegaly permeability of BBB limited to site of
o HSV: psychiatric features, memory deficits, injury in CNS but along distal stump in
aphasia PNS, oligodendrocytes inhibit regeneration)
  regeneration of 1mm/day of distal o Degeneration of corticospinal tracts (from
segment in PNS, much slower or absent in Betz cells aka UMN)
CNS o Degeneration of anterior horn cells (motor
 Remyelination tends to be faster (less to repair) neurons)
 Renervation is slower o Inclusion and cytoskeletal disruption is sign
o Normal nerve  Wallerian degeneration  of degeneration
phagocytosis and reconstruction  axonal o Ubiquitinated inclusions (brown) in
regeneration and remyelination neurons  ubiquitin attaches to damaged
o Time for Wallerian degeneration cell proteins to aid in degradation
o Time for axons to travel back to target  Brainstem pathology similar findings: loss of
motor neurons, gliosis, cytoskeletal disruption,
ALS ubiquitinated inclusions
 Amytrophic lateral sclerosis  B12 deficiency: can cause subacute combined
 Slowly progressive degenerative disease affecting degeneration = combined myelopathy +
motor neurons in brain (UMN) and spinal cord neuropathy, thus can mimic ALS
(LMN)  Up to 10% of patients with ALS have cognitive
 Spasticity/hyper-reflexia due to UMN degeneration dysfunction, usually frontotemporal dementia
 Muscle atrophy/weakness secondary to LMN  Cause of death likely aspiration
degeneration  EMG
o Muscles show neurogenic changes as it o Conduction shows decreased in motor
atrophies due to loss of trophic support signals, normal sensory signals
o Some necrosis can occur  creatine kinase o Needle EMG: muscle irritability (from
and aldolase denervation)
 UMN/LMN weakness starts in one part of body and
spread contiguously
 MUSCLE BIOPSY
o Grouped fiber atrophy
o Motor unit: functional unit consisting of
one lower motor neuron and all fibers it
innervates. Consists one type of motor fiber
o If motor neuron dies, all of downstream
fibers (same type) will atrophy unless
‘rescued’ by renervation from nearby
neuron
o At which point it will convert to that motor
neuron’s new fiber type if necessary
o ATPase stains
 Normal muscle = cherkerboard
pattern of type 1 and 2  Syrinomyelia = central cord syndrome
 Muscle with fiber-type grouping  C4-C6 injury = tetraplegia
(no longer checkerboard, indicates  T6-L1 injury = paraplegia
renervation)  Movement disorders described by Rs
o Gomori trichrome o Region (where does it occur)
 Neurogenic-type atrophy no ragged o Range (big or small)
red fibers o Rate (fast or slow)
 Ragged red fibers due to abnormal
mitochondrial congregation; occurs o Rhythmicity (rhythmic or sudden)
in mitochondrial disorders o Revealing/relieving factors
o ATP stain  Tremors
 If show fibre type grouping, sign of o Involuntary, rhythmic movement of part of
chronic denervation with some body
reinnervation o Rest, postural, action
 Type 1 (slow twitch, darker) and  Reveals at rest
type 2 (fast twitch, lighter)  Occurs when limb positioned
o More severe fiber atrophy with larger against gravity
groups (almost fascicular) indicating more  Action/kinetic/intentional: during
severe neurogenic changes of longer any type of movement
duration  Parkinsonian: resting, small, 3Hz,
 SPINAL CORD AT AUTOPSY pronation/supination, asymmetric in hands
o Smaller (atrophic) ventral (motor) root in  Essential: postural/kinetic, 4-11Hz, mostly
ALS due to degeneration of neuronal cell symmetric, hands+head+voice
bodies in ventral grey matter  Cerebellar: kinetic, slow, high-amplitude tremor of
o Dorsal roots do not degenerate as much hands/feet, at end-target
  Rubral: 3-4Hz flexion/extension, present at rest, o Remove vision to see if sensory or
exacerbated by postural + action vestibular
o More dramatic with sensory because:
HUNTINGTON DISEASE vestibular has direct input to oculomotor
 Progressive neurodegenerative disorder system – can affect visual input; vestibular
characterized by chorea and/or neuropsychiatric dysfunction causes positive sensation of
changes (depression, psychosis, dementia) movement (sensory simply lack of
 Autosomal-dominant inheritance with anticipation sensation of movement vs. not)
o HTT gene on chromosome 4p16.3  Cerebellar ataxia
o Incomplete penetrance at 36-40 repeats; o All are impaired because integration is
fully penetrant if >=41 repeats impaired
 Gene codes for Huntingtin protein – function o Vertigo but less intense, less nausea
unknown o Additional non-postural ataxias (speech,
o Accumulates in caudate and putamen = eye movement, finger movements)
cellular trafficking disruption = death o What happens when you’re drunk
 Preferentially disrupts striatal output of indirect
pathway; so blocks putamen to globus pallidus VERTIGO
externa  Central = brainstem vestibular apparatus (CNS)
o Not a problem with dopamine  Peripheral = peripheral vestibular system from
o “Inhibitory” stops working = chorea, inner ear to vestibular division of VIIIth cranial
involuntary, irregular, unpredictable muscle nerve
movements (dancing, restless, fidgety)
 Biopsy
o Caudate nucleus atrophy
o Ubiquitin stain; intranuclear inclusions in
neurons reflect accumulation of tagged,
abnormal Huntingtin protein
o GFAP stain: mark of reactive astrogliosis
(scarring). Marked gliosis in caudate
 Differential for chorea
o Parkinson (drug side effect) COMA PROGNOSTICATION
o Drugs (tardive dyskinesia from  Few signs that tell if patient will do poorly; and
antipsychotics, cocaine) very few signs that will do ‘well’
o The rest… Huntington-like disease 1-3,  Negative prognostic signs
spinocerebellar ataxia 1/3/17, o Being absent does not mean patient will do
neuroacanthocytosis, etc. well
o Are not infallible
BALANCE  Favorable
o Normal EEG within 24 hours insult
 Need 2/3 major inputs for balance  Poor outcome
o Visual
o Vestibular (rotational, translational)
o Proprioceptive (body movements)
 Mismatch = dizzy
 Brain needs to function to consolidate inputs to
maintain balance. Loss of bloodflow (e.g.
positional) = dysfunction = presyncope
o Tunnel-vision, grey out, hearing change,
light-headedness
o Sympathetic NS redistributes blood supply
to maintain brain function: pallor, epigastric
discomfort, diaphoresis
 Vestibular ataxia (no vestibular input)
o Mismatched signaling from vestibular
system
o Vertigo, sensation of motion/spinning
Brain death determination
o Dizzy, nystagmus, nausea  Established cause
 Sensory ataxia (no proprioception)  Comatose state with absence of motor responses
o Hard to maintain posture because don’t excluding spinal reflex
know where joints are  Absent brainstem reflexes gag, cough
 Romberg sign  Bilateral absent corneal, pupillary reflex, VOR
response
 Absent respiratory effort (apnea testing) prior evidence of CO retention (e.g.
2

 Absence of confounding variables that can mimic COPD, severe obesity)

neurologic death b. Positive if no respiratory response to
PaCO >60 mmHg or 20 mmHg greater
2

1. Establish clinical prerequisites than baseline values and final arterial

a. Cause of brain death is known (history, pH of <7.28
examination, neuroimaging, and 4. Perform ancillary tests if clinical criteria cannot
laboratory tests) be confidently applied (e.g. cranial nerves
b. Core temperature >36C (97F); warming cannot be adequately examined,
blanket may be required neuromuscular paralysis present, heavy
c. Systolic BP >100 mmHg; vasopressors sedation, apnea test not valid or cannot be
may be required completed, confounders such as multi-organ
d. No severe electrolyte, acid-base, failure render clinical examination unreliable,
endocrine, or circulatory disturbance shorten duration of observation period)
e. No drug intoxication or poisoning, a. Cerebral angiography approximates
including CNS depressants and gold standard but invasive, risky
neuromuscular blocking agents i. Cerebral angiography
2. Perform neurologic examination. Must ii. Transcranial Doppler
demonstrate absent cerebral and brainstem iii. MR angiography
function with all of following findings: iv. CT angiography
a. Coma v. Nuclear medicine
i. Lack all evidence of b. Profound hypotension and when cranial
responsiveness: eye opening or vault breached by trauma, surgery,
eye movement to noxious ventricular drain, or cranial sutures →
stimuli absent electroencephalography or
b. Absent brain-originating motor somatosensory evoked potentials may
response, including response to pain be superior
stimulus above neck (e.g. pressure
over supraorbital nerve, angle of lower GBM
jaw normally produces facial muscle  Biopsy
movement) o High nuclear/cytoplasmic ratio
c. Absent pupillary light reflex in both eyes o Numerous mitotic bodies: lesion is actively
using bright light growing/dividing
i. Normally fixd in midsize or o Central necrosis: lesion growing so fast it’s
dilated position (4-9 mm) outstripping own vascular supply
o Abnormal nuclei
ii. Constricted pupils suggest
o Vascular proliferation
possibility of drug intoxication o Stains strongly for GFAP (astrocytic in
d. Absent corneal reflex (cornea touched constituent cells)
with cotton swab or squirts of o Numerous Ki-67+ nuclei (monoclonal
water/saline, normal if eyelid moves) antibody that reacts with nuclei at all stages
e. Absent oculoencephalic (move head of cell division = lesion is
and neck; normal if eyes do not turn reproducing/growing faster than it should)
with head) and oculovestibular reflexes  GBM most common primary malignancy in adults
(irrigate ear canal, normal if eyes  Felt to arise from astrocyte-type cell (e.g. glial cell)
conjugately move toward irrigated side)  Grades I-IV (more aggressive)
o Pilocytic astrocytoma = slow growing,
f. Absent jaw jerk well-defined borders
g. Absent gag reflex (posterior pharyngeal o Low-grade = above but not borders well
wall touched with tongue depressor and defined
palate observed for elevation) o Anaplastic = above but mitotic bodies and
h. Absent cough with tracheal suctioning atypical nuclei
i. Absent sucking or rooting reflexes o GBM = above but with necrosis and
j. Apnea as demonstrated by apnea test vascular proliferation (try to keep feeding
3. Perform apnea test (CO challenge)
2
high-demand)
a. Core temperature >36C (97F), systolic  Poor prognosis even with chemo/radiation (median
14.6 months)
BP >100 mmHg, euvolemia, eucapnia  MRI
(35-45 PaCO ), absence of hypoxia, no
2
 o Contrast ‘ring’ enhancing, irregularly  Brief Huntington’s
shaped  Romberg (vision, proprioception, vestibular)
o Surrounding edema o Vestibular vs. sensory ataxia
o Satellite lesion  Midbrain, pons, medulla functions
o Areas of necrosis, hemorrhage, calcification  Dysdiadochokinesia
 Even if slow growing/benign, if growing in place  Ischemic cascade
with dense real estate (e.g. brainstem) = poor  Seizure video B&B
outcome  CHADS-2 for AF coagulation or not
o 0 = no anticoagulation
TESTS o 1 = weigh risk and benefits
 EEG assesses function o 2 = anticoagulation
 MRI assesses anatomy  Nystagmus (interest)
 Lumbar puncture looks for infection, inflammation,
malignancy
 MIGRAINE
 Rescue: triptans, OTC analgesics (keep <8d/m to
prevent overuse)
 Avoid narcotics: not effective, addiction potential
 Prophylaxis: non-opioid, non OTC analgesics.
Chosen based on side effects, overlapping effects
with comorbid conditions
o Supplements: riboflavin, magnesium
citrate, coenzyme Q10
o Beta-blcokers: propranolol, metoprolol
o Antiepileptics: valproic acid, topriamate
o Antidepressants: amitriptyline, nortriptyline
o Other antihypertesives: candesartan,
lisinopril
o Biologis
 RETURN TO FUNCTION
 Extended rest (>48h) not good
 Encourage but don’t rush graded return to function
 Be OK with back-trapping

EXTRA
 Finish spinal tracts and visual stuff
 ALS