TEST 1 Flashcards
1
Q
Chemical Transmission
A
- uses chemical synapse
- unidirectional communication
- relatively SLOW
==> Better Control - used by most neurons in CNS
excitiatory or inhibitory
2
Q
Electrical Transmission
A
- uses Gap Junction
- Bidirectional communication
- FASTER than chemical
- rare in mammals
3
Q
4 Criteria to be Neut?
A
1) Localization - present at nerve terminal
2) Release - released after AP reaches nerve terminal
3) Mimicry - can synthesize it in lab, and observe the same response
4) Inactivation - it should be inactivated by a specific mech
4
Q
Neut Property 1: Synthesis
A
Neut Synthesis and Packaging into Synaptic Vesicles:
- synthesis from precursors
- Enzymatic control of synthesis
- usually involves a Rate-limiting Step
- Localization: some synthesized at terminal (terminal synthesis), and some in the soma (somatic synthesis)
- inhibitory feedback on synthetic machinery via autoreceptors
5
Q
Neut Property 2: Release
A
AP Dependent release of synaptic vesicles contents into the Synaptic Cleft:
==> Depolarization==> Ca2+ influx at nerve terminal ==> exocytosis of vesicles
6
Q
Neut Property 3: Action
A
Binding of Neut to Postsynaptic Receptor:
- a single neut may bind to multiple receptor types
- binding is usually REVERSIBLE
- the effect is CONCENTRATION DEPENDENT:
- low [ ] can activate specific receptors
- high [ ] can bind to specific and non-specific receptors, causing undesirable side effects b/c of non-specific receptor activation
7
Q
Neut Property 4: Inactivation
A
Termination of Neut Action:
- extracellular degradative enzymes
- specific reuptake proteins
- diffusion of Neut away
- internalization of ligand-receptor complex
8
Q
postsynaptic receptors, 2 major classes:
A
ionotropic
metabotropic
9
Q
ionotropic receptor
A
==> Ligand-gated receptor ==> ACh Nicotinic
- the receptor itself is an ion channel
- onset: FAST
- duration: SHORT
- an ion channel?: YES
- direct effect on channel?: YES
- second messenger: NO
- amplification: NO
10
Q
metabotropic receptor
A
==> G-protein coupled receptor ==> ACh Muscarinic
- receptor is linked to ion channel with help of G-protein
- onset: SLOW
- duration: LONG
- an ion channel?: NO
- direct effect on channel?: NO
- second messenger: YES
- amplification: YES
11
Q
neut excitation or inhibition is determined by:
A
the receptor
12
Q
Excitation:
A
excitation ==> Depolarization of membrane potential towards firing threshold
- EPSP
13
Q
Inhibition:
A
inhibition==> Hyperpolarization of membrane potential away from firing threshold
- IPSP
14
Q
unique about peptide neuts:
A
- synthesis directed by mRNA
- usually exist as INACTIVE protein first
- MADE IN CELL BODY and transported to axonal terminal
- during transport, are cut by peptidase into smaller pieces becoming ACTIVE
15
Q
specific NEUTS: Amines, list
A
- ACh Nicotinic, muscarinic
- Dopamine D1, D2
- Norepinephrine alpha, beta
- epinephrine alpha, beta
- serotonin many
- histamine H1, H2
16
Q
specific NEUTS: Amino Acids, list
A
- Glutamate ionotropic: NMDA, non-NMDA
metabo: IP3, DAG - GABA iono: GABAa
metabo: GABAb - glycine
17
Q
specific NEUTS: Neuropeptides, list
A
- opiod peptides - beta-endorphin, enkephalin, dynorphin
- peptides that also act in the GI system
- pituitary peptides: oxytocin, vasopressin
- others
18
Q
specific NEUTS: Gases, list
A
- NO
- CO
19
Q
specific NEUTS: Amines, Catecholamines
A
Catecholamines: Dopamine, Epinephrine, NE
- all derived from TYROSINE (catechol nucleus)
- rate-limiting enzyme: Tyrosine Hydroxylase
- major player in NS, in many COLD MEDICINES as they mimic activation of Sympathetic NS ==> “sympathomimetics”
20
Q
specific NEUTS: Amines, Serotonin
A
Serotonin
- precursor ==> TRYPTOPHAN (mood)
- zoloft and others are SSRIs
21
Q
specific NEUTS: Amines, Histamine
A
Histamine:
- precursor ==> HISTIDINE
- helps cold-related symptoms
- anti-itch, anti-allergy
22
Q
specific NEUTS: Amines, ACh
A
ACh
- precursor ==> CHOLINE
- rate-limiting step: UPTAKE OF CHOLINE
- biosynthetic enzyme: Choline Acetyl Transferase (CAT)
- degradative enzyme: Acetylcholine Esterase (ACE)
- nicotinic receptors are at NMJ
23
Q
specific NEUTS: Amino Acids, Glutamate
A
Glutamate
- precursor: GLUTAMINE
- taken up by axon terminals and recycled after function is complete
- EXCITATORY NEUT
24
Q
NMDA - important for learning and memory
excessive glutamate release during stroke and CNS damage can lead to neuronal death ==> a type of EXCITOTOXICITY
A
- ionotropic receptor for Glutamate
- activated by endogenous release of glutamate
- REQS: co-activation of its Glycine binding site and partial depolarization of membrane
- with ligand binding: opening of non-specific cation conducting channels (Ca2+, Na+) // second messenger effect of Ca2+ influx
25
specific NEUTS: Amino Acids, GABA
GABA
- precursor: GLUTAMATE
- GABAa ==> ionotropic ==> Cl- influx
- GABAb ==> metabotropic ==> K+ efflux
- INHIBITORY NEUT
26
specific NEUTS: Amino Acids, Glycine
Glycine
- with receptor activation ==> CL-influx ==> hyperpolarization
- INHIBITORY NEUT
27
NO as a novel chemical messenger
NO
- a GAS, made and released by Neurons in the CNS and PNS
- RETROGRADE messenger
- no vesicular machinery needed for release
- in periphery, causes smooth muscle DILATION
- VIAGRA, increases erection
28
alpha-bungarotoxin
blocks binding of ACh to its Nicotinic receptor in PNS
| antagonist
29
atropine
muscarinic receptor blocker (used clinically to block postganglionic parasympathetics)
30
baclofen
GABAb agonist (used clinically to treat spasticity and some forms of epilepsy)
31
barbituate sedatives (phenobarbital)
increase the DURATION of GABAa Cl- channel opening
32
benzodiazepine (valium)
increases the FREQUENCY of GABAa Cl- channel opening
33
botulism toxin
blocks release of ACh
34
cocaine
blocks monoamine re-uptake at synapse to prolong action of Neuts
35
Curare
blocks binding of acetylcholine to its nicotinic receptor on skeletal muscle
36
LSD
acts as an agonist at postsynaptic serotonin receptors
37
morphine
mimics binding of opioid peptides to their receptors to produce analgesia
38
neostigimine
- inhibit acetylcholinesterase activity, prolonging acetylcholine activity
39
organophosphates (insecticides)
- irreversibly inactivates acetylcholinesterase
40
phenylcycldine (PCP)
an NMDA glutamte receptor blocker
41
strychnine
glycine receptro blocker
42
tricyclic antidepressants
block monoamine reuptake
43
zoloft and other SSRIs
selective serotonin reuptake inhibitors
44
Neuron types:
pseudounipolar
bipolar
multipolar
45
pseudounipolar
- have one process
- general sensory
- have cell body in DRG
46
bipolar
have 2 processes: a dendrite and a axon
| - special sensory
47
multipolar
- have one axon and 2 or more dendrites
| - MOTOR
48
Neuron organelles: Rough ER
ROugh ER
- in larger neurons is organized in to parallel cisternae with numerous polyribosomes between them ==> NISSL substance
- found in all parts of the neuron except the Axon Hillock
49
Neuron organelles: microtubules
Microtubules
- involved in movement and of structures and organelles in neuronal cytoplasm
- anterograde - transport away from soma
- retrograde - transport towards soma
50
Neuron organelles: lysosomes
Lysosomes
- contain degradative enzymes and INCLUSION
- Lipofuscin Granule - residues of enurons undigested by lysosomes
- Melanin - by product of catecholamine synthesis
51
Neurons: Dendrites
Dendrites:
- process of pseudounipolar neuron; structurally an axon divided into peripheral process bringing info to soma in DRG and a central process entering CNS via dorsal rootlets
- degree of myelination of peripheral DRG processes, along with diameter, the conduction velocity of the process: increased myelination ==> increased conduction velocity of AP
- neuronal dendrites are highly ARBORIZED - increases area of cell that can recieve synapses
- branches or arbors of dendrites decrease in diameter away from the soma
- cytoplasmic composition is the same as soma, EXCEPT they lack GOLGI COMPLEXES and their NISSL substances are often restricted to larger, more proximal portions of the branch
52
Neurons: Axons
Axons:
- one per neuron
- Axon Hillock - nissl substance and polyribosomes absent, can be distinguished form other cytoplasmic extensions by lack of nissl substance
- cannot synthesize or metabolize proteins
- axons within CNS are highly branched
- unlike dendrite, axon of a neuron in CNS can leave the CNS and enter the periphery
53
Anterograde Transport, 2 types
- Slow - 2-4mm/day, structural proteins and enzymes
| - Fast - 200-400 mm/day, membranes, mitochondria, synaptic vessels
54
Cells of CNS: Glial Cells
Glial Cells:
| Astrocytes and Oligodendrocytes
55
Cells of CNS: Astrocytes- processes of some are rich in GFAP
- with abundant GFAP ==> Fibrous Astrocytes, in BOTH grey and white matter
- with little GFAP ==> protoplasmic, are in grey matter
astrocytes
- PROLIFERATE after injury to CNS
- essential for dev. and maintenace of the BBB
- transport material to and from the vasculature and the substance of the CNS
- play vital role in modulation ionic environment in CNS and removing excess NEUTS
56
BBB
BBB = zona occludens junctions b/w endothelial cells
57
Cells of CNS: Oligodendrocytes
Oligodendrocytes
- MYELINATION of the CNS AXONS
- some provide trophic support to close proximity neuronal somata
58
Cells of CNS: Microglia
Microglia
- MESODERMAL ORIGIN
- arise from monocyte- macrophage system
- pop, in CNS slowly turns over as they migrate into and out of the CNS
- participate in INFLAMMATORY responses and PHAGOCYTIC activity
59
Cells of CNS: Ependyma
```
Ependyma
- line the 'interior of the CNS
-remains of proliferative layer of neural tube
- STEM CELLS for CNS
-
```
60
Cells of CNS: Choroidal Epithelial cells
Choroidal epithelial cells
- cells constituting epithelial covering of the choroid plexus
- start life as ependyma, then turn into choroidal cells when encountering the Pia
- forms the BLOOD -CSF BARRIER
- SECRETE CSF
61
Grey Matter
| protoplasmic
Grey Matter
- contains NEUROPIL - areas of gray matter consisting of intermingled processes like dendrites and axonal endings
- contain many more microglia than white
- has rich vasculature to bring O2 and glucose
62
Neuronal cell body organization, 2 ways
1) Nucleus - clusters of neuronal cell bodies having similar origin and function
2) Laminar - neuronal somata organized into LAyers, in cortex are organizes into columns perpendicular to pial surface
63
White matter
white matter
- mostly myelinated axons
- many oligodendrocytes, fibrous astrocytes and microglia
- no neuronal cell bodies==> poorly dev. vasculature
64
Synapse
| a Neuronal- Neuronal Interaction
Synapse
- contact of the axon of one neuron with a part of another neuron
- DETERMINES DIRECTION OF TRANSMISSION OF A NERVE IMPULSE
- in postsynaptic element, just below the thick membrane, there is the POSTSYNAPTIC DENSITY - contains numerous ion channels and Neut receptors that are linked to large complexes of several proteins ==> SIGNALING MACHINES
-
65
Synapse Classification ==>5
- chemical
- electrical
- neuromuscular - if synapse on skeletal muscle ==> Motor-End Plate, release Neuts at small specialized site on skeletal muscle
- cardiac and smooth ==>axon terminates in number of small Boutons and release neuts over wide area of cardiac and smooth muscle
- secretomotor - neuronal-glandular cell terminations
- neurosecretory - axons terminating freely near fenestrated capillaries and releasing large vesicles which enter blood stream
66
Neuronal-glial interactions
Neuronal/astrocyte
- astrocytes play major role in maintaining ionic environment of neuropil and the axon at the node of ranvier
- during dev, astrocytes determine the sites of the Nodes of ranvier
Neuronal/oligodendrocyte
- make myelin, can myelinate multiple neurons at once
67
CSF
CSF
- ultrafiltrate of PLASSA
- reabsorbed by Arachnoid Granulations
- 80% made in choroid plexus in lateral and 4th ventricles
- made by filtration across fenestrated capillary endothelial cells walls into chorodial epithelial cells
- composition closely controlled by limiting production to one site and by BBB and blood -CSF barrier
68
CSF pathophysiology ==> Hydrocephalus
| treat with CSF diverting shunts
CSF pathophys
- Non-communicating or Obstructuve Hydrocephalus
- stenosis of cerebral aqueduct preventing CSF flow and resulting in dilated lateral and 3rd ventricles
- CSF is unable to leave brain via cerebral aqueduct
- Communicating Hydrocephalus
- problems with CSF resorption via arachnoid granulations: pressure-dependent valves into venous system
69
AP characteristics: phases
ion currents during AP ==>
Na+ and K+
1) Rising Phase
2) Overshoot
3) Peak
4) Falling phase - K channels open
5) After hyperpolarization
70
-55mv
threshold, where Na channles begin to open
71
-70mv
resting membrane potential
72
Na channels
have 2 gates:
activation/deactivation
inactivation/deinactivation
73
K channels
are slower to inactivate b/c they don't have a inactivation gate
74
amplitude of AP is considered constant under normal (all or none) circumstances
yes it is
75
propagation of AP
Eddy Currents - regenerates the AP along the axon
- caused by influx of Na, the entering Na is attracted to nearby (-) region
- this depolarizes the nearby membrane to threshold generating an AP
- the Na entering from this AP evoke more eddy currents which depolarize to threshold the adj. membrane ==> propagating the AP
76
unmyelinated fibers
AP is generated sequentially on every piece of membrane, making for slow conduction
77
myelinated fibers
faster, b/c eddy currents skip the internodal segments and depolarize the membrane only at the nodes where Na channels congregate
- AP skipping node to node ==> Saltatory Conduction
- repolarization due to K leakage channels that are NOT actively opened ==> NO hyperpolarization ==> faster AP
78
refactory period
| - ensure FORWARD PROGRESS of AP
- Absolute refactory period - during spike of AP, another AP cannot be initiated, Na channels are NOT reset
- Relative Refactory period - during early part of after-depolarization, another AP can be initiated if the stimulus is strong enough, K channels are still open
- Subnormal Period - after-hyperpolarization phase, K channels are still open and MP is near equilibrium point for K but another AP can elicited by stimulus if its large enough to shift the MP to threshold
79
normal conduction away from soma
orthodromic
80
conduction towards somas
antidromic
81
APs cannot reverse direction
| normal conduction direction:
orthodromic
| APs can be conducted in either direction
82
Electrotonic (GRADED) Potentials
- changes in MP occurring in a small region of the cytoplasmic membrane
- if not large enough to cause MP to reach threshold. theyre not propagated
- ALL RESPONSES, WHETHER DE- OR HYPERPOLARIZING, THAT DO NOT MOVE THE MP TO THRESHOLD = ELECTROTONIC POTENtIALS, they are not propagated and dissipate quickly
83
cytoplasmic membrane acts like a electrical capacitor
- charge on one side of the membrane affects the charge on the other side of the membrane
- a change in MP w/o actual flow of ions across the membrane
- can depolarize neurons with a Cathode placed near the nerve
- can also elicit APs by mechanical pressure ==> funny bone
84
unhealthy nerve
has slowed conduction velocity ==> neuropathy
85
compound AP
produced by peripheral nerves, is the summation of many APs in a individual axons
86
if neuron remains above the threshold, the neuron is in:
Depolarization block
- can occur due to hypoxia and anoxia
- anoxia can be tolerated for 4 minutes
- hypoxia can be tolerated for a much longer period
- after restoration of blood, fibers repolarize and recover, and as MP repolarizes it crosses threshold and numerous APs are initiated, but b/c CNS does not interpret these as a sensation, tingling is felt
87
if neuron remains below the threshold, the neuron is in:
Hyperpolarization Block
- hypoxia or Local Anesthetics
- local anesthetics block voltage-gated Na channels
88
clusters of neurons outside the CNS
Ganglion
89
clusters of neurons inside the CNS
Nucleus
90
purkinje neurons
in the cerebellar cortex
- have characteristic fan shaped dendritic arbor
- if damaged, ataxia and tremors
91
pyramidal neurons
= UMN
- cell body in cerebral cortex
- if damaged, muscle spasicity
92
alpha motor neurons
= LMN
| - cell body in ventral horn of spinal cord and brainstem motor nuclei
93
preganglionic neurons
cell bodies in brainstem nuclei and lateral horn of spinal cord
- send axons to the postganglionic neurons (cell boy in PNS)
94
Neut in PSNS
ONLY ACh
95
neut in SNS
preganglionic neurons use ACh
| postganglionic neurons use NE, except at sweat glands, where ACh is used
96
ANS neuron locations, SNS
in spinal cord lateral horn at levels: T1 - L2
| and in chain and collateral ganglia
97
ANS neurons locations, PSNS
- cranial parasympathetics: brainstem nuclei and ganglia
| - sacral parasympathetics: spinal cord lateral horn S2-S4 and ganglia in organs
98
astrocyte functions
- both types have GFAP
- protoplasmic in grey
- fibrous in both
- has no visible nuclelus
- scavenge for ions and Nuets
- glycogen storage and release
- tells endothelial cells to form BBB
- form GLIAL scar - prevents CNS axon regeneration
99
oligodendrocytes
- few processes
- pycnotic nucleus
- no basal lamina
- near neurons
100
microglia
- migrate and phagocytose
- bone marrow origin
- infected by HIV
- crescent to triangular nucleus
MHC I and II
101
neuropil
collection of neuronal and glial processes
102
ependyma
- brain - csf barrier
- are ciliated to move CSF
- line ventricles and central canal(spinal cord)
103
BBB =
= endothelial cell tight junctions
- astrocytes signal endothelial cells to form tight junctions
- absent at CIRCUMVENTRICULAR ORGANS (pineal gland)
104
choroid plexus =
```
pia, ependyma and blood vessels
- in ventricles
- blood-csf barrier, make CSF
- tigh junction b/w choroid epithelial cells
-
```
105
fibroblasts
make meninges
106
excitotoxic injury
inappropriate activation of NMDA receptor ==> membrane depolarization ==> calcium influx ==> mitochondrial dysfunction
CNS ==> SELECTIVE VULNERABILITY
Excitotoxic injury is specifically seen in the CNS and is a cascade of events that results in spreading of neuronal injury to the surrounding, initially intact neurons. It starts when the actual injured neurons die and release their excitatory amino acids, which result in depolarization in the surrounding neurons through the NMDA receptors.
-This results in a calcium influx that interferes with the functions of the mitochondria, which further disrupts the energy-dependent functions and eventual cell death. Through excitotoxicity, a small injury can continue expanding. perpetuate
107
acute neuronal injury
shrunken neuron or red neuron, eosinophilic neuronal necrosis is the microscopic appearance of acute neuronal injury, which indicates neuron death, most commonly seen in hypoxic-ischemic injury
- can be seen 12hrs after insult by light microscopy
108
subacute/ chronic neuronal injury
degeneration (alzheimers)
109
axonal rxn
Axonal reaction refers to the changes that occur in the neuron body in response to axonal injury. It was named central chromatolysis, because of the impression that the cell was dying. In essence, it is a regenerative attempt by the neuron.
- margiantion of nissl substance
- central clearing of cytoplasm
- peripheral displacement of nucleus
- rounding of cell body
110
axonal spheroids
If an axon is transected, all the axonal transport material travelling from the cell body towards the synapse will start accumulating at the site of injury, since it cannot move any further. This will result in what is called axonal spheroids. Their identification is helpful in confirming the presence of an infarct next to them
111
silver stains
highlight axons as black lines, so that one may see swellings
112
```
neuronal inclusions
include: pigments: melanin, lipofuscin
viral inclusions
lewy body
pick body
neurofibrillary triangles
axonal spheroids
storage disease
```
Inclusion is an abnormal accumulation in the cell.
113
trans-synaptic degeneration
secondary degeneration of a neuron connected to a dying neuron
- can be anterograde or retrograde
- Therefore, there can be findings that are not necessarily indicative of the location of the initial lesion
114
Neurogenic Atrophy
progression:
1) normal muscle
2) motor unit loss with small group atrophy, the denervated fiber have a 'angulated atrophic' appearance
3) collateral axonal sprouting, reinnervation, and fiber type grouping with giant motor units
When the initially denervated “orphan” fibers are taken over by the other type of nerve fibers, they all become the same type, called fiber type grouping. They may now start contracting (functioning), but since the fibers a single neuron is responsible for is greatly increased, their activity is weak.
4) Further motor unit loss with large group atrophy
If the cause of denervation is an ongoing neurodegenerative disorder, then at some point, the neuron innervating the large group of one type of fibers that formed after reinnervation process will also degenerate, leaving the entire group atrophic.
115
early denervation
loss of motor units leads to:
- small angular fibers, assumes an angulated atrophic appearance with concave contours due to the pressure of the surrounding fibers
- involvement of both fibers
116
chronic denervation
axonal sprouting and reinnervation leads to:
- large motor units
- fiber type grouping, When the intact nerve fibers sprout to reinnervate the denervated myofibers, those myofibers switch to the type of that new nerve. This results in the loss of the normal chekerboard appearance on ATPase reactions. Now, large groups have same fiber type, alternating with other lerge groups
117
late denervation
loss of large motor units leads to:
- grouped atrophy,When the nerve that has reinnervated a large fascicle and resulted in fiber type grouping dies, then that entire fascicle becomes atrophic.
118
@ NMJ:
| Myasthenia Gravis
- autoantibodies against ACh receptors on pst-synaptic membrane
- immunological destruction of NMJ
- rapidly fading strength due to depletion of synaptic ACh
- association with thymoma
- simplified postsynaptic folds, compensatory proliferation of presynaptic vesicles
119
lambert - eaton syndrome
result of not being able to secret the acetylcholine into the synaptic cleft because of autoantibodies inhibiting the presynaptic calcium channel and blocking the release of acetylcholine into the synaptic cleft.
120
botulism
acts by blocking acetylcholine release by interfering with the fusion proteins involved in membrane fusion between the axon membrane and the synaptic vesicle membrane.
121
general myopathic changes
- Myofiber degeneration and/or regeneration
- Internalization of nuclei
- Increased endomysial connective tissue (scar formation)
- Inflammation
- Vacuolation
122
muscular dystrophy, general
Note the fiber size variation due to the presence of atrophic and hypertrophic fibers, as well as increased endomysial connective tissue as part of the scarring process due to the degeneration of fibers. Identification of the specific dystrophy type requires special stains and genetic testing. There are immunohistochemical stains for the components of this large transmembrane protein, such as dystrophin, merosin, laminin, etc. Normally, every stain will stain the sarcolemma in a linear fashion. The missing protein will not show staining, revealing what is missing.
123
ragged red fiber
result of compensatory proliferation of mitochondria in mitochondrial disorders
124
type II atrophy of muscle
may mimic neurogenic atrophy, but fiber typing reveals that only the type 2 fibers are uniformly atrophic.
125
inflammatory myopathies
polymyositis
dermatopolymyositis
inclusion body myositis
126
polymyositis
- intrafascicular inflammation
- due to CTL
- pain
127
dermatopolymyositis
- extrafascicular inflammation, with perifascicular atrophy
- due to humoral immunity
- rash and pain
128
inclusion body polymyositis
- inclusion; rimmed vacuoles
- degenerative
- steroid resistance
129
duchenne MD
- becker MD is a milder form
- myotonic dystrophy - a trinucleotide repeat disorder
- def of dystrophin
| - endomysial fibrosis with fiber ‘rounding,’ variation in fiber size, and myofiber regeneration
130
congenital myopathies
- fixed, structural defects
- weakness at birth, but nonprogressive
- Central core myopathy: note central pale areas
- rod-body, material similar to Z-accumulates into rod-shaped structures
- centronuclear myopathy - There is one central nucleus uniformly in essentially every fiber
131
disease of white matter overview:
- Loss of myelin is a general term that refers to the loss of previously-formed myelin
- Demyelination specifically refers to loss of previously-formed and intact myelin due to a specific problem destroying it, such as multiple sclerosis (MS) and related conditions
- Myelin Loss: Myelin damage with relative preservation of axons
- Interference with axonal transmission of impulses
- Regenerative capacity
- Secondary damage to axons
132
overview of myelin diseases
- Dysmyelinating diseases (a.k.a., leukodystrophies) are diseases where myelin is defective from the start and either cannot be produced or maintained appropriately
- Primary myelin diseases (multiple sclerosis)
- Diseases with indirect damage to myelin (e.g., HIV leukoencephalopathy, progressive multifocal leukoencephalopathy-PML,carbon monoxide poisoning)
- Dysmyelinating diseases- leukodystrophies
133
MS
- classical MS = Charcot type
- most common myelinating disorder
- relapsing/remitting episodes, gradual deterioration
- no definitive anatomical distribution
- autoimmune attack against myelin components
- mainly CD4+ T cells and CD 8+ T cells and macrophages
- most common lesions: optic nerve (unilateral visual problem), spinal cord (motor,sensory problem, bladder control problems), brain stem(cranial nerve deficits, ataxia)
134
MS, acute lesion
In the acute phase, inflammatory cells emigrate from the blood vessels (that is why we see perivascular inflammatory cells on sections) and attack the myelin sheaths, resulting in demyelination
135
MS, chronic lesion
In the chronic MS lesion, inflammation has subsided, there is reactive astrocytosis (black star-shaped cells), some axons degenerated (dotted line) and new myelin is forming on others
136
MS, diagnosis
MRI, together with typical clinical presentation, is diagnostic of MS by identifying the plaques (MS lesions).
- Oligoclonal bands are reduced numbers of immunoglobulin bands identified by electrophoresis of CSF
- increased Ig
137
MS, pathology
-On cross section of the brain, MS plaques are irregular tan-grey lesions randomly distributed in the white matter, typically deep and in some connection to the ventricular surface.
-
138
Devic disease (neuromyelitis optica)
- optic nerve and spinal cord involvement
- synchronous blindness and paraplegia
- autoantibodies to aquaporin-4 receptors
139
other demyelinating disease:
ADEM
ANHE
- main point about these dangerous conditions is that they tend to develop a few weeks after various infections/vaccinations, suggesting a cross reaction with and autoimmunity against myelin. All lesions tend to be of the same microscopic appearance, indicating a monophasic process. They are largely similar in both entities with the exception of hemorrhagic component in ANHE.
- acute dissemianted encephalomyelitis: Acute, monophasic, children and adults, with headache, lethargy, coma, rapid progression; viral infections/vaccinations
- acute necrotizing hemorrhagic encephalomyelitis: After urinary tract infection, M. pneumoniae infection, in children and young adults
140
other primary demyelinating diseases:
central pontine and extrapontine myelinolysis:Rapid correction of electrolyte imbalance, pons, internal capsule
- typical lesion is a demyelinating lesion in the center of base of pons (see slide 23). Its difference from MS involvement is its perfectly central location and symmetry, while MS lesions are irregular and usually have a connection to the surface of the brainstem.
- Osmotic demyelination syndrome, pontine and/or extrapontine, tends to occur in areas of the brain where grey and white matter are in close association, such as base of pons, internal capsule, lateral geniculate nuclei, cortex-white matter junction. The main culprit is rapid correction of hyponatremia
141
infectious demyelination:
HIV
PML
- HIV
- Progressive multifocal leukoencephalopathy (PML):
- viral infection of oligodendrogliocytes, interfering with their myelin-forming function. There are multiple white matter demyelinating lesions with characteristic intranuclear inclusions, enlarging the oligodendroglial nuclei and giving them a ground-glass and plum-colored appearance.
142
N. Meningitidis
causes meningitis
- is gram - diplococci
-
143
meningits
- sudden onset fever, headache, and neck stiffness
- petechiae may occur
- brudzinskis and kernig signs
- DIC
-
144
waterhouse - friederich syndrome
adrenal infarction leading ot acute adrenal insufficiency
- necrosis of adrenal gland, associated with DIC and WIDESPREAD petechial rash
- meningitis absent
- death from pulomnary insufficiency resulting form interstitial edema
145
neisseria pathogenesis
- Capsule - significant role in pathogenesis
- pili - for adherence to mucosla cells
- IgA protrease
- LOS - activates macrophages, to produce proinflammatory cytokines: TNF-alpha
- induces macrophage production of procoagulant tissue factor (DIC) ==> clotting and subsequent hemorrhage
146
meningitis diagnosis
- culture CSF on blood and chocolate agars
| - gram stain of CSF
147
toxoplasma gondii
- cause toxoplasmosis
| - cat = definitive host
148
toxoplasmosis
| - usually manifests as CNS disease like encephalopathy or meningoencephalitis
- real bad in immunocompromised ppl
- can be congenital:
- 1st trimester: spontaneous abortion, stillbirth, severe disease
- 2nd trimester: epilepsy, encephalitis, CHORIORETINITIS
149
toxoplasmosis, diagnosis
- serology ==> 4-fold increase in titer
150
primary amoebic meningoencephalitis
- caused by:
Naegleria fowleri
acanthamoeba
151
naegleria fowleri
- acquired by getting water into nose and penetration of cribiform plate
- produces meningoencephalitis: severe frontal headache, lethargy and fever ==> rapid progression
- death in 6-17 days
- will detect amoeba in CSF
152
acanthamoeba
-acquired by getting water into nose and penetration of cribiform plate
- CNS infection: a longer infection course than naegleria,
known as CHRONIC GRANULOMATOUS ENCEPHALITIS
- Ocular infection: KERTINITIS, due to contamination of contact lense or burised eye
153
exterceptor in skin
1) mechanoceptor A beta
2) nociceptor A delta + C
3) thermoceptor A delta + C
154
muscle receptors
golgi tendon organ
| muscle spindel
155
golgi tendon
- in tendon of muscle
- arranges in 'series' in muscle mass
- detects tension from BOTH stretches and constrictions
- innervation: A alpha = Ib
156
```
muscle spindel
-muscle length changes => position
-rate of change of muscle length => velocity
2 types of intrafuscal fiber:
1) nuclear chain fiber
2) nuclear bag fiber
```
- in belly of muscle
- arranges in 'parallel'
- contain intrafuscal muscle fibers that are iinervated by gamma motorneurons
- detect ONLY MUSCLE STRETCH
- innervation: A alpha = Ia
and A beta = II
157
alpha - gamma linkage
When the α-motor neuron causes muscle contraction,
we also use γ-motor neuron to activate the intrafusal muscle fibers, and cause it to contract.
As a result, muscle spindle does not become floppy and will remain sensitive to the length of the muscle mass.
- keeps the muscle spindle sensitive
158
joint position sense
, a good joint position sense depends on sensory receptors in the joints as well as those in the muscle and on the skin surrounding the joint.
159
abnormal reflex
if: 4+ or asymmetrical
160
syringomyelia
- cystic cavity (syrinx) within the spinal cord
| - 'cape-like' bilateral loss of pain and temp sensation in UE
161
friedrich's ataxia
- AR
- due to unstable trinucleotide repeat in FRATAXIN gene which leads to impairment in mitochondrial function
- ataxia
- loss of vibration sense and proprioception
- areflexia with + babinski sign
- hypertrophiccardiomyopathy
162
adrenomyeloneuropathy
- myelopathy with progressive paraparesis (LE) ( UMN signs)
- peripheral neuropathy
- +/- adrenal insufficiency
- variant of adrenoleukodystrophy
- demyelinative disorder
- abnormal peroxisomal FA beta oxidation
- VL chain FA accumulation in oligodendroctyes, adrenal cortex ...
- white matter degeneration and adrenal insufficiency
163
hereditary spastic paraparesis
- Age at onset – Infancy -> 7th decade
-Phenotype:
Progressive LE weakness with UMN signs
Bladder dysfunction
Variable impaired vibration sensation
164
neoplastic spinal cord disorders
==> epidural compression, an emergency
- primary tumors
- secondary (metastaic) tumors:
165
```
vascular spinal cord diseases
arteriovenous malformation (AVMs)
```
infarctions
abnormal tangle of blood vessels on, in or near spinal cord
| - can lead to hemorrhage or compression
166
trauma: hyperflexion (hangmans Fx), hyperextension, compression
```
- complications:
Paresis & paralysis
Bladder dysfunction – spastic bladder or dyssynergia
Pressure sores
Infections
Depression & suicide
```
167
NM diseases: categories
- only category with sensory probs: peripheral nerve disorders
- peripheral: distal > proximal weakness
- NMJ and Muscle: proximal > distal
-
disorders of the MOTOR UNIT:
- Motor neuron disease
- Peripheral nerve disorders
- Neuromuscular junction disease
- Muscle disease
168
motor neuron disease, general:
| UMN lesions
```
Signs
Weakness or paralysis
Spasticity
Increased reflexes
An extensor plantar
(Babinski) response
Loss of superficial
abdominal reflexes
Little, if any, muscle atrophy
```
169
motor neuron disease, general:
| LMN lesions
```
Signs
Weakness or paralysis
Wasting and fasciculations
Hypotonia (flaccidity)
Loss of tendon reflexes
Normal abdominal and plantar reflexes
```
170
peripheral nerve disease, general:
Clinical Presentation:
- Numbness
- Impaired vibration perception
- Atrophy of small muscles of hands and feet
- Weakness
- Ataxia
- Pain (early hyperesthesia and hyperalgesia)
- Risk for Charcot foot
171
NMJ disease, general:
symptoms not bad in morning, but get worse as day progresses
Signs
- Normal or reduced muscle tone
- Normal or depressed tendon and superficial reflexes.
- No sensory changes
- Weakness, often patchy in distribution, not conforming to the distribution of any single anatomic structure; frequently involves the cranial muscles and may fluctuate in severity over short periods, particularly in relation to activity
172
muscle disease (myopathic disease), general:
Signs
- Weakness, usually most marked proximally rather than distally
- No muscle wasting or depression of tendon reflexes until at least an advanced stage of the disorder
- Normal abdominal and plantar reflexes
- No sensory loss or sphincter disturbances
173
motor neuron disease:
ALS
risk factor: smoking
better prognosis:
- male
- extremity onset
- young age
amyotrophic lateral sclerosis:
- caused by a variety of different mutations: genetic susceptibility with an environmental insult
- Loss of motor neurons in the cortex, brainstem and spinal cord
- MIX OF UMN AND LMN FINDINGS:
- Weakness, atrophy, fasciculations
- Slurred speech, difficulty swallowing, shortness of breath
- Can start in any extremity or the bulbar musculature
- NO SENSORY OR AUTONOMIC CHANGES
- 15% have frontotemporal dementia (FTD)
- Relentlessly progressive => eventually involves motor neurons to breathing muscles => death
174
ALS treatment
Riluzole:
- Antiglutamate agent
- Prolonged survival - modest benefits
- Only agent with proven efficacy
- Many other agents tried
- Other antiglutamatergic meds, trophic factors, immunosuppressants, vitamins E & C (antixoidants)
- Supportive care
- Noninvasive Ventilation
175
motor neuron diseases
The MNDs are a spectrum, and PMA, PLS and PBP can all evolve into ALS
176
spinal muscular atrophy (SMA/PMA)
Most common form of inherited MND - autosomal recessive
Age of onset:
- Infancy - Werdnig Hoffman disease
- Adolescence - Kugelberg Welander disease
- Late onset
Survival motor neuron gene with a modifier gene that effects onset age
177
peripheral nerve disorders:
```
Mononeuropathy:
- Pattern of weakness and sensory loss conforms to the distribution of a single nerve
- Carpal tunnel syndrome
- Peroneal palsy at the fibular head
Mononeuritis multiplex:
- Multiple nerves affected in a random pattern
- Acute onset, frequently painful
- Diabetes mellitus, vasculitis
Polyneuropathy (peripheral neuropathy):
- Distal, symmetric
```
178
polyneuropathies, affect what types of fiber:
- Autonomic
- Motor
- Sensory
- Large well myelinated
- Vibration and proprioception
- Small poorly myelinated or unmyelinated
- Pain and temperature
179
polyneuropathy:
| sensory symtoms
- Start in feet, move proximally
- Hand sxs appear when LE sxs up to knees
-Positive
Pins and needles
Tingling
Burning
- Negative
Numbness
Deadness
“Like I’m walking with thick socks on”
180
polyneuropathy:
| motor symptoms
```
Weakness first in feet
- Tripping
- Turn ankles
Progress to weakness in hands
- Trouble opening jars
- Trouble turning key in lock
```
181
polyneuropathy:
| autonomic symtoms
- Dry eyes
- Dry mouth
- Changes in sweating
- Lightheadness on standing (orthostatic hypotension)
- Bladder dysfunction
- Particularly incontinence
- Bowel dysfunction
- Post prandial (after eating) diarrhea
- Intermittent diarrhea/constipation
- Incontinence
- Erectile dysfunction
182
polyneuropathy: signs
```
Distal sensory loss
- Large fiber
- Small fiber
Distal weakness and atrophy
Decreased or absent reflexes
- Ankle jerks lost first
```
183
acute polyneuropathies
- Guillain Barre Syndrome
- Porphyria
- Neuropathy, psychiatric disorder, unexplained GI complaints
- Toxins
- Glue sniffing (n-hexane)
- Arsenic
184
guillain barre syndrome
- Most common cause of rapidly progressive weakness
- Demyelinating neuropathy
- Ascending weakness which may include cranial neuropathies
- Exam reveals symmetric weakness with areflexia and large fiber sensory loss
- Bowel and bladder usually preserved
- Respiratory failure can be precipitous
- Other causes of morbidity and mortality
- Autonomic instability
- DVT
- Infection
- Immune mediated, may be post infectious
- Treatment
- Plasma exchange
- Intravenous immunoglobulin
185
subacute polyneuropathies
```
Vasculitis
- Can be isolated to peripheral nerves or part of a more systemic process
- Pain
Paraneoplastic
- May be presenting symptom of the cancer
Chronic inflammatory demyelinating polyneuropathy
- With or without a gammopathy
Amyloid
Toxins
Drug
- Prescribed
- Recreational
```
186
chronic polyneuropathy
```
Metabolic:
- DIABETES MELLITUS
- Chronic renal failure
- Chronic liver failure
- Thyroid disease
Nutritional:
- B12 deficiency
- Copper deficiency
Infections:
- HIV
- Leprosy
Inherited
```
187
NMJ disorders:
```
Pre-synaptic:
- Lambert Eaton myasthenic syndrome
- Botulism
Post-synaptic:
- Myasthenia Gravis most common post synaptic, associated with Ach receptors
```
188
myasthenia gravis: cause
simplification of motor end plates
Acetylcholine receptor autoantibody
- Antibody that alters the acetylcholine receptor
- Binding
- Blocking
- Modulating
- Antibody detected in
- 50% of pts with pure ocular MG
- 90-95% of pts with generalized MG
Muscle Specific Kinase Antibody (MUSK)
- Found in about 20-30% of the ab negative patients
-Primarily in patients with generalized disease
189
myasthenia gravis, clinical manifestations
- Sxs worsen with exercise, end of day (Fatigue)
- Ocular
- Droopy eyelids (ptosis)
- Double vision (diplopia)
- Extremity weakness
- ARMS > LEGS
- Bulbar
- Dysarthria
- Dysphagia
- Respiratory
- Shortness of breath
190
WEAKNESS OF EYEMOVEMENTS AND PTOSIS
==>myasthenia gravis
191
approach to treating MG
- Remove any exacerbating factors
- Infections, medication, endocrine disease
- Acetylcholinesterase inhibitors
- Plasma exchange/ intravenous immunoglobulin
- Thymectomy
- Immunosuppressants
- Prednisone
- Imuran (Azathioprine), Mycophenolate (Cellcept), Methotrexate
192
botulism
- Presynaptic part of the NMJ
- Prevents release of acetylcholine
- Food borne
- Infants at particular risk
- Features
- Weakness, may be profound
- Autonomic system dysfunction
- Pupillary involvement
- Dx:
- Nerve conduction studies
- Stool culture
- Rx: Antitoxin, supportive
193
lambert eaton myasthenic syndrome (LEMS)
- Presynaptic disorder of the NMJ
- Voltage gated calcium channel antibodies impede release of acetylcholine
- Weakness -
- MORE LE THAN UE
- bulbar and ocular muscles less often involved
- Decreased reflexes - post tetanic potentiation?
- ANS involvement
- Associated with a cancer in 40-60% of patients (paraneoplastic)
- Underlying cancer may be previously unrecognized
- Small cell lung cancer the most common
- Rx :
- Underlying cancer
- Guanidine
- 3,4 diamino pyridine
194
myopathies, outline
```
Dystrophies:
- Duchenne’s Muscular Dystrophy
- Myotonic Dystrophy
Congenital Myopathies:
- Glycogenoses
- Mitochondrial
Acquired Myopathies:
- Polymyositis
- Dermatomyositis
- Inclusion body myositis
- Drug related
```
195
duchenne's MD
gower's sign: indicates weakness of proximal muscles
- X-linked recessive
- ABSENCE OF DYSTROPHIN
- Slow to reach motor milestones, sxs by age 3
- All walk, may never run
- End up in wheelchair by age 10-12
- MUSCLES REPLACED BY FAT may appear hypertrophic
- Frequently mildly mentally retarded
- Life expectancy < 20 years with death related to respiratory failure or cardiomyopathy
196
myotonic dystrophy, general
- Most common of the adult dystrophies
- Autosomal dominant
- Age of onset varies
- Myotonia -
- Failure of relaxation of the muscle following contraction
- “Hands get stuck” cramping
- May or may not be painful
197
myotonic dystrophy, neuromuscular features:
- Distal weakness
- Temporal wasting
- Ptosis
- Facial weakness
- Tongue weakness - dysarthria and dysphagia
- Involvement of respiratory muscles
198
myotonic dystrophy, involvement outside the NM system
- Heart
- Conduction block
- Decreased fertility, undescended testicles
- Diabetes mellitus
- Mild MR
- Frontal balding
199
idiopathic inflammatory myopathies
- Polymyositis (PM)
- Inclusion body myositis (IBM)
- Dermatomyositis (DM)
- Together - incidence ~ 1:100,000
- Common Features:
Weakness
Muscle aches and pains
Elevated CK (creatinine kinase)
- May occur at any age but rare under 18
- Subacute onset of proximal > distal weakness
- Muscle pain and tenderness
Seen in 50%
- Respiratory involvement
Mostly late, in patients with severe, unresponsive disease
200
polymyositis
- 1/3 of all cases of inflammatory myopathies
- Symmetric and proximal
- Dysphagia occurs in 25% of patients
- Cardiac disturbance in 30%:
Conduction disturbances
Tachyarrhythmias
CHF
- Respiratory impairment in 5%:
Interstitial lung disease-fibrosis and pneumonitis in 10%
- Biopsy of muscle confirms diagnosis
- Treatment with immunosuppression:
Prednisone
Methotrexate
Azathioprine
201
dermatopolymyositis
- Affects children (Ages 5-15) as well as adults
- Females more affected than males
- Subacute onset of proximal > distal weakness
- Dysphagia in 1/3
- Fulminant cases:
More rapid onset, with very high CPKs
ARF (acute renal failure)
- Skin changes - present in 60%, frequently first
202
DM, associated conditions
```
Malignancy:
- Increased, particularly in adults over 40
- Risk greatest within 5 yrs of dx of DM
- Most common cancers:
Ovarian
Lung
Pancreatic
Colorectal
Joint disease:
- Arthritis
- Arthralgias
Treatment:
- Prednisone
- Intravenous immunoglobulin (IVIG)
```
203
inclusion body myositis
proximal LE
distal UE
does not respond to immunosuppression
- The most common idiopathic inflammatory myopathy in adults (>60yo)
- Indolent onset
- Sxs up to 10 yrs before medical care sought
- Typical pattern of weakness - majority but not all pts:
- Asymmetric
- Wrist and finger flexors
- Quadriceps
In contrast to PM:
- Dysphagia (40-60%) and facial weakness (30%) more common
- Etiology unclear
“aging” of muscle?
- Do not respond to immunosuppression
204
cholesterol agent lowering myopathy (CLAM)
```
Presentations:
- Asymptomatic myopathy
- Symptomatic myopathy
- Clinical important rhabdomyolysis
Up to 35% of patients taking a statin have elevation in CK
When do symptoms occur?
- Statin alone – average 1 year
- Statin + fibrate – 32 days
```
205
CLAM, factors assocaited with increased riskof CLAM
```
Female gender
Small size
Renal impairment
Liver impairment
Increased age
Hypothyroidism
Diabetes mellitus
Genetics
Underlying muscle disease
Severe Hypertriglyceridemia
?Asian heritage
```
206
CLAM treatment
- If sxs tolerable, and CPK < 10 X ULN, can continue statin and monitor sxs
- Stop the statin:
- If sxs intolerable
- If CPK > 10 x ULN
- If elevation of BUN / Cr develops
- Most have sxs resolve within 3 months
- Nearly 60% chance of having recurrence of symptoms with another agent
- Weigh the pros / cons
