Unit I, Week 2 Flashcards
1
Q
Cholinergic receptor for:
Heart Blood vessels Lung Eye GI/GU CNS NMJ
A
Heart - M2 Blood vessels - M3 (no direct innervation - via NO synthesis) Lung - M3 Eye - M3 GI/GU - M3 CNS - M1 NMJ - N-M
2
Q
Adrenergic receptor for:
Heart Blood vessels Lung Eye GI/GU CNS NMJ
A
Heart - B1 Blood vessels - a1 and B2 Lung - B2 Eye - a1 GI/GU - B2, a1, B2 CNS - a1 NMJ - B2
3
Q
Cholinergic agonist effect on:
Heart - (3)
Blood vessels - (1)
Lung - (2)
A
Heart - decrease HR (SA node), decrease conduction (AV node), decrease contractility (atria only)
Blood vessels - Vasodilation (not innervated by PNS, due to NO synthesis)
Lung - Bronchoconstriction, increase secretions
4
Q
Cholinergic agonist effect on:
Eye - (3) + one disease it can treat
GI/GU - (3) + 2 diseases it can treat
CNS - (3) + 1 disease it can treat
NMJ - (1) + 1 disease it can treat
A
Eye - Miosis (constriction), focus (accommodation), increase
[Glaucoma treatment]
GI/GU - salivation, increased detrusor contraction (increase urinary flow), increase GI motility
[Xerostomia (salivation)]
[Paralytic Ileus (GI motility)]
CNS - memory, cognition, movement
[Alzheimers]
NMJ - muscle contraction
[Myasthenia Gravis - ab to postsynaptic ACh receptor]
5
Q
Cholinergic antagonist effect on:
Heart - (3)
Blood vessels - (1)
Lung - (2) + 2 diseases it can treat
A
Heart - increase HR (SA node), increase conduction (AV node), increase contractility (atria)
Blood vessels - Vasoconstriction
Lung - Bronchodilation, decrease secretions
[COPD and Asthma]
6
Q
Anti-Cholinergic effect on:
Eye - (3)
GI/GU - (3) + 2 diseases it can treat
CNS - 2 diseases it can treat
NMJ - (1) + 1 clinical use
A
Eye - dilation, blurred vision, decrease aqueous humor outflow (NO SEE)
–> makes glaucoma worse, used for eye exams
GI/GU - decrease salivation, block detrusor muscle, decrease GI motility (NO PEE, NO SHIT, NO SPIT)
[OAB]
[Diarrhea]
CNS - Parkinson’s, Anti-Emetic
NMJ - Flaccid paralysis
[surgery, muscle relaxation]
7
Q
Adrenergic Agonist effect on: (via what receptor)
Heart - (2)
Blood vessels - (2) + 2 diseases it can treat
Lung - (1) + 1 disease
A
Heart - increase HR, increase contractility (B1)
Blood Vessels -
a1 –> vasoconstriction [hypotensive shock, decongestant]
B2 –> vasodilation
Lung - B2 –> bronchodilation [asthma]
8
Q
______ and ______ drugs can be used to treat asthma via ____ and ____ receptors
A
Cholinergic antagonists (M3) Adrenergic agonists (B2)
9
Q
Adrenergic Agonist effect on: (via what receptor)
Eye
A
Dilation (Mydriasis) - a1
10
Q
Adrenergic Agonist effect on: (via what receptor)
GI/GU - (3) + 3 diseases
A
Detrusor muscle relaxation (B2) - [OAB] Close sphincter (a1) --> [promote continence] Uterine relaxation (B2) --> [premature labor]
11
Q
Adrenergic Agonist effect on: (via what receptor)
CNS - (2) + 1 disease it treats
NMJ - (1)
A
CNS - increased vigilance and focus [ADHD]
NMJ - Muscle tremors
12
Q
Adrenergic Antagonist effect on: (via what receptor)
Heart
Blood vessels
Lung
A
Heart - (B1 block) decrease HR, decrease contractility
Blood vessels -
(a1 block) –> vasodilation
(B2 block) –> vasoconstriction
Lung -
(B2 block) –> bronchoconstriction
13
Q
Adrenergic Antagonist effect on: (via what receptor)
Eye - 1 effect, 1 disease it can treat
A
B1 and B2 –> decrease aqueous humor production (decrease IOP)
[glaucoma]
(*No effect seen with a1 receptor)
14
Q
Adrenergic Antagonist effect on: (via what receptor)
GI/GU - (1) + 2 diseases it can treat
A
a1 block –> open sphincter
[micturition disorders, BPH]
15
Q
Bethanechol and Pilocarpine are (direct/indirect) ________________
A
DIRECT
cholinergic agonists
16
Q
Neostigmine and Pyridostigmine are (direct/indirect) ______________
A
INDIRECT
cholinergic agonists (via acetylcholine esterase inhibition)
17
Q
Edrophonium and donepezil are (direct/Indirect) _____________
A
INDIRECT
cholinergic agonists (via acetylcholine esterase inhibition)
18
Q
Organophosphate nerve gases are (direct/Indirect) _____________
A
INDIRECT
cholinergic agonists (via acetylcholine esterase inhibition)
19
Q
activation of Gq via _____ and ______ muscarinic receptors causes what?
A
M1, M3
Gq –> increase PLC –> IP3 + DAG –> increase Ca2+ into cell and PKC activation
20
Q
activation of Gi/o via _____ and ______ muscarinic receptors causes what?
A
M2, M4
Gi/o –> decrease AC –> decrease cAMP –> increase K+ out of cell, and decrease Ca2+ into cell
21
Q
activation of Gq via _____ adrenergic receptor causes what?
A
a1
Gq –> increase PLC –> IP3 + DAG –> increase Ca2+ into cell and PKC activation
22
Q
activation of Gi/o via _____ adrenergic receptor causes what?
A
a2
Gi protein inhibits AC –> decrease cAMP levels or opens K+ channels (hyperpolarization)
couples to Go to decrease Ca++ movement through L- and N- type channels
23
Q
activation of Gs via _____ and ______ adrenergic receptor causes what?
A
B1 and B2
Gs –> increase AC –> increase cAMP, activate PKA
B1 –> increase L-type Ca2+ channels movement of Ca2+ in
24
Q
Process by which M3 receptor activation can cause vasodilation
A
M3 receptor activation on endothelial cell –> NO synthesis –> diffuse to smooth muscle cell in vessel wall –> activates G-cyclase –> increase cGMP –> smooth muscle relaxation
25
Pilocarpine can be used to treat _______ and ______
glaucoma and xerostomia
long acting topical agent
26
Urinary retention can be treated with _____ and ______
bethanechol and neostigmine
27
Xerostomia
- salivary gland hypofunction from radiotherapy for cancer or in patients with Sjogren's syndrome
- can also occur with antimuscarinic side effects
28
Atropine
antidote - used to block excessive muscarinic receptor stimulation
29
Adverse effects of muscarinic receptor agonists (6)
SLUDGE BB
```
Salivation
Lacrimation
Urination
Defecation
GI --> cramping and emesis
Eye (miosis), Emesis
```
30
Initial sign and adverse reactions of indirect acting muscarinic receptor agonists
Initial sign = muscarinic excess and double vision
SLUDGE + BB
```
Bradycardia
Bronchoconstriction (and increased secretions)
```
31
Initial sign and adverse reactions of indirect acting nicotinic receptor agonists
Initial sign = muscarinic excess and double vision
MATCH
1) Muscle weakness, fasiculations (NM) --> flaccid paralysis (respiratory failure possible)
2) Adrenal medulla activity increases (NN)
3) Tachycardia (NN)
4) Cramping of skeletal muscle (NM)
5) Hypertension (NN)
32
Pralidoxime
mechanism of action and use
regenerates AChE --> ANTI cholinergic, increases ACh break down
Prevents over-activation of NM receptors (this over-activation can cause flaccid paralysis and respiratory failure)
33
Atropine and Scopolamine are (direct/indirect), (selective, nonselective) ____________
can be used to treat ______ and _______
direct, nonselective ANTImuscarinic drugs
severe bradycardia and overdose of muscarinic agonist (e.g. organophosphate nerve gas)
34
Atracurium, Rocuronium, and Succinylcholine are ________________ that act on the _____ receptor
```
neuromuscular blockers (N-M receptor)
antinicotinic drugs
```
35
Effect of muscarinic agonist on sweating? Via what receptor?
what effect about antimuscarinic drugs on sweating?
M3
Increase sweating and heat loss
antimuscarinic drugs can cause an increase in body temperature due to an inhibition of sweating
36
Ipratropium and tiotropium are _________ and are used to treat _____ and _______
anticholinergic/antimuscarinic drugs
asthma and COPD
37
Oxybutynin and Tolterodine are __________ and are used to treat ______
anticholinergic/antimuscarinic drugs
overactive bladder (OAB)
38
Adverse reactions of anticholinergic (antimuscarinic) drugs include...
CNS effects (drowsiness, sedation, delerium)
```
NO PEE (urinary retention)
NO SEE (blurred vision)
NO SPIT (dry mouth)
NO SHIT (constipation)
```
Tachycardia - minimal effect on BP because there is no muscarinic tone in vasculature
39
Epinephrine
acts on what receptors, selective or nonselective?
a1-a2-B1-B2
NON SELECTIVE
40
Norepinephrine
acts on what receptors, selective or nonselective?
a1-a2-B1
NON SELECTIVE
41
Isoproterenol
acts on what receptors, selective or nonselective?
B1-B2 NON SELECTIVE
42
Albuterol
acts on what receptors, selective or nonselective?
B2 selective
43
Phenylephrine
acts on what receptors, selective or nonselective?
a1-selective
44
Pseudoephedrine
mechanism?
indirect acting activator of adrenergic system via release of NE at a1 receptor --> vasoconstriction (in nose, etc.)
45
Dobutamine
acts on what receptors, selective or nonselective?
B1 selective
46
Dopamine (cocaine)
mechanism?
Adrenergic reuptake inhibitor --> adrenergic agonist
47
Clonidine
a2 selective agonist (CNS only)
actually is ANTI ADRENERGIC - opposed PNS by inhibiting release of ACh
48
a1 receptor activators cause _______ --> ______ and _____ which can then result in what side effect?
VASOCONSTRICTION
increase TPR and BP
--> reflex bradycardia
49
B2 receptor activators cause _______ --> ______ and _____ which can then result in what side effect?
VASODILATION
decrease TPR and BP
--> reflex tachycardia
50
Doxazosin, Terazosin, Prazosin
what receptor, selective/nonselective?
uses?
a1 - selective ANTAGONIST
--> sphincter relaxation
Urinary obstruction (BPH)
51
Metoprolol, Atenolol
what receptor, selective/nonselective?
B1 selective
52
Propranolol
what receptor, selective/nonselective?
B1-B2 nonselective
53
Labetolol-Carvedilol
what receptor, selective/nonselective?
a1-B1-B2 nonselective
54
When does myelination occur?
MOST myelination during postnatal development
- Begins during embryonic stages in periphery
- CNS myelination first observed in spinal cord near end of first trimester, by third trimester, myelination present in brain
- Myelination of cortical tracts involved in higher functions occurs AFTER birth
- Corticospinal tract begins to be myelinated prior to birth, but only extends past medulla after birth
55
Developmental regulation of GABA receptors in adult vs. during development
In adult: equilibrium potential (ECl) near or negative to resting membrane potential → GABA is INHIBITORY
During development: intracellular levels of chloride are elevated, ECl more positive
-GABA → depolarization and EXCITATION
56
Normal Postnatal Changes in Brain Morphology
At birth, low density of neural connections → in childhood has very high density
Postnatal development leads to a dramatic increase in the number of dendrites and number of interconnections
57
Autism Spectrum Disorder and postnatal changes in brain morphology
Autism = disease of synapse maturation and maintenance
- At birth - normal or smaller brain size
- First postnatal years - brain size increases abnormally, especially in white matter and neuronal cell bodies are smaller with dendrites branching less
May be due to abnormal pruning and/or synapse maturation processes that require neuronal interactions
58
Factors that influence axon regeneration in CNS (3)
1) The ability to grow
2) The presence of molecules that promote growth
3) The presence of molecules and receptors that inhibit growth
59
Are CNS axons CAPABLE or regenerating?
YES -
CNS axons capable of regenerating long distances if peripheral nerve is implanted at site of injury to the spinal cord → CNS axons can grow many centimeters in the peripheral nerve
HOWEVER - CNS axons do not regrow because of the inhibitory molecules present that prevent growth
60
What molecules are present that promote growth of axons and which cells secrete them?
Glial environment through which the axon grows affects its ability to regenerate
Schwann cell → NGF or other factor to promote axon growth
61
What molecules are present that inhibit growth of axons and which cells secrete them?
CNS myelin (oligodendrocytes) expresses molecule (Nogo) that prevents axonal regeneration in adult CNS → hostile environment to growth
62
Growth cone of axon
growing tip of axon
Continuously extends and retracts filopodia that “sniff” biochemical environment to “sense” which way to grow
-NOT a passive growth along a physical matrix
63
Two types of guidance information the growth cone uses
Long-range chemotaxis and local substrate cues (short-range guidance molecules)
64
Long Range axon guidance molecules
Attractive (1)
Repulsive (2)
Diffusible
Attractive = Netrins
Repulsive = Semaphorins, netrins
65
Short-Range Axon Guidance Molecules
bound to cell membrane of extracellular matrix - requires direct cell contact
66
Attractive Short-Range Axon Guidance Molecules include...
Cell surface = cadherins, cell adhesion molecules (CAMs)
ECM = collagen, laminin, fibronectin, proteoglycans
67
Repulsive Short-Range Axon Guidance Molecules
Repulsive:
Cell surface = semaphorins, ephrins
ECM = tenascin
68
Neurotrophins
- “Trophic factors” from pre and postsynaptic cells and non-neuronal cells (glia) that promote cell survival - inhibit apoptotic cell death programs via intracellular signaling cascades
- Important regulators of neuronal survival, development, and function in CNS and PNS
- Play an early “permissive” role in axon outgrowth - allow cells to extend axonal processes rather than guiding them to targets (pathfinding)
69
NGF and BDNF are _______
neurotrophins
70
Neurotrophins interact with ____________ membrane receptors
tropomyosin-related kinase (Trk) family membrane receptors
Each neurotrophin can activate one or more Trk
71
What happens when a neurotrophin activates Trk receptor?
Activation of Trk receptor → Trk dimerization and phosphorylation of cytoplasmic signaling domains
→ recruitment of intracellular signaling molecules
→ typically promotes cell survival
72
Presynaptic requirements for synapse formation
Growth cone matures and is converted to presynaptic terminal
Presynaptically - must have efficient active zone with lots of SNARE complex with vesicles and Ca2+ channels together
73
Postsynaptic requirements for synapse formation
Postsynaptic membrane must have receptor accumulation and scaffold formation
Post synaptically - must have receptor accumulation
Scaffold allows receptors to be localized together postsynaptically and ensure that presynaptic release efficiently stimulates postsynaptic cascade
74
Proper synapse formation involves intense dialogue between presynaptic terminal and postsynaptic membrane
what are 4 proteins important for pre-post alignment?
1) Cadherins
2) Contactin and contactin associated proteins
3) Neurexins (associated with Ca2+ channels presynaptically) → 4) neuroligands (postsynaptically interact with scaffold proteins PSD95)
75
Selective synapse elimination in PNS
initial excess of contacted cells between muscle fibers and neurons reduced
Competitive process
Inappropriate synapses eliminated so that in mature system, each muscle fiber innervated by only one motor neuron
76
In selective synapse elimination, are the total number of synapses reduced?
Total number of synapses may not decrease (may increase) - motor neuron will generate more synapses with the same muscle fiber
77
What two processes modulate selective synapse elimination
1) Electrical Activity
| 2) Neurotrophins (from postsynaptic cell)
78
How does electrical activity affect selective synapse elimination
Electrical activity of innervating neuron important - correlated firing of pre and postsynaptic cells favors selective synapse stabilization
Uncorrelated/asynchronous firing → elimination
“Cells that fire together wire together”
79
How do neurotrophins affect selective synapse elimination
Neurotrophins released by postsynaptic cell taken up into presynaptic terminal and promotes maintenance of synapse
Repetitive neuronal activity → increased expression/secretion of neurotrophins from postsynaptic cells
→ act on pre or postsynaptic cell → modulate synaptic efficacy and promote structural changes that later alter patterns of connectivity
80
Cell Death in the Nervous System
Lots of mitoses during embryogenesis results in initial overproduction of cells → subsequent periods of cell death result in almost half the original cell population
Cell death responsible for pattern formation, brain morphogenesis, removal of unnecessary neurons, and matching neuronal populations to target fields
81
Stages of neuronal migration (3)
1) Onset of neuronal migration
2) Ongoing Migration
3) Migration stop
82
Which disease (and gene mutation) is associated with problems with onset of neuronal migration?
Periventricular Heterotopia (PH)
filamin A gene (FLNA)
83
Periventricular Heterotopia
mutation in filamin A gene (FLNA) --> prevents neurons from leaving ventricular zone
X-linked dominant (fatal for males)
84
Diseases (2) (and gene mutations) associated with defect in ongoing migration
Type I Lissencephaly
--> LIS1 gene mutation
Double cortex syndrome
--> DCX gene mutation
85
Type I Lissencephaly
Problem during ongoing migration
Neurons exit ventricular zone and migrate towards cortical plate, but halt migration prematurely, before reaching CP
→ Smooth surface
Mutation in LIS1 gene
Neurons derail from glia at inappropriate positions
86
Double Cortex Syndrome
Problem during ongoing migration
Neurons exit ventricular zone and migrate towards cortical plate, but halt migration prematurely, before reaching CP
→ Smooth surface
Mutation in Doublecortin (DCX) gene
DCX produces novel protein that coalesces and interferes with the microtubular cytoskeleton
--> Affects ability to stay on cytoskeleton
X linked
Heterozygous females may have less severe symptoms than affected males
87
The ______ protein is a required for neurons to stop migration. It is secreted by ___________
Reelin protein
secreted by Cajal-Retzius cells
88
Cajal-Retzius cells
Reelin protein normally expressed by Cajal-Retzius cells
transiently present during embryogenesis in marginal zone and preplate
89
What happens if you have a mutation in the reeler gene
reelin protein defective → inverted cortex inside-out pattern because neurons do not travel past earlier born neurons
Known as LCH (Lissencephaly with Cerebral Hypoplasia)
90
Apoptosis
- occurs under normal physiological conditions,
- programmed cell death
- Cell actively participates in its own demise
- Nuclear and cytoplasmic condensation and DNA fragmentation
- Removal of cells by phagocytosis
- Neighboring cells shielded from intracellular contents of dying cell
- Most common cell death during development
91
Necrosis
occurs in response to extreme changes in physiological conditions leading to death of cells by loss of membrane integrity
- Neighboring cells exposed to contents of dying cell
- Mitochondria and ER swell
- Associated with trauma or other external injury
92
Normal Development
an individual who grows and matures on an expected path and achieves developmental milestones appropriately
93
Abnormal development
an individual who is unable to achieve developmental milestones as expected compared to those of similar age
94
Developmental Delay
- 2 standard deviations below mean for a child’s chronological age
- Delay can occur in one, two, or more domains (gross motor, fine motor, language, cognitive, social)
NOT the same as intellectual disability - all children with intellectual disability have developmental delay, but not all children with developmental delay have intellectual disability
95
Developmental quotient
developmental age/chronological age
| >85 give reassurance, 70-85 close monitoring, less than 70 refer
96
Intellectual Disability
- Present from childhood (18 yrs or less)
- Intellectual functioning at least 2 SD below mean (IQ 2 adaptive skill areas (communication, self care, home living, social skills, community use, self direction, health and safety, functional academics, leisure and work)
97
Cerebral Palsy
acquired, non-progressive, motor impairment
Onset in utero, infancy, or early development
98
What is the most common type of cerebral palsy and what is usually its cause?
Diplegic (spastic)
most common cause is prematurity and vascular insufficiency (stroke)
99
Autism
- Problems with social interaction and communication
- Restricted repertoire of interests, behaviors, and activities
- Delays/abnormal functioning in at least one of the following areas (onset before age 3)
1) Social interaction
2) Language as used in social communications
3) Symbolic or imaginative play
100
Congenital developmental disorders (some acquired causes?)
(CNS malformations)
-Malformations of cortical development or neurocutaneous disorders
- Intrauterine, “acquired”
1) Infections (CMV, toxoplasmosis)
2) Toxic (fetal alcohol)
3) Stroke
4) Unknown (congenital hydrocephalus)
101
Fragile X
clinical features?
mutated gene?
affects mostly ______
Genetic/heritable developmental disorder
Long jaw, high forehead, large/protuberant ears, hyperflexible joints, soft/velvety palmar skin, enlarged testes, initially shy with poor eye contact, then friendly and verbose, family history of MR
Mutation in FMR1 gene from a CGG trinucleotide repeat
Mostly affects boys
102
Rett Syndrome
clinical features?
mutated gene?
affects mostly ______
Microcephaly, ataxia, autistic features, stereotypical hand movements, hyperventilation, seizures
X linked MECP2 gene (affects girls)
103
Angelman Syndrome
clinical features?
mutated gene?
Wide mouth and prominent chin, seizures, microcephaly, nonverbal, happy demeanor/frequent smiling, ataxia, hand flapping
Chromosome 15q11-13, methylation/deletion
104
Lead can cause ______
some risks of lead poisoning
developmental disorders
Risks:
- House built before 1950 or earlier
- Victims of abuse and neglect
- Parents that are exposed to lead
- Low income families
105
Hypothyroidism can cause _________
developmental disorders
virtually eliminated with newborn screen
106
Signs/symptoms of Autism Spectrum disorders (general)
i. Qualitative impairment in reciprocal social communication
ii. Repetitive behaviors and restricted interests
- Limited ability to adapt to unexpected conditions, ability to attention shift, ability to modify behaviors based on changes in context
- Limited openness to novel ideas and activities
iii. Majority are “high functioning” - average or above IQ
107
Signs/symptoms of Autism Spectrum disorders (first 12 months)
Dyssynchrony with caregiver, lack of social smile, delayed response to name and poor social orienting, fewer vocalizations, poor vocal imitation
108
Signs/symptoms of Autism Spectrum disorders (folks under 3)
Lack of appropriate gaze, lack of warm, joyful expressions with directed gaze, lack of sharing interest or enjoyment, lack of response to name when called, lack of coordination of gaze, facial expression, gestures and sounds
109
Signs/symptoms of Autism Spectrum disorders (school aged youth)
Poor social reciprocity, impaired social-emotional understanding, difficulty modulating and integrating nonverbal behaviors, restricted/repetitive play, insistence on sameness, language often disordered
110
Signs/symptoms of Autism Spectrum disorders (Older children and adults) (5)
1. Limited reciprocity (usually improved from younger days)
2. Impaired gestures, unusual prosody, failure to understand nonverbal behaviors of others
3. Difficulty understanding motivations of other people
4. For some, there is much improvement in symptom severity - for others, more functional impairment around puberty
5. Mood and anxiety become increasingly relevant in day-to-day interactions
111
Prevalence of ASD
1/110 individuals, more common in males
i. Lifelong developmental disorder - clinical picture changes through development
ii. Identified between 2 and 5 years old
112
Conus Medullaris and spinal tethering
-typically located at level of L3 vertebral body at birth and should not be below L2 vertebral body by 3 months (at L1-L2 in adult)
Neural tube defects can cause “tethering” of spinal cord, preventing ascension of conus medullaris
Physical tension on cord can compromise blood supply → spinal cord dysfunction
113
Signs/symptoms of spinal cord tethering (prevention of conus medullaris ascension)
pain, upper motor neuron signs (hyperreflexia, spasticity), urinary incontinence
114
Neural Tube Defects
- neuropores fail to fuse (4th week) → persistent connection between amniotic cavity and spinal canal
- Associated with low folic acid intake before conception and during pregnancy
- Increased a-fetoprotein (AFP) in blood and amniotic fluid and increased acetylcholinesterase in amniotic fluid
- Most occur in lumbar region
115
Craniorachischisis totalis
most severe neural tube defect
Complete failure of primary neurulation
116
Anencephaly
failure of rostral (anterior) neuropore to close
- Forebrain neuroectoderm fails to separate from cutaneous ectoderm
- Open calvarium
- Spinal cord looks fine, but there is no forebrain
- Associated with maternal type I diabetes
- Maternal folate supplementation can reduce risk for anencephaly
117
Encephalocele
defect in skull with protrusion of leptomeninges +/- brain
- Has epidermal covering over cranial neural tube closure defect
- ->Some degree of skin closure present
-Survivable if minimal tissue in protrusion (surgery to remove big balloon off the top of the head)
118
Meningomyelocele
failure of closure of posterior (caudal) neuropore
- Neural tube continuous with skin
- Problem with innervation at level of defect and below
- Meninges AND neural tissue herniate through bony defect (can get CSF leak)
- Associated with tethering of spinal cord
119
Meningocele
skin covered CSF filled mass, continuous with CSF in spinal canal
- Meninges, but no neural tissue, herniate through bony defect
- Associated with tethering of spinal cord
120
Lipomyelocele/ Lipomyelomeningocele
- lipoma extends from subcutaneous tissues to dorsal aspect of cord → tether cord inferiorly
- Due to premature separation of cutaneous ectoderm during neurulation that allows mesenchyme to enter unclosed neural tube and differentiate into fat
121
Bony spina bifida occulta
- common incidental finding in kids and adults at L5-S1
- May or may not be symptomatic
- Failure of bony spinal canal to close, but no structural herniation
- Dura is intact
- Associated with tuft of hair, or skin dimple at level of bony defect
122
What is signs are often present with a neural tube defect
Cutaneous abnormalities can indicate underlying neural tube defect → dermal dimple, hairy patch of skin, lipoma, dermal sinus, capillary hemangioma
123
Holoprosencephaly
disorder of telencephalic development
- Failure of left and right hemispheres to separate (weeks 5-6)
- Single ventricle in early embryonic forebrain (prosencephalon) fails to form properly into two lateral ventricles and one third ventricle
- May be due to problems with SHH signaling pathway
124
3 degrees of holoprosencephaly severity
1) Alobar holoprosencephaly
2) Semilobar holoprosencephaly
3) Lobar holoprosencephaly
125
Alobar holoprosencephaly
no division of cerebral cortex (single forebrain + single ventricle)
Lethal in first year of life
126
Semilobar holoprosencephaly
partial cleavage of cerebral hemispheres, with hemisphere fusion at frontal region + single central ventricle
May survive into infancy
127
Lobar holoprosencephaly
cerebral hemispheres separate anteriorly and posteriorly with some fusion of structures
Normal life expectancy - severe mental and physical impairment
128
Cerebellar aplasia
complete absence of formation of cerebellum
129
Cerebellar hypoplasia (aka Dandy-Walker Malformation)
typically sporadic
- Partial/complete absence of formation of cerebellar vermis
- Cystic dilation of 4th ventricle
- Associated with hydrocephalus and spina bifida
130
Disorders of neuronal proliferation (2)
Megalencephaly
| Microcephaly
131
Disorders of neuronal migration (3)
Agyria (aka Lissencephaly) - cortex too thick
Polymicrogyria (thin cortex)
Heterotopias (out of place neurons, can get “double cortex”)
132
Intrauterine ischemic events late in pregnancy --> ?
Porencephaly, hyraencephaly, schizencephaly
microglia are functional, but astrocytes are not → end up with big empty hole
133
Causes of perinatal stroke in full term infants? (3)
what percent are ischemic vs. hemorrhagic?
1) Genetic
2) Malformative
3) Difficult delivery (breech, face, or cephalopelvic disproportion) → distortion of infant’s neck, stretching of carotids → vascular insufficiency during birth process
55% = ischemic, 45% = hemorrhagic
134
Consequences of stroke in perinatal period of full term infants?
Watershed zone infarcts between anterior, middle, and posterior cerebral arteries
Infant brain still growing after stroke event → viable cortex at less injured crest of gyri would continue to develop, more severely infarcted cortex at depths of sulci could not
--> Ulegyria = mushroom-shaped gyri
→ Cerebral palsy: motor-sensory cerebral disorders
135
Why are preterm infants particularly susceptible to stroke?
Immature infants → majority of blood supply directed to deep structures (periventricular, subependymal germinal matrix “growth plate” for neurons and glia)
- Preterm infants less than 32-34 weeks → vascular complications, hemorrhage into vulnerable germinal matrix
- Major cause of morbidity and mortality in preterm infants
136
Chiari I malformation
cerebellar tonsils elongated and pushed down through foramen magnum → blocks normal flow of CSF out aperture into subarachnoid space
- associated with syringomyelia
- can also cause hydrocephalus
- NOT associated with myelomeningocele
(NOT a neural tube defect)
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Syringomyelia
cystic cavity within spinal cord
Associated with chiari I malformation
Formation of CSF-filled cyst that breaks out of the central canal and dissects into the substance of the cord --> affect crossing fibers in anterior white commissure
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Symptoms of syringomyelia
Crossing anterior commissure fibers damaged first → “Cape-Like” loss of pain and temperature sensation in upper extremities
Fine touch is preserved
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Chiari II malformation
4 features
failure of neural folds to completely close → dorsal defect
Features:
1) Elongation of cerebellar VERMIS into foramen magnum (herniation of cerebellum)
2) → blockage of foramen magnum to block CSF flow → hydrocephalus
3) Always seen in conjunction with thoracolumbar myelomeningocele
4) paralysis below defect
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Myasthenia Gravis Immune-Pathogenesis
autoimmune disorder, ab to NMJ acetylcholine receptor
Diagnosis via presence of ACHR antibodies in serum
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Myasthenia Gravis
Treatment (5)
1) Cholinesterase inhibitor
2) Immunosuppression
3) Plasma exchange
4) IVIG infusion
5) Thymectomy
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Why would you use AChEIs in Myasthenia Gravis, what happens?
Name of two drugs used
→ temporary increase in strength and improve decrement following repetitive nerve stimulation
Edrophonium (IV) - used for diagnosis
Pyridostigmine (oral)
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Immunosuppression in Myasthenia Gravis (2 drugs used)
1) Predisone (corticosteroids)
| 2) Immunosuppressive agents (azathioprine, mycophenolate, mofitil)
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Why do you do thymectomy in Myasthenia Gravis?
thymus contributes in MG due to abnormal thymus hyperplasia
Can’t be too old or too young (less than 65 yrs old) to have a thymectomy
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Clinical features of myasthenia gravis (7)
1) Ptosis (droopy eye lids)
2) Speaking/swallowing abnormalities
3) Jaw and neck weakness
4) Limb muscle weakness not very common
5) Repetitive nerve stimulation of peripheral nerve → decremental response in train of muscle twitches
6) Rapidly developing weakness (hours to days) - characteristic of NMJ disorders
7) Acute remission and relapses
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Charcot-Marie-Tooth Disease
genetic defect (most common one)
over 33 different genetic mutations possible
AD (CMT1 and CMT2)
CMT1A = Duplication in DNA containing peripheral myelin protein gene (PMP22)
- Slow nerve conduction velocities + demyelinating neuropathy
- Hereditary motor and sensory neuropathy
Side note: (Deletion in PMP22 → HNPP disease)
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Pathological changes in Charcot-Marie-Tooth
- Peripheral nerve disease - hands and feet are weak
- Nerves die at the end
Neuropathy = DISTAL weakness
(Causes foot drop)
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Treatment of Charcot-Marie-Tooth (3)
Physical therapy - exercise and ROM
Occupational therapy - orthotics, cane, walker
Orthopedic surgery - correct deformities
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Becker Muscular Dystrophy (how is it different from Duchenne?)
Differs from Duchenne, only in that it has a later onset, has more benign course, and survival is longer
Mental impairment seen less often
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Duchenne Muscular Dystrophy
Genetic defect
XR (Only boys)
Mutation, deletion, or duplication of dystrophin protein
Dystrophin is a large protein that anchors cytoskeleton (actin filaments) of muscle fiber to ECM
Causes fibrosis, and degeneration of muscle
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Duchenne Muscular Dystrophy
Clinical features (5)
1) Waddling gait
2) Calf enlargement
3) Gower's maneuver (trouble rising from floor)
4) Toe walking
5) Lumbar lordosis
-Eye movements, swallowing and sensation unaffected
Increasing proximal weakness with age
Eventually wheelchair bound, and succumb to respiratory or heart failure by late teens or 20s
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Duchenne Muscular Dystrophy diagnosed with what 3 results
Elevated CK
EMG → characteristic myopathic features
DNA testing
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Amyotrophic Lateral Sclerosis (ALS)
PAthological changes
both upper and lower nerve degeneration
Progressive weakness and wasting due to degeneration of brainstem and spinal cord lower motor neurons
Coexisting spasticity and hyperreflexia due to degeneration of upper motor neurons
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ALS natural history
Increased frequency with age, more common in males
Typically sporadic (don't know a specific gene mutation)
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How do patients with ALS first present?
1) Weakness in legs (typically spreads along neuraxis - in one leg, will spread to other leg)
--> Weakness in arms
- -> Bulbar weakness
- speaking (slurred or spastic)
- swallowing (aspiration pneumonia common)
--> Respiratory weakness (diaphragm weakness)
**Normal sensory exam**
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Mononeuropahty
neuropathy of single nerve - severe nerve deficit in one specific region
Cranial nerve (3, 6, 7) or peripheral (median, ulnar, peroneal)
EX) Carpal tunnel syndrome (median nerve)
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Polyneuropathy is different from mononeuropathy how?
worse in distal regions, plus mild sensory loss more proximal
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Diabetic Neuropathies
typically a distal sensory or sensorimotor polyneuropathy
Very common
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Diabetic Neuropathies
Initial complaints
numbness, burning in feet → spreads up legs, into hands
Weakness of foot dorsiflexor muscles → slapping foot drop gait
Grip strength and fine hand dexterity diminished
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Diabetic neuropathy exam findings
- Pin sensation loss in “stocking-glove” distribution
- Loss of position, vibration, and light touch
- Loss of pain and temperature sensation
- Decreased reflexes
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Cholinesterase inhibitors effect on nondepolarizing vs. depolarizing neuromuscular blocking agents
AChEIs can help overcome a block of AChRs by curare (nondepolarizing blocking agent), but AChEIs potentiate effects of succinylcholine (depolarizing neuromuscular blocking agent)
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Botulinum toxin
cleaves synaptobrevin, prevents vesicle fusion and ACh release = FLACCID paralysis of skeletal muscle
→ death by respiratory failure
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Black widow spider venom
(a-latrotoxin) forms pores in terminal membrane → excessive Ca2+ influx → explosive release of ACh
→ depolarization block of muscle contraction
→ death by respiratory failure (FLACCID paralysis)
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Curare (and other "CUR" drugs)
Affect of AChEIs?
N-M receptor competitive antagonist
Prevent N-M opening → FLACCID paralysis
Blockade is surmountable, and can be REVERSED by AChEIs
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Succinylcholine
Affect of AChEIs
N-M receptor agonist (2-ACh molecules joined)
Initial stimulation → muscle fasciculations → then prolonged depolarization
Continuous depolarization does not allow repolarization and subsequent AP → FLACCID paralysis (due to depolarization blockade)
Flaccid paralysis is POTENTIATED by AChEIs
AChEIs can WORSEN neuromuscular blockade caused by depolarizing agents
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Neostigmine (aka nerve gas)
Toxic dose vs. therapeutic dose?
ompetitive cholinesterase inhibitor → increase ACh binding to receptor
Therapeutic range = increase muscle contraction strength
Toxic-Overdose range = prolonged stimulation → depolarization block (similar to succinylcholine), makes patient weaker
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A patient with myasthenia gravis comes in after they adjusted their medication with problems of eye droop, et.c
How do you differentiate between an OD of neostigmine and an under-dose of neostigmine?
Edrophonium (fast acting AChEI)
Weakness worsens --> dose is too high
Weakness improves --> dose is too low
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Brief vs. prolonged nicotinic cholinergic receptor stimulation
Prolonged receptor activation prevents the muscle cell membrane from repolarizing, thus preventing subsequent AP → flaccid paralysis
Brief stimulation allows depolarization, repolarization, and then finally a subsequent AP to take place
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Neuronal cell bodies for preganglionic parasympathetics are located in the _______ and __________
brainstem and intermediate gray matter of sacral spinal cord
