Pathophysiology of the Nervous System Flashcards
1
Q
The patient with progressive diplopia and weakness with mastication (both worse at night), along with ptosis and proximal muscle weakness on examination likely has
A
Myasthenia Gravis
2
Q
Myasthenia Gravis is characterized by
A
- Fluctuating weakness of certain voluntary muscles particularly those innervated by motor nuclei of the brainstem (eg. ocular and bulbar muscles)
- Progressive weakening over the course of the day or after exercise (fatigability)
- Decreased compound muscle action potential amplitude (the summed action potentials of all the muscle fibers in a motor unit) on EMG with repeated excitation
- Rapid restoration of strength of affected muscles with rest
- Improvement in strength following the administration of cholinesterase inhibitors
3
Q
Myasthenia Gravis is most commonly caused by
A
autoantibodies against postsynaptic nicotinic acetylcholine receptors. Binding of these receptors results in blockade of the receptor’s active site, receptor internalization and degradation, and damage to the motor end plate due to complement fixation. Overall this leads to decreased numbers of functional acetylcholine receptors at the neuromuscular junction. The decrease in the number of available cation channels reduces the end plate potential following acetylcholine release. Because the threshold potential is not reached the muscle cells do not depolarize. Synaptic concentrations of acetylcholine are unaffected, unlike in botulism or Lambert-Eaton Syndrome
4
Q
What changes involving postsynaptic muscle cells most likely explains the symptoms of a patient with Myasthenia Gravis
A
Reduced amplitude of motor end plate potential
5
Q
Excitation-contraction coupling refers to the process
A
whereby an action potential within the muscle cell causes contraction of the muscle.
6
Q
In the skeletal muscle excitation contraction coupling proceeds by
A
the release of calcium into the cytoplasm, which subsequently binds troponin C and induces a conformational change allowing actin and myosin to bind.
7
Q
Impaired excitation coupling implies
A
that an action potential occurs but the skeletal muscle is unable to contract (impaired actin and myosin binding)
8
Q
Myasthenia gravis is caused by a failure to
A
achieve the threshold for an action potential to occur
9
Q
The action potential amplitude of the postsynaptic muscle cell is
A
determined by the properties of the cell membrane and is not affected by the quality of the stimulus at the muscle end plate.
10
Q
The absolute refractory period for muscles in patients with Myasthenia Gravis is
A
normal
11
Q
The compound muscle action potential in patients with Myasthenia Gravis
A
decreases with repeated excitation due to depolarization of fewer myofibers
12
Q
Once the threshold voltage is exceeded at the neuromuscular end plate
A
an action potential propagates at a velocity determined by the particular properties of the muscle cell membrane
13
Q
Education Objective: Myasthenia Gravis
A
- Myasthenia Gravis is an autoimmune disease that causes a decrease in the number of functional acetylcholine receptors within the neuromuscular junction. This reduces the number of postsynaptic cation channels that can open in response to acetylcholine, which reduces the amplitude of motor end plate potential and prevents muscle fiber depolarization
14
Q
What are the muscarinc symptoms of cholinergic Toxicity
A
- Diarrhea
- Diaphoresis
- Urination
- Miosis
- Bronchospasm
- Bronchorrhea
- Bradycardia
- Emesis
- Lacrimation
- Salivation
15
Q
What are the nicotinic symptoms of cholinergic toxicity
A
- Muscle weakness
- Paralysis
- Fasciculations
16
Q
What are the symptoms of cholinergic toxicity
A
- Diarrhea
- Diaphoresis
- Urination
- Miosis
- Bronchospasm
- Bronchorrhea
- Bradycardia
- Emesis
- Lacrimation
- Salivation
- Muscle weakness
- Paralysis
- Fasciculations
17
Q
The treatment of myasthenia gravis typically involves the use of
A
- a cholinesterase inhibitor
- an immunosuppressive agent
- possible thymectomy
18
Q
An example of a cholinesterase inhibitor is
A
Pyridostigmine
19
Q
Cholinesterase inhibitors function by
A
inhibiting the degradation of acetylcholine in the neuromuscular junction.
20
Q
Selective muscarinic antagonists can be used to
A
reduce the side effects of cholinesterase inhibitors in sites where acetylcholine action is mediated by muscarinic receptors (ex. GI tract). Because of their selectivity these drugs improve side effects without affecting the action of cholinesterase inhibitors on skeletal muscle which uses nicotinic receptors
21
Q
Examples of selective muscarinic antagonists include
A
- Glycopyrrolate
- Hyoscyamine
- Propantheline
22
Q
Fluoxetine
A
is a selective serotonin reuptake inhibitor used primarily in the treatment of depression. It acts in a fashion similar to the cholinesterase inhibitors in that it prolongs the activity of the neurotransmitter on its target tissue.
23
Q
Pilocarpine
A
is a nonselective muscarinic receptor agonist
24
Q
Prazosin
A
is an alpha-1 adrenergic antagonist
25
Propranolol
beta adrenergic antagonist
26
Education Objective: Treatment of myasthenia gravis
The treatment of myasthenia gravis involves the use of a cholinesterase inhibitor, immunosuppressants, and possible thymectomy. Cholinesterase inhibitors may cause adverse effects related to muscarinic over stimulation, which can be ameliorated by the use of an antimuscarinic agent such as glycopyrrolate, hyoscyamine, or propantheline
27
What causes tetanus
Clostridium tetani spores inoculate skin wound and germinate and then produce tetanus toxin which then is transported to the CNS via retrograde axonal transport and blocks inhibitory interneurons
28
What are the risk factors for tetanus
Incomplete childhood vaccines or lack of 10- year booster shot
29
What are the symptoms of Tetanus
1. Trismus (lockjaw)
2. Difficulty swallowing
3. Intermittent intense muscular spams
4. Opisthotonos (extremely arched back)
5. Risus sardonicus (facial muscle spasm while smiling)
30
What is the prevention for tetanus
tetanus toxoid vaccination
31
Tetanus Clinical Picture
The majority of patients who develop tetanus have a history of a puncture wound approximately a week prior to symptoms, which led to inoculation with clostridium tetani spores. The spores germinate in anaerobic conditions into vegetative, rod shaped bacteria and produce tetanus toxin (tetanospasmin). Tetanus toxin travels through lower motor neurons to the CNS where it inactivates inhibitory interneurons. Common manifestations include masseter muscle spasm (lockjaw/trismus), muscle pain and stiffness, and difficulty swallowing
32
Tetanus is a _______ diagnosis that should be suspected in patients who have characteristic symptoms, particularly if they are unlikely to be adequately vaccinated or have a history of recent cutaneous trauma.
clinical
33
Why would blood cultures not be helpful in the diagnosis of tetanus
Blood cultures are not helpful in the diagnosis of tetanus because C. Tetani only grows at the inoculation site (the clinical syndrome stems from toxin elaboration not bacterial invasion.
34
The neurologic manifestations of tetanus are caused by
toxin mediated blockade of inhibitory interneurons at the level of the anterior horn cells
35
Positive antitetanustoxoid serology indicates that
an individual is adequately vaccinated and reduces the chances that a patient has tetanus
36
Educational Objective: Tetanus
Tetanus is a clinical diagnosis that should be suspected in patients who have characteristic symptoms (lockjaw, muscle pain/spasms, difficulty swallowing), particularly if they are unlikely to be adequately vaccinated to have an antecedent cutaneous injury
37
A nerve conduction study
measures the amplitude, velocity and latency of an electrical stimulus applied to an isolated nerve and can help differentiate between demyelinating and axonal neuropathies
38
Demyelinating neuropathies are caused by
damage to the myelin sheath. Loss of insulation results in delayed (or blocked) nerve conduction velocity
39
Axonal neuropathies are caused by
damage to the nerve axon. Loss of axon fibers results in reduced signal amplitude
40
On nerve conduction studies loss of myelin (insulation) results in
delayed or blocked nerve conduction velocity
41
On nerve conduction studies loss of axon fibers results in
reduced signal amplitude
42
Ulnar neuropathy is most commonly caused by
focal nerve compression of the ulnar nerve at the elbow which leads to nerve ischemia which leads to apoptosis of Schwann cells and localized demyelination
43
Symptoms of ulnar neuropathy
1. weakness of fourth and fifth digits
2. elbow pain
3. worsening of symptoms with elbow or wrist flexion
4. ulnar claw deformity
5. sensory symptoms
44
Common causes of axonal neuropathy
1. Diabetes mellitus
2. Toxins (chemotherapy drugs)
3. Hypothyroidism
4. Vitamin B12 deficiency
5. Vasculitis
45
Neuronal cell bodies are located in the
dorsal root ganglia and the anterior horn of the spinal cord
46
Myasthenia Gravis is due to
autoimmune attack on the acetylcholine receptors of the postsynaptic membrane. This causes fatigable weakness of the ocular, facial and proximal muscles. Nerve conduction studies are typically normal but muscle stimulation studies demonstrate a reduction in motor signal strength with repetitive stimuli
47
Botulinum Toxin
blocks acetylcholine release from presynaptic membranes of the neuromuscular junction by impairing fusion of secretory vesicles with the synaptic membrane. Patients typically develop cranial neuropathies with symmetric descending flaccid paralysis. Nerve conduction studies are typically normal while muscle stimulation studies may show a reduction in motor signal strength that improves with repetitive motor stimuli
48
Educational Objective: Ulnar neuropathy
Ulnar neuropathy is characterized by numbness of the fourth and fifth digits, pain and weakness. It is most commonly caused by compressive injury, leading to tissue ischemia and demyelination (Schwann cell injury). A nerve conduction study can help differentiate demyelinating versus axonal neuropathies; demyelination causes slowed or blocked nerve conduction velocity whereas axonal injury leads to a reduction in signal strength
49
List the 4 voltage gated sodium channel toxins
1. Tetrodotoxin (puffer fish)
2. Saxitoxin (dinoflagellates in red ride)
3. Ciguatoxin (exotic fish, Moray eel)
4. Batrachotoxin (South American Frogs)
50
Which 2 voltage gated sodium channel toxins work by binding to Na+ channels, inhibiting Na+ influx and preventing action potential conduction
Tetrodotoxin and Saxitoxin
51
Which 2 voltage gated sodium channel toxins work by binding to the sodium channel keeping it open and causing persistent depolarization
Ciguatoxin and Batrachotoxin
52
The constellation of symptoms of paresthesias, weakness, dizziness, nausea and history of fish consumption are strongly suggestive of
food poisoning by pufferfish
53
Tetrodotoxin binds to
voltage gated sodium channels in nerve and cardiac tissue preventing sodium influx and depolarization.
54
Symptoms of tetrodotoxin poisoning occur
quickly after ingestion
55
Symptoms of tetrodotoxin poisoning include
1. Dizziness
2. Weakness
3. Loss of Reflexes
4. Paresthesias of the face and extremities
5. Nausea
6. Vomiting
7. Diarrhea
8. Hypotension
9. General paralysis
10. Respiratory failure
56
Treatment of tetrodotoxin poisoning includes
supportive care and intestinal decontamination with gut lavage and charcoal
57
The resting membrane potential is
equal to approximately -70 mv
58
The resting membrane potential is maintained by
high membrane K+ permeability and low Na+ permeability. K+ efflux occurs via non gated K+ leak channels
59
Overshoot on an action potential graph represents the
maximal value of the action potential during which the membrane potential is positive. At this point, open sodium channels become inactivated and close, preventing further increase in membrane potential.
60
Repolarization of the Membrane results from
closure of Na+ channels and simultaneous opening of K+ channels. This results in a sharp decrease in Na+ conductance and a significant increase in K+ conductance. Potassium efflux is responsible for returning the membrane potential to the resting potential
61
Hyperpolarization of the Membrane occurs for a
short moment following repolarization due to the slow closure of voltage gated potassium channels. The membrane potential becomes more negative than the normal resting potential and approaches the K+ equilibrium potential of -85 mV. When the voltage gated K+ channels close, the membrane potential returns to the resting value.
62
Educational Objective: Tetrodotoxin
Pufferfish poisoning is caused by tetrodotoxin, a neurotoxin produced by microorganisms associated with the fish. Tetrodotoxin binds to voltage gated sodium channels in nerve and cardiac tissue preventing sodium influx and depolarization
63
Tetrodotoxin works by
binding to Na+ voltage gated channels inhibiting Na+ influx and preventing action potential conduction
64
Saxitoxin works by
binding to Na+ voltage gated channels inhibiting Na+ influx and preventing action potential conduction
65
Ciguatoxin works by
binding to Na+ voltage gated channels and keeping them open and causing persistent depolarization
66
Batrachotoxin works by
binding to Na+ voltage gated channels and keeping them open and causing persistent depolarization
67
Pseudobulbar palsy
dysarthria, dysphagia and dysphonia
68
Osmotic demyelination syndrome
Decreased plasma osmolality from hyponatremia (commonly seen in patients with alcohol abuse) results in water flowing across the osmotic gradient into brain cells; if this happens acutely, life threatening cerebral edema can occur, However, with slowly developing (chronic) hyponatremia, astrocytes and oligodendrocytes excrete osmotically active orgnaic solutes (glutamate, myoinositol) to cause compensatory intracellular water loss and normalization of brain volume. Therefore chronic hyponatremia can present with minimal neurologic syndrome. However, overly rapid correction of chronic hyponatremia reverses the osmotic gradient drawing water from the cells into the plasma. The astrocytes and oligodendrocytes are unable to rapidly re-accumulate the lost organic solutes, resulting in cell shrinkage, dehydration, and apoptosis. This resultant demyelination preferentially affects the pons, possibly because the cells there are less metabolically active and less able to rapidly regenerate organic solutes
69
Presentation suggestive of osmotic demyelination syndrome (central pontine myelinolysis)
1. Pseudobulbar palsy
2. Quadriparesis
3. Demyelination of the Pons
4. History of alcohol abuse
5. Horizontal gaze paralysis
6. Obtundation
7. Locked in syndrome
70
Locked in syndrome is when
patients are aware but unable to move or communicate verbally
71
Osmotic Demyelination Syndrome
Decreased plasma osmolality from hyponatremia (commonly seen in patients with alcohol abuse) results in water flowing across the osmotic gradient into brain cells; if this happens acutely, life threatening cerebral edema can occur, However, with slowly developing (chronic) hyponatremia, astrocytes and oligodendrocytes excrete osmotically active organic solutes (glutamate, myoinositol) to cause compensatory intracellular water loss and normalization of brain volume. Therefore chronic hyponatremia can present with minimal neurologic syndrome. However, overly rapid correction of chronic hyponatremia reverses the osmotic gradient drawing water from the cells into the plasma. The astrocytes and oligodendrocytes are unable to rapidly re-accumulate the lost organic solutes, resulting in cell shrinkage, dehydration, and apoptosis. This resultant demyelination preferentially affects the pons, possibly because the cells there are less metabolically active and less able to rapidly regenerate organic solutes
72
Symptomatic brain abcesses MRI would demonstrate
ring enhancement with vasogenic edema
73
Wernicke encephalopathy symptoms
1. ataxia
2. oculomotor dysfunction
3. encephalopathy
74
Kosrakoff syndrome is
chronic memory impairment
75
Symptomatic brain abscesses MRI would demonstrate
ring enhancement with vasogenic edema
76
The administration of glucose containing fluids to patients with thiamine deficiency (common in patients with alcohol abuse) can cause
1. Wernicke Encephalopathy
| 2. Korsakoff Syndrome
77
Korsakoff syndrome is
chronic memory impairment
78
In Wernicke encephalopathy and Korsakoff syndrome ________ ______ ______ is often visible on MRI
mamillary body atrophy
79
Osmotic Demyelination Syndrome
results from overly rapid correction of chronic hyponatremia. Clinical features include quadriplegia, pseudobulbar palsy, and reduced level of consciousness. MRI demonstrates focal demyelination of the pons.
80
Tetanus is a
Tetanus is a clinical diagnosis that should be suspected in patients who have characteristic symptoms, particularly if they are unlikely to be adequately vaccinated or have a history of recent cutaneous trauma.
81
Tetanus is a
Tetanus is a clinical diagnosis that should be suspected in patients who have characteristic symptoms, particularly if they are unlikely to be adequately vaccinated or have a history of recent cutaneous trauma.
82
C. tetani causes disease by
producing a potent metalloprotease exotoxin (tetanospsmin) that is deadly in nanogram quantities. The toxin first binds to receptors on the presynaptic membranes of peripheral motor neurons. From there it migrates by retrograde axonal transport to central inhibitory neurons in the spinal cord and brain stem and prevents release of the inhibitory neurotransmitters glycine and GABA. Supression of inhibitory nerve activity results in increased activation of motor nerves, causing muscle spasms and hyperreflexia.
83
Classic features of tetanus include
1. difficulty opening the jaw (lockjaw or trismus)
2. a fixed sardonic smile (risus sardonicus)
3. contractions of back muscles resulting in backward arching (opisthotonos)
4. irritability
5. tetanic spasms in response to minor stimuli such as loud noises
84
Acetylcholine release is inhibited by which toxin
botulinum toxin from C botulinum, leading to the flaccid paralysis seen in clinical botulism
85
Serotonin release from enterochromaffin cells in the GI tract is stimulated by which toxin
Vibrio cholera enterotoxin
86
Increased serotonin release caused by cholera toxin contributes to the
extreme fluid secretion seen in cholera
87
Educational Objective: Tetanoplasmin
Tetanoplasmin is a nuero-exotoxin released by clostirdium tetani. The toxin blocks the release of glycine and GABA from the spinal inhibitory interneurons that regulate the lower motor neurons. These disinhibited motor neurons cause increased activation of muscles, leading to spasms and hyperreflexia.
88
Tetanus blocks the release of
Glycine and GABA
89
Long standing rheumatoid arthritis frequently involves the cervical spine and causes
joint destruction with vertebral malalignment (subluxation). The atlantoaxial joint is most often involved as the atlas (C1) has a high degree of mobility relative to the axis (C2 odontoid and body).
90
Chronic symptoms of cervical subluxation include
1. neck pain
2. stiffness
3. neurologic findings (sensory loss, muscle weakness)
91
Endotracheal intubation can acutely worsen
subluxation
92
Endotracheal intubation can acutely worsen subluxation and cause
compression of the spinal cord and or vertebral arteries.
93
Acute spinal cord injury from acute exacerbation of subluxation caused by endotracheal intubation results in
flaccid paralysis with decreased or absent reflexes below the level of compression due to spinal shock; the paralysis eventually becomes spastic as spinal shock resolves over the ensuing days to weeks.
94
Cerebral septic emboli are usually due to
infective endocarditis of the left sided heart valves.
95
Diabetic neuropathy presents with
a slowly progressive decrease in vibratory sensation, proprioception and temperature sensation.
96
Early diabetic neuropathy causes
decreased ankle reflexes
97
Late diabetic neuropathy causes
widespread loss of reflexes with motor weakness
98
Guillain-Barre Syndrome presents with
progressively worsening symmetrical flaccid muscle weakness with absent or decreased reflexes. The abnormalities typically start in the lower extremities and ascend upward over the course of days to weeks
99
Malignant hyperthermia is usually due to
anesthesia exposure (halothane, succinylcholine) causing increased and sustained muscle contraction with myocyte breakdown. Patients typically develop diffuse muscle rigidity followed by hyperthermia and possible myoglobinuria
100
Education objective: Long-standing rheumatoid arthritis
Long-standing rheumatoid arthritis can affect the cervical spine, causing vertebral malaignment (subluxation) that can affect the atlantoaxial joint. Extension of the neck during endotracheal intubation can worsen the subluxation, leading to acute compression of the spinal cord and/or vertebral arteries
101
What are the causes of congenital hydrocephalus
1. Congenital obstruction
| 2. Acquired obstruction
102
Causes of Congenital Obstructions that can cause Congenital Hydrocephalus include
1. Aqueductal stenosis
| 2. Chiari Malformation
103
Causes of Acquired Obstruction that can cause Congenital Hydrocephalus include
1. Congenital infection
| 2. Posthemorrhagic
104
Symptoms of Congenital Hydrocephalus
1. Macrocephaly
2. Bulging Fontanelle
3. Developmental Delay
4. Spasticity and Hyperreflexia
105
Treatment of Congenital Hydrocephalus
Cerebral shunting
106
A complication of congenital hydrocephalus is
muscle hypertonicity
107
Hydrocephalus is caused by
abnormal accumulation of CSF in the brain due to either overproduction or impaired drainage of CSF.
108
Congenital hydrocephalus results from a
1. structural malformation that causes impaired CSF drainage
2. obstruction secondary to infection with CMV, meningitis, toxoplasmosis
3. Intraventricular hemorrhage
109
Congenital hydrocephalus results from what 3 syndromes
1. aqueductal stenosis
2. Chiari malformations
3. Dandy-Walker syndrome
110
Hydrocephalus must be distinguished from
hydrocephalus ex-vacuo
111
Hydrocephalus ex-vacuo
normal CSF expansion following cerebral volume loss rather than abnormal CSF accumulation
112
Infants with hydrocephalus typically develop
1. Macrocephaly
3. Poor feeding
3. Muscle hypertonicity
4. Hyperreflexia
113
Hypertonicity and hyperreflexia in congenital hydrocephalus result from
upper motor neuron injury caused by stretching of the periventricular pyramidal tracts.
114
Untreated hydrocephalus can lead to
developmental delay and seizures.
115
Treatment of hydrocephalus requires
surgical placement of a shunt to bypass the obstruction, most often via the ventriculoperitoneal route
116
Lower extremity hyporeflexia would result from
damage to the lower motor neurons which can occur in poliomyelitis or spinal muscular atrophy
117
Learning Objective: Congenital Hydrocephalus
Hydrocephalus in infants presents with macrocephaly and poor feeding. Imaging studies showing enlarged ventricles are characteristic. Untreated hydrocephalus leads to spasticity due to stretching of the periventricular pyramidal tracts, developmental delays, and seizures
118
Breathing
Intrapleural pressure (ie, between the lung and chest wall pleura) is slightly negative at rest due to the inward elastic recoil of the lungs and outward recoil of the chest wall. During inspiration diaphragmatic contraction is primarily responsible for creating a more negative intrapleural pressure that causes expansion of the thoracic cavity, drawing air into the lungs. Passive expiration occurs with respiratory muscle relaxation and relies on the natural inward elastic recoil of the lungs to expel air as the intrapleural pressure returns to baseline.
119
Breathing Pattern in Myasthenia Gravis
Progressive attenuation of the intrapleural pressure change that occurs during deep repetitive inspiration. Because there is no apparent decrement in phrenic nerve activity, this patient's progressively weaker diaphragmatic contractions are likely due to excessive skeletal muscle fatigue (eg, severe obstructive or restrictive lung disease) or impaired neuromuscular transmission.
120
Women in the postpartum period are at particularly high risk of developing
myasthenia gravis
121
In myasthenia gravis, autoantibodies against postsynaptic acetylcholine receptors cause
fatigable skeletal muscle weakness as acetylcholine stores within the presynaptic nerve terminal become progressively depleted with repetitive stimulation
122
Impairment of the respiratory control centers in the brain stem can result in
decreased frequency and/or amplitude of involuntary respiration (Ondine curse). Voluntary breathing is unaffected
123
Metastatic disease to the pericardium could compress the phrenic nerve causing
uniform weak inspirations during maximal voluntary ventilation rather than progressively weaker diapharagmatic contractions
124
Educational Objective: Respiratory Neuromuscular Junction Pathology
Progressively weakening diaphragmatic contractions during maximal voluntary ventilation with intact phrenic nerve stimulation indicate neuromuscular junction pathology (eg, myasthenia gravis) and/or abnormally rapid diaphragmatic muscle fatigue (eg, restrictive lung or chest wall disease)
