Neurochemistry, toxic/metabolic

Question 1

Ionotropic vs metabotropic receptors

Answer 1

Ionotropic receptors are ion channels gated by the binding of a neurotransmitter. Example: GABA-A receptor is a chloride channel.
Metabotropic receptors activate intracellular signaling pathways via G-proteins. Example: GABA-B receptor is G-protein coupled

Question 2

Sodium

Answer 2

Low inside, high outside, causes depolarizing currents

Question 3

Potassium

Answer 3

High inside, low outside, inhibitory/stabilizing currents
** Critical role in setting resting membrane potential due to high resting conductance in excitable cells

Question 4

Chloride

Answer 4

May be high or low depending on the cell, so could be either excitatory or inhibitory

(GABA-A receptor uses chloride currents, mostly inhibitory in adult brain)

Question 5

Calcium

Answer 5

Very low (nanomolar range) inside, high outside (10 mM)
Excitatory currents but, more importantly raising calcium can trigger intracellular signals for neurotransmitter release, LTP, and other events

Question 6

Voltage gated sodium channels

Answer 6

Genes for the major subunits are called “SCN”
Proteins are called “Nav”
Inhibited by tetrodotoxin, local anesthetics (lidocaine)
Gate in response to depolarizationallow rapid sodium influxmore depolarization
Very useful for propagating action potentials
Activate in response to depolarization but also inactivate (action potentials terminate)

Question 7

Voltage gated calcium channels

Answer 7

Voltage-gated calcium channels (VGCC) can open in response to depolarization like Nav channels
Can rapidly raise calcium levels inside the cell – transforming the electrical signal to a chemical signal
In the presynaptic terminal, VGCCs trigger neurotransmitter release
In cardiac muscle, calcium influx triggers contraction
skeletal muscle is different – relies on releasing intracellular stores of calcium using a protein complex that includes the ryanodine receptor and the DHPR (which is like a modified calcium channel)

Question 8

Voltage gated potassium channels

Answer 8

Relatively high K conductance at rest keeps most cells resting membrane potential near the potassium reversal potential (-70mV to -90mV or so) – neurons, cardiac myocytes, skeletal muscle, etc.
VGKCs (or “Kv” channels) open in response to depolarization
They are an inhibitory influence, help terminate action potentials
Think of them as opposing Nav channels – the main brake to counter the sodium channel acceleration
There is an incredible diversity of families of potassium channels

Question 9

VGKCC antibodies

Answer 9

VGKC antibodies do not actually target potassium channel subunits per se but rather associated proteins LGI1 or Caspr2

Question 10

Cl channels

Answer 10

Chloride may be high or low inside cells by using one of two transporters:
– KCC2 (K-Cl cotransporter) keeps chloride low, making chloride current inhibitory
– NKCC (Na-K-Cl cotransporter, 2 forms exists) keeps chloride high, making chloride currents excitatory
Big chloride channels: GABA-A, glycine receptor, CLC1 (skeletal muscle)

Question 11

GABA metabolism

Answer 11

GAD is the enzymes that makes GABA from glutamate
• GAD67 form of the enzymes is ubiquitous
• GAD65 isoform is concentrated in presynaptic terminals of GABA-ergic neurons, and rapidly replenishes synaptic vesicles with GABA

Question 12

GABA-A receptors

Answer 12

Pentameric choride channels activated by GABA – incredible subunit diversity: ionotropic receptors
Primary fast inhibitory receptor in the brain

Barbiturates prolong channel opening
Benzodiazepines increase frequency of channel opening
Clobazam (Onfi) acts on the benzodiazepine site
Both have a nasty withdrawal profile with risk of seizures
Flumazenil is a benzodiazepine antagonist (rapid treatment of benzodiazepine overdose)

Anti-GABA-A receptor encephalitis is a rare autoimmune brain disease with severe seizures/status

Question 13

Glycine

Answer 13

Very similar to GABA-A receptors – chloride channels
Primary rapid inhibitory signaling system in the spinal cord
Antagonist strychnine produces painful muscle contractions, spasms, exaggerate startle – due to spinal hyperexcitability

Glycine mutations associate with human startle disease
Glycine antibodies associate with PERM (progressive encephalomyelitis with rigidity and myoclonus) – like stiff person syndrome with startle and encephalitis

Question 14

GABA-B receptors

Answer 14

Metabotropic receptors activited by GABA
Shut down presynaptic release and indirectly trigger post-synaptic inhibitory potassium currents via GIRK channels

Baclofen is an agonist, widely used for spasticity. Has nasty withdrawal syndrome
Phaclofen is an antagonist

Anti-GABA-B encephalitis is an autoimmune encephalitis with severe seizures. Antibodies disrupt GABA-B receptor function.

Question 15

Glutamate receptors

Answer 15

Glutamate is the major excitatory neurotransmitter in the CNS
Several types of ionotropic receptor (AMPA receptor, Kainate receptor, NMDA receptor) accomplish routine rapid transmission
A family of metabotropic receptors (mGluR1, etc.) modulate neuronal function in complex ways

Question 16

AMPA receptor

Answer 16

Ionotropic glutamate receptors with significant sodium permeability (create strong depolarization)
Useful for routine fast excitatory signals in the CNS
Cannot by itself trigger long-term potentiation due to low calcium permeability
Creates an electrical signal but not a chemical signal
Kainate receptors are similar to AMPA receptors

Question 17

NMDA receptor

Answer 17

The NMDA receptor integrates a presynaptic signal (glutamate release) with post-synaptic
depolarization because it requires both to gate. NMDARs open only when there is glutamate release at its synapse from the pre-synaptic neuron AND the post- synaptic neuron is strongly excited.
NMDA receptors are ion channels (ionotropic) that have significant calcium permeability (Na/K/Ca), raising post-synaptic calcium levels to trigger LTP.
Long-term potentiation (LTP) triggered by calcium will strengthen that synapse.

Question 18

Anti-NMDA encephalitis

Answer 18

Characteristic autoimmune brain disease with psychosis, memory impairment, dysautonomia, catatonia, seizures, coma. Antibodies disrupt NMDAR function

Question 19

NMDA and drugs of abuse, medications

Answer 19

Phencyclidine (PCP, “Angel dust”) – hallucinogenic drug of abuse, an NMDA receptor antagonist
Ketamine – anesthetic, also an NMDA receptor antagonist
Memantine – weaker NMDA receptor antagonist, used in treating Alzheimer’s Disease

Question 20

Cholinergic neurochemistry

Answer 20

Acetylcholine (Ach) is made from acetyl-CoA + choline by choline acyl transferase (ChAT) in presynaptic terminals
Ach is packed into vesicles by vesicular Ach transferase (vACht)
Acetylcholine is broken down in the synaptic cleft by acetylcholinesterase (ACE) to acetate + choline
Choline is taken back up by presynaptic terminal – recycle!

Question 21

Nicotinic vs cholinergic receptors

Answer 21

Nicotinic AchRs are ionotropic (sodium, potassium, calcium), used for rapid transmission in the brain, autonomic ganglia, and NMJ – many subtypes
Muscarinic AchRs are metabotropic, widely used in autonomic target tissues (sweat glands pancreas, GI, salivary, lacrimal, pupils, etc.) and in the brain

Question 22

Cholinergic toxicity

Answer 22

Insecticides bind and disrupt acetylchlinesterase->can’t break down Ach->weakness due to NMJ effects and also SLUDGE toxidrome
– Salivation
– Lacrimation
– Urination
– Diaphoresis
– GI upset
– Emesis
Atropine blocks muscarinic AChRs->blocks SLUDGE symptoms
Nerve gas (Sarin, VX) irreversibly bind acetylcholinesterase

Question 23

Donepezil (Aricept)

Answer 23

Binds and reversibly inactivates the cholinesterases, thus inhibiting hydrolysis of acetylcholine. This increases acetylcholine concentrations at cholinergic synapses

Question 24

Pyrdistigmine

Answer 24

Weakly blocks acetylcholinesterase, used to treat myasthenia gravis– excess causes SLUDGE

Question 25

Parasympathetic vs sympathetic

Answer 25

Question 26

Botox and tetanus toxin

Answer 26

ACE - SNAP 25

BDEF - synaptobrevin

Question 27

Tetanus vs botox

Answer 27

Question 28

PKAN

Answer 28

Toxic metabolic disease of the globes pallidus - this is where the tiger eyes come in
Neurodegeneration with Brain Iron Accumulation Type I (Pantothenate Kinase 2 deficiency)
Presents before age 6 in almost 90% of patients with gait or postural difficulty. Patients develop spasticity, hyperreflexia and prominent dystonia, particularly oromandibular dystonia.
Iron deposition in the globus pallidus with resulting tan discoloration on gross specimen

Question 29

Carbon monoxide

Answer 29

Toxic-metabolic diseases of the globes pallidus
In the acute setting, there is reddish discoloration of the brain.
Chronically, there is bilateral liquefactive necrosis of the globus pallidus

Question 30

Wilson’s disease

Answer 30

Toxic-metabolic diseases of the putamen
Atrophy and copper accumulation in the putamen
Alzheimer type 2 astrocytes:
– Swollen irregular nuclei with peripheral displacement of the chromatin resulting in central clearing
– Cytoplasm is not prominent
– Seen in all hyperammonemic states

Question 31

Methanol toxicity

Answer 31

Toxic-metabolic diseases of the putamen
Hemorrhagic necrosis of the putamen
It also causes retinal ganglion cell degeneration
Severe edema and white matter hemorrhage

Question 32

Ethanol toxicity

Answer 32

Atrophy of the anterior superior vermis – This results in prominent truncal ataxia
Rarely, patients with chronic alcohol use develop necrosis of the middle 2/3 of the corpus callosum (Marchiafava-Bignami)

Question 33

Wernicke’s Encephalopathy

Answer 33

Characterized by hemorrhage into: mammillary bodies, walls of the 3rd ventricle, periaqueductal gray
Central chromatolysis: the center of the neuron is homogenously eosinophilic with peripheral displacement of the nucleus and Nisl substance

Question 34

Central pontine myelinolysis

Answer 34

Symmetric central pontine demyelination
Ma also affect the corpus callosum

Question 35

Subacute combined degeneration (B12 deficiency)

Answer 35

Secondary demyelination of the dorsal columns and lateral corticospinal tracts
– also causes optic neuropathy, peripheral neuropathy, and cortical dysfunction

Question 36

Vitamin A deficiency/excess

Answer 36

Fat soluble vitamin
Nightblindness, xerophthalmia (dry conjunctiva), corneal ulceration
Hypervitaminosis A can cause pseudotumor cerebri

Question 37

Vitamin D deficiency

Answer 37

Fat soluble vitamin deficiency
Hypocalcemia and resulting bone pain and muscle weakness or tetany, hearing impairment

Question 38

Vitamin E deficiency

Answer 38

Fat soluble vitamin deficiency
Ophthalmoplegia, dysarthrias, pigmentary degeneration of retina, spinocerebellar ataxia, myopathy, axonal polyneuropathy
Can be inherited as a syndrome identical to Friedreich’s ataxia
Bassen-Kornzweig syndrome (Vit E def, retinitis pigmentosa, acanthocytosis and abetalipoproteinemia)

Question 39

Vitamin K deficiency

Answer 39

Fat soluble vitamin deficiency
Decreased prothrombin activity and resulting hemorrhages

Question 40

Vitamin B1/thiamine deficiency

Answer 40

Water-soluble vitamin deficiency
Due to malnutrition associated with chronic alcoholism, pregnancy, hyperthyroidism
Acute Wernicke’s encephalopathy, axonal polyneuropathy, Korsakoff’s psychosis, visual loss, cerebellar degeneration

Question 41

B3/Niacin deficiency

Answer 41

Water-soluble vitamin deficiency
Due to malnutrition associated with chronic alcoholism
Pellagra (dermatitis,diarrhea,dementia) rare today,
‘Nicotinic acid encephalopathy’ – confusion, lethargy, rigidity in elderly that is reversible

Question 42

Vitamin B2/Riboflavin deficiency

Answer 42

Water-soluble vitamin deficiency
Due to inadequate dietary intake of meat, dairy products, and some leafy vegetables
Photophobia, excessive lacrimation and eye itching

Question 43

B3/Niacin deficiency

Answer 43

Water-soluble vitamin deficiency
Due to malnutrition associated with chronic alcoholism
Pellagra (dermatitis,diarrhea,dementia) rare today,
‘Nicotinic acid encephalopathy’ – confusion, lethargy, rigidity in elderly that is reversible

Question 44

B6/pyridoxine deficiency

Answer 44

Water-soluble vitamin deficiency
Due to malnutrition or a pyridoxine antagonist like isoniazid
Severe polyneuropathy in adults, as inherited form in infants causes seizures, slowed psychomotor development

Question 45

Folic acid deficiency

Answer 45

Usually seen in isolation due to folate antagonists
Distal polyneuropathy with paresthesias, burning, weakness (concomitant folate deficiency is probably what accounts for reports of polyneuropathy in cobalamin deficiency)

Question 46

B12/cobalamin deficiency

Answer 46

Water-soluble vitamin deficiency
– Due to diet (vegans, alcoholics, elderly), malabsorption (pernicious anemia, gastrectomy, prolonged use of PPIs, H2 receptor blockers, Sprue, Crohn’s, ileal resection, fish tapeworm), increased metabolic demand (pregnancy, thyrotoxicosis, neoplasia)
– Causes subacute combined degeneration, mental status abnormalities, optic neuropathy
– Treatment with intramuscular B12 (100-1000 mcg QOD for two weeks with concurrent folate replacement) followed by oral B12 (1 mg QD) for long term therapy

Question 47

Drugs for orthostatic hypotension

Answer 47

Primary therapies: fludrocortisone (mineralocorticoid, increases plasa volume b promoting renal sodium reabsorption and increases vascular sensitivity to NE, SE: supine hypertension, hypokalemia, peripheral edema/weight gain, cardiomegaly, headache, retinopathy, exacerbation of DM), proamatine: midodrine - alpha-1-agonist, vasoconstriction of arterioles and the venous capacitance bed, does not cross BBB so no stimulant effect
Second therapies:
– Other vasoconstrictors (ephedrine, methylphenidate, phenylpropanolamine) – can be effective but usually more SEs than proamatine
– NSAIDS (ibuprofen, indomethacin) - ?blocking prostaglandin synthesis blocks vasodilation – only modestly effective
– Beta blockers (propranolol, pindolol) – sometimes effective – risk of heart failure
– Ergots (DHE, intranasal ergotamine) – sometimes effective but can cause supine hypertension, ergotism

Question 48

Treatment for neurogenic bladders

Answer 48

Primary therapies (Antimuscarinics)
– Oxybutinin (Ditropan 5-30mg 2-3x/day; Ditropan XL 5-30mg QD)
– Tolterodine (Detrol 2mg BID; Detrol LA 2-4mg QD)
– SEs (for both): Dry mouth, HA, constipation, blurred vision
Secondary therapies
– TCAs (imipramine, amitriptyline, nortriptyline) have some antimuscarinic properties
– Desmopressin (DDAVP)
– ?Botox

Question 49

Drugs that cause tremor

Answer 49

Adrenergic drugs (caffeine, amphetamine, ephedrine)
Anticonvulsants (VPA, lamotrigine, phenytoin)
Lithium
Calcium channel blockers
H2 blockers
Corticosteroids
TCAs
Thyroid hormone replacement

Question 50

Drugs that cause Parkinsonism

Answer 50

Typical neuroleptics (also olanzapine and risperidone but less with clozapine and quetiapine)
Dopamine-blocking antiemetics (metoclopramide, compazine, perfenazine, promethazine, trimethobenzamide, etc.)
Calcium channel blockers (esp. flunarizine and cinnarizine)
Amiodarone
VPA
Lithium
Meperidine
SSRIs
Reserpine

Question 51

Drugs that cause myoclonus

Answer 51

Antidepressants(TCAs,SSRIs)
Anticonvulsants (CBZ, phenytoin, VPA)
Metoclopramide
Neuroleptics
Opiods
Levodopa
Lithium
Penicillins
Morphine

Question 52

Drugs that cause tics

Answer 52

Methylphenidate
TCAs
Dextroamphetamine
Carbamazepine
Pemoline
Cocaine

Question 53

Drugs that cause dystonia

Answer 53

Levodopa
Antihistamines
Metoclopramide, Ondansetron
Anticonvulsants (CBZ, phenytoin)
Fluoxetine
H2 blockers
Midazolam
Baclofen
Chloroquine

Question 54

Drugs that cause chorea

Answer 54

Levodopa and dopamine agonists
Amphetamines
Anticholinergics
Neuroleptics (tardive dyskinesia)
Anticonvulsants (CBZ, phenytoin, VPA, phenobarb, ethosuximide)
Anabolic steroids
Methylphenidate
Oral contraceptives
H2 blockers
Antidepressants (TCAs, SSRIs)

Question 55

Drugs that cause Restless Legs Syndrome

Answer 55

Benzodiazepines
Levodopa
H2 blockers
Caffeine
Withdrawal from anticonvulsants, barbiturates, benzos and other hypnotics
Carbamazepine
Droperidol

Question 56

Drugs that cause akathisia

Answer 56

Antidepressants
Benzos
Levodopa
Lithium
Carbamazepine
Neuroleptics

Question 57

Drugs that cause leukoencephalopathy

Answer 57

Chemotherapy (cisplatin, 5-fluorouracil, methotrexate, cytosine arabinoside). Corticosteroids Cyclosporin Interferon Interleukin-2 Amphotericin

Question 58

Drugs that cause ototoxicity

Answer 58

Aminoglycoside and non-aminoglycoside antibiotics (ampicillin, azithromycin, cephalosporins, erythromycin, sulfonomides, vancomycin) Antineoplastic agents (cisplatin, cytosine arabinoside, nitrogen mustard) Diuretics Antimalarials Anti-inflammatory agents Beta-blockers, calcium channel blockers Oral contraceptives Interferon Lidocaine

Question 59

Drugs that cause NMS

Answer 59

Neuroleptics (typical and atypical). Withdrawal of Parkinsonian meds (levodopa, amantadine, dopamine agonists). Anti-emetics (metoclopramide, prochlorperazine) Lithium Amphetamines Antidepressants Carbamazepine Cocaine PCP

Question 60

Drugs that cause cerebellar disorders

Answer 60

Etoh
Phenytoin
Cytosine arabinoside, cytarabine, 5-FU • Isoniazid
Lithium
Antidepressants
Cyclosporin
Metronidazole
Procainamide

Question 61

Drugs that cause myopathy

Answer 61

Neuromuscular blockers Statins Etoh Organophosphates Amiodarone Chloroquine Cimetidine Corticosteroids Cyclosporin Phenytoin Vincristine Interferon

Question 62

Drugs that cause myalgia

Answer 62

ACE inhibitors
Anticholinesterases
Beta agonists
Calcium channel blockers Cimetidine
Diuretics
Lithium
Procainamide
Colchicine
Clofibrate

Question 63

Drugs that worse NMJ disorders

Answer 63

Antibiotics (aminoglycosides, flouroquinolones, sulfonamides, tetracyclines, penicillins, azithromycin, clarithromycin, macrolides) Quinolones (quinidine, quinine, chloroquine) Anesthetics (diazepam, halothane, ketamine, lidocaine, methoxyflurane) Anticonvulsants (phenytoin, CBZ, barbiturates, ethosuximide) Antiarrhymics, calcium channel blockers and -blockers Corticosteroids Thyroid hormone replacement Lithium Chlorpromazine

Question 64

Drugs that cause nystagmus

Answer 64

Anticonvulsants (phenytoin, CBZ, benzos, barbiturates, VPA) Antineoplastic agents (cytosine arabinoside, 5-FU, naladixic acid) Sedatives and hypnotics (chloral hydrate, meprobamate) MAOIs. Cephalosporins Amitriptyline Ibuprofen, aspirin, salicylates Lithium (downbeat nystagmus) Phenelzine Chlorpromazine Amiodarone Meperidine Streptomycin

Question 65

Drugs that cause nystagmus

Answer 65

Anticonvulsants (phenytoin, CBZ, benzos, barbiturates, VPA) Antineoplastic agents (cytosine arabinoside, 5-FU, naladixic acid) Sedatives and hypnotics (chloral hydrate, meprobamate) MAOIs. Cephalosporins Amitriptyline Ibuprofen, aspirin, salicylates Lithium (downbeat nystagmus) Phenelzine Chlorpromazine Amiodarone Meperidine Streptomycin

Question 66

Excitatory

Answer 66

Glutamate in CNS

Question 67

Excitatory

Answer 67

Glutamate in CNS

Question 68

Inhibitory

Answer 68

GABA in CNS

Glycine in PNS

Question 69

LSD

Answer 69

Lysergic acid is one of the ergot fungus’ diverse alkaloid components, and it is a potent mood-changing and hallucinogenic drug

It does not cause withdrawal

Question 70

Marijuana

Answer 70

A marijuana (Cannabis) withdrawal syndrome has been debated. The World Health Organization’s International Classification of Diseases-10th Revision does recognize a cannabis withdrawal syndrome. This withdrawal syndrome was not previously recognized in the DSM-IV but included in the DSM-V. Symptoms of cannabis withdrawal syndrome may include nervousness or anxiety, decreased appetite or weight loss, insomnia, restlessness, irritability, anger or aggression, depressed mood, and physical symptoms such as headache, fever, chills, sweating, tremors and/or abdominal pain. Marijuana is typically smoked, although it is also ingested orally when added to other foods or drinks. One of the most studied cannabinoids in cannabis is δ-9-tetrahydrocannabinol (THC), and this accounts for its psychoactive effects. This is in contrast to cannabidiol (CBD), which has no psychoactive effects and accounts for many of the medicinal properties of cannabis. Common side effects include increased appetite (THC is sometimes used for anorexia and as an antiemetic in cancer and AIDS patients), tachycardia, dry mouth, conjunctival injection, excessive laughter, memory impairment, poor attention span, sedation, paranoia, anxiety, delusions, impaired coordination, and poor insight and judgment. Chronic use may cause flat affect, apathy, lack of motivation, and neurocognitive and memory impairments, especially when used in adolescence.

THC is active in the ventral tegmental area, nucleus accumbens, hippocampus, caudate nucleus, and cerebellum. THC’s effects on the hippocampus may help explain the memory problems that can develop with the use of cannabis, and those on the cerebellum may help explain the loss of coordination and imbalance sometimes seen.

Question 71

Opiate use intoxication/treatment

Answer 71

Opiate use and intoxication classically are associated with miosis, or pinpoint pupils, not mydriasis. Of note, this must be differentiated from pontine lesions, which can also cause pinpoint. decreased body temperature and coma. In addition to these findings, common side effects include euphoria, drowsiness, analgesia, and constipation (hence the use of opiates and opiate derivatives as antidiarrheals). Opiate toxicity/overdose creates a “silent gut”, which can help in the diagnosis. Because of its cough suppressant effects, codeine is sometimes used in cough medicines.

Treatment of suspected opiate overdose includes the opioid antagonist naloxone at 0.4 to 2 mg intravenously every 2 to 3 minutes. The diagnosis should be questioned if there is no response even after administration of 10 mg. Naltrexone is also an opioid antagonist, but used in longer-term treatment of opioid and alcohol dependence as opposed to naloxone, which is used in emergency settings. NOT NALTAREXONE - also an opioid antagonist, but used in longer-term treatment of opioid and alcohol dependence as opposed to naloxone, which is used in emergency settings

Question 72

Opiate withdrawal

Answer 72

Opiate withdrawal occurs within hours to several days of cessation. Withdrawal symptoms are often quite severe and cause significant functional impairment. They include dysphoria, myalgias, nausea, vomiting, rhinorrhea, lacrimation, piloerection, diaphoresis, diarrhea, mydriasis, fever, and insomnia. Difficulty often exists in differentiating opiate from sedative (e.g., alcohol, benzodiazepines) withdrawal. Hyperactive deep tendon reflexes (DTRs) can help in this differentiation because increased DTRs are typical in alcohol or sedative withdrawal but not opioid withdrawal. Therefore, if you see increased DTRs and give more opioids for suspected opioid withdrawal in the setting of actual sedative withdrawal, benzodiazepine or alcohol withdrawal seizures will be a likely complication.

Question 73

Rewards circuit

Answer 73

Ventral tegmental area and nucleus accumbens

All euphoria-producing drugs cause release of dopamine from the midbrain to the forebrain in the reward circuit (ventral tegmental area and the nucleus accumbens).

The caudate nucleus is included in this pathway. These areas contain especially high concentrations of dopaminergic synapses.

Question 74

Opiate effects on reward circuit

Answer 74

Rewards circuit: ventral tegmentum and nucleus accumbens and release of dopamine, also effects caudate, other structures modulated by endorphins, including the amygdala, locus coeruleus, arcuate nucleus, thalamus, and the periaqueductal gray matter, which influence dopaminergic pathways indirectly.

Question 75

Opiate receptors

Answer 75

Opioid receptors are a group of G-protein coupled receptors, with opioids acting as ligands. There are four major subtypes of opioid receptors.

• The first is δ, including subtypes δ1 and δ2. They are involved with analgesia, antidepressant effects, and physical dependence.
• The second is κ and includes κ1, κ2, and κ3. These are involved in spinal analgesia, sedation, miosis, and inhibition of antidiuretic hormone release.
• The third is μ and includes μ1, μ2, and μ3. The subtype μ1 is involved in supraspinal analgesia and physical dependence; μ2 is involved in respiratory depression, miosis, euphoria, reduced gastrointestinal motility, and physical dependence. The actions of μ3 are not clear.
• The fourth is ORL1/orphanin (or nociceptin receptor), which is involved in anxiety, depression, appetite, and development of tolerance to μ agonists.

Question 76

Amphetamines MOA

Answer 76

Direct release of dopamine and norepinephrine (like Bupropion) and inhibiting their reuptake. (Similar to bupropion, which inhibits reuptake of dopamine and norepinephrine)

Acts on reward circuit

Question 77

Cocaine MOA

Answer 77

Cocaine works by primarily inhibiting p_resynaptic reuptake of dopamine (as well as serotonin and norepinephrine)._

Question 78

Cocaine MOA

Answer 78

Cocaine works by primarily inhibiting presynaptic reuptake of dopamine (as well as serotonin and norepinephrine).

Acts on reward circuit

Question 79

Amphetamine and cocaine

Answer 79

Amphetamine and cocaine use present with similar findings, which include mydriasis (as opposed to opiates, which cause miosis), euphoria, tachycardia, cardiac arrhythmias, hypertension, nausea/vomiting, weight loss, diaphoresis, agitation, anxiety, respiratory depression, seizures, psychosis, formication (sensation of crawling bugs on skin), dyskinesias, and dystonia. Stroke and myocardial infarction can occur.

Withdrawal symptoms are also similar with amphetamines and cocaine and include dysphoria, vivid/unpleasant dreams, increased appetite, insomnia or hypersomnia, agitation, or psychomotor retardation. The routes of amphetamine use are oral, nasal (snorting), inhalational (smoking), or intravenous. The routes of cocaine use are nasal (snorting), inhalational (smoking; crack cocaine), intravenous, or oral (chewing coca leaves).

Question 80

MRI findings in Wernicke’s encephalopathy

Answer 80

MRI findings in Wernicke’s encephalopathy may include petechial hemorrhages classically in the mammillary bodies, but also in hypothalamus, medial thalami, and periaqueductal gray matter, sometimes even extending into the medulla, with atrophy seen in chronic stages. Acute thiamine deficiency does not typically lead to changes in the caudate nucleus.

Question 80

MRI findings in Wernicke’s encephalopathy

Answer 80

MRI findings in Wernicke’s encephalopathy may include petechial hemorrhages classically in the mammillary bodies, but also in hypothalamus, medial thalami, and periaqueductal gray matter, sometimes even extending into the medulla, with atrophy seen in chronic stages. Acute thiamine deficiency does not typically lead to changes in the caudate nucleus.

Question 81

MOA of alcohol and other sedative-hypnotic drugs

Answer 81

Affects basic structures of the reward circuit but also several other structures that use GABA as a neurotransmitter. GABA is one of the most widespread neurotransmitters in several parts of the brain, including the cortex, the cerebellum, hippocampus, amygdala, and superior and inferior colliculi. Alcohol exerts its effects by stimulation of the GABAA receptor, similar to the mechanism of action of benzodiazepines. This is why benzodiazepines are used to prevent withdrawal symptoms. Alcohol also inhibits glutamate- induced excitation, which leads to additive CNS-depressant effects.

Question 82

Alcohol withdrawal

Answer 82

Minor withdrawal symptoms begin within 6 to 36 hours from the last drink and include headache, tremors, diaphoresis, palpitations, insomnia, gastrointestinal upset, diarrhea, anorexia, agitation, and anxiety. Mentation is preserved during this period. Seizures can occur generally 6 to 48 hours after the last drink. Alcoholic hallucinosis begins at 12 to 48 hours and includes hallucinations (mostly visual but can also be auditory and tactile), intact orientation, and stable vital signs. Delirium tremens occurs at 48 to 96 hours if adequate prophylaxis is not initiated and is characterized by delirium, hallucinations, disorientation, agitation, encephalopathy, hypertension, tachycardia, arrhythmias, low-grade fever, and diaphoresis. In severe cases, delirium tremens can be fatal. β-Blockers and calcium channel blockers can be used for hypertension and tachycardia, although these will merely mask symptoms. Use of phenytoin or other anticonvulsants is appropriate in those with seizures and pre-existing epilepsy. This history is not present in the patient described, and antiepileptic agents are not indicated in this case. Benzodiazepines such as lorazepam should be given as scheduled doses to prevent withdrawal symptoms (including seizures), and these are the most important medications to add in this setting. Alcohol withdrawal symptoms often occur in unrecognized alcoholic patients who are admitted for surgeries or other reasons.

To summarize so you remember: 6-36 hours - minor withdrawal symptoms, 6-48 - seizures, 12-48 alcohol hours is alcoholic hallucinosis, 48-96 hours is delirium tremens

Question 83

Nicotine MOA

Answer 83

Agonist at nicotinic acetylcholine receptors. Nicotine leads to increased levels of several neurotransmitters, especially dopamine, in the reward circuits of the brain. This leads to euphoria, relaxation, and addiction. Nicotine in tobacco stimulates several areas in the reward circuit and its connections, such as the noradrenergic neurons of the locus coeruleus. Several other areas in the brain that secrete acetylcholine, such as the hippocampus and cortex, also appear to be affected by nicotine, and this may explain the increased attentiveness that smokers often describe after nicotine ingestion.

Acetylcholine agonist at nicotinic receptors (preganglionic for ANS)

Question 84

Caffeine and adenosine

Answer 84

Adenosine is a purine nucleotide that is released in the brain, primarily from astrocytes_. Adenosine normally inhibits release of excitatory neurotransmitters, leading to reduced neuronal firing rate and decreased cortical excitability. Caffeine competitively antagonizes the adenosine A1 and A2A G-protein–coupled receptor subtypes_. The resulting decreased activity of adenosine by caffeine leads to increased release of excitatory neurotransmitters, and thus the stimulating effects noted with caffeine.

Adenosine receptor antagonist

Question 85

Effects of PCP

Answer 85

Hypertension, tachycardia, nystagmus (vertical, lateral, horizontal, or rotatory), decreased pain sensation (often causing superhuman appearance of strength), rage, muscle rigidity, seizures, bizarre behaviors, hallucinations, delusions, impaired judgment, confusion, dysarthria, ataxia, and myoclonic jerks are all characteristic findings in PCP intoxication. Its use can also lead to hyperthermia, autonomic instability, and multiorgan failure.

Question 86

PCP MOA

Answer 86

PCP is used by oral, intravenous, or intranasal routes. It acts as a noncompetitive antagonist at the glutamate NMDA receptor. PCP has been shown to affect biogenic amine (dopamine, norepinephrine, serotonin) release and reuptake. These actions probably account for the sympathomimetic effects of PCP.

PCP is structurally similar to ketamine, but it differs from ketamine in that it is longer acting, is more likely to cause seizures, and tends to cause more emergent confusion and delirium. Ketamine also acts as a noncompetitive antagonist of the NMDA receptor. It also has interactions with muscarinic, nicotinic, and cholinergic receptors and inhibits reuptake of norepinephrine, dopamine, and serotonin.

The -ines seem to be NMDA receptor antagonists - ketamine, memantine, not so much amphetamine though - that acts on dopamine and NE

Question 86

PCP MOA

Answer 86

PCP is used by oral, intravenous, or intranasal routes. It acts as a noncompetitive antagonist at the glutamate NMDA receptor. PCP has been shown to affect biogenic amine (dopamine, norepinephrine, serotonin) release and reuptake. These actions probably account for the sympathomimetic effects of PCP.

PCP is structurally similar to ketamine, but it differs from ketamine in that it is longer acting, is more likely to cause seizures, and tends to cause more emergent confusion and delirium. Ketamine also acts as a noncompetitive antagonist of the NMDA receptor. It also has interactions with muscarinic, nicotinic, and cholinergic receptors and inhibits reuptake of norepinephrine, dopamine, and serotonin.

Question 87

Psychedelic or hallucinogens drugs

Answer 87

silocybin (4-phosphoryloxy-N, N-dimethyltryptamine) comes from specific types of mushrooms, and mescaline comes from the peyote cactus. Lysergic acid is one of the ergot fungus’ diverse alkaloid components, and lysergic acid diethylamide was popularized as a potent mood-changing and hallucinogenic drug. Use of the different hallucinogens leads to many similar symptoms including sensory distortions (such as synesthesias; “feeling” colors, “seeing” sound), illusions, hallucinations, euphoria, anxiety, tachycardia, palpitations, pupillary dilation (as opposed to opiates, which cause miosis), and diaphoresis. The hallucinogens primarily work at various serotonergic receptors. Different receptor subtypes are modulated by these various drugs, some of which may do so through agonism, whereas others through antagonism. The serotonin 5HT2 receptor is particularly thought to be involved in the action of these drugs. Some of these drugs may have some effects at dopamine and norepinephrine receptors. In addition, 3, 4- methylenedioxymethamphetamine (MDMA), or ecstasy, blocks reuptake of serotonin, and prolonged use of MDMA results in destruction of serotonergic neurons in the brain.

Question 88

Copper deficiency

Answer 88

This patient has copper deficiency related to excess zinc intake, and treatment should include copper supplementation and decreasing zinc intake. This can be related to excess dietary intake (as in this case), overuse of denture cream, parenteral feeding deficiency, and gastrointestinal surgery. This syndrome occurs because zinc increases enterocyte metallothionein synthesis. These excess enterocyte metallothioneins easily bind copper. The resultant excessively bound copper within the enterocytes is then excreted when the enterocytes are sloughed off, resulting in impaired absorption. Copper deficiency myelopathy syndrome resembles the subacute combined degeneration seen with vitamin B12 deficiency. Copper deficiency causes a sensorimotor peripheral neuropathy with axonal loss features on electrodiagnostic studies combined with myelopathy in the form of spastic paraparesis and posterior column dysfunction. Pancytopenia is also frequently associated.

Question 89

Vitamin E deficiency - neurological effects

Answer 89

Vitamin E deficiency related to chronic diarrhea and subsequent malabsorption of fat-soluble vitamins, that is, vitamins D, A, K, and E. These vitamins need to be supplemented, especially vitamin E as in this case. Symptoms resemble a spinocerebellar ataxia syndrome such as Friedrich ataxia and may include ataxia, dysarthria, areflexia, extensor plantar responses, and large-fiber sensory loss. Presentation can occur at any age in the setting of chronic diarrhea and malabsorption disorders. Vitamin E deficiency is more likely to occur in childhood when a genetic etiology is present, such as α- tocopherol-transfer protein mutation or abetalipoproteinemia (Bassen–Kornzweig syndrome). Abetalipoproteinemia is caused by a mutation of a microsomal triglyceride transfer protein resulting in absence of apolipoprotein B–containing proteins. This affects absorption of fat-soluble vitamins, and laboratory findings show low vitamin E levels. Acanthocytosis may also be seen on peripheral smear.

Question 90

Thiamine deficiency PNS

Answer 90

Extensor plantar responses would not be seen in thiamine (vitamin B1) deficiency. This deficiency would be more likely to cause peripheral neuropathy (with mute or flexor plantar responses). hiamine deficiency causes an axonal, sensorimotor peripheral neuropathy with weakness and distal sensory loss. This is termed “dry beriberi.” When it is associated with cardiac involvement in the form of cardiomegaly, cardiomyopathy, congestive heart failure, arrhythmia and tachycardia, and peripheral edema, it is called “wet beriberi.” Thiamine deficiency has also been reported to cause Leigh syndrome (Leigh subacute necrotizing encephalomyelopathy).

Laboratory findings of thiamine deficiency may include decreased serum thiamine, erythrocyte transketolase activity and urinary thiamine. Erythrocyte thiamine transketolase should be measured before and after administration of thiamine pyrophosphate, and low levels with increase of more than 25% after administration supports the diagnosis of thiamine deficiency.

In the setting of a neuropathy, electrodiagnostic findings may be consistent with an axonal sensorimotor polyneuropathy.

Question 91

Methionine in B12

Answer 91

Vitamin B12 is a cofactor for methionine synthase, which is involved in conversion of homocysteine → methionine and production of methylmalonyl-CoA→ succinyl-CoA . Methionine is subsequently a precursor for S-adenosyl-L-methionine, which helps with methylation of myelin basic protein.

Without this process, abnormal myelin structure results in neurologic deficit. The syndrome resulting from vitamin B12 deficiency is called subacute combined degeneration because of sensorimotor peripheral neuropathy combined with myelopathy, spastic paraparesis and posterior column dysfunction. Complete blood cell count may reveal a macrocytic anemia. Occasionally, vitamin B12 levels may be in the low normal or even normal range despite true deficiency. If clinical suspicion is present for deficiency, the levels of metabolic intermediaries homocysteine and methylmalonic acid should be checked, both of which would be elevated in vitamin B12 deficiency. Animal products (meat and dairy) provide the primary dietary source of vitamin B12 for humans. This puts older adults, alcoholics, patients with malnutrition, and strict vegans at high risk for development of this deficiency.

Question 92

Arsenic toxicity

Answer 92

Arsenic is a naturally occurring element most commonly incorporated into organic or inorganic compounds, both of which are very toxic. It can also occur in gas form.

With acute exposure, symptoms may develop within minutes to hours and usually begin with gastrointestinal symptoms such as abdominal pain, nausea, vomiting, and diarrhea. A garlic odor on the breath is characteristic. These symptoms can be followed by hypotension, dehydration, and cardiac and respiratory instability. Delirium, encephalopathy, coma, and seizures may occur. Other acute manifestations include proteinuria, hematuria, and acute tubular necrosis. If patients survive, within 1 to 3 weeks, they can develop hepatitis, pancytopenia, and a symmetric sensorimotor peripheral neuropathy, which typically begins with distal paresthesias, followed rapidly by an ascending sensory loss and weakness, which mimics Guillain–Barré syndrome. _The neuropathy can progress to intense burning pain, especially in the soles. In addition, dermatologic lesions can occur and may include alopecia, oral mucosal ulcerations, diffuse pruritic macular rash, and scaly rash on the palms and soles. A dry hacking cough and Mees lines (horizontal 1 to 2 mm white lines on the nails) may also occur. In chronic poisoning, the peripheral neuropathy and dermatologic symptoms are usually more prominent than the gastrointestinal symptom_s. Cancers of the liver, bladder, kidney, skin, lung, nasal mucosa, and prostate have been reported with chronic exposure.

After a suspected acute ingestion of arsenic, abdominal radiographs may reveal gastrointestinal radiopaque material. Urine arsenic levels are preferable to blood arsenic levels, but both can be used. Fish or shellfish intake within the previous 48 to 72 hours can cause falsely elevated levels of arsenic. For chronic exposure, hair and nail samples can be analyzed for the presence of arsenic, and 24-hour urine arsenic or spot urine arsenic and creatinine levels can be checked. Additional evaluations should include renal and liver function tests, complete blood cell count, urinalysis, and electrodiagnostic testing if there are symptoms of peripheral neuropathy. A distal sensorimotor axonopathy is the typical finding.

Acute treatment includes fluid and electrolyte replacement, cardiac monitoring, activated charcoal, and chelation therapy. Chelation agents typically used include dimercaprol (British Anti- Lewisite) and meso-2,3-dimercaptosuccinic acid (succimer).

Question 93

Arsenic toxicity

Answer 93

Arsenic is a naturally occurring element most commonly incorporated into organic or inorganic compounds, both of which are very toxic. It can also occur in gas form.

With acute exposure, symptoms may develop within minutes to hours and usually begin with gastrointestinal symptoms such as abdominal pain, nausea, vomiting, and diarrhea. A garlic odor on the breath is characteristic. These symptoms can be followed by hypotension, dehydration, and cardiac and respiratory instability. Delirium, encephalopathy, coma, and seizures may occur. Other acute manifestations include proteinuria, hematuria, and acute tubular necrosis. If patients survive, within 1 to 3 weeks, they can develop hepatitis, pancytopenia, and a symmetric sensorimotor peripheral neuropathy, which typically begins with distal paresthesias, followed rapidly by an ascending sensory loss and weakness, which mimics Guillain–Barré syndrome. _The neuropathy can progress to intense burning pain, especially in the soles. In addition, dermatologic lesions can occur and may include alopecia, oral mucosal ulcerations, diffuse pruritic macular rash, and scaly rash on the palms and soles. A dry hacking cough and Mees lines (horizontal 1 to 2 mm white lines on the nails) may also occur. In chronic poisoning, the peripheral neuropathy and dermatologic symptoms are usually more prominent than the gastrointestinal symptom_s. Cancers of the liver, bladder, kidney, skin, lung, nasal mucosa, and prostate have been reported with chronic exposure.

After a suspected acute ingestion of arsenic, abdominal radiographs may reveal gastrointestinal radiopaque material. Urine arsenic levels are preferable to blood arsenic levels, but both can be used. Fish or shellfish intake within the previous 48 to 72 hours can cause falsely elevated levels of arsenic. For chronic exposure, hair and nail samples can be analyzed for the presence of arsenic, and 24-hour urine arsenic or spot urine arsenic and creatinine levels can be checked. Additional evaluations should include renal and liver function tests, complete blood cell count, urinalysis, and electrodiagnostic testing if there are symptoms of peripheral neuropathy. A distal sensorimotor axonopathy is the typical finding.

Acute treatment includes fluid and electrolyte replacement, cardiac monitoring, activated charcoal, and chelation therapy. Chelation agents typically used include dimercaprol (British Anti- Lewisite) and meso-2,3-dimercaptosuccinic acid (succimer).

Activated charcoal, chelation

Question 94

Cyanide toxicity

Answer 94

In industrialized countries, the most common cause of cyanide poisoning are domestic fires due to combustion of products containing carbon and nitrogen, such as wool, silk, polyurethane (insulation/upholstery), and plastics. There are many industrial causes, such as electroplating in this case. There are also dietary causes, especially from ingestion of plant products from the family Rosaceae, including the seeds and pits of the plum, peach, pear, bitter almond, cherry laurel, apricot, and apple.

Cyanide is a rapidly lethal mitochondrial toxin that can cause death within minutes to hours of exposure. Cyanide competes with oxygen and binds to the ferric ion (Fe3+) of cytochrome oxidase a3, which inhibits this final enzyme in the mitochondrial cytochrome complex, resulting in cessation of oxidative phosphorylation. As a result, cells cannot use oxygen in their electron transport chain and must switch to anaerobic metabolism. Because of the decreased utilization of oxygen by tissues, venous oxyhemoglobin concentration will be high, making venous blood appear bright red and thus, the bright red coloration of skin, similar to the effects of carbon monoxide. Cyanide also causes toxic oxygen free radicals, release of glutamate, and inhibition of glutamic acid decarboxylase (the enzyme that helps form the inhibitory neurotransmitter GABA). CNS symptoms include headache, anxiety, abnormal taste, encephalopathy, vertigo, and seizures. Cardiovascular symptoms include chest pain, initial tachycardia, and hypertension, then bradycardia and hypotension, atrioventricular block, and arrhythmias. Respiratory symptoms include initial tachypnea, then bradypnea and pulmonary edema. Gastrointestinal symptoms include nausea, vomiting, and abdominal pain. Skin symptoms include flushing, cherry-red color. Cyanosis may occur late. Renal and hepatic failure may also occur.

Laboratory evaluation reveals severe metabolic acidosis with increased anion gap, elevated lactate level, and elevated blood cyanide level. Levels of more than 3.0 mg/L are fatal. Treatment must be initiated quickly, and includes removal of the cyanide source (such as from the skin) and activated charcoal. The Taylor Cyanide Antidote Package may be used. This includes amyl nitrite, sodium nitrite, and sodium thiosulfate. Hydroxocobalamin is also used to directly bind and neutralize cyanide and is often combined with sodium thiosulfate.

Activated charcoal, Taylor cyanide antidote pack, hydroxocobalamin

Question 95

Mercury toxicity

Answer 95

This man exhibits symptoms consistent with mercury toxicity, likely from years of exposure in a mercury mine. The organic forms of mercury are the most toxic, such as dimethylmercury and methylmercury. Some fish and shellfish concentrate mercury in the form of methylmercury. However, inorganic forms of mercury, such as cinnabar, are also highly toxic by ingestion or inhalation of the dust. Besides mining, other occupational exposures to mercury include dentistry, chloralkali industries, and thermometer factories. It was called “mad hatter’s disease” in the past because hat makers frequently worked with mercury to set and shape hats. If inhaled, a fatal interstitial pneumonitis may occur. It can be absorbed through the skin and orally ingested. Other symptoms include severe intention tremor, cerebellar ataxia, paresthesias, tender and inflamed gums, excessive salivation, swollen salivary glands, change in personality, and psychiatric symptoms such as anxiety, irritability, fearfulness, memory loss, depression, and fatigue. Treatment includes chelation therapy with British Anti-Lewisite, penicillamine, 2,3 dimercaptopropane-1-sulfonate, and dimercaptosuccinic acid.

Chelation

Question 95

Mercury toxicity

Answer 95

This man exhibits symptoms consistent with mercury toxicity, likely from years of exposure in a mercury mine. The organic forms of mercury are the most toxic, such as dimethylmercury and methylmercury. Some fish and shellfish concentrate mercury in the form of methylmercury. However, inorganic forms of mercury, such as cinnabar, are also highly toxic by ingestion or inhalation of the dust. Besides mining, other occupational exposures to mercury include dentistry, chloralkali industries, and thermometer factories. It was called “mad hatter’s disease” in the past because hat makers frequently worked with mercury to set and shape hats. If inhaled, a fatal interstitial pneumonitis may occur. It can be absorbed through the skin and orally ingested. Other symptoms include severe intention tremor, cerebellar ataxia, paresthesias, tender and inflamed gums, excessive salivation, swollen salivary glands, change in personality, and psychiatric symptoms such as anxiety, irritability, fearfulness, memory loss, depression, and fatigue. Treatment includes chelation therapy with British Anti-Lewisite, penicillamine, 2,3 dimercaptopropane-1-sulfonate, and dimercaptosuccinic acid. See discussion to question 33 for lead poisoning, question 34 for manganese toxicity, Chapter 12 for frontotemporal dementia, and questions 28 and 29 for thallium toxicity.

Question 96

Carbon monoxide toxicity

Answer 96

This woman has carbon monoxide (CO) poisoning. It commonly occurs at the change of seasons as winter months approach and people turn on their furnaces. Other family members in the same household may have similar symptoms, which gives a clue to diagnosis. CO is an odorless, tasteless, colorless gas. It binds to the iron moiety of heme in hemoglobin with much higher affinity than does oxygen, forming carboxyhemoglobin, which results in impaired oxygen transport and utilization. It competes with oxygen in binding hemoglobin. This binding leads to a structural change, which limits the ability of the other three oxygen binding sites to release oxygen to peripheral tissues and hence the cherry-red flushed coloration. It can also lead to CNS lipid peroxidation and delayed neurologic sequelae. Some sources include poorly functioning heating systems and improperly vented fuel-burning devices such as kerosene heaters, charcoal grills, camping stoves, gasoline-powered generators, and motor vehicles. Symptoms most commonly include headache, nausea, malaise, dizziness, and cherry-red skin coloration. Similar to arsenic but without the garlic taste and other skin changes. Severe toxicity can cause seizures, encephalopathy, coma, and cardiovascular instability. Diagnosis is based on clinical history and elevated carboxyhemoglobin levels (which may be normally elevated to an extent in smokers). Treatment should include high-flow 100% oxygen via a nonrebreather mask. In severe cases, histopathology in chronic stages reveals necrosis in the globus pallidus and confluent areas of necrosis in subcortical white matter.

High flow O2

Question 97

Lead toxicity

Answer 97

This boy most likely has lead intoxication, especially given the timing of symptoms in relation to moving into a very old house. Given this scenario, one must be concerned about the possibility of lead intoxication as lead-based paint in old houses has been a frequent etiology, especially in children. Many other occupational exposures are possible but would be seen more in adults. Lead inhibits the sulfhydryl-dependent enzymes such as γ-aminolevulinic acid dehydratase and ferrochelatase in heme synthesis, which causes disruption of hemoglobin synthesis and leads to the production of free erythrocyte protoporphyrins. Lead also competes with calcium in several biologic systems and processes, such as mitochondrial respiration and nerve functions, and has been implicated as contributing mechanisms in neurotoxicity.

Common symptoms of lead toxicity include abdominal pain (lead colic), constipation, myalgias, arthralgias, seizures, psychomotor slowing, headache, and anorexia. Basophilic stippling of red blood cells and microcytic hypochromic anemia are often seen. In addition, a bluish pigmentation at the gum-tooth line is sometimes seen. A peripheral neuropathy classically with extensor weakness or “wrist/ankle drop” is associated with lead toxicity and is due to an axonal degeneration that primarily affects motor nerves. Generally, removal from the lead source is the only treatment needed, although chelation therapy with 2,3-dimercaptosuccinic acid (succimer), and calcium disodium ethylenediaminetetraacetate are also available.

Chelation

Question 98

Manganese toxicity

Answer 98

This patient most likely has manganese toxicity. It is most commonly seen in those with chronic liver disease (impaired biliary excretion), those receiving total parenteral nutrition containing manganese, and those in the welding and steel industries. Symptoms include parkinsonian features, tremors, incoordination, confusion, personality changes, hallucinations, agitation, psychosis (manganese madness), memory disturbances, headache, and aggression. Brain MRI may show high T1 signal predominantly in the globus pallidus. Chelation therapy with ethylenediaminetetraacetate has been used as treatment.

Chelation

Question 99

Methanol toxicity

Answer 99

This man likely has methanol poisoning from ingestion of a household product in an attempt to ingest alcohol. Methanol and ethylene glycol are found in automotive antifreeze, de-icing solutions, antifreeze, and windshield wiper fluid and solvents, among others. Symptoms include nausea, headache, visual complaints, blindness, dizziness and encephalopathy, inebriation, and sedatio_n. Findings classically include necrosis of optic nerves and the putamen on neuroimaging. Toxicity occurs when methanol is oxidized by alcohol dehydrogenase and aldehyde dehydrogenase, forming the metabolite formate. Formate causes retinal injury and permanent blindness and injury to the basal ganglia (especially putamen)._ Fomepizole can be used as treatment, which acts as an alcohol dehydrogenase inhibitor. Ethanol can also be used to competitively bind to alcohol dehydrogenase, preventing breakdown of methanol into its toxic metabolites. Treatment also consists of correction of systemic acidosis.

Question 100

Organophosphate toxicity

Answer 100

This patient likely has organophosphate/carbamate poisoning related to the use of insecticide/pesticide. The only listed item that is not recommended in this clinical situation is gastric lavage because of a substantial risk of aspiration, given the increased secretions and decreased mental status in many patients. Organophosphates and carbamates are potent cholinesterase inhibitors leading to severe cholinergic toxicity. Toxicity can result from ingestion, cutaneous exposure, or inhalation. Some organophosphates are also used as terrorist nerve agents and include tabun, sarin, and soman.

Two common mnemonics used to remember the cholinergic/muscarinic crisis signs are attached:

Often these patients will develop the “intermediate syndrome,” approximately 12 to 96 hours after exposure that consists of weakness, fasciculations, tachycardia, hypertension, decreased deep tendon reflexes, cranial nerve abnormalities, proximal muscle weakness, and respiratory insufficiency. In addition, some organophosphates can cause organophosphorus-induced delayed neuropathy, occurring 2 to 3 weeks after exposure. Symptoms include painful but transient “stocking-glove” paresthesias followed by a symmetrical motor polyneuropathy with flaccid weakness of the lower extremities, which ascends to the upper extremities. Neurobehavioral symptoms may also occur as chronic sequelae.

Atropine competes with acetylcholine at muscarinic receptors to help prevent cholinergic activation. _Since atropine does not bind to nicotinic receptors, it is ineffective in treating neuromuscular dysfunction, so the cholinesterase-reactivating agent pralidoxime is typically given concurrently with atropine and is effective in treating manifestations resulting from activation of both muscarinic and nicotinic recepto_rs. Benzodiazepines are used for organophosphate-related seizures and sometimes for seizure prophylaxis. Activated charcoal is recommended if presentation is within 1 hour of ingestion. Gastric lavage is not recommended as mentioned earlier.

Question 101

Botulinism

Answer 101

This patient describes symptoms most consistent with botulism, likely related to foodborne source from home canning. Botulism is a potentially life-threatening neuroparalytic syndrome resulting from exposure to botulinum toxin, produced by Clostridium botulinum. There are at least eight distinct types of botulinum toxin, although the most commonly involved is botulinum toxin A. There are multiple forms of botulism including foodborne botulism (ingestion of food contaminated by botulinum toxin), wound botulism (infection of a wound by C. botulinum, with subsequent production of neurotoxin), infantile botulism (ingestion of clostridial spores that then colonize the gastrointestinal tract and release toxin), adult enteric infectious botulism (toxin produced in the gastrointestinal tract), and inhalational botulism (aerosolized toxin related to acts of bioterrorism).

Botulinum toxin binds to the synaptotagmin II receptor on presynaptic cholinergic synapses and neuromuscular junctions. After the heavy chain of the toxin binds to the receptors, the light chain translocates into the nerve cell via endocytosis. Upon entering the cytoplasm, the toxin irreversibly inhibits acetylcholine release by cleaving various proteins involved in neuroexocytosis of acetylcholine. B_otulinum toxin A and E cleave SNAP-25; botulinum toxin C cleaves SNAP-25 and syntaxin; and botulinum B, D, F, and G cleave synaptobrevin. Reversal of this inhibition requires sprouting of a new presynaptic terminal and formation of a new synapse. This generally takes 3 to 6 months_. Although the toxin can be quite harmful, these effects are used for therapeutic purposes, such as for the treatment of dystonia, spasticity, and other neurologic disorders.

Symptoms related to foodborne botulism may begin within 12 to 36 hours after ingestion of the toxin but may be delayed for several days. Symptoms include acute onset of multiple cranial neuropathies, blurred vision (due to fixed pupillary dilation), symmetric descending weakness, urinary retention, and constipation. Gastrointestinal symptoms such as diarrhea, abdominal pain, nausea, and vomiting often precede neurologic symptoms in foodborne botulism.

Question 102

MC side-effect of chemotherapies

Answer 102

There are many clinical neurologic syndromes that occur secondary to side effects of chemotherapy. Overall, peripheral neuropathy is the most common clinical neurologic syndrome caused by these agents. There are a multitude of chemotherapies associated with peripheral neuropathy that have been developed since the older medications such as vincristine and cisplatin, which are well recognized to cause peripheral neuropathy.

Question 103

Leukoencephalopathy and chemotherapy

Answer 103

Leukoencephalopathy is most commonly associated with high-dose or intrathecal methotrexate, and is caused by toxicity to the white matter. Clinically, patients have neurocognitive deficits, confusion, lethargy, and in severe cases, spastic quadriparesis, seizures, and dementia. Intrathecal methotrexate is also associated with aseptic meningitis, but liposomal cytarabine has also been associated with aseptic meningitis.

Question 104

Pancerebellar syndrome

Answer 104

High-dose intravenous cytarabine (often given for leukemia or lymphoma) can cause a dose-related subacute pancerebellar syndrome in 10% to 20% of patients. The cerebellar dysfunction is often associated with lethargy, confusion, and sometimes seizures. 5-Fluorouracil can also cause a subacute pancerebellar syndrome in up to 5% of patients.

Question 105

Bevacizumb side-effects

Answer 105

Bevacizumab has been associated with hemorrhagic stroke and intracerebral hemorrhage, as well as ischemic stroke.

Question 106

Rituximab

Answer 106

Rituximab is a monoclonal antibody commonly used in combination with other cytoxic chemotherapy. It is not directly toxic to the brain, but has been linked to progressive multifocal leukoencephalopathy, a condition secondary to the opportunistic infection with John Cunningham virus (JC virus).s

Question 107

AchE inhibitors, organophosphates

Answer 107

Atropine, pralidoxime

Question 108

Arsenic

Answer 108

Dimercaprol, succimer

Question 109

Benodiazepines

Answer 109

Flumazenil

Question 110

CO

Answer 110

100% O2, hyperbaric oxygen

Question 111

Cyanide

Answer 111

Hydroxocobalamin, nitrites+ sodium thiosulfate

Question 112

Dabigatran

Answer 112

Idarucizumab

Question 113

Direct factor Xa inhibitors

Answer 113

Andexanet alfa

Question 114

Heparin

Answer 114

Protamine sulfate

Question 115

Lead

Answer 115

Calcium disodium EDTA, EDTA, penicilline, dimercaprol, succimer: last two similar to arsenic

Question 116

Methanol, ethylene glycol (antifreeze)

Answer 116

Fomepizole>ethanol, dialysis

Question 117

Opioids

Answer 117

Naloxone

Question 118

MTX

Answer 118

Leucovorin

Question 119

TCAs

Answer 119

NaHCO3 to stabilize cell membrane