Neurochemistry, toxic/metabolic Flashcards

Question

Parasympathetic vs sympathetic

Answer 1

ACE - SNAP 25 BDEF - synaptobrevin

Answer 2

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

Answer 3

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

Answer 4

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

Answer 5

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

Answer 6

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)

Answer 7

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

Answer 8

Symmetric central pontine demyelination Ma also affect the corpus callosum

Answer 9

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

Answer 10

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

Answer 11

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

Answer 12

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)

Answer 13

Fat soluble vitamin deficiency Decreased prothrombin activity and resulting hemorrhages

Answer 14

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

Answer 15

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

Answer 16

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

Answer 17

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

Answer 18

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

Answer 19

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)

Answer 20

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

Answer 21

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

Answer 22

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

Answer 23

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

Answer 24

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

Answer 25

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

Answer 26

Methylphenidate TCAs Dextroamphetamine Carbamazepine Pemoline Cocaine

Answer 27

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

Answer 28

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)

Answer 29

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

Answer 30

Antidepressants Benzos Levodopa Lithium Carbamazepine Neuroleptics

Answer 31

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

Answer 32

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

Answer 33

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

Answer 34

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

Answer 35

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

Answer 36

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

Answer 37

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

Answer 38

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

Answer 39

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

Answer 40

Glutamate in CNS

Answer 41

Glutamate in CNS

Answer 42

GABA in CNS Glycine in PNS

Answer 43

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

Answer 44

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.

Answer 45

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

Answer 46

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.

Answer 47

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.

Answer 48

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.

Answer 49

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.

Answer 50

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

Answer 51

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

Answer 52

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

Answer 53

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).

Answer 54

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.

Answer 55

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.

Answer 56

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.

Answer 57

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

Answer 58

_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)

Answer 59

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

Answer 60

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.

Answer 61

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

Answer 62

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.

Answer 63

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.

Answer 64

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.

Answer 65

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.

Answer 66

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.

Answer 67

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.

Answer 68

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_).

Answer 69

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**

Answer 70

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**

Answer 71

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. ## Footnote **Chelation**

Answer 72

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.

Answer 73

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. ## Footnote **High flow O2**

Answer 74

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

Answer 75

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_

Answer 76

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._

Answer 77

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.

Answer 78

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._

Answer 79

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.

Answer 80

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.

Answer 81

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.

Answer 82

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

Answer 83

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

Answer 84

Atropine, pralidoxime

Answer 85

Dimercaprol, succimer

Answer 86

Flumazenil

Answer 87

100% O2, hyperbaric oxygen

Answer 88

Hydroxocobalamin, nitrites+ sodium thiosulfate

Answer 89

Idarucizumab

Answer 90

Andexanet alfa

Answer 91

Protamine sulfate

Answer 92

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

Answer 93

Fomepizole\>ethanol, dialysis

Answer 94

Leucovorin

Answer 95

NaHCO3 to stabilize cell membrane