1 TOXIC/METABOLIC DISORDERSRITE REVIEW

2 Toxin 1 A 44-yo man presented with a 5 year history of numbness, tingling pain in his extremities and pain in the epigastrium. He has worked for many years in a battery-recycling unit. On exam, he is slightly weak in the radial distribution bilaterally and he has a bluish discoloration to his gums.

3 Toxin 1

4 Toxin 1

5 LEAD Nonspecific - Neuropathy (axonal, sensory and motor)- Abdominal pain Specific - Bluish discoloration of the gums - Radial motor nerves particularly affected - Microcytic anemia with basophilic stippling - Increased coproporphyrin levels Lead has direct effects on porphyrin metabolism by inhibiting gamma-aminolevulinic acid dehydrase. Lead intoxication produces a motor neuropathy that affects predominantly, but not exclusively, the radial nerve. Associated features include abdominal pain, bluish decoloration of the gums just below the teeth, microcytic hypochromic anemia with basophilic stippling of the red cells, and increase coproporphyrin levels.

6 LEAD Microcytic anemia, Basophilic Stippling

7 LEAD Thickened Metaphyseal Lines (Lead Accumulation)

8 Toxin 2 Based on a true story…..A Chinese man presents with 1-2 weeks of headache, abdominal pain, vertigo, lethargy, constipation, and numbness and tingling of the extremities. He has noticed some double vision and lack of visual acuity in the past few days. He has also noticed that his hair is beginning to come out quite easily.

9 Toxin 2 He notes that he recently requested a divorce from his wife and moved out, but she requested that he move back in to help care for the children last month, which he did. What could be going on?

10 Thallium Nonspecific Specific GI Symptoms Small fiber neuropathyCranial nerve and autonomic involvement Alopecia [was a depilatory] Acts at Na+/K+ ATPase system

11 Thallium Sources Murderpedia.org (case of Tianle Li, 2011)“The poisoner’s poison,” “inheritance powder” Used to be used as a depilatory Used to be used as a rodenticide, now banned bcs of accidental deaths. Foreign Cases Occupational Exposures (electronics, lenses, semiconductors, alloys, gamma radiation detection equipment, imitation jewelry, artist's paints, low temperature thermometers, and green fireworks.) Murderpedia.org (case of Tianle Li, 2011)

12 Thallium – Case Cont’d. Thallium levels are “off the charts.”Investigators learned subsequently that the patient’s wife had ordered four bottles of thallium from Bristol Myers Squib in the two months before her husband’s hospitalization.

13 Thallium What is the antidote?

14 Thallium What is the antidote? PRUSSIAN BLUE

15 Toxin 3 A 35-year-old man comes into clinic 3 months of insidious onset of numbness and tingling in his toes and fingertips, progressing slowly in the ensuing weeks to involve the feet and hands. For the past 2-3 weeks, he has had burning pain and has noted weakness in gripping tools. Further questioning reveals the patient has been a carpenter since completing high school 17 years ago. For the last 10 years, he has lived in a rural, wooded area in a home he built.

16 Toxin 3 EXAM: Skin has brown patches of hyperpigmentation, with scattered overlying pale spots in and around the axillae, groin, nipples, and neck. The palms and soles show multiple hyperkeratotic corn-like elevations 4 to 10 mm in diameter. Three irregularly shaped, sharply demarcated, erythematous, scaly plaques, measuring 2 to 3 cm, are noted on the patient’s torso. The remainder of the physical examination is normal.

18 Arsenic Nonspecific Specific Neuropathy Rash and GI upsetAffects skin, hair, bone, fingernails Acute neuropathy

19 Arsenic Mechanism SourceReacts with sulfhydryl groups of proteins to disturb oxidative metabolism of neuron Source Semiconductors, treated woods, pesticides/herbicides/insecticides Another “inheritance powder”

20 Toxin 4 A 46 yo male CEO comes to clinic with diffuse pain. He feels like he is becoming gradually weaker and is feeling like his walk is becoming somewhat clumsier. He is also feeling more panicky, has difficulty sleeping, and was recently diagnosed with a new anxiety disorder. He has had several months of abdominal pain and nausea with a 16 pound unintentional weight loss in the past 3 months.

21 Toxin 4 EXAM Mental Status: anxiousCranial nerves: visual fields mildly constricted, mild ataxic dysarthria Motor: tremulous Sensory: distal sensory loss Coordination/Gait: ataxic gait

22 Toxin 4 When you ask about general health practices, he says he is very health-conscious, eating fish at every meal for the past year or so.

23 METHYL MERCURY Nonspecific: - Distal paresthesiasSomewhat More Specific: - Hallucinations, dementia, personality change - Ataxia - Choreoathetosis - Constricted visual fields - Hearing loss

24 METHYL MERCURY Absorbed through the skin and GI tractCerebellar granular cell neuron degeneration Depletes cellular selenium (essential micronutrient)

25 METHYL MERCURY Treatment?

26 METHYL MERCURY Tx: penicillamine or dimercaptosuccinic acid.

27 Metals Causing NeuropathyMercury - Psych Sx - Visual field - Hearing Arsenic - Skin changes Lead - Radial neuropathy - Blue gums - Anemia with basophilic stippling Thallium - Hair loss M.A.L.T.

28 Toxin 5 A 30-year-old male welder presented with a two-year history of gait disturbance. A neurological assessment revealed hypophonia, hypomimia, mild bradykinesia and rigidity with no resting tremor, a reduction in arm swing.

29 Toxin 5

30 Manganese Presentation:Initial reduced response speed, irritability, mood changes, and compulsive behaviors Then: Dystonia, Parkinsonism

31 Manganese Imaging: T1 weighted hyperintensity in the globus pallidusCauses/Risk Factors: Liver disease (hepatically cleared) Biliary atresia Prolonged parenteral

32 Manganese Treatment

33 Manganese Treatment: Chelation with EDTA, Levodopa (both have limited efficacy)

34 Toxin 6

35 Toxin 6 A family experienced flu-like (headache, fatigue, nausea, dizziness) symptoms over several weeks. A daughter in the family presented to the ED with convulsions and seizures. At 3 a.m. the day of presentation, the father awoke, extremely ill. He tried arousing other members of the family without success. Completely disoriented and passing in and out of consciousness he searched for a phone. Two hours later he managed to dial 911 before again passing out. Emergency workers found him collapsed over the phone. The entire family received treatment at a local emergency room.

36 Toxin 6

37 Carbon Monoxide Nonspecific: Specific Headache, vomiting ParkinsonismCNS demyelination days to weeks after exposure A cherry-red color in the tissues, including the brain Necrosis of the bilateral globus pallidus

38 Carbon Monoxide The culprit in this case was the FURNACE, which, during a remodeling project, was enclosed in a small room with no combustion air openings. The problem was compounded by a disconnected cold air return which depressurized the furnace room, drawing cold air back into the house through the chimney and spilling all the combustion products into the home. Although the furnace operated several years under these conditions, as the burners built up dirt and burned less efficiently, CO levels increased to the point of severe poisoning. Both the carpenter and heating contractor were unaware of the dangers of the disconnected cold air return.

39 Carbon Monoxide Mechanism?

40 Carbon Monoxide Mechanism: Binds to hemoglobin with an affinity times that of oxygen

41 Carbon Monoxide Source Interesting fact: FurnaceCar in a closed garage or clogged exhaust pipe  Interesting fact: Weird Al’s parents died from this

42 Carbon Monoxide Treatment:

43 Carbon Monoxide Treatment: high flow hyperbaric oxygen

44 Toxin 7 A 22-year-old man presented after waking the previous day with numbness below his knees. His symptoms progressed over a few days to paraesthesia in the fingers, and difficulty with walking and performing fine tasks with his hands On exam Flaccid tone with distal>proximal weakness Broad-based gait Positive Romberg. Sensation to light touch and pinprick was reduced below the knees, vibration sense was absent below the anterior superior iliac spines and joint position sense absent below the ankles. CBC, CMP, TSH, B12 nl.

45

46 Nitrous Oxide Nonspecific Somewhat More SpecificParesthesias in the limbs Somewhat More Specific Dorsal columns and corticospinal tracts affected (subacute combined degeneration picture) “Reverse Lhermitte’s Sign”

47 Nitrous Oxide Source Mechanism:Oxidizes the cobalt moiety of methylcobalamin Interferes with transformation of homocysteine to methionine Schilling test (normal – B12 absorption). B12 and/or MMA may be abnormal or normal. Source Whippits Nitrous balloons

48 Nitrous Oxide – Case ContinuedThought to be AIDP, treated with IVIG He admitted to using ‘whippits’ increasingly over the six weeks before presentation, now up to 120 g (15 whippits) per day. Although B12 was normal, methylmalonic acid levels were markedly raised at 29 653 nmol/L (<280). Treated with IM vitamin B12. His sensory symptoms and strength gradually improved over the next six months, though he still requires a stick to walk.

49 Nitrous Oxide = “hippie crack”

50 A Whippets Case

51

52 Toxin 8 A couple was in California having a romantic evening on the beach. At midnight, they gathered mussels and made a soup out of them (yum). He serenades her with a saxophone number.

53 Toxin 8 The evening took an unfortunate turn when, approximately 1–2 hours after eating, they began experiencing nausea, vomiting, and diarrhea, then paresthesias, weakness, and shortness of breath. They went to the ED, where the woman became ataxic, fell and could not stand up. In addition, her exam revealed pronounced dysarthria and diminished gag reflex in addition to her subjective dyspnea, oral paresthesia, and sensation of her throat closing up. She was intubated, but was able to be extubated shortly thereafter

54 Toxin 8 What is going on? The toxin is….

55 Saxitoxin New England and the West CoastFound in mussels, clams, oysters, scallops Reversibly binds to membrane voltage gated sodium channels

56 Toxin 9 A group of Neurology residents in their early 30s went to a conference in NYC. Feeling adventurous, they purchased a mysterious dried fish described as “globefish” from a street vendor. Six hours after rehydrating and eating the fish, they presented to the ED.

57 Toxin 9 They reported that, thirty minutes after consumption, they experienced perioral and tongue numbness, numbness and weakness in the extremities, extreme fatigue, and dyspnea. One of them complained that "my teeth can't feel themselves.” In the ED, they were slightly tachypneic and hypertensive, but exam was unremarkable. They were observed for several hours, after which symptoms resolved.

58 Toxin 9 What is going on here? The toxin is….

59 Tetrodotoxin

60 Tetrodotoxin Pufferfish, porcupinefish, ocean sunfish, triggerfish Fugu (“river pig” in Japanese), balloonfish, blowfish, bubblefish, globefish, Patka fish, swellfish, toadfish, toadies, honey toads, sugar toads, and sea squab - Indo-Pacific Ocean - Reversibly binds to membrane voltage gated sodium channels

61 Tetrodotoxin Samples were collected by the CDCMass spec showed significant concentrations of tetrodotoxin mean of 19.8 ppm, range of 5.7–72.3 ppm. FDA has not established a guidance level for tetrodotoxin, but for comparison, the guidance level for the paralytic shellfish toxin saxitoxin (similar potency), is 0.8 ppm.

62 Tetrodotoxin Though enjoyed safely in some Asian countries where they have special training, most puffer fish is not allowed in the US. Only the frozen meat, skin, and male gonad from one species of puffer fish (Takifugu rubripes) from Japan, processed according to Japanese safety guidelines, is permitted to be imported into the United States a limited number of times per year. All other imported puffer fish products are prohibited.

63 Toxins 8 & 9 Reversibly binds to membrane voltage gated sodium channels Indo-Pacific Ocean Source: TETRODOTOXIN Pufferfish, porcupinefish, ocean sunfish, triggerfish Paralysis without sensory symptoms Reversibly binds to membrane voltage gated sodium channels New England and the West Coast Source: SAXITOXIN Mussels, clams, oysters, scallops Tetrodotoxin – No antidote. Supportive care. Some use of neostigmine, but no evidence. Admit to ICU as symptoms can be delayed. Saxitoxin – No antidote. Supportive care. Bulbar Limb weakness respiratory weakness

64 Toxin 10 Two medical students, aged 23 and 24, spent a 6-week elective placement in Rarotonga, Cook Islands.

65 Toxin 10 Twelve hours after eating a parrotfish and a trevally they both developed mild nausea, followed by fatigue, lethargy and generalised weakness which lasted for 48 h.

66 Toxin 10 Thirty-six hours after eating the fish they developed extremity pruritis, paraesthesia of mouth, hands and feet, myalgia and cold allodynia. Cold fluids and objects were felt as a hot, burning sensation; hot fluid and objects were still felt as hot. Drinking cold fluids produced a tingling sensation in the mouth. The symptoms were unpredictable and fluctuating in nature, except for the cold allodynia which was triggered by touching cold objects and pruritis which was worse later in the day.

67 Toxin 10 The toxin is…. Florida and HawaiiCiguatoxin (CTX) is a thermostable toxin produced by marine microorganisms (dinoflagellates) in coral reefs and then passed up the food chain where it becomes concentrated in large reef fish like grouper, red snapper, and barracuda. CTX opens voltage-gated sodium channels in peripheral nerves at the nodes of Ranvier causing spontaneous depolarization. The clinical manifestations are usually sensory. Paradoxical sensory disturbances are particularly common (ie, hot feels cold and vice versa).

68 Ciguatera/CiguatoxinSx: Usually causes sensory disturbances Paradoxical sensory disturbances are classic (hot feels cold and cold feels hot.) Mechanism: Opens voltage gated Na channels in peripheral nerves at nodes of Ranvier causing spontaneous depolarization Source: Reef fish grouper, barracuda, red snapper, parrot fish, tiger fish Produced by marine micro-organisms and passed up the food chain Florida and Hawaii Ciguatoxin (CTX) is a thermostable toxin produced by marine microorganisms (dinoflagellates) in coral reefs and then passed up the food chain where it becomes concentrated in large reef fish like grouper, red snapper, and barracuda. CTX opens voltage-gated sodium channels in peripheral nerves at the nodes of Ranvier causing spontaneous depolarization. The clinical manifestations are usually sensory. Paradoxical sensory disturbances are particularly common (ie, hot feels cold and vice versa).

69 Prologue “…at the time we developed ciguatera poisoning, we were undertaking an audit looking at the prevalence of peripheral neuropathy in the Cook Islands. While we wondered whether we would see any rare causes of neuropathy, it never occurred to us that we might experience an unusual neurological disease first-hand. Before experiencing several of our symptoms, it was difficult to imagine what they might actually be like. Fatigue for example, we had always just imagined as the feeling you get when you have not had enough sleep or have been on a long walk. However, the reality of feeling too exhausted to walk to the sink and get a glass of water was far worse than either of us had previously realised. Both of us feel that this has informed our future practice, and are very grateful that the symptoms resolved!”

70 Toxin 11 A 2-year-old girl in Washington state presented to the ED with two days of unsteady gait, difficulty standing, and reluctance to walk. Other than a recent history of cough, she had been healthy and had not been injured. On physical examination, she was afebrile, alert, and active but could stand only briefly before requiring assistance. Cranial nerve function was intact. However, she exhibited marked extremity and mild truncal ataxia, and deep tendon reflexes were absent. What does it sound like?

71 Toxin 11 She was admitted with a tentative diagnosis of either Guillain-Barre syndrome or postinfectious polyradiculopathy. Within several hours of hospitalization, she had onset of drooling and tachypnea. A nurse incidentally detected an engorged tick on the girl's hairline by an ear and removed the tick. Within 7 hours after tick removal, tachypnea subsided and reflexes were present but diminished. The patient recovered fully and was discharged on April 11. The tick species was not identified.

72 Toxin 11 Can look like Guillain-Barre SyndromePresynaptic neuromuscular block Impaired excitation-secretion coupling due to reduced calcium availability What is the toxin?

73 Toxin 11 Paralysis without sensory symptomsPresynaptic neuromuscular block Impaired excitation-secretion coupling due to reduced calcium availability TICK PARALYSIS Holocylotoxin 41 different species of tick implicated, usually occurs in children under 10 or animals Other ticks associated with neuropathy by working on sodium channels Ascending paralysis, can involve bulbar and respiratory muscles. Recovery begins 8-48 hours after removal of tick, full recovery is common

74 Toxin 12 A 35 year old previously healthy man arrived in the ED. He was doing yard work when he felt a sudden pain in his toe. When he removed the boot to investigate, a black spider ran out. Within 5 minutes of the incident, he began feeling severe pain, cramping, and paresthesias in his left leg. The pain progressed to include his abdomen, low back, and chest. In the ED, the patient complained that the pain was so severe that it was difficult to sit or lie down. What is the toxin?

75 Latrotoxin BLACK WIDOW SPIDER biteSymptoms: sweaty, HTN, tachycardia, pain Mechanism: acute presynaptic release of acetylcholine and norepinephrine

76 Toxin 13 A 47-year-old resident of Oklahoma was admitted to an Arkansas hospital with subacute onset of progressive dizziness, blurred vision, slurred speech, difficulty swallowing, and nausea. On exam, he had ptosis, extraocular palsies, facial paralysis, palatal weakness, and impaired gag reflex. He developed respiratory compromise and required mechanical ventilation. What does it sound like?

77 Toxin 13 Electromyography demonstrated an incremental response to rapid repetitive stimulation. The patient was hospitalized for 49 days, including 42 days on mechanical ventilation, before being discharged.

78 Toxin 13 It was noted that, one day prior to onset of symptoms, he had eaten home-canned green beans and a stew containing roast beef and potatoes. Due to suspicion for toxic cause of his symptoms, food was tested.

79 Toxin 13 Although testing of the left-over green beans was negative for botulism toxin, type A toxin was detected in the stew. The stew had been cooked, covered with a heavy lid, and left on the stove for 3 days before being eaten without reheating. No other persons had eaten the stew.

80 Botulism Sx: Double vision, droopy eyelids, dysphagia(A constipated, hypotonic infant with unreactive pupils) Exam: Fixed, dilated pupils and dry mouth Lab: Toxin can be found in the stool. EMG: Incremental response on high frequency repetitive stimulation Mechanism: Inhibition of release of acetylcholine from presynaptic terminals SNARE = soluble NSF attachment protein receptor SNAP 25 = (cleaved by botulinum toxin A, more severe, I think this is the one in Botox) synaptosomal protein of 25 kDa. Inhibits presynaptic P/Q Ca++ channels VAMP – (cleaved by botulinum toxin B) vesicle associated membrane protein, aka synaptobrevin Infantile botulism 3-18 weeks of age, often breast fed. The classic symptoms of botulism include double vision, blurred vision, drooping eyelids, slurred speech, difficulty swallowing, dry mouth, and muscle weakness. Symptoms generally begin 18 to 36 hours after eating a contaminated food and mental status is usually normal. Can infect wounds in black tar heroin users Botulism immune globulin (antibodies), supportive care. (Antitoxin and antibiotics not effective)

81 Botulism

82 Botulism

83 Toxin 14 A 38-year–old man came to the office with a chief complaint of jaw discomfort and inability to open his mouth fully for 3 days.

84 Toxin 14 He said he had struck his right shin with a hammer 10 days earlier while attempting to fix his lawn mower. The hammer had penetrated deeply through the skin, and although the wound hurt and bled, he had not sought medical attention. Seven days after the orig- inal insult, he started noticing jaw discomfort and the inability to open his mouth completely. Exam: he was unable to open his jaw further than one inch. Otherwise, exam was unremarkable.

85 Toxin 14 What is the toxin?

86 Tetanus What is the mechanism of action?

87 Tetanus Mechanism:Targets synaptobrevins in the presynaptic nerve terminals in the brainstem and spinal cord. Impairs release of inhibitory neurotransmitters.

88 Opisthotonus

89 Tetanus Pupils are spared Trismus, facial rigidity, opisthotonos

90 Tetanus Risk factors

91 Tetanus Risk Factors: Children born at home to unimmunized mothers from an infected umbilical stump. Rusty nails

92 Tetanus Targets synaptobrevins in the presynaptic nerve terminals in the brainstem and spinal cord. Impairs release of inhibitory neurotransmitters. Pupils are spared Trismus, facial rigidity, opisthotonos Children born at home to unimmunized mothers from an infected umbilical stump. Rusty nails

93 Tetanus Targets synaptobrevins in the presynaptic nerve terminals in the brainstem and spinal cord. Impairs release of inhibitory neurotransmitters. Pupils are spared Trismus, facial rigidity, opisthotonos Children born at home to unimmunized mothers from an infected umbilical stump. Rusty nails

94 Tetanus Treatment

95 Tetanus Treatment: Human antitetanus immunoglobulin (Hyper-Tet 250 U) IM. Diphtheria booster into the left deltoid muscle. Metronidazole, 500 mg orally four times per day, was prescribed for 10 days.

96 Toxin 15 A middle aged Asian woman with depression was brought to emergency attention after drinking something from the garage in a suicidal attempt. She had vomiting, excessive retching, diarrhoea, miosis, hypersalivation and bilateral crepitation on chest during admission. On the fifth day of management she complained of generalized weakness, inability to control her neck and to sit or stand without support. But there was no respiratory muscle involvement and all deep tendon reflexes were normal.

97 Toxin 15 What is going on here? The toxin is….

98 Organophosphate Pinpoint pupils that do not dilate with any stimulusHypersecretion (salivation, sweating) and fascics Unconsciousness and respiratory depression Delayed axonal motor neuropathy with ataxia and spasticity

99 Organophosphate Mechanism:

100 Organophosphate PoisoningMechanism: Inhibition of acetylcholinesterase

101 Organophosphate PoisoningTreatment:

102 Organophosphate PoisoningTreatment: atropine

103 Organophosphates Where are they found?

104 Organophosphates Nerve gases (i.e. Sarin), and pesticides

105 Toxin 15 ORGANOPHOSPHATESPinpoint pupils that do not dilate with any stimulus Hypersecretion (salivation, sweating) and fascics Unconsciousness and respiratory depression Inhibition of acetylcholinesterase Delayed axonal motor neuropathy with ataxia and spasticity Treat with atropine Nerve gases (i.e. Sarin), and pesticides ORGANOPHOSPHATES

106 Quick Fact Section

107 Toxin 16 Nonspecific: Parkinsonism Specific:Potent inhibitor of mitochondrial complex I Selective loss of substantia nigra compacta neurons

108 Toxin 16 ROTENONE Nonspecific: Parkinsonism Specific:Potent inhibitor of mitochondrial complex I Selective loss of substantia nigra compacta neurons ROTENONE

109 Toxin 17 Acute onset neuropathy [like arsenic]Nerve biopsy: Paranodal giant axonal enlargements or “balloons.”

110 Toxin 17 Acute onset neuropathy [like arsenic]Nerve biopsy: Paranodal giant axonal enlargements or “balloons.”

111 n-HEXANE (hexacarbon)Toxin 17 Acute onset neuropathy [like arsenic] Nerve biopsy: Paranodal giant axonal enlargements or “balloons.” n-HEXANE (hexacarbon)

112 Toxin 18 Cerebral edema and petechial hemorrhagesBirefringent calcium oxalate crystal deposition in tissues Oxalic acid crystals in the urine Treat with ethanol, dialysis, correction of acidosis, and correction of hypocalcemia.

113 Toxin 18 ETHYLENE GLYCOL Cerebral edema and petechial hemorrhagesBirefringent calcium oxalate crystal deposition in tissues Oxalic acid crystals in the urine Treat with ethanol, dialysis, correction of acidosis, and correction of hypocalcemia. ETHYLENE GLYCOL

114 Toxin 19 White matter abnormalitiesSubcortical dementia and paranoid psychosis Cerebellar ataxia Hypointense lesions in thalamus and/or basal ganglia Glue sniffers

115 Toxin 19 TOLUENE White matter abnormalitiesSubcortical dementia and paranoid psychosis Cerebellar ataxia Hypointense lesions in thalamus and/or basal ganglia Glue sniffers (but not n-Hexane based glue sniffers) TOLUENE

116 Toxin 20

117 Toxin 20 Hemorrhagic lesions in the putamenImpaired vision from destruction of retinal ganglion cells Metabolized to formaldehyde and then to formic acid, which is the true toxin Treat with bicarbonate and ethanol

118 Toxin 20 METHANOL Hemorrhagic lesions in the putamenImpaired vision from destruction of retinal ganglion cells Metabolized to formaldehyde and then to formic acid, which is the true toxin Treat with bicarbonate and ethanol METHANOL

119 Toxin 21 Blocks reuptake of norepinephrineRaises dopamine levels in the nucleus accumbens May cause opsoclonus Withdrawal causes dysphoria, agitation, craving sweets Preferred treatment of withdrawal is a dopaminergic drug Predered treatment of withdrawal is a dopaminergic drug/dopamine agonist.

120 Toxin 21 Blocks reuptake of norepinephrineRaises dopamine levels in the nucleus accumbens May cause opsoclonus Withdrawal causes dysphoria, agitation, craving sweets Preferred treatment of withdrawal is a dopaminergic drug Predered treatment of withdrawal is a dopaminergic drug/dopamine agonist.

121 Toxin 21 COCAINE Blocks reuptake of norepinephrineRaises dopamine levels in the nucleus accumbens May cause opsoclonus Withdrawal causes dysphoria, agitation, craving sweets Treat withdrawal with a dopaminergic drug COCAINE Predered treatment of withdrawal is a dopaminergic drug/dopamine agonist.

122 Toxin 22 Prescription drug that causes ragged red fibersMyalgias, weakness, elevated CK levels Reverse transcriptase inhibitor that depletes mitochondrial DNA Gomori Trichrome stain

123 Toxin 22 ZIDOVUDINE (AZT)Prescription drug that causes ragged red fibers Myalgias, weakness, elevated CK levels Reverse transcriptase inhibitor that depletes mitochondrial DNA ZIDOVUDINE (AZT) Gomori Trichrome stain

124 Toxin 23 Peripheral neuropathyOccasionally affects proximal muscles first, mimicking a myopathy Can also cause psychosis, chorea, Parkinsonism, and catatonia Causes headache and nausea when it’s working Blocks the conversion of acetaldehyde to acetic acid

125 DISULFIRAM (Antabuse)Toxin 23 Peripheral neuropathy Occasionally affects proximal muscles first, mimicking a myopathy Can also cause psychosis, chorea, Parkinsonism, and catatonia Causes headache and nausea when it’s working Blocks the conversion of acetaldehyde to acetic acid DISULFIRAM (Antabuse)

126 Toxin 24 - Toxic optic neuropathy - Symmetric insidious visual loss- Yellow-green dyschromotopsia is the earliest symptom

127 Toxin 24 ETHAMBUTOL - Toxic optic neuropathy- Symmetric insidious visual loss - Yellow-green dyschromotopsia is the earliest symptom ETHAMBUTOL tuberculosis, Mycobacterium avium complex, and Mycobacterium kansasii.[3]

128 Toxin 25 First, small fiber sensory loss with autonomic dysfunctionLater, distal symmetric weakness Impaired function of microtubules involved in axonal transport

129 Toxin 25 VINCRISTINE toxicityFirst, small fiber sensory loss with autonomic dysfunction Later, distal symmetric weakness Impaired function of microtubules involved in axonal transport VINCRISTINE toxicity

130 Toxin 26 Neuropathy EMG: Myopathic units and fibrillationsMuscle biopsy: vacuolar myopathy Inhibits microtubular polymerization by interacting with tubulin Used to treat gout and Familial Mediterranean Fever Used in the U.S. since 19th century, but wasn’t FDA approved until 2009 Ancient Greeks used it 3000 years ago, available since 19th century in US, predating FDA FDA required all new drugs be tested before being released, but not ones already on the market. Starting in 1960s, FDA began evaluating older drugs, but colchicine was never one. In 2009, URL Pharma got FDA approval for Colcrys, charging $4.84 per pill instead of $0.09. The company argues that prior formulations were untested, potentially impure, and not generic because there was nothing to compare them to.

131 Toxin 26 COLCHICINE toxicity NeuropathyEMG: Myopathic units and fibrillations Muscle biopsy: vacuolar myopathy Inhibits microtubular polymerization by interacting with tubulin Used to treat gout and Familial Mediterranean Fever Used in the U.S. since 19th century, but wasn’t FDA approved until 2009 COLCHICINE toxicity Ancient Greeks used it 3000 years ago, available since 19th century in US, predating FDA FDA required all new drugs be tested before being released, but not ones already on the market. Starting in 1960s, FDA began evaluating older drugs, but colchicine was never one. In 2009, URL Pharma got FDA approval for Colcrys, charging $4.84 per pill instead of $0.09. The company argues that prior formulations were untested, potentially impure, and not generic because there was nothing to compare them to.

132 Toxin 27 Chemo agent that causes leukoencephalopathyLesions are frequently periventricular Leukemia, lymphoma The oral form doesn’t have good CNS penetration, but there are reported cases of it causing this problem

133 Toxin 27 METHOTREXATE Chemo agent that causes leukoencephalopathyLesions are frequently periventricular METHOTREXATE Leukemia, lymphoma The oral form doesn’t have good CNS penetration, but there are reported cases of it causing this problem

134 Toxin 28 Toxicity comes from inhibition of mevalonic acid, a precursor of Coenzyme Q10 Necrotizing myopathy Myalgias much more common than true myopathy Toxic action potentiated by use of clofibrate, gemfibrozil, or cyclosporine

135 Toxin 28 Toxicity comes from inhibition of mevalonic acid, a precursor of Coenzyme Q10 Necrotizing myopathy Myalgias much more common than true myopathy Toxic action potentiated by use of clofibrate, gemfibrozil, or cyclosporine STATINS

136 Toxin 29 Calcineurin inhibitor: causes neuro and nephrotoxicityCortical blindness Tremor Encephalopathy and seizure Kidney toxicity →wasting of magnesium → Lowers seizure threshold

137 Toxin 29 Calcineurin inhibitor: causes neuro and nephrotoxicity Cortical blindness Tremor Encephalopathy and seizure Kidney toxicity →wasting of magnesium → Lowers seizure threshold CYCLOSPORINE

138 Toxin 30 Common cause of tardive dyskinesiaAcute dystonic reaction, usually in younger patients within 48 hours of administration Treat with anticholinergic like benztropine Neuroleptic malignant syndrome Used to treat gastroparesis

139 Toxin 30 METOCLOPRAMIDE Common cause of tardive dyskinesiaAcute dystonic reaction, usually in younger patients within 48 hours of administration - treat with anticholinergic like benztropine Neuroleptic malignant syndrome Used to treat gastroparesis METOCLOPRAMIDE

140 Toxin 31 Used to treat pain Can cause seizures or myoclonusMixed with selegiline leads to central excitatory syndrome with HTN, tremor, MS Δ’s The combination of selegiline and meperidine cause cause a “central excitatory syndrome” of HTN, diaphoresis, tremulousness, and confusion

141 Toxin 31 MEPERIDINE Used to treat pain Can cause seizures or myoclonusMixed with selegiline leads to central excitatory syndrome with HTN, tremor, MS Δ’s MEPERIDINE The combination of selegiline and meperidine cause cause a “central excitatory syndrome” of HTN, diaphoresis, tremulousness, and confusion

142 Toxin 32 Induces myopathy in patients with mitochondrial disorders (MELAS) or CPT2 deficiency Hepatotoxicity [especially if POLG or <2 years old] Side effects include alopecia, obesity, and tremor Neural tube defects Used to treat epilepsy, bipolar disorder, and migraines

143 VALPROIC ACID toxicityToxin 32 Induces myopathy in patients with mitochondrial disorders (MELAS) or CPT2 deficiency Hepatotoxicity [especially if POLG or <2 years old] Side effects include alopecia, obesity, and tremor Neural tube defects Used to treat epilepsy, bipolar disorder, and migraines VALPROIC ACID toxicity

144 Toxin 33 Very common medication that causes myopathyCK is usually normal Treatment of other myopathies. Buffalo hump, moon facies. Osteoporosis, psychosis, weight gain, etc. Myosin ATPase 9.4 showing selective atrophy of type 2 (dark) fibers

145 CORTICOSTEROID toxicityToxin 33 Very common medication that causes myopathy CK is usually normal Treatment of other myopathies. Buffalo hump, moon facies. Osteoporosis, psychosis, weight gain, etc. CORTICOSTEROID toxicity Myosin ATPase 9.4 showing selective atrophy of type 2 (dark) fibers

146 Toxin 34 Primary site of damage is dorsal root ganglionCan also affect large myelinated sensory axons Disruption of fast axonal transport Ovarian, and small cell lung cancer, specifically Induction of apoptosis in DRG

147 Toxin 34 CISPLATIN toxicityPrimary site of damage is dorsal root ganglion Can also affect large myelinated sensory axons Disruption of fast axonal transport Ovarian, and small cell lung cancer, specifically CISPLATIN toxicity Induction of apoptosis in DRG

148 Toxin 35 Headaches, increased ICP Abducens palsyHigh concentrations in the livers of polar bears, seals, and walruses, and huskies.

149 Toxin 35 VITAMIN A Headaches, increased ICP Abducens palsyHigh concentrations in the livers of polar bears, seals, and walruses, and huskies. VITAMIN A

150 DEFICIENCIES

151 Deficiency 1 Hemorrhagic necrosis in mammillary bodiesConfusion, extraocular defects, ataxia An amnestic disorder with abnormalities limited to memory and learning Precipitated by carbohydrate or glucose loading Involved in function of pyruvate dehydrogenase. Deficiency produces activity in a shunt pathway which in turn causes hemorrhagic necrosis of deep brain structures Amnesia (isolated impaired memory) rather than global dementia

152 Deficiency 1 THIAMINE (Vitamin B1) deficiencyHemorrhagic necrosis in mammillary bodies Confusion, extraocular defects, ataxia An amnestic disorder with abnormalities limited to memory and learning Precipitated by carbohydrate or glucose loading THIAMINE (Vitamin B1) deficiency Involved in function of pyruvate dehydrogenase. Deficiency produces activity in a shunt pathway which in turn causes hemorrhagic necrosis of deep brain structures Amnesia (isolated impaired memory) rather than global dementia

153 Deficiency 2 Spinocerebellar degeneration mimics Friedreich's ataxiaDystrophic axons in the posterior columns Celiac disease or fat malabsorption are risks May be caused by a mutation of the gene that encodes alpha-tocopheral transport protein Bassen-Kornzweig disease (abetalipoproteinemia) causes this deficiency, and causes neuropathy and retinopathy. Cognitive disorders, ataxia

154 Deficiency 2 VITAMIN E deficiencySpinocerebellar degeneration mimics Friedreich's ataxia Dystrophic axons in the posterior columns Celiac disease or fat malabsorption are risks May be caused by a mutation of the gene that encodes alpha-tocopheral transport protein Bassen-Kornzweig disease (abetalipoproteinemia) causes this deficiency, and causes neuropathy and retinopathy. Cognitive disorders, ataxia VITAMIN E deficiency

155 Deficiency 3 Corticospinal tract dysfunction Dorsal column dysfunctionPancytopenia Excess zinc ingestion is a risk Gastric bypass surgery is a risk

156 Deficiency 3 COPPER deficiency Corticospinal tract dysfunctionDorsal column dysfunction Pancytopenia Excess zinc ingestion is a risk Gastric bypass surgery is a risk COPPER deficiency

157 Deficiency 4 Autosomal recessive deficiency can cause neonatal onset seizures Vitamin supplementation prevents seizures Diminished activity of glutamic acid decarboxylase Neuropathy from too much OR not enough of this vitamin

158 PYRIDOXINE (Vitamin B6) deficiencyAutosomal recessive deficiency can cause neonatal onset seizures Vitamin supplementation prevents seizures Diminished activity of glutamic acid decarboxylase Neuropathy from too much OR not enough of this vitamin PYRIDOXINE (Vitamin B6) deficiency

159 Deficiency 5 Dorsal column and corticospinal tract dysfunctionDementia, psychosis, and neuropathy Upper motor neuron signs AND distal hyporeflexia High MCV anemia Elevated homocysteine and methylmalonic acid Risk factors: gastric bypass, pernicious anemia, H2 blockers

160 Deficiency 5 COBALAMIN (Vitamin B12)Dorsal column and corticospinal tract dysfunction Dementia, psychosis, and neuropathy Upper motor neuron signs AND distal hyporeflexia High MCV anemia Elevated homocysteine and methylmalonic acid Risk factors: gastric bypass, pernicious anemia, H2 blockers COBALAMIN (Vitamin B12)

161 Presynaptic Neuromuscular Block (3)

162 Presynaptic Neuromuscular BlockHolocylotoxin – Tick Paralysis Tetanus Botulism

163 Excess Acetylcholine (2)

164 Excess Acetylcholine Latrotoxin – Black Widow Organophosphates

165 Subacute Combined Degeneration (4)

166 Subacute Combined DegenerationVitamin E Copper Nitrous Oxide - Whippits

167 Myopathy (3+1 special circumstance + 1 mimic)

168 Myopathy (3+1 special circumstance + 1 mimic)Colchicine Statins Corticosteroids Valproic Acid (in pts with mitochondrial disorder) (Disulfuram can seem like a myopathy, causing proximal neuropathy)

169 Putamenal Hemorrhage

170 Putamenal Hemorrhage

171 Putamanal Hemorrhage Methanol

172 Hemorrhagic Necrosis in Mamillary Bodies

173 Hemorrhagic Necrosis in Mamillary BodiesB1 Deficiency – Wernicke’s

174 Damages DRG (dorsal root ganglion)

175 Damages DRG (dorsal root ganglion)Cisplatin

176 Neuropathy with Hair Loss

177 Neuropathy with Hair LossThallium

178 Paradoxical Sensory Disturbances

179 Paradoxical Sensory DisturbancesCiguatoxin

180

181

182 Necrosis of the Globus PallidusCARBON MONOXIDE POISONING!!!!

183 Necrosis of the Globus Pallidus

184 THE END