By: Laurence Poliquin-Lasnier R4 Neurology

By: Laurence Poliquin-Lasnier R4 Neurology
Neurotoxicology By: Laurence Poliquin-Lasnier R4 Neurology

Outline General principles Terrestrial biotoxins Metal intoxications
Organic chemicals intoxications Marine Neurotoxins

General Principles Peripheral neuropathy of the distal axonopathy type is the most common presentation of North American neurotoxic disease Detailed history is important to establish causative agent Virtually all neurotoxic disease improves or stabilizes following withdrawal from exposure Progression of illness for years following removal strongly suggests the condition is not due to an exogenous chemical Laboratory data are available for heavy metals and drugs of abuse, but not for most industrial or environmental agents and electrodiagnostic studies are nonspecific Age and preexisting conditions (eg.: hereditary neuropathy) can increase vulnerability to neurotoxic agents Eg.: a person with Charcot-Marie-Tooth disease given vinca alkaloid tx may develop an unusually severe neuropathy

Vulnerability of peripheral nervous system motor unit and subcellular structures

Terrestrial biotoxins
Bacterial Clostridial Envenomation Botanical

1-Bacterial toxin: Diphteria
Diphtheria is an acute, contagious disease caused by the gram- positive bacillus Corynebacterium diphtheriae There are two forms of symptomatic infection (respiratory and cutaneous) and an asymptomatic carrier state The respiratory form of diphtheria causes the characteristic pseudomembranous pharyngitis Other common complications of severe infection include myocarditis, neuritis, and less often nephritis C. diphtheriae solely lives in the mucous membrane and skin of humans and infects via airborne respiratory droplets, direct contact with respiratory secretions of symptomatic individuals, or infected skin lesions Asymptomatic carriers are an important mode of transmission What is the most common severe complication of C. diphteria?

Diphteria Acute demyelinating polyneuropathy - >most common severe complication Diphtheritic neuropathy is an uncommon disease in Western Europe and the United States due to vaccination Large epidemic from 1990 to 1995 was reported in the former Soviet Union Fatality rate 2-3%

Diphteria 15% incidence of neurologic complications was reported in adults Correlation between the severity of the diphtheritic polyneuropathy and the severity of the diphtheria infection Latency in development of diphtheritic polyneuropathy varies from 18 to 46 days from the initial infection (mean 30 days) Approximately 2/3 of patients who developed a diphtheritic polyneuropathy had a preceding serious diphtheria infection with both cardiac and renal impairment Neurologic manifestations of diphtheria are biphasic Early bulbar disturbance (wks 3 to 5) with cranial neuropathies (ocular and lower CN may be affected) Late motor weakness in the trunk and extremities (wks 5 to 8) Improvement in cranial nerves occurs with ongoing motor disturbance in trunk and extremities

Diphteria Weakness in the limbs can be both proximal and distal with associated atrophy in severe cases Paralysis of the diaphragm and respiratory failure can occur Sensory disturbances in all modalities with paraesthesias of distal extremities and often a sensory ataxia Hypotonia, hyporeflexia, and downgoing plantar responses Significant abnormalities of parasympathetic and sympathetic function are often present and more common with severe cases

Diphteria Pathogenesis: paranodal demyelination and segmental demyelination both at ventral and dorsal spinal roots and peripheral nerve

Diphteria Large DDx Diagnosis: Isolation of C. diphtheriae on culture with toxigenic testing with nasopharyngeal swab from the patient and his/her contacts C. diphtheriae requires special culture median containing tellurite Elek test is performed to determine if the bacillus produces toxin and is an important test in the diagnostic process Measurement of serum antibodies to diphtheria toxin may also help assess the probability of diphtheria PCR available for confirmation NCS: demyelinating

Diphteria Treatment: Antibiotic therapy in combination with antitoxin administration within 48 hours of diagnosis to decrease the chances of developing diphtheritic polyneuropathy Antitoxin does not neutralize toxin that is already bound to tissues -> delaying its administration is associated with an increase in mortality risk Antibiotics to eradicate and avoid transmission

Case #1 57-year-old farmer was admitted to the hospital with a 1- week history of right lower extremity muscular rigidity that over a period of a week started to spread to his axial muscles including the neck, back, and abdominal muscles He reported stepping on a nail in the barn 2 weeks prior to the onset of symptoms and still had an open festering wound at the puncture site He then developed laryngospasms that led to respiratory compromise requiring intubation His sensorium remained clear Diagnosis?

2- Bacterial toxin: Clostridial-> Tetanus
Clostridium tetani Anaerobic, gram positive rod Metabolizes in anaerobic conditions and reproduces via spores that can survive in aerobic conditions The spores are the common mode of transmission The bacterium survives in soil and in the intestines and feces of animals, from which the spore invades the body through seemingly insignificant wounds and subsequently multiplies

Tetanus Early manifestations of generalized tetanus include rigidity of the masseter muscles (trismus aka lockjaw) and of facial muscles with a distinct straightening of the upper lip causing a grimacing posture to the face (risus sardonicus) Frequent localized stiffness near the site of the penetrating wound followed by rigidity of the axial muscles involving the neck, back muscles (opisthotonus), and abdomen With progression, extremities become stiff with relative sparing of the distal muscles Spasms can be significant enough to break long bones of the extremities Paroxysmal reflex spasms can occur in severe cases, generally in response to voluntary movements or to external and internal stimuli In severe cases, muscles of deglutition may also go into trismus, causing dysphagia and dysarthria -> laryngospasms can lead to respiratory compromise and asphyxia Over a period of approximately 2 wks, the severity of symptoms can worsen, and by 4 weeks recovery usually begins A hypersympathetic state may be a manifestation of more severe cases with fluctuations of BP and HR Profuse sweating, high fever, and hypersalivation are also common signs of autonomic instability

Tetanus Neonatal tetanus usually occurs in the generalized form and tends to carry a high mortality rate The most common symptoms of neonatal tetanus are a failure to suck and muscular twitching Neonatal tetanus generally develops in the first 2 wks of life in children born to mothers who have been poorly immunized These infants often have umbilical stump infections In some underdeveloped countries, some practices occur in the birthing process that put infants at risk, including the application of clarified butter with contaminated dung fuel on umbilical cords

Tetanus Pathogenesis:
Tetanus is transported to the spinal cord from the neuromuscular junction and then transported by transcytosis to the inhibitory Renshaw cell and to the upper motor neurons Blocks the release of glycine and GABA from inhibitory neurons, leading to spastic paralysis -> no relaxation of the antagonistic muscle during normal contraction

Tetanus Diagnosis: Clinical
Positive spatula test on physical: reflex spasm of the masseter muscle on touching the posterior pharyngeal wall Continuous, spontaneous motor unit discharges on EMG reported but not diagnostic of tetanus In some serious cases, elevated CSF protein and immunoglobulin levels have been documented C. tetani can be cultured in about 1/3 of confirmed cases from wounds PCR assays for neurotoxin gene fragments available The presence of serum antitoxin of 0.01 unit per mL or higher is considered protective and makes a diagnosis of tetanus unlikely Prognosis: related to degree of autonomic instability and type of wound/injury. Burns, infected umbilical stumps, and compound fractures are frequently related to a poor prognosis

Tetanus Treatment: elimination of the source of toxin, toxin neutralization, control of muscle rigidity and spasms, and ventilatory support If no wound is found, careful examination for signs of parenteral drug abuse, otitis, and careful rectal and vaginal examinations are recommended A retained foreign body may result in continuous toxin production Although controversial, the use of metronidazole (500 mg IV every 6 hours for 7 to 10 days) is the drug of choice Penicillin has a central GABA antagonistic effect and can worsen spasms Administration of human tetanus immunoglobulin is recommended before manipulating a wound -> recommended dose is 500 units IM Combined intrathecal (1000 units) and IM antitetanus immunoglobulin administration gives better clinical outcomes than IM administration alone

Bacterial toxins Another clostridial toxin -> clostridium botulinum (covered in neuromuscular talk) with the typical descending flaccid paralysis Anthrax (Bacillus anthracis) -> hemorrhagic meningoencephalitis

3-Envenomation/Snake With the exception of the coral snake, all the venomous snakes in the United States are pit vipers (rattlesnakes, cottonmouths, and copperheads) The incidence of venomous snake bites in the United States is approximately to 8000 per year, but only 5-6 result in death Confident diagnosis of a venomous snakebite requires a positive identification of the snake and recognition of the clinical manifestations of the envenomation Rarely a snake will be brought in alive or dead for inspection at the clinic Caution should be taken handling dead snakes as a bite reflex can occur even after the death Envenomation does not always occur with venomous snakes (25% of all viper bites are dry)

3-Envenomation/Snake Toxins
α-Bungarotoxin and cobrotoxin: postsynaptic blockade of acetylcholine receptors (AChRs) β-Bungarotoxin and crotoxin: presynaptic inhibition of acetylcholine (ACh) release Local pain, swelling, and erythema at site of the bite Focal weakness or compartment syndrome Diffuse proximal weakness resembling myasthenia gravis Ptosis, cranial neuropathies, myokimia, dysphagia, areflexia, fasciculations, respiratory distress Systemic manifestations, including hypotension and shock

3-Envenomation/Snake With pit viper envenomations, incision and suctioning at the bite site within minutes can remove venom Antivenin, most effective when given within 4 hrs of bite Beware of anaphylactic reaction

3- Envenomation/Scorpion
Tityustoxin, produced by Tityus serrulatus, causes presynaptic facilitation of ACh release and postsynaptic activation of voltage-gated sodium channels Local pain and erythema at site of the bite Excess cholinergic activity: salivation, lacrimation, urinary incontinence, defecation, gastroenteritis, and emesis (SLUDGE) Local paresthesias, followed by diffuse paresthesias (thalamic involvement) , fasciculations, tremors, hyperreflexia, ptosis, nystagmus, blurred vision, dysarthria, and dysphagia Pandysautonomia: hypertension, hyperthermia, hypersalivation, diaphoresis, urinary frequency, fecal urgency

3- Envenomation/Scorpion
Treatment: supportive care Anti-venin With the use of Centruroides antivenin, moderate to severe neurologic symptoms may reverse in 15 to 90 minutes

3- Envenomation/Female black widow spider(Latrodectus mactans)
Most important spider to cause potentially significant morbidity Poorly lighted area-> often sting genitalia Toxin: α-latrotoxin, causing presynaptic facilitation of ACh release and depletion of Ach Erythema at site of the bite, intense pain, and involuntary muscle spasms involving the limbs, trunk, and diaphragm (latter causing respiratory arrest), dysarthria, chest pain Autonomic symptoms: hypertension, piloerection, diaphoresis, brochospasm Acute symptoms increase in severity during the first day after a bite. Most symptoms generally decline after 2 to 3 days, but some mild residua may continue for several wks Tx: antivenin

Case #2 12-year-old girl presents to the ER with progressive gait instability, ascending weakness, shortness of breath on exertion, slurred speech, and swallowing difficulties over 3 days No GI or pulmonary symptoms, nor fever preceding the onset of symptoms On examination, she was alert with some facial weakness, dysarthria, and diffuse 3-4/5 weakness worse in the legs than the arms Reflexes were absent, and she had no sensory abnormalities A neurologist saw the patient in the ER and thought Guillain-Barré syndrome was likely CSF analysis and NCVs including repetitive stimulation were normal, except for low- amplitude CMAPs, making the diagnosis of Guillain-Barré syndrome unlikely A careful examination of the patient with a comb revealed a tick at the nape of her neck. Within hours of its removal, the patient started to get better and eventually made an uneventful recovery within a week Diagnosis?

3- Tick paralysis Results from inoculation of toxin contained in the tick saliva at the time of a blood mea Tick paralysis is associated with over 40 species of tick worldwide, including five species in North America; yet only four tick species cause human disease The tick species responsible for most cases of human tick paralysis in the United States and Canada are Dermacentor andersoni (the Rocky Mountain wood tick), and Dermacentor variabilis (the American dog tick) Other areas of the body involved include the nose, ear canals, and genital area The incidence is most frequent in spring and summer

3-Tick paralysis Acute ascending paralysis over days without sensory symptoms Unlike Lyme disease, symptoms regularly resolve after tick is removed Symptoms usually begin 2 to 6 days after the tick becomes attached Constitutional symptoms such as fever are lacking, but generalized fatigue is not an uncommon initial symptom Often mistaken for GBS-> Gait instability -> falling -> total inability to walk is a common presentation over a couple of days and may quickly involve respiratory muscles and cranial and bulbar muscle -> intubation Weakness worse in the LE and ass. with hypotonia and hypo/areflexia Isolated facial weakness has been described, although more diffuse involvement of the cranial nerves leading to ophthalmoplegia, dysarthria, and dysphagia is more common Reports in children of ataxia, mild encephalopathy, minor sensory disturbances

3- Tick paralysis Pathogenesis not entirely understood but thought to block axonal Na+ channels and to inhibit the release of ACh at presynaptic motor nerve terminals, causing total neuromuscular blockade EMG/NCVs are well described and suggest axonal involvement with evidence of denervation CMAPs are of low amplitude and improve with the removal of the tick as does the clinical status Treatment: Remove the tick Coating the tick with petroleum jelly to make it release its hold is helpful and one should attempt to grasp the tick as close to skin as possible and make sure to remove all of the tick's capitulum (head) Detection and removal of the tick usually results in rapid improvement (hours to 1 or 2 days) in the patient's condition Antiserum is generally neither recommended, nor necessary

4- Botanical toxin: Amanita mushrooms
After consumption, there are initially no signs of toxicity, but a severe gastroenteritis ensues after about 6 to 12 hrs with N/V, abdo cramping, and diarrhea For the next 24 to 48 hrs, the patient may improve clinically, giving a sense of false hope as during that time renal and hepatic function deteriorate Toxicity begins upon active transport into hepatocytes where it binds to and inhibits RNA polymerase II, leading to inhibition of protein synthesis and ultimately hepatocyte death Hepatotoxicity and renal failure develop in the next 3 to 5 days, followed by secondary metabolic encephalopathy Neurologic compromise may be related to direct effects of α-amatoxin and indirect effects of brain edema from liver failure The key psychoactive constituents in these mushrooms are ibotenic acid, muscimol, and muscazone The GABA receptor agonist, muscimol, is somewhat sedating, Ibotenic acid binds to glutamate receptors and induces an agitated delirium Tx: supportive

Metal intoxication Arsenic Lead Manganese Mercury

Industrial/environmental toxins
A few caveats…

General principles of industrial and environmental toxins

Case #3 A 62-year-old woman was evaluated for a 3-year history of slowly progressive, ascending, distal lower limb paresthesias. She was on no medications and did not give a history of potential toxic exposure. Her examination was remarkable for decreased perception of vibration and position at the toes and a graded decreased perception of pinprick and touch distal to the mid-shin level. Her ankle jerks were absent. No other abnormalities were noted on her general and systemic examination. Nerve conductions studies revealed an axonal, symmetric, length- dependent, predominantly sensory PN. Extensive investigations examining various causes of neuropathy were unrewarding. A urine heavy metal screen was, however, remarkable for a 24-hour arsenic excretion of 862 μg (normal: less than 120 μg/24 h) What’s your diagnosis?

Case #3 Elevation in urinary arsenic excretion is sometimes due to the organic, nontoxic form resulting from prior seafood ingestion Within hours of seafood ingestion total urinary arsenic concentration may be in the range of 100 μg/L to 10,000 μg/L Seafood should be avoided for 3 to 4 days prior to a urine arsenic determination This patient admitted to seafood ingestion during and prior to the urine collection and a repeat collection was normal

Arsenic May be due to poisoning or man-made sources (eg.: metal smelting, mining, abrasive blasting, pesticide manufacturing, combustion of coal, and burning of agricultural wastes, burning of chromated copper arsenate-treated wood in fireplaces or wood stoves), found in tap water in Bangladesh Arsenic is also used in the ceramic industry and manufacture of semiconductors, light-emitting diodes, transistors, lasers, computer microchips, and microwave circuits Shortly after ingestion, arsenic is stored in reticuloendothelial system, kidney and intestines and is slowly released Slow excretion via kidney and feces Deposited in hair within 2 wks and remains in hair for years

Arsenic Clinical features
Acute or subacute exposure: abdo pain, nausea, vomiting, hyperthermia, headaches, anxiety, vertigo, possibly seizure, encephalopathy Fatal acute poisoning: precipitous development of lethargy and coma followed by death in few days, may be due to diffuse edema and/or hemorrhagic encephalopathy Low-dose chronic exposure: similar clinical features but much less severe (abdo pain, vertigo, longstanding cognitive disturbance, persistent headaches and development of peripheral neuropathy Optic neuropathy: possible delayed manifestation Metallic taste Mee’s lines: white lines in nails, usually appear 2-3 wks after exposure Peripheral neuropathy Painful, distal, axonal, may mimic GBS in severe cases Glove-stocking distribution with involvement of small and large fibers leading to pseudoathetosis and allodynia Distal weakness Hypo/areflexia Associated with exfolliative dermatitis

Arsenic Diagnosis: 24h urine heavy metal arsenic level (may be falsely elevated by shellfish ingestion), serum levels unreliable Increased arsenic levels in nail clippings or pubic hair (preferable to scalp as less chance of environmental contamination) Treatment Acute: supportive (hydration, pain control, gastric lavage) Chelation therapy with dimercaprol or its water soluble derivative dimercaptosuccinic acid (DMSA); or penicillamine (best if started early)

Inorganic lead Children absorb lead more effectively than adults
Lead reaches bones, teeth, and soft tissue, and long-term storage occurs in the skeletal system Bone resorption causes reentry of lead into the blood stream with the potential of causing delayed deleterious effects Pregnancy, lactation, menopause, osteoporosis, and other events that lead to increased bone resorption may lead to increased blood level in individuals with substantial amount of lead stored in bone Found in old paints, drinking water through dissolution of lead in old plumbing, manufacture of lead-acid batteries, battery recycling plants, crushing and smelting of lead and other metal ores, radiation shielding, blasting and sanding of lead-coated surfaces, and soil contaminated from vehicle exhaust and industrial emissions, ammunition, cosmetics

Inorganic lead Children
Acute intoxicatio(90 μg/dL): acute GI illness, confusion, lethargy, seizures, coma, and respiratory arrest with high levels of exposure Chronic, low-level exposure (10 μg/dL): gradual onset of listlessness, behavioral changes, psychomotor slowing, sleep disturbance, seizures, gait disorder characterized by clumsiness or frank ataxia

Inorganic lead Adults Polyneuropathy: predominantly motor neuropathy, with distal weakness, atrophy, and fasciculations (pain uncommon) Motor manifestation may be more prominent in upper extremities: may present with bilateral wrist drop, with or without distal lower limb weakness, often asymmetric Motor neuropathy commonly involves radial nerve (wristdrop is most common) There may or may not be sensory symptoms, predominantly paresthesias (allodynia and dysesthesias are uncommon)

Inorganic lead Laboratory diagnosis Microcytic, hypochromic anemia
Basophilic stippling of red blood cells on blood smear Renal insufficiency, azotemia Elevated blood levels of lead Lead interferes with hemoglobin synthesis by inhibiting the enzymes δ- aminolevulinic acid dehydratase and ferrochelatase and results in elevated free erythrocyte protoporphyrin (FEP) which is more accurate than serum lead levels for chronic toxicity but because of poor sensitivity, serum lead level is still the preferred screening method Treatment: chelation with DMSA, intravenous calcium disodium- EDTA, or penicillamine

Manganese Exposure Primary source of exposure (occupational): miners, ferromanganese smelting plant workers, workers in manganese ore-crushing plants, welders, and those involved in the manufacture of dry batteries Patients receiving total parenteral nutrition containing manganese Pathology: neuronal loss and gliosis affecting the globus pallidus and subthalamic nucleus; uncommon involvement of substantia nigra Main source of disposal is biliary excretion: patients with biliary atresia or chronic liver disease are prone to develop manganese toxicity (may explain high T1 signal in pallidum observed in chronic liver disease) Mechanism: oxidative stress generated through mitochondrial perturbation, NMDA-mediated excitotoxicity, and disruption in iron metabolism

Manganese Clinical features
Onset of symptoms may occur early (1-2 months after exposure) or may be delayed (about 20 years after exposure) Headaches, neuropsychiatric manifestations (memory disturbance, hallucinations, aggressive behavior, apathy, irritability, social withdrawal, personality changes, and psychosis, referred to as “manganese madness”) Extrapyramidal symptoms: parkinsonism Hypophonic and monotonous speech Absence of typical parkinsonian rest tremor, but there may be a fine, low-amplitude, high-frequency tremor Gait: retropulsion, propulsion, often tendency to walk on toes with elbows flexed and erect posture

Manganese Symmetric abnormally increased signal in the globus pallidus (A) and substantia nigra (B) (may be transient) The typical finding is really the increased pallidal signal

Manganese Diagnosis: Treatment:
Manganese can be detected in blood for days to weeks after exposure ceases Manganese levels in urine and feces may be used as a marker for exposure within the previous few hours Brain MRI: high T1 signal in the globus pallidus (also striatum and midbrain) bilaterally because of manganese accumulation Treatment: Levodopa: partial to no benefit Chelation with EDTA: improvement in some patients

Mercury

Inorganic Mercury Acute intoxication: acute colitis, vomiting, renal failure, stomatitis, little cognitive impairment except for irritability and delirium with acute poisoning Chronic, low-grade toxicity: tremor, peripheral neuropathy Personality changes, anxiety, but little cognitive impairment Peripheral neuropathy: sensorimotor axonopathy, associated with sensory loss, sensory ataxia, pain, paresthesias, distal weakness, atrophy

Organic Mercury Methylmercury: better penetrance of blood-brain barrier Predilection for dorsal root ganglia, calcarine cortex, and cerebellar granular layer (may also affect parietal cortex)

Organic Mercury Clinical features
Classic triad: gingivitis, tremor, and a neuropsychiatric illness Cerebellar and sensory ataxia Peripheral neuropathy Cortical blindness from involvement of the calcarine cortex Sensory disturbance due to involvement of dosal root ganglia and sensory cortex Deafness, dysarthria Choreoathetosis Motor neuron syndrome resembling ALS, with both LMN features (atrophy and fasciculations) and UMN features (hyperreflexia) Cognitive impairment (“mad as a hatter”): short-term memory loss, depression, hallucinations, other features of psychosis

Organic Mercury Diagnosis Treatment:
Because of the distribution of mercury throughout the body, blood mercury levels are not reliable indicators of excessive mercury burdens Blood mercury levels are recommended for acute intoxications (as elevations in blood levels will precede elevations in urine levels) and for suspected organic poisoning Urinary mercury concentrations correlate well with exposure to elemental or inorganic mercury but poor correlation with clinical severity Treatment: Chelation with penicillamine or DMSA Check fish consumption

Organic chemicals intoxication
Acrylamide Hexacarbon solvents Carbon disulfide Carbon monoxide Toluene Trichloroethylene Methanol Organophosphate

Acrylamide Monomeric acrylamide (not polyacrylamide) is neurotoxic
Found in ore processing, wastewater management, gel chromatography and in the production of polyacrylamide Acute intoxication with severely high exposure: seizures, encephalopathy Chronic, moderately high exposure: gradual onset of encephalopathy and peripheral neuropathy Chronic, low-grade exposure: peripheral neuropathy

Acrylamide Features of peripheral neuropathy
Predominantly axonal, distal neuropathy Preceded by skin irritation and peeling Neurotoxicity may occur in abnormalities of axonal (retrograde) transport; accumulation of neurofilaments and axonal loss are evident in sural nerve biopsy specimens Predominantly sensory neuropathy, involving both small and large fibers Reduced proprioceptive and vibratory sensation, sensory ataxia, hyporeflexia, numbness, paresthesias, incoordination Motor involvement (distal weakness) may be present with repetitive, high-grade exposure

Hexacarbon solvents (n-hexane and methyl n-butyl ketone)
Both converted to 2,5-hexanediol, which is toxic to peripheral nerve axons and affects axonal transport (hence, giant multifocal axonal enlargements from accumulation of neurofilaments) Used as paint, varnish, and glue (exposure may occur in person sniffing glue) Acute exposure: euphoria, hallucinations, headaches (encephalopathy does not occur) Progressive sensorimotor peripheral neuropathy with slowed conduction velocities on electrodiagnostic testing, may look like GBS if severe Despite cessation of exposure, continued progression may occur for wks (coasting) prior to arrest and significant subsequent improvement

Carbon disulfide Used in manufacturing rayon and cellophane
Primary route of intoxication: inhalation (or ingestion) Acute inhalation of large amounts of the compound can produce encephalopathy (varying severity) Sensorimotor peripheral neuropathy with chronic exposure: predominantly sensory involvement, with paresthesias and numbness and some motor involvement Cranial nerve involvement with vestibular, auditory, and ocular symptoms has also been observed Long-term exposure could also possibly cause: minor affective or cognitive disorder, pyramidal or extrapyramidal symptoms (parkinsonism), optic neuropathy Diagnosis: urine metabolite 2-thiothiazolidine-4-carboxylic acid

Carbon monoxide Pure form: odorless, colorless gas
Produced by combustion of carbon-based fuels Mechanism of action: Binds to hemoglobin with greater affinity than oxygen (forming carboxyhemoglobin), competes with binding of oxygen to hemoglobin Prevents oxygenation of tissues Severity of clinical presentation depends on concentration of the gas in the exposed environment and duration of exposure

Carbon monoxide Clinical features of acute intoxication may range from headaches, nausea, dizziness to confusion, encephalopathy, pyramidal and extrapyramidal symptoms, seizures, coma, death Survivors of acute intoxication who have partial or complete recovery may suffer from delayed deterioration and recurrence of the aforementioned symptoms; some may progress to persistent vegetative state The classic cherry-red discoloration of the skin and cyanosis are rarely seen Pathology of acute or subacute stage: diffuse cerebral edema, scattered petechial hemorrhages in white matter and more prominent hemorrhagic foci in the globus pallidus bilaterally Pathology of chronic stage: necrosis and cavitation of the globus pallidus, confluent foci of necrosis in subcortical white matter

Carbon monoxide CO poisoning = MRI lesions involving globus pallidus and cerebral deep WM Symmetric high signal intensity lesions in bilateral globus pallidi MRI in same pt as in A reveals high signal lesions in bilateral substantia nigra (dotted arrow) in addition to bilateral pallidal lesions MRI obtained 2 months after exposure shows confluent high signal lesions in the bilateral periventricular deep white matter

Toluene Used as solvent in paint, varnishes, thinners, glues, dyes; used to synthesize benzene Acute intoxication: encephalopathy with euphoria, incoordination and ataxia, confusion, headache Chronic use: euphoria, disihnibition, memory and attentional deficits, tremor, cerebellar symptoms, optic neuropathy and other cranial neuropathies Exposure to high concentrations may lead to bone marrow suppression Diagnosis: hippuric acid (urine metabolite)

Trichloroethylene Industrial solvent
Typical presentation with high-level exposure: cranial neuropathies, especially trigeminal neuropathy Trigeminal neuropathy: typically facial numbness, followed by weakness of muscles of mastication There may also be ptosis, weakness of muscles of facial expression, abnormalities of extraocular movements Other nonspecific symptoms: headaches, dizziness, fatigue, insomnia

Methanol Causes necrosis of optic nerves and putamina bilaterally
Acute intoxication Presentation often delayed for several hours until methanol is metabolized to formaldehyde and formic acid Headache, dizziness, nausea, blurred vision Permanent visual loss may occur Parkinsonism Severe effects: encephalopathy, seizures, cardiopulmonary failure, coma, death Pathology: likely caused by formate metabolites, hypoxemia, and metabolic acidosis 4-Methyl-1H-pyrazole (fomepizole) may be used to treat patients >12 years: acts as effective inhibitor of alcohol dehydrogenase

Methanol Abnormal signal in bilateral putamen

Organophosphates Mainly used in insecticides but also in fuel additives, hydraulic fluids, and lubricants Acts as ACEI Absorbed through GI or respiratory tract or skin

Organophosphate *May occur without the other phases *In 20% of pts

Marine neurotoxins Ciguatera fish poisoning
Paralytic shellfish poisoning Neurotoxic shellfish poisoning Amnestic shellfish poisoning Pufferfish poisoning

Case #4 A 48-year-old woman vacationing in Jamaica for 1 month beginning in June ate local fish daily. After 3 weeks, she and her father both developed nausea and emesis within a few hours of eating a large, cooked barracuda That afternoon, she began having fatigue and pruritus without rash, involving chest, arms, and thighs. Sensation to pinprick and temperature were grossly intact by self- examination (patient is a physician) By the next morning, she was experiencing burning sensations in her hands and feet bilaterally. Standing barefoot on cool floor tiles was perceived as burning pain. The burning sensations in her hands increased with holding them under cool running water. Drinking cold beverages caused burning sensations of her mouth and tongue By the fifth day, the pruritus, burning dysesthesias, and paradoxical perceptions of temperature had resolved, although her fatigue persisted, somewhat worse than usual (past history of multiple sclerosis) Neurologic examination after she returned home 3 weeks later was without significant change from prior examinations (baseline generalized hyperreflexia due to multiple sclerosis). Cerebral MRI showed no actively enhancing plaques. A few more white matter hyperintensities were noted as interval change from her last MRI obtained 3 years before Should you be worried? Is this MS exacerbation or intoxication?

Case #4 Typical case of ciguatera poisoning
Barracuda are reef predators Release of CTX by the microorganisms on the reef is more likely to occur in the warmer summer months The onset of GI symptoms in both the patient and her father implicates the shared fish ingestion as the source of the gGI symptoms The principal initial differential diagnoses would be scombroid toxicity (spoiled fish) or a relapse of her MS The occurrence of pruritus without rash distinguishes ciguatera from scombroid toxicity The emergence of sensory symptoms the next day, with paradoxical thermal perceptions, is clinically confirmatory of an ingested fish toxin such as CTX and distinguishes her sensory symptoms from a demyelinative etiology

Ciguatera fish poisoning
Most common nonbacterial form of food poisoning related to seafood ingestion in the United States, Canada, and Europe Caused by ciguatera toxins produced by dinoflagellates in different species of reef fish Ciguatoxins: increase sodium permeability via tetrodotoxin-sensitive voltage-gated sodium channels in nerves and muscles, causing membrane depolarization Maitotoxin: increases calcium permeability of voltage-gated calcium channels

Ciguatera fish poisoning
Clinical symptoms at onset: abdo pain and cramps, hypersalivation, nausea, vomiting, diarrhea Neurologic manifestations typically follow: dysesthesias of extremities, spreading paresthesias (including circumoral), pruritis (either generalized or on palms and soles) Other: inverted sensory phenomenon (e.g., cold objects feel warm), sensation of having loose teeth, headache, vertigo, dizziness, dry mouth, metallic taste Cardiovascular manifestations: hypotension, bradycardia, hypertension, tachycardia, arrhythmias, heart block, pulmonary edema, congestive heart failure Most symptoms remit in 1 week after exposure, but certain symptoms may persist for years after original exposure

Paralytic shellfish poisoning
Caused by saxitoxins and related compounds from dinoflagellates found in certain shellfish Toxin blocks voltage-dependent Na+ channels in nerve and muscle Abrupt onset (within min after ingestion) of symptoms: paresthesias of face, tongue, perioral areas, and lips; vertigo; dysarthria; ophthalmoplegia; pupillary abnormalities; ataxia Weakness does not occur in every patient (despite name): when present, may involve the limbs, cranial musculature, swallowing, and respiratory muscles Lack of GI illness at onset: toxin has some anticholinergic activity and may act to slow gastric emptying; this, together with absence of emesis, may enhance absorption of the toxin

Neurotoxic shellfish poisoning
Caused by brevetoxins, polyether neurotoxin produced by the marine dinoflagellate Karenia brevis and found in shellfish Brevetoxins Potent lipid-soluble neurotoxins that bind to sodium channels on nerve and muscle cell membranes Produce excessive influx of sodium ions across membranes, causing cellular dysfunction or death Similar to, but less severe than, ciguatera Onset of symptoms: minutes to several hours after ingestion of contaminated food

Neurotoxic shellfish poisoning
Illness begins with GI symptoms: nausea, vomiting, diarrhea, abdo pain and cramping, rectal burning Neurologic manifestations occur concurrently with GI illness: Circumoral paresthesias progressing to involve pharynx, torso, and extremities Muscle weakness; myalgias; tremor; dysphagia; mydriasis Inverted temperature sensory phenomenon (as with ciguatera fish poisoning) Diagnosis: ELISA assay

Amnestic shellfish poisoning
Caused by domoic acid: glutamate receptor agonist, excitatory neurotoxin acting on various CNS glutamate receptors, especially those of hippocampus Domoic acid: found in shellfish, including certain species of mussel Initial GI symptoms, usually within first 24 hours after ingestion: nausea, vomiting, abdominal cramps, diarrhea Neurologic symptoms within 48 hours after ingestion: seizures, hemiparesis, ophthalmoplegia, neuropathy, altered mentation, coma Memory impairment: anterograde and, less common but more severe, retrograde Gradual improvement over 3 months

Pufferfish poisoning Most cases associated with consumption of pufferfish from waters of Indo-Pacific ocean regions Due to tetrodotoxins in various fish, including puffer fish; block voltage-gated Na+ channels First symptom of intoxication: perioral paresthesias, appearing 20 minutes to 3 hours after consuming contaminated food Paresthesias spread to face and limbs Other symptoms: headaches, sensation of floating, epigastric pain, nausea/vomiting, diarrhea Following these symptoms: paralysis May be respiratory distress, dysarthria, dyspnea, convulsions, altered mentation, and death within 4 to 6 hours Coma and seizures may occur, High mortality rate Death may be due to cardiac arrhythmias or respiratory paralysis; patients may remain completely alert and lucid until death

Conclusion General principles Terrestrial biotoxins
Peripheral neuropathy is the most common presentation of North American neurotoxic disease Detailed history is important to establish causative agent Virtually all neurotoxic disease improves or stabilizes following withdrawal from exposure Terrestrial biotoxins Diphteria -> GBS like, anti-toxin + antibx Tetanus -> spasms, trismus, anti-toxin before you wash the wound, think about umbilical stumps in children as a source Envenomation -> don’t play with vipers, scorpions or spiders Tick paralysis -> GBS like

Conclusion Metal intoxications Organic chemicals intoxications
Manganese = increased T1 signal in the globus pallidus Organic chemicals intoxications Most organic chemicals are solvents that cause encephalopathy CO poisoning = increased T2 in globus pallidus and cerebral deep WM Methanol = increased T2 signal in putamen, visual loss Marine Neurotoxins Often cause unusual paresthesias and may lead to paralysis

References Neurotoxicology continuum Mayo clinic board review

By: Laurence Poliquin-Lasnier R4 Neurology

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By: Laurence Poliquin-Lasnier R4 Neurology

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Presentation on theme: "By: Laurence Poliquin-Lasnier R4 Neurology"— Presentation transcript:

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