ABSTRACT
A. Folate and Vitamin B12 Deficiencies (see Chapter 20)
B. Vitamin E Deficiency (see Chapter 9) 1. Associated with
a. Cystic fibrosis in children b. Severe malabsorption because of disease of the alimentary
tract c. Inherited conditions, including ataxia with isolated vita-
min E deficiency (due to mutation of α-tocopherol transfer protein gene on chromosome 8q) or abetalipoproteinemia (see Chapter 9)
2. Vitamin E: radical scavenger and antioxidant 3. Clinical features: spinocerebellar syndrome (cerebellar
ataxia and large-fiber sensory loss), areflexia, ataxic dysarthria, cerebellar and sensory gait ataxia, extensor plantar responses, acanthocytosis, hemolytic anemia, retinitis pigmentosa
4. Pathology: acanthocytosis (peripheral blood smear); swollen axons in affected central nervous system (CNS) structures, including posterior columns
C. Niacin (nicotinic acid) Deficiency (pellagra) 1. Niacin
a. Nicotinic acid and nicotinamide (latter is readily deaminated in the body to form nicotinic acid)
b. Nicotinic acid and nicotinamide form nicotinamide adenosine dinucleotide (NAD+) and NAD phosphate (NADP+), important coenzymes in carbohydrate metabolism
c. Niacin is derived from enriched grains and cereals, milk, meat and, in small quantities, as end product of tryptophan metabolism
2. Prevalence of pellagra has decreased with fortification of bread and cereals with niacin
3. Nonendemic pellagra may occur in context of alcoholism or nutritional deficiency due to gastrointestinal tract disease
4. Clinical triad of “3Ds”: dermatitis, diarrhea, dementia 5. Gastrointestinal features: stomatitis, diarrhea, abdomi-
nal pain, vomiting 6. Neurologic: myelopathy and spastic paraparesis, irri-
tability, depression, apathy, memory loss 7. Dermatitis: hyperkeratotic, hyperpigmented, diffuse,
extensive rash 8. Treatment: oral or parenteral nicotinic acid or
nicotinamide
D. Vitamin B6 1. Vitamin B6: pyridoxine, pyridoxal, pyridoxamine-all
are precursors of coenzyme pyridoxal phosphate 2. Ubiquitous in corn, wheat, egg yolk, and lean meat 3. Clinical syndrome of deficiency
a. Infantile onset 1) Occurs in setting of syndrome of pyridoxine deficiency-
related seizures (due to malnutrition of mothers) or congenital dependency on pyridoxine (not true deficiency) (see Chapter 12)
2) Normal prenatal and peripartum course, followed by poor feeding, irritability, exaggerated startle, and abrupt onset of seizures (may be intractable and lead to status epilepticus)
b. Adult onset 1) Rare: adults are much more resistant to vitamin B6
deficiency 2) Often due to intake of isoniazid, hydralazine, or
penicillamine 3) Distal sensorimotor peripheral neuropathy (predomi-
nant features of sensory symptoms and axonal degeneration)
4) Treatment: slow improvement with withdrawal of offending drug or initiation of low-dose vitamin B6 supplementation
5) Primary prevention: coadministration of vitamin B6 prevents this neuropathy
4. Pyridoxine excess
a. Sensory polyneuropathy: length-dependent axonal neuropathy with predominant features of sensory loss or sensory ataxia due to polyganglionopathy (see Chapter 21)
b. Partial or complete resolution with withdrawal of offending agent
E. Vitamin A 1. Hypervitaminosis A (vitamin A toxicity) may cause
a. Pseudotumor cerebri b. Birth defects and pervasive developmental disorders in
children born to mothers with this condition 2. Vitamin A deficiency: rare, may present with night
blindness
F. Thiamine Deficiency 1. Most frequently occurs in setting of alcoholism 2. Thiamine is a precursor for the biologically active thi-
amine pyrophosphate 3. Thiamine pyrophosphate acts as a coenzyme for
a. Transketolase reaction in hexose monophosphate shunt b. Oxidative decarboxylation of pyruvate to form acetyl
coenzyme A (CoA) by pyruvate dehydrogenase c. Conversion of α-ketoglutarate to succinyl CoA by α-
ketoglutarate dehydrogenase 4. Thiamine requirements are greatest during periods of
high metabolic demand and/or high glucose intake: this may partly explain occurrence of Wernicke’s encephalopathy with administration of intravenous glucose to a thiamine-deficient patient
5. Beriberi a. Length-dependent, axonal, sensorimotor peripheral neu-
ropathy with distal sensory loss, paresthesias, weakness (termed “dry beriberi” in absence of cardiac involvement)
b. Associated with cardiac involvement: cardiomyopathy, arrhythmias, congestive heart failure (termed “wet beriberi”)
c. Laboratory diagnosis 1) Decreased serum and urine levels of thiamine 2) Decreased erythrocyte transketolase activity (functional
assay) 3) Increased serum pyruvate levels 4) Electromyographic evidence of axonal, distal periph-
eral neuropathy 6. Wernicke-Korsakoff syndrome (see Chapter 7)
G. Other Nervous System Conditions Associated With Alcoholism
1. Alcoholic neuropathy a. Associated with severe, prolonged alcohol use b. Predominantly sensory neuropathy: painful neuropathy,
painful dysesthesias, paresthesias, allodynia
c. Weakness is mild, usually involves distal lower extremity d. Autonomic involvement e. Predisposition to compression mononeuropathies f. Associated with other alcohol-related complications:
Wernicke-Korsakoff syndrome and cerebellar degeneration g. Patients should receive parenteral thiamine
supplementation 2. Ethanol-induced myopathy
a. Usually develops in setting of chronic, heavy ethanol intake and binge drinking
b. Occurs as acute necrotizing myopathy or chronic myopathy with muscle wasting
c. Acute necrotizing myopathy 1) Acute onset of myonecrosis, often in the midst of
heavy bout of drinking (in context of chronic alcoholism)
2) Acute onset of muscle pain and myoedema, often associated with myoglobinuria
3) Weakness: often proximal and symmetric or there may be focal weakness of the quadriceps or calves
4) Pathology: patchy, segmental necrotizing process, with degeneration and regeneration of the muscle fibers
d. Chronic alcoholic myopathy 1) Gradual onset and progression of proximal weakness,
muscle wasting, cramps, and myalgias 2) Increased serum levels of creatine kinase and
myoglobinuria 3. Marchiafava-Bignami disease (see Chapter 7) 4. Alcoholic dementia (see Chapter 7) 5. Acute withdrawal syndrome, including delirium
tremens and alcohol withdrawal seizures 6. Alcohol-related cerebellar degeneration
a. Usually in context of long-standing alcohol abuse b. Insidious and gradual onset and progression of cerebellar
ataxia c. Often associated with alcoholic neuropathy and with-
drawal seizures d. Abstinence may yield improvement: gradual, often
incomplete e. Pathology
1) Cerebellar atrophy: predilection for anterior and superior vermis
2) Diffuse loss of Purkinje cells, patchy loss of granule cells
3) Often concomitant diffuse cerebral atrophy 7. Fetal alcohol syndrome
a. Occurs in infants whose mothers drink alcohol during pregnancy: most afflicted infants are born to mothers with alcohol-related complications during pregnancy,
but there is no minimum safe amount of alcohol intake during the gestational period; expectant mothers must abstain completely
b. Intrauterine growth retardation: low birth weight, small head circumference
c. Craniofacial and joint deformities d. Congenital developmental malformations of brain,
including microcephaly, agenesis of corpus callosum, cerebellar dysplasia, heterotopic gray matter
e. Afflicted infants: irritability, poor feeding f. High infant mortality rate: 1 in 6 afflicted infants die g. Many infants who survive infancy have psychomotor
developmental delay, mental retardation, and pervasive developmental disorders marked by poor learning, memory, attention, and problem solving; social and behavioral problems
H. Copper Deficiency 1. Acquired (see Chapter 20) 2. Congenital: Menke syndrome
I. Postgastroplasty Polyneuropathy 1. Associated with jejunoileal bypass, gastrojejunectomy,
gastric stapling, gastroplasty, gastrectomy with Rouxen-Y anastomosis
2. Neurologic syndrome always follows intractable vomiting and precipitous weight loss
3. Acute or subacute onset of symmetric sensory loss and paresthesias, distal and/or proximal weakness, which may progress to quadriparesis
4. Few patients develop encephalopathy
A. Metal Intoxication 1. Arsenic
a. Usually associated with deliberate poisoning, may also occur in the context of accidental exposure
b. Shortly after ingestion, arsenic is stored in reticuloendothelial system, kidney, and intestines; is slowly released
c. Slow excretion via kidney and feces d. Deposited in hair within 2 weeks; remains in the hair for
years e. Clinical features vary, depending on the dose
1) Acute or subacute exposure: abdominal pain, nausea, vomiting, hyperthermia, headaches, anxiety, vertigo, possibly seizures, encephalopathy, and coma (if severe)
2) 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
3) Low-dose chronic exposure: similar clinical features but much less severe; abdominal pain, vertigo, longstanding cognitive disturbance, persistent headaches, and development of peripheral neuropathy
4) Sphincter dysfunction 5) Optic neuropathy: possible delayed manifestation 6) Mees’ lines: white lines in nails, usually appear 2 to 3
weeks after acute exposure 7) Peripheral neuropathy
a) Painful, distal peripheral neuropathy (axonopathy) b) Distal pansensory loss in a glove-stocking distribu-
tion involving both small-fiber and large-fiber modalities and causing dense proprioceptive loss and pseudoathetosis, reduced temperature sensation, hyperesthesia, dysesthesia, and allodynia
c) Weakness involving the distal extremity, hand, and foot muscles: effort may be poor because of dense proprioceptive loss
d) Hyporeflexia or areflexia distally e) Associated with exfoliative dermatitis
f. Diagnosis 1) 24-Hour urine heavy metal arsenic levels: may be
falsely elevated by ingestion of shellfish 2) Increased arsenic levels in nail clippings or pubic hair
(preferable to scalp hair because of less chance of environmental contamination)
g. Treatment 1) Acute treatment: supportive measures, including
hydration and morphine for abdominal pain, gastric lavage
2) Chelation therapy with dimercaprol or its water-soluble derivative, dimercaptosuccinic acid (DMSA); or penicillamine (best if started early)
2. Inorganic lead a. Toxicity due to occupational or nonoccupational expo-
sure or, in children, old lead-based paint b. Lead inhibits erythrocyte γ-aminolevulinic acid dehy-
dratase in biochemical pathways of porphyrin metabolism c. Children
1) Acute intoxication: acute gastrointestinal illness, confusion, lethargy, seizures, coma, and respiratory arrest with high levels of exposure
2) Chronic, low-level exposure: gradual onset of listlessness, behavioral changes, psychomotor slowing, sleep disturbance, seizures, gait disorder characterized by clumsiness or frank ataxia
d. Adults 1) Polyneuropathy: predominantly motor neuropathy,
with distal weakness, atrophy, and fasciculations (pain uncommon)
2) Motor manifestation may be more prominent in upper extremities: may present with bilateral wristdrop, with or without distal lower limb weakness
3) Motor neuropathy commonly involves radial nerve (wristdrop is most common)
4) There may or may not be sensory symptoms, predominantly paresthesias (allodynia and dysesthesias are uncommon)
e. Laboratory diagnosis 1) Microcytic, hypochromic anemia 2) Basophilic stippling of red blood cells on peripheral
blood smear 3) Renal insufficiency, azotemia 4) Elevated blood and urine levels of lead
f. Treatment: chelation with DMSA, intravenous calcium disodium-EDTA, or penicillamine
3. Manganese a. Exposure
1) Primary source of exposure (occupational): inhalation, primarily mine workers
2) Patients receiving total parenteral nutrition containing manganese
b. Pathology: neuronal loss and gliosis affecting the globus pallidus and subthalamic nucleus; uncommon involvement of substantia nigra
c. 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)
d. Clinical features 1) Onset of symptoms may occur early (1-2 months
after exposure) or may be delayed (about 20 years after exposure)
2) Headaches, neuropsychiatric manifestations (memory disturbance, hallucinations, aggressive behavior, apathy, irritability, social withdrawal, personality changes, and psychosis, referred to as “manganese madness”)
3) Extrapyramidal symptoms: parkinsonism with hypomimia (decreased facial expression), bradykinesia, micrographia
4) Hypophonic and monotonous speech 5) Absence of typical parkinsonian rest tremor, but there
may be a fine, low-amplitude, high-frequency tremor 6) Gait: retropulsion, propulsion, often tendency to
walk on toes with elbows flexed and erect posture e. Diagnosis
1) Brain MRI: high T1 signal in the globus pallidus (also striatum and midbrain) bilaterally because of manganese accumulation
f. Treatment 1) Levodopa: partial to no benefit 2) Chelation with EDTA: improvement in some patients
4. Inorganic mercury a. Acute intoxication: acute colitis, vomiting, renal failure,
stomatitis, little cognitive impairment except for irritability and delirium with acute poisoning
b. Chronic, low-grade toxicity: tremor, peripheral neuropathy c. Personality changes, anxiety, but little cognitive impairment d. Peripheral neuropathy: sensorimotor axonopathy, associ-
ated with sensory loss, sensory ataxia, pain, paresthesias, distal weakness, atrophy
5. Organic mercury a. Methylmercury: better penetrance of blood-brain barrier b. Predilection for dorsal root ganglia, calcarine cortex, and
cerebellar granular layer (may also affect parietal cortex) c. Clinical features
1) Cerebellar and sensory ataxia 2) Peripheral neuropathy 3) Cortical blindness from involvement of the calcarine
cortex 4) Sensory disturbance due to involvement of dosal root
ganglia and sensory cortex 5) Deafness, dysarthria 6) Choreoathetosis 7) Motor neuron syndrome resembling amyotrophic lat-
eral sclerosis, with both lower motor neuron features (atrophy and fasciculations) and upper motor neuron features (hyperreflexia)
8) Cognitive impairment (“mad as a hatter”): shortterm memory loss, depression, hallucinations, other features of psychosis
d. Diagnosis 1) Elevated mercury levels in serum, urine, saliva, hair
samples 2) Urine mercury levels: poor correlation with clinical
severity 3) Serum mercury levels: variable, unpredictable
e. Treatment: chelation with penicillamine or DMSA 6. Thallium
a. Competes with potassium ions in transport by the Na/K adenosine triphosphatase (ATPase) system
b. Used in pesticides c. Acute intoxication from exposure to large quantities:
acute gastrointestinal illness with nausea, vomiting, and diarrhea; irritability, confusion, and coma (severe cases)
d. Ingestion of large quantities: a painful, predominantly
sensory neuropathy may occur, possibly with autonomic features
e. Initial stage may be followed by progressive weakness, ataxia, chorea
f. Respiratory weakness and cranial neuropathies may occur in severe cases
g. Chronic, low-grade exposure: distal, predominantly sensory, large-fiber more than small-fiber peripheral neuropathy with or without mild distal weakness (axonopathy)
h. Alopecia: occurs about 2 to 4 weeks after acute intoxication i. Diagnosis: measurement of urine thallium levels
B. Organic Chemicals 1. Acrylamide
a. Monomeric acrylamide (not polyacrylamide) is neurotoxic b. Acute intoxication with severely high exposure: seizures,
encephalopathy c. Chronic, moderately high exposure: gradual onset of
encephalopathy and peripheral neuropathy d. Chronic, low-grade exposure: peripheral neuropathy e. Features of peripheral neuropathy
1) Predominantly axonal, distal neuropathy 2) Preceded by skin irritation and peeling 3) Neurotoxicity may occur in abnormalities of axonal
(retrograde) transport; accumulation of neurofilaments and axonal loss are evident in sural nerve biopsy specimens
4) Predominantly sensory neuropathy, involving both small-fiber and large-fiber modalities
5) Reduced proprioceptive and vibratory sensation, sensory ataxia, hyporeflexia, numbness, paresthesias, incoordination
6) Motor involvement (distal weakness) may be present with repetitive, high-grade exposure
2. Hexacarbon solvents (n-hexane and methyl n-butyl ketone) a. n-Hexane and methyl n-butyl ketone are 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)
b. Used as paint, varnish, and glue (exposure may occur in person sniffing glue)
c. Acute exposure: euphoria, hallucinations, headaches (encephalopathy does not occur)
d. Progressive sensorimotor peripheral neuropathy with slowed conduction velocities on electrodiagnostic testing
3. Carbon disulfide a. Used in manufacturing rayon and cellophane b. Primary route of intoxication: inhalation (or ingestion) c. Acute inhalation of large amounts of the compound can
produce encephalopathy (varying severity) d. Sensorimotor peripheral neuropathy with chronic expo-
sure: predominantly sensory involvement, with paresthesias and numbness and some motor involvement
e. Peripheral nerve histologic characteristics of long-term exposure to carbon disulfide: focal paranodal axonal swellings, accumulation of neurofilaments, and secondary demyelination
f. Long-term exposure could also possibly cause: minor affective or cognitive disorder, pyramidal or extrapyramidal symptoms (parkinsonism), optic neuropathy
g. Diagnosis: urine metabolite 2-thiothiazolidine-4-carboxylic acid
4. Carbon monoxide a. Pure form: odorless, colorless gas b. Produced by combustion of carbon-based fuels c. Mechanism of action
1) Binds to hemoglobin with greater affinity than oxygen (forming carboxyhemoglobin), competes with binding of oxygen to hemoglobin
2) Impairs release of oxygen from oxyhemoglobin 3) In essence, prevents oxygenation of tissues
d. Severity of clinical presentation depends on concentration of the gas in the exposed environment and duration of exposure
e. Clinical features of acute intoxication may range from headaches, nausea, dizziness to confusion, encephalopathy, pyramidal and extrapyramidal symptoms (including tremors), seizures, coma, death
f. 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
g. Pathology of acute or subacute stage (Fig. 17-1): diffuse cerebral edema, scattered petechial hemorrhages in white matter and more prominent hemorrhagic foci in the globus pallidus bilaterally
h. Pathology of chronic stage: necrosis and cavitation of the globus pallidus, confluent foci of necrosis in subcortical white matter
5. Toluene a. Used as solvent in paint, varnishes, thinners, glues, dyes;
used to synthesize benzene b. Acute intoxication: euphoria, incoordination and ataxia,
confusion, headache c. Chronic use: euphoria, disihibition, memory and atten-
tional deficits, tremor, cerebellar symptoms (intention tremor, titubation, truncal ataxia), optic neuropathy and other cranial neuropathies
d. Diagnosis: hippuric acid (urine metabolite)
6. Trichloroethylene a. Typical presentation with high-level exposure: cranial
neuropathies, especially trigeminal neuropathy b. Trigeminal neuropathy: typically facial numbness, fol-
lowed by weakness of muscles of mastication c. There may also be ptosis, weakness of muscles of facial
expression, abnormalities of extraocular movements d. Other nonspecific symptoms: headaches, dizziness,
fatigue, insomnia 7. Methanol toxicity
a. Causes necrosis of optic nerves and putamina bilaterally b. Acute intoxication
1) Presentation often delayed for several hours until methanol is metabolized to formaldehyde and formic acid
2) Headache, dizziness, nausea, blurred vision 3) Permanent visual loss may occur 4) Severe effects: encephalopathy, seizures, cardiopul-
monary failure, coma, death c. Pathology: likely caused by formate metabolites, hypox-
emia, and metabolic acidosis d. 4-Methyl-1H-pyrazole (fomepizole) may be used to treat
patients older than 12 years: acts as effective inhibitor of alcohol dehydrogenase
8. Organophosphates
a. Mainly used in insecticides b. Absorbed through gastrointestinal or respiratory tract or
skin c. Act as acetylcholinesterase inhibitors d. Acute cholinergic toxicity (type I syndrome): nausea,
hypersalivation, increased bronchial secretions, bronchospasms, increased lacrimation, diarrhea, miosis, fasciculations, pulmonary edema, bradycardia, seizures, coma
e. Intermediate (type II) syndrome 1) Occurs within 12 to 96 hours after exposure and
resolves in 2 to 3 weeks 2) Cholinergic stimulation of nicotinic receptors 3) Characterized by respiratory, bulbar, and proximal
limb weakness, fasciculations, tachycardia, hypertension, and cardiac failure in severe cases
f. Delayed polyneuropathy may occur after 2 to 3 weeks 1) Subacute onset 2) Early cramps in calves and paresthesias in feet, fol-
lowed by weakness (predominantly in feet and ascending proximally)
3) Predominantly motor and few sensory symptoms 4) Depressed Achilles reflexes, relatively preserved reflex-
es proximally 5) May be concurrent involvement of spinal cord, with
long tract signs
C. Plant and Animal Neurotoxins 1. Snake
a. Toxins 1) α-Bungarotoxin and cobrotoxin: postsynaptic block-
ade of acetylcholine receptors (AChRs) 2) β-Bungarotoxin and crotoxin: presynaptic inhibition
of acetylcholine (ACh) release b. Local pain, swelling, and erythema at site of the bite c. Focal weakness or compartment syndrome d. Diffuse proximal weakness resembling myasthenia gravis e. Ptosis, cranial neuropathies, dysphagia, areflexia, fascicu-
lations, respiratory distress f. Systemic manifestations, including hypotension and shock
2. Female black widow spider (Latrodectus mactans) a. Most important spider to cause potentially significant
morbidity b. Toxin: α-latrotoxin, causing presynaptic facilitation of
ACh release and depletion of ACh c. Erythema at site of the bite, intense pain, and involun-
tary muscle spasms involving the limbs, truncal muscles, and diaphragm (latter causing respiratory arrest)
d. Autonomic symptoms: hypertension, piloerection, diaphoresis, brochospasm
3. Scorpion
a. Tityustoxin, produced by Tityus serrulatus, causes presynaptic facilitation of ACh release and postsynaptic activation of voltage-gated sodium channels
b. Local pain and erythema at site of the bite, local paresthesias, followed by diffuse paresthesias, fasciculations, tremors, hyperreflexia
c. Pandysautonomia: hypertension, hyperthermia, hypersalivation, diaphoresis, urinary frequency, fecal urgency
4. Amanita mushrooms a. Potent anticholinergic effects; block both cholinergic and γ-aminobutyric acid (GABA) synapses
b. Acute intoxication (6-8 hours after ingestion): intractable emesis and bloody diarrhea, altered mentation, agitation, convulsions, muscle spasms
c. Hepatotoxicity and renal failure develop in the next 3 to 5 days, followed by secondary metabolic encephalopathy
D. Marine Neurotoxins 1. Ciguatera fish poisoning
a. Most common nonbacterial form of food poisoning related to seafood ingestion in the United States, Canada, and Europe
b. Caused by ciguatera toxins produced by dinoflagellates in different species of reef fish 1) Ciguatoxins: increase sodium permeability via
tetrodotoxin-sensitive voltage-gated sodium channels in nerves and muscles, causing membrane depolarization
2) Maitotoxin: increases calcium permeability of voltage-gated calcium channels
c. Clinical symptoms at onset: abdominal pain and cramps, hypersalivation, nausea, vomiting, diarrhea
d. Neurologic manifestations typically follow: dysesthesias of extremities, spreading paresthesias (including circumoral), pruritis (either generalized or on palms and soles)
e. Other: inverted sensory phenomenon (e.g., cold objects feel warm), sensation of having loose teeth, headache, vertigo, dizziness, dry mouth, metallic taste
f. Cardiovascular manifestations: hypotension, bradycardia, hypertension, tachycardia, arrhythmias, heart block, pulmonary edema, congestive heart failure
g. Most symptoms remit in 1 week after exposure, but certain symptoms may persist for years after original exposure
2. Paralytic shellfish poisoning a. Caused by saxitoxins and related compounds from
dinoflagellates found in certain shellfish b. Toxin blocks voltage-dependent sodium channels in
nerve and muscle c. Abrupt onset (within 30-60 minutes after ingestion) of
symptoms: paresthesias of face, tongue, perioral areas, and lips; numbness; vertigo; dysarthria; ophthalmoplegia; pupillary abnormalities; ataxia
d. Weakness does not occur in every patient (despite name): when present, may involve the limbs, cranial musculature, swallowing, and respiratory muscles
e. Lack of gastrointestinal 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
3. Neurotoxic shellfish poisoning a. Caused by brevetoxins, polyether neurotoxin produced
by the marine dinoflagellate Karenia brevis and found in shellfish
b. Brevetoxins 1) Potent lipid-soluble neurotoxins that bind to sodium
channels on nerve and muscle cell membranes 2) Produce excessive influx of sodium ions across mem-
branes, causing cellular dysfunction or death c. Similar to, but less severe than, ciguatera d. Onset of symptoms: minutes to several hours after
ingestion of contaminated food e. Illness begins with gastrointestinal symptoms: nausea,
vomiting, diarrhea, abdominal pain and cramping, rectal burning
f. Neurologic manifestations occur concurrently with gastrointestinal 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)
g. ELISA assay available for diagnosis 4. Amnestic shellfish poisoning
a. Caused by domoic acid: glutamate receptor agonist, excitatory neurotoxin acting on various CNS glutamate receptors, especially those of hippocampus
b. Source of domoic acid: diatoms c. Domoic acid: found in shellfish, including certain
species of mussel d. Initial gastrointestinal symptoms, usually within first 24
hours after ingestion: nausea, vomiting, abdominal cramps, diarrhea
e. Neurologic symptoms within 48 hours after ingestion: seizures, hemiparesis, ophthalmoplegia, neuropathy, altered mentation, coma
f. Memory impairment: anterograde and, less common but more severe, retrograde
g. Gradual improvement over 3 months 5. Pufferfish poisoning
a. Most cases associated with consumption of pufferfish
from waters of Indo-Pacific ocean regions b. Due to tetrodotoxins in various fish, including puffer
fish; block voltage-gated sodium channels c. First symptom of intoxication: perioral paresthesias,
appearing 20 minutes to 3 hours after consuming contaminated food
d. Paresthesias spread to face and limbs e. Other symptoms: headaches, sensation of floating, epi-
gastric pain, nausea, vomiting, diarrhea f. Following these symptoms: paralysis g. May be respiratory distress, dysarthria, dyspnea, convul-
sions, altered mentation, and death within 4 to 6 hours h. Coma and seizures may occur i. High mortality rate j. Death may be due to cardiac arrhythmias or respiratory
paralysis; patients may remain completely alert and lucid until death
A. Nonketotic Hyperosmolar State 1. Hyperglycemia without ketosis, dehydration 2. Reduced level of consciousness, progressing to coma 3. Focal signs or symptoms, including hemiparesis or focal
seizures: unique to nonketotic hyperosmolar state, absent in other metabolic derangements; occurrence of focal deficits may be due to previous silent cerebrovascular events
4. Transient T2 signal changes may be present in deep gray matter
B. Diabetic Ketoacidotic Coma 1. Hyperglycemia with ketosis, acidosis, and
hyperosmolarity 2. Focal signs uncommon; should raise the possibility of
alternative etiology 3. Most patients have benign prognosis, with no residual
neurologic deficits 4. May be complicated by diffuse cerebral edema, which
presents as recurrence of coma after initial improvement; patients may rapidly lose all brainstem reflexes, including pupillary responses, and meet criteria for brain death within 1 to 2 hours
5. May be associated with abrupt onset of predominantly motor polyneuropathy, with improvement expected some time after treatment of ketoacidosis
C. Hepatic Encephalopathy 1. Pathophysiology
a. Hyperammonemia 1) Increased ammonia production due to excess dietary
protein, constipation, gastrointestinal hemorrhage 2) Liver: important role in detoxification of ammonia 3) Degree of encephalopathy: related to blood ammonia
levels b. Endogenous benzodiazepines
1) Excess endozepine-4 in serum and cerebrospinal fluid; also occurs in relapsing coma due to idiopathic recurring stupor, i.e., spontaneous stupor or coma not associated with known metabolic, toxic, or structural abnormalities but reversed with flumazenil, a pure benzodiazepine antagonist
2) Cause CNS inhibition by stimulating GABA-benzodiazepine complex
c. Decreased liver metabolism of toxins due to portal-systemic shunting or reduced liver parenchymal reserves because of liver damage
d. Deposition of manganese in brain, especially in deep gray matter
2. Fulminant hepatic failure a. Often no previous history of liver disease, may be precip-
itated by viral illness or hepatotoxin b. Common presenting symptoms: abdominal pain, nausea,
vomiting c. Precipitous onset of mania, hyperexcitability, and delirium,
which may rapidly progress to coma if untreated d. Low incidence of seizures, possibly because of presence of
endogenous benzodiazepines e. Characterized by diffuse brain edema, increased intracra-
nial pressure, possibly brain herniation 3. Chronic hepatic encephalopathy
a. Grade I 1) Insomnia and abnormal sleep pattern, apathy, irri-
tability, anxiety, inattention, agitation, depression 2) Fine postural tremor, poor coordination
b. Grade II 1) Lethargy, disorientation, inappropriate behavior 2) Asterixis, dysarthria, paratonia, ataxia, hypoactive
reflexes, disorientation, personality change, poor recall c. Grade III
1) Somnolent, arousable, disorientation 2) Signs of hyperexcitability: asterixis, myoclonus, exag-
gerated startle response, hyperactive reflexes, extensor plantar responses, rigidity and paratonia, hyperventilation
d. Grade IV: coma, posturing e. Asterixis: nonspecific; may be seen in other metabolic
conditions, including uremia and dialysis-related encephalopathy, pulmonary disease, nonketotic hyper-
glycemia, hypokalemia, hypomagnesemia, drugs (lithium, carbamazepine, phenytoin, barbiturates), recovery phase following general anesthesia, structural lesions (typically unilateral asterixis)
f. Unilateral asterixis 1) Always raises possibility of structural lesion involving
genu and anterior portion of internal capsule or ventrolateral thalamus and, less commonly, midbrain, parietal cortex, medial frontal cortex
2) Most common cause: thalamic hemorrhage 4. Brain magnetic resonance imaging (MRI): increased
T1 signal in globus pallidus, likely from increased concentrations of manganese
5. Electroencephalography (EEG): slowing of background activity (delta slowing when advanced grade encephalopathy) or triphasic waves
6. Blood ammonia levels: arterial blood must be drawn and hand-carried to laboratory for immediate analysis; ammonia levels from venous blood may be artificially increased because applying a tourniquet causes local ischemia of the underlying muscle tissue, from which excess ammonia is released
7. Pathology a. Alzheimer type II cells: in neocortex, deep gray matter,
brainstem, dentate nucleus b. May be microcavitation with gliosis and neuronal loss in
these regions 8. Treatment
a. Symptomatic treatment, including management of intracranial hypertension in cases of fulminant hepatic failure
b. Specific treatment of precipitating factor or cause c. Lactulose, dietary protein restriction, antibiotics (against
urea-producing organisms, e.g., neomycin) d. Flumazenil (benzodiazepine receptor antagonist) e. Embolization or surgical ligation of portal-systemic shunts f. Liver transplantation: generally needed for fulminant
hepatic failure
D. Neurologic Manifestations of Renal Failure and Dialysis
1. Uremic encephalopathy a. Encephalopathy in setting of renal failure, often with
multiple concomitant metabolic derangements, including hyponatremia, hypocalcemia, hyperkalemia, hypermagnesemia, metabolic acidosis
b. Headache, fatigue, malaise, apathy, poor concentration, sleep disturbance, decreased libido, irritability, paranoid ideation, slurred speech, and abnormal movements, including postural tremor, myoclonus (multifocal
myoclonus or minipolymyoclonus), asterixis c. Frank delirium may occur d. Persistent focal deficits suggest alternate diagnosis e. To be differentiated from dialysis dementia (discussed
below) f. EEG: diffuse slowing, triphasic waves when advanced g. Improved with dialysis (as opposed to dialysis
encephalopathy, which is worsened by dialysis) 2. Dialysis encephalopathy
a. Characterized by progressive cognitive decline, nonfluent aphasia and dysarthria (aphasia uncommon in uremic encephalopathy), myoclonus, tremor, asterixis, seizures, and improvement with diazepam (uremic encephalopathy does not respond to diazepam)
b. Associated with proximal myopathy c. Rare entity since establishment of limitations on use of
aluminum in dialysis 3. Dialysis disequilibrium syndrome
a. Occurs with institution of dialysis in setting of chronic renal failure
b. Pathophysiology 1) Cytotoxic edema due to osmotic shifts of water,
which may be caused by reverse osmotic shift induced by urea and decrease in cerebral intracellular pH
2) Hemodialysis rapidly removes small solutes such as urea from plasma; permeation of urea molecules across plasma membranes may take several hours to occur
3) Reduction in plasma urea decreases plasma osmolality and produces transient osmotic gradient that promotes movement of water molecules into cells
c. Symptoms often occur during or shortly after hemodialysis
d. Clinical features 1) Mild disease: headaches, nausea, vomiting, malaise,
myalgias, anorexia, restlessness, blurred vision 2) More severe disease: movement disorders
(myoclonus, tremors), seizures, coma, possibly death e. Treatment: gentle initial dialysis with goals of slow urea
removal and gradual reduction in blood urea nitrogen (BUN)
4. Uremic polyneuropathy a. Distal sensorimotor peripheral neuropathy, with pre-
dominant electrophysiologic features of axonal loss (predominantly sensory neuropathy until advanced)
b. Occurs in 60% of patients with end-stage chronic renal failure requiring dialysis
c. Most common initial clinical features: paresthesias, dysesthesias, burning feet, restless legs syndrome, cramps (latter two may be present without neuropathy)
d. Mild autonomic symptoms e. Weakness develops with progression (often first involving
lower extremities and ascending) f. Incidence of severe disease reduced with advent of dialysis g. Uremic mononeuropathies: higher incidence of entrap-
ment neuropathies and occurrence of ischemic monomelic neuropathy in patients with arteriovenous fistula for dialysis (see Chapter 21, Part B)
h. A fulminant, severe, and rapidly progressive, predominantly motor polyneuropathy may occur, often in setting of concomitant sepsis; critical illness polyneuropathy (see Chapter 21)
E. Central Pontine and Extrapontine Myelinolysis 1. Usually occurs in alcoholics 2. Risk factors: chronic liver disease, chronic illness, mal-
nutrition, anorexia, diuretic use, cancer, liver transplantation
3. Pathophysiology likely associated with rapid correction of hyponatremia, but undefined
4. Monophasic demyelinating illness, predominantly involving basis pontis, with or without extrapontine lesions in subcortical white matter, cerebellum, lateral geniculate body, basal ganglia, thalamus, internal capsule (Fig. 17-2)
5. Clinical features: spastic paraparesis, pseudobulbar palsy and dysarthria (from involvement of corticobulbar tracts), lethargy, confusion, locked-in-syndrome, and coma (in most severe form)
6. Clinical course may be complicated by superimposed Wernicke’s encephalopathy, ethanol withdrawal, hepatic encephalopathy
F. Hypertensive Encephalopathy 1. Occurs in setting of hypertensive emergency (defined as
severely increased blood pressure in presence of endorgan damage)
2. May occur in eclampsia (hypertensive emergency of pregnancy), associated with peripheral edema and proteinuria
3. Usually occurs in context of abrupt increase in blood pressure in normotensive patients
4. May be precipitated by use of stimulant drugs such as cocaine or amphetamines
5. Pathophysiology a. Vasogenic edema (cytotoxic edema may also occur when
there is concomitant cerebral ischemia) b. There may be a component of vasoconstriction and
resultant hypoperfusion c. Seems to be predilection for involvement of parenchyma
supplied by posterior circulation; may be related to relatively deficient sympathetic innervation of posterior circulation compared with that of anterior circulation
d. Predilection for posterior circulation explains the common occurrence of reversible posterior leukoencephalopathy (RPLE) in this setting
e. RPLE may also occur from immunosuppressive drugs such as cyclosporine, likely due to direct toxic effect on vascular endothelium, vasoconstriction caused by endothelin, and formation of microthrombi
f. Predisposing (or causative) factors: eclampsia, pheochromocytoma, acute glomerulonephritis, sympathomimetic agents (e.g., cocaine, amphetamines), vasculitis and collagen vascular disease, withdrawal from antihypertensive agents
6. Neuroimaging characteristics a. T2-hyperintense (T1-hypointense) lesions, with
predilection for occipital and posterior parietal lobes (RPLE)
b. Increased values on acute diffusion coefficient (ADC) mapping (in contrast to decreased values seen in cytotoxic edema of subacute infarcts): indicative of vasogenic edema
c. Changes may also be present in cerebral white matter and basal ganglia
7. Clinical features a. Headaches, nausea, seizures, altered mentation b. Visual obscurations or loss of vision (due to papilledema
secondary to increased intracranial pressure or RPLE) c. Upward transtentorial herniation and hydrocephalus due
to cerebellar edema has rarely been reported 8. Treatment
a. Discontinuation of offending agent, if there is one (e.g., immunosuppresants)
b. Emergent initiation of antihypertensives: goal should be baseline blood pressure before presentation
c. If untreated, cerebral ischemia and hemorrhage may occur, producing irreversible brain injury
d. “Set point” for autoregulation of cerebral vasculature changes within several hours: aggressive and rapid control of hypertension could potentially precipitate cerebral ischemia
e. β-Blockers or calcium channel blockers (particularly those with rapid onset and short duration of action) are preferred agents (e.g., labetalol or esmolol, nicardipine)
f. Vasodilators such as nitroglycerine should be avoided because they can increase intracranial pressure
g. Hydralazine (arterial vasodilator) also has potential to increase intracranial pressure
1. A 62-year-old woman with hypertension presents with unilateral asterixis. The most likely cause is: a. Uremia b.Nonketotic hyperglycemic state c. Reversible posterior leukoencephalopathy d.Thalamic hemorrhage e. Pontine infarct
2. All the following clinical features may be used to distinguish between uremic encephalopathy and dialysis encephalopathy (dementia) except: a. Clinical response to dialysis b.Aphasia c. EEG characteristics d.Response to diazepam
MATCHING. Match the toxins in the left column with the syndrome in the right column. A choice from the right column may be usued once, more than once, or not at all.
