Toxic Disorders of the Nervous System

• -primarily hematogenous
• -occasionally deposited locally through trauma

• -varies
• -usually subacute
• -highly dependent on amount of toxin and rate of exposure
• -single relatively time-limited exposure
• -multiple intermittent exposures
• -ongoing, long lasting exposure

• Affects nervous system many ways:
• -acute intoxication
• -toxicity from chronic exposure
• -toxicity from nutritional deficits
• -withdrawal

• 30mg/dL: mild euphoria
• 200mg/dL: confusion, mental slowing
• 400mg/dL: life threatening sedation and dysautonomia

Patients may become habituated (tolerance)

• Pathophysiology:
• -enhances GABA_A inhibitory signaling
• -inhibits NMDA receptor
• -potentiates seratonin currents (reward)
• -dissolves in the lipid membrane and changes rigidity of the membrane

• -90% oxidation
• -<10% excreted in urine, perspiration, breath
• -alcohol dehydrogenase in liver

• 1. Alcoholic Dementia
• -controversial
• -at risk for disorders that cause cognitive dysfunction
• -most believe long term heavy use can cause mild dementia with frontal dysfunction
• -brain atrophy

• 2. Cerebellar Degeneration
• -atrophy of anterior and superior vermis
• -may actually be due to nutrition deficit
• -tx: thiamine

• 3. Alcoholic Myopathy
• -acute: during binge drinking (severe muscle pain and tenderness, elevated CK)
• -chronic: painless proximal weakness of lower > upper extremeties

• 4. Depression
• -mood swings
• -can resemble major depressive episode

• -full syndrome is know as Delirium Tremens
• 
• 1. Tremor: typically first sign of withdrawal
• 2. Hallucinations: animate objects, unpleasant
• 3. Seizures: 1-2 days, generalized tonic clonic, almost always self limited
• 4. Delirium Tremens: autonomic instability (changes in BP, HR, temp etc), life threatening

• Treatment:
• -benzos

• -overdose intoxication
• -withdrawal

• Presentation:
• -acute onset
• -decreased LOC
• -shallow respirations
• -slowed respiratory rate
• -pinpoint pupils
• -bradycardia
• -hypothermia

***some ppl are more susceptible to overdose: children, adults with myxedema, chronic liver disease, pneumonia

***opiate OD should be suspected in anyone with decreased LOC or hypoventilation of unknown etiology!!!

• Treatment:
• -Naloxone (due to very short half life may need multiple doses)
• -gastric lavage in oral OD

• -high dosages of opiates have a very high rate of withdrawal sx
• -withdrawal is miserable, but won't kill you

• Presentation:
• 1. 8-16 hours: sweating, yawning, piloerection, tearing
• 2. 36 hours: severe restlessness, hot and cold flashes, N/V, diarrhea
• 3. 72 hours: peak, decline over the next two weeks

• Treatment = Symptomatic
• -autonomic overactivity: alpha agonist
• -abdominal pain: loperamide
• -NSAIDs: analgesics
• -anxiety: benzos
• **oral methadone: controversial

• -amphetamines
• -cocaine

• -Rx: disorders of sleep and attention
• -illicit

• -energy and mental acuity at low doses
• -ecstasy at high doses

-common in San Diego

-very high risk for addiction

• Presentation:
• -restlessness
• -agitation
• -hallucinations
• -paranoia
• -psychosis
• -increased sympathetic function:
•      -hypertension
•      -cerebral infarct (vasospasm)
•      -intracerebral hematoma

• Treatment:
• -support through abstinence

• Presentation:
• -fatigue
• -depression
• -sleepiness
• -problems concentrating
• -intense hunger

• Treatment:
• -support through abstinence

• -snorted, smoked, injected
• -applied topically as a local anesthetic (ENT, ophtho)

Crack: heat stable, can be smoked

• Intoxication:
• -cognitive effects
• -emotional effects
• -tachycardia
• -hypertension
• -vasoconstriction leading to infarct
• -seizures
• -hyperpyrexia

• Pathophysiology:
• -blocks reuptake of central DA and peripheral NE

• -fatigue
• -depression
• -sleepiness
• -problems concentrating
• -intense hunger

• -Barbituates
• -Benzos
• -Non-benzo hypnotics

• Presentation:
• 100-300mg:
• -drowsy or asleep
• -mildly incoordinated
• -mentally slow

• 5-10x:
• -stupor
• -depressed deep tendon reflexes
• -slow, full respirations

• 10-20x:
• -comatose
• -slow, shallow respirations
• -flaccid
• -decreased or absent reflexes

• Pathophysiology:
• -enhance inhibitory GABA_A transmission
• ***strongly potentiated by alcohol or other CNS depressant

• Clinical Role:
• -anxiolytics
• -anticonvulsants
• -anti-tremor
• -anti-spasticity
• -anesthetics

different types of benzos differ in potency and half life but are very similar

-it is harder to OD on benzos

• Presentation:
• -unsteadiness of gait
• -drowsiness
• -depressed consciousness at high doses
• -rarely depressed respiration or cardiac dysfunction

• Treatment:
• -flumazenil (benzo antagonist)

• Presentation:
• -anxiety
• -jitteriness
• -insomnia
• -seizures (rare)

-seen within d3-7 of abstinence

• Treatment:
• -slow taper off benzos
• -start benzo with longer half life

-Zolpidem

-acts at GABA_A site

• Clinical Uses:
• -decrease sleep latency
• -increase sleep duration
• -w/o anxiolytic, anticonvulsant, or anti-spasticity properties of benzos

• Intoxication:
• -idiosyncratic effects (may occur suddenly)
• -sonambulism
• -amnestic episodes

-little evidence for dependence or addiction

-synthetic amphetamine

• Intoxication:
• -euphoria
• -hypersexuality
• -hallucinogen-like feeling

• Pathophysiology:
• -increased serotonin release in the CNS
• -followed by interference with serotonin synthesis

• Overdose:
• -seizures
• -cerebral hemorrhage
• -psychotic behaviour

• Intoxication:
• -transient drowsiness
• -euphoria
• -perceptual distortions
• -mild-moderate psychomotor retardation
• -hallucination with higher doses
• -even higher doses may cause severe depression and stupor
• -death is extremely rare

• Pathophysiology:
• -THC interacts with cannabinoid receptors of endogenous system

• Chronic Use:
• **NOT clear if there is chronic dependence or withdrawal syndrome
• -some deficits in short term memory and attention even with abstinence
• -no clear pathologic changes

• Clinical Use:
• -meaningful antiemetic and appetite stimulant
• -role in anti-spasticity or neuropathic pain not supported

• -LSD
• -mescaline
• -PCP

• Intoxication:
• -vivid hallucinations
• -distortions of visual perceptions
• -unusual dreams
• -depersonalization
• -dizziness, nausea, paresthesias, blurry vision, sympathomimetic effects

• Presentation:
• -rapid subacute onset diffuse weakness
• -First: anorexia, nausea, vomiting
• -Later: severe constipation
• -First Neuro: blurred vision and diplopia
• -Later Neuro: failure of pupil reactivity, diffuse motor weakness, paralysis, respiratory failure

• Pathophysiology:
• -canned food, honey
• -G+ rod, anaerobic, creates spores in soil
• -produces toxins
• -toxin binds gangliosides on motor neurons and enters cell
• -once inside cell it blocks the ability of Ach vesicles to fuse with PM

• Rule out:
• -Myasthenia Gravis: prominent eye findings
• -Guillain Barre:prominent weakness worsening over days, descending weakness, somatosensation is normal, CSF is normal

• Treatment:
• -advanced life support
• -trivalent antiserum
• -tx infected wounds (PCN, metronidazole)

• Prognosis:
• -good recovery (weeks to months)

• -dystonia/spasticity
• -cosmetic use
• -refractory migraines

***chronic use may lead to development of neutralizing antibodies (can switch to a different type)

• -rare adverse effect of general anesthesia (1/50,000)
• -usually with inhalation agent

• Presentation:
• -paradoxical stiffening of jaw muscles (given succinylcholine)
• -diffuse muscle stiffness
• -rise in body temp
• -frank rhabdomyolysis
• -acidemia
• -elevated CK
• -myoglobinuria
• -death

• Pathophysiology:
• -increase in SKM intracellular Ca leading to sustained muscle contraction and hyperthermia
• -genetic abnormality in RyR1

• Treatment:
• -cease anesthetic
• -Dantrolene (CCB)

• -idiopathic intracranial hypertension
• -secondary pseudotumor cerebri

• Epidemiology:
• -overweight adolescent girls
• -short stature
• -menstrual irregularties

• Presentation (over months):
• -increased ICP w/o localizing signs
• -HA (worse when supine, progressive)
• -visual obscurations
• - sometimes mild double vision
• -papilledema
• -abducens nerve palsy
• -NO: hydrocephalus, mass lesion

• Diagnosis:
• -fundoscopic exam
• -test visual acuity and fields
• -venography
• -LP
• -long term serial visual testing

• Treatment:
• -weight reduction
• -acetazolamide (reduces CSF production)
• -CSF shunting
• -optic nerve sheath fenestration (effective up to 1 year)

• Causes:
• 1. otherwise asymptomatic occlusion of cerebral dural venous sinuses, this causes cerebral venous hypertension leading to a decreased outflow of CSF
• 2. meningeal diseases
• 3. hypervitaminosis A
• 4. tetracycline

• Diagnosis:
• -fundoscopic exam
• -test visual acuity and fields
• -venography
• -LP
• -longer term serial visual testing

• Treatment:
• -tx underlying lesions
• -anticoagulants
• -immunosuppresives
• -antimicrobials

• Epidemiology:
• -more common in women than men
• -3rd to 5th decades of life

• Presentation:
• -persistent and disabling fatigue for at least 6 months, with 6 of the following:
• -recurrent somatic or neuropsych sx
• -low grade fever
• -cervical or axillary lymphadenopathy
• -myalgias
• -migrating arthralgias
• -sore throat
• -forgetfulness
• -HAs
• -difficulty concentrating/thinking
• -irritability
• -sleep disturbances

• Causes:
• -associated with depression and anxiety
• -maybe after non-specific viral illness
• -often no clear cause

• Treatment:
• -education
• -CBT
• -antidepressants

• Epidemiology:
• -more common in children

• Presentation:
• -In kids --> encephalopathy: lowered intelligence, decreased attention, hyperactivity
• -In adults --> motor polyneuropathy, bilateral "wrist drop"
• 

• Pathology:
• -cerebral edema
• -necrosis of cortical neurons
• -astrocytic proliferation
• -demyelination of cerebral and cerebellar hemispheres
• -axonal degeneration

• Pathophysiology:
• -lead competes with calcium

• Epidemiology:
• -in adults due to intoxication with herbicides, insecticides or rodenticides
• -may be fatal

• Presentation:
• -low dose: subacute onset sensorimotor polyneuropathy
• -high dose: acute encephalopathy, multi-organ failure, death

• Pathology:
• -multiple punctate hemorrhages in the white matter
• -capillary necrosis
• -sensorimotor polyneuropathy

• Pathophysiology:
• -may interfere with ox phos

• Epidemiology:
• -victims of fires
• -suicide attempts
• -faulty ventilation

• Presentation:
• -amnesia
• -ataxia
• -UMN dysfunction
• -additional cognitive dysfunction
• -parkinsonism

• Pathophysiology:
• -same effects as anoxic ischemia
• -also binds globus pallidus (iron rich)
• -CO binds to Hbg --> global ischemia
• -selectively vulnerable: hippocampus, purkinje cells, outer layers of cerebral cortex, GP

• Epidemiology:
• -pesticides

• Presentation:
• -HA
• -vomiting
• -sweating
• -abdominal cramping
• -salivation
• -wheezing
• -miosis
• -weakness
• -fasciculations
• -high dose: cardiovascular collapse
• -late effects (d-wks): distal symmetrical motor > somatosensory polyneuropathy, UMN findings

• Pathophysiology:
• -acute anticholinesterase activity

• Pathophysiology:
• -metabolized to a toxic metabolite which binds melanin in DA neurons of substantia nigra leading to their death

• Presentation:
• -Parkinsonism (acute, bilateral)

• -NO, hydrocarbons
• -propellants and solvents in household products

• Presentation:
• -euphoria
• -irritability
• -aggression
• -depressed mood
• -bizarre thoughts
• -Chronic exposure: distal polyneuropathy

***can be an occupational hazard for OR staff

• -black widows
• -snake venom
• -scorpion venom
• -jimson weed
• -ciguatera
• -fish and shellfish toxins

• Pathophysiology:
• -toxins affect peripheral nerve function and neuromuscular transmission
• -Dinoflagellates block axonal transmission by impairing Na channels

• -C. tetani exotoxin
• -spores can live in soil for decades

• Presentation:
• -sustained muscle contractions
• -lockjaw (masseter particularly susceptible)

• Pathophysiology:
• -toxin carried to CNS by retrograde axonal transport
• -toxin prevents exocytosis of GABA vesicles
• -loss of inhibitory neurons in reflex arcs causes neuronal hyperexcitability

• Treatment:
• -DPT vaccine

• Pathophysiology:
• -damage to DNA
• -more rapid delivery, larger volume and greater rapidity of cell division in the affected area --> greater injury

• Pathology:
• -late response: recurrent and de novo tumor formation
• -demyelination and necrosis (secondary to vascular injury)

-UV, visible light, infrared, microwave, radiofrequency emissions

• Presentation:
• -burns and cataracts
• -unclear if specific nervous system injury can result

1. Direct injury of superficial structures with crystallization of intra and extracellular water

2. peripheral vasoconstriction --> vascular sludging --> local ischemia

Can lead to significant CNS depression

• Causes:
• -cessation of sweating
• -marked peripheral vasodilation
• -venous pooling
• -systemic shock

• Multiorgan system failure (> 42C)
• Injury due to lack of perfusion

• Epidemiology:
• -increased incidence of disorders in Vietnam vets

• Presentation:
• -polyneuropathy
• -Parkinson's Disease
• -cancers of brain and nervous system (eye)
• -neuropsychiatric disorders
• -etc!!!

"medically unexplained multi-symptom illness reported by Gulf War veterans"

• Presentation:
• -chronic fatigue
• -HAs
• -joint pain
• -indigestion
• -insomnia
• -dizziness
• -respiratory disorders
• -memory problems

No pathology or pathophysiology

• Causal relationship with:
• -PTSD

• Significant Association with:
• -psychiatric disorders
• -GI sx
• -multisystem illness
• -chronic fatigue syndrome