Also see page 998 for plumbism (lead poisoning) from retained bullets.
11.1. Ethanol
The acute and chronic effects of ethyl alcohol (ethanol, EtOH) abuse on the nervous system are protean1, and are beyond the scope of this text (not to mention the effects of EtOH on other organ systems). Neuromuscular effects include:
1. acute intoxication: see below
2. effects of chronic alcohol abuse
A. Wernicke’s encephalopathy: see page 275
B. cerebellar degeneration: due to degeneration of Purkinje cells in the cerebellar cortex, predominantly in the anterior superior vermis
C. central pontine myelinolysis: see page 11
D. stroke: increased risk of
1. intracerebral hemorrhage: see page 1121
2. ischemic stroke2
3. possibly aneurysmal SAH: see page 1035
E. peripheral neuropathy: see page 794
F. skeletal myopathy
3. effects of alcohol withdrawal: usually seen in habituated drinkers with cessation or reduction of ethanol intake
A. alcohol withdrawal syndromes: see below
B. seizures: up to 33% of patients have a generalized tonic-clonic seizure 7-30 hrs after cessation of drinking (see Alcohol withdrawal seizures, page 399)
C. delerium tremens (DTs): see below
ACUTE INTOXICATION
The primary effect of EtOH on the CNS is depression of neuronal excitability, impulse conduction, and neurotransmitter release due to direct effects on the cell membranes. Table 11-1 shows the clinical effects associated with specific EtOH concentrations. Mellanby effect: the severity of intoxication is greater when blood alcohol levels are rising than when falling.
In most jurisdictions, individuals with blood ethanol levels ≥ 21.7 mmol/l (100 mg/dl) are defined as legally intoxicated, and a number of states have changed this to 80 mg/dl. However, even levels of 10.2 mmol/l (47 mg/dl) are associated with increased risk of involvement in motor vehicle accidents. Chronic alcoholism leads to increased tolerance; in habituated individuals survival with levels exceeding 1000 mg/dl has been reported.
Table 11-1 Blood ethanol concentrations (in non-alcoholic patients)
|
[blood EtOH] |
Clinical effect |
|
|
mmol/liter |
mg/dl |
|
|
5.4 |
25 |
mild intoxication: altered mood, impaired cognition, incoordination |
|
> 21.7 |
100 |
vestibular and cerebellar dysfunction: increased nystagmus, diplopia, dysarthria, ataxia |
|
> 108.5 |
500 |
usually fatal from respiratory depression |
ALCOHOL WITHDRAWAL SYNDROME
Compensation for the CNS depressant effects of EtOH occurs in chronic alcoholism. Consequently, rebound CNS hyperactivity may result from falling EtOH levels. Clinical signs of EtOH withdrawal are classified as major or minor (the degree of autonomic hyperactivity and the presence/absence of DTs differentiates these), as well as early (24-48 hrs) or late (> 48 hrs).
Signs/symptoms include: tremulousness, hyperreflexia, insomnia, N/V, autonomic hyperactivity (tachycardia, systolic HTN), agitation, myalgias, mild confusion. If EtOH withdrawal seizures occur, they tend to be early (see page 399). Perceptual disturbances or frank hallucinosis may also occur early. Hallucinosis consists of visual and/or auditory hallucinations with an otherwise clear sensorium (which distinguishes this from the hallucinations of DTs). DTs can occur 3-4 days after cessation of drinking (see below).
Suppressed by benzodiazepines, resumption of drinking, ß-adrenergic antagonists, or α2-agonists.
PREVENTION OF AND TREATMENT FOR ALCOHOL WITHDRAWAL SYNDROME3
Mild EtOH withdrawal is managed with a quiet, supportive environment, reorientation and one-to-one contact. If symptoms progress, institute pharmacologic treatment.
Benzodiazepines
Benzodiazepines (BDZs) are the mainstay of treatment. They reduce autonomic hyperactivity, and may prevent seizures and/or DTs. All BDZs are effective. Initial doses are shown in Table 11-2 and are higher than those used for treating anxiety. Symptom triggered dosing with repeated evaluation utilizing a standardized protocol (e.g. CIWA-Ar5) may be more efficacious than fixed-dose schedules6. Avoid IM administration (erratic absorption).
Table 11-2 BDZ doses for EtOH withdrawal*
|
Drug |
Dose |
|
|
Oral |
IV |
|
|
chlordiazep-oxide (Librium®) |
100 mg initially, then 25-50 mg PO TID-QID, gradually taper over ≈ 4 days). Additional doses may be needed for continuing agitation, up to 50 mg PO hourly4 |
– |
|
lorazepam† (Ativan®) |
4 mg initially, then 1-2 mg PO q 4 hrs |
1-2 mg q 1-2 hrs |
|
diazepam (Valium®) |
20 mg PO initially, then 10 mg PO BID-QID |
5-10 mg initially |
|
midazolam (Versed®) |
titrate drip to desired effect |
|
* modify as appropriate based on patient response
Adjunctive medications
Associated conditions commonly seen in patients experiencing alcohol withdrawal syndrome include dehydration, fluid and electrolyte disturbances, infection, pancreatitis, and alcoholic ketoacidosis, and should be treated accordingly.
Other medications used for EtOH withdrawal itself include:
1. drugs useful for controlling HTN (caution: these agents should not be used alone because they do not prevent progression to more severe levels of withdrawal, and they may mask symptoms of withdrawal)
A. ß-blockers: also treat most associated tachyarrhythmias
1. atenolol (Tenormin®): reduces length of withdrawal and BDZ requirement
2. ✖ avoid propranolol (psychotoxic reactions)
B. α-agonists: do not use together with ß-blockers. Clonidine (see page 21) has been extensively studied, and can be given in patch form (takes ≈ 2 days)
2. phenobarbital: an alternative to BDZs. Long acting, and helps prophylax against seizures
3. baclofen: a small study7 found 10 mg PO q d X 30 days resulted in rapid reduction of symptoms after the initial dose and continued abstinence
4. “supportive” medications
A. thiamine: 100 mg IM q d x 3 d (can be given IV if needed, but there is risk of adverse reaction). Rationale: high-concentration glucose may precipitate acute Wernicke’s encephalopathy in patients with thiamine deficiency
B. folate 1 mg IM, IV or PO q d x 3 d
C. MgSO4 1 gm x 1 on admission: helpful only if magnesium levels are low, reduces seizure risk. Be sure renal function is normal before administering
D. vitamin B12 for macrocytic anemia: 100 μg IM (do not give before folate)
E. multivitamins: of benefit only if patient is malnourished
5. seizures: see page 399 for indications for treatment
A. phenytoin (Dilantin®): load with 18 mg/kg = 1200 mg/70 kg (see page 409)
6. ethanol drip: not widely used. 5% EtOH in D5W, start at 20 cc/hr, and titrate to a blood level of 100-150 mg/dl
DELERIUM TREMENS (DTS)
When DTs occur, they usually begin within 4 days of the onset of EtOH withdrawal, and typically persist for 1-3 days.
Signs and symptoms include: profound disorientation, agitation, tremor, insomnia, hallucinations, severe autonomic instability (tachycardia, HTN, diaphoresis, hyperthermia)8. Mortality is 5-10% (higher in elderly), but can be reduced with treatment (including treating associated medical problems and treatment for seizures).
Haloperidol and phenothiazines may control hallucinations, but can lower the seizure threshold. HTN and tachyarrhythmias should be treated as outline above under alcohol withdrawal syndrome.
WERNICKE’S ENCEPHALOPATHY (WE)
AKA Wernicke-Korsakoff encephalopathy. Classic triad: encephalopathy (consisting of global confusion), ophthalmoplegia, and ataxia (NB: all 3 are present in only 10-33% of cases).
Due to thiamine deficiency. Body stores of thiamine are adequate only for up to ≈ 18 days. May be seen in:
1. a certain susceptible subset of thiamine deficient alcoholics. Thiamine deficiency here is due to a combination of inadequate intake, reduced absorption, decreased hepatic storage, and impaired utilization
2. hyperemesis (as in some pregnancies)
3. starvation: including anorexia nervosa, rapid weight loss
4. gastroplication (bariatric surgery)
5. hemodialysis
6. cancers
7. AIDS
8. prolonged IV hyperalimentation
Oculomotor abnormalities occur in 96% and include: nystagmus (horizontal > vertical), lateral rectus palsy, conjugate-gaze palsies.
Gait ataxia is seen in 87%, and results from a combination of polyneuropathy, cerebellar dysfunction, and vestibular impairment.
Systemic symptoms may include: vomiting, fever.
MRI: May show high signal in T2WI and FLAIR images in the paraventricular (medial) thalamus, the floor of the 4th ventricle, and periaqueductal gray of the midbrain. These changes may resolve with treatment9. Atrophy of the mammillary bodies may also be seen. Normal MRI does not R/O the diagnosis.
Treatment
Wernicke’s encephalopathy (WE) is a medical emergency. When WE is suspected, 100 mg thiamine should be given IM or IV (oral route is unreliable, see above) daily for 5 days. ✖ IV glucose can precipitate acute WE in thiamine deficient patients, 
give thiamine first.
Thiamine administration improves eye findings within hours to days; ataxia and confusion improve in days to weeks. Many patients that survive are left with horizontal nystagmus, ataxia, and 80% have Korsakoff’s syndrome(AKA Korsakoff’s psychosis), a disabling memory disturbance involving retrograde and anterograde amnesia.
11.2. Opioids
Includes heroin (which is usually injected IV, but the powder can be snorted or smoked) as well as prescription drugs. Opioids produce small pupils (miosis).
Overdose produces:
1. respiratory depression
2. pulmonary edema
3. coma
4. hypotension and bradycardia
5. seizures may occur with: propoxyphene, meperidine (Demerol®) which may also cause delerium, and the street drug combination of “T’s and blues” (see page 397)
6. fatal overdose may occur with any agent, but is more likely with synthetic opioids such as fentanyl (Sublimaze®) among users unfamiliar with their high potency
Reversal of intoxication10
A test dose of naloxone (Narcan®) 0.2 mg IV avoids sudden complete reversal of all opioid effects. If no significant reaction occurs, an additional 1.8 mg (for a total dose of 2 mg) will reverse the toxicity of most opioids. If needed, the dose may be repeated q 2-3 minutes up to a total of 10 mg, although even larger doses may be needed with propoxyphene, pentazocine or buprenorphine (Buprenex®). Naloxone may precipitate narcotic withdrawal symptoms in opioid dependent patients, with anxiety or agitation, piloerection, yawning, sneezing, rhinorrhea, nausea, vomiting, diarrhea, abdominal cramps, muscle spasms… which are uncomfortable but not life threatening. Clonidine (Catapres®) may be helpful for some narcotic withdrawal symptoms.
With longer acting opioids, especially methadone (Dolophine®), repeat doses of naloxone may be obviated by the use of nalmefene (Revex®), a long-acting narcotic antagonist which is not appropriate for the initial treatment of opioid overdosage.
11.3. Cocaine
The increasing use of cocaine in its various forms (including crack) is resulting in a rise in the incidence and recognition of its deleterious effects on the CNS. Effects on other body systems (tachycardia, acute myocardial infarction, arrhythmias, rupture of ascending aorta (aortic dissection), abruptio placenta, hyperthermia, intestinal ischemia, sudden death…) are well documented elsewhere, and are not further discussed here.
Cocaine is extracted from Erythroxylon coca leaves (and other Erythroxylon species) and is thus unrelated to opioids. It blocks the re-uptake of nor-epinephrine by presynaptic adrenergic nerve terminals. It is available in 2 forms: cocaine hydrochloride (heat labile and water soluble, it is usually taken PO, IV or by nasal insufflation) and as the highly purified cocaine alkaloid (free base or crack cocaine, which is heat stable but insoluble in water and is usually smoked).
Peak toxicity occurs 60-90 minutes after ingestion (except for “body packers”), 30-60 minutes after snorting, and minutes after IV injection or smoking (freebase or crack)10.
Acute pharmacologic effects of cocaine
Acute pharmacologic effects pertinent to the nervous system include:
1. mental status: initial CNS stimulation that first manifests as a sense of well-being and euphoria. Sometimes dysphoric agitation results, occasionally with delerium. Stimulation is followed by depression. Paranoia and toxic psychosis may occur with overdosage or chronic use. Addiction may occur
2. pupillary dilatation (mydriasis)
3. hypertension: from adrenergic stimulation
Non-pharmacologic effects related to the nervous system
1. pituitary degeneration: from chronic intranasal use
2. cerebral vasculitis: less common than with amphetamines
3. seizures: possibly related to the local anesthetic properties of cocaine
4. cerebrovascular accident (CVA, stroke)11
A. intracerebral hemorrhage: see Intracerebral hemorrhage, Etiologies on page 1119
B. subarachnoid hemorrhage12, 13: possibly as a result of HTN in the presence of aneurysms or AVMs, however, sometimes no lesion is demonstrated on angiography14. May possibly be due to cerebral vasculitis
C. ischemic stroke15: may result from vasoconstriction
D. thrombotic stroke10
E. TIA16
5. anterior spinal artery syndrome16
6. effects of maternal cocaine use on the fetal nervous system include17: microcephaly, disorders of neuronal migration, neuronal differentiation and myelination, cerebral infarction, subarachnoid and intracerebral hemorrhage, and sudden infant death syndrome (SIDS) in the postnatal period
TREATMENT OF TOXICITY
Most cocaine toxicity is too short-lived to be treated. Anxiety, agitation or seizures may be treated with IV benzodiazepines (e.g. lorazepam, see page 405). Refractory HTN may be treated with nitroprusside (see page 19) or phentolamine (Regitine®, see page 681). IV lidocaine used to treat cardiac arrhythmias may cause seizures10.
11.4. Amphetamines
Toxicity is similar to that of cocaine (see above), but longer in duration (may last up to several hours). Cerebral vasculitis may occur with prolonged abuse (see page 79) which may lead to cerebral infarction (see page 1024).
Elimination of amphetamines requires adequate urine output. Antipsychotic drugs such as haloperidol (Haldol®) should not be used because of risk of seizures.
11.5. Carbon monoxide
Carbon monoxide (CO) is the largest source of death from poisoning in the U.S.A.
Normal cellular function requires ≈ 5 ml O2/100 ml blood. Blood normally contains ≈ 20 ml O2/100 ml.
CO binds to hemoglobin (Hb) with an affinity ≈ 250 times that of O2, and it causes a left shift of the Hb/O2 dissociation curve. It also binds to intracellular myoglobin.
Only ≈ 6% of patients show the classic “cherry-red” color of blood.
Clinical findings
Related to CO-Hb level as shown in Table 11-3.
Diagnostic studies
EKG changes are common, usually non-specific ST-T wave changes.
In cases of severe intoxication, CT may show symmetrical low attenuation in the globus pallidus (see page 1229 for differential diagnosis).
Outcome
Prognosticators
1. outcome is more closely correlated with hypotension than with actual CO-Hb level
2. coma
3. metabolic acidosis
4. EEG
5. CT/MRI changes: in one study, the presence of MRI lesions after 1 month did not accurately predict subsequent outcome
6. CO-Hb level
7. other factors probably have an effect, including: age, severity of exposure
Table 11-3 Levels of CO-Hb
|
CO-Hb level(%) |
Signs/symptoms* |
|
0-10 |
none |
|
10-20* |
mild H/A, mild DOE |
|
20-30 |
throbbing H/A |
|
30-40 |
severe H/A, dizziness, dimming of vision, impaired judgement |
|
40-50 |
confusion, tachypnea, tachycardia, possible syncope |
|
50-60 |
syncope, seizures, coma |
|
60-70 |
coma, hypotension, respiratory failure, death |
|
> 70 |
rapidly fatal |
* NB: smokers may have CO-Hb levels of 15% without signs or symptoms
Approximately 40% of patients exposed to significant levels of CO die. 30-40% have transient symptoms but make a full recovery. 10-30% have persistent neurological sequelae including CO-encephalopathy (may be delayed in onset) - impaired memory, irritability, parietal lobe symptoms including various agnosias.
Brain lesions
1. white matter lesions:
A. multifocal small necrotic lesions in deep hemispheres
B. extensive necrotic zones along lateral ventricles
C. Grinker’s myelinopathy (not necrosis)
2. grey matter lesions
A. bilateral necrosis of globus pallidus
B. lesions of hippocampal formation and focal cortical necrosis
11.6. References
1. Charness M E, Simon R P, Greenberg D A: Ethanol and the nervous system. N Engl J Med 321: 442-54, 1989.
2. Gorelick P B: Alcohol and stroke. Stroke 18: 268-71, 1987.
3. Lohr R H: Treatment of alcohol withdrawal in hospitalized patients. Mayo Clin Proc 70: 777-82, 1995.
4. Lechtenberg R, Worner T M: Seizure risk with recurrent alcohol detoxification. Arch Neurol 47: 535-8, 1990.
5. Sullivan J T, Sykora K, Schneiderman J, et al.: Assessment of alcohol withdrawal: The revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict 84: 1353-7, 1989.
6. Saitz R, Mayo-Smith M F, Roberts M S, et al.: Individualized treatment for alcohol withdrawal: A randomized double-blind controlled trial. JAMA 272: 519-23, 1994.
7. Addolorato G, Caputo F, Capristo E, et al.: Rapid suppression of alcohol withdrawal syndrome by baclofen. Am J Med 112 (3): 226-9, 2002.
8. Treatment of alcohol withdrawal. Med Letter 28: 75-6, 1986.
9. Watson W D, Verma A, Lenart M J, et al.: MRI in acute Wernicke’s encephalopathy. Neurology 61 (4): 527, 2003.
10. Acute reactions to drugs of abuse. Med Letter 38: 43-6, 1996.
11. Fessler R D, Esshaki C M, Stankewitz R C, et al.: The neurovascular complications of cocaine. Surg Neurol 47: 339-45, 1997.
12. Lichtenfeld P J, Rubin D B, Feldman R S: Subarachnoid hemorrhage precipitated by cocaine snorting. Arch Neurol 41: 223-4, 1984.
13. Oyesiku N M, Collohan A R T, Barrow D L, et al.: Cocaine-induced aneurysmal rupture: An emergent negative factor in the natural history of intracranial aneurysms? Neurosurgery 32: 518-26, 1993.
14. Schwartz K A, Cohen J A: Subarachnoid hemorrhage precipitated by cocaine snorting. Arch Neurol 41: 705, 1984 (letter).
15. Levine S R, Brust J C M, Futrell N, et al.: Cerebrovascular complications of the use of the ‘crack’ form of alkaloidal cocaine. N Engl J Med 323: 699-704, 1990.
16. Mody C K, Miller B L, McIntyre H B, et al.: Neurologic complications of cocaine abuse. Neurology 38: 1189-93, 1988.
17. Volpe J J: Effect of cocaine use on the fetus. N Engl J Med 327: 399-407, 1992.