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202 ADVERSE DRUG REACTIONS

202 ADVERSE DRUG REACTIONS
Harrison’s Manual of Medicine

202

ADVERSE DRUG REACTIONS

Bibliography

Adverse drug reactions are among the most frequent problems encountered clinically and represent a common cause for hospitalization. They occur most frequent in pts receiving multiple drugs and are caused by

1.
Errors in self-administration of prescribed drugs (quite common in the elderly).

2.
Exaggeration of intended pharmacologic effect (e.g., hypotension in a pt given antihypertensive drugs).

3.
Concomitant administration of drugs with synergistic effects (e.g., aspirin and warfarin).

4.
Cytotoxic reactions (e.g., hepatic necrosis due to acetaminophen).

5.
Immunologic mechanisms (e.g., quinidine-induced thrombocytopenia, hydralazine-induced SLE).

6.
Genetically determined enzymatic defects (e.g., primaquine-induced hemolytic anemia in G6PD deficiency).

7.
Idiosyncratic reactions (e.g., chloramphenicol-induced aplastic anemia).
RECOGNITION   History is of prime importance. Consider (1) nonprescription drugs and topical agents as potential offenders; (2) previous reaction to identical drugs; (3) temporal association between drug administration and development of clinical manifestations; (4) subsidence of manifestations when the agent is discontinued or reduced in dose; (5) recurrence of manifestations with cautious readministration (for less hazardous reactions); (6) rare: (a) biochemical abnormalities, e.g., red cell G6PD deficiency as cause of drug-induced hemolytic anemia, (b) abnormal serum antibody in pts with agranulocytosis, thrombocytopenia, hemolytic anemia.
Table 202-1 lists a number of clinical manifestations of adverse effects of drugs. It is not designed to be complete or exhaustive.

Table 202-1

Clinical Manifestations of Adverse Reactions to Drugs

MULTISYSTEM MANIFESTATIONS

Anaphylaxis
Cephalosporins
Dextran
Insulin
Iodinated drugs or contrast media
Lidocaine
Penicillins
Procaine
Angioedema
ACE inhibitors
Drug-induced lupus erythematosus
Cephalosporins
Hydralazine
Iodides
Isoniazid
Methyldopa
Phenytoin
Procainamide
Quinidine
Sulfonamides
Thiouracil
Fever
Aminosalicylic acid
Amphotericin B
Antihistamines
Penicillins
Hyperpyrexia
Antipsychotics
Serum sickness
Aspirin
Penicillins
Propylthiouracil
Sulfonamides
ENDOCRINE MANIFESTATIONS

Addisonian-like syndrome
Busulfan
Ketoconazole
Galactorrhea (may also cause amenorrhea)
Methyldopa
Phenothiazines
Tricyclic antidepressants
Gynecomastia
Calcium channel antagonists
Digitalis
Estrogens
Griseofulvin
Isoniazid
Methyldopa
Phenytoin
Spironolactone
Testosterone
Sexual dysfunction
Beta blockers
Clonidine
Diuretics
Guanethidine
Lithium
Major tranquilizers
Methyldopa
Oral contraceptives
Sedatives
Thyroid function tests, disorders of
Acetazolamide
Amiodarone
Chlorpropamide
Clofibrate
Colestipol and nicotinic acid
Gold salts
Iodides
Lithium
Oral contraceptives
Phenothiazines
Phenylbutazone
Phenytoin
Sulfonamides
Tolbutamide
METABOLIC MANIFESTATIONS

Hyperbilirubinemia
Rifampin
Hypercalcemia
Antacids with absorbable alkali
Thiazides
Vitamin D
Hyperglycemia
Chlorthalidone
Diazoxide
Encainide
Ethacrynic acid
Furosemide
Glucocorticoids
Growth hormone
Oral contraceptives
Thiazides
Hypoglycemia
Insulin
Oral hypoglycemics
Quinine
Hyperkalemia
ACE inhibitors
Amiloride
Cytotoxics
Digitalis overdose
Heparin
Lithium
Potassium preparations including salt substitute
Potassium salts of drugs
Spironolactone
Succinylcholine
Triamterene
Hypokalemia
Alkali-induced alkalosis
Amphotericin B
Diuretics
Gentamicin
Insulin
Laxative abuse
Mineralocorticoids, some glucocorticoids
Osmotic diuretics
Sympathomimetics
Tetracycline
Theophylline
Vitamin B12
Hyperuricemia
Aspirin
Cytotoxics
Ethacrynic acid
Furosemide
Hyperalimentation
Thiazides
Hyponatremia

1.
Dilutional
Carbamazepine
Chlorpropamide
Cyclophosphamide
Diuretics
Vincristine

2.
Salt wasting
Diuretics
Enemas
Mannitol
Metabolic acidosis
Acetazolamide
Paraldehyde
Salicylates
Spironolactone
DERMATOLOGIC MANIFESTATIONS

Acne
Anabolic and androgenic steroids
Bromides
Glucocorticoids
Iodides
Isoniazid
Oral contraceptives
Alopecia
Cytotoxics
Ethionamide
Heparin
Oral contraceptives (withdrawal)
Eczema
Captopril
Cream and lotion perservatives
Lanolin
Topical antihistamines
Topical antimicrobials
Topical local anesthetics
Erythema multiforme or Steven Johnson syndrome
Barbiturates
Chlorpropamide
Codeine
Penicillins
Phenylbutazone
Phenytoin
Salicylates
Sulfonamides
Sulfones
Tetracyclines
Thiazides
Erythema nodosum
Oral contraceptives
Penicillins
Sulfonamides
Exfoliative dermatitis
Barbiturates
Gold salts
Penicillins
Phenylbutazone
Phenytoin
Quinidine
Sulfonamides
Fixed drug eruptions
Barbiturates
Captopril
Phenylbutazone
Quinine
Salicylates
Sulfonamides
Hyperpigmentation
Bleomycin
Busulfan
Chloroquine and other antimalarials
Corticotropin
Cyclophosphamide
Gold salts
Hypervitaminosis A
Oral contraceptives
Phenothiazines
Lichenoid eruptions
Aminosalicylic acid
Antimalarials
Chlorpropamide
Gold salts
Methyldopa
Phenothiazines
Photodermatitis
Captopril
Chlordiazepoxide
Furosemide
Griseofulvin
Nalidixic acid
Oral contraceptives
Phenothiazines
Sulfonamides
Sulfonylureas
Tetracyclines, particularly demeclocycline
Thiazides
Purpura (see also thrombocytopenia)
Allopurinol
Ampicillin
Aspirin
Glucocorticoids
Rashes (nonspecific)
Allopurinol
Ampicillin
Barbiturates
Indapamide
Methyldopa
Phenytoin
Skin necrosis
Warfarin
Toxic epidermal necrolysis (bullous)
Allopurinol
Barbiturates
Bromides
Iodides
Nalidixic acid
Penicillins
Phenylbutazone
Phenytoin
Sulfonamides
Urticaria
Aspirin
Barbiturates
Captopril
Enalapril
Penicillins
Sulfonamides
HEMATOLOGIC MANIFESTATIONS

Agranulocytosis (see also Pancytopenia)
Captopril
Carbimazole
Chloramphenicol
Cytotoxics
Gold salts
Indomethacin
Methimazole
Oxyphenbutazone
Phenothiazines
Phenylbutazone
Propylthiouracil
Sulfonamides
Tolbutamide
Tricyclic antidepressants
Clotting abnormalities/hypothrombinemia
Cefamandole
Cefoperazone
Moxalactam
Eosinophilia
Aminosalicylic acid
Chlorpropamide
Erythromycin estolate
Imipramine
L-Tryptophan
Methotrexate
Nitrofurantoin
Procarbazine
Sulfonamides
Hemolytic anemia
Aminosalicylic acid
Cephalosporins
Chlorpromazine
Dapsone
Insulin
Isoniazid
Levodopa
Mefenamic acid
Melphalan
Methyldopa
Penicillins
Phenacetin
Procainamide
Quinidine
Rifampin
Sulfonamides
Hemolytic anemias in G6PD deficiency
See Table 58-3
Leukocytosis
Glucocorticoids
Lithium
Lymphadenopathy
Phenytoin
Primidone
Megaloblastic anemia
Folate antagonists
Nitrous oxide
Oral contraceptives
Phenobarbital
Phenytoin
Primidone
Triamterene
Trimethroprim
Pancytopenia (aplastic anemia)
Carbamazepine
Chloramphenicol
Cytotoxics
Gold salts
Mephenytoin
Phenylbutazone
Phenytoin
Quinacrine
Sulfonamides
Trimethadione
Zidovudine (AZT)
Pure red cell aplasia
Azathioprine
Chlorpropamide
Isoniazid
Phenytoin
Thrombocytopenia (see also Pancytopenia)
Acetazolamine
Aspirin
Carbamazepine
Carbenicillin
Chlorpropamide
Chlorthalidone
Furosemide
Gold salts
Heparin
Indomethacin
Isoniazid
Methyldopa
Moxalactam
Phenylbutazone
Phenytoin and other hydantoins
Quinidine
Quinine
Thiazides
Ticarcillin
CARDIOVASCULAR MANIFESTATIONS

Angina exacerbation
Alpha blockers
Beta blocker withdrawal
Ergotamine
Excessive thyroxine
Hydralazine
Methysergide
Minoxidil
Nifedipine
Oxytocin
Vasopressin
Arrhythmias
Adriamycin
Antiarrhythmic drugs
Atropine
Anticholinesterases
Beta blockers
Digitalis
Emetine
Lithium
Phenothiazines
Sympathomimetics
Thyroid hormone
Tricyclic antidepressants
Verapamil
AV block
Clonidine
Methyldopa
Verapamil
Cardiomyopathy
Adriamycin
Daunorubicin
Emetine
Lithium
Phenothiazines
Sulfonamides
Sympathomimetics
Fluid retention or congestive heart failure
Beta blockers
Calcium antagonists
Estrogens
Indomethacin
Mannitol
Minoxidil
Phenylbutazone
Steroids
Hypotension
Calcium antagonists
Citrated blood
Diuretics
Levodopa
Morphine
Nitroglycerin
Phenothiazines
Protamine
Quinidine
Hypertension
Clonidine withdrawal
Corticotropin
Cyclosporine
Glucocorticoids
Monoamine oxidase inhibitors with sympathomimetics
NSAIDs
Oral contraceptives
Sympathomimetics
Tricyclic antidepressants with sympathomimetics
Pericarditis
Emetine
Hydralazine
Methysergide
Procainamide
Thromboembolism
Oral contraceptives
RESPIRATORY MANIFESTATIONS

Airway obstruction
Beta blockers
Cephalosporins
Cholinergic drugs
NSAIDs
Penicillins
Pentazocine
Streptomycin
Tartrazine (drugs with yellow dye)
Cough
ACE inhibitors
Pulmonary edema
Contrast media
Heroin
Methadone
Propoxyphene
Pulmonary infiltrates
Acyclovir
Amiodarone
Azathioprine
Bleomycin
Busulfan
Carmustine (BCNU)
Chlorambucil
Cyclophosphamide
Melphalan
Methotrexate
Methysergide
Mitomycin C
Nitrofurantoin
Procarbazine
Sulfonamides
GASTROINTESTINAL MANIFESTATIONS

Cholestatic jaundice
Anabolic steroids
Androgens
Chlorpropamide
Erythromycin estolate
Gold salts
Methimazole
Nitrofurantoin
Oral contraceptives
Phenothiazines
Constipation or ileus
Aluminum hydroxide
Barium sulfate
Calcium carbonate
Ferrous sulfate
Ion exchange resins
Opiates
Phenothiazines
Tricyclic antidepressants
Verapamil
Diarrhea or colitis
Antibiotics (broad-spectrum)
Colchicine
Digitalis
Magnesium in antacids
Methyldopa
Diffuse hepatocellular damage
Acetaminophen (paracetamol)
Allopurinol
Aminosalicylic acid
Dapsone
Erythromycin estolate
Ethionamide
Glyburide
Halothane
Isoniazid
Ketoconazole
Methimazole
Methotrexate
Methoxyflurane
Methyldopa
Monoamine oxidase inhibitors
Niacin
Nifedipine
Nitrofurantoin
Phenytoin
Propoxyphene
Propylthiouracil
Pyridium
Rifampin
Salicylates
Sodium valproate
Sulfonamides
Tetracyclines
Verapamil
Zidovudine (AZT)
Intestinal ulceration
Solid KCl preparations
Malabsorption
Aminosalicylic acid
Antibiotics (broad-spectrum)
Cholestyramine
Colchicine
Colestipol
Cytotoxics
Neomycin
Phenobarbital
Phenytoin
Nausea or vomiting
Digitalis
Estrogens
Ferrous sulfate
Levodopa
Opiates
Potassium chloride
Tetracyclines
Theophylline
Oral conditions

1.
Gingival hyperplasia
Calcium antagonists
Cyclosporine
Phenytoin

2.
Salivary gland swelling
Bretylium
Clonidine
Guanethidine
Iodides
Phenylbutazone

3.
Taste disturbances
Biguanides
Captopril
Griseofulvin
Lithium
Metronidazole
Penicillamine
Rifampin

4.
Ulceration
Aspirin
Cytotoxics
Gentian violet
Isoproterenol (sublingual)
Pancreatin
Pancreatitis
Azathioprine
Ethacrynic acid
Furosemide
Glucocorticoids
Opiates
Oral contraceptives
Sulfonamides
Thiazides
Peptic ulceration or hemorrhage
Aspirin
Ethacrynic acid
Glucocoricoids
NSAIDs
RENAL/URINARY MANIFESTATIONS

Bladder dysfunction
Anticholinergics
Disopyramide
Monoamine oxidase inhibitors
Tricyclic antidepressants
Calculi
Acetazolamide
Vitamin D
Concentrating defect with polyuria (or nephrogenic diabetes insipidus)
Demeclocycline
Lithium
Methoxyflurane
Vitamin D
Hemorrhagic cystitis
Cyclophosphamide
Interstitial nephritis
Allopurinol
Furosemide
Penicillins, esp. methicillin
Phenindione
Sulfonamides
Thiazides
Nephropathies
Due to analgesics (e.g., phenacetin)
Nephrotic syndrome
Captopril
Gold salts
Penicillamine
Phenindione
Probenecid
Obstructive uropathy
Extrarenal: methysergide
Intrarenal: cytotoxics
Renal dysfunction
Cyclosporine
NSAIDS
Triamterene
Renal tubular acidosis
Acetazolamide
Amphotericin B
Degraded tetracycline
Tubular necrosis
Aminoglycosides
Amphotericin B
Colistin
Cyclosporine
Methoxyflurane
Polymyxins
Radioiodinated contrast medium
Sulfonamides
Tetracyclines
NEUROLOGIC MANIFESTATIONS

Exacerbation of myasthenia
Aminoglycosides
Polymyxins
Extrapyramidal effects
Butyrophenones, e.g., haloperidol
Levodopa
Methyldopa
Metoclopramide
Oral contraceptives
Phenothiazines
Tricyclic antidepressants
Headache
Ergotamine (withdrawal)
Glyceryl trinitrate
Hydralazine
Indomethacin
Peripheral neuropathy
Amiodarone
Chloramphenicol
Chloroquine
Chlorpropamide
Clofibrate
Demeclocycline
Disopyramide
Ethambutol
Ethionamide
Glutethimide
Hydralazine
Isoniazid
Methysergide
Metronidazole
Nalidixic acid
Nitrofurantoin
Phenytoin
Polymyxin, colistin
Procarbazine
Streptomycin
Tolbutamide
Tricyclic antidepressants
Vincristine
Pseudotumor cerebri (or intracranial hypertension)
Amiodarone
Glucocorticoids, mineralocorticoids
Hypervitaminosis A
Oral contraceptives
Tetracyclines
Seizures
Amphetamines
Analeptics
Isoniazid
Lidocaine
Lithium
Nalidixic acid
Penicillins
Phenothiazines
Physostigmine
Theophylline
Tricyclic antidepressants
Vincristine
Stroke
Oral contraceptives
OCULAR MANIFESTATIONS

Cataracts
Busulfan
Chlorambucil
Glucocorticoids
Phenothiazines
Color vision alteration
Barbiturates
Digitalis
Methaqualone
Streptomycin
Thiazides
Corneal edema
Oral contraceptives
Corneal opacities
Chloroquine
Indomethacin
Vitamin D
Glaucoma
Mydriatics
Sympathomimetics
Optic neuritis
Aminosalicylic acid
Chloramphenicol
Ethambutol
Isoniazid
Penicillamine
Phenothiazines
Phenylbutazone
Quinine
Streptomycin
Retinopathy
Chloroquine
Phenothiazines
EAR MANIFESTATIONS

Deafness
Aminoglycosides
Aspirin
Bleomycin
Chloroquine
Erythromycin
Ethacrynic acid
Furosemide
Nortriptyline
Quinine
Vestibular disorders
Aminoglycosides
Quinine
MUSCULOSKELETAL MANIFESTATIONS

Bone disorders

1.
Osteoporosis
Glucocorticoids
Heparin

2.
Osteomalacia
Aluminum hydroxide
Anticonvulsants
Glutethimide
Myopathy or myalgia
Amphotericin B
Chloroquine
Clofibrate
Glucocorticoids
Oral contraceptives
Myositis
Gemfibrozil
Lovastatin
PSYCHIATRIC MANIFESTATIONS

Delirious or confusional states
Amantadine
Aminophylline
Anticholinergics
Antidepressants
Cimetidine
Digitalis
Glucocorticoids
Isoniazid
Levodopa
Methyldopa
Penicillins
Phenothiazines
Sedatives and hypnotics
Depression
Amphetamine withdrawal
Beta blockers
Centrally acting antihypertensives (reserpine, methyldopa, clonidine)
Glucocorticoids
Levodopa
Drowsiness
Antihistamines
Anxiolytic drugs
Clonidine
Major tranquilizers
Methyldopa
Tricyclic antidepressants
Hallucinatory states
Amantadine
Beta blockers
Levodopa
Meperidine
Narcotics
Pentazocine
Tricyclic antidepressants
Hypomania, mania, or excited reactions
Glucocorticoids
Levodopa
Monoamine oxidase inhibitors
Sympathomimetics
Tricyclic antidepressants
Schizophrenic-like or paranoid reactions
Amphetamines
Bromides
Glucocorticoids
Levodopa
Lysergic acid
Monoamine oxidase inhibitors
Tricyclic antidepressants
Sleep disturbances
Anorexiants
Levodopa
Monoamine oxidase inhibitors
Sympathomimetics

SOURCE: Adapted from AJJ Wood: HPIM-15, pp. 432–436.

Bibliography

For a more detailed discussion, see Wood AJJ: Adverse Reactions to Drugs, Chap. 71, p. 430, in HPIM-15.

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201 NARCOTIC ABUSE

201 NARCOTIC ABUSE
Harrison’s Manual of Medicine

201

NARCOTIC ABUSE

Clinical Features
Bibliography

Narcotics, or opiates, bind to specific opioid receptors in the CNS and elsewhere in the body. These receptors mediate the opiate effects of analgesia, euphoria, respiratory depression, and constipation. Endogenous opiate peptides (enkephalins and endorphins) are natural ligands for the opioid receptors and play a role in analgesia, memory, learning, reward, mood regulation, and stress tolerance.
The prototypic opiates, morphine and codeine, are derived from the juice of the opium poppy, Papaver somniferum. The semisynthetic drugs produced from morphine include hydromorphone (Dilaudid), diacetylmorphine (heroin), and oxycodone. Purely synthetic agents are meperidine (Demerol), propoxyphene (Darvon), and methadone. All of these substances produce analgesia and euphoria as well as physical dependence when taken in high enough doses for prolonged periods of time.
1% of the U.S. population meets criteria for narcotic abuse or dependence at some time in their lives. 70% of narcotic-addicted individuals have another psychiatric disorder (usually major depression, alcoholism, or a personality disorder). Three groups of abusers can be identified: (1) “medical” abusers—pts with chronic pain syndromes who misuse their prescribed analgesics; (2) physicians, nurses, dentists, and pharmacists with easy access to narcotics; and (3) “street” abusers. The street abuser is typically a higher functioning individual who began by using tobacco, alcohol, and marijuana and then moved on to opiates.
Clinical Features
Acutely, all opiates have the following CNS effects: sedation, euphoria, decreased pain perception, decreased respiratory drive, and vomiting. In larger doses, markedly decreased respirations, bradycardia, pupillary miosis, stupor, and coma ensue. Additionally, the adulterants used to “cut” street drugs (quinine, phenacetin, strychnine, antipyrine, caffeine, powdered milk) can produce permanent neurologic damage, including peripheral neuropathy, amblyopia, and myelopathy. The shared use of contaminated needles is a major cause of brain abscesses, acute endocarditis, hepatitis B, AIDS, septic arthritis, and soft tissue infections. At least 25% of street abusers die within 10–20 years of starting active opiate abuse.
Chronic use of opiates will result in tolerance (requiring higher doses to achieve psychotropic effects) and physical dependence. With shorter-acting opiates such as heroin, morphine, or oxycodone, withdrawal signs begin 8–12 h after the last dose, peak at 2–3 days, and subside over 7–10 days. With longer- acting opiates such as methadone, withdrawal begins 2–4 days after the last dose, peaks at 3–4 days, and lasts several weeks.
Withdrawal produces diarrhea, coughing, lacrimation, rhinorrhea, diaphoresis, twitching muscles, piloerection, fever, tachypnea, hypertension, diffuse body pain, insomnia, and yawning. Relief of these exceedingly unpleasant symptoms by narcotic administration leads to more frequent narcotic use. Eventually, all of the person’s efforts are consumed by drug-seeking behavior.

TREATMENT
Overdose High doses of opiates, whether taken in a suicide attempt or accidentally when the potency is misjudged, are frequently lethal. Toxicity occurs immediately after IV administration and with a variable delay after oral ingestion. Symptoms include miosis, shallow respirations, bradycardia, hypothermia, stupor or coma, and pulmonary edema. Treatment requires cardiorespiratory support and administration of the opiate antagonist naloxone (0.4 mg IV repeated in 3–10 min if no or only partial response). Because the effects of naloxone diminish in 2–3 h compared with longer-lasting effects of heroin (up to 24 h) or methadone (up to 72 h), pts must be observed for at least 1–3 days for reappearance of the toxic state.
Withdrawal or Abstinence Syndromes Clonidine is effective in decreasing the sympathetic nervous system hyperactivity observed in opiate withdrawal. Doses of 0.3–0.5 mg/d are used for the 2–3 weeks of the withdrawal period. Although it is highly unpleasant, opiate withdrawal is not physically dangerous or life-threatening per se in adults (unlike alcohol withdrawal). However, withdrawal syndromes in newborns of street abusers are fatal in 3–30% of cases.
Methadone maintenance (to avoid withdrawal or abstinence syndromes) is a widely used treatment strategy in the management of opiate addiction. Long-acting oral methadone is most convenient: 1 mg methadone is equivalent to 3 mg morphine, 1 mg heroin, or 20 mg meperidine. Most patients receive 10–25 mg methadone bid, with higher doses given if withdrawal symptoms break through. Although methadone has mood-elevating effects in some individuals, maintenance nevertheless leads to reduced opiate and nonopiate drug use, reduced criminal behavior, and decreased symptoms of depression.
L-Alpha-acetylmethadol (LAAM) is a long-acting synthetic narcotic that may be given only 3 times a week; however, some pts experience nervousness and stimulation on LAAM. Buprenorphine is a partial receptor agonist that blocks some of the subjective effects of narcotics and may be as effective as low-dose methadone in maintenance treatment.
To help prevent relapses in the abstinent pt, the oral antagonist naltrexone is used in doses of 50–150 mg/d. It blocks the euphoric and analgesic effects of the opiate when a pt relapses and uses narcotics.
Chronic Pain Syndromes   Physicians should avoid encouraging narcotic addiction in pts with established chronic pain syndromes (this is to be distinguished from prescribing adequate analgesia in pts with acute pain). Once tolerance and physical dependence are established in the pt with a chronic pain syndrome, withdrawal and abstinence syndromes will intensify the pt’s pain and confuse the management of an already difficult problem. Pts should be educated that medications will be used to minimize the effects of pain on their physical function but that they will not abolish the pain entirely. Nonpharmacologic approaches to pain management should also be part of the treatment plan.
Identification of the Chronic Narcotic User Blood and urine screens for opiates, or the naloxone challenge test, can be used to identify chronic narcotic users. In the naloxone challenge test, 0.4 mg is given slowly IV over 5 min, and the pt is observed for 1–2 h for signs of withdrawal.
Realistic expectations for rehabilitation are possible only when the pt is motivated to make a long-term commitment to a drug-free lifestyle. Specialized counseling and peer programs, including Narcotics Anonymous, are a mainstay of treatment. In many cases, adjunctive pharmacologic management is helpful, either to block the euphoric effects of opiates or to impede withdrawal/abstinence syndromes (discussed above). Any co-morbid psychiatric diagnoses (the “dual diagnosis” pt) must be evaluated and treated vigorously.
Special issues exist for medical staff. Physicians should never prescribe opiates for themselves or members of their families. Medical organizations need to be prepared to identify and rehabilitate substance-impaired physicians as quickly as possible.

Bibliography

For a more detailed discussion, see Shuckit MA, Segal DS: Opioid Drug Abuse and Dependence, Chap. 388, p. 2567, in HPIM-15.

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200 ALCOHOLISM

200 ALCOHOLISM
Harrison’s Manual of Medicine

200

ALCOHOLISM

Clinical Features
Laboratory Findings
Bibliography

Alcoholism and alcohol abuse are defined by the regular and excessive use of alcohol with concomitant social, occupational, and/or physical problems; alcohol is associated with half of all traffic fatalities and half of all homicides. In alcohol dependence, the regular use of alcohol has resulted in a state of physiologic tolerance and dependence. A pt may never suffer from withdrawal symptoms and still meet criteria for alcohol abuse.
Alcoholism is a multifactorial disorder in which genetic, biologic, and sociocultural factors interact. Typically, the first major life problem from excessive alcohol use appears in early adulthood, followed by periods of exacerbation and remission; the lifespan of the alcoholic is shortened by an average of 15 years due to increased risk of death from heart disease, cancer, accidents, or suicide.
Clinical Features
One out of five of the average physician’s pts will suffer from alcoholism. Routine medical care requires attention to potential alcohol-related illness and to alcoholism itself:

1.
Neurologic—blackouts, seizures, delirium tremens, cerebellar degeneration, neuropathy, myopathy

2.
Gastrointestinal—esophagitis, gastritis, pancreatitis, hepatitis, cirrhosis, GI hemorrhage

3.
Cardiovascular—hypertension, cardiomyopathy

4.
Hematologic—macrocytosis, folate deficiency, thrombocytopenia, leukopenia

5.
Endocrine—gynecomastia, testicular atrophy, amenorrhea, infertility

6.
Skeletal—fractures, osteonecrosis

7.
Cancer—breast cancer, oral and esophageal cancers, rectal cancers.
Most alcoholic pts do not have dramatic physical symptoms but instead present with psychosocial difficulties. Most common are marital difficulties, job problems (tardiness, absenteeism), and legal problems resulting from driving while intoxicated. A positive answer to any of the “CAGE questions” indicates a high probability of alcoholism: Are you . . . Cutting down, or feel the need to? Annoyed when people criticize your drinking? Guilty about your drinking? Eye-opening with a drink in the morning? Typically, pts will describe a host of difficulties but will then deny that they have a problem with alcohol abuse. Denial is a characteristic, if not the core, symptom of alcoholism.
Alcohol is a CNS depressant that acts on receptors for g-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the nervous system. Behavioral, cognitive, and psychomotor changes can occur at blood alcohol levels as low as 4–7 mmol/L (20–30 mg/dL), a level achieved after the ingestion of one or two typical drinks. Mild to moderate intoxication occurs at 17–43 mmol/L (80–200 mg/dL). Incoordination, tremor, ataxia, confusion, stupor, coma, and even death occur at progressively higher blood alcohol levels.
Chronic alcohol use produces CNS dependence. In such individuals, the earliest sign of alcohol withdrawal is tremulousness (“shakes” or “jitters”), which usually occurs 8–24 h after the last drink. This may be followed by generalized seizures (“rum fits”) in the first 24–48 h; these do not require initiation of anti-seizure medications. With severe withdrawal, autonomic hyperactivity ensues (sweating, hypertension, tachycardia, tachypnea, fever), accompanied by insomnia, nightmares, anxiety, and GI symptoms.
Delirium tremens (DTs), which may begin 3–5 days after the last drink, is a very severe withdrawal syndrome characterized by profound autonomic hyperactivity, extreme confusion, agitation, vivid delusions, and hallucinations (often visual and tactile); mortality is 5–15%. Wernicke’s encephalopathy is an alcohol-related syndrome characterized by ataxia, ophthalmoplegia, and confusion, often with associated nystagmus, peripheral neuropathy, cerebellar signs, and hypotension; there is impaired short-term memory, inattention, and emotional lability. Korsakoff’s syndrome follows as the encephalopathy and ocular findings resolve; it is characterized by anterograde and retrograde amnesia and confabulation. Wernicke-Korsakoff’s syndrome is caused by chronic thiamine deficiency, resulting in damage to thalamic nuclei, mamillary bodies, and brainstem and cerebellar structures.
Laboratory Findings
Clues to alcoholism include mild anemia with macrocytosis, folate deficiency, thrombocytopenia, granulocytopenia, abnormal LFTs, hyperuricemia, and elevated triglycerides. Decreases in serum K, Mg, Zn, and PO4 levels are common. Diagnostic studies such as GI radiology or endoscopy, abdominal ultrasound or CT, liver-spleen scan, liver biopsy, ECG, echocardiogram, brain CT or MRI, EEG, and nerve conduction studies may show evidence of alcohol-related organ dysfunction.

TREATMENT
Acute Withdrawal Acute alcohol withdrawal is treated with thiamine (50–100 mg IV or 100 mg PO daily for 5 d) to replenish depleted stores; if Wernicke-Korsakoff’s syndrome is suspected, the IV route must be used, since intestinal absorption is unreliable in alcoholics. CNS depressant drugs that enhance GABA-mediated inhibition are used when seizures or autonomic hyperactivity are present. These drugs halt the rapid state of withdrawal in the CNS and allow for a slower, more controlled reduction of the substance. Low-potency benzodiazepines with long half-lives are the medication of choice (e.g., diazepam, chlordiazepoxide), because they produce fairly steady blood levels of drug and there is a wide dose range within which to work. These benefits must be weighed against the risk of overmedication and oversedation, which occur less commonly with shorter-acting agents (e.g. oxazepam, lorazepam). Typical doses are diazepam 5–10 mg or chlordiazepoxide 25–50 mg PO every 1–4 h prn objective signs of alcohol withdrawal (such as pulse < 90). Extremely high doses are sometimes required for the chronic alcoholic.
In severe withdrawal or DTs, the physician must also look for evidence of trauma or infection that may be masked by prominent withdrawal symptoms or that contribute to the pt’s debilitated state. Fluid and electrolyte status and blood glucose levels should be closely followed as well. Cardiovascular and hemodynamic monitoring are crucial, as hemodynamic collapse and cardiac arrhythmia are not uncommon.
Recovery and Sobriety The definitive treatment of alcoholism requires a successful confrontation of the pt’s denial, followed by the pt’s motivation to change. It may take multiple encounters between physician and pt over a period of years for a pt to achieve this level of motivation. Once pts commit to treatment, an initial stage of recovery (early abstinence) is followed by ongoing sobriety. The physician should counsel the pt about the need for continued abstinence as a primary treatment goal and about the usefulness of regular participation in self-help resources such as AA (and Alanon for family members).
Once sobriety has been achieved, pts should be evaluated for the presence of any other underlying psychiatric disorder (such as major depression) and vigorously treated. The physician should also recognize the relapsing/remitting nature of alcoholism, and be prepared to help pts reenter treatment periodically.
Disulfiram (Antabuse), a drug that inhibits aldehyde dehydrogenase and results in toxic symptoms (nausea, vomiting, diarrhea, tremor) if the pt consumes alcohol, is used in some centers but is not an effective therapy in the absence of psychosocial intervention. Preliminary studies show that naltrexone and acamprosate may reduce recidivism in abstinent alcoholics.

Bibliography

For a more detailed discussion, see Schuckit MA: Alcohol and Alcoholism, Chap. 387, p. 2561, in HPIM-15.

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199 PSYCHIATRIC MEDICATIONS

199 PSYCHIATRIC MEDICATIONS
Harrison’s Manual of Medicine

199

PSYCHIATRIC MEDICATIONS

General Principles of Use

Antidepressants
Anxiolytics
Antipsychotic Medications
Mood-Stabilizing Agents
Bibliography

Four major classes of psychiatric medications are commonly used in adults: (1) antidepressants, (2) anxiolytics, (3) antipsychotics, and (4) mood stabilizing agents. Nonpsychiatric physicians should become familiar with one or two drugs in each of the first three classes so that the indications, dose range, efficacy, potential side effects, and interactions with other medications are well known.
GENERAL PRINCIPLES OF USE

1.
Most treatment failures are due to undermedication and impatience. For a proper medication trial to take place, an effective dose must be taken for an adequate amount of time. For antidepressants, antipsychotics, and mood stabilizers, full effects may take weeks or months to occur.

2.
History of a positive response to a medication usually indicates that a response to the same drug will occur again. A family history of a positive response to a specific medication is also useful.

3.
Pts who fail to respond to one drug will often respond to another in the same class; one should attempt another trial with a drug that has a different mechanism of action or a different chemical structure. Treatment failures should be referred to a psychiatrist, as should all pts with psychotic symptoms or who require mood stabilizers.

4.
Avoid polypharmacy; a pt who is not responding to standard monotherapy requires referral to a psychiatrist.

5.
Pharmacokinetics may be altered in the elderly, with smaller volumes of distribution, reduced renal and hepatic clearance, longer biologic half-lives, and greater potential for CNS toxicity. The rule with elderly pts is to “start low and go slow.”

6.
Never stop treatment abruptly; especially true for antidepressants and anxiolytics. In general, medications should be slowly tapered and discontinued over 2–4 weeks.

7.
Review possible side effects each time a drug is prescribed; educate pts and family members about side effects and need for patience in awaiting a response.
Antidepressants
Useful to group according to known actions on CNS monoaminergic systems (Table 199-1). The selective serotonin reuptake inhibitors (SSRIs) have predominant effects on serotonergic neurotransmission, also reflected in side effect profile. The TCAs, or tricyclic antidepressants (ADs), affect noradrenergic and, to a lesser extent, serotonergic neurotransmission but also have anticholinergic and antihistaminic effects. Venlafaxine and mirtazapine have relatively “pure” noradrenergic and serotonergic effects. Bupropion has dopamine reuptake inhibitor properties. Trazodone and nefazodone have mixed effects on serotonin receptors and on other neurotransmitter systems. The MAOIs inhibit monoamine oxidase, the primary enzyme responsible for the degradation of monoamines in the synaptic cleft.

Table 199-1 Antidepressants

ADs are effective against major depression, particularly when neurovegetative symptoms and signs are present. In very severe depression with many endogenous features, TCAs or MAOIs are more efficacious than SSRIs. ADs are also useful in treatment of panic disorder, posttraumatic stress disorder, chronic pain syndromes, and generalized anxiety disorder. The SSRIs and the TCA clomipramine successfully treat obsessive-compulsive disorder.
All ADs require at least 2 weeks at a therapeutic dose before clinical improvement is observed. All ADs also have the potential to trigger a manic episode or rapid cycling when given to a pt with bipolar disorder. The MAOIs must not be prescribed concurrently with other ADs or with narcotics, as potentially fatal reactions may occur. “Withdrawal syndromes” usually consisting of malaise can occur when ADs are stopped abruptly.
ANXIOLYTICS
Antianxiety agents include the benzodiazepines and the nonbenzodiazepine buspirone.
Benzodiazepines bind to stereospecific sites on the g-aminobutyric acid receptor and are cross-tolerant with alcohol and with barbiturates. Four clinical properties: (1) sedative, (2) anxiolytic, (3) skeletal muscle relaxant, and (4) antiepileptic. Individual drugs differ in terms of potency, onset of action, duration of action (related to half-life and presence of active metabolites), and metabolism (Table 199-2). Benzodiazepines have additive effects with alcohol; like alcohol, they can produce tolerance and physiologic dependence, with serious withdrawal syndromes (tremors, seizures, delirium, and autonomic hyperactivity) if discontinued too quickly, especially for those with short half- lives.

Table 199-2 Anxiolytics

Buspirone is an anxiolytic that is nonsedating, is not cross-tolerant with alcohol, and does not induce tolerance or dependence. It acts via serotonergic pathways and requires at least 2 weeks at therapeutic doses to achieve full effects.
ANTIPSYCHOTIC MEDICATIONS
These include the typical (or conventional) neuroleptics, which act by blocking dopamine D2 receptors, and the atypical (or novel) neuroleptics, which act on dopamine, serotonin, and other neuroreceptor systems. Some antipsychotic effect may occur within hours or days of initiating treatment, but full effects usually require 6 weeks to several months of daily, therapeutic dosing.
CONVENTIONAL ANTIPSYCHOTICS   Useful to group into high-, mid-, and low-potency neuroleptics (Table 199-3). High-potency neuroleptics are least sedating, have almost no anticholinergic side effects, and have a strong tendency to induce extrapyramidal side effects (EPSEs) secondary to dopamine receptor blockade. The EPSEs occur within several hours to several weeks of beginning treatment and include acute dystonias, akathisia, and pseudo-parkinsonism. They are treated by judicious dose reduction and by use of anticholinergic and dopamine agonist medications. Low-potency neuroleptics are very sedating, may cause orthostasis, are anticholinergic, and therefore tend not to induce EPSEs. Mid-potency agents are best tolerated by the average pt.

Table 199-3 Antipsychotic Agents

10–20% of pts treated with conventional antipsychotic agents for >1 year develop tardive dyskinesia (probably due to dopamine receptor supersensitivity), an abnormal involuntary movement disorder most often observed in the face and distal extremities. Treatment includes gradual withdrawal of the neuroleptic, with possible switch to a novel neuroleptic; anticholinergic agents can worsen the disorder.
1–2% of pts exposed to neuroleptics develop neuroleptic malignant syndrome (NMS), a life-threatening complication with a mortality rate as high as 25%; hyperpyrexia, autonomic hyperactivity, muscle rigidity, obtundation, and agitation are characteristic, associated with increased WBC, increased CPK, and myoglobinuria. Treatment involves immediate discontinuation of neuroleptics, supportive care, and use of dantrolene and bromocriptine.
NOVEL ANTIPSYCHOTICS   A new class of agents that has become the first line of treatment (Table 199-3); efficacious in treatment-resistant pts, tend not to induce EPSEs or tardive dyskinesia, and appear to have uniquely beneficial properties on negative symptoms and cognitive dysfunction. Main problem is side effect of weight gain (most prominent in clozapine and in olanzapine; can induce onset of diabetes mellitus).
MOOD-STABILIZING AGENTS
Three mood stabilizers in common use: lithium, carbamazepine, and valproic acid or divalproex sodium. Three additional mood stabilizers being increasingly used: gabapentin, lamotrigine, topiramate (Table 199-4). Lithium is the “gold standard” and the best studied, and along with carbamazepine and valproic acid, is used for treatment of acute manic episodes; 1–2 weeks to reach full effect. As prophylaxis, the mood stabilizers reduce frequency and severity of both manic and depressed episodes in cyclical mood disorders. Believed to work at various sites of gaba-ergic and glutamenergic neurotransmission and second- messenger signal transduction systems in the CNS. In refractory bipolar disorder, combinations of mood stabilizers are often beneficial.

Table 199-4 Mood-stabilizing Agents

Bibliography

For a more detailed discussion, see Reus VI: Mental Disorders, Chap. 385, p. 2542, in HPIM-15.

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198 APPROACH TO THE PATIENT WITH PSYCHIATRIC SYMPTOMS

198 APPROACH TO THE PATIENT WITH PSYCHIATRIC SYMPTOMS
Harrison’s Manual of Medicine

198

APPROACH TO THE PATIENT WITH PSYCHIATRIC SYMPTOMS

Major Psychiatric Disorders (Axis I Diagnoses)

Mood Disorders (Major Affective Disorders)

Schizophrenia and Other Psychotic Disorders

Anxiety Disorders
Personality Disorders (Axis Ii Diagnoses)

Cluster A Personality Disorders

Cluster B Personality Disorders

Cluster C Personality Disorders
Bibliography

Disorders of mood, thinking and behavior may be due to a primary psychiatric diagnosis (DSM-IV* Axis I major psychiatric disorders) or a personality disorder (DSM-IV Axis II disorders) or may be secondary to metabolic abnormalities, drug toxicities, focal cerebral lesions, seizure disorders, or degenerative neurologic disease. Any pt presenting with new onset of psychiatric symptoms must be evaluated for underlying psychoactive substance abuse and/ or medical or neurologic illness. Specific psychiatric medications are discussed in Chap. 199. The DSM-IV-PC (Primary Care) Manual provides a synopsis of mental disorders commonly seen in medical practice.
MAJOR PSYCHIATRIC DISORDERS (AXIS I DIAGNOSES)
Mood Disorders (Major Affective Disorders)
MAJOR DEPRESSION   Clinical Features   Affects 15% of the general population at some point in life and extracts high disability and societal cost. Diagnosis is made when a depressed/irritable mood or a lack of normal interest/ pleasure exists for at least 2 weeks, in combination with four or more of the following symptoms: (1) change in appetite plus change in weight; (2) insomnia or hypersomnia; (3) fatigue or loss of energy; (4) motor agitation or retardation; (5) feelings of worthlessness, self-reproach, or guilt; (6) decreased ability to concentrate and make decisions; (7) recurrent thoughts of death or suicide. A small number of pts with major depression will have psychotic symptoms— hallucinations and delusions—with their depressed mood; many present with a “masked depression,” unable to describe their psychological distress but with multiple diffuse somatic complaints.
Onset of a first depressive episode is typically in the thirties or forties, although major depression is found in children and adolescents as well as geriatric pts. Untreated episodes generally resolve spontaneously in 5–9 months; however, a sizeable number of pts suffer from chronic, unremitting depression or from partial treatment response. Half of all pts experiencing a first depressive episode will go on to a recurrent course, with a second episode occurring within 2 years. Untreated or partially treated episodes put the pt at risk for future problems with mood disorder. A family history of mood disorder is common and tends to predict a recurrent course. Major depression can also be the initial presentation of bipolar disorder (manic depressive illness).
Suicide   Most suicides occur in pts with a mood disorder, and many pts seek contact with a physician prior to their suicide attempt. Physicians must always inquire about suicide when evaluating a pt with depression. Features that place a pt at high risk for suicidal behavior include: (1) a formulated plan and a method, as well as an intent; (2) prior attempts; (3) concomitant alcohol or other psychoactive substance use; (4) psychotic symptoms; (5) older age; (6) male gender; (7) Caucasian; (8) social isolation; (9) serious medical illness; (10) recent loss and/or profound hopelessness.

TREATMENT
Pts with suicidal ideation require treatment by a psychiatrist and may require hospitalization. Most other pts with an uncomplicated unipolar major depression (a major depression that is not part of a cyclical mood disorder, such as a bipolar disorder) can be successfully treated by a nonpsychiatric physician. Vigorous intervention and successful treatment appear to decrease the risk of future relapse. Pts who do not respond fully to standard treatment should be referred to a psychiatrist.
Antidepressant medication is the mainstay of treatment; symptoms are ameliorated after 2–6 weeks at a therapeutic dose. Antidepressants should be continued for 9–12 months, then tapered slowly. Pts must be monitored carefully after termination of treatment since relapse is common. The combination of pharmacotherapy with psychotherapy [usually cognitive-behavioral therapy (CBT) or interpersonal therapy (IPT)] produces better and longer-lasting results than drug therapy alone. Electroconvulsive therapy is generally reserved for pts with life-threatening depression unresponsive to medication or for pts in whom the use of antidepressants is medically contraindicated.

BIPOLAR DISORDER (MANIC DEPRESSIVE ILLNESS)   Clinical Features   A cyclical mood disorder in which episodes of major depression are interspersed with episodes of mania or hypomania; 1–2% of the population is affected. Most pts initially present with a manic episode in adolescence or young adulthood, but 20% present with a major depression. Antidepressant therapy is usually contraindicated in pts with a cyclical mood disorder because it may provoke a manic episode or make the cycles between mania and depression more frequent and more intense (“rapid cycling”). Pts with a major depressive episode and a prior history of “highs” (mania or hypomania—which can be pleasant/euphoric or irritable/impulsive) and/or a family history of bipolar disorder should not be treated with antidepressants but must be referred promptly to a psychiatrist.
With mania, an elevated, expansive mood, irritability, angry outbursts, and impulsivity are characteristic. Specific symptoms include: (1) increased motor activity and restlessness; (2) unusual talkativeness; (3) flight of ideas and racing thoughts; (4) inflated self-esteem that can become delusional; (5) decreased need for sleep (often the first feature of an incipient manic episode); (6) decreased appetite; (7) distractability; (8) excessive involvement in risky activities (buying sprees, sexual indiscretions). Pts with full-blown mania can become psychotic. Hypomania is characterized by attenuated manic symptoms and is greatly underdiagnosed, especially in nonpsychiatric settings. “Mixed episodes,” where both depressive and manic or hypomanic symptoms co-exist simultaneously, are also underrecognized and misdiagnosed.
Untreated, a manic or depressive episode typically lasts for 1–3 months, with cycles of 1–2 episodes per year. Risk for manic episodes increases in the spring and fall. Variants of bipolar disorder include rapid and ultrarapid cycling (manic and depressed episodes occurring at cycles of weeks, days, or hours). In many pts, especially females, antidepressants trigger rapid cycling and worsen the course of illness. Pts with bipolar disorder are at risk for psychoactive substance use, especially alcohol abuse, and for medical consequences of risky sexual behavior (STDs).
Bipolar disorder has a strong genetic component. Pts with bipolar disorder are vulnerable to sleep deprivation, to changes in the photoperiod, and to the effects of jet lag.

TREATMENT
Bipolar disorder is a serious, chronic illness that requires lifelong monitoring by a psychiatrist. Acutely manic pts often require hospitalization to reduce environmental stimulation and to protect themselves and others from the consequences of their reckless behavior. Mood stabilizers (lithium, carbamazepine, valproic acid, gabapentin, lamotrigine, topiramate) are effective treatment and are used for the resolution of acute episodes and for prophylaxis of future episodes. Antipsychotic medication, benzodiazepines, and antidepressants such as buproprion may be part of the treatment regimen. As in unipolar depression, rapid therapeutic intervention may decrease the risk of future relapse.

Schizophrenia and Other Psychotic Disorders
SCHIZOPHRENIA   Clinical Features   Occurs in 1% of the population worldwide; 30–40% of the homeless are affected. Characterized by a waxing and waning vulnerability to psychosis, i.e., an impaired ability to monitor reality, resulting in altered mood, thinking, language, perceptions, behavior, and interpersonal interactions. Pts usually present between late adolescence and the third decade, often after an insidious premorbid course of subtle psychosocial difficulties. Core psychotic features last ³6 months and include: (1) delusions, which can be paranoid, jealous, somatic, grandiose, religious, nihilistic, or simply bizarre; (2) hallucinations, often auditory hallucinations of a voice or voices maintaining a running commentary; (3) disorders of language and thinking: incoherence, loosening of associations, tangentiality, illogical thinking; (4) inappropriate affect and bizarre, catatonic, or grossly disorganized behavior.
Many pts stabilize after the first 5 years of illness. 30–40% show a deteriorating course, but at least 25% do well, especially with early intervention. Females tend to have a later age of onset and a more benign course than males. Comorbid substance abuse is common, especially of nicotine, alcohol, and stimulants.

TREATMENT
Hospitalization is required for acutely psychotic pts, especially those with violent command hallucinations, who may be dangerous to themselves or others. Conventional antipsychotic medications are effective against hallucinations, agitation, and thought disorder (the so-called positive symptoms) in 60% of pts but are often less useful for apathy, blunted affect, social isolation, and anhedonia (negative symptoms). The novel antipsychotic medications—clozapine, risperidone, olanzapine, quetiapine, and others—have become the mainstay of treatment as they are helpful in pts unresponsive to conventional neuroleptics and may also be useful for negative and cognitive symptoms. Long-acting injectable forms of haloperidol and fluphenazine are ideal for noncompliant pts. Psychosocial intervention, rehabilitation, and family support are also essential.

OTHER PSYCHOTIC DISORDERS   These include schizoaffective disorder (where symptoms of chronic psychosis are interspersed with major mood episodes) and delusional disorders (in which a fixed, unshakable delusional belief is held in the absence of the other stigmata of schizophrenia). Pts with somatic delusions can be especially difficult to diagnose; they may become violent towards the physician if they feel misunderstood or thwarted and they almost always resist referral to a psychiatrist.
Anxiety Disorders
Characterized by severe, persistent anxiety or sense of dread in the absence of psychosis or a severe change in mood. Most prevalent psychiatric illness seen in the community; present in 15–20% of medical clinic patients.
PANIC DISORDER   Occurs in 1–2% of the population; female:male ratio of 2:1. Familial aggregation may occur. Onset in second or third decade. Initial presentation is almost always to a nonpsychiatric physician, frequently in the ER, as a possible heart attack or serious respiratory problem. The disorder is often initially unrecognized or misdiagnosed. Prompt diagnosis and treatment can greatly reduce morbidity.
Clinical Features   Characterized by panic attacks, which are sudden, unexpected, overwhelming paroxysms of terror and apprehension with multiple associated somatic symptoms. Attacks usually last 10–20 min, then slowly resolve spontaneously. Diagnostic criteria for panic disorder require four or more panic attacks within 4 weeks occurring in nonthreatening or nonexertional settings, and attacks must be accompanied by at least four of the following: dyspnea, palpitations, chest pain or discomfort, choking/smothering feelings, dizziness/vertigo/unsteady feelings, feelings of unreality, paresthesia, hot and cold flashes, sweating, faintness, trembling, and fear of dying, going crazy, or doing something uncontrolled during an attack. Panic disorder is often associated with a concomitant major depression.
When the disorder goes unrecognized and untreated, pts often experience significant morbidity: they become afraid of leaving home and may develop anticipatory anxiety, agoraphobia, and other spreading phobias; many turn to self-medication with alcohol or benzodiazepines.
Panic disorder must be differentiated from cardiovascular and respiratory disorders. Conditions that may mimic or worsen panic attacks include hyper- and hypothyroidism, pheochromocytoma, complex partial seizures, hypoglycemia, drug ingestions (amphetamines, cocaine, caffeine, sympathomimetic nasal decongestants), and drug withdrawal (alcohol, barbiturates, opiates, minor tranquilizers).

TREATMENT
Cognitive-behavioral psychotherapy (identifying and aborting panic attacks through relaxation and breathing techniques)—either alone or combined with medication—is highly effective. Selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and monoamine oxidase inhibitors all treat the disorder and prevent spontaneous attacks. Clonazepam, lorazepam, or other benzodiazepines may be used in the short term while waiting for antidepressants to take effect (2–3 weeks).

GENERALIZED ANXIETY DISORDER (GAD)   Characterized by persistent, chronic anxiety but without the specific symptoms of phobic, panic, or obsessive-compulsive disorders; occurs in 2–3% of the population.
Clinical Features   Pts experience persistent motor hyperactivity (shakiness, trembling, restlessness, easy startle), autonomic hyperactivity, apprehensive expectation (anxiety, fear, rumination, anticipation of misfortune, etc.), and vigilance (distractability, poor concentration, insomnia, impatience, and irritability). These symptoms are chronic and pervasive, rather than situational. Secondary depression is common.

TREATMENT
Benzodiazepines are the initial agents of choice when generalized anxiety is severe and acute enough to warrant drug therapy. A trial of an SSRI antidepressant should then be started as many pts will experience significant relief with this class of medications. Physicians must be alert to psychological and physical dependence on benzodiazepines. A subgroup of pts respond to buspirone, a nonbenzodiazepine anxiolytic. Psychotherapy and relaxation training can be useful.

OBSESSIVE-COMPULSIVE DISORDER (OCD)   A severe disorder present in 4–6% of the population and characterized by recurrent obsessions (persistent intrusive thoughts) and compulsions (repetitive behaviors) that the pt experiences as involuntary, senseless, or repugnant. Pts are often ashamed of their symptoms and only seek help after they have become debilitated.
Clinical Features   Common obsessions include thoughts of violence (such as killing a loved one), obsessive slowness for fear of making a mistake, fears of germs or contamination, and excessive doubt or uncertainty. Examples of compulsions include repeated checking to be assured that something was done properly, hand washing, extreme neatness and ordering behavior, and counting rituals, such as numbering one’s steps while walking.
Onset is usually in adolescence, with 65% of cases manifest before age 25. It is more common in males and in first-born children. In families of OCD patients, an increased incidence of both OCD and Tourette’s syndrome is found. The course of OCD is usually episodic with periods of incomplete remission. Pts with severe disease may become completely housebound. Major depression, substance abuse, and social impairment are common.

TREATMENT
Clomipramine and the SSRIs are highly effective. A combination of drug therapy and CBT is most effective for the majority of pts. Education and referral to a national support organization is also useful.

POSTTRAUMATIC STRESS DISORDER (PTSD)   Occurs in a subgroup of individuals exposed to a severe life-threatening trauma. Predisposing factors include a prior history of traumatization and/or a diathesis toward anxiety responses. Early psychological intervention following a traumatic event may reduce the risk for chronic PTSD.
Clinical Features   Three core sets of symptoms: (1) reexperiencing, where the pt unwillingly reexperiences the trauma through recurrent intrusive recollections, recurrent dreams, or by suddenly feeling as if the traumatic event is recurring; (2) avoidance and numbing, where the pt experiences reduced responsiveness to, and involvement with, the external world, a sense of a foreshortened future, and avoidance of activities that arouse recollection of the traumatic event; (3) arousal, characterized by hypervigilance, hyperalertness, an exaggerated startle response, sleep disturbance, guilt about having survived when others have not or about behavior required for survival, memory impairment or trouble concentrating, and intensification of symptoms by exposure to events that symbolize or resemble the traumatic event. Comorbid substance abuse and other mood and anxiety disorders are common. This disorder is extremely debilitating, particularly as it becomes chronic and affects psychosocial functioning. Most pts require referral to a psychiatrist for ongoing care.

TREATMENT
Medications used with varying success include a combination of an SSRI and trazodone, 50–200 mg qhs for sleep; tricyclic antidepressants; and mood stabilizers. Group psychotherapy (with other trauma survivors), alone or with individual psychotherapy, is useful.

PHOBIC DISORDERS   Clinical Features   Recurring, irrational fears of specific objects, activities, or situations, with subsequent avoidance behavior of the phobic stimulus. Diagnosis is made only when the avoidance behavior is a significant source of distress or interferes with social or occupational functioning.
1.   Agoraphobia: Fear of being in public places. May occur in absence of panic disorder, but is almost invariably preceded by that condition.
2.   Social phobia: Persistent irrational fear of, and need to avoid, any situation where there is risk of scrutiny by others, with potential for embarassment or humiliation. Common examples include excessive fear of public speaking and excessive fear of social engagements.
3.   Simple phobias: Persistent irrational fears and avoidance of specific objects. Common examples include fear of heights (acrophobia), closed spaces (claustrophobia), and animals.

TREATMENT
Agoraphobia is treated as for panic disorder. SSRIs are very helpful in treating social phobias. Social and simple phobias respond well to CBT and relaxation techniques and to systematic desensitization and exposure treatment.

SOMATOFORM DISORDERS   Clinical Features   Pts with multiple somatic complaints that cannot be explained by a known medical condition or by the effects of substances; seen commonly in primary care practice (prevalence of 5%). In somatization disorder, the pt presents with multiple physical complaints referable to different organ systems. Onset is before age 30, and the disorder is persistent; pts with somatization disorder can be impulsive and demanding. In conversion disorder, the symptoms involve voluntary motor or sensory function. In hypochondriasis, the pt believes there is a serious medical illness, despite reassurance and appropriate medical evaluation. As with somatization disorder, these pts have a history of poor relationships with physicians due to their sense that they have not received adequate evaluation. Hypochondriasis can be disabling and show a waxing and waning course. In factitious illnesses, the pt consciously and voluntarily produces physical symptoms; the sick role is gratifying. Munchausen’s syndrome refers to individuals with dramatic, chronic, or severe factitious illness. A variety of signs, symptoms, and diseases have been simulated in factitious illnesses; most common are chronic diarrhea, fever of unknown origin, intestinal bleeding, hematuria, seizures, hypoglycemia. In malingering, the fabrication of illness derives from a desire for an external gain (narcotics, disability).

TREATMENT
Pts with somatoform disorders are usually subjected to multiple diagnostic tests and exploratory surgeries in an attempt to find their “real” illness. This approach is doomed to failure. Successful treatment is achieved through behavior modification, in which access to the physician is adjusted to provide a consistent, sustained, and predictable level of support that is not contingent on the pt’s level of presenting symptoms or distress. Visits are brief, supportive, and structured and are not associated with a need for diagnostic or treatment action. Pts often benefit from antidepressant treatment. Consultation with a psychiatrist is essential.

PERSONALITY DISORDERS (AXIS II DIAGNOSES)
Defined as an inappropriate, stereotyped, maladaptive use of a certain set of psychological characteristics; affects 5–15% of the general population. The pattern of behavior is enduring and affects the person’s relationships and ability to function satisfactorily in life.
Comorbid Axis I diagnosis is common, as is a psychoactive substance use disorder. In medical and surgical settings, pts with personality disorders often become engaged in hostile, manipulative, or unproductive relationships with their physicians. Long-term psychotherapy is beneficial for pts who are motivated to change. Antidepressants and antipsychotic medications can be helpful, particularly for episodes of decompensation, but should be prescribed in consultation with a psychiatrist as misdiagnosis is common.
DSM-IV describes three major categories of personality disorders; pts usually present with a combination of features.
Cluster A Personality Disorders
Affected pts are often characterized as “wild” or “mad.” The paranoid personality is suspicious, hypersensitive, guarded, hostile, and can occasionally become threatening or dangerous. The schizoid personality is interpersonally isolated, cold, and indifferent, while the schizotypal personality is eccentric and superstitious, with magical thinking and unusual beliefs resembling schizophrenia.
Cluster B Personality Disorders
Patients with these disorders are often “wild” or “bad.” The borderline personality is impulsive and manipulative, with unpredictable and fluctuating intense moods and unstable relationships, a fear of abandonment, and occasional rageful micropsychotic episodes. The histrionic pt is dramatic, engaging, seductive, and attention-seeking. The narcissistic pt is self-centered and has an inflated sense of self-importance combined with a tendency to devalue or demean others, while pts with antisocial personality disorder use other people to achieve their own ends and engage in exploitative and manipulative behavior with no sense of remorse. Some aspects of the Cluster B personality disorders appear related to mood disorders.
Cluster C Personality Disorders
Patients with these disorders are often “whiny” or “sad.” The dependent pt fears separation, tries to engage others to assume responsibility, and often has a help- rejecting style. Pts with compulsive personality disorder are meticulous and perfectionistic but also inflexible and indecisive, while those who are passive- aggressive request help, appear compliant on the surface, but undo or resist all efforts aimed at change. Avoidant pts are anxious about social contact and have difficulty assuming responsibility for their isolation. The personality disorders share some features with the anxiety disorders

* Diagnostic and Statistical Manual, Fourth Edition, American Psychiatric Association
Bibliography

For a more detailed discussion, see Reus VI: Mental Disorders, Chap. 385, p. 2542, in HPIM-15.

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197 MUSCLE DISEASES
Harrison’s Manual of Medicine

197

MUSCLE DISEASES

Muscular Dystrophies

Duchenne Dystrophy

Myotonic Dystrophy

Facioscapulohumeral Dystrophy

Limb-Girdle Dystrophy

Oculopharyngeal Dystrophy (Progressive External Ophthalmoplegia)
Inflammatory Myopathies
Metabolic Myopathies
Mitochondrial Myopathies
Periodic Paralyses
Miscellaneous Disorders
Bibliography

Muscle diseases usually present as intermittent or persistent weakness. These disorders are usually painless; however, myalgias, or muscle pains, may occur. Myalgias must be distinguished from muscle cramps, i.e., painful muscle contractions, usually due to neurogenic disorders. A muscle contracture due to an inability to relax after an active muscle contraction is associated with energy failure in glycolytic disorders. Myotonia is a condition of prolonged muscle contraction followed by slow muscle relaxation. It is important to distinguish between true muscle weakness and a complaint of fatigue; fatigue without abnormal clinical or laboratory findings almost never indicates a true muscle disorder. An approach to pts with muscle weakness is summarized in Fig. 197-1 and Fig. 197-2.

FIGURE 197-1. Diagnostic evaluation for intermittent weakness. EOMs, extraocular muscles; AChR AB, acetylcholine receptor antibody; PP, periodic paralysis, CPT, carnitine palmityl transferase; MG, myasthenia gravis.

FIGURE 197-2. Diagnostic evaluation for persistent weakness. EOM, extraocular muscle; OPMD, oculopharyngeal muscular dystrophy; FSHD, facioscapulohumeral muscular dystrophy; IBM, inclusion body myositis; DM, dermatomyositis; PM, polymyositis; MG, myasthenia gravis, ALS, amyotrophic lateral sclerosis; CK, creatine kinase.

MUSCULAR DYSTROPHIES
A group of inherited, progressive degenerations of muscle that vary widely in their clinical and pathologic features and mode of inheritance.
Duchenne Dystrophy
X-linked recessive mutation of the dystrophin gene that affects males almost exclusively. Onset is by age 5; symmetric and progressive weakness in hip and shoulder girdle muscles leading to difficulty in climbing, running, jumping, hopping, etc. By age 8–10, most children require leg braces; by age 12, the majority are nonambulatory. Survival beyond age 25 is rare. Becker dystrophy is a less severe form, with a slower course and later age of onset (5–15) but similar clinical, laboratory, and genetic features.
Associated problems include tendon and muscle contractures (e.g., heel cords), progressive kyphoscoliosis, impaired pulmonary function, cardiomyopathy, and intellectual impairment. Palpable enlargement and firmness of some muscles (e.g., calves) results initially from hypertrophy and later from replacement of muscle by fat and connective tissue.
Laboratory Findings   Include massive elevations (20–100 × normal) of muscle enzymes (CK, aldolase), a myopathic pattern on EMG testing, and evidence of groups of necrotic muscle fibers with regeneration, phagocytosis, and fatty replacement of muscle on biopsy. Diagnosis is established by determination of dystrophin in muscle tissue by western blot and/or immunochemical staining. Mutations in the dystrophin gene can be identified in approximately two-thirds of pts using a battery of cDNA probes. ECG abnormalities (increased net RS in V1, deep Q in precordial leads) reflect the presence of cardiomyopathy. Serum CK is elevated in 50% of female carriers. Testing is now available for detecting carriers and prenatal diagnosis.

TREATMENT
Glucocorticoids [prednisone, 0.75 (mg/kg)/d] may significantly alter progression of disease for up to 3 years, but complications of chronic use often outweigh the benefits. Passive stretching of muscles, tenotomy, bracing, physiotherapy, mechanical assistance devices, and avoidance of prolonged immobility provide symptomatic benefit.

Myotonic Dystrophy
The most common adult muscular dystrophy. Autosomal dominant with genetic anticipation. Weakness typically becomes obvious in the second to third decade and initially involves the muscles of the face, neck, and distal extremities. This results in a distinctive facial appearance (“hatchet face”) characterized by ptosis, temporal wasting, drooping of the lower lip, and sagging of the jaw. Myotonia manifests as a peculiar inability to relax muscles rapidly following a strong exertion (e.g., after tight hand grip), as well as by sustained contraction of muscles following percussion (e.g., of tongue or thenar eminence).
Associated problems can include frontal baldness, posterior subcapsular cataracts, gonadal atrophy, respiratory and cardiac problems, endocrine abnormalities, intellectual impairment, and hypersomnia. Cardiac complications, including complete heart block, may be life-threatening. Respiratory function should be carefully followed, as chronic hypoxia may lead to cor pulmonale.
Laboratory Studies   Normal or mildly elevated CK, characteristic myotonia and myopathic features on EMG, and a typical pattern of muscle fiber injury on biopsy, including selective type I fiber atrophy. Pts have an unstable region of DNA with an increased number of trinucleotide CTG repeats at chromosome location 19q13.3. The expanded repeat may alter expression of a nearby protein kinase gene. Genetic testing for early detection and prenatal diagnosis is possible.

TREATMENT
Phenytoin, procainamide, and quinine may help myotonia, but they must be used carefully in pts with heart disease as they may worsen cardiac conduction. Pacemaker insertion may be required for syncope or heart block. Orthoses may control foot drop, stabilize the ankle, and decrease falling.

Facioscapulohumeral Dystrophy
An autosomal dominant, slowly progressive disorder with onset in the third to fourth decade. Weakness involves facial, shoulder girdle, and proximal arm muscles and can result in atrophy of biceps, triceps, scapular winging, and slope shoulders. Facial weakness results in inability to whistle and loss of facial expressivity. Foot drop and leg weakness may cause falls and progressive difficulty with ambulation.
Laboratory Studies   Normal or slightly elevated CK and mixed myopathic- neuropathic features on EMG and muscle biopsy. Pts have deletions at chromosome 4q35. A genetic probe can be used in carrier detection and prenatal diagnosis. Orthoses and other stabilization procedures may be of benefit for selected pts.
Limb-Girdle Dystrophy
A constellation of diseases with proximal muscle weakness involving the arms and legs as the core symptom. Age of onset, rate of progression, severity of manifestations, inheritance pattern (autosomal dominant or autosomal recessive) and associated complications (e.g., cardiac, respiratory) vary with the specific subtype of disease. Laboratory findings include elevated CK and myopathic features on EMG and muscle biopsy. At least eight autosomal recessive forms have been identified by molecular genetic analysis.
Oculopharyngeal Dystrophy (Progressive External Ophthalmoplegia)
Onset in the fifth to sixth decade of ptosis, limitation of extraocular movements, and facial and cricopharyngeal weakness. Most patients are Hispanic or of French-Canadian descent.
INFLAMMATORY MYOPATHIES
The most common group of acquired and potentially treatable skeletal muscle disorders. Three major forms: polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). Usually present as progressive and symmetric muscle weakness; extraocular muscles spared but pharyngeal weakness and neck drop common. IBM is characterized by early involvement of quadriceps and distal muscles. Progression is over weeks or months in PM and DM, but typically over years in IBM. Skin involvement in DM may consist of a heliotrope rash (blue-purple discoloration) on the upper eyelids with edema, a flat red rash on the face and upper trunk, or erythema over knuckles. A variety of cancers, including ovarian, breast, melanoma, and colon cancer, are associated with DM. Diagnostic criteria are summarized in Table 197-1.

Table 197-1 Criteria for Definite Diagnosis of Inflammatory Myopathies

TREATMENT
Often effective for PM and DM but not for IBM. Step 1: Glucocorticoids [prednisone, 1 (mg/kg)/d for 3–4 weeks, then tapered very gradually]; step 2: Azathioprine [up to 3 (mg/kg)/d] or methotrexate (7.5 mg/week gradually increasing to 25 mg/week); step 3: Intravenous immunoglobulin (2 g/kg divided over 2–5 d); step 4: Cyclosporine, chlorambucil, cyclophosphamide, or mycophenolate mofetil. IBM is generally resistant to immunosuppressive therapies; many experts recommend a short trial of glucocorticoids together with azathioprine or methotrexate.

METABOLIC MYOPATHIES
These disorders result from abnormalities in utilization by muscle of glucose or fatty acids as sources of energy. Pts present with either an acute syndrome of myalgia, myolysis, and myoglobinuria or chronic progressive muscle weakness. Definitive diagnosis requires biochemical-enzymatic studies of biopsied muscle. However, muscle enzymes, EMG, and muscle biopsy are all typically abnormal and may suggest specific disorders.
Glycogen storage disorders can mimic muscular dystrophy or polymyositis. In some types the presentation is one of episodic muscle cramps and fatigue provoked by exercise. The ischemic forearm lactate test is helpful as normal postexercise rise in serum lactic acid does not occur. In adults, progressive muscle weakness beginning in the third or fourth decade can be due to the adult form of acid maltase deficiency, or debranching enzyme deficiency. Exercise intolerance with recurrent myoglobinuria may be due to myophosphorylase deficiency (McArdle’s disease) or phosphofructokinase deficiency. Disorders of fatty acid metabolism present with similar clinical picture. In adults, the most common cause is carnitine palmitoyltransferase deficiency. Exercise-induced cramps, myolysis, and myoglobinuria are common; the picture can resemble polymyositis or muscular dystrophy. Some pts benefit from special diets (medium-chain triglyceride-enriched), oral carnitine supplements, or glucocorticoids.
MITOCHONDRIAL MYOPATHIES
More accurately referred to as mitochondrial cytopathies because multiple tissues are usually affected, these disorders result from defects in mitochondrial DNA. The clinical presentations vary enormously: muscle symptoms may include weakness, ophthalmoparesis, pain, stiffness, or may even be absent; age of onset ranges from infancy to adulthood; associated clinical presentations include ataxia, encephalopathy, seizures, strokelike episodes, and recurrent vomiting. The characteristic finding on muscle biopsy is “ragged red fibers,” which are muscle fibers with accumulations of abnormal mitochondria. Genetics show a maternal pattern of inheritance because mitochondrial genes are inherited almost exclusively from the oocyte.
PERIODIC PARALYSES
Characterized by muscle stiffness due to electrical irritability of the muscle membrane (myotonia), usually without significant muscle weakness until late in the course. Onset is usually in childhood or adolescence. Episodes typically occur after rest or sleep, often following earlier exercise. May be due to genetic disorders of calcium (hypokalemic periodic paralysis), sodium (hyperkalemic period paralysis), or chloride channels. Acute attacks of hypokalemic periodic paralysis are treated with potassium chloride, and prophylaxis with acetazolamide (125–1000 mg/d in divided doses) or dichorphenamide (50–200 mg/d) is usually effective.
MISCELLANEOUS DISORDERS
Myopathies may be associated with endocrine disorders, especially those involving hypo- or hyperfunction of the thyroid, parathyroid, pituitary, and adrenal glands. Drugs (esp. glucocorticoids) and certain toxins (e.g., alcohol) are commonly associated with myopathies (Table 197-2), as are deficiencies of vitamins D and E. In most cases weakness is symmetric and involves proximal limb girdle muscles. Weakness, myalgia, and cramps are common symptoms. Diagnosis often depends on resolution of signs and symptoms with correction of underlying disorder or removal of offending agent.

Table 197-2 Toxic Myopathies

Bibliography

For a more detailed discussion, see Mendell JR: Approach to the Patient with Muscle Disease, Chap. 381, p. 2520; Dalakas MC: Polymyositis, Dermatomyositis, and Inclusion Body Myositis, Chap. 382, p. 2524; Brown RH Jr., Mendell JR: Muscular Dystrophies and Other Muscle Diseases, Chap. 383, p. 2529, in HPIM-15.

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196 MYASTHENIA GRAVIS (MG)

196 MYASTHENIA GRAVIS (MG)
Harrison’s Manual of Medicine

196

MYASTHENIA GRAVIS (MG)

Clinical Features
Pathophysiology
Differential Diagnosis
Laboratory Evaluation
Bibliography

An autoimmune neuromuscular disorder resulting in weakness and fatiguability of skeletal muscles, due to autoantibodies directed against acetylcholine receptors (AChRs) at neuromuscular junctions (NMJs).
Clinical Features
May present at any age. Symptoms fluctuate throughout the day and are provoked by exertion. Characteristic distribution: cranial muscles (lids, extraocular muscles, facial weakness, “nasal” or slurred speech, dysphagia); in 85%, limb muscles (often proximal and asymmetric) become involved. Reflexes and sensation normal. May be limited to extraocular muscles only—particularly in elderly. Complications: aspiration pneumonia (weak bulbar muscles), respiratory failure (weak chest wall muscles), exacerbation of myasthenia due to administration of drugs with neuromuscular junction blocking effects (tetracycline, aminoglycosides, procainamide, propranolol, phenothiazines, lithium).
Pathophysiology
Specific anti-AChR antibodies reduce the number of AChRs at the NMJ. Postsynaptic folds are flattened or “simplified,” with resulting inefficient neuromuscular transmission. During repeated or sustained muscle contraction, decrease in amount of ACh released per nerve impulse, combined with decrease in postsynaptic AChRs, results in pathologic fatigue. Thymus is abnormal in 75% of pts (65% hyperplasia, 10% thymoma). Other autoimmune diseases in 10%; thyroiditis, Graves’ disease, rheumatoid arthritis, lupus erythematosus, red cell aplasia.
Differential Diagnosis

1.
Lambert-Eaton syndrome (autoantibodies to calcium channels in presynaptic motor nerve terminals)—reduced ACh release; associated with malignancy or idiopathic

2.
Neurasthenia—weakness/fatigue without underlying organic disorder

3.
Penicillamine may cause MG; resolves weeks to months after discontinuing drug

4.
Hyperthyroidism

5.
Botulism—toxin inhibits presynaptic ACh release

6.
Intracranial mass lesion—compression of nerves to extraocular muscles

7.
Progressive external ophthalmoplegia—seen in mitochondrial disorders
Laboratory Evaluation

AChR antibodies—no correlation with disease severity; 80% of all MG patients positive; 50% with ocular findings only are positive; positive antibodies are diagnostic.

Tensilon (edrophonium) test—a short-acting anticholinesterase—look for rapid and transient improvement of strength; false-positive (placebo response, motor neuron disease) and false-negative tests occur.

EMG—low frequency (2–4 Hz) repetitive stimulation produces decrement in amplitude of evoked motor responses.

Chest CT/MRI—search for thymoma.

Consider thyroid and other studies (e.g., ANA) for associated autoimmune disease.

TREATMENT
(See Fig. 196-1) The anticholinesterase drug pyridostigmine (Mestinon) titrated to assist pt with functional activities (chewing, swallowing, strength during exertion); usual initial dose of 60 mg 3–5 times daily; long-acting tablets help at night. Muscarinic side effects (diarrhea, abdominal cramps, salivation, nausea) blocked with propantheline if required. Plasmapheresis and IV immune globulin [IVIg; 400 (mg/kg)/d × 5 d] provide temporary boost for seriously ill pts; used to improve condition prior to surgery or during myasthenic crisis (severe exacerbation of weakness). Thymectomy improves likelihood of long-term remission in adult (less consistently in elderly) pts. Glucocorticoids are a mainstay of treatment; begin prednisone at low dose (15–25 mg/d), increase by 5 mg/d q2–3 d until marked clinical improvement or dose of 50 mg/d is reached. Maintain high dose for 1–3 months, then decrease to alternate-day regimen. Long-term treatment with low-dose prednisone usual. Immunosuppressive drugs (azathioprine, cyclosporine, mycophenolate mofetil, cyclophosphamide) may spare dose of prednisone required to control symptoms; azathioprine [2–3 (mg/kg)/d] most often used. Myasthenic crisis is defined as an exacerbation of weakness, usually with respiratory failure, sufficient to endanger life; expert management in an intensive care setting essential.

FIGURE 196-1. Algorithm for the management of myasthenia gravis. FVC, forced vital capacity. (From DM Drachman: HPIM-15, p. 2518)

Bibliography

For a more detailed discussion, see Drachman DB: Myasthenia Gravis and Other Diseases of the Neuromuscular Junction, Chap. 380, p. 2515, in HPIM-15.