Neurology_Adams

Neurology_Adams. Habituation, the equivalent of emotional or psychologic dependence, refers to the substitution of drug-seeking activities for all other aims and objectives in life. It is this feature that fosters relapse to the use of the drug long after the physiologic (“nonpurposive”) abstinence changes seem to have disappeared. The cause for relapse is not fully understood. Theoretically, fragments of the abstinence syndrome may remain as a conditioned response, and these abstinence signs may be evoked by the appropriate environmental stimuli. Thus, when a “cured” addict returns to a situation where narcotic drugs are readily available or in a setting that was associated with the initial use of drugs, the incompletely extinguished drug-seeking behavior may reassert itself.


Neurology_Adams

Neurology_Adams. The characteristics of addiction and of abstinence are qualitatively similar with all drugs of the opiate group as well as the related synthetic analgesics. The differences are quantitative and are related to the differences in dosage, potency, and length of action. Heroin is 2 to 3 times more potent than morphine but the heroin withdrawal syndrome encountered in hospital practice is usually mild in degree because of the low dosage of the drug in the street product. Dilaudid (hydromorphone) is more potent than morphine and has a shorter duration of action; hence the addict requires more doses per day, and the abstinence syndrome comes on and subsides more rapidly. Abstinence symptoms from codeine, while definite, are less severe than those from morphine. The addiction liabilities of propoxyphene, a weak opioid, are negligible. Abstinence symptoms from methadone are less intense than those from morphine and do not become evident until 3 or 4 days after withdrawal; for these reasons


Neurology_Adams

Neurology_Adams. a weak opioid, are negligible. Abstinence symptoms from methadone are less intense than those from morphine and do not become evident until 3 or 4 days after withdrawal; for these reasons methadone can be used in the treatment of morphine and heroin dependency (see further on). Meperidine addiction is of particular importance because of its high incidence among physicians and nurses. Tolerance to the drug’s toxic effects is not complete, so that the addict may show tremors, twitching of muscles, confusion, hallucinations, and sometimes convulsions. Signs of abstinence appear 3 to 4 h after the last dose and reach their maximum intensity in 8 to 12 h, at which time they may be worse than those of morphine abstinence.


Neurology_Adams

Neurology_Adams. As to the biologic basis of addiction and physical dependence, our understanding is still very limited. Experiments in animals have provided insights into the neurotransmitter and neuronal systems involved. As a result of microdialyzing opiates and their antagonists into the central brain structures of animals, it has been tentatively concluded that mesolimbic structures, particularly the nucleus accumbens, ventral tegmentum of the midbrain, and locus ceruleus are activated or depressed under conditions of repeated opiate exposure. Thus, chronic opiate usage increases the levels of intracellular messengers (G-proteins) as noted earlier that drive cAMP activity in the locus ceruleus and in the nucleus accumbens; blocking the expression of these proteins markedly increases the self-administration of opiates by addicted rats. As in alcoholism, certain subtypes of the serotonin and dopamine receptors in limbic structures have been implicated in the psychic aspects of addiction and


Neurology_Adams

Neurology_Adams. of opiates by addicted rats. As in alcoholism, certain subtypes of the serotonin and dopamine receptors in limbic structures have been implicated in the psychic aspects of addiction and habituation. These same structures are conceived as a common pathway for the impulse to human drives such as sex, hunger, and psychic fulfillment. Camí and Farré reviewed the neurochemical mechanism of addiction.


Neurology_Adams

Neurology_Adams. The diagnosis of addiction is usually made when the patient admits to using and needing drugs. Should the patient conceal this fact, one relies on collateral evidence such as miosis, needle marks, emaciation, abscess scars, or chemical analyses. Meperidine addicts are likely to have dilated pupils and twitching of muscles. The finding of morphine or opiate derivatives (heroin is excreted as morphine) in the urine is confirmatory evidence that the patient has taken or has been given a dose of such drugs within 24 h of the test. The diagnosis of opiate addiction is also at once apparent when the treatment of acute opiate intoxication precipitates a characteristic abstinence syndrome. Treatment of the Opioid Abstinence Syndrome


Neurology_Adams

Neurology_Adams. Treatment of the Opioid Abstinence Syndrome Views on the nature of drug addiction and appropriate methods of treatment are as much national and sociologic as they are biologic. One approach that has achieved some degree of success over the past 40 years has been the substitution of methadone for opioid, in the ratio of 1 mg methadone for 3 mg morphine, 1 mg heroin, or 20 mg meperidine. Because methadone is long acting and effective orally, it needs to be given only twice daily by mouth—10 to 20 mg per dose being sufficient to suppress abstinence symptoms. After a stabilization period of 3 to 5 days, this dosage of methadone is reduced and the drug is withdrawn over a similar period. An alternative but probably less effective method has been the use of clonidine (0.2 to 0.6 mg bid for a week), a drug that counteracts most of the noradrenergic withdrawal symptoms; however, the hypotension that is induced by this drug may be a problem (Jasinski et al).


Neurology_Adams

Neurology_Adams. In Europe, addicts who could not be detoxified and kept free of drugs by any other means have been given diacetylmorphine, the active ingredient in heroin, with some success when compared in clinical trials to methadone (see Oviedo-Joekes et al). Special settings that are capable of medical reversal of overdose are required but the notion of overall reduction in personal and societal harm seems to be attained by even this seemingly extreme measure.


Neurology_Adams

Neurology_Adams. A rapid detoxification regimen that is conducted under general anesthesia was popular in a number of centers as a means of treating opiate addiction has now been largely abandoned for reasons of safety but it could be resurrected if other more conventional approaches continue to be futile. The technique consisted of administering increasing doses of opioid receptor antagonists (naloxone or naltrexone) over several hours while the autonomic and other features of the withdrawal syndrome were suppressed by the infusion of propofol or a similar anesthetic, supplemented by intravenous fluids. Medications such as clonidine and sedatives were also given in the immediate postanesthetic period. There are substantial risks involved in this procedure and several deaths have occurred for which reason it has been all but abandoned. Furthermore, a number of patients continue to manifest signs of withdrawal after the procedure and require continued hospitalization.


Neurology_Adams

Neurology_Adams. Treatment of opiate habituation This is in some ways far more demanding than the treatment of opioid withdrawal and can be best accomplished in special facilities and programs that are devoted wholly to the problem. These are available in most communities. The most effective ones have been the ambulatory methadone maintenance clinics, where more than 100,000 former heroin addicts are participating in rehabilitation programs approved by the FDA. Methadone, in a dosage of 60 to 100 mg daily (sufficient to suppress the craving for heroin), is given under supervision day by day (less often with long-acting methadone) for months or years. Various forms of psychotherapy and social service counseling often administered by former heroin addicts are integral parts of the program.


Neurology_Adams

Neurology_Adams. The results of methadone treatment are difficult to assess and vary considerably from one program to another. Even the most successful programs suffer an attrition rate of approximately 25 percent when they are evaluated after several years. Of the patients who remain, the majority achieves a degree of social rehabilitation, that is, they are gainfully employed and no longer engage in criminal behavior. The usual practice of methadone programs is to accept only addicts older than age 16 years with a history of heroin addiction for at least 1 year. This leaves many adolescent addicts untreated. The number of addicts who can fully withdraw from methadone and maintain a drug-free existence is very small. This means that the large majority of addicts now enrolled in methadone programs are committed to an indefinite period of methadone maintenance and the effects of such a regimen are uncertain.


Neurology_Adams

Neurology_Adams. An alternative method of ambulatory treatment of the opiate addict involves the use of narcotic antagonists, of which naloxone and naltrexone are the best known. The physical effects of abusing narcotics are thereby partially blocked, and there may be some degree of aversive conditioning if withdrawal symptoms are produced. Naltrexone is favored because it has a longer effect than naloxone, is almost free of agonist effects, and can be administered orally. Similar results have also been achieved with cyclazocine in a small number of highly motivated patients; this drug is administered orally in increasing amounts until a dosage of 2 mg/70 kg body weight is attained. The drug is taken bid (for 2 to 6 weeks) and is then withdrawn slowly.


Neurology_Adams

Neurology_Adams. More recently, interest has centered on the use of sublingual buprenorphine for the treatment of heroin (and cocaine) abuse; this drug has both opioid agonist and antagonist properties; it mutes the effect of withdrawal, also serves as an aversive agent, and its abuse potential is relatively low. A randomized trial conducted by Fudala and colleagues has demonstrated the superiority over methadone of a combination of buprenorphine and naloxone combined with brief counseling in keeping opioid addicts in treatment and abstinent of abused drugs. This approach has been available in Europe for many years and has been adopted in the United States under a Department of Health–supervised program for primary care offices. In addition, there is evidence, based on animal experiments and experience with small numbers of addicts, that it may be useful for the treatment of dual dependence on cocaine and opiates (see Mello and Mendelson), but this has not been confirmed in other clinical trials.


Neurology_Adams

Neurology_Adams. Medical and Neurologic Complications of Opioid Use


Neurology_Adams

Neurology_Adams. In addition to the toxic effects of the opioid itself, the addict may suffer a variety of neurologic and infectious complications resulting from the injection of contaminated adulterants (quinine, talc, lactose, powdered milk, and fruit sugars) and of various infectious agents (injections administered by unsterile methods). The most important of these is HIV infection, but septicemia, endocarditis, and viral hepatitis may also occur. Particulate matter that is injected with heroin or a vasculitis that is induced by chronic heroin abuse may cause stroke by an incompletely understood occlusion of cerebral arteries, with hemiplegia or other focal cerebral signs. Amblyopia, probably as a result of the toxic effects of quinine in the heroin mixtures, has been reported, as well as transverse myelopathy and several types of peripheral neuropathy. The spinal cord disorder expresses itself clinically by the abrupt onset of paraplegia with a level on the trunk below which motor function and


Neurology_Adams

Neurology_Adams. myelopathy and several types of peripheral neuropathy. The spinal cord disorder expresses itself clinically by the abrupt onset of paraplegia with a level on the trunk below which motor function and sensation are lost or impaired and by urinary retention. Pathologically, there is an acute necrotizing lesion involving both gray and white matter over a considerable vertical extent of the thoracic and occasionally the cervical cord. In some cases, a myelopathy has followed the first intravenous injection of heroin after a prolonged period of abstinence. We have also seen two cases of cervical myelopathy from heroin-induced stupor and a prolonged period of immobility with the neck hyperextended over the back of a chair or sofa.


Neurology_Adams

Neurology_Adams. In addition, we and others have observed instances of a subacute progressive cerebral leukoencephalopathy after heroin use, similar to ones that occurred in Amsterdam in the 1980s, the result of inhalation of heroin or an adulterant (Wolters et al; Tan et al). Most instances of this leukoencephalopathy are the result of inhalation of heated heroin vapor in a practice known as “chasing the dragon.” The clinical presentation has varied but generally includes stupor, coma, and death, after a latent period of hours or days. In one of our patients, the white matter changes were concentrated in the posterior regions of the hemispheres and in the internal capsules and, in one striking case, in the cerebellar white matter. The MRI is fairly characteristic—widespread white matter hyperintensity involving supratentorial and infratentorial structures, with a predilection for corticospinal fibers above and below the internal capsules, and with sparing of subcortical U-fibers and gray matter


Neurology_Adams

Neurology_Adams. involving supratentorial and infratentorial structures, with a predilection for corticospinal fibers above and below the internal capsules, and with sparing of subcortical U-fibers and gray matter structures. The white matter is vacuolated, as indicated by Ryan and colleagues, with an appearance that simulates the spongiform change of prion disease. The pathophysiology is unknown but mitochondrial damage has been suggested. A similar leukoencephalopathy has also been reported in cocaine users, although a hypertensive encephalopathy or an adrenergic-induced vasculopathy may have played a role in these cases.


Neurology_Adams

Neurology_Adams. Damage to single peripheral nerves at the site of injection of heroin and from compression is a relatively common occurrence. However, bilateral compression of the sciatic nerves, the result of sitting or lying for a prolonged period in a stuporous state or in the lotus position, has occurred in several of our patients. In sciatic compression of this type, the peroneal branch has been more affected than the tibial, causing foot-drop with less weakness of plantar flexion. More difficult to understand in heroin abusers is the involvement of other individual nerves, particularly the radial nerve, and painful affection of the brachial plexus, apparently unrelated to compression and remote from the sites of injection. Possibly in some instances there was a vasculitis affecting peripheral nerves.


Neurology_Adams

Neurology_Adams. An acute generalized myonecrosis with myoglobinuria and renal failure has been ascribed to the intravenous injection of adulterated heroin. Brawny edema and fibrosing myopathy (Volkmann contracture) are the sequelae of venous thrombosis resulting from the administration of heroin and its adulterants by the intramuscular and subcutaneous routes. Occasionally, there may be massive swelling of an extremity into which heroin had been injected subcutaneously or intramuscularly; infection and venous thrombosis appears to be involved in its causation. The diagnosis of drug addiction always raises the possibility of an assortment of infectious complications: AIDS, syphilis, abscesses and cellulitis at injection sites, septic thrombophlebitis, hepatitis, and periarteritis from circulating immune complexes. Tetanus, endocarditis (mainly caused by Staphylococcus aureus), spinal epidural abscess, meningitis, brain abscess, and tuberculosis have occurred less frequently.


Neurology_Adams

Neurology_Adams. This class of drugs consists of two main groups. The first includes the barbiturates, meprobamate, and chloral hydrate. These drugs are now little used, having been largely replaced by a second group, the benzodiazepines, the most important of which are chlordiazepoxide (Librium), lorazepam (Ativan), alprazolam (Xanax), clonazepam (Klonopin), and diazepam (Valium). Closely related are the nonbenzodiazepine hypnotics, typified by zolpidem (Ambien). The advantages of the benzodiazepine drugs are their relatively low toxicity and addictive potential and their minimal interactions with other drugs. In the past, about 50 barbiturates were marketed for clinical use, but now only a few are encountered: pentobarbital (Nembutal), secobarbital (Seconal), amobarbital (Amytal), thiopental (Pentothal), and phenobarbital. The first three were the ones most commonly abused. Barbiturates are also a component of combination preparations for the treatment of migraine (e.g., butalbital in Fiorinal).


Neurology_Adams

Mechanism of Action

Neurology_Adams. Mechanism of Action


Neurology_Adams

Neurology_Adams. All the common barbiturates are derived from barbituric acid; the differences among them depend on variations in the side chains of the parent molecule. The potency of each drug is a function of the ionization constant and lipid solubility. The higher its lipid solubility, the greater the drug’s central nervous system potency and the quicker and briefer its action. The lowering of plasma pH increases the rate of entry of the ionized form into the brain. The action of barbiturates is to suppress neuronal transmission, presumably by enhancing GABA inhibition at preand postsynaptic receptor sites, and to reduce excitatory postsynaptic potentials. The major points of action in the CNS are similar to those of alcohol and other coma-producing drugs; impaired consciousness or coma relates to inactivation of neurons in the reticular formation of the upper brainstem. The liver is the main locus of drug metabolism and the kidney is the method of elimination of the metabolites. The clinical


Neurology_Adams

Neurology_Adams. inactivation of neurons in the reticular formation of the upper brainstem. The liver is the main locus of drug metabolism and the kidney is the method of elimination of the metabolites. The clinical problems posed by the barbiturates are different depending on whether the intoxication is acute or chronic.


Neurology_Adams

Neurology_Adams. The symptoms and signs vary with the type and amount of drug as well as with the length of time that has elapsed since it was ingested. Pentobarbital and secobarbital produce their effects quickly and recovery is relatively rapid. Phenobarbital induces coma more slowly and its effects tend to be prolonged. In the case of long-acting barbiturates, such as phenobarbital, the hypnotic-sedative effect lasts 6 h or more after an average oral dose; with the intermediate-acting drugs such as amobarbital, 3 to 6 h; and with the short-acting drugs, secobarbital and pentobarbital, less than 3 h. Most fatalities follow the ingestion of secobarbital, amobarbital, or pentobarbital. The ingestion by adults of more than 3 g of these drugs at one time will prove fatal unless intensive treatment is applied promptly. The potentially fatal dose of phenobarbital is 6 to 10 g. The lowest plasma concentration associated with lethal overdosage of phenobarbital or barbital has been approximately 60 mg/mL and


Neurology_Adams

Neurology_Adams. promptly. The potentially fatal dose of phenobarbital is 6 to 10 g. The lowest plasma concentration associated with lethal overdosage of phenobarbital or barbital has been approximately 60 mg/mL and that of amobarbital and pentobarbital, 10 mg/mL.


Neurology_Adams

Neurology_Adams. Severe intoxication occurs with the ingestion of 10 to 20 times the oral hypnotic dose. The patient cannot be roused by any means, that is, the patient is comatose. Respiration is slow and shallow or irregular, and pulmonary edema and cyanosis may be present. The tendon reflexes are usually, but not invariably, absent. Most patients show no response to plantar stimulation, but in those who do, the responses are extensor. With deep coma, the corneal and gag reflexes may also be abolished. Ordinarily the pupillary light reflex is retained in severe intoxication and is lost only if the patient is asphyxiated; but in advanced cases, the pupils become miotic and poorly reactive, simulating opiate intoxication. At this point respiration is greatly depressed and oculocephalic and oculovestibular reflex responses are usually abolished. In the early hours of coma, there may be a phase of flexor or extensor posturing or rigidity of the limbs, hyperactive reflexes, ankle clonus, and extensor


Neurology_Adams

Neurology_Adams. reflex responses are usually abolished. In the early hours of coma, there may be a phase of flexor or extensor posturing or rigidity of the limbs, hyperactive reflexes, ankle clonus, and extensor plantar signs; persistence of these signs indicates that anoxic damage has been added. The temperature may be subnormal, the pulse is faint and rapid, and the blood pressure is greatly reduced. Failure of respiration to quicken on painful stimulation is an ominous sign.


Neurology_Adams

Neurology_Adams. There are few conditions other than barbiturate intoxication that cause a flaccid coma with small reactive pupils, hypothermia, and hypotension. A pontine hemorrhage may do so, but a hysterical trance or catatonic stupor does not present a problem in differential diagnosis. Serum toxicology studies provide a reliable means of identifying the type and amount of barbiturate in the blood. A patient who has also ingested alcohol may be comatose with relatively low blood barbiturate concentrations. Contrariwise, the barbiturate addict may show only mild signs of intoxication with very high blood barbiturate concentrations.


Neurology_Adams

Neurology_Adams. Management In mild or moderate intoxication, recovery is the rule and special treatment is not required except to prevent aspiration. If the patient is unresponsive, special measures must be taken to maintain respiration and prevent infection. An endotracheal tube should be inserted, with suctioning as necessary. Any risk of respiratory depression or underventilation requires the use of a mechanical ventilator. Hemodialysis or hemofiltration with charcoal may be used in comatose patients who have ingested long-acting barbiturates and these treatments are particularly advisable if anuria or uremia has developed. Occasionally, in the case of a barbiturate addict who has taken an overdose of the drug, recovery from coma is followed by the development of abstinence symptoms, as described later. Barbiturate Abstinence, or Withdrawal, Syndrome


Neurology_Adams

Neurology_Adams. Immediately following withdrawal, the patient seemingly improves over a period of 8 to 12 h, as the symptoms of intoxication diminish. Then a new group of symptoms develops, consisting of nervousness, tremor, insomnia, postural hypotension, and weakness. With chronic phenobarbital or barbital intoxication, withdrawal symptoms may not become apparent until 48 to 72 h after the final dose or it does not occur at all because of the slow metabolism and long half-life of these drugs. Generalized seizures with loss of consciousness may occur, usually between the second and fourth days of abstinence, but occasionally as long as 6 or 7 days after withdrawal. There may be a single seizure, several seizures, or, rarely, status epilepticus. Characteristically, in the withdrawal period, there is a greatly heightened sensitivity to photic stimulation, to which the patient responds with myoclonus or a seizure accompanied by paroxysmal changes in the EEG. The convulsive phase may be followed


Neurology_Adams

Neurology_Adams. is a greatly heightened sensitivity to photic stimulation, to which the patient responds with myoclonus or a seizure accompanied by paroxysmal changes in the EEG. The convulsive phase may be followed directly by a delusional-hallucinatory state or, as occurred in one of our cases (Romero et al), a full-blown delirium indistinguishable from delirium tremens. Death has been reported under these circumstances. The abstinence syndrome may occur in varying degrees of completeness; some patients have seizures and recover without developing delirium, and others have a delirium without preceding seizures.


Neurology_Adams

Neurology_Adams. This is the oldest and one of the safest, most effective, and most inexpensive of the sedative-hypnotic drugs. After oral administration, chloral hydrate is reduced rapidly to trichloroethanol, which is responsible for the depressant effects on the CNS. A significant portion of the trichloroethanol is excreted in the urine as the glucuronide, which may give a false-positive test for glucose.


Neurology_Adams

Neurology_Adams. Tolerance and addiction to chloral hydrate develop only rarely; for this reason, it was in the past commonly used for insomnia. Poisoning with chloral hydrate is a rare occurrence and resembles acute barbiturate intoxication except for the finding of miosis, which is said to characterize the former. Treatment follows along the same lines as for barbiturate poisoning. Death from poisoning is because of respiratory depression and hypotension; patients who survive may show signs of liver and kidney disease. Combining alcohol and chloral hydrate, the popular “Mickey-Finn” of detective stories in the mid-last century, produced severe intoxication and amnesia. Paraldehyde, another member of this group of sedative drugs, is no longer being manufactured in the United States, and chloral hydrate is now available mainly as an elixir for pediatric use.


Neurology_Adams

Neurology_Adams. With the introduction of chlordiazepoxide in 1960 and the benzodiazepine drugs that followed (particularly diazepam), the older sedative drugs (barbiturates, paraldehyde, chloral hydrate) have become virtually obsolete. Indeed, the benzodiazepines are among the most commonly prescribed drugs in the world today. According to Hollister (1990), 15 percent of all adults in the United States use a benzodiazepine at least once yearly and about half this number use the drug for a month or longer.


Neurology_Adams

Neurology_Adams. The benzodiazepines have been prescribed frequently for the treatment of anxiety and insomnia, and they are especially effective when the anxiety symptoms are severe. Also, they have been used to control overactivity and destructive behavior in children and the symptoms of alcohol withdrawal in adults. The benzodiazepines possess anticonvulsant properties, and the intravenous use of diazepam, lorazepam, and midazolam is an effective means of controlling status epilepticus, as described in Chap. 15. Diazepam in massive doses has been used with considerable success in the management of muscle spasm in tetanus and in the “stiff man” syndrome (see Chap. 45). Alprazolam may have a place in the treatment of panic attacks and other anxiety states, and as an adjunct in some depressive illnesses. It may, however, create more dependence than some of the others in its class.


Neurology_Adams

Neurology_Adams. Other important benzodiazepine drugs are lorazepam (Ativan), flurazepam (Dalmane), triazolam (Halcion), clorazepate (Tranxene), temazepam (Restoril), oxazepam (Serax), alprazolam (Xanax) and other newer varieties, all widely used in the treatment of insomnia (see Chap. 18), and clonazepam (Klonopin), which is useful in the treatment of myoclonic seizures (see Chap. 15) and intention myoclonus (see Chaps. 4 and 46). Midazolam (Versed), a short-acting parenteral agent, is given frequently to achieve the brief sedation required for procedures such as MRI or endoscopy and is also useful in the treatment of status epilepticus. Many other benzodiazepine compounds have appeared in recent years, but a clear advantage over the original ones remains to be demonstrated (Hollister, 1990).


Neurology_Adams

Neurology_Adams. The benzodiazepine drugs, like barbiturates, have a depressant action on the CNS by binding to specific receptors on GABA inhibitory systems. The newer nonbenzodiazepine sleeping medication differs from the benzodiazepines structurally but is pharmacologically similar in binding to similar GABA-ergic receptors. The benzodiazepines act in concert with GABA to open chloride ion channels and hyperpolarize postsynaptic neurons and reduce their firing rate. The primary sites of their action are the cerebral cortex and limbic system, which accounts for their anticonvulsant and anxiolytic effects.


Neurology_Adams

Neurology_Adams. While quite safe in the recommended dosages, they are far from ideal. They frequently cause unsteadiness of gait and drowsiness and at times syncope, confusion, and impairment of memory, especially in the elderly. If taken in large doses, the benzodiazepines can depress the state of consciousness, resembling that of other sedative-hypnotic drugs, but with less respiratory suppression and hypotension. Flumazenil, a specific pharmacologic antagonist of the CNS effects of benzodiazepines, rapidly but briefly reverses most of the symptoms and signs of benzodiazepine overdose (see Krisanda). It acts by binding to CNS diazepine receptors and thereby blocking the activation of inhibitory GABA-ergic synapses. Flumazenil also may be diagnostically useful in cases of coma of unknown etiology and in hepatic encephalopathy.


Neurology_Adams

Neurology_Adams. Signs of physical dependence and true addiction, although relatively rare, undoubtedly occur in chronic benzodiazepine users, even in those taking therapeutic doses. The withdrawal symptoms are much the same as those that follow the chronic use of other sedative drugs (anxiety, jitteriness, insomnia, seizures) but may not appear until the third day after the cessation of the drug and may not reach their peak of severity until the fifth day (Hollister, 1990). In chronic benzodiazepine users, the gradual tapering of dosage over a period of 1 to 2 weeks minimizes the withdrawal effects. However, we have observed numerous cases over the years in which the cessation of moderate doses of chronically used diazepines has resulted in one or more seizures. This is likely to happen when the patient is hospitalized for other reasons and the accustomed sleeping or anxiolytic medication is omitted.


Neurology_Adams

Neurology_Adams. A class of antianxiety agents, exemplified by the selective 5-HT1A receptor serotonergic agonist buspirone, is chemically and pharmacologically different from the benzodiazepines, barbiturates, and other sedatives. Its distinctive nature is confirmed by the observation that it does not block the withdrawal syndrome of other sedative-hypnotic drugs. Because of its apparently reduced potential for abuse and tolerance, it is not included in the list of controlled pharmaceutical substances in the United States but adverse interactions with monoamine oxidase (MAO) inhibitors are known. Its use with other psychotropic drugs is still under investigation (see Chap. 49).


Neurology_Adams

Neurology_Adams. Also mentioned here, because neurologists are often asked to consult on these cases, is a curious effect of the anesthetic propofol. Seizures and myoclonic-like movements have been seen in a small number of individuals, presumably as an idiosyncratic effect. Sometimes these take the form of less-organized twitching, opisthotonus, or involuntary movements. Some inhaled anesthetics such as enflurane can cause seizures in susceptible patients. In our own experience, the seizures have occurred in the first hour after emergence from anesthesia, but as many cases are reported with seizures occurring during induction, emergence, and after the use of the drug (see Walder et al).


Neurology_Adams

Neurology_Adams. In the mid-1950s, a large series of pharmacologic agents, originally referred to as tranquilizers (later, as psychotropic or neuroleptic drugs), came into prominent use, mainly for the control of schizophrenia, psychotic states associated with “organic brain syndromes,” and affective disorders (depression and bipolar disease). The mechanisms by which these drugs ameliorate disturbances of thought and affect in psychotic states are not fully understood, but presumably they act by blocking the postsynaptic mesolimbic dopamine receptors of which there are four subtypes, termed D1 through D4 on neuronal membranes (see Table 4-2, and discussion of dopamine receptor subtypes). The D2 receptors are located mainly in the frontal cortex, hippocampus, and limbic cortex, and the D1 receptors are in the striatum, as discussed in Chap. 4. The blockade of dopamine receptors in the striatum is probably responsible for the parkinsonian side effects of this entire class of drugs, and the blockade of


Neurology_Adams

Neurology_Adams. the striatum, as discussed in Chap. 4. The blockade of dopamine receptors in the striatum is probably responsible for the parkinsonian side effects of this entire class of drugs, and the blockade of another dopaminergic (tuberoinfundibular) system, for the increased prolactin secretion by the pituitary. These drugs also produce some adrenergic blocking effect. The newer “atypical” antipsychotic drugs, exemplified by clozapine, apparently achieve the same degree of D2 and D3 blockade in the temporal and limbic lobes while exhibiting substantially less antagonistic activity in the striatum—accounting also for their lesser parkinsonian side effects. These drugs also block subsets of serotonin receptors.


Neurology_Adams

Neurology_Adams. Since the introduction in the 1950s of the phenothiazine chlorpromazine as an anesthetic agent and the serendipitous discovery of its antipsychotic effect, a large number of antipsychotic drugs have been marketed for clinical use. No attempt is made here to describe or even list all of them. Some have had only an evanescent popularity and others have yet to prove their value. Chemically, these compounds form a heterogeneous group. Eight classes of them are of particular clinical importance: (1) the phenothiazines; (2) the thioxanthenes; (3) the butyrophenones; (4) the rauwolfias alkaloids; (5) an indole derivative, loxapine, and a unique dihydroindolone, molindone; (6) a diphenylbutylpiperidine, pimozide; (7) dibenzodiazepines, typified by clozapine and olanzapine; and (8) a benzisoxazole derivative, risperidone. Molindone and loxapine are about as effective as the phenothiazines in the management of schizophrenia and their side effects are similar, although claims have been made that


Neurology_Adams

Neurology_Adams. derivative, risperidone. Molindone and loxapine are about as effective as the phenothiazines in the management of schizophrenia and their side effects are similar, although claims have been made that they are less likely to induce tardive dyskinesias and seizures. Their main use is in patients who are not responsive to the older drugs or who suffer intolerable side effects from them.


Neurology_Adams

Neurology_Adams. The antipsychotic agents in the class of clozapine (which is less used than other agents in the class because of cases of aplastic anemia) have attracted great interest, because—as already mentioned—they are associated with relatively fewer extrapyramidal side effects. For this reason, they are particularly favored in controlling the confusion and psychosis of parkinsonian patients. The other new class of drugs, of which risperidone is the main example, also has fewer extrapyramidal side effects than the phenothiazines and a more rapid onset of action than the traditional antipsychotic medications. All of these newer medications produce the “metabolic syndrome” of weight gain, adverse lipid changes, and glucose intolerance. Pimozide may be useful in the treatment of haloperidol-refractory cases of Gilles de la Tourette syndrome (see Chap. 4); its main danger is its tendency to produce cardiac arrhythmias.


Neurology_Adams

Neurology_Adams. This group comprises chlorpromazine (Thorazine), promazine (Sparine), triflupromazine (Vesprin), prochlorperazine (Compazine), perphenazine (Trilafon), fluphenazine (Permitil, Prolixin), thioridazine (Mellaril), mesoridazine (Serentil), and trifluoperazine (Stelazine). In addition to their psychotherapeutic effects, these drugs have a number of other actions, so that certain members of this group are used as antiemetics (prochlorperazine) and antihistaminics (promethazine).


Neurology_Adams

Neurology_Adams. The phenothiazines have had their widest application in the treatment of the major psychoses, namely schizophrenia and, to a lesser extent, bipolar psychosis, but they are being replaced by newer agents with fewer side extrapyramidal effects (but with problematic issues of their own). Under the influence of these drugs, many patients who would otherwise have been hospitalized were able to live at home and even work productively. In the hospital, the use of these drugs has facilitated the care of hyperactive, delirious, and combative patients (see Chaps. 48 and 49 for details of this clinical use).


Neurology_Adams

Neurology_Adams. Side effects of the phenothiazines are frequent and often serious. All of them may cause a cholestatic type of jaundice, agranulocytosis, seizures, orthostatic hypotension, skin sensitivity reactions, mental depression, and, most importantly, immediate or delayed extrapyramidal motor disorders. The neuroleptic malignant syndrome is the most extreme complication and is discussed separately further on and in Chap. 49. The following types of extrapyramidal symptoms, also discussed in Chap. 4, have been noted in association with all of the phenothiazines as well as the butyrophenones, and to a lesser extent with metoclopramide and pimozide, which block dopaminergic receptors. These are summarized in Table 49-1.


Neurology_Adams

Neurology_Adams. 1. A parkinsonian syndrome is the most common complication—masked facies, slight symmetric tremor, reduced blinking, generalized rigidity, shuffling gait, and slowness of movement. These symptoms may appear after several days of drug therapy but more often after several weeks. Suppression of dopamine in the striatum (similar to the effect of loss of dopaminergic nigral cells that project to the striatum) is presumably the basis of the parkinsonian signs.


Neurology_Adams

Neurology_Adams. 2. Acute dyskinetic and dystonic reactions, taking the form of involuntary movements of lower facial muscles (mainly around the mouth) and protrusion of the tongue (buccolingual or oral-masticatory syndrome), dysphagia, torticollis and retrocollis, oculogyric crises, and tonic spasms of a limb. These complications usually occur early in the course of administration of the drug, sometimes after the initial dose, in which case they recede dramatically upon immediate discontinuation of the drug and the intravenous administration of diphenhydramine hydrochloride or benztropine. 3. Akathisia, which is an inner restlessness reflected by a persistent shifting of the body and feet and an inability to sit still, such that the patient paces the floor or jiggles the legs constantly (see Chap. 4). Of all the phenothiazines, molindone has a tendency to cause akathisia. This disorder often responds to oral propranolol.


Neurology_Adams

Neurology_Adams. 4. Tardive dyskinesias are a group of late and persistent complications of neuroleptic therapy, which may continue after removal of the offending drug, that comprises lingual-facial-buccal-cervical dyskinesias, choreoathetotic and dystonic movements of the trunk and limbs, diffuse myoclonus (rare), perioral tremor (“rabbit” syndrome), and dysarthria or anarthria. Snyder postulated that the movements are because of hypersensitivity of dopamine receptors in the basal ganglia, secondary to prolonged blockade of the receptors by antipsychotic medication. Baldessarini estimates that as many as 40 percent of patients receiving long-term antipsychotic medication develop tardive dyskinesia of some degree. The effect is likely a result of subcellular pathophysiologic alterations in the basal ganglia. Treatment is discussed later. 5. The neuroleptic malignant syndrome is discussed separately later because of its gravity and requirement for specific treatment.


Neurology_Adams

Neurology_Adams. 5. The neuroleptic malignant syndrome is discussed separately later because of its gravity and requirement for specific treatment. Haloperidol (Haldol) is the only member of this group approved for use as an antipsychotic in the United States. It has much the same therapeutic effects as the phenothiazines in the management of acute psychoses and shares the same side effects as the phenothiazines, but exhibits little or no adrenergic blocking action. It is an effective substitute for the phenothiazines in patients who are intolerant of the latter drugs, particularly of their autonomic effects. It is also one of the main drugs for the treatment of Gilles de la Tourette syndrome (the other being pimozide; see Chap. 4) and the movement disorder of Huntington chorea. It has been widely used in critical care practice to reduce the duration of delirium but at least one randomized trial has failed to show that it is any different than treatment with placebo (Girard et al).


Neurology_Adams

Neurology_Adams. Treatment of Neuroleptic Side Effects As indicated earlier, acute dystonic spasms usually respond to cessation of the offending drug and to the administration of diphenhydramine. Administration of antiparkinsonian drugs of the anticholinergic type (trihexyphenidyl, procyclidine, and benztropine) may hasten recovery from some of the acute symptoms. The purely parkinsonian syndrome usually improves as well, but the tardive dyskinesias stand apart because they may persist for months or years and may be permanent.


Neurology_Adams

Neurology_Adams. Oral, lingual, and laryngeal dyskinesias of the tardive type are affected relatively little by any antiparkinsonian drugs. Amantadine in doses of 50 to 100 mg tid has been useful in a few of the cases of post-phenothiazine dyskinesia. Other drugs such as benztropine have been tried in the treatment of regional and more generalized tardive dyskinesia with uncertain results. Nevertheless, there is a tendency for most of the obstinate forms to subside slowly even after several years of unsuccessful therapy. Once a tardive syndrome has been identified, an immediate tapering of the offending medication is recommended, though the efficacy of this strategy has not been evaluated prospectively, and furthermore there is risk of exacerbation of psychotic symptoms. Substitution of the offending medication with one of the second generation “atypical” antipsychotic medications is a reasonable strategy, though the reduced dyskinetic effects of these medications is only relative.


Neurology_Adams

Neurology_Adams. This is the most dreaded complication of phenothiazine and haloperidol use; rare instances have been reported after the institution or the withdrawal of l-dopa and similar dopaminergic agents, as well as a few instances reported with the newer antipsychosis drugs. Its incidence has been calculated to be only 0.2 percent of all patients receiving neuroleptics (Caroff and Mann) but its seriousness is underscored by a mortality rate of 15 to 30 percent if not recognized and treated promptly. It may occur days, weeks, or months after neuroleptic treatment is begun.


Neurology_Adams

Neurology_Adams. The syndrome consists of hyperthermia, rigidity, stupor, unstable blood pressure, diaphoresis, and other signs of sympathetic overactivity, high serum creatine kinase (CK) values (up to 60,000 units), and, in some cases, renal failure because of myoglobinuria. The syndrome was first observed in patients treated with haloperidol, but since then other neuroleptic drugs have been incriminated, particularly the highly potent thioxanthene derivatives and the phenothiazines—chlorpromazine, fluphenazine, and thioridazine—but also, on rare occasions, the less potent drugs that are used to control nausea, such as promethazine. It has become evident that the newer antipsychotic drugs, and specifically olanzapine, are also capable of inducing the syndrome but the risk in comparison to the first generation of antipsychotic drugs has not been established.


Neurology_Adams

Neurology_Adams. If treatment of the neuroleptic malignant syndrome is started early, when consciousness is first altered and the temperature is rising, bromocriptine in oral doses of 5 mg tid (up to 20 mg tid) will terminate the condition in a few hours. If oral medication can no longer be taken because of the patient’s condition, dantrolene, 0.25 to 3.0 mg intravenously, may be lifesaving. Once coma has supervened, shock and anuria may prove fatal or leave the patient in a vegetative state. The rigors during high fever may cause muscle damage and myoglobinuria, and shock may lead to hypoxic-ischemic brain injury.


Neurology_Adams

Neurology_Adams. One pitfall is to mistake neuroleptic malignant syndrome for worsening of the psychosis and inadvisably administer more antipsychosis medication. Meningitis, heat stroke, lithium intoxication, catatonia, malignant hyperthermia, and acute dystonic reactions figure in the differential diagnosis. Of course, neuroleptic medication must be discontinued as soon as any of the severe extrapyramidal reactions are recognized. It has been common practice to avoid future administration of the offending neuroleptic but the risk of using another class of antipsychotic agents has not been fully addressed.


Neurology_Adams

Neurology_Adams. The neuroleptic malignant syndrome bears an uncertain relationship to malignant hyperthermia by way of its clinical aspects but also in its response to bromocriptine and dantrolene (see later). Malignant hyperthermia in susceptible individuals is triggered by inhalation anesthetics and skeletal muscle relaxants (see Chap. 45). This disorder was described before the introduction of neuroleptic drugs, and in a small proportion of cases, has been related to a mutation of the ryanodine receptor gene. A genetic factor may underlie a small number of cases of the neuroleptic malignant syndrome (a polymorphism in the D2 receptor gene; see Suzuki et al) possibly provoked by fatigue and dehydration. There is no evidence that the occurrence of one of these syndromes confers a susceptibility to the other.


Neurology_Adams

Neurology_Adams. Four classes of drugs—the MAO inhibitors, the tricyclic compounds, the serotonergic drugs, and lithium—are particularly useful in the treatment of depressive illnesses. The adjective antidepressant refers to their therapeutic effect and is employed here in deference to common clinical practice. Antidepressive or antidepression drugs would be preferable, as the term depressant still has a pharmacologic connotation that does not necessarily equate with the therapeutic effect.


Neurology_Adams

Neurology_Adams. The observation that iproniazid, an inhibitor of MAO, had a mood-elevating effect in tuberculous patients initiated a great deal of interest in compounds of this type and led quickly to their exploitation in the treatment of depression. Iproniazid proved exceedingly toxic to the liver, as were several subsequently developed MAO inhibitors; but other drugs in this class, much better tolerated, are still available. These include isocarboxazid (Marplan), phenelzine (Nardil), and tranylcypromine (Parnate), the latter two being the more frequently used. Tranylcypromine, which bears a close chemical resemblance to dextroamphetamine, may produce unwanted stimulation, but the most common adverse effect of all the MAO inhibitors is postural hypotension. Also, interactions with a wide array of other drugs and ingested substances may induce severe hypertension.


Neurology_Adams

Neurology_Adams. Monoamine oxidase is located on the outer surface of the mitochondria in neurons and is used in the catabolism of catecholamines. In the gut and liver, the isoenzyme MAO-A normally serves to deaminate phenethylamine, tyramine, and tryptamine—all of which are products of protein catabolism. Inhibition of MAO-A allows these dietary amines, which have an amphetamine-like action, to enter the systemic circulation in increased quantities, thus releasing norepinephrine from sympathetic nerve endings and increasing heart rate and blood pressure. Most antidepressant medications are of this class. Medications used in Parkinson disease (see Chap. 38) inhibit the MAO-B isoenzyme, which deaminates phenylethylamine and trace amines, with a correspondingly lower risk of causing hypertension.


Neurology_Adams

Neurology_Adams. More relevant to their action as antidepressants, the MAO inhibitors have in common the ability to block the intraneuronal oxidative deamination of naturally occurring amines (norepinephrine, epinephrine, dopamine, and serotonin) and it has been suggested that the accumulation of these substances is responsible for the antidepressant effect. However, many enzymes other than monoamine oxidase are inhibited by MAO inhibitors, and the latter drugs have numerous actions unrelated to enzyme inhibition. Furthermore, many agents with antidepressant effects like those of the MAO inhibitors do not inhibit MAO. Therefore, one cannot assume that the therapeutic effect of these drugs has a direct relation to MAO inhibition in the brain.


Neurology_Adams

Neurology_Adams. The MAO inhibitors must be dispensed with caution and awareness of their potentially serious side effects. They may at times cause excitement, restlessness, agitation, insomnia, and anxiety, occasionally with the usual dose but more often with an overdose. Mania and convulsions may occur (especially in epileptic patients). Other side effects are muscle twitching and involuntary movements, urinary retention, skin rashes, tachycardia, jaundice, visual impairment, enhancement of glaucoma, impotence, sweating, muscle spasms, paresthesias, and a serious degree of orthostatic hypotension.


Neurology_Adams

Neurology_Adams. Patients taking MAO-A inhibitors must be warned against the use of phenothiazines, CNS stimulants, and tricyclic and serotoninergic antidepressants (see later), as well as sympathomimetic amines and tyramine-containing foods. The combination of a MAO inhibitor and any of these drugs or amines may induce hypertension, atrial and ventricular arrhythmia, pulmonary edema, stroke, or death. Sympathomimetic amines are contained in some commonly used cold remedies, nasal sprays, nose drops, and certain foods—aged cheese, beer, red wine, pickled herring, sardines, sausages, and certain preserved meat or fish. Exaggerated responses to the usual dose of meperidine (Demerol) and other narcotic drugs have also been observed sporadically; in these cases, respiratory function may be depressed to a serious degree, and hyperpyrexia, agitation, and pronounced hypotension may occur as well, sometimes with fatal issue. Unpredictable side effects may also accompany the simultaneous administration of


Neurology_Adams

Neurology_Adams. serious degree, and hyperpyrexia, agitation, and pronounced hypotension may occur as well, sometimes with fatal issue. Unpredictable side effects may also accompany the simultaneous administration of barbiturates and MAO inhibitors. The abrupt occurrence of severe occipital headache, nausea, vomiting, pupillary dilatation, or visual blurring should suggest a hypertensive crisis. Treatment is with intravenous phentolamine 5 mg, nitroprusside, labetalol, or a calcium channel blocker administered slowly to prevent hypotension. Overdosage of MAO inhibitors may lead to coma, for which there is no treatment other than supportive care.


Neurology_Adams

Neurology_Adams. The therapeutic use of MAO inhibitors for depression is discussed in Chaps. 47 and 48, and for Parkinson disease, in Chap. 38. Soon after the first successes with MAO inhibitors, another class of tricyclic compounds appeared. The mode of action of these agents is not fully understood, but there is evidence that they block the reuptake of amine neurotransmitters, both norepinephrine and serotonin. Blocking this amine pump mechanism (called the presynaptic plasma transporter), which ordinarily terminates synaptic transmission, permits the persistence of neurotransmitter substances in the synaptic cleft and does no more than support the hypothesis that endogenous depression is associated with a deficiency of noradrenergic or serotonergic transmission.


Neurology_Adams

Neurology_Adams. These medications have been divided into classes of tertiary amines (imipramine, amitriptyline and doxepin, trimipramine), which have activity as reuptake inhibitors of norepinephrine and serotonin, and the secondary amines (desipramine, amoxapine, maprotiline, nortriptyline, protriptyline), which have a preferential effect on reuptake of norepinephrine. Subsequently, a number of additional antidepressant drugs were introduced. A full account of these drugs, which will not be attempted here, can be found in the chapters by Baldessarini and Nelson listed in the references.


Neurology_Adams

Neurology_Adams. The tricyclic antidepressants and the serotonergic drugs discussed in the next section, are presently the most effective drugs for the treatment of patients with depressive illnesses, the former being particularly useful for those with anergic depressions, early morning awakening, and decreased appetite and libido. The side effects of the tricyclic drugs are less frequent and far less serious than those of the MAO inhibitors. The tricyclic compounds are also potent anticholinergic agents, which accounts for their most prominent and bothersome side effects—orthostatic hypotension, urinary bladder weakness, drowsiness, confusion, blurred vision, and dry mouth. They may also occasionally produce CNS excitation—leading to insomnia, agitation, and restlessness—but usually these effects are readily controlled by small doses of benzodiazepines given concurrently or in the evenings.


Neurology_Adams

Neurology_Adams. CNS excitation—leading to insomnia, agitation, and restlessness—but usually these effects are readily controlled by small doses of benzodiazepines given concurrently or in the evenings. As indicated earlier, the tricyclic drugs should not be given with a MAO inhibitor; serious reactions have occurred when small doses of imipramine were given to patients who had discontinued the MAO in the previous days or week. Both the MAO inhibitors and the tricyclic antidepressants are dangerous drugs when taken in excess.


Neurology_Adams

Neurology_Adams. Tricyclic compounds are a cause of accidental poisoning and suicide of depressed patients. It is common for the intoxicated patient to have taken several drugs, in which case chemical analyses of the blood and urine are particularly helpful in determining the drugs involved and in sorting out therapeutic and toxic concentrations. Mortality from overdose is mostly a result of cardiac rhythm disturbances, particularly tachyarrhythmias, and impaired conduction (atrioventricular block). Treatment consists of gastric aspiration and instillation of activated charcoal and the addition of physostigmine to reverse serious arrhythmias; the short duration of action of physostigmine requires that frequent doses be given. Dialysis is of no value because of the low plasma concentrations of the drug.


Neurology_Adams

Neurology_Adams. The selective serotonin reuptake inhibitors (SSRIs) constitute a newer class of antidepressants; paroxetine (Paxil), fluoxetine (Prozac), and sertraline (Zoloft) are common examples but they continue to be developed at a rapid pace. Of the several related drugs such as venlafaxine (Effexor), nefazodone (Serzone), mirtazapine (Remeron), citalopram (Celexa), trazodone (Desyrel), and bupropion (Wellbutrin), each has a novel structure that is not analogous to that of the other categories of antidepressants. They are believed to act similarly to the SSRI class by inhibiting the reuptake of serotonin and norepinephrine. This results in a potentiation of the actions of these neurotransmitters.


Neurology_Adams

Neurology_Adams. Because they do not bind as avidly as tricyclic drugs to the muscarinic and adrenergic receptors in the brain, they produce fewer side effects, but some patients complain of anxiety or insomnia when they are first introduced. These drugs share the same side effects to varying degrees, including the danger of concomitant MAO inhibitor administration. The risk of seizures related to the taking of certain of these medications has been much discussed. For the most part, the risk is quite small but there is little information to guide their use in known epileptics. Several studies suggest that the frequency of convulsions may increase in such patients. Bupropion has been particularly associated with seizures in about 0.5 percent of patients treated at higher dose levels (over 400 mg/d) and this drug should not be used in individuals with a history of seizures.


Neurology_Adams

Neurology_Adams. The SSRI drugs are well tolerated, may be effective in a shorter time than the tricyclic agents and are very popular at the moment, but their long-term therapeutic usefulness in comparison with their predecessors remains to be determined (see review of Richelson). Fluoxetine has also been used with benefit in a group of autistic children (see “Course, Treatment, and Prognosis” under “Autism” in Chap. 37). Constipation, dry mouth, and reduced sexual potency are to be expected to some, but varying degrees. Hyponatremia is a rare complication.


Neurology_Adams

Neurology_Adams. The symptoms of a “serotonin syndrome” that results from excessive intake of the above listed drugs or from the concurrent use of MAO inhibitors include confusion and restlessness, tremor, tachycardia, hypertension, clonus and hyperreflexia, shivering, and diaphoresis, as summarized by Boyer and Shannon. The long list of other medications, when used concurrently with SSRIs can produce the syndrome (including “triptans” for migraine), are noted in this reference. The treatment is discontinuation of the medication, reduction of temperature and hypertension, benzodiazepines to control agitation, and in severe cases, the addition of cyproheptadine, a 5-HT2A receptor blocker. The typical dose is 4 to 8 mg every 4 to 6 h (or a higher initial dose); tablets are crushed and administered by nasogastric tube. Atypical antipsychosis agents with similar serotonin antagonist activity have also been used as treatment (olanzapine, chlorpromazine).


Neurology_Adams

Neurology_Adams. The discovery of the therapeutic effects of lithium salts in mania has led to its widespread use in the treatment of bipolar disease (bipolar disorder). The drug has proved relatively safe and blood levels are easily monitored. Its value is much more certain in treatment of the manic phase of bipolar disorder and prevention of recurrences of cyclic mood shifts than it is in treatment of anxiety and depression. Guidelines for the clinical use of lithium are given in Chap. 48. Its mechanism of action is unclear but there is experimental evidence that lithium blocks the stimulus-induced release of norepinephrine and dopamine and enhances the reuptake of this amine—the opposite in a sense, of what occurs with the other classes of antidepressants.


Neurology_Adams

Neurology_Adams. With blood levels of lithium in the upper therapeutic range (therapeutic 0.6 to 1.2 mEq/L), it is not uncommon to observe a fast-frequency action tremor or asterixis, together with nausea, loose stools, fatigue, polydipsia, and polyuria. These symptoms usually subside with time. Above a level of 1.5 to 2 mEq/L, particularly in patients with impaired renal function or in those taking a thiazide diuretic, serious intoxication becomes manifest—clouding of consciousness, confusion, delirium, dizziness, nystagmus, ataxia, stammering, diffuse myoclonic twitching, and nephrogenic diabetes insipidus. Vertical (downbeating) nystagmus and opsoclonus (see Chap. 13) may also be prominent. A variety of skin problems is common including worsening of acne vulgaris. An uncommon toxic effect is the development of goiter but most patients remain euthyroid although the thyroid-stimulating hormone (TSH) levels may increase slightly. The goiter usually requires no treatment but it is possible to


Neurology_Adams

Neurology_Adams. development of goiter but most patients remain euthyroid although the thyroid-stimulating hormone (TSH) levels may increase slightly. The goiter usually requires no treatment but it is possible to administer thyroid hormone so as to cause the thyroid enlargement to regress.


Neurology_Adams

Neurology_Adams. The myoclonic state, particularly when combined with confusion and sharp waves in the EEG, may mimic Creutzfeldt-Jakob disease (see Chap. 32) but there should be no problem in diagnosis if the setting of the illness and the administration of lithium are known. At blood lithium concentrations above 3.5 mEq/L, these symptoms are replaced by stupor and coma, sometimes with convulsions, and may prove fatal. Discontinuing lithium in the intoxicated patient, which is the initial step in therapy, does not result in immediate disappearance of toxic symptoms. This may be delayed by a week or two, and the diabetes insipidus may persist even longer. Fluids, sodium chloride, aminophylline, and acetazolamide promote the excretion of lithium. Lithium coma may require hemodialysis, which has proved to be the most rapid means of reducing the blood lithium concentration.


Neurology_Adams

Neurology_Adams. Drugs that act primarily as CNS stimulants assume clinical importance for several reasons, mainly in their use for sleep disorders and attention deficit disorder. Some members of this group, the amphetamines, are much abused and others are not infrequent causes of poisoning. Their main mechanism of action is the release of endogenous catecholamine from vesicles in the presynaptic terminals.


Neurology_Adams

Neurology_Adams. The amphetamines (d-amphetamine, d,l-amphetamine, pemoline, methamphetamine, methylphenidate) are analeptics (CNS stimulants) and in addition have significant hypertensive, respiratory-stimulant, and appetite-depressant effects. They are effective in the management of narcolepsy but have been more widely and sometimes indiscriminately used for the control of obesity, the abolition of fatigue, and the treatment of hyperactivity in children (see Chap. 37 for full discussion). Undoubtedly, they are able to reverse fatigue, postpone the need for sleep, and elevate mood but these effects are not entirely predictable and the user must compensate for the period of wakefulness with even greater fatigue and often with depression that follows. The intravenous use of a high dose of amphetamine produces an immediate feeling of ecstasy.


Neurology_Adams

Neurology_Adams. Because of the popularity of the amphetamines and the ease with which they can be procured, instances of acute and chronic intoxication are not uncommon. Methamphetamine is the most frequently abused in this category, as intravenous “crystal” or smoked as “ice.” The toxic signs are essentially an exaggeration of the activating effects— restlessness, excessive speech and motor activity, tremor, and insomnia. Severe intoxication gives rise to hallucinations, delusions, and changes in affect and thought processes—a state that may be indistinguishable from paranoid schizophrenia. An amphetamine-associated vasculopathy and intracerebral and subarachnoid hemorrhage are well recognized but rare complications of chronic or acute intoxication (Harrington et al and Chap. 33). Similar cerebrovascular complications may appear with sympathomimetic agents contained in over-the-counter cold medications and in dieting aids. Phenylpropanolamine has been implicated most often but ephedrine, cocaine


Neurology_Adams

Neurology_Adams. complications may appear with sympathomimetic agents contained in over-the-counter cold medications and in dieting aids. Phenylpropanolamine has been implicated most often but ephedrine, cocaine (see below), and similar agents rarely have the same effects and induce a vasculopathy. The pathogenesis of the vascular lesion is unknown (both vasospasm and arteritis have been reported).


Neurology_Adams

Neurology_Adams. Chronic use of amphetamines can lead to a high degree of tolerance and psychologic dependence. Withdrawal of the drug after sustained oral or intravenous use is regularly followed by a period of prolonged sleep (a disproportionate amount of which is rapid eye movement [REM] sleep), from which the patient awakens with a ravenous appetite, muscle pains, and feelings of profound fatigue and depression. Treatment consists of discontinuing the use of amphetamine and administering antipsychosis drugs. Hypertension may need to be treated until the effect of the drug has waned.


Neurology_Adams

Neurology_Adams. The conventional use of cocaine as a local anesthetic has for many years been overshadowed by its illicit and widespread use as a stimulant and mood elevator. Cocaine is abused intranasally (“snorted”), smoked, or injected intravenously or intramuscularly. There has been an alarming escalation in the use of cocaine, mainly because a relatively pure and inexpensive form of the free alkaloid base (“crack”) became readily available in the 1980s. This form of cocaine is heat-stable and therefore suitable for smoking. According to the National Household Survey on Drug Abuse, there are an estimated 600,000 frequent cocaine users in the United States. (Frequent use was arbitrarily defined as use on 51 or more days during the preceding year.) The number of occasional users (less than 12 days in the preceding year) was 2.4 million. These figures are probably subject to significant underreporting.


Neurology_Adams

Neurology_Adams. A sense of well-being, euphoria, loquacity, and restlessness are the familiar effects. Pharmacologically, cocaine is thought to act like the tricyclic antidepressants; that is, it blocks the presynaptic reuptake of biogenic amines, thus producing vasoconstriction, hypertension, and tachycardia and predisposing to generalized tremor, myoclonus, seizures, and psychotic behavior. It has an additional weaker action, similar to amphetamines, of causing the release of endogenous monoamines. The cocaine abuser readily develops psychologic dependence and habituation, that is, an inability to abstain from frequent compulsive use. The manifestations of physical dependence are more subtle and difficult to recognize. Nevertheless, abstinence from cocaine following a period of chronic abuse is regularly attended by insomnia, restlessness, anorexia, depression, hyperprolactinemia, and signs of dopaminergic hypersensitivity—a symptom complex that constitutes an identifiable withdrawal syndrome.


Neurology_Adams

Neurology_Adams. With the increasingly widespread use of cocaine, a variety of complications continues to emerge (see review by Cregler and Mark). The symptoms of severe intoxication (overdose), noted above, may lead to coma and death and require emergency treatment in an intensive care unit, along the lines indicated for the management of other forms of coma. Seizures often occur in this setting and are treated more effectively with benzodiazepines than with standard anticonvulsant drugs. Spontaneous subarachnoid or intracerebral hemorrhage and cerebral infarction have rarely followed the intranasal use and smoking of cocaine (Levine et al). These complications could be the result of acute hypertension induced by the sympathomimetic actions of cocaine and the incidence of vascular malformations appears to be higher in those patients who have a cerebral hemorrhage (see Chap. 33). Cocaine and amphetamines also, on occasion, produce a state of generalized vasospasm leading to multiple cortical


Neurology_Adams

Neurology_Adams. appears to be higher in those patients who have a cerebral hemorrhage (see Chap. 33). Cocaine and amphetamines also, on occasion, produce a state of generalized vasospasm leading to multiple cortical infarctions and posterior white matter changes that are evident on imaging studies, essentially a form of hypertensive, or posterior reversible encephalopathy (PRES) (see Altura and Altura and also Chap. 33). Roth and colleagues have described 39 patients who developed acute rhabdomyolysis after cocaine use; 13 of these had acute renal failure, severe liver dysfunction, and disseminated intravascular coagulation and 6 of them died. Some reports indicate that cocaine use during pregnancy may cause fetal damage, abortion, or persistent signs of toxicity in the newborn infant.


Neurology_Adams

Neurology_Adams. Anxiety, paranoia, and other manifestations of psychosis may develop within several hours of cocaine use. These complications are best treated with antipsychosis drugs, particularly haloperidol.


Neurology_Adams

Neurology_Adams. The psychostimulant khat is used widely in certain countries, almost as a cultural norm in restricted populations, mainly in the Far East. The khat leaf is chewed to release cathionine that produces euphoria by an amphetamine-like effect. A chemically designed congener, the N-methyl analog of cathionine, or methcathinone (“Jeff,” “Cat,” “mulka,” and other street names), is manufactured from over-the-counter cold medications such as ephedrine, pseudoephedrine, and phenylpropanolamine and is frequently abused. Potassium permanganate may be used to reduce the basic substances and is a source of a manganese-induced extrapyramidal syndrome. Furthermore, entirely synthetic cathinones, often called “bath salts,” although they have no relation to that original product, are amphetamine-like substances that are taken orally or nasally and produce rapid activation of behavior and sympathetic hyperactivity.


Neurology_Adams

Neurology_Adams. Included in this category is a heterogeneous group of drugs, the primary effect of which is to alter perception, mood, and thinking out of proportion to other aspects of cognitive function and consciousness. This group of drugs comprises lysergic acid diethylamide (LSD), phenylethylamine derivatives (mescaline or peyote), psilocybin, certain indolic derivatives, cannabis (marijuana), phencyclidine (PCP), and a number of other compounds. They are also referred to as psychoactive or psychotomimetic drugs or as hallucinogens and psychedelics. The problems raised by the nontherapeutic use of these drugs have been reviewed by Nicholi and by Verebey and their associates.


Neurology_Adams

Neurology_Adams. Marijuana is the most commonly used illicit drug in the United States. The effects, when taken by inhaling the smoke from cigarettes or pipe, are prompt in onset and evanescent. With low doses, the symptoms are like those of mild alcohol intoxication (drowsiness, euphoria, and perceptual distortions). With increasing amounts, the effects may become similar to hallucinogens (see later); they may be quite disabling for many hours. With even larger doses, severe depression and stupor may occur, but death is rare (for a full account, see Hollister [1988]). No damage to the nervous system has been found after chronic use. As summarized by Iverson, this agent activates the CB1 receptor, mainly on GABA-ergic neurons in the hippocampus, amygdala, and cortex. Activation of the receptor inhibits the release of oligopeptide neurotransmitters and monoamines. They also have complex electrophysiologic effects on neurons.


Neurology_Adams

Neurology_Adams. Reverse tolerance to marijuana (i.e., increasing sensitization) may be observed initially, but on continued use, tolerance to the euphoriant effects develops. In one of the few experimental studies of chronic marijuana use, the subjects reported feeling “jittery” during the first 24 h after abrupt cessation of smoking marijuana, although no objective withdrawal signs could be detected. Chronic intoxicated users demonstrate reduced cognitive performance, but according to Iverson, a persistent cognitive decline has not been shown definitely. The mild antiemetic effects of marijuana coupled with euphoria have led to its therapeutic use to ameliorate the effects of chemotherapy. Putative effects on spasticity and, more popularly on neuropathic pain have not been fully substantiated (see commentaries by Caulley, Caplan and Ross).


Neurology_Adams

Neurology_Adams. With the cathionines discussed above, this is a newer class of synthetic drugs; they go by street names of “Spice,” “K2,” “K4,” and many others. These agents bind even more avidly to cannabinoid receptors than does the original drug (marijuana) and produce a heightened stimulant effect. Agitation, delusions, and paranoia result, a veritable psychosis, and some patients we have admitted have been physically almost uncontrollable, only to awaken and have entirely normal affect and cognition. Because the synthetic agents are chemically quite different from cannabis, they do not appear on conventional toxicology-drug screens. Small regional outbreaks of “zombie” like have been attributed to these agents and the difficulty in rapidly identifying the agent has been highlighted by Adams and colleagues. Treatment of intoxication is generally by diazepines and haloperidol but often to little avail until the drug is metabolized. Mescaline, LSD, and Psilocybin


Neurology_Adams

Neurology_Adams. Mescaline, LSD, and Psilocybin These drugs produce much the same clinical effects if given in comparable amounts. The perceptual changes are the most dramatic: the user describes vivid visual hallucinations, alterations in the shape and color of objects, unusual dreams, and feelings of depersonalization. An increase in auditory acuity has been described but auditory hallucinations are rare. Cognitive functions are difficult to assess because of inattention, drowsiness, and inability to cooperate in mental testing. The somatic symptoms consist of dizziness, nausea, paresthesia, and blurring of vision. Sympathomimetic effects—pupillary dilatation, piloerection, hyperthermia, and tachycardia—are prominent, and the user may also show hyperreflexia, incoordination of the limbs, and ataxia.


Neurology_Adams

Neurology_Adams. Tolerance to LSD, mescaline, and psilocybin develops rapidly, even on a once-daily dosage. Furthermore, subjects tolerant to any one of these three drugs are cross-tolerant to the other two. Tolerance is lost rapidly when the drugs are discontinued and no characteristic signs of physical dependence ensue. In this sense, addiction does not develop, although users may become psychologically dependent upon the drugs. These drugs are taken by “drugheads” (a colorful term we have retained from the original authors of this book to describe individuals who use any agent that alters consciousness) and by many college and high school students for a way of socializing, for conformity, or for reasons that even they cannot ascertain.


Neurology_Adams

Neurology_Adams. The use of these drugs may be attended by a number of serious adverse reactions taking the form of acute panic attacks (“bad trip”), long-lasting psychotic states resembling paranoid schizophrenia, and flashbacks (spontaneous recurrences of the original LSD experience, sometimes precipitated by smoking marijuana and accompanied by panic attacks). Serious physical injury may follow upon impairment of the user’s critical faculties. Numerous claims have been made that LSD and related drugs are effective in the treatment of mental disease and a wide variety of social ills, and that they have the capacity to increase one’s intellectual performance, creativity, and self-understanding. To date, no acceptable studies validate any of these claims.


Neurology_Adams

Neurology_Adams. During the early 1970s, the abuse of phencyclidine (PCP) and its analogues was a significant problem. The popularity of these drugs has dropped, but some illicit use continues because they are relatively cheap, easily available, and quite potent. (Their manufacture as a veterinary anesthetic was stopped in 1979.) Phencyclidine is taken in the form of a granular powder, frequently mixed with other drugs, and is smoked or snorted. It is usually classified as a hallucinogen, although it also has stimulant and depressant properties. The effects of intoxication are like those of LSD and other hallucinogens, and resemble those of an acute schizophrenic episode, which may last several days to a week or longer. After the ingestion of a large amount (10 mg or more) of phencyclidine, it is present in the blood and urine for only a few hours sometimes making its detection difficult.


Neurology_Adams

Neurology_Adams. Toxicity from the illicit use of “ecstasy” (methylene-dioxymethamphetamine [MDMA]) during parties (“raves”) has increased as a result of its ill-founded reputation for safety. It appears to cause a release of both serotonin and dopamine in the brain and produces an elated state similar to the effects of cocaine. Seizures, cerebral hemorrhages, and psychosis have been reported in previously healthy individuals (Verebey et al). The most important diseases in this category are tetanus, botulism, and diphtheria. Each is caused by an extraordinarily powerful bacterial toxin that acts primarily on the nervous system.


Neurology_Adams

Neurology_Adams. The cause of this disease is the anaerobic, spore-forming rod Clostridium tetani. The organisms are found in the feces of some humans and many animals, particularly horses, from which they readily contaminate the soil. The spores may remain dormant for many months or years, but when they are introduced into a wound, especially if a foreign body or purulent bacteria are present, they are converted into their vegetative forms, which produce the exotoxin tetanospasmin. In developing countries, tetanus is still a common disease, particularly in newborns, in whom the spores are introduced via the umbilical cord (tetanus neonatorum). In the United States, the incidence rate of tetanus is about 1 per million people per year. Injection of contaminated heroin is a significant cause. Approximately 67 percent of all injuries leading to tetanus occur from deep scratches and puncture wounds in the home, and approximately 20 percent from deep scratches and puncture wounds in gardens and on farms.


Neurology_Adams

Neurology_Adams. Since 1903, when Morax and Marie proposed their theory of centripetal migration of the tetanus toxin, it has been taught that spread to the nervous system occurs via the peripheral nerves, the toxin ascending in the axis cylinders or the perineural sheaths. Modern studies, using fluorescein-labeled tetanus antitoxin, have disclosed that the toxin is also widely disseminated via blood or lymphatics, probably accounting for the generalized form of the disease. However, in local tetanus (see Chap. 45), the likely mode of spread to the CNS is indeed by retrograde axonal transport. Mode of Action of Tetanus Toxin


Neurology_Adams

Neurology_Adams. Like botulinum toxin, the tetanus toxin is a zinc-dependent protease. It blocks neurotransmitter release by cleaving surface proteins of the synaptic vesicles, thus preventing the normal exocytosis of neurotransmitter. The toxin interferes with the function of the reflex arc by the blockade of inhibitory transmitters, mainly GABA, at presynaptic sites in the spinal cord and brainstem. The Renshaw cell, the source of recurrent inhibition of spinal and brainstem motor neurons, is preferentially affected. Elicitation of the jaw jerk, for example, is normally followed by the abrupt suppression of motor neuron activity, manifested in the electromyogram (EMG) as a “silent period” (see further on). In the patient with tetanus, there is a failure of this inhibitory mechanism, with a resulting increase in activation of the neurons that innervate the masseter muscles (trismus, or lockjaw). Of all neuromuscular systems, the masseter innervation seems to be the most sensitive to the toxin. Not


Neurology_Adams

Neurology_Adams. in activation of the neurons that innervate the masseter muscles (trismus, or lockjaw). Of all neuromuscular systems, the masseter innervation seems to be the most sensitive to the toxin. Not only do afferent stimuli produce an exaggerated effect, but they also abolish reciprocal innervation, allowing both agonists and antagonists to contract, giving rise to the characteristic muscular spasm of tetanus (see below). In addition to its generalized effects on the motor neurons of the spinal cord and brainstem, there is evidence that the toxin acts directly on skeletal muscle at the point where the axon forms the endplate (accounting perhaps for localized tetanus) and also upon the cerebral cortex and the sympathetic nervous system in the hypothalamus. Many of these features have been reviewed by Sanford.


Neurology_Adams

Neurology_Adams. The incubation period varies greatly, from one or two days after exposure to a month or longer. Long incubation periods are associated with mild and localized types of the disease. There are several clinical types of tetanus, usually designated as local, cephalic, and generalized.


Neurology_Adams

Neurology_Adams. Generalized tetanus This is the most common form. It may begin as local tetanus that becomes generalized after a few days, or it may be diffuse from the beginning. Trismus is frequently the first manifestation. In some cases this is preceded by a feeling of stiffness in the jaw or neck, slight fever, and other general symptoms of infection. The localized muscle stiffness and spasms spread quickly to other bulbar muscles as well as those of the neck, trunk, and limbs. A state of unremitting rigidity develops in all the involved muscles: the abdomen is board-like, the legs are rigidly extended, and the lips are pursed or retracted (risus sardonicus); the eyes are partially closed by contraction of the orbicularis oculi, or the eyebrows are elevated by spasm of the frontalis. Superimposed on this persistent state of enhanced muscle activity are paroxysms of tonic contraction or spasm of muscles (tetanic seizures or “convulsions”), which occur spontaneously or in response to the slightest


Neurology_Adams

Neurology_Adams. this persistent state of enhanced muscle activity are paroxysms of tonic contraction or spasm of muscles (tetanic seizures or “convulsions”), which occur spontaneously or in response to the slightest external stimulus (see Weinstein for a review). They are agonizingly painful. Consciousness is not lost during these paroxysms. The tonic contraction of groups of muscles results in opisthotonos or in forward flexion of the trunk, flexion and adduction of the arms, clenching of the fists, and extension of the legs. Spasms of the pharyngeal, laryngeal, or respiratory muscles carry the constant threat of apnea or suffocation. Fever and pneumonia are common complications. Large swings in blood pressure and heart rate as well as profuse diaphoresis are typical, mainly in response to the intense muscular contractions but they may also be related to the action of the toxin on the CNS. Death is usually attributable to asphyxia from laryngospasm, to heart failure, or to shock, the latter


Neurology_Adams

Neurology_Adams. muscular contractions but they may also be related to the action of the toxin on the CNS. Death is usually attributable to asphyxia from laryngospasm, to heart failure, or to shock, the latter resulting from the action of the toxin on the hypothalamus and sympathetic nervous system.


Neurology_Adams

Neurology_Adams. Generalized spasms and rigidity of trunk and limbs developing in a neonate a few days after birth should always suggest the diagnosis of tetanus. This form of tetanus occurs when there has been inadequate sterile treatment of the umbilical cord stump in a neonate born to an unimmunized mother.


Neurology_Adams

Neurology_Adams. Local tetanus This is the most benign form. The initial symptoms are stiffness, tightness, and pain in the muscles in the neighborhood of a wound, followed by twitchings and brief spasms of the affected muscles. Local tetanus occurs most often in relation to a wound of the hand or forearm, rarely in the abdominal or paravertebral muscles. Gradually, some degree of continuous involuntary spasm becomes evident. There is sustained tautness of the affected muscles and resistance of the part to passive movement. Superimposed on this background of more or less continuous motor activity are brief, intense spasms, lasting from a few seconds to minutes and occurring spontaneously or in response to all variety of stimulation (Struppler et al). Early in the course of the illness there may be periods when the affected muscles are palpably soft and appear to be relaxed. A useful diagnostic maneuver at this stage is to have the patient perform some repetitive voluntary movements, such as opening


Neurology_Adams

Neurology_Adams. when the affected muscles are palpably soft and appear to be relaxed. A useful diagnostic maneuver at this stage is to have the patient perform some repetitive voluntary movements, such as opening and closing the hand, in response to which there occurs a gradual increase in the tonic contraction and spasms of the affected muscles, followed by spread to neighboring muscle groups (recruitment spasm). Even with mild localized tetanus there may be slight trismus, a useful diagnostic sign.


Neurology_Adams

Neurology_Adams. Symptoms may persist in localized form for several weeks or months. Gradually the spasms become less frequent and more difficult to evoke, and they finally disappear without residue. Complete recovery is to be expected, as there are no pathologic changes in muscles, nerves, spinal cord, or brain, even in the most severe generalized forms of tetanus.


Neurology_Adams

Neurology_Adams. Cephalic tetanus This form of tetanus follows wounds of the face and head. The incubation period is short, 1 or 2 days as a rule. The affected muscles (most often facial) are weak or paralyzed. Nevertheless, during accessions of tetanic spasm, the palsied muscles are seen to contract. Apparently, the disturbance in the facial motoneurons is sufficient to prevent voluntary movement but insufficient to prevent the strong reflex impulses that elicit facial spasm. The spasms may involve the tongue and throat, with persistent dysarthria, dysphonia, and dysphagia. Ophthalmoparesis is known to occur but is difficult to verify because of severe blepharospasm. In a strict sense, these cephalic forms of tetanus are examples of local tetanus that frequently becomes generalized. Many cases prove fatal.


Neurology_Adams

Neurology_Adams. This is made from the clinical features and a history of preceding injury. The latter is sometimes disclosed only after careful questioning, the injury having been trivial, forgotten and entirely healed. The organisms may or may not be recovered from the wound by the time the patient receives medical attention; other laboratory tests, apart from the EMG, are of little value. Serum CK may be moderately elevated if the rigidity is generalized. The EMG recorded from muscles in spasm shows continuous discharges of normal motor units like those recorded from a forceful voluntary muscle contraction. Most characteristic of tetanus, as mentioned earlier, is a loss of the physiologic silent period that occurs 50 to 100 ms after reflex contraction. This pause, normally produced by the recurrent inhibition of Renshaw cells, is blocked by tetanus toxin. In generalized tetanus the loss of the silent period can almost always be demonstrated in the masseter, and it is found in a muscle affected by


Neurology_Adams

Neurology_Adams. of Renshaw cells, is blocked by tetanus toxin. In generalized tetanus the loss of the silent period can almost always be demonstrated in the masseter, and it is found in a muscle affected by local tetanus. Interestingly, the silent period is preserved in the stiff man syndrome (see Chap. 45).


Neurology_Adams

Neurology_Adams. Tetany caused by hypocalcemia, the spasms of strychnine poisoning or black widow spider bite, trismus as a result of painful conditions in and around the jaw, the dysphagia of rabies, hysterical spasms, rigidity and dystonic spasms caused by neuroleptic drugs, and the spasms of the stiff man syndrome all resemble the spasms of tetanus but should not be difficult to distinguish when all aspects of these disorders are considered. Nonetheless, the diagnosis is difficult to bring to mind in a nonendemic area. The death rate from tetanus is approximately 50 percent overall; it is highest in newborns, heroin addicts, and patients with the cephalic form of the disease. The patient usually recovers if there are no severe generalized muscle spasms during the course of the illness or if the spasms remain localized.


Neurology_Adams

Neurology_Adams. This is directed along several lines. At the outset, a single dose of antitoxin (3,000 to 6,000 U of tetanus human immune globulin) should be given along with a 10-day course of penicillin (1.2 million U of procaine penicillin daily), metronidazole (500 mg q6h intravenously or 400 mg rectally), or tetracycline (2 g daily). These drugs are effective against the vegetative forms of C. tetani. Immediate surgical treatment of the wound (excision or debridement) is imperative, and the tissue around the wound should be infiltrated with antitoxin.


Neurology_Adams

Neurology_Adams. Survival depends on expert and constant nursing in an intensive care unit and may be necessary for weeks. Tracheostomy is a requisite in all patients with recurrent generalized tonic spasms and should not be delayed until apnea or cyanosis has occurred. The patient must be kept as quiet as possible to avoid stimulus-induced spasms. This requires a darkened, quiet room and the judicious use of sedation. The benzodiazepines are the most useful drugs for both sedation and muscle relaxation; diazepam 120 mg/d or more can be given in frequent divided doses if ventilatory support is available; alternatively, midazolam or propofol can be used in a continuous intravenous infusion. Short-acting barbiturates and chlorpromazine may also be useful, as may be morphine. Intrathecal baclofen and continuous atropine infusions have been used with success in severe cases, and intramuscular injections of botulinum toxin may be used for trismus and local spasm. The aim of therapy is to suppress muscle


Neurology_Adams

Neurology_Adams. atropine infusions have been used with success in severe cases, and intramuscular injections of botulinum toxin may be used for trismus and local spasm. The aim of therapy is to suppress muscle spasms and to keep the patient drowsy to avoid the horrible discomfort of the spasms. All treatments and manipulations should be kept to a minimum and coordinated so that the patient may be sedated beforehand.


Neurology_Adams

Neurology_Adams. Failure of these measures to control the tetanic paroxysms requires that intravenous administration of neuromuscular blocking agents such as pancuronium or vecuronium be used to abolish all muscle activity; appropriate sedative medication is instituted for as long as necessary, breathing being maintained by mechanical ventilation. Many intensive care units favor the use of neuromuscular paralytic drugs in all but the mildest cases. Further details concerning treatment can be found in the review by Farrar and colleagues.


Neurology_Adams

Neurology_Adams. All persons should be immunized against tetanus and receive a booster dose of toxoid every 10 years—a practice that is frequently neglected in the elderly. Injuries that carry a threat of tetanus should receive toxoid if the patient has not received a booster injection in the preceding year, and a second dose of toxoid is needed 6 weeks later. If the injured person has not received a booster injection since the original immunization, he should receive an injection of both toxoid and human antitoxin; the same applies to the injured person who has never been immunized. An attack of tetanus does not confer permanent immunity and persons who recover should be actively immunized. Diphtheria, an acute infectious disease caused by


Neurology_Adams

Neurology_Adams. Diphtheria, an acute infectious disease caused by Corynebacterium diphtheriae, is now quite rare in the United States and Western Europe. The faucial-pharyngeal form of the disease, which is the most common clinical type, is characterized by the formation of an inflammatory exudate of the throat and trachea; at this site, the bacteria elaborate an exotoxin, which affects the heart and nervous system in approximately 20 percent of cases.


Neurology_Adams

Neurology_Adams. The involvement of the nervous system follows a predictable and biphasic pattern (Fisher and Adams). It begins locally, with palatal paralysis (nasal voice, regurgitation, and dysphagia) between the 5th and 12th days of illness. At this time or shortly afterward, other cranial nerves (trigeminal, facial, vagus, and hypoglossal) may also be affected. Ciliary body paralysis with loss of accommodation and blurring of vision but with preserved light reaction usually appears in the second or third week (the opposite of the Argyll Robertson reaction). Rarely, the extraocular muscles are weakened. The cranial nerve signs may clear without further involvement of the nervous system, or a delayed sensorimotor polyneuropathy may develop between the fifth and eighth weeks of the disease. The latter varies in severity from a mild, predominantly distal polyneuropathy of the limbs to a rapidly evolving, ascending paralysis, like that of the Guillain-Barré syndrome; CSF findings are similar as well


Neurology_Adams

Neurology_Adams. varies in severity from a mild, predominantly distal polyneuropathy of the limbs to a rapidly evolving, ascending paralysis, like that of the Guillain-Barré syndrome; CSF findings are similar as well (acellular fluid with elevated protein). The neuropathic symptoms progress for a week or two, and if the patient does not succumb to respiratory paralysis or cardiac failure (cardiomyopathy), these conditions stabilize and then improve slowly and more or less completely.


Neurology_Adams

Neurology_Adams. The early oropharyngeal symptoms, the ciliary paralysis with relatively retained pupillary response to light, and subacute evolution of a delayed symmetrical sensorimotor peripheral neuropathy distinguish diphtheria from other forms of polyneuropathy. The long latency between the initial infection and the involvement of the nervous system has no clear explanation. In experimental animals, Waksman and colleagues demonstrated that the toxin reaches the Schwann cells in the most vascular parts of the peripheral nervous system within 24 to 48 h of infection but its metabolic effect on cell membranes extends over a period of weeks. The toxin produces demyelination in the proximal parts of spinal nerves, in dorsal root ganglia, and in spinal roots. The cardiac musculature and the conducting system of the heart undergo mild focal necrosis.


Neurology_Adams

Neurology_Adams. The source of diphtheritic infection may be extrafaucial—a penetrating wound, skin ulcer, or infection of the umbilicus in the neonate. The systemic and neurologic complications of faucial diphtheria can also be observed in the extrafaucial form of the disease (wound infection) after a similar latent period. It is probable, therefore, that the toxin reaches neural sites via the bloodstream; but in addition, some action is exerted locally, as evidenced by palatal paralysis in faucial cases and by initial weakness and sensory impairment in the neighborhood of the infected wound. There is no specific treatment for the neurologic complications of diphtheria. It is generally agreed that the administration of antitoxin within 48 h of the earliest symptoms of the primary diphtheritic infection lessens the incidence and severity of the peripheral nerve complications. The polyneuropathy of diphtheria is discussed further in Chap. 43 (see also McDonald and Kocen).


Neurology_Adams

Neurology_Adams. Botulism is a rare form of food-borne illness caused by the exotoxin of Clostridium botulinum. Outbreaks of poisoning are most often caused by ingested bacteria contained in home-preserved than in commercially canned products, and vegetables and home-cured ham are incriminated more commonly than are other food products. Very rarely, a contaminated wound is the source of infection. Although the disease is ubiquitous, five western states (California, Washington, Colorado, New Mexico, and Oregon) account for more than half of all reported outbreaks in the United States. Neonatal and infantile forms of the disease have been reported. These are a result of absorption of the toxin formed by germination of ingested spores (rather than ingestion of preformed toxin), an important source of which is contaminated natural (raw) honey. A few adult cases may have a similar source.


Neurology_Adams

Neurology_Adams. It is now well established on the basis of observations in both animals and humans that the primary site of action of toxin is at a neuromuscular junction, more specifically on the presynaptic membrane. The toxin interferes with the release of acetylcholine from peripheral motor nerves at the neuromuscular synapse. The physiologic defect is similar to the one that characterizes the myasthenic syndrome of Lambert-Eaton (see Chap. 46) but different from that of myasthenia gravis.


Neurology_Adams

Neurology_Adams. Symptoms usually appear within 12 to 36 h of ingestion of the tainted food. Anorexia, nausea, and vomiting occur in most patients. As a rule, blurred vision and diplopia are the initial neural symptoms; their association with ptosis, strabismus, and extraocular muscle palsies, particularly of the sixth nerve, may at first suggest a diagnosis of myasthenia gravis. In botulism, however, accommodation is lost and the pupils are often unreactive to light. Other symptoms of bulbar involvement—nasality of voice, hoarseness, dysarthria, dysphagia, and an inability to phonate—follow in quick succession. These, in turn, are followed by progressive weakness of the muscles of the face, neck, trunk, and limbs, and by respiratory insufficiency. Despite the oropharyngeal weakness, it is not unusual for the gag reflex to be retained. Tendon reflexes are lost in cases of severe generalized weakness. These symptoms and signs evolve rapidly, over 2 to 4 days as a rule, and may be mistaken for those of