Toxic Damage to the Nervous System

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[edit] Toxic Damage to the Nervous System

William Pryse-Phillips

T. Jock Murray

James Boyd

Many chemicals, drugs, and other agents may cause permanent or reversible damage to the central nervous system (CNS). When it is recalled that over 10% of inpatients at any one time have primary symptoms related to toxicity from treatment agents (as opposed to intrinsic disease), it will be understood that a knowledge of intoxications is of great importance. Sometimes the CNS symptom results from the normal pharmacologic actions of a drug (e.g., coma with sedative overdose). Sometimes it will be due to direct damage to neurons (e.g., lead or carbon monoxide poisoning). Competition for enzymes in the nervous system or in the liver may also produce symptoms; thus phenothiazines may produce dyskinesias, phenytoin induces rickets, and isoniazid induces neuropathy through pyridoxine deficiency. Other methods include alterations in the secretion or drainage of cerebrospinal fluid (CSF), producing intracranial hypertension, and in the membrane potential on the neurons, with resultant epilepsy. Other toxic effects still cannot be explained, such as the production of glare photophobia related to tridione use.

[edit] DRUGS DIRECTLY AFFECTING CENTRAL NERVOUS SYSTEM FUNCTION

[edit] Encephalopathy

Many drugs and toxins can result in alteration in consciousness, personality change, delirium, seizures, lethargy, raised intracranial pressure (ICP), or coma with or without focal signs of neurologic dysfunction and with evidence of intact brainstem function (Box 166-1).

[edit] Seizures

Epileptic seizures may occur in patients taking a variety of drugs, sometimes in normal dosage; but in other situations, seizures only occur in the presence of toxic levels of a given drug or if the patient has a preexisting low threshold for seizures (Box 166-2). Usually, the manifestation is of generalized epilepsy, but if there is any preexisting brain disease that had not formerly produced seizures, the reduction of threshold caused by the toxic agent may produce a focal seizure.

[edit] Dementia

Dementing syndromes are usually regarded as being irreversible, but in the case of drug-induced dementia this is incorrect. Focal neurologic signs referable to the frontal lobe, the cerebellum, or the basal ganglia may also be present along with the altered mental state. It is even more common for patients with organic brain syndromes to have their conditions worsened by drugs, particularly sedatives, hypnotics, and tranquilizers; dialysis is another cause. In recent years progressive dementia caused by solvent sniffing (e.g., glue, gasoline) has become an increasing problem (Box 166-3).

[edit] Insomnia

Insomnia is obviously to be expected with stimulants such as methylphenidate and caffeine, but other agents are also able to produce insomnia (Box 166-4).

[edit] Reduction in Levels of Consciousness

Patients who are comatose as a result of drugs and toxins ingested show evidence of normal brainstem function with retained doll's head movements and ice-water caloric responses and with normal pupillary reactions. This is not true with drugs that have an anticholinergic effect (Box 166-5). Respiratory and/or cardiovascular depression may be marked and cause further brain damage from hypoxia. In severe intoxication the electroencephalogram (EEG) may be isoelectric; this is not a sign of brain death in this circumstance. Almost any drug in sufficient quantity can cause coma.

[edit] Stroke

Indirect causes of stroke are legion, operating as risk factors through the mechanism of accelerated atherosclerosis or induction of hypertension. Direct causes are few; cocaine (especially in the form of “crack”) is a prime example. Oral contraceptives may increase the risk of stroke, especially in women with migraine headaches.

[edit] Extrapyramidal Syndromes

[edit] Chorea.

Some patients who have had Sydenham's chorea in childhood, usually women, may again develop abnormal jerking movements if they are given l-dopa or phenytoin. Choreic movements in patients with Parkinson's disease treated with l-dopa are a common toxic manifestation. Agents that may cause chorea are listed in Box 166-6.

[edit] Parkinsonism.

The four classic features of parkinsonism (tremor, rigidity, akinesia, and postural changes) are produced by a number of agents. Tremor, however, is less prominent in drug-induced parkinsonism. Drugs may also induce oculogyric crises, which are otherwise only seen in the postencephalitic form of parkinsonism. The effects are reversible when the drug is withdrawn. Responsible agents are listed in Box 166-6.

Following MPTP, cyanide, CS2, or CO poisoning, and with most other causes of severe hypoxia, a parkinsonian syndrome may occur, but without oculogyric crises and due to permanent neuronal damage in the basal ganglia. It should be noted that although tricyclic drugs may produce a parkinsonian syndrome rarely, they are also of value in treatment of depression in Parkinson's disease.

[edit] Acute Extrapyramidal Symptoms.

The severe disorders of movement included under this heading include dystonias, facial tics and spasms, and akathisia. The symptoms usually occur in young males given bromocriptine, butyrophenones, phenothiazines (with a piperazine ring), phenytoin, or metoclopramide and also in people stung by insects. In older patients, methyldopa, tricyclics, and levodopa produce severe extrapyramidal symptoms of this type. Cyanide is an unusual cause of dystonia.

Akathisia and other dyskinesias may also occur with benztropine, which is otherwise a reasonable choice among synthetic anticholinergic agents used to treat parkinsonism and which can be given intramuscularly in doses of 1 to 2 mg for acute extrapyramidal symptoms. Intramuscular diphenydramine or intravenous diazepam, 10 to 20 mg given slowly, usually stops the acute symptoms in these cases, but it must be coupled with withdrawal or reduction in the dose of the drug. Intravenous diazepam is most safely given when respiratory support is available, should it be required.

[edit] Tremor.

Regular and repetitive tremor, usually fast and of small amplitude (thus not very much like that of Parkinson's disease), can be produced by amiodarone, oral beta-agonists, cyclosporine, ephedrine, epinephrine and all sympathomimetics, lithium, metoclopramide, sodium valproate, tacrolimus (an immunosuppressant), theophylline and other methylxanthines, thyroxine, tricyclics, and vidarabine.

[edit] Cerebellar Ataxia.

The usual cerebellar syndrome with horizontal jerk nystagmus, limb or truncal ataxia, and failure of motor control may be due to such agents as seen in Box 166-6.

[edit] Nystagmus.

Toxicity may cause both horizontal and vertical jerk nystagmus to occur without other evidence of a cerebellar syndrome. Cerebellar connections are probably involved, but there may also be damage to the medial longitudinal fasciculus. Substances incriminated include amiodarone, barbiturates, phenytoin, carbamazepine, primidone, glucose (in vitamin B₁-deficient subjects), and 5-fluorouracil.

[edit] Myelopathy.

Spinal diseases are discussed in Chapter 127 . Upper motor neuron and long tract signs, usually without a discrete cord level and with or without evidence of anterior horn cell or dorsal root ganglion cell involvement, can occur with the agents listed in Box 166-6. Tetracycline and colchicine may induce vitamin B₁₂ deficiency with resulting myelopathy.

[edit] DRUGS AFFECTING OTHER INTRACRANIAL COMPONENTS

[edit] Meningism

Stiff neck with positive Kernig's and Brudzinski's signs, fever, and photophobia may occur as a drug reaction. The CSF usually contains either no cells or only a few mononuclear cells, but the pressure may be slightly raised. The CSF should be sterile on culture. Agents responsible for causing meningism are listed in Box 166-7.

[edit] Chemical Meningitis.

Meningism may occur after intrathecal injection of a number of agents, in which case the CSF contains many mononuclear cells, increased protein, and sometimes reduced sugar levels. Agents responsible for causing chemical meningitis are listed in Box 166-7.

[edit] Fungal Meningitis.

The picture of acute or chronic meningitis with markedly raised protein, low sugar, mainly mononuclear cells, and the presence of fungi (usually Candida albicans) may complicate treatment with immunosuppressive agents and steroids. Fungal meningitis may also be seen in patients with diabetes or with alcoholism.

[edit] Idiopathic Intracranial Hypertension

Idiopathic intracranial hypertension is characterized by papilledema unaccompanied by focal neurologic signs and investigations are negative. A computed tomography (CT) scan shows the ventricles to be normal or small in size. The patient's usual complaint is headache, sometimes with visual obscurations. Substances that can produce this syndrome are listed in Box 166-7.

[edit] Migrainous and Other Vascular Headaches

Typical vascular headaches may occur de novo, or preexisting migraine may be made more severe or more frequent if the patient takes substances listed in Box 166-7. Headaches caused by a sudden marked rise in systolic blood pressure may occur in patients who eat foods high in tyramine while they are taking MAO inhibitors. Other causes of vascular headache include ingestion of alcohol by patients who are taking disulfiram. Withdrawal from caffeine is a common but poorly recognized cause of headaches.

[edit] DRUGS AFFECTING NERVES

[edit] Cranial Nerves

Parosmia is a common result of the chronic use of nasal decongestant sprays and drops, which causes severe damage to the unmyelinated fibers of the first nerve. In time, loss of olfactory acuity supervenes. Toluene also causes hyposmia.

[edit] Optic Atrophy.

Pallor of the optic discs may be caused by the agents in Box 166-8, from which it will be seen that many are either derivatives of the original sulfonamide drugs or are agents used in the treatment of rheumatoid arthritis. Visual acuity may not be greatly affected despite marked primary optic atrophy.

[edit] Subacute Myeloopticoneuropathy.

A virtual epidemic of a disease marked by optic neuropathy, encephalopathy, and transverse myelopathy has occurred in Japan and in the Western world in the last 10 years. The distinction from multiple sclerosis is hard to make, but the CSF is normal. Toxicity from halogenated hydroxyquinolines (EnteroVioform) and/or a herpes-related virus are incriminated.

[edit] Miosis.

Small pupils that do not appear to react but are not usually associated with any subjective complaint may occur with the use of opiates, pilocarpine, organophosphates, sedatives, and physostigmine.

[edit] Mydriasis.

Dilation of the pupils bilaterally, with subjective difficulty in accommodation and focusing and sometimes with photophobia, may occur as a drug effect. In such cases, pupillary constriction to light may be reduced. Drugs responsible include: amphetamines, antihistamines, cocaine, disopyramide, glutethimide, haloperidol, l-dopa, muscarinic blockers (e.g., atropine), phenothiazines, phenytoin, and tricyclics.

[edit] Ophthalmoplegia.

Carbamazepine and tricyclic drugs have been incriminated as causes of ophthalmoplegia in cases of overdose. Beta-blocking drugs may cause diplopia. Chymopapain has been the cause of a third nerve palsy.

[edit] Trigeminal Sensory Loss.

Trigeminal sensory loss is usually unilateral but can extend to both sides of the face in any of the three divisions of the nerve. Apart from the patient's subjective complaint of numbness, which is objectively verifiable, no motor signs and no other sensory changes are usually detected. The agents that are responsible include stilbamidine, trilene (a solvent), and streptomycin.

[edit] VII Nerve Palsy.

Unilateral facial palsy is more common in women taking oral contraceptives. Angiotensin-converting enzyme (ACE) inhibitors, clarithromycin, cisplatin, penicillamine, synthetic thyrotropin-releasing hormone (TRH), and zopiclone may alter taste sensation.

[edit] VIII Nerve Involvement.

Different agents affect the cochlear and vestibular components of the VIII nerve to a different extent. The typical picture is of vestibular impairment with streptomycin, compared with the primarily cochlear damage caused by dihydrostreptomycin, neomycin, cisplatin/carboplatin, kanamycin, and valproic acid. However, both divisions are involved to some extent with most of the drugs listed in Box 166-9.

[edit] Impairment of Taste Sensation.

Agents that can impair taste sensation include ACE inhibitors, cisplatin, clarithromycin, penicillamine, synthetic TRH, and zopiclone.

[edit] Recurrent Laryngeal Palsy.

Recurrent laryngeal palsy is an uncommon complication of the vinca alkaloids.

[edit] Peripheral Nerves

Most of the agents listed in Box 166-10 have been shown to produce neuropathy. In some, the association is less certain. In almost all cases, the pathology is primary axonal degeneration with secondary demyelination, but primary Schwann-cell damage is a possible cause. The clinical picture produced is of distal symmetric polyneuropathy. In patients with diabetes or rheumatoid arthritis and associated neuropathy, steroids seem to worsen the condition, perhaps by damaging the small vasa nervorum. Steroid withdrawal may be involved in the severe neuropathy that occurs in some patients with rheumatoid arthritis. Sensory functions are almost invariably affected first, and motor involvement is seen less severely and at a later stage.

[edit] Autonomic Nerves

[edit] Impotence.

Most drugs that cause impotence are either ganglion blockers or specific parasympatholytics, but most antihypertensives, including thiazide diuretics, are causal. Other responsible agents include anticholinergic drugs, barbiturates, ganglion blockers, guanethidine, haloperidol, phenothiazines, primidone, thioridazine, tricyclic drugs, and vasodilators.

[edit] DRUGS AFFECTING MUSCLE

[edit] Myopathy

The usual features of primary proximal muscle disease with atrophy and weakness and usually without pain can occur in patients who have taken drugs listed in Box 166-11.

Hypokalemia secondary to the administration of diuretics, liquorice, or amphotericin B may also be associated with severe proximal weakness, pain, and wasting. Intramuscular paraldehyde, phenytoin, and lidocaine cause local pain, muscle fibrosis, and atrophy. Clofibrate and the other drugs above may cause elevation of serum creatine kinase (CK) levels. Phenytoin may cause metabolic bone disease associated with proximal myopathy. l-Tryptophan can cause the newly diagnosed eosinophilia-myalgia syndrome.

[edit] Neuromuscular Blockade

The cardinal symptom of myasthenia is fatigability, particularly seen in the ocular bulbar and proximal limb muscles. Patients with myasthenia may have an exacerbation of their symptoms, or a myasthenia-like syndrome may occur in patients without previous evidence of that condition in the presence of hypokalemia from any cause, such as steroids, muscle relaxants, or ether, or after enemas or wasp stings. Botulinum toxin is designed to induce this symptom, but may diffuse away from the region injected to produce systemic fatigability. The drugs listed in Box 166-12 tend to increase neuromuscular block and should not be given to patients with myasthenia gravis. In the event of myasthenic symptoms being produced or exacerbated when these agents are administered, intravenous calcium may reverse the immediate severe weakness and fatigability.

[edit] Acute Muscle Necrosis

Acute muscle necrosis, an uncommon complication of a number of drugs, produces a rise in serum CK levels and myoglobinuria with pain and proximal weakness. It is more likely to happen in patients who are dehydrated. Agents incriminated include alcohol, amphetamines, amphotericin, barbiturates, carbenoxolone, diazepam, epsilon amino caproic acid (EACA), heroin, INH, methadone, and phencyclidine.

[edit] Muscle Cramps

Drugs that can cause muscle cramps are listed in Box 166-13.

[edit] Malignant Hyperpyrexia

Malignant hyperpyrexia is a genetically determined syndrome that may be precipitated by a number of drugs in susceptible patients who have subclinical myopathy but often raised serum CK levels. These drugs include anesthetics (inhalational and local), tricyclic drugs, MAO inhibitors, and succinylcholine.

[edit] Fasciculations

Brief rippling, irregular contractions of motor units occur in patients poisoned with organophosphorus compounds and patients undergoing anesthesia who are given succinylcholine as a muscle relaxant. Neuromyotonia may be caused by penicillamine.

[edit] DRUGS WITH AN INDIRECT EFFECT ON THE CENTRAL NERVOUS SYSTEM

[edit] Inappropriate ADH Syndrome

Inappropriate ADH syndrome may be induced by carbamazepine, carbenoxolone, chlorpropamide, cyclophosphamide, fluphenazine, oxytocin, thiothixene, thioridazine, theophylline (and other methylxanthines), and vincristine.

[edit] Hypoglycemia

Propranolol may mask the signs and symptoms of hypoglycemia and must be carefully used in diabetics. The usual symptoms and signs of hypoglycemia may be induced by alcohol, insulin, and sulfonylureas (especially if used with phenylbutazone or salicylates).

[edit] Alterations in Blood Pressure

The clinical manifestations of hypotension and hypertension will not be described here, nor shall we attempt to list any of the huge range of drugs that affects blood pressure. Any patient with abnormal blood pressure readings, or even symptoms of postural hypotension, should be questioned carefully about all drugs taken because these drugs are often at least partly responsible for the abnormality. The dangers of taking sympathomimetic drugs (including cold remedies), meperidine, phenothiazines, methyldopa, and numerous foods at the same time as MAO inhibitors may be mentioned again in this context because headaches, subarachnoid or intracerebral hemorrhage, delirium, or severe hypertension may result. Carbamazepine may cause Stokes-Adams attacks with loss of consciousness.

[edit] Hypercoagulability

The increased susceptibility to venous (and possibly to arterial) thrombotic occlusions in women taking oral contraceptives has been noted.

[edit] Vasculitis

Vasculitis may complicate ingestion of organic arsenicals, iodides, DDT, mercurial diuretics, gold, phenothiazines, hydantoins, and sulfonamides and their derivatives. These same agents, along with those that follow, have been incriminated in the production of the syndrome of onset of systemic lupus erythematosus (SLE): carbamazepine, griseofulvin, hydralazine, isoniazid, methyldopa, PAS, phenylbutazone, phenytoin, procainamide, streptomycin, and tetracycline.

[edit] MISCELLANEOUS ASSOCIATIONS

[edit] Neoplasia

Lymphoma has been described in patients who have been given immunosuppressive agents after renal transplantation and in patients taking phenytoin. Although lymphoma is an uncommon neurologic malignancy, lymphomas may present with features of chronic basal meningitis, scattered demyelination, and, rarely, intracranial mass lesions.

[edit] Photophobia

Complaints of pain in the eyes and excessive glare may be heard in any patient with dilated pupils caused by the use of mydriatics, and in patients taking lithium. Glare photophobia is commonly associated with the use of trimethadione, an antiepileptic drug of slight value in true petit mal epilepsy.

[edit] INTERACTIONS INVOLVING DRUGS USED IN NEUROLOGY

[edit] Enzyme Induction

Through enzyme induction, warfarin and phenytoin may be mutually antagonistic and less clinically effective. Phenytoin, phenobarbitone, and valproic acid induce hepatic microsomal enzymes. Although a reduction in the availability of each drug would be expected, serum levels nevertheless usually change but little. Drugs that inhibit oral anticoagulants include barbiturates, tranquilizers, meprobamate, and tricyclics.

Interactions between anticonvulsants are many and involve increased or decreased metabolism, substrate competition, and reduced absorption. In addition, serum phenytoin levels may be markedly increased or decreased by other drugs, and phenytoin, phenobarbital, or carbamazepine may reduce other drug levels.

[edit] The Serotonin Syndrome

The serotonin syndrome is a constellation of symptoms that occur after the use of serotonomimetic agents, alone or in combination with MAOIs, that are typically seen soon after initiation, dose increase, or addition of another agent. It was originally detected in animals given l-tryptophan and MAOIs or other 5HT precursors, producing a hypermetabolic state with fever, myoclonus, involuntary movements, and autonomic overactivity. Hyperstimulation of 5HT 1a receptors in the brainstem and spinal cord can lead to the following clinical features:

• Change in mental status (confusion, disorientation, impaired judgment and planning, agitation)
  
• Headache, coma
  
• Myoclonus, rigidity, multifocal myoclonus, incoordination, hyperreflexia
  
• Dysautonomia (dilated pupils, sweating, low-grade fever, nausea, diarrhea, tachycardia, tachypnea, increased blood pressure, flushing, shivering)
  
• Rarely, high fever, nystagmus, oculogyric crises, dysarthria, pyramidal syndrome, myoglobinuria, renal failure, disseminated intravascular coagulation (DIC), cardiac arrhythmia, death
  

Mild and partial manifestations of the syndrome (e.g., slight confusion, occasional myoclonus, headache, restlessness, impaired concentration) are probably rather common and underdiagnosed (Box 166-14).

Often no treatment is needed because symptoms usually remit after withdrawal of the selective serotonin reuptake inhibitor (SSRI) or the other drug. In general, one should observe electrolytes and vital signs and treat deviations from normal levels (e.g., cooling if required using aspirin and intravenous fluids). Serotonin antagonists such as cyproheptadine, 4 mg orally tid, or methysergide and propranolol may be useful but their value is unproven. For muscle rigidity and myoclonus, clonazepam, lorazepam, benztropine, diphenhydramine, or chlorpromazine should be of benefit.

Many of the drugs listed in Box 166-14 enhance serotonin activity by blocking its reuptake and increasing presynaptic release. Bromocriptine is a 5HT agonist. l-Dopa myoclonus likely is due to serotonomimetic activity. Lithium is able to enhance all aspects of the syndrome, but it has not so far been reported with 5HT1b/d agonists such as the triptans, although the package insert lists many of its components as potential side effects. One should not prescribe SSRIs and MAOIs within 2 months of each other.

An imbalance of 5HT and dopamine may cause a relatively hypodopaminergic state capable of inducing neuroleptic malignant syndrome, which is characterized by changes in mental state; muscle rigidity; severe hyperthermia; autonomic nervous system dysfunction; hypertension or hypotension; fever; cardiac arrhythmias; and a huge rise in CK levels. Treatment is with dantrolene and muscle paralysis. The overlap of the two conditions is notable.

[edit] THE NEUROLOGIC COMPLICATIONS OF ALCOHOL

The complications of alcohol abuse include those related to acute intoxication, withdrawal, and nutritional disease in chronic alcoholism, but there is also a group of CNS disorders that occurs in alcoholics that is due to unknown causes. A chronic alcoholic is a person whose dependence on alcohol interferes with his health, interpersonal relationships, social adjustments, job, or economic efficiency. About 5% of the adult population are so classifiable, constituting one of the major health problems in North America.

[edit] Intoxication

[edit] Acute Drunkenness.

The symptoms of acute alcoholic intoxication are well known. Initial exhilaration, relaxation, and excitement are followed by signs of decreased inhibition, slurred speech, ataxia, irritability, combativeness, and drowsiness. After very heavy drinking, the person may pass into a state of stupor and possibly even into coma. Because 90% of the ingested alcohol is oxidized by the liver at a fairly constant rate, the time taken to recover from the bout is variable. However, the next morning the ghost of the evening past may return in the form of a vascular headache with its accompanying irritability, nausea, hyperacusis, photophobia, and anorexia. Although eating increases the metabolism and slows absorption of alcohol somewhat, most methods of treating a hangover are probably ineffective.

[edit] Pathologic Intoxication.

Occasionally a person develops a marked excitatory response to even a small amount of alcohol. Symptoms of this acute psychosis include excessive excitement, combativeness, destructive behavior, and motor restlessness. The patient should be sedated and protected until the episode has passed, usually in a few hours.

[edit] Alcoholic Coma.

Because alcohol depresses both subcortical (brainstem) and cortical structures in the same way as do anesthetics, a patient who ingests a large amount may pass through a state of stupor to actual coma. With high blood levels of ethanol (300 mg/dl), reduction in consciousness is usual, but this may also occur at lower levels. A comatose patient with alcohol on his breath may have any number of different problems, and the coma may have nothing to do with drinking. He or she could be comatose from alcohol, but also from a seizure, a head injury, a subdural hematoma, hypoglycemia, or a cerebral infarction. He or she may have ingested other drugs with the alcohol in a suicide attempt. Occasionally a well-meaning bystander tries to revive an unconscious person with brandy or whiskey, so the patient arrives in the emergency room with the smell of alcohol on his breath. Meningitis, pneumonia, liver failure, or gastrointestinal hemorrhage may be present in an alcoholic who has a decreased level of consciousness. The patient will require intravenous glucose and saline. Thiamine should be added to glucose because Wernicke-Korsakoff syndrome can be precipitated by glucose infusion in someone who is thiamine deficient. Gastric lavage is not helpful because alcohol is absorbed too rapidly from the gastrointestinal tract. The patient should be placed in a semiprone position to avoid aspiration: failing that, intubation may be needed.

[edit] Alcohol Withdrawal Symptoms

[edit] Alcoholic Tremulousness.

In a chronic alcoholic, even one night without alcohol may produce the early symptoms of withdrawal, including tremulousness, irritability, headache, anorexia, sweating, depression, and anxiety. An alcoholic quickly learns that another drink in the morning will relieve “the shakes.” If he or she cannot get any alcohol, the tremulousness increases to a peak at 24 hours and is associated with general irritability, nausea, and vomiting. The face is flushed and the conjunctivae are injected. He or she appears generally weakened, with a rapid pulse and an irregular gross tremor that involves the hands and forearms, though it can be generalized and so marked that the patient has difficulty walking, speaking, or eating. Alcoholics are extremely susceptible to startle and tend to remain preoccupied with their own misery and relatively inattentive to those around them. They should be encouraged to eat and drink fluids and should be given moderate doses of chlordiazepoxide, lorazepam, or chlorpromazine. A multivitamin preparation should be given, particularly to provide vitamin B₁.

If hospitalized for a few days an alcoholic patient will get over the most uncomfortable period of withdrawal and may be able to accept long-term help, but to discharge an alcoholic from the emergency room will almost certainly send him or her back to alcohol as a form of relief.

[edit] Alcoholic Hallucinosis.

The tremulous patient in withdrawal may develop fearful visual or auditory hallucinations similar to bad dreams that result from rebound after the deprivation of rapid eye movement (REM) sleep that occurs while drinking. This state is treated like acute tremulousness. An unusual variant of this is the more persistent auditory hallucinosis. In this form, the hallucinations are of voices that are often reproachful, critical, or threatening. The episode usually lasts about a week but occasionally much longer. Although initially the alcoholic lacks insight, he or she begins to question the voices' reality as the episode ends and thereafter can discuss the contents of these abnormal experiences.

[edit] Alcohol Withdrawal Seizures.

The withdrawal seizures of alcoholism are of generalized type. Ninety percent of them occur within 48 hours of the last drink. Usually there is only one seizure. Tremulousness and hallucinosis also occur and may be followed by delirium tremens (the “DTs”), but seizures do not follow the appearance of delirium. Seizures caused by the withdrawal of alcohol have been termed “rum fits,” but it is important to remember that people with a low convulsive threshold for other reasons may have seizures provoked by alcohol or its withdrawal. Thus some epileptic persons may have seizures whether they drink a little alcohol or a lot. If the seizure is focal (“partial”) in type, then a focal lesion is present and the patient does not have rum fits. Respiratory alkalosis and a low serum magnesium level may be factors in the advent of withdrawal seizures. Alcohol can also induce hypoglycemia in 6 to 12 hours, possibly caused by a reduction in the amount of glycogen stored in the liver through a reduction in the capacity for hepatic gluconeogenesis; this may be another cause of seizures.

Anticonvulsants are not usually required after a single withdrawal seizure, and long-term anticonvulsants are neither logical nor practical because both cause and prevention lie in the alcoholism. However, prophylactic carbamazepine may prevent seizure occurrence and decrease withdrawal symptoms. In rare instances status epilepticus develops.

[edit] Delirium Tremens

[edit] Clinical Features.

After 12 to 24 hours without alcohol, the chronic alcoholic may become irritable, nauseated, sweaty, restless, sleepless, and tremulous, with the dramatic appearance of delusions, confusion, irritability, vivid hallucinations, and marked agitation. Other evidence of increased autonomic activity includes fever, dilated pupils, hypertension, and tachycardia. In this state it is hard to keep the patient calm because his or her agitation reflects confusion, fear of delusions, and hallucinations. An irregular tremor involves the hands, face, and tongue and is increased with activity. A tendency to tug at clothing and bedclothes is also characteristic. Speech becomes more difficult to understand, and screaming, whimpering, and mumbling of garbled sentences may follow.

The DTs may clear after a week, almost as quickly as they developed, leaving the patient with little memory of the delirious period. Patients may die during the acute stage because of hyperthermia, hypokalemia, and peripheral circulatory collapse, but the cause of death cannot always be determined.

Management of these cases includes a search for other underlying problems, including infection, subdural hematoma, and meningitis. Correction of fluid and electrolyte imbalance and the addition of thiamine are vital steps. Shock should be treated immediately with fluids and vasopressor drugs, and if hyperthermia develops, ice packs, fans, and a cooling mattress should be used. The patient's room should be well-lighted because he or she will be fearful of every shadow. Sound should be kept to a minimum, and the patient requires continuous reassurance. Family members are sometimes helpful in keeping the patient calm. High doses of chlordiazepoxide (25 to 50 mg every 6 hours), lorazepam, or chlorpromazine help to reduce agitation and consequent exhaustion. Steroids should not be used except in the event of shock, but propranolol may be useful for the agitated, tremulous patient with autonomic overactivity. Small doses of alcohol have been used as a temporary measure.

[edit] Nutritional Disorders

[edit] Wernicke-Korsakoff Syndrome.

In 1881 Karl Wernicke described three patients with similar symptoms. Two were alcoholic and one was a young woman with chronic vomiting after a suicide attempt in which she had ingested sulfuric acid. Symptoms included in the Wernicke syndrome are ophthalmoplegia, ataxia, and mental disturbance resulting from edema, petechiae, and demyelination in the walls of the third and fourth ventricles and aqueduct and in the medial dorsal nucleus of the thalamus and mammillary bodies. It can occur with any chronic cause of thiamine deficiency but is more common in alcoholism. Korsakoff psychosis refers to the loss of ability to record new data, sometimes seen in (mainly male) chronic alcoholics. Korsakoff also described a peripheral neuropathy accompanying this memory loss. Korsakoff syndrome is a residuum from an episode of Wernicke encephalopathy, which may not have been evident clinically in its acute stages, and one designates the term Wernicke-Korsakoff syndrome to encompass both the acute syndrome and its residua. The odd distribution of the demyelination and petechiae is probably because the oligodendroglia in these areas contain thiamine-dependent transketolase enzymes.

The clinical features of Wernicke-Korsakoff syndrome are first of headache, nausea, vomiting, and depression, and are followed by delirium. This may be a typical agitated and excited DT or a quiet confusional state that occurs with a decreasing level of consciousness, sometimes amounting to coma. The brainstem involvement accounts for both ocular muscle and gaze palsies, but the pupils are normal. Nystagmus and poor caloric responses probably result from lesions around the vestibular nuclei, and truncal ataxia results from involvement of the cerebellum or vestibular nuclei. Most of these patients have a peripheral neuropathy caused by thiamine deficiency, but cardiac involvement is unusual. Complications in the acute stage include hyperthermia, seizures, and a syndrome of inappropriate ADH secretion.

The picture of Korsakoff psychosis becomes apparent as the patient recovers. The ataxia and eye signs improve relatively quickly in the first few days or weeks after treatment but the memory abnormality becomes more evident and may never be entirely clear. It may be so bad that the patient remembers nothing that happened more than 45 seconds ago, although he or she retains previously learned skills. Confabulation is usual; that is, the patient tends to answer with incorrect statements any question that the examiner puts forth. The patient is not lying in order to cover up poor memory, but rather his or her answers are disjointed memories from the past that are out of temporal sequence. Confabulation is not always present in Korsakoff syndrome and it clears fairly rapidly, so one should not depend on it to make the diagnosis. The lesion responsible is probably in the medial dorsal nucleus of the thalamus, rather than the mammillary bodies.

Wernicke-Korsakoff syndrome is an emergency because the patient can die if untreated, or he or she may be left at least with serious memory loss. Initial treatment should be 50 mg of thiamine intravenously and another 50 mg intramuscularly; larger doses are unnecessary. Sedation with phenothiazines or diazepam may be necessary during the early stages. Oral thiamine must be continued. Treated as above, the eye signs begin to improve within 12 hours. Rehabilitation starts thereafter.

[edit] Alcoholic Peripheral Neuropathy.

The neuropathy of chronic alcoholism is due to chronic deficiency of thiamine. There is a degeneration of both sensory and motor peripheral nerves distally with destruction of both the myelin sheath and axon (see Chapter 167 ). Although sensory symptoms are common, the chronic alcoholic usually does not complain unless motor changes are marked or a burning feet syndrome develops. Examination shows a distal loss of all modalities of sensation, with mild motor weakness or atrophy in most cases. Reflexes are absent distally. Treatment (alcohol withdrawal, vitamins) leads to a very slow improvement; residual sensory and sometimes motor losses are common.

[edit] Alcoholic Amblyopia.

Some alcoholics develop blurring of vision with decreased acuity caused by central scotomas. Examination shows mild hyperemia of the disc or, later, optic atrophy. There may be a relationship with tobacco amblyopia in these patients, but alcoholic amblyopia is due to nutritional deficiency and is not a toxic effect of alcohol or tobacco. Treatment is by a balanced diet and B vitamins.

[edit] Pellagra.

Nicotinamide deficiency results in mental changes, insomnia, irritability, and depression. Advanced cases have dementia, dermatitis, and diarrhea. Neurologic signs include posterior and lateral column involvement and peripheral neuropathy.

[edit] Alcoholic Cerebellar Degeneration.

Some chronic alcoholics develop bilateral cerebellar incoordination and instability in the legs. There is little abnormality in the arms, and evidence of nystagmus or cerebellar speech difficulty is unusual. This involvement is due to selective atrophy of the anterior lobe or vermis of the cerebellum, best shown by magnetic resonance imaging (MRI) scans. Occasionally the syndrome can be reversed by stopping the intake of alcohol, but in the chronic form this is not so, although at least it should not get worse. This chronic cerebellar degeneration may represent a residuum from a previous Wernicke-Korsakoff syndrome, suggesting it is due to a nutritional deficiency.

[edit] Complications of Alcoholism of Uncertain Origin

[edit] Marchiafava-Bignami Disease.

Marchiafava-Bignami disease is a rare complication of alcoholism that is characterized by degeneration of the corpus callosum, leading to a progressive decrease in mental function, convulsions, tremor, rigidity, paralysis, akinetic mutism, and coma. Some contaminant in the alcohol or a nutritional deficiency may be the cause.

[edit] Central Pontine Myelinolysis.

Central pontine myelinolysis is characterized by rapidly progressing demyelination in the central pons, which results in pseudobulbar palsy and spastic quadriplegia with a decreasing level of consciousness leading to coma and often death. Although usually seen in alcoholics, it also occurs with underlying malignancy, chronic renal disease, and other debilitating disorders. This syndrome is usually caused by the inappropriately fast restoration of a low serum sodium level after a prolonged period during which the serum level had been low (below 120 mmol/L). The syndrome of inappropriate ADH secretion and any condition producing severe hyponatremia are other causes.

[edit] Cerebral Cortical Atrophy.

Many chronic alcoholics show evidence of diffuse cortical atrophy, especially of the frontal lobes, with enlargement of the ventricles. This is evidenced by an organic mental deficit, even long after they have stopped drinking. CT scans suggest, however, that some reexpansion can occur.

[edit] Alcoholic Myopathy.

Three myopathies are associated with alcoholism. The acute syndrome is characterized by painful, swollen, and tender muscles, occasionally with myoglobinuria and renal damage. Another type shows subacute girdle weakness and atrophy with aching pains; a third resembles McArdle disease, with muscle cramps and a flat lactic acid curve after ischemic exercise. Alcoholic cardiomyopathy, sometimes associated with hyperkinetic heart failure, is probably part of a deficiency syndrome, but one outbreak was traced to the use of cobalt as a preservative in beer.

[edit] Other Complications of Chronic Alcoholism

Chronic alcoholics who develop hepatic insufficiency may show evidence of encephalopathy or coma.

Pressure palsies are common in alcoholics. One common variation affects the radial nerve when the drunk person falls asleep with his or her arm hanging over the back of a chair (Saturday night palsy). Half of the patients in any large series of subdural hemorrhages will be alcoholics. The hematomas may be bilateral. Occasionally, chronic alcoholics may show an enlarged sella turcica on skull radiographs. Nobody knows why. They also have an increased incidence of carcinoma of the stomach, and some show evidence of B₁₂ deficiency caused by chronic gastritis, gastrectomy for ulcers, or poor dietary intake. Dupuytren's contractures in the hands, chronic infections, venereal disease, and tuberculosis are all much more common in alcoholics than in the general population.