Penicillin and related agents rarely cause nervous system toxic effects, although seizures and myoclonic jerks have been reported with high intravenous (IV) doses. Such effects appear more commonly in elderly patients with compromised renal function. Meningitic inflammation may enhance neurotoxic effects by promoting the penetration of these drugs into the central nervous system (CNS) and decreasing their egress. Polyneuritis, with paresthesias, paralysis, and loss of tendon reflexes, also has been reported.

Cephalosporins may cause a number of neurotoxic effects, especially in patients with renal dysfunction or in those receiving high doses. Symptoms can include confusion, coma, tremor, myoclonic jerks, asterixis, and hyperexcitability. Status epilepticus that did not respond to anticonvulsant therapy and subsequently resolved with discontinuation of cefepime has been described in two patients receiving this fourthgeneration cephalosporin.

The toxicities of all aminoglycoside antibiotics—neomycin, kanamycin, streptomycin, gentamycin, tobramycin, and amikacin—are similar. The two major adverse effects are (a) damage of the eighth cranial nerve and hearing apparatus and (b) a potentiation of neuromuscular blockade. Cochlear and vestibular damage is the result of direct toxicity of these drugs. Auditory toxicity is more common with the use of amikacin and kanamycin, whereas vestibular toxicity predominates following gentamycin and streptomycin therapy. Tobramycin is associated equally with vestibular and auditory damage. The incidence of clinical ototoxicity as a result of use of these drugs ranges from 5% to 25%, depending on whether audiometry is used to detect hearing deficits. Aminoglycoside hearing loss is usually irreversible and may even progress after the discontinuation of drug therapy.

The aminoglycosides act similarly to curare, blocking the neuromuscular junction. Aminoglycosides also possibly potentiate ether and other anesthetics during surgery. Sudden or prolonged respiratory paralysis resulting from aminoglycoside use may be reversed by the administration of calcium or neostigmine.

The polymyxins are related closely to the aminoglycosides in structure and neurotoxicity. The incidence of neurotoxic reaction has been estimated at 7%, and syndromes other than neuromuscular blockade include paresthesias, peripheral neuropathy, dizziness, and seizures. Respiratory paralysis, however, is the most serious neurotoxic reaction. An underlying renal dysfunction predisposes to the neuromuscular blockade induced by this drug group. Signs of neuromuscular blockade include diplopia, dysphagia, and weakness.

Amphotericin B is widely used against systemic fungal infection. When the drug is used intrathecally, seizures, pain along the lumbar nerves, mononeuropathies (including foot drop), and chemical meningitis have occurred.

Isoniazid (INH) has been associated with neurotoxic effects felt to be related to drug binding of pyridoxine and resultant excessive vitamin excretion. A prominent polyneuropathy is associated with chronic INH administration, and symptoms include paresthesias; diminished pain, touch, and temperature discrimination; and eventual weakness. Seizures, emotional irritability, euphoria, depression, headache,
and psychosis rarely may occur. The neurotoxic reactions from INH use are dose related and are more common in “slow inactivators.” In these patients, neurotoxic reactions can be prevented or diminished by the administration of pyridoxine at a dose of 50 mg daily. Patients who intentionally or inadvertently overdose acutely with INH may develop severe ataxia, generalized seizures, and coma. Supportive measures, anticonvulsants, and pyridoxine should be administered to these patients.

Rifamycin frequently is administered with INH. Neurologic side effects are uncommon but may include headache, dizziness, inability to concentrate, and confusion. Less commonly, signs of peripheral neuropathy may develop. Ethambutol precipitates a reversible optic neuritis as well as a more generalized peripheral neuropathy. A metallic taste in the oral cavity frequently is associated with ethambutol therapy and may be due to the result of an impairment of receptor activity.

The treatment of selected viral infections in individuals who are not positive for the human immunodeficiency virus (HIV) has become possible over the past few years. The neurologic complications of HIV and the drugs used to treat it will be discussed elsewhere.

Acyclovir can be administered either intravenously or orally. Acyclovir is used orally for the treatment of localized or ophthalmic varicella zoster, treatment of minor herpes simplex virus, and reducing the severity of varicella. It is used intravenously to treat herpes encephalitis. Neurologic side effects rarely are associated with oral acyclovir. However, seizures, encephalopathy, hallucinations, and coma have been described, as has tremor.

Amantadine has been used to prevent influenza A infections. This agent appears to have, in addition to its antiviral action, anticholinergic and dopaminergic effects, which has led to its use in mild Parkinson disease. The neurologic side effects associated with amantadine include, confusion, myoclonus, hallucinations, delirium, and seizures. As amantadine is excreted through the kidney, the presence of renal impairment may reduce its clearance, causing it to accumulate in the body and resulting in amantadine toxicity.

Neurotoxicity is a well-recognized sequela of cyclosporine, and the most common complications are tremor and altered mental status. Cyclosporine neurotoxicity can occur in 1 in 10 patients after liver transplantation. Behavioral signs include acute psychosis, restlessness, wide mood swings with inappropriate crying and laughing, cortical blindness, visual hallucinations, stupor, and akinetic mutism. Additionally, seizures, extrapyramidal symptoms, action
myoclonus, and quadriparesis have been reported. In patients with neurologic signs, cyclosporin levels are usually outside the normal range, and after lowering the dose or withholding administration, neurotoxicity clears in most cases. MRI abnormalities are consistent with cortical or white matter high-signal changes with a predilection for the occipital lobes. The mechanism of cyclosporine neurotoxicity has not been fully elucidated. Both the clinical manifestations and the neuroimaging abnormalities of cyclosporine neurotoxicity usually resolve with a reduction or discontinuation of cyclosporine.

Other transplant immunosuppressives include basiliximab, daclizumab, mycophenolate mofetil, sirolimus and tacrolimus. Typical neurologic effects of long-term immunosuppression include infections such as meningitis, encephalitis, and abscess formation and are similar with the newer agents as they were with the older ones. Direct neurologic toxicity is more common with tacrolimus, a calcineurin inhibitor-like cyclosporine, while the others exhibit toxicity that spares the nervous system.

Although tacrolimus may be a better immunosuppressant than cyclosporine, its neurologic effects may be worse. In a multicenter, randomized, parallel-group study of 545 patients undergoing primary liver transplantation, tacrolimus was associated with a higher incidence of neurologic symptoms than cyclosporine. The risk of tacrolimus-treated patients developing tremor was related to the initial IV dose, the rate of administration, and the total daily dose. Headache was significantly correlated with dose, while insomnia was not. Factors that may promote the development of serious complications include advanced liver failure, hypertension, hypocholesterolemia, elevated serum levels, hypomagnesemia, and methylprednisone. The symptoms may be reversed by reducing the dose of immunosuppressant or by discontinuation. However, some patients have experienced permanent or even fatal neurologic damage even after discontinuation of tacrolimus. Occipital white matter appears to be uniquely susceptible to the neurotoxic effects of tacrolimus as is the case with cyclosporine. Magnetic resonance imaging has been reported to reveal bilateral symmetric regions of signal abnormality with abnormal contrast enhancement. The abnormal signal was more evident in FLAIR (fluidattenuated inversion recovery) sequences. Epilepsy and cerebral hemorrhage have been reported to be associated with tacrolimusinduced neurotoxicity.

Digitalis and related agents are the mainstay of treatment for congestive heart failure. Neurologic complications of digitalis therapy have been recognized for almost 200 years and are characterized by nausea, vomiting, visual disturbances, seizures, and syncope. Adverse effects on the CNS reportedly occur in 40% to 50% of patients with clinical digitalis toxicity and may occur before, simultaneously with, or after the signs of cardiac toxicity develop.

The most frequent and often the first sign of clinical intoxication is nausea, which appears to be the result of central mechanisms rather than gastrointestinal irritation. The incidence of digitalis-related visual disturbances has been estimated at 40%, and although these symptoms may occur as an isolated symptom, they usually occur concomitantly with other toxic signs. Blurred vision, reversible scotomas, diplopia, defects of color vision, and total amaurosis represent the spectrum of optic side effects.

Seizures most commonly are seen in pediatric patients. The incidence of digitalis-related seizures is difficult to estimate because other seizure etiologies (e.g., arrhythmia) are so high in cardiac patients. Transient mental aberrations felt to be caused by intermittent cerebral
hypoperfusion resemble transient global amnesia. Syncope, probably the result of conduction delay or hyperactivity of baroreceptors, also has occurred in digitalis toxicity. Other neurotoxic reactions include facial neuralgia, paresthesias, headache, weakness, and fatigue. Cerebral symptoms consisting of confusion, delirium, mania, and hallucinosis have been reported in as many as 15% of patients with digitalis toxicity. Although the mechanism for the symptoms is unknown, it is felt that they are not the result of altered cardiac function.

Nitroglycerin and nitrate therapy frequently is associated with headache. According to currently proposed mechanisms, nitric oxide is the common mediator in experimental vascular headaches. Nitroglycerin produces a throbbing or pulsating sensation in many patients and an overt headache in many others. Often, the headaches attenuate or disappear with time, but 15% to 20% of patients will not be able to tolerate long-acting nitrates because of headache. Patients should be encouraged to use analgesics during the initial days or weeks of nitrate therapy and should be educated as to the nature of this problem and its probable resolution with time.

Nitroglycerin therapy can cause doserelated increases in intracranial pressure, which in rare cases can result in a clinically overt syndrome. Furthermore, the hypotensive effects of nitroglycerin can result in dizziness and light-headedness or even syncope.

Quinidine is used mainly to treat atrial fibrillation. Nervous system manifestations are usually not significant, but with overdosage or in susceptible individuals the following may occur: headache, nausea, vomiting, blurring of vision, ringing of the ears, flushing, palpitations, and even convulsions. A precipitous decrease in blood pressure related to vagal influences can cause syncope, vertigo, and respiratory arrest (on rare occasions).

Lidocaine-induced CNS toxicity occurs commonly and may relate to its rapid absorption across the blood-brain barrier. The syndrome appears to relate to a diffuse excitement of neuronal systems, with an early prodrome of altered behavior. Garrulousness and loss of inhibitions may be the prominent feature, as may agitation or psychosis. Circumoral numbness, diplopia, and tinnitus also may occur, with progressive muscle twitches and tremors. Generalized myoclonic seizures and finally CNS and respiratory depression are seen with higher doses. In both cardiac and surgical patients, hypoxia and acidosis develop rapidly if the lidocaine syndrome is not reversed. Treatment focuses on adequate oxygenation and support because the half-life of bolus lidocaine given acutely is 6 to 8 minutes. Because repeated injections change the kinetics of lidocaine and prolong its half-life to approximately 90 minutes, however, more long-lasting effects can be seen.

Procainamide may cause light-headedness and even syncope because of the hypotensive action. Additionally, a lupus erythematosus syndrome can develop in patients taking procainamide, and 80% of patients receiving the drug for 6 months have antinuclear antibodies; these antibodies clear with the withdrawal of the agent. During lupus-like syndrome, encephalopathy with confusion and agitation can develop. Procainamide also has a curare-like effect at the neuromuscular junction and hence can precipitate myasthenia gravis or exacerbate it.

Tocainide hydrochloride is an antiarrhythmic agent that is structurally and pharmacologically similar to lidocaine, except that it is well absorbed when given orally. Tocainide has been proven effective in managing various ventricular arrhythmias; however, because it crosses the blood-brain barrier, it frequently causes several neurologic side effects, which include light-headedness, dizziness, tremor, twitching, paresthesias, sweating, hot flashes, blurred vision, diplopia, and mood changes. Peak plasma
concentrations of tocainide occur within 1 to 2 hours of ingestion; the plasma half-life is 12 to 15 hours in patients with unimpaired renal and hepatic systems. CNS side effects appear to be linearly related to the dose.

Bretylium is a parenteral antiarrhythmic drug used in the prophylaxis and treatment of ventricular fibrillation and life-threatening ventricular arrhythmias that do not respond to first-line agents such as lidocaine. The antiarrhythmic mechanisms of bretylium in humans are not clearly defined, but in animals it increases the ventricular fibrillatory threshold and also the action potential duration and effective refractory period. It induces a state of chemical sympathectomy.

The most significant side effect of this drug is severe supine and orthostatic hypotension. Patients report dizziness, light-headedness, vertigo, and faintness. Bretylium may also rarely cause flushing, hyperthermia, confusion, paranoid psychosis, mood changes, anxiety, lethargy, and nasal stuffiness.

Amiodarone is an orally effective antiarrhythmic drug that, like bretylium, slows repolarization in various myocardial fibers and raises the threshold for ventricular fibrillation. Early reports of adverse effects include corneal microdeposits, thyroid dysfunction, and cutaneous photosensitivity. However, toxic neurologic side effects now have been described, and in a series of 54 patients studied, these side effects were the most common reason for either altering or discontinuing amiodarone therapy.

A reversible syndrome of tremor, ataxia, and peripheral neuropathy without nystagmus, dizziness, encephalopathy, or long-tract signs developed in 54% of these patients. Tremor occurred earliest and most frequently (29%). The 6- to 10-Hz flexion-extension movements in the fingers, wrists, and elbows were indistinguishable from essential tremor. Of the patients, 37% reported ataxia associated with falls, staggering, and difficulty in dressing the lower limbs. The ability to walk was seriously impaired in 18% of the patients. None of these patients had preexisting gait problems, and none had sensory or long-tract abnormalities on examination. Peripheral neuropathy associated with this drug was first reported in 1974 and continues to account for a significant portion of the neurologic toxicity reported today. The neuropathy is sensorimotor in type and generally causes numbness and tingling of all four extremities. Proximal weakness occasionally accompanies the paresthesias. Sural nerve biopsies have been examined and have revealed demyelination with mild axonal loss in some cases. Lamellated inclusions of lysosomal origin were found in all cell types in the nerves and are a characteristic finding of this neuropathy.

Diuretics are divided into three principal groups: thiazide, loop, and potassium sparing. Diuretics most frequently cause extracardiac side effects as a direct result of the electrolytes lost or retained in the renal system. Each group, however, can cause adverse effects that are linked indirectly to electrolyte and water balance.

The thiazide diuretics have been reported to cause syncope, acute muscle cramps and pain, hyporeflexia, weakness, flaccid paralysis, and epileptiform movements. The deterioration of mental function, including the development of coma, can be precipitated with thiazide administration in patients being treated for cirrhosis. Thiazides given concomitantly with triamterene and amantadine can increase the likelihood of neurotoxicity from the amantadine.

If loop diuretics, particularly furosemide, are given quickly and in high doses, they can cause deafness and paresthesias. If they are given to a patient who also is receiving lithium chronically, loop diuretics can alter the renal clearance of lithium and increase the risk of lithium toxicity and fluid electrolyte abnormalities. Loop diuretics also potentially can increase the success with which succinylcholine blocks the neuromuscular junction in anesthetized patients.

Potassium-sparing diuretics, including spironolactone and triamterene, have been reported to cause confusion, drowsiness, muscle weakness, paresthesias, dizziness (although this may be a result of cardiac rhythm changes), and headache.

Clonidine is an alpha 2-noradrenergic agonist, and some have suggested that this drug induces an overall decrease in norepinephrine release, possibly through a presynaptic mechanism. Sedation is the most common adverse neurologic effect of clonidine. Other less common neurotoxic reactions include depression, nightmares, and reversible dementia syndrome.

Neuropsychiatric symptoms occur frequently during treatment with beta blockers. The pharmacology of CNS side effects is unclear, although presynaptic and postsynaptic adrenergic inhibition has been implicated, as has serotonergic antagonism. Nonselective beta blockers seem to cause CNS-related side effects to a greater extent than beta 1-selective blockers. It is unclear to what degree lipophilicity is responsible for this kind of side effect. Lassitude or insomnia and depression are the most common reactions, although vivid dreams, nightmares, hypnagogic hallucinations, and psychotic behavior have been reported with high doses (more than 500 mg/day of propranolol). Preexisting major psychiatric illness and hyperthyroidism may predispose to the previously mentioned symptoms.

Prazosin competitively blocks the vascular postsynaptic alpha-adrenergic receptors and is the first of a class of similar antagonists derived from quinazoline. The selective affinity of prazosin for alpha-receptors allows it to block the contractile response of vascular smooth muscle to norepinephrine, consequently lowering mean arterial pressure and peripheral resistance. Like other antihypertensives that cause vasodilatation, prazosin causes hypotension; dizziness and faintness have been reported in up to 50% of patients receiving this drug. These are most pronounced after the first dose(s) or in patients who have had a hiatus from the drug and are reinstituting treatment. Hypotension can be minimized if the initial dose is small and is given at bedtime. Other CNS side effects include headache, dry mouth, nasal stuffiness, lassitude, hallucinations, depression, paresthesias, nervousness, and priapism.

Hydralazine is the only direct-acting vasodilator generally available for the treatment of chronic hypertension. The neurologic side effects of hydralazine are few and uncommon in clinical practice. Peripheral neuropathy characterized by diffuse numbness and tingling is the only consistent neurotoxic reaction and is felt to be the result of a direct toxic effect of the drug.

Calcium channel blockers, particularly flunarizine and cinnarizine, have been associated with dystonia, parkinsonism, akathisia, and tardive dyskinesia (TD). Theoretic explanations for these events include the inhibition of calcium influx into striatal cells and direct dopaminergic antagonistic properties. Evidence also suggests that inhibition of proton pumping and catecholamine uptake are possible mechanisms. In addition, the chemical structures of flunarizine and cinnarizine, which are related to neuroleptics, may explain the greater incidence of such side effects with these agents compared with those of calcium channel blockers available in the United States. Suggested risk factors appear to be advanced age and a family history of tremors or Parkinson disease, or both. The onset and type of presentation are unpredictable. The long-term evolution was assessed in a prospective follow-up study of 32 patients with diagnoses of calcium channel blocker-induced parkinsonism. Eighteen months following discontinuation of the offending agent, 44% of the patients had depression, 88% had tremor, and 33% still had criteria for diagnosis of parkinsonism.

Angiotensin-converting enzyme inhibitors have been used in the United States to treat moderate to severe hypertension, based on its effect on the renin-angiotensin-aldosterone (RAA) axis. This cascading hormonal axis simultaneously maintains systemic arterial pressure and sodium balance by detecting and correcting even small changes in renal perfusion. Alongside the increased understanding of the RAA axis has come the discovery of drugs that specifically and selectively inhibit the RAA cascade.

Few neurologic side effects have been reported; however, in a large multinational study, 5% of the participating patients reported symptoms of hypotension, including dizziness, light-headedness, and vertigo. These symptoms were generally transient and mild and most frequently occurred in patients who were sodium or water depleted. Dysgeusia occurred in 2% to 4% of patients participating in this small trial. The incidence of taste change or loss increased in patients with impaired renal function.

Clofibrate, an aromatic monocarboxylic acid, is capable of inducing myotonia in humans and experimental animals and is clinically significant because it is widely used to reduce serum triglyceride levels. The mechanism by which it induces myotonia is believed to be through a decrease in chloride conductance.

HMG-CoA reductase inhibitors or statins have been implicated in causing toxic myopathy. Statin myotoxicity ranges from asymptomatic creatine kinase elevations or myalgias to muscles necrosis and fatal rhabdomyolysis. Statins may also cause an autoimmune myopathy requiring immunosuppressive treatment. The mechanisms of statin myotoxicity are unclear. If unrecognized in its early manifestations, complications from continued statin therapy may lead to rhabdomyolysis and death. Risk factors for myotoxicity are concomitant medication use and medical conditions that alter statin metabolism as well as the patient’s underlying genetic constitution. According to findings from 21 clinical trials providing 180,000 person-years of follow-up in patients treated with statin or placebo, myopathy (defined as muscle symptoms plus creatine kinase [CK] >10 times the upper limit of normal) occurs in 5 patients per 100,000 person-years and rhabdomyolysis in 1.6 patients per 100,000 person-years (placebo corrected). The most common muscle side effects remain myalgia (i.e., muscle pain or soreness), weakness, and/or cramps without CK elevations. These symptoms are most often tolerable, but occasionally can be intolerable and debilitating, requiring the statin to be withdrawn. Muscle symptoms have been reported in clinical trials to occur in 1.5% to 3.0% of patients receiving statin therapy, most often without an elevation in the CK level, and at an equivalent rate in patients given placebo. The incidence of muscle complaints among patients being treated in a practice setting ranges from 0.3% to 33% (Bays, 2006). The higher rate may occur partly because statin-intolerant patients and those with risk factors for muscle toxicity are more likely to be excluded from clinical trials.