Clinical manifestations

Presentation and course

• Dementia due to drug use does not have any characteristic features except association with the drug(s) or accompanied by other adverse reactions of the drug.

Drug-induced dementia has no characteristic features, except in the situations where it is accompanied by other drug-induced symptoms. Anticholinergic drugs used to treat parkinsonism may mimic or exacerbate the clinical signs of Alzheimer disease. Dementia may be a part of the neurotoxic manifestations of a drug, eg, interferon dementia in "interferon syndrome."

Prognosis and complications

Drug-induced dementia is usually reversible with the discontinuation of the offending drug. In situations where structural changes are present in the brain, cognitive deficits may persist. The complications would be no different from those that occur in patients with dementias due to other causes. Creutzfeldt-Jakob disease is an exception as some cases occur due to contamination of the therapeutic material and not due to pharmacological effect of any substance.

Biological basis

Etiology and pathogenesis

	• Drugs are the leading cause of dementia in the elderly.
	• Pathogenesis varies according to the pharmacological category of the offending drug.

Adverse drug reactions are commonly associated with dementia in elderly persons on polypharmacy. Drugs reported to be associated with dementia are shown in Table 1. The causal effect is not proven in all cases, but the association, even though in single case reports, is sufficient to consider these drugs when investigating drug-induced dementia. Improvement after discontinuation of a suspected drug is strongly suggestive of the drug causing the dementia.

Table 1. Drugs Associated with Dementia

• Anticholinergic drugs • Antiepileptics • Antihypertensives • Antineoplastic drugs • Antipsychotic drugs • Anti-TNFα treatment-induced reversible dementia • Benzodiazepines • Corticosteroids • Cyclosporine • Cytokines: interferons and interleukins • Deferoxamine • Drugs of abuse • Neuroleptics • Sedative-hypnotics: diphenhydramine • Opioids • Tricyclic antidepressants • Z-hypnotics: zolpidem, zaleplon, and eszopiclone (stereoisomer of zopiclone) • Drug combinations, eg, benzodiazepines and z-hypnotics

Anticholinergic drugs. A nested case control study showed that among drugs with anticholinergic action used in CNS disorders, there are significant increases in risk associated with use of antidepressants, antiparkinson drugs, antipsychotics, antiepileptic drugs, bladder antimuscarinics, and antivertigo/antiemetic drugs (10). This observational study has shown associations, but causality cannot be evaluated. However, if this association is causal, approximately 10% of dementia diagnoses are attributable to anticholinergic drug exposure. There were no significant increases in risk associated with antihistamines, skeletal muscle relaxants, gastrointestinal antispasmodics, antiarrhythmics, and antimuscarinic bronchodilators.

Anticholinergic drugs are common causes of both acute and chronic cognitive impairment (35). Patients with Alzheimer disease show deterioration at serum levels of anticholinergic drugs, which cause no impairment in psychogeriatric patients without dementia. Cognitive impairment at 3 hours following administration of a low dose of scopolamine with full cognitive recovery within 5 hours can be used as a test to identify individuals who are likely to develop preclinical Alzheimer disease (36).

A study has used neuroimaging biomarkers of brain metabolism and atrophy to investigate the underlying biology of the clinical effects of anticholinergic medications in cognitively normal older adults from the Alzheimer's Disease Neuroimaging Initiative and the Indiana Memory and Aging Study (33). Results showed that the use of anticholinergic medications was associated with increased brain atrophy and dysfunction as well as clinical decline. This forms the basis of recommendation that use of anticholinergics in older adults should be discouraged if alternative therapies are available. A further study showed that cognitively normal older adults taking at least 1 anticholinergic drug were 47% more likely to develop mild cognitive impairment over the next decade than people who were not taking such drugs (41). The study also found that persons with biomarkers for Alzheimer disease in their cerebrospinal fluid who were taking anticholinergic drugs were 4 times more likely to later develop mild cognitive impairment than people who were not taking the drugs and did not have the biomarkers. Similarly, persons who had genetic risk factors for Alzheimer disease and took anticholinergic drugs were about 2.5 times as likely to develop mild cognitive impairment than those without the genetic risk factors and who were not taking the drugs.

A population-based study has shown that elderly patients on anticholinergic drugs are at increased risk for dementia, and discontinuation of drugs was associated with a decreased risk (07). Oxybutynin, an anticholinergic agent used for treatment of overactive bladder, is associated with cognitive impairment. A population-based retrospective analysis of oxybutynin versus other anticholinergics in older adults showed that the proportion of patients with cognitive impairment initiated on oral oxybutynin increased from 24.1% in 2008 to 41.1% in 2011; it was replaced by other more expensive anticholinergic agents that were less likely to cause impairment in only 5% of cases because of cost restrictions (39).

Patients with Parkinson disease show deterioration of mental function when treated with anticholinergics, whether alone or in combination with levodopa, whereas those treated with levodopa alone do not show any decline of mental function. Cases of chronic dementia have been reported in patients with Parkinson disease who had been treated for over 6 months with anticholinergic drugs and had no other adverse reactions. All these patients improved after discontinuation of the anticholinergics, and the improvement was documented by neuropsychological testing as well as by SPECT and PET scans.

Antihypertensive drugs. Older antihypertensive agents (reserpine and clonidine) have negative effects on cognition; however, large clinical trials in the elderly indicate that commonly used agents, such as thiazide diuretics, calcium antagonists (amlodipine, diltiazem), angiotensin-converting enzyme inhibitors (captopril, enalapril), and beta-blockers (atenolol), have minimal effects on cognition.

Antineoplastic drugs. Antineoplastic drugs are known to be associated with leukoencephalopathy. 5-fluorouracil-induced leukoencephalopathy can manifest by impairment of cognitive function and ataxic gait. Symptoms of leukoencephalopathy due to carmofur, a drug widely used in Japan for carcinomas of the gastrointestinal tract, are gait disturbance followed by dysarthria and dementia in that order of frequency (25). However, findings from a study on a large population-based cohort found no relation between chemotherapy use and cognitive impairments in older women with breast cancer (13). Significant association between chemotherapy and the risk of developing drug-induced dementia was demonstrated in a large series of patients with colorectal cancer without mood disorder, whereas risk of developing other dementias was decreased (12). Results of several clinical studies suggest that the most frequent neurotoxic adverse effects of chemotherapy are impairment of memory and learning, attention, concentration, processing speeds, and executive function. According to 1 hypothesis, inflammatory cytokines disrupt blood brain barrier permeability and increase direct access of chemotherapeutic agents into the CNS to cause neurotoxicity (40).

Results of a cohort study indicate that androgen deprivation therapy in the treatment of prostate cancer may be associated with an increased risk of dementia, but this finding should be further evaluated in prospective studies (28).

Antiepileptic drugs. Valproic acid-induced dementia is well known. Reversible cerebral atrophy has been documented by CT scan in valproate-induced parkinsonism-dementia syndrome. Several cases of dementia associated with extrapyramidal disorders have been reported in elderly patients, and all improved after discontinuation of valproic acid. Rapid cognitive decline and extrapyramidal manifestations can be considered drug induced in patients who are being treated with valproate, as they can improve after discontinuation of the drug.

Phenytoin intoxication with cerebellar dysfunction and dementia may occur in nonepileptic patients who receive phenytoin for cardiac arrhythmias. Withdrawal of phenytoin leads to slow improvement of neurologic status.

Topiramate can cause cognitive impairment as an adverse effect. A double-blind, randomized, placebo-controlled, crossover study of topiramate's impact on cognition on healthy volunteers showed that it led to a decline in behavioral performance through impairment of the primary task network by reducing its efficiency (02). This triggers compensatory recruitment of additional resources to maintain task performance as revealed by increase in event-related potential responses to high load, the magnitude of which was positively correlated with task performance.

Anti-TNFα treatment-induced reversible dementia. A case is reported of a reversible rapidly progressive dementia occurring in a patient with ankylosing spondylitis a few months after the beginning of a TNFα inhibitor treatment (21). The exhaustive neurologic explorations were negative and no cause was found to explain dementia, which slowly improved after TNFα inhibitor withdrawal.

Benzodiazepines. Benzodiazepine use by elderly patients is associated with cognitive impairment. A prospective population-based study showed that new use of benzodiazepines in subjects who were free from cognitive impairment at the start of therapy was associated with increased risk of dementia (05). A case control study has shown that benzodiazepine use is associated with an increased risk of Alzheimer disease (06).

Corticosteroids. Steroid-induced psychosis is well recognized, but steroid-induced impairment of cognitive function is rare. Steroid dementia syndrome describes the signs and symptoms of hippocampal and prefrontal cortical dysfunction, such as deficits in memory, attention, and executive function, induced by glucocorticoids. Reversible dementia-like cognitive changes are included in a review of corticosteroid-induced neuropsychiatric disorders (04). An increased risk of these disorders was observed in most cases when daily prednisone-equivalent dose was greater than or equal to 40 mg and in those suffering from systemic lupus erythematosus where they may mimic symptoms that may occur in the natural course of the disease. Corticosteroid-induced dementia usually recovers after discontinuation of the corticosteroids. High-dose steroid therapy can cause persisting cognitive disorders.

Cytokines. Cytokines, particularly interleukin-2 and interferon-alpha, have been associated with neuropsychiatric disturbances when given systemically. Disorders of cerebral function associated with interferons are:

	• Neuropsychiatric
		- confusion - thought blockage - memory disturbance - hallucinations - visuospatial disorientation
	• Leukoencephalopathy
		- lethargy - anorexia - somnolence - confusion

Recombinant interferon-alpha-induced frontal subcortical dementia was first described in 2002 (26). Other cases have been reported since then. Dementia after several months of interferon-alpha therapy may persist for 3 years despite cessation of interferon treatment.

Sedative-hypnotics. Diphenhydramine, an over-the-counter hypnotic-sedative, is associated with cognitive impairment in elderly persons without preexisting dementia.

Drug combinations. A cohort study found that compared with nonusers, older people who used benzodiazepines or z-hypnotics for more than 28 days during each quarter of the year had a greater risk of dementia during the follow-up period and the risk was even more pronounced in patients who took both types of drugs at the same time (37). Short-acting benzodiazepines were associated with a greater risk of dementia than long-acting benzodiazepines. Persons who used a combination of short-acting and long-acting benzodiazepines as well as a z-hypnotic were nearly 5 times more likely to be diagnosed with dementia than people who did not use any of the drugs.

Therapeutic substances involved in the transmission of Creutzfeldt-Jakob disease. Creutzfeldt-Jakob disease is a transmissible spongiform encephalopathy characterized by a long incubation period that precedes clinical symptoms related to the degeneration of the CNS, resulting in dementia. Various therapeutic procedures are reported to be associated with the transmission of Creutzfeldt-Jakob disease, shown in Table 2. These include corneal transplants, dural grafts, neurosurgical instrumentation, stereotactic placement of EEG electrodes, blood transfusion, drugs containing bovine-derived tissues, and administration of cadaver pituitary-derived human growth hormone.

Table 2. Therapeutic Substances Associated with Creutzfeldt-Jakob Disease

	• Human growth hormone from cadaver pituitary • Dural grafts (human) • Corneal grafts (human) • Bovine somatotrophin (equivalent of human growth hormone used in France)* • Pharmaceutical preparations containing bovine material • Blood for transfusion and blood products obtained from patients with Creutzfeldt-Jakob disease
	*This drug was banned in 1992.

Human growth hormone. Numerous studies have reported the emergence of Creutzfeldt-Jakob disease following the use of human pituitary-derived growth hormone. Seven neuropathologically confirmed cases of Creutzfeldt-Jakob disease were detected during epidemiological follow-up of 6284 recipients of human growth factor in 1991 (17). All 7 cases occurred among a group of 700 recipients who received human growth hormone before 1970. Contaminated human growth hormone-induced Creutzfeldt-Jakob disease is like the iatrogenic transmission-induced Creutzfeldt-Jakob disease that occurred during neurosurgical procedures in the 1970s. The brains of Creutzfeldt-Jakob disease-infected cadavers contain particles of an abnormal form of prion protein that is highly resistant to most common sterilization procedures. A preparation of 1 batch of hormone requires several thousand pituitary glands, and it is likely that a batch could become contaminated. This problem has been eliminated by the current use of recombinant human growth hormone, but cases of Creutzfeldt-Jakob disease may still show up years after treatment with contaminated growth hormone. The United States and the United Kingdom banned the use of cadaver-derived pituitary growth hormone in 1985, but France continued its use until 1993, only if it had been treated with urea, a procedure known to deactivate the prion; however, there were cases of Creutzfeldt-Jakob disease in France due to the distribution of potentially contaminated hormone after it was prohibited.

Cases of iatrogenic Creutzfeldt-Jakob disease are rare when considering the large number of subjects treated with human growth hormone. Genetic susceptibility to prion infection has been considered as a predisposing factor. Iatrogenic Creutzfeldt-Jakob disease has been reported to manifest up to 24 years after human growth hormone administration.

As of 2012, 77 cases of Creutzfeldt-Jakob disease were likely to have resulted in the U.K. from iatrogenic transmission among recipients of therapeutic products: 64 cases from human-derived growth hormone; 8 cases from dura mater grafts; 4 cases from blood transfusions; and 1 case that received a plasma product (20). Strategies to reduce iatrogenic transmission of Creutzfeldt-Jakob disease included recall of suspected products, improvements in decontaminating surgical instruments, and instructing approximately 6000 asymptomatic individuals who were at increased risk of Creutzfeldt-Jakob disease to follow public health precautions.

In a study on human growth hormone (hGH) recipients in the United Kingdom, amyloid beta, which can accumulate in the pituitary gland, was present in the inoculated hGH preparations and had a seeding effect in the brains of around 50% of all hGH recipients, producing an Alzheimer disease-like neuropathology and cerebral amyloid angiopathy regardless of whether Creutzfeldt-Jakob disease neuropathology had occurred (34).

Antipsychotic drugs. Use of antipsychotic drugs has been observed to be associated with acceleration of cognitive decline in patients with Alzheimer disease, multiinfarct dementia, and those who had a previous leucotomy. In institutionalized older adults with dementia, impairment of cognitive function is associated with antipsychotic medication use (14). This has not been a problem with modern atypical antipsychotic agents, which are used to manage the behavioral disorders in patients with dementia. However, other studies show that patients taking antipsychotic drugs in combination with sedatives have a significantly higher risk of cognitive deterioration than those who are taking none.

Tricyclic antidepressants. Tricyclic antidepressants are among the offenders for causing dementia. Newer antidepressants, such as selective serotonin reuptake inhibitors and reversible inhibitors of monoamine oxidase A, have not been shown to have negative effects on cognition.

Gabapentin toxicity. Creutzfeldt-Jakob-like syndrome with characteristic EEG changes has been reported in an elderly man who received gabapentin for treatment of trigeminal neuralgia and was predisposed to toxic effects of the drug because of renal insufficiency (09). The symptoms and signs resolved after discontinuation of gabapentin.

Pathomechanism. Drugs may induce dementia by several different mechanisms, of which only a few are understood. Pathomechanisms of some of the drug-induced dementias are the following:

Anticholinergic-induced dementia. Data from the German Study on Aging, Cognition and Dementia in Primary Care Patients showed an increase in risk of dementia resulting from anticholinergic drug use and recommended strict avoidance of centrally acting anticholinergic drugs (22). Anticholinergic drugs block the cholinergic neurotransmission and produce a condition like the dementia of Alzheimer disease. Long-term anticholinergic therapy in patients with Parkinson disease causes intellectual impairment that is correlated with bilateral diffuse glucose hypometabolism demonstrated by PET.

Acetylcholinesterase inhibitors should theoretically benefit dementia, and most therapeutic agents that are currently available for the treatment of Alzheimer disease are based on this hypothesis (a condition in which cholinergic pathways are damaged). Acetylcholinesterase inhibitors may decrease the cholinergic tone as a delayed effect. This can be exacerbated by stress and may disrupt cognition. Both stress and acetylcholinesterase inhibitors increase the postsynaptic concentration of calcium in the cytosol. This causes a rapid induction of the transcription factor c-Fos. This has been offered as an explanation of the neuropsychological features seen in "Gulf War syndrome," a syndrome seen in soldiers who were given acetylcholinesterase inhibitors as a prophylactic against some of the poisonous war gases.

Antihypertensive drugs. Control of hypertension is expected to reduce the development of dementia or stroke in these patients. Prospective observational studies have shown that antihypertensive drug use is associated with 8% dementia risk reduction per year of use for persons over 75 years of age (19).

Two important categories of drugs for this purpose are calcium channel blockers and adrenergic antagonists. Noradrenergic transmission is important for cognitive function. Antihypertensive drugs adversely affect cognitive function through the central noradrenergic system. Calcium channel blockers can have an inhibitory influence on neurotransmission by impairment of calcium and intracellular messenger systems as neurotransmitter release is calcium-dependent.

Benzodiazepines. The sedative action of benzodiazepines is related to omega1 receptors, whereas omega2 receptors are responsible for their effects on memory and cognitive functioning. Nonbenzodiazepine sedatives such as zolpidem act on omega1 receptors, whereas benzodiazepines also interact with omega2 receptors with adverse effects on cognitive performance and memory.

Pathomechanism of valproate-induced dementia. Valproic acid-induced dementia in patients with epilepsy can be explained by the following:

(1) A direct toxic effect of valproic acid on the CNS. (2) An indirect CNS toxic effect mediated by valproic acid-induced hyperammonemia. (3) A paradoxical epileptogenic effect secondary to valproic acid.

The relation between valproate, brain atrophy, and dementia is likely to be exceedingly complex. These side effects may be related to a disturbance in the GABAergic pathways in the basal ganglia system. A placebo-controlled study of patients treated with valproic acid showed accelerated brain volume loss over 1 year as measured by MRI and likely associated with greater cognitive impairment (16).

Pathomechanism of cytokine-induced dementia. Cytokines are involved in the neuroinflammatory process, which has been reported in numerous neurodegenerative disorders. Interleukins and interferons are considered to have neurotoxic effects. Possible mechanisms include competition on the membrane receptors with neurotropic hormones. The pathomechanism of CNS toxicity of cytokines may involve direct interaction of these proteins at the level of the circumventricular organs (area postrema, hypothalamic neurosecretory centers, vascular organ of the lamina terminalis), but it appears unlikely to be on cortical neurons. Adeno-associated virus-mediated expression of interleukin-10 in the brains of transgenic mouse models of Alzheimer disease was shown to result in increased Aβ accumulation by inhibition of its clearance by microglia and impaired memory (08). Interleukin-2 has an adverse effect on cognition. It may act by the following mechanisms:

• By increasing blood-brain barrier permeability • By activation of inappropriate central neuropeptidergic systems that impair memory • By direct neurotoxic effect

Characteristics of interferon neurotoxicity are:

• Usually, no structural alterations are present in the brain. • Neurotoxicity is dose related and is not due to any impurities in the drug. • It is reversible. • Areas of the brain with opiate receptors are the most susceptible.

The pathomechanism of interferon neurotoxicity is not well understood. Factors that predispose to this neurotoxicity are:

• High dosage • A route of administration with slow absorption • Intrathecal use of interferon • Use by elderly patients with cerebral atrophy • Use by HIV-positive patients • Acute viral infection with increased production of endogenous interferon

Pathomechanism of desferrioxamine-induced dementia. Desferrioxamine is a chelating agent that is useful for the treatment of aluminum intoxication as a complication of renal failure but has been reported to precipitate dialysis dementia in patients with chronic renal failure. The pathomechanism is not known, but patients are at high risk for development of this complication if they demonstrate high levels of aluminum either before or after the standard desferrioxamine infusion test. Direct desferrioxamine CNS toxicity is unlikely, but desferrioxamine-aluminum complex has a relatively low molecular weight and may cross the blood-brain barrier more readily than the naturally occurring serum aluminum that is bound to serum albumin.

Pathomechanism of neuroleptic-induced acceleration of dementia. Elderly patients with Alzheimer disease are more susceptible to this adverse effect because drug metabolism and clearance slow down with aging, and target cells in the CNS may become more sensitive and vulnerable to drugs due to altered metabolism or cellular loss. Repetitive sharp EEG discharges, reversible on withdrawal of neuroleptic drugs, are seen in multiinfarct dementia. The EEG changes have been correlated with dysfunction of the adrenergic transmission.

Drugs that increase permeability of the blood-brain barrier. Cyclosporin, by increasing blood-brain barrier permeability, may explain the aluminum-induced dementia in renal transplant patients.

Cognitive dysfunction in drug-induced parkinsonism. The results of a clinical study suggest that cognitive impairment in patients with drug-induced parkinsonism reflects the toxic/metabolic symptoms associated with the offending drug in addition to being a risk factor for drug-induced parkinsonism (23). Results of a retrospective study suggest that cognitive dysfunction in drug-induced parkinsonism caused by prokinetics/antiemetics is associated with structural changes in the brain, including cortical atrophy and reduction in hippocampal volume demonstrated by 3D MRI (01).

Drug-induced cognitive disorders in AIDS patients. Drugs of abuse consumed by AIDS patients may be important cofactors in the development of HIV-associated neurocognitive disorders (HAND) syndrome. Increases in CNS dopamine induced by drugs of abuse may aggravate HIV infection in monocytes, macrophages, and T cells of the brain by dysregulating their functions (18).

Epidemiology

	• No definite epidemiological studies are available for the incidence or prevalence of drug-induced dementia.
	• Advancing age has significant association with drug-induced dementia.
	• There is a greater use of drugs associated with dementia in patients who present with cognitive impairment some years before the diagnosis of Alzheimer disease.

Medication toxicity accounts for 2% to 12% of dementia in several older studies. In a review of 516 cases in the literature, toxic effect of medications accounted for 2.7% of the dementia cases, whereas cerebral atrophies (including Alzheimer disease and unknown causes) constituted 52.1% of the cases (27). Among 263,962 adverse effects of drugs recorded between 1985 and 2005 in the French pharmacovigilance database, 79 (0.03%) are dementia (15). Drug-induced, dementia-associated and non-dementia, non-drug delirium hospitalizations in the United States have been analyzed from the years 1998 to 2005 (24). The presence of dementia and adverse drug effects had the strongest associations with dementia-associated and drug-induced delirium. Age had significant associations with drug-induced and dementia-associated delirium as well. In a study on community-dwelling persons between 2005 and 2011 in Finland, use of antipsychotic drugs was found to be almost 8 times more common among patients with clinically verified Alzheimer disease 5 years before their diagnosis than other groups (29). Four years after the diagnosis, psychotropic drug use was 3 times more common in Alzheimer disease suffers than other comparable groups. Use of at least 2 psychotropics at the same time was 3 times more common among patients with Alzheimer disease 4 years after their diagnosis. The most common combination included an antidepressant plus either an antipsychotic or a benzodiazepine.

Prevention

Drugs known to produce dementia such as anticholinergics should be avoided in persons who have risk factors predisposing them to dementia.

Anticholinergic drugs must be avoided in Parkinson disease patients with some cognitive decline and those who have incipient Alzheimer disease or vascular dementia.

Patients with dementia who are on cholinesterase inhibitor therapy for dementia may receive anticholinergic medication for urge incontinence. This combination would seem to be inappropriate as anticholinergic medications are notorious for worsening cognitive function in susceptible patients. However, this combination can be clinically effective without risk of aggravation of dementia.

Avoiding human-derived tissue extracts or cells can prevent iatrogenic Creutzfeldt-Jakob disease. Bovine products used for medicinal purposes require strict control to eliminate the possibility of transmission of bovine spongy encephalopathy.

Differential diagnosis

Confusing conditions

It is important to differentiate drug-induced dementia from other disorders of the brain associated with dementia. Drug-induced cognitive disturbance is a broad term that refers mostly to delirium. Delirium is characterized by a reduction of the level of consciousness, and this is manifested clinically by disorientation. In patients with dementia, the risk of delirium is enhanced due to diminished "cognitive reserve."

Most of the drug-induced dementias are reversible after discontinuation of the causal drug. Elderly people taking anticholinergic drugs have significant deficits in cognitive functioning and are likely to be misdiagnosed as having mild cognitive impairment that might be an early stage of Alzheimer disease. Use of anticholinergic drugs in elderly persons with mild cognitive impairment should be determined before considering administration of acetylcholinesterase inhibitors.

Drug-induced dementia may mimic glucose metabolism and clinical symptoms of Alzheimer disease. In an elderly subject on polypharmacy, including lithium and primidone, imaging and clinical findings reversed to normal on discontinuation of drugs (32). In this case, amyloid PET was a helpful tool to rule out underlying Alzheimer disease.

It is important to recognize the adverse effects of lithium-induced Creutzfeldt-Jakob disease-like syndrome and to avoid the costly and unnecessary investigative procedures for Creutzfeldt-Jakob disease. This syndrome clears up after discontinuation of lithium. The clinical picture of an elderly man who presented with subacute onset of severe cognitive impairment, ataxia, tremor, and stimulus-sensitive myoclonus following treatment with a combination of tricyclic mimicked Creutzfeldt-Jakob disease, which could be excluded by CSF analysis that showed normal level of tau protein and Aβ1-42 as well as being negative for CSF 14-3-3 protein (30).

Associated or underlying disorders

Disorders that predispose to drug-induced dementia include the following:

	• Aging patients with cognitive impairment.
	• Persons at risk for development of Alzheimer disease including those with genetic links.
	• Use of combinations of hypnotics with other CNS drugs with risk of synergic effect or interactions.

Diagnostic workup

• Key tests for suspected drug-induced dementia are blood levels of drugs, cognitive assessment, brain imaging, and EEG.

The DSM-IV diagnostic criteria for substance-induced persisting dementia are shown in Table 3.

Table 3. DSM-IV Diagnostic Criteria for Substance-Induced Persisting Dementia

A. The development of multiple cognitive deficits manifested by both of the following:
	1. memory impairment (impaired ability to learn new information or to recall previously learned information)
	2. one or more of the following cognitive disturbances
		a. aphasia (language disturbance) b. apraxia (impaired ability to carry out motor activities despite intact motor function) c. agnosia (failure to recognize or identify objects despite intact sensory function) d. disturbances in executive functioning (eg, planning, organization, sequencing, etc.)
B. The cognitive deficits in criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning.
C. The deficits do not occur exclusively during the course of a delirium and persist beyond the usual duration of substance intoxication or withdrawal.
D. Evidence acquired from the history, physical examination, or laboratory findings suggests that the deficits are etiologically related to the persisting effects of substance intoxication or withdrawal.

The central nervous system in the elderly is particularly sensitive to drugs, and an iatrogenic cause must be sought for all recent or sudden alterations in memory functions. The diagnostic workup of a patient with suspected drug-induced dementia includes the following investigations:

• Serum levels of suspected drugs • Cognitive functioning tests • CT scan to detect cerebral atrophy • MRI to detect leukoencephalopathy • EEG from patients showing neurotoxic effects of interferon (interferon syndrome) who reveal a diffuse slowing of the alpha rhythm and an appearance of theta and delta waves, prominent in the frontal lobes and consistent with a diffuse encephalopathy. EEG in patients with lithium-induced Creutzfeldt-Jakob disease-like syndrome shows slow activity with synchronic periodic complexes.

Management

• Management is supportive, and there should be a withdrawal of the offending medication.

Management is supportive, and there should be a withdrawal of the offending medication. Anticholinergic medications should be withdrawn in patients with Parkinson disease if they develop dementia. These patients may also improve after reduction of anticholinergic therapy, and cholinesterase inhibitors might partially improve cognitive deficits. In the case of recent alterations in memory of elderly patients, all nonessential drugs, especially psychotropic agents, should be withdrawn or reduced. Caution should be exercised in the prescription of anticholinergic agents for patients at risk of cognitive decline.

Possible pharmacologic interventions to decrease neurotoxicity associated with interferon-alpha therapy include the use of antidepressants, psychostimulants, and opioid antagonists.

Identification of drug-induced cognitive impairment is important, as early detection and discontinuation of the offending medications may lead to resolution of symptoms. Preventive strategies should include avoidance of high-risk medications where possible and adjustment of doses according to age-related changes.

Special considerations

Geriatric

Elderly persons are more susceptible than younger persons to develop cognitive impairments associated with medication use, and one of the reasons for this is the frequent impairment of renal and liver functions the elderly, leading to impaired excretion and detoxification of drugs. Use of anticholinergic medication in this age group is linked to cognitive impairment and an increased risk of dementia.

Pregnancy

Exposure to drugs such as phenobarbital during pregnancy can produce intellectual impairment in the offspring. Exposure in the third trimester is the most deleterious. Exposure of pregnant women to medications that can impair cognitive function should be avoided.

Anesthesia

Most general anesthetics produce cognitive impairment for several hours after the medical or surgical procedure has ended. Whether long-term cognitive impairment occurs with various general anesthetics remains a question. The mechanism is not certain, but it is possible that inhibition of central nicotinic acetylcholine receptors contributes to secondary effects attributed to anesthesia such as impairment in memory and cognitive performance. The type of procedure performed, rather than the anesthetic agent used, appears to be a more important factor. Severe brain damage is more likely to develop following cardiac surgical procedures rather than following noncardiac surgery. The most common anesthetic techniques for cardiac surgery include the use of high-dose opioids with adjuvant inhalational agents and benzodiazepines or a low-dose opioid combined with standard doses of inhalational agents (isoflurane, enflurane, and halothane).