Joseph S. Goveas, MD

Mr. R, age 67, presents with what he describes as uncharacteristic “memory loss” that is affecting his ability to run his accounting business. He and his wife relate that he was doing well until approximately 9 months ago, when he started showing difficulties remembering clients’ names and addresses.

His wife became extremely concerned when he made serious accounting errors in a 1-month period that resulted in the loss of a longtime customer. Mr. R has become easily distracted and absentminded as well, and his wife reports he is misplacing things around the house.

Screening for mild cognitive impairment (MCI) is not recommended for asymptomatic, cognitively healthy older persons, but memory complaints in individuals age >50—especially when corroborated by a reliable informant—warrant further assessment. Your challenge is to determine whether subtle cognitive changes in patients such as Mr. R are part of normal aging, caused by medical or mental illnesses, or a harbinger of Alzheimer’s disease (AD) or another dementia.

Although no treatments can yet prevent dementia, substantial new research is defining the MCI diagnosis for clinicians. This article describes:

• the evolving understanding of MCI and its subtypes
  
• risk factors for converting from MCI to AD
  
• an evidence-based work-up (including functional, cognitive, and neuropsychological testing)
  
• neuroprotective strategies for patients with an MCI diagnosis, including evidence on cholinesterase inhibitors, vitamin E, and anti-inflammatory agents.
  

MCI’s evolving definition

MCI is characterized by subjective and objective cognitive decline greater than expected for an individual’s age and education but less than the functional deficit required for a dementia diagnosis. MCI is proposed to identify persons with early but pathologic cognitive impairment that has a high risk to progress to AD and possibly other dementias.

MCI is thought to be a transitional state between normal aging and dementia.¹ Its estimated prevalence in the general population is 19% among individuals age 85.²

MCI subtypes. Some experts view MCI as a single entity, whereas others suggest amnestic (aMCI) and nonamnestic (nMCI) subtypes.^1,3 Each subtype is further divided into single and multiple cognitive domains. So, for example, the diagnosis would be:

• aMCI-single cognitive domain for memory impairment only
  
• aMCI-multiple cognitive domains for memory impairment plus nonmemory deficits, such as in language, executive function, or visuospatial function
  
• nMCI-single or multiple cognitive domains for nonmemory deficits without memory impairment.
  

MCI subtypes may have different outcomes for progression to dementia, and all progressive dementias may have their own predementia states.⁴ Vascular MCI, for instance, is thought to result from cerebrovascular disease and is proposed to describe a prodrome of vascular dementia.⁵

Determining a patient’s MCI subtype is still a research activity and calls for comprehensive neuropsychological testing. MCI patients perform at least 1.5 standard deviations below the average for age- and education-matched healthy individuals on objective measures of memory.¹

Conversion to dementia

In longitudinal population studies patients with MCI have shown an 11% to 33% risk of developing dementia within 2 years, whereas 44% reverted to normal 1 year later. Reasons for reversibility may include variable definitions of MCI among the longitudinal studies and the possibility that patients who recovered or improved may have had reversible causes of dementia.¹

When patients with MCI are followed over time, they progress not only to AD but also to non-AD dementias. For example, patients with Parkinson’s disease (PD) and MCI may be at higher risk of progressing to dementia than cognitively intact PD patients.⁶ MCI patients with the e4 allele of the apolipoprotein E gene (ApoE e4) are at increased risk to convert from MCI to AD.⁷

Individuals with aMCI (Table 1)⁸ progress to AD at a rate of 10% to 15% per year, compared with 1% to 2% per year in normal elderly persons. The Mayo AD research center studies reported a conversion rate of up to 80% from aMCI to AD within 6 years.⁹

Research focuses on identifying preclinical AD states and potential targets for intervention using disease-modifying therapies. Some experts consider MCI to be the earliest clinical manifestation of AD, at least in a subgroup of patients.

Identifying markers to predict which patients are likely to convert from MCI to dementia also is a major research objective. In addition to ApoE status (Table 2),^7,9-15 predictors of conversion may include:

 

• hippocampal atrophy¹³
  
• reduced metabolism in the temporoparietal cortex and posterior cingulum¹⁴
  
• elevated CSF tau and the 42 amino acid form of ß-amyloid (Aß 42).¹⁵
  

Research techniques such as structural neuroimaging, positron-emission tomography, functional magnetic resonance imaging (fMRI), and cerebrospinal fluid biomarkers have not been defined for clinical use, however.

Neuropsychiatric symptoms. Individuals with MCI and neuropsychiatric symptoms may be at particular risk for progressing to dementia. Agitation or depression are more prevalent in persons with MCI than in normal elderly but less prevalent than in those with dementia (Table 3).^10,16

The cross-sectional, community-based Cardiovascular Health Study showed one or more neuropsychiatric symptom in:

• 16% of normal healthy elderly
  
• 43% of MCI patients
  
• 75% of dementia patients.¹⁶
  

Depression (20%), apathy (15%), and irritability (15%) were the neuropsychiatric symptoms reported most frequently in MCI patients, compared with apathy (36%), depression (32%), and agitation/aggression (30%) in dementia patients.

Sleep disturbances and anxiety in persons with MCI may predict progression to AD.¹⁰ A baseline high frequency of apathy in aMCI patients has been associated with progression to AD within 1 year.¹¹

Table 1

Amnestic MCI: Proposed diagnostic criteria

Subjective memory impairment, preferably corroborated by a reliable informant
Reduced performance on objective memory tests, compared with persons of similar age and educational background
Typical general cognitive function
Intact basic activities of daily living and intact or minimally impaired instrumental activities of daily living
Absence of dementia
MCI: mild cognitive impairment
Source: Reference 8

Table 2

Factors shown to predict conversion from MCI to dementia

Category	Predictors of conversion
Clinical	Cognitive: Amnestic MCI Neuropsychiatric: Depression, apathy, and possibly nighttime behaviors and anxiety
Neuropsychological tests	Clock-drawing test, Trail-Making Test B, Symbol Digit Modalities Test, Delayed 10-Word List Recall, New York University Paragraph Recall Test (Delayed), ADAS-Cog total score
Neuroimaging	MRI: Entorhinal cortex and hippocampal atrophy PET: Medial temporal region, parietotemporal association cortex, and posterior cingulate hypometabolism fMRI: Abnormal hippocampal, posterior cingulate, and medial temporal region activation on memory tasks
CSF markers	Increase: t-tau, p-tau Decrease: Aß 42
Genetic markers	ApoE e4 carriers
ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive subscale; ApoE e4: apolipoprotein E gene, e4 allele; CSF: cerebrospinal fluid; MCI: mild cognitive impairment; MRI: magnetic resonance imaging; fMRI: functional MRI; PET: positron-emission tomography
Source: References 7,9-15

Table 3

Neuropsychiatric symptoms: Rising prevalence mirrors cognitive deterioration in elderly patients*

Neuropsychiatric symptoms	Normal elderly	MCI	Mild AD
Depressed mood/dysphoria	+	++	+++
Nighttime behaviors/sleep	+	++	+++
Irritability	+	++	+++
Anxiety	+/-	++	+++
Apathy/indifference	+/-	++	+++
Agitation/aggression	+/-	+/++	+++
Eating/appetite disturbance	+/-	+	++
Disinhibition	+/-	+/-	++
Aberrant motor behavior	0	+	++
Delusions	0	+/-	++
Euphoria	0	+/-	+/-
Hallucinations	0	0	+
* 0 = 0%; +/- = 1% to 5%; + = 6% to 10%; ++ = 11% to 20%; +++ = 21% to 40%
MCI: mild cognitive impairment; AD: Alzheimer’s disease
Source: References 10,16

Depression and MCI

Depression and cognitive complaints overlap considerably in older adults. Depressed patients without dementia show persistent cognitive deficits even after depression remits. In some patients, new-onset geriatric depression is considered a prodrome of MCI and AD. Given that AD neuropathologic changes precede clinical symptoms by many years, depression and AD have been proposed as different clinical manifestations of AD pathology.¹⁷

Among patients with MCI, 20% meet criteria for major depression and 26% for minor depression. Symptoms often include sadness, poor concentration, inner tension, pessimistic thoughts, lassitude, and insomnia.¹⁸

Depressed MCI patients are at higher risk of developing dementia than those without depression, especially if cognitive measures do not improve after depression is treated.¹² Similarly, cognitively intact older persons who develop depression are at increased risk for MCI, particularly if they carry the ApoE e4 genotype.¹⁹

In the only study in which MCI patients’ neuropsychiatric symptoms have been treated, 39 elderly patients with depression and MCI received open-label sertraline, ≤200 mg/d, for 12 weeks. Among the 26 patients who completed the trial, 17 showed moderate improvement in depressive symptoms, attention, and executive function, and 9 showed no response.²⁰

Recommendation. In clinical practice, antidepressant treatment—usually a selective serotonin reuptake inhibitor (SSRI), with or without psychotherapy—is recommended for the MCI patient with comorbid major depression.

CASE CONTINUED: No signs of depression

Mr. R’s medical, neurologic, and substance use history is unremarkable. Family history includes AD in a paternal aunt diagnosed at age 82. Mr. R reports no history of mood, sleep, or appetite changes and no psychotic symptoms. He shows no deficits in activities of daily living (ADL), although his wife recently took over paying household bills after he forgot to make a payment.

Evidence-based workup

Functional assessment. In the differential diagnosis of MCI, give special attention to functional impairment, which points toward dementia. ADL generally are preserved in MCI, and minimal deterioration is seen in instrumental activities of daily living (IADL). A relatively easy way to assess function is to use the Alzheimer’s Disease Functional Assessment and Change Scale (ADFACS), which is based on 16 ADL and IADL items (Table 4).²¹

 

A substantial functional decline precludes an MCI diagnosis, although the degree of functional decline can be difficult to assess in older adults with physical limitations caused by medical comorbidities.

Cognitive assessment. Because most individuals with MCI score in the normal range on the Folstein Mini-Mental State Examination (MMSE), the modified MMSE (3MS)²² may be more sensitive for detecting MCI. The 3MS retains the MMSE’s brevity (≤10 minutes to administer) but incorporates 4 additional items, has more graded scoring responses, and broadens the score range to 0 to 100. The clock-drawing test also is sensitive for MCI, especially in detecting early visuoconstructional dysfunction.

The Montreal Cognitive Assessment (MoCA) is a 10-minute, 30-point scale designed to help clinicians detect MCI (see Related Resources). The MoCA usually is given with the modified MMSE for a comprehensive cognitive assessment.

Nasreddine et al²³ administered the MoCA and MMSE to 94 patients who met clinical criteria for MCI, 93 patients with mild AD, and 90 healthy cognitively normal elderly persons, using a cutoff score of 26. MoCA showed:

• 90% sensitivity for detecting MCI (compared with 18% for the MMSE)
  
• 87% specificity to exclude normal elderly persons.
  

The average MoCA score in patients with AD was much lower than in individuals with MCI, but score ranges of these 2 groups overlapped. Therefore, a score

Neuropsychological testing can be more sensitive than office-based screening tools in defining MCI subtypes. In the Alzheimer’s Disease Cooperative Study (ADCS), the neuropsychological measures that most accurately predicted progression of patients with aMCI to AD within 36 months were the:

• Symbol Digit Modalities Test
  
• New York University Paragraph Recall Test (Delayed)
  
• Delayed 10-Word List Recall
  
• Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score.²⁴
  

Laboratory tests, imaging. Use laboratory studies (Table 5) to rule out reversible causes of MCI symptoms.⁸ Reserve CSF studies for suspected CNS infection (such as meningitis, human immunodeficiency virus, or neurosyphilis) and brain imaging for suspected cerebral pathology (such as infarct, subdural hematoma, normal pressure hydrocephalus, or tumor).

Table 4

Alzheimer’s Disease Functional Assessment and Change Scale (ADFACS)

Basic ADL	Instrumental ADL (IADL)
Toileting	Use of telephone
Feeding	Household tasks
Dressing	Using household appliances
Personal hygiene and grooming	Managing money
	Shopping
Bathing	Food preparation
Walking	Ability to get around inside and outside home
	Hobbies and leisure activities
	Handling personal mail
	Grasp of situations and explanations
The 16-item ADFACS total score ranges from 0 to 54 (best to worst): Rate basic ADLs from 0 (no impairment) to 4 (very severe impairment), for a total score range of 0 to 24. Rate IADLs from 0 (no impairment) to 3 (severe impairment), for a total score range of 0 to 30.
Use total scores to assess for functional decline from baseline. A decline from 0 to 1 on individual ADL and IADL items is not considered clinically significant.
ADL: activities of daily living
Source: Reprinted with permission from reference 21

Table 5

Lab studies to rule out reversible causes of MCI

Complete blood count with differential
Basic metabolic panel
Liver function tests
Serum calcium
Serum vitamin B12 and folate
Thyroid function tests
Rapid plasma reagin
HIV in high-risk individuals
CSF studies if CNS infection is suspected
CSF: cerebrospinal fluid; HIV: human immunodeficiency virus; MCI: mild cognitive impairment
Source: Reference 8

CASE CONTINUED: Subtle cognitive deficits

Mr. R scores 27/30 on the MMSE (losing 3 points on recall) and 25/30 on the MoCA (losing points on visuospatial/executive function, fluency, and delayed recall). Thyroid stimulating hormone, vitamin B12, folate, and rapid plasma reagin tests are unremarkable; brain MRI shows no significant abnormalities.

You refer Mr. R for neuropsychological testing, and most cognitive domains are normal. Exceptions include moderate impairment in immediate and delayed verbal and visual memory and mild executive dysfunction.

Based on your clinical evaluation and neuropsychological testing, you diagnose amnestic MCI. Mr. R shows abnormalities in memory and executive functioning without significant decline in basic and instrumental ADLs, is not taking medications, and has no other medical or psychiatric condition that could explain his cognitive deficits.

You discuss the diagnosis with him and his wife, including evidence on his risk for progression to dementia, neuroprotective strategies, and medications.

After an MCI diagnosis

Neuroprotection. Eliminate medications with anticholinergic effects, including:

• tricyclic antidepressants
  
• conventional antipsychotics
  
• antihistamines
  
• drugs used to treat urinary incontinence, such as oxybutynin
  
• muscle relaxants, such as cyclobenzaprine
  
• certain antiparkinsonian drugs, such as benztropine.
  

Encourage patients to avoid alcohol and sedatives. Collaborate with primary care providers to control cerebrovascular risk factors such as hyperlipidemia, diabetes mellitus, hypertension, and obesity. Treat depression, which may be a risk factor for developing dementia.

 

Monitoring. The American Academy of Neurology recommends monitoring patients diagnosed with MCI every 6 to 12 months for cognitive and functional decline.

In these visits, include:

• repeat office-based cognitive assessment, especially the modified MMSE, clock-drawing test, and MoCA
  
• careful history-taking from the patient and reliable informant
  
• repeat neuropsychological testing annually or when dementia is suspected
  
• assessment of the caregiver for distress.
  

Compensating for memory loss. Many individuals with MCI have insight into their cognitive deficits and are interested in making lifestyle changes. Experts recommend:

• moderate exercise (at least 30 minutes per session, 3 times a week)
  
• cognitively stimulating activities that involve language and psychomotor coordination, such as dancing, crossword puzzles, and volunteer work.
  

Potentially helpful tools include calendars, reminder notes, electronic cuing devices, pill boxes, and “speed-dial” telephones. Encourage patients to participate in local senior organizations and to use community resources.¹

Medications—yes or no? Cholinesterase inhibitors, rofecoxib, and vitamin E have not been shown to prevent MCI from progressing to AD. Thus, insufficient evidence exists to recommend medications for patients with MCI.

Donepezil has shown possible short-term benefits, however, and patients may choose to try this medication. Some find comfort in seeking this “extra time” to make decisions about advanced directives, attend to estate and will issues, and optimize relationships while they have only mild cognitive deficits and possess decision-making capacity.

Donepezil. The Alzheimer’s Disease Cooperative Study—supported by the National Institute on Aging—was designed to determine whether daily doses of donepezil or vitamin E can delay or prevent progression of aMCI to AD.²⁵ In the double-blind, placebo-controlled, parallel group study, 769 patients with aMCI were randomly assigned to receive donepezil, 10 mg/d; vitamin E, 1,000 IU bid; or placebo for 3 years.

Overall progression to AD was 16% per year, and the 3-year risk of progression was the same in all 3 groups. Donepezil therapy was associated with a reduced rate of progression to AD compared with placebo during the first year of treatment. Donepezil’s benefit was evident among ApoE e4 carriers at 2-year follow-up, but none of the 3 groups showed statistically significant differences after 3 years. Vitamin E showed no effect on AD progression throughout the study.

Rivastigmine. A randomized, placebo-controlled trial in which 1,018 MCI patients received rivastigmine or placebo for 4 years found no statistically significant benefit of rivastigmine on AD progression.²⁶

Galantamine. Two international randomized, double-blind, placebo-controlled trials failed to show a statistically significant benefit of galantamine in slowing progression from aMCI to AD. MRI data from one of these studies suggested that galantamine may have reduced the rate of brain atrophy over a 2-year period.²⁷

Rofecoxib. Epidemiologic studies indicate that anti-inflammatory drugs may reduce the risk of developing AD, but the COX-2 inhibitor rofecoxib did not delay progression to AD among aMCI patients in a large, placebo-controlled trial.²⁸

Educate patients and family members about supportive nonpharmacologic treatments and cholinesterase inhibitors. The Alzheimer’s Association, National Institute on Aging, and local department of aging agencies offer useful resources (see Related Resources).

CASE CONTINUED: Dealing with uncertainty

Mr. R and his wife are unsettled by his MCI diagnosis. They prefer to take a “wait and watch” approach, decline initiation of a cholinesterase inhibitor, and agree to adhere to nonpharmacologic interventions you discussed. You schedule a follow-up visit in 6 months and encourage them to call you with questions.

Related resources

• Rosenberg PB, Johnston D, Lyketsos CG. A clinical approach to mild cognitive impairment. Am J Psychiatry 2006;163: 1884-90.
  
• Montreal Cognitive Assessment (MoCA). 10-minute screening test designed to help clinicians detect mild cognitive impairment. www.mocatest.org.
  
• Alzheimer’s Association. www.alz.org.
  
• National Institute on Aging. www.nia.nih.gov.
  

Drug brand name

• Benztropine • Cogentin
  
• Cyclobenzaprine • Flexeril
  
• Donepezil • Aricept
  
• Galantamine • Razadyne
  
• Oxybutynin • Ditropan
  
• Rivastigmine • Exelon
  
• Rofecoxib • Vioxx
  
• Sertraline • Zoloft
  

Disclosure

Dr. Goveas and Dr. Dixon-Holbrook report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Kerwin is a consultant to Pfizer and a speaker for Pfizer and Novartis.

Dr. Antuono receives research support from Eisai, Pfizer, and Elan and is a speaker for Pfizer and Forest Pharmaceuticals.

Mr. R, age 67, presents with what he describes as uncharacteristic “memory loss” that is affecting his ability to run his accounting business. He and his wife relate that he was doing well until approximately 9 months ago, when he started showing difficulties remembering clients’ names and addresses.

His wife became extremely concerned when he made serious accounting errors in a 1-month period that resulted in the loss of a longtime customer. Mr. R has become easily distracted and absentminded as well, and his wife reports he is misplacing things around the house.

Screening for mild cognitive impairment (MCI) is not recommended for asymptomatic, cognitively healthy older persons, but memory complaints in individuals age >50—especially when corroborated by a reliable informant—warrant further assessment. Your challenge is to determine whether subtle cognitive changes in patients such as Mr. R are part of normal aging, caused by medical or mental illnesses, or a harbinger of Alzheimer’s disease (AD) or another dementia.

Although no treatments can yet prevent dementia, substantial new research is defining the MCI diagnosis for clinicians. This article describes:

• the evolving understanding of MCI and its subtypes
  
• risk factors for converting from MCI to AD
  
• an evidence-based work-up (including functional, cognitive, and neuropsychological testing)
  
• neuroprotective strategies for patients with an MCI diagnosis, including evidence on cholinesterase inhibitors, vitamin E, and anti-inflammatory agents.
  

MCI’s evolving definition

MCI is characterized by subjective and objective cognitive decline greater than expected for an individual’s age and education but less than the functional deficit required for a dementia diagnosis. MCI is proposed to identify persons with early but pathologic cognitive impairment that has a high risk to progress to AD and possibly other dementias.

MCI is thought to be a transitional state between normal aging and dementia.¹ Its estimated prevalence in the general population is 19% among individuals age 85.²

MCI subtypes. Some experts view MCI as a single entity, whereas others suggest amnestic (aMCI) and nonamnestic (nMCI) subtypes.^1,3 Each subtype is further divided into single and multiple cognitive domains. So, for example, the diagnosis would be:

• aMCI-single cognitive domain for memory impairment only
  
• aMCI-multiple cognitive domains for memory impairment plus nonmemory deficits, such as in language, executive function, or visuospatial function
  
• nMCI-single or multiple cognitive domains for nonmemory deficits without memory impairment.
  

MCI subtypes may have different outcomes for progression to dementia, and all progressive dementias may have their own predementia states.⁴ Vascular MCI, for instance, is thought to result from cerebrovascular disease and is proposed to describe a prodrome of vascular dementia.⁵

Determining a patient’s MCI subtype is still a research activity and calls for comprehensive neuropsychological testing. MCI patients perform at least 1.5 standard deviations below the average for age- and education-matched healthy individuals on objective measures of memory.¹

Conversion to dementia

In longitudinal population studies patients with MCI have shown an 11% to 33% risk of developing dementia within 2 years, whereas 44% reverted to normal 1 year later. Reasons for reversibility may include variable definitions of MCI among the longitudinal studies and the possibility that patients who recovered or improved may have had reversible causes of dementia.¹

When patients with MCI are followed over time, they progress not only to AD but also to non-AD dementias. For example, patients with Parkinson’s disease (PD) and MCI may be at higher risk of progressing to dementia than cognitively intact PD patients.⁶ MCI patients with the e4 allele of the apolipoprotein E gene (ApoE e4) are at increased risk to convert from MCI to AD.⁷

Individuals with aMCI (Table 1)⁸ progress to AD at a rate of 10% to 15% per year, compared with 1% to 2% per year in normal elderly persons. The Mayo AD research center studies reported a conversion rate of up to 80% from aMCI to AD within 6 years.⁹

Research focuses on identifying preclinical AD states and potential targets for intervention using disease-modifying therapies. Some experts consider MCI to be the earliest clinical manifestation of AD, at least in a subgroup of patients.

Identifying markers to predict which patients are likely to convert from MCI to dementia also is a major research objective. In addition to ApoE status (Table 2),^7,9-15 predictors of conversion may include:

 

• hippocampal atrophy¹³
  
• reduced metabolism in the temporoparietal cortex and posterior cingulum¹⁴
  
• elevated CSF tau and the 42 amino acid form of ß-amyloid (Aß 42).¹⁵
  

Research techniques such as structural neuroimaging, positron-emission tomography, functional magnetic resonance imaging (fMRI), and cerebrospinal fluid biomarkers have not been defined for clinical use, however.

Neuropsychiatric symptoms. Individuals with MCI and neuropsychiatric symptoms may be at particular risk for progressing to dementia. Agitation or depression are more prevalent in persons with MCI than in normal elderly but less prevalent than in those with dementia (Table 3).^10,16

The cross-sectional, community-based Cardiovascular Health Study showed one or more neuropsychiatric symptom in:

• 16% of normal healthy elderly
  
• 43% of MCI patients
  
• 75% of dementia patients.¹⁶
  

Depression (20%), apathy (15%), and irritability (15%) were the neuropsychiatric symptoms reported most frequently in MCI patients, compared with apathy (36%), depression (32%), and agitation/aggression (30%) in dementia patients.

Sleep disturbances and anxiety in persons with MCI may predict progression to AD.¹⁰ A baseline high frequency of apathy in aMCI patients has been associated with progression to AD within 1 year.¹¹

Table 1

Amnestic MCI: Proposed diagnostic criteria

Subjective memory impairment, preferably corroborated by a reliable informant
Reduced performance on objective memory tests, compared with persons of similar age and educational background
Typical general cognitive function
Intact basic activities of daily living and intact or minimally impaired instrumental activities of daily living
Absence of dementia
MCI: mild cognitive impairment
Source: Reference 8

Table 2

Factors shown to predict conversion from MCI to dementia

Category	Predictors of conversion
Clinical	Cognitive: Amnestic MCI Neuropsychiatric: Depression, apathy, and possibly nighttime behaviors and anxiety
Neuropsychological tests	Clock-drawing test, Trail-Making Test B, Symbol Digit Modalities Test, Delayed 10-Word List Recall, New York University Paragraph Recall Test (Delayed), ADAS-Cog total score
Neuroimaging	MRI: Entorhinal cortex and hippocampal atrophy PET: Medial temporal region, parietotemporal association cortex, and posterior cingulate hypometabolism fMRI: Abnormal hippocampal, posterior cingulate, and medial temporal region activation on memory tasks
CSF markers	Increase: t-tau, p-tau Decrease: Aß 42
Genetic markers	ApoE e4 carriers
ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive subscale; ApoE e4: apolipoprotein E gene, e4 allele; CSF: cerebrospinal fluid; MCI: mild cognitive impairment; MRI: magnetic resonance imaging; fMRI: functional MRI; PET: positron-emission tomography
Source: References 7,9-15

Table 3

Neuropsychiatric symptoms: Rising prevalence mirrors cognitive deterioration in elderly patients*

Neuropsychiatric symptoms	Normal elderly	MCI	Mild AD
Depressed mood/dysphoria	+	++	+++
Nighttime behaviors/sleep	+	++	+++
Irritability	+	++	+++
Anxiety	+/-	++	+++
Apathy/indifference	+/-	++	+++
Agitation/aggression	+/-	+/++	+++
Eating/appetite disturbance	+/-	+	++
Disinhibition	+/-	+/-	++
Aberrant motor behavior	0	+	++
Delusions	0	+/-	++
Euphoria	0	+/-	+/-
Hallucinations	0	0	+
* 0 = 0%; +/- = 1% to 5%; + = 6% to 10%; ++ = 11% to 20%; +++ = 21% to 40%
MCI: mild cognitive impairment; AD: Alzheimer’s disease
Source: References 10,16

Depression and MCI

Depression and cognitive complaints overlap considerably in older adults. Depressed patients without dementia show persistent cognitive deficits even after depression remits. In some patients, new-onset geriatric depression is considered a prodrome of MCI and AD. Given that AD neuropathologic changes precede clinical symptoms by many years, depression and AD have been proposed as different clinical manifestations of AD pathology.¹⁷

Among patients with MCI, 20% meet criteria for major depression and 26% for minor depression. Symptoms often include sadness, poor concentration, inner tension, pessimistic thoughts, lassitude, and insomnia.¹⁸

Depressed MCI patients are at higher risk of developing dementia than those without depression, especially if cognitive measures do not improve after depression is treated.¹² Similarly, cognitively intact older persons who develop depression are at increased risk for MCI, particularly if they carry the ApoE e4 genotype.¹⁹

In the only study in which MCI patients’ neuropsychiatric symptoms have been treated, 39 elderly patients with depression and MCI received open-label sertraline, ≤200 mg/d, for 12 weeks. Among the 26 patients who completed the trial, 17 showed moderate improvement in depressive symptoms, attention, and executive function, and 9 showed no response.²⁰

Recommendation. In clinical practice, antidepressant treatment—usually a selective serotonin reuptake inhibitor (SSRI), with or without psychotherapy—is recommended for the MCI patient with comorbid major depression.

CASE CONTINUED: No signs of depression

Mr. R’s medical, neurologic, and substance use history is unremarkable. Family history includes AD in a paternal aunt diagnosed at age 82. Mr. R reports no history of mood, sleep, or appetite changes and no psychotic symptoms. He shows no deficits in activities of daily living (ADL), although his wife recently took over paying household bills after he forgot to make a payment.

Evidence-based workup

Functional assessment. In the differential diagnosis of MCI, give special attention to functional impairment, which points toward dementia. ADL generally are preserved in MCI, and minimal deterioration is seen in instrumental activities of daily living (IADL). A relatively easy way to assess function is to use the Alzheimer’s Disease Functional Assessment and Change Scale (ADFACS), which is based on 16 ADL and IADL items (Table 4).²¹

 

A substantial functional decline precludes an MCI diagnosis, although the degree of functional decline can be difficult to assess in older adults with physical limitations caused by medical comorbidities.

Cognitive assessment. Because most individuals with MCI score in the normal range on the Folstein Mini-Mental State Examination (MMSE), the modified MMSE (3MS)²² may be more sensitive for detecting MCI. The 3MS retains the MMSE’s brevity (≤10 minutes to administer) but incorporates 4 additional items, has more graded scoring responses, and broadens the score range to 0 to 100. The clock-drawing test also is sensitive for MCI, especially in detecting early visuoconstructional dysfunction.

The Montreal Cognitive Assessment (MoCA) is a 10-minute, 30-point scale designed to help clinicians detect MCI (see Related Resources). The MoCA usually is given with the modified MMSE for a comprehensive cognitive assessment.

Nasreddine et al²³ administered the MoCA and MMSE to 94 patients who met clinical criteria for MCI, 93 patients with mild AD, and 90 healthy cognitively normal elderly persons, using a cutoff score of 26. MoCA showed:

• 90% sensitivity for detecting MCI (compared with 18% for the MMSE)
  
• 87% specificity to exclude normal elderly persons.
  

The average MoCA score in patients with AD was much lower than in individuals with MCI, but score ranges of these 2 groups overlapped. Therefore, a score

Neuropsychological testing can be more sensitive than office-based screening tools in defining MCI subtypes. In the Alzheimer’s Disease Cooperative Study (ADCS), the neuropsychological measures that most accurately predicted progression of patients with aMCI to AD within 36 months were the:

• Symbol Digit Modalities Test
  
• New York University Paragraph Recall Test (Delayed)
  
• Delayed 10-Word List Recall
  
• Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score.²⁴
  

Laboratory tests, imaging. Use laboratory studies (Table 5) to rule out reversible causes of MCI symptoms.⁸ Reserve CSF studies for suspected CNS infection (such as meningitis, human immunodeficiency virus, or neurosyphilis) and brain imaging for suspected cerebral pathology (such as infarct, subdural hematoma, normal pressure hydrocephalus, or tumor).

Table 4

Alzheimer’s Disease Functional Assessment and Change Scale (ADFACS)

Basic ADL	Instrumental ADL (IADL)
Toileting	Use of telephone
Feeding	Household tasks
Dressing	Using household appliances
Personal hygiene and grooming	Managing money
	Shopping
Bathing	Food preparation
Walking	Ability to get around inside and outside home
	Hobbies and leisure activities
	Handling personal mail
	Grasp of situations and explanations
The 16-item ADFACS total score ranges from 0 to 54 (best to worst): Rate basic ADLs from 0 (no impairment) to 4 (very severe impairment), for a total score range of 0 to 24. Rate IADLs from 0 (no impairment) to 3 (severe impairment), for a total score range of 0 to 30.
Use total scores to assess for functional decline from baseline. A decline from 0 to 1 on individual ADL and IADL items is not considered clinically significant.
ADL: activities of daily living
Source: Reprinted with permission from reference 21

Table 5

Lab studies to rule out reversible causes of MCI

Complete blood count with differential
Basic metabolic panel
Liver function tests
Serum calcium
Serum vitamin B12 and folate
Thyroid function tests
Rapid plasma reagin
HIV in high-risk individuals
CSF studies if CNS infection is suspected
CSF: cerebrospinal fluid; HIV: human immunodeficiency virus; MCI: mild cognitive impairment
Source: Reference 8

CASE CONTINUED: Subtle cognitive deficits

Mr. R scores 27/30 on the MMSE (losing 3 points on recall) and 25/30 on the MoCA (losing points on visuospatial/executive function, fluency, and delayed recall). Thyroid stimulating hormone, vitamin B12, folate, and rapid plasma reagin tests are unremarkable; brain MRI shows no significant abnormalities.

You refer Mr. R for neuropsychological testing, and most cognitive domains are normal. Exceptions include moderate impairment in immediate and delayed verbal and visual memory and mild executive dysfunction.

Based on your clinical evaluation and neuropsychological testing, you diagnose amnestic MCI. Mr. R shows abnormalities in memory and executive functioning without significant decline in basic and instrumental ADLs, is not taking medications, and has no other medical or psychiatric condition that could explain his cognitive deficits.

You discuss the diagnosis with him and his wife, including evidence on his risk for progression to dementia, neuroprotective strategies, and medications.

After an MCI diagnosis

Neuroprotection. Eliminate medications with anticholinergic effects, including:

• tricyclic antidepressants
  
• conventional antipsychotics
  
• antihistamines
  
• drugs used to treat urinary incontinence, such as oxybutynin
  
• muscle relaxants, such as cyclobenzaprine
  
• certain antiparkinsonian drugs, such as benztropine.
  

Encourage patients to avoid alcohol and sedatives. Collaborate with primary care providers to control cerebrovascular risk factors such as hyperlipidemia, diabetes mellitus, hypertension, and obesity. Treat depression, which may be a risk factor for developing dementia.

 

Monitoring. The American Academy of Neurology recommends monitoring patients diagnosed with MCI every 6 to 12 months for cognitive and functional decline.

In these visits, include:

• repeat office-based cognitive assessment, especially the modified MMSE, clock-drawing test, and MoCA
  
• careful history-taking from the patient and reliable informant
  
• repeat neuropsychological testing annually or when dementia is suspected
  
• assessment of the caregiver for distress.
  

Compensating for memory loss. Many individuals with MCI have insight into their cognitive deficits and are interested in making lifestyle changes. Experts recommend:

• moderate exercise (at least 30 minutes per session, 3 times a week)
  
• cognitively stimulating activities that involve language and psychomotor coordination, such as dancing, crossword puzzles, and volunteer work.
  

Potentially helpful tools include calendars, reminder notes, electronic cuing devices, pill boxes, and “speed-dial” telephones. Encourage patients to participate in local senior organizations and to use community resources.¹

Medications—yes or no? Cholinesterase inhibitors, rofecoxib, and vitamin E have not been shown to prevent MCI from progressing to AD. Thus, insufficient evidence exists to recommend medications for patients with MCI.

Donepezil has shown possible short-term benefits, however, and patients may choose to try this medication. Some find comfort in seeking this “extra time” to make decisions about advanced directives, attend to estate and will issues, and optimize relationships while they have only mild cognitive deficits and possess decision-making capacity.

Donepezil. The Alzheimer’s Disease Cooperative Study—supported by the National Institute on Aging—was designed to determine whether daily doses of donepezil or vitamin E can delay or prevent progression of aMCI to AD.²⁵ In the double-blind, placebo-controlled, parallel group study, 769 patients with aMCI were randomly assigned to receive donepezil, 10 mg/d; vitamin E, 1,000 IU bid; or placebo for 3 years.

Overall progression to AD was 16% per year, and the 3-year risk of progression was the same in all 3 groups. Donepezil therapy was associated with a reduced rate of progression to AD compared with placebo during the first year of treatment. Donepezil’s benefit was evident among ApoE e4 carriers at 2-year follow-up, but none of the 3 groups showed statistically significant differences after 3 years. Vitamin E showed no effect on AD progression throughout the study.

Rivastigmine. A randomized, placebo-controlled trial in which 1,018 MCI patients received rivastigmine or placebo for 4 years found no statistically significant benefit of rivastigmine on AD progression.²⁶

Galantamine. Two international randomized, double-blind, placebo-controlled trials failed to show a statistically significant benefit of galantamine in slowing progression from aMCI to AD. MRI data from one of these studies suggested that galantamine may have reduced the rate of brain atrophy over a 2-year period.²⁷

Rofecoxib. Epidemiologic studies indicate that anti-inflammatory drugs may reduce the risk of developing AD, but the COX-2 inhibitor rofecoxib did not delay progression to AD among aMCI patients in a large, placebo-controlled trial.²⁸

Educate patients and family members about supportive nonpharmacologic treatments and cholinesterase inhibitors. The Alzheimer’s Association, National Institute on Aging, and local department of aging agencies offer useful resources (see Related Resources).

CASE CONTINUED: Dealing with uncertainty

Mr. R and his wife are unsettled by his MCI diagnosis. They prefer to take a “wait and watch” approach, decline initiation of a cholinesterase inhibitor, and agree to adhere to nonpharmacologic interventions you discussed. You schedule a follow-up visit in 6 months and encourage them to call you with questions.

Related resources

• Rosenberg PB, Johnston D, Lyketsos CG. A clinical approach to mild cognitive impairment. Am J Psychiatry 2006;163: 1884-90.
  
• Montreal Cognitive Assessment (MoCA). 10-minute screening test designed to help clinicians detect mild cognitive impairment. www.mocatest.org.
  
• Alzheimer’s Association. www.alz.org.
  
• National Institute on Aging. www.nia.nih.gov.
  

Drug brand name

• Benztropine • Cogentin
  
• Cyclobenzaprine • Flexeril
  
• Donepezil • Aricept
  
• Galantamine • Razadyne
  
• Oxybutynin • Ditropan
  
• Rivastigmine • Exelon
  
• Rofecoxib • Vioxx
  
• Sertraline • Zoloft
  

Disclosure

Dr. Goveas and Dr. Dixon-Holbrook report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Kerwin is a consultant to Pfizer and a speaker for Pfizer and Novartis.

Dr. Antuono receives research support from Eisai, Pfizer, and Elan and is a speaker for Pfizer and Forest Pharmaceuticals.

Mr. R, age 67, presents with what he describes as uncharacteristic “memory loss” that is affecting his ability to run his accounting business. He and his wife relate that he was doing well until approximately 9 months ago, when he started showing difficulties remembering clients’ names and addresses.

His wife became extremely concerned when he made serious accounting errors in a 1-month period that resulted in the loss of a longtime customer. Mr. R has become easily distracted and absentminded as well, and his wife reports he is misplacing things around the house.

Screening for mild cognitive impairment (MCI) is not recommended for asymptomatic, cognitively healthy older persons, but memory complaints in individuals age >50—especially when corroborated by a reliable informant—warrant further assessment. Your challenge is to determine whether subtle cognitive changes in patients such as Mr. R are part of normal aging, caused by medical or mental illnesses, or a harbinger of Alzheimer’s disease (AD) or another dementia.

Although no treatments can yet prevent dementia, substantial new research is defining the MCI diagnosis for clinicians. This article describes:

• the evolving understanding of MCI and its subtypes
  
• risk factors for converting from MCI to AD
  
• an evidence-based work-up (including functional, cognitive, and neuropsychological testing)
  
• neuroprotective strategies for patients with an MCI diagnosis, including evidence on cholinesterase inhibitors, vitamin E, and anti-inflammatory agents.
  

MCI’s evolving definition

MCI is characterized by subjective and objective cognitive decline greater than expected for an individual’s age and education but less than the functional deficit required for a dementia diagnosis. MCI is proposed to identify persons with early but pathologic cognitive impairment that has a high risk to progress to AD and possibly other dementias.

MCI is thought to be a transitional state between normal aging and dementia.¹ Its estimated prevalence in the general population is 19% among individuals age 85.²

MCI subtypes. Some experts view MCI as a single entity, whereas others suggest amnestic (aMCI) and nonamnestic (nMCI) subtypes.^1,3 Each subtype is further divided into single and multiple cognitive domains. So, for example, the diagnosis would be:

• aMCI-single cognitive domain for memory impairment only
  
• aMCI-multiple cognitive domains for memory impairment plus nonmemory deficits, such as in language, executive function, or visuospatial function
  
• nMCI-single or multiple cognitive domains for nonmemory deficits without memory impairment.
  

MCI subtypes may have different outcomes for progression to dementia, and all progressive dementias may have their own predementia states.⁴ Vascular MCI, for instance, is thought to result from cerebrovascular disease and is proposed to describe a prodrome of vascular dementia.⁵

Determining a patient’s MCI subtype is still a research activity and calls for comprehensive neuropsychological testing. MCI patients perform at least 1.5 standard deviations below the average for age- and education-matched healthy individuals on objective measures of memory.¹

Conversion to dementia

In longitudinal population studies patients with MCI have shown an 11% to 33% risk of developing dementia within 2 years, whereas 44% reverted to normal 1 year later. Reasons for reversibility may include variable definitions of MCI among the longitudinal studies and the possibility that patients who recovered or improved may have had reversible causes of dementia.¹

When patients with MCI are followed over time, they progress not only to AD but also to non-AD dementias. For example, patients with Parkinson’s disease (PD) and MCI may be at higher risk of progressing to dementia than cognitively intact PD patients.⁶ MCI patients with the e4 allele of the apolipoprotein E gene (ApoE e4) are at increased risk to convert from MCI to AD.⁷

Individuals with aMCI (Table 1)⁸ progress to AD at a rate of 10% to 15% per year, compared with 1% to 2% per year in normal elderly persons. The Mayo AD research center studies reported a conversion rate of up to 80% from aMCI to AD within 6 years.⁹

Research focuses on identifying preclinical AD states and potential targets for intervention using disease-modifying therapies. Some experts consider MCI to be the earliest clinical manifestation of AD, at least in a subgroup of patients.

Identifying markers to predict which patients are likely to convert from MCI to dementia also is a major research objective. In addition to ApoE status (Table 2),^7,9-15 predictors of conversion may include:

 

• hippocampal atrophy¹³
  
• reduced metabolism in the temporoparietal cortex and posterior cingulum¹⁴
  
• elevated CSF tau and the 42 amino acid form of ß-amyloid (Aß 42).¹⁵
  

Research techniques such as structural neuroimaging, positron-emission tomography, functional magnetic resonance imaging (fMRI), and cerebrospinal fluid biomarkers have not been defined for clinical use, however.

Neuropsychiatric symptoms. Individuals with MCI and neuropsychiatric symptoms may be at particular risk for progressing to dementia. Agitation or depression are more prevalent in persons with MCI than in normal elderly but less prevalent than in those with dementia (Table 3).^10,16

The cross-sectional, community-based Cardiovascular Health Study showed one or more neuropsychiatric symptom in:

• 16% of normal healthy elderly
  
• 43% of MCI patients
  
• 75% of dementia patients.¹⁶
  

Depression (20%), apathy (15%), and irritability (15%) were the neuropsychiatric symptoms reported most frequently in MCI patients, compared with apathy (36%), depression (32%), and agitation/aggression (30%) in dementia patients.

Sleep disturbances and anxiety in persons with MCI may predict progression to AD.¹⁰ A baseline high frequency of apathy in aMCI patients has been associated with progression to AD within 1 year.¹¹

Table 1

Amnestic MCI: Proposed diagnostic criteria

Subjective memory impairment, preferably corroborated by a reliable informant
Reduced performance on objective memory tests, compared with persons of similar age and educational background
Typical general cognitive function
Intact basic activities of daily living and intact or minimally impaired instrumental activities of daily living
Absence of dementia
MCI: mild cognitive impairment
Source: Reference 8

Table 2

Factors shown to predict conversion from MCI to dementia

Category	Predictors of conversion
Clinical	Cognitive: Amnestic MCI Neuropsychiatric: Depression, apathy, and possibly nighttime behaviors and anxiety
Neuropsychological tests	Clock-drawing test, Trail-Making Test B, Symbol Digit Modalities Test, Delayed 10-Word List Recall, New York University Paragraph Recall Test (Delayed), ADAS-Cog total score
Neuroimaging	MRI: Entorhinal cortex and hippocampal atrophy PET: Medial temporal region, parietotemporal association cortex, and posterior cingulate hypometabolism fMRI: Abnormal hippocampal, posterior cingulate, and medial temporal region activation on memory tasks
CSF markers	Increase: t-tau, p-tau Decrease: Aß 42
Genetic markers	ApoE e4 carriers
ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive subscale; ApoE e4: apolipoprotein E gene, e4 allele; CSF: cerebrospinal fluid; MCI: mild cognitive impairment; MRI: magnetic resonance imaging; fMRI: functional MRI; PET: positron-emission tomography
Source: References 7,9-15

Table 3

Neuropsychiatric symptoms: Rising prevalence mirrors cognitive deterioration in elderly patients*

Neuropsychiatric symptoms	Normal elderly	MCI	Mild AD
Depressed mood/dysphoria	+	++	+++
Nighttime behaviors/sleep	+	++	+++
Irritability	+	++	+++
Anxiety	+/-	++	+++
Apathy/indifference	+/-	++	+++
Agitation/aggression	+/-	+/++	+++
Eating/appetite disturbance	+/-	+	++
Disinhibition	+/-	+/-	++
Aberrant motor behavior	0	+	++
Delusions	0	+/-	++
Euphoria	0	+/-	+/-
Hallucinations	0	0	+
* 0 = 0%; +/- = 1% to 5%; + = 6% to 10%; ++ = 11% to 20%; +++ = 21% to 40%
MCI: mild cognitive impairment; AD: Alzheimer’s disease
Source: References 10,16

Depression and MCI

Depression and cognitive complaints overlap considerably in older adults. Depressed patients without dementia show persistent cognitive deficits even after depression remits. In some patients, new-onset geriatric depression is considered a prodrome of MCI and AD. Given that AD neuropathologic changes precede clinical symptoms by many years, depression and AD have been proposed as different clinical manifestations of AD pathology.¹⁷

Among patients with MCI, 20% meet criteria for major depression and 26% for minor depression. Symptoms often include sadness, poor concentration, inner tension, pessimistic thoughts, lassitude, and insomnia.¹⁸

Depressed MCI patients are at higher risk of developing dementia than those without depression, especially if cognitive measures do not improve after depression is treated.¹² Similarly, cognitively intact older persons who develop depression are at increased risk for MCI, particularly if they carry the ApoE e4 genotype.¹⁹

In the only study in which MCI patients’ neuropsychiatric symptoms have been treated, 39 elderly patients with depression and MCI received open-label sertraline, ≤200 mg/d, for 12 weeks. Among the 26 patients who completed the trial, 17 showed moderate improvement in depressive symptoms, attention, and executive function, and 9 showed no response.²⁰

Recommendation. In clinical practice, antidepressant treatment—usually a selective serotonin reuptake inhibitor (SSRI), with or without psychotherapy—is recommended for the MCI patient with comorbid major depression.

CASE CONTINUED: No signs of depression

Mr. R’s medical, neurologic, and substance use history is unremarkable. Family history includes AD in a paternal aunt diagnosed at age 82. Mr. R reports no history of mood, sleep, or appetite changes and no psychotic symptoms. He shows no deficits in activities of daily living (ADL), although his wife recently took over paying household bills after he forgot to make a payment.

Evidence-based workup

Functional assessment. In the differential diagnosis of MCI, give special attention to functional impairment, which points toward dementia. ADL generally are preserved in MCI, and minimal deterioration is seen in instrumental activities of daily living (IADL). A relatively easy way to assess function is to use the Alzheimer’s Disease Functional Assessment and Change Scale (ADFACS), which is based on 16 ADL and IADL items (Table 4).²¹

 

A substantial functional decline precludes an MCI diagnosis, although the degree of functional decline can be difficult to assess in older adults with physical limitations caused by medical comorbidities.

Cognitive assessment. Because most individuals with MCI score in the normal range on the Folstein Mini-Mental State Examination (MMSE), the modified MMSE (3MS)²² may be more sensitive for detecting MCI. The 3MS retains the MMSE’s brevity (≤10 minutes to administer) but incorporates 4 additional items, has more graded scoring responses, and broadens the score range to 0 to 100. The clock-drawing test also is sensitive for MCI, especially in detecting early visuoconstructional dysfunction.

The Montreal Cognitive Assessment (MoCA) is a 10-minute, 30-point scale designed to help clinicians detect MCI (see Related Resources). The MoCA usually is given with the modified MMSE for a comprehensive cognitive assessment.

Nasreddine et al²³ administered the MoCA and MMSE to 94 patients who met clinical criteria for MCI, 93 patients with mild AD, and 90 healthy cognitively normal elderly persons, using a cutoff score of 26. MoCA showed:

• 90% sensitivity for detecting MCI (compared with 18% for the MMSE)
  
• 87% specificity to exclude normal elderly persons.
  

The average MoCA score in patients with AD was much lower than in individuals with MCI, but score ranges of these 2 groups overlapped. Therefore, a score

Neuropsychological testing can be more sensitive than office-based screening tools in defining MCI subtypes. In the Alzheimer’s Disease Cooperative Study (ADCS), the neuropsychological measures that most accurately predicted progression of patients with aMCI to AD within 36 months were the:

• Symbol Digit Modalities Test
  
• New York University Paragraph Recall Test (Delayed)
  
• Delayed 10-Word List Recall
  
• Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score.²⁴
  

Laboratory tests, imaging. Use laboratory studies (Table 5) to rule out reversible causes of MCI symptoms.⁸ Reserve CSF studies for suspected CNS infection (such as meningitis, human immunodeficiency virus, or neurosyphilis) and brain imaging for suspected cerebral pathology (such as infarct, subdural hematoma, normal pressure hydrocephalus, or tumor).

Table 4

Alzheimer’s Disease Functional Assessment and Change Scale (ADFACS)

Basic ADL	Instrumental ADL (IADL)
Toileting	Use of telephone
Feeding	Household tasks
Dressing	Using household appliances
Personal hygiene and grooming	Managing money
	Shopping
Bathing	Food preparation
Walking	Ability to get around inside and outside home
	Hobbies and leisure activities
	Handling personal mail
	Grasp of situations and explanations
The 16-item ADFACS total score ranges from 0 to 54 (best to worst): Rate basic ADLs from 0 (no impairment) to 4 (very severe impairment), for a total score range of 0 to 24. Rate IADLs from 0 (no impairment) to 3 (severe impairment), for a total score range of 0 to 30.
Use total scores to assess for functional decline from baseline. A decline from 0 to 1 on individual ADL and IADL items is not considered clinically significant.
ADL: activities of daily living
Source: Reprinted with permission from reference 21

Table 5

Lab studies to rule out reversible causes of MCI

Complete blood count with differential
Basic metabolic panel
Liver function tests
Serum calcium
Serum vitamin B12 and folate
Thyroid function tests
Rapid plasma reagin
HIV in high-risk individuals
CSF studies if CNS infection is suspected
CSF: cerebrospinal fluid; HIV: human immunodeficiency virus; MCI: mild cognitive impairment
Source: Reference 8

CASE CONTINUED: Subtle cognitive deficits

Mr. R scores 27/30 on the MMSE (losing 3 points on recall) and 25/30 on the MoCA (losing points on visuospatial/executive function, fluency, and delayed recall). Thyroid stimulating hormone, vitamin B12, folate, and rapid plasma reagin tests are unremarkable; brain MRI shows no significant abnormalities.

You refer Mr. R for neuropsychological testing, and most cognitive domains are normal. Exceptions include moderate impairment in immediate and delayed verbal and visual memory and mild executive dysfunction.

Based on your clinical evaluation and neuropsychological testing, you diagnose amnestic MCI. Mr. R shows abnormalities in memory and executive functioning without significant decline in basic and instrumental ADLs, is not taking medications, and has no other medical or psychiatric condition that could explain his cognitive deficits.

You discuss the diagnosis with him and his wife, including evidence on his risk for progression to dementia, neuroprotective strategies, and medications.

After an MCI diagnosis

Neuroprotection. Eliminate medications with anticholinergic effects, including:

• tricyclic antidepressants
  
• conventional antipsychotics
  
• antihistamines
  
• drugs used to treat urinary incontinence, such as oxybutynin
  
• muscle relaxants, such as cyclobenzaprine
  
• certain antiparkinsonian drugs, such as benztropine.
  

Encourage patients to avoid alcohol and sedatives. Collaborate with primary care providers to control cerebrovascular risk factors such as hyperlipidemia, diabetes mellitus, hypertension, and obesity. Treat depression, which may be a risk factor for developing dementia.

 

Monitoring. The American Academy of Neurology recommends monitoring patients diagnosed with MCI every 6 to 12 months for cognitive and functional decline.

In these visits, include:

• repeat office-based cognitive assessment, especially the modified MMSE, clock-drawing test, and MoCA
  
• careful history-taking from the patient and reliable informant
  
• repeat neuropsychological testing annually or when dementia is suspected
  
• assessment of the caregiver for distress.
  

Compensating for memory loss. Many individuals with MCI have insight into their cognitive deficits and are interested in making lifestyle changes. Experts recommend:

• moderate exercise (at least 30 minutes per session, 3 times a week)
  
• cognitively stimulating activities that involve language and psychomotor coordination, such as dancing, crossword puzzles, and volunteer work.
  

Potentially helpful tools include calendars, reminder notes, electronic cuing devices, pill boxes, and “speed-dial” telephones. Encourage patients to participate in local senior organizations and to use community resources.¹

Medications—yes or no? Cholinesterase inhibitors, rofecoxib, and vitamin E have not been shown to prevent MCI from progressing to AD. Thus, insufficient evidence exists to recommend medications for patients with MCI.

Donepezil has shown possible short-term benefits, however, and patients may choose to try this medication. Some find comfort in seeking this “extra time” to make decisions about advanced directives, attend to estate and will issues, and optimize relationships while they have only mild cognitive deficits and possess decision-making capacity.

Donepezil. The Alzheimer’s Disease Cooperative Study—supported by the National Institute on Aging—was designed to determine whether daily doses of donepezil or vitamin E can delay or prevent progression of aMCI to AD.²⁵ In the double-blind, placebo-controlled, parallel group study, 769 patients with aMCI were randomly assigned to receive donepezil, 10 mg/d; vitamin E, 1,000 IU bid; or placebo for 3 years.

Overall progression to AD was 16% per year, and the 3-year risk of progression was the same in all 3 groups. Donepezil therapy was associated with a reduced rate of progression to AD compared with placebo during the first year of treatment. Donepezil’s benefit was evident among ApoE e4 carriers at 2-year follow-up, but none of the 3 groups showed statistically significant differences after 3 years. Vitamin E showed no effect on AD progression throughout the study.

Rivastigmine. A randomized, placebo-controlled trial in which 1,018 MCI patients received rivastigmine or placebo for 4 years found no statistically significant benefit of rivastigmine on AD progression.²⁶

Galantamine. Two international randomized, double-blind, placebo-controlled trials failed to show a statistically significant benefit of galantamine in slowing progression from aMCI to AD. MRI data from one of these studies suggested that galantamine may have reduced the rate of brain atrophy over a 2-year period.²⁷

Rofecoxib. Epidemiologic studies indicate that anti-inflammatory drugs may reduce the risk of developing AD, but the COX-2 inhibitor rofecoxib did not delay progression to AD among aMCI patients in a large, placebo-controlled trial.²⁸

Educate patients and family members about supportive nonpharmacologic treatments and cholinesterase inhibitors. The Alzheimer’s Association, National Institute on Aging, and local department of aging agencies offer useful resources (see Related Resources).

CASE CONTINUED: Dealing with uncertainty

Mr. R and his wife are unsettled by his MCI diagnosis. They prefer to take a “wait and watch” approach, decline initiation of a cholinesterase inhibitor, and agree to adhere to nonpharmacologic interventions you discussed. You schedule a follow-up visit in 6 months and encourage them to call you with questions.

Related resources

• Rosenberg PB, Johnston D, Lyketsos CG. A clinical approach to mild cognitive impairment. Am J Psychiatry 2006;163: 1884-90.
  
• Montreal Cognitive Assessment (MoCA). 10-minute screening test designed to help clinicians detect mild cognitive impairment. www.mocatest.org.
  
• Alzheimer’s Association. www.alz.org.
  
• National Institute on Aging. www.nia.nih.gov.
  

Drug brand name

• Benztropine • Cogentin
  
• Cyclobenzaprine • Flexeril
  
• Donepezil • Aricept
  
• Galantamine • Razadyne
  
• Oxybutynin • Ditropan
  
• Rivastigmine • Exelon
  
• Rofecoxib • Vioxx
  
• Sertraline • Zoloft
  

Disclosure

Dr. Goveas and Dr. Dixon-Holbrook report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Kerwin is a consultant to Pfizer and a speaker for Pfizer and Novartis.

Dr. Antuono receives research support from Eisai, Pfizer, and Elan and is a speaker for Pfizer and Forest Pharmaceuticals.

Nonconvulsive status epilepticus (NCSE) is marked by neurobehavioral disturbances that resemble primary psychiatric disorders. Mistaken diagnosis and delayed treatment increase the risk of neurologic damage, so recognizing NCSE symptoms early is important.

To help you make a timely diagnosis, this article describes:

• neuropsychiatric manifestations of NCSE
  
• how to narrow the differential diagnosis by reviewing clinical symptoms and using electroencephalography (EEG)
  
• techniques used to rapidly halt ictal activity.
  

Box

Triggers, neurologic symptoms

NCSE is an acute but treatable medical emergency that calls for assessing and supporting cardiac and respiratory function, monitoring vital signs, temperature reduction, and fluid replacement. Prognosis is usually good unless NCSE is associated with a serious medical illness (Box).^1-11

Many metabolic, neurologic, pharmacologic, and medical abnormalities can precipitate NCSE (Table 1). The most common causes are hypoxia/anoxia, stroke, infection, subtherapeutic antiepileptic levels, alcohol and benzodiazepine intoxication/withdrawal, and metabolic abnormalities.^4,7,10,12

NCSE manifests as absence status epilepticus (ASE) or complex partial status epilepticus (CPSE). A generally accepted diagnostic definition is ≥30 minutes of behavioral change from baseline, with diagnostic EEG findings.^4,13 EEG is indispensable because the clinical manifestations of NCSE are predominantly behavioral, with minimal or no motor activity.

Table 1

Clinical factors that may precipitate NCSE

Medical	Recent infection, hyperventilation, trauma, menstruation, pregnancy, renal dialysis, postoperative period, sleep deprivation
Metabolic	Hypoparathyroidism, renal failure, hyper/hyponatremia, hyper/hypoglycemia, hypocalcemia
Neurologic	Mental retardation, dementia, stroke
Pharmacologic	Low serum levels or abrupt discontinuation of anticonvulsants, alcohol intoxication/withdrawal, benzodiazepine withdrawal lithium and neuroleptic use, psychotropic overdose
Source : References 9,10,12,16

ASE, a primary generalized process, is characterized by confusion or diminished responsiveness; it may be associated with occasional blinking or other minor motor activity and can last for hours to days. It usually occurs in patients with known epilepsy, particularly absence seizures.

ASE is reported primarily in children, although de novo cases have been described in elderly patients with no history of epilepsy.^10,14

CPSE is usually associated with a history of focal epilepsy and vascular disease. CPSE has a focal onset, with subsequent secondary generalization. Onset is usually temporal in origin but also can be extratemporal.

Patients with CPSE often cycle between an “epileptic twilight state” with confusion and complete unresponsiveness with stereotyped automatisms. It can present with marked behavioral fluctuation or a change in mental status and is generally followed by a prolonged postictal state.^4,7,13-15 Several NCSE cases have occurred in patients with no history of seizures.^9,10,16

Historically, CPSE was reported to be less common than ASE, but this misconception was most likely caused by failure to recognize CPSE’s clinical presentation and rapid generalization on EEG.^7,15

Neuropsychiatric features

Patients with NCSE may be referred for evaluation of an array of behavioral changes commonly seen in psychiatric practice. The differential diagnosis is extensive (Table 2) and includes neurologic and medical conditions often associated with catatonic syndrome.^17,18

In a retrospective study, Kaplan¹² assessed clinical presentations and reasons for diagnostic delay in 23 adults eventually diagnosed with NCSE. Presenting symptoms included:

• confusion, agitation, aggressive behavior
  
• lethargy, mutism, verbal perseveration, echolalia
  
• delirium, blinking, staring, chewing or picking behaviors
  
• tremulousness or myoclonus
  
• bizarre behavior (inappropriate laughing, crying, or singing)
  
• rigidity with waxy flexibility
  
• delusions, hallucinations.
  

Clinicians mistook hallucinations and mood lability for a primary psychiatric condition in 7 patients, presumed catalepsy was psychogenic in 3 patients, and thought obtundation was caused by alcohol or drug intoxication in 4 cases.

A prospective study of 22 patients with NCSE found that 7 had a history of psychotic depression, schizophrenia, self-mutilation, bipolar disorder, or episodic severe aggression; 12 of 18 with ASE had a history of epilepsy, and 3 of 4 with CPSE had experienced seizures associated with cerebrovascular accident, right cerebral embolus, and thiazide-induced hyponatremia, respectively.¹⁶

 

Table 2

Differential diagnosis of NCSE

Metabolic disorders	Hypo/hyperglycemia, hypercalcemia, Addison’s disease, Cushing’s disease, uremia
Neurologic disorders	Stroke, CNS tumors, closed head trauma, transient global amnesia, seizures, inflammatory and infectious encephalopathies
Psychiatric disorders	Schizophrenia, mood disorders, catatonia, malignant catatonia, somatoform disorders, conversion disorder, Asperger’s syndrome, malingering
Toxic disorders	Toxic encephalopathy, neuroleptic malignant syndrome, serotonin syndrome, alcohol and sedative-hypnotic withdrawal, drugs (lithium toxicity, tricyclics, baclofen, tiagabine, overdose)
Source: Reference 17,18

NCSE in the elderly can be difficult to diagnose, especially in patients with comorbid severe medical illnesses and other confusional states.⁴CPSE with possible generalization is more common than ASE in the elderly. Hyperreligiosity, intermittent agitation, motor perseveration, ictal fear, catatonic signs, delusional preoccupation, and auditory and visual hallucinations have been observed during NCSE in the elderly and misdiagnosed as primary psychiatric conditions.

Cerebrovascular disease, tumors, and trauma are the most common causes of late-life NCSE.^4,19 De novo NCSE occasionally presents:

• after benzodiazepine withdrawal
  
• with neuroleptic, tricyclic antidepressant, or lithium treatment^10,16
  
• with metabolic abnormalities and nonpsychotropic medications.¹⁰
  

Clinical symptoms

Clinical features of NCSE include cognitive changes, speech abnormalities, affective disturbances, psychosis, poor impulse control, and bizarre behaviors (Table 3). Some patients develop ictal phenomena resembling catatonia or clinical and EEG changes that mimic neuroleptic malignant syndrome (NMS).^20-23

Table 3

Clinical features that raise suspicion of NCSE

Domain	Features
Cognitive changes	Prolonged confusion, executive dysfunction, obtundation, attention/memory difficulties, lack of initiative, perseveration, stupor
Speech	Poverty of speech with monosyllabic answers, verbal perseveration, echolalia, palilalia, aphasia, paraphasic errors, confabulation, mutism
Affective	Prolonged fear, affective indifferent state with blank facial expression, hypomania, psychotic depression, inappropriate laughing and crying, anxiety states
Psychosis	Visual, auditory and cenesthetic hallucinations, delusions
Impulse control	Hostility, agitation, violence, groping, genital manipulation, picking, posturing
Others	Catatonic signs, autonomic disturbances
Source: References 5,7-9,12,15-17,20-23

Catatonia. Lim et al²⁴ described three patients with EEG-confirmed NCSE that manifested as ictal catatonia. A prolonged, trance-like, stuporous state during epilepsy has been reported, as has CPSE presenting with psychogenic unresponsiveness. Drury et al²⁵ described a patient who presented with catatonia and increased muscle tone but had prominent EEG abnormalities implicating an organic cause.

Among 29 patients with acute catatonic syndromes, epileptic activity was identified in 4. One patient with absence status was diagnosed with NMS during the catatonic period.²⁶ Conversely, the commonality of clinical features has led to misdiagnosis of psychogenic catatonia as NCSE. EEG is necessary to exclude NCSE in these cases.

NMS. Yoshino et al²⁷ described two patients taking neuroleptics who met criteria for NMS and had EEG changes consistent with NCSE. They later reported another patient with NCSE complicating NMS; the point at which NCSE developed was unknown, however, because EEG activity was not recorded at NMS onset.²⁸ Based on NMS diagnostic criteria proposed by Caroff et al,²⁹ these patients could have developed NCSE mimicking NMS.

EEG for diagnosis

Candidates. Because differentiating NCSE from similar conditions can be difficult, use EEG to confirm your clinical observations. No guidelines exist, but consider EEG when the patient’s history suggests NCSE. Ask the patient or family about:

• changes in mental status from baseline, especially new-onset catatonia or unexplained altered consciousness
  
• duration of events
  
• presence or absence of motor activity
  
• behavioral fluctuations
  
• presence or absence of automatisms or blinking.
  

List the patient’s medications, ask about illicit substance or alcohol use, and gather a comprehensive history of medical, neurologic, and psychiatric illnesses. Include NCSE in the differential diagnosis of elderly patients with acute prolonged confusion. Try to obtain EEG early to differentiate focal from secondary generalized seizures.

EEG patterns. Table 4 summarized NCSE diagnostic criteria. NCSE shows characteristic patterns in ASE and CPSE,^9,10,16,23 and EEG changes can be continuous or nearly continuous in both.

Table 4

EEG findings that support a clinical diagnosis of NCSE

Clear-cut criteria
Frequent or continuous focal seizures, with ictal patterns that wax and wane with change in amplitude, frequency, and/or spatial distribution
Frequent or continuous generalized spike wave discharges:
in patients without history of epilepsy in patients with epilepsy, when discharges show significant changes in intensity or frequency compared with baseline EEG
Periodic lateralized epileptiform discharges (“PLEDs”) or bilateral periodic epileptiform discharges (“biPEDs") occurring in patients with coma from generalized tonic-clonic status epilepticus (subtle SE)
Probable (equivocal) criteria
Patients with acute cerebral damage who also show frequent or continuous EEG abnormalities without previous similar findings
Patients with epilepsy who show frequent or continuous generalized EEG abnormalities and similar interictal EEG patterns but whose clinical symptoms suggest NCSE
Source: References 4,12-14,17

In ASE, a generalized, bilaterally synchronous, rhythmic, 3- to 3.5-second spike with a bifrontal maximum is seen in 40% of cases.³⁰ Also described in ASE are fragmented spike waves, multiple spikes and waves, and generalized bilateral discharges with focal predominance. This last pattern might suggest an underlying focal origin of the epileptic discharge with secondary generalization.

 

^31,32

In CPSE, less-synchronous epileptiform activity has been described, including rhythmical slow, rhythmic spikes, or rhythmic spike and slow waves. Two types of CPSE of frontal origin have been described:

• Type 1 presents clinically with mood disturbance and minimal confusion. EEG shows a frontal focus with a normal background.
  
• Type 2 presents clinically with confusion. EEG shows bilateral asymmetric frontal discharges.⁸
  

Not always clear. Making a clear distinction between primary and secondary generalization on EEG is not always possible.¹⁵ In a large series of NCSE cases,³¹ ictal discharges on EEG were:

• generalized in 69%
  
• diffuse with focal predominance in 18%
  
• focal in 13%.
  

Although most EEGs showed a generalized pattern, many cases probably started focally with immediate generalization. Morphologies seen—in descending order of frequency—were atypical spike and wave, multiple spike waves, rhythmic delta with intermittent spikes, and typical spike and wave patterns. Ictal discharge frequency also was variable and

Distinguish between ictal and interictal EEG findings with epileptiform activity, because only the former is diagnostic for NCSE. Intravenous benzodiazepines might be necessary during EEG to verify the diagnosis.³³

NCSE has developed after electroconvulsive therapy (ECT), but a cause-effect relationship is debatable. Interictal and abnormal EEG findings after ECT may be misdiagnosed as NCSE.³⁴

Neuroimaging has limited clinical value because of the need for patient cooperation and specialized equipment.⁴ Head CT or MRI can exclude structural abnormalities. PET and SPECT show increased metabolism and blood flow, respectively, in NCSE. MR spectroscopy shows elevated lactate and decreased N-acetyl aspartate.

Halting ictal activity

To rapidly stop ictal activity—the main goal of treatment—recognizing and correcting precipitant factors is vital:

• Consider discontinuing medications that could lower the seizure threshold.
  
• Order a complete blood count, serum electrolytes, calcium, arterial-blood gas, liver and renal function tests, urine toxicology screen, and serum antiepileptic drug concentrations.
  
• When possible, obtain neuroimaging and EEG in the emergency room for accurate diagnosis and prompt treatment.¹²
  

Medications. Benzodiazepines such as lorazepam, diazepam, and clonazepam are used most often to interrupt seizure activity. Use them cautiously in medically fragile patients, however, to prevent hypotension and respiratory depression.

Response to benzodiazepines might be transient, lasting only hours or days. For instance, diazepam’s anticonvulsant effect may last

Newer antiepileptics—such as lamotrigine, levetiracetam, or topiramate—have been used with varying results, and their role in first-line treatment of NCSE is evolving. Rarely, the antiepileptic tiagabine precipitates or worsens NCSE.^4,13,14

Related resources

• Epilepsy Foundation. www.epilepsyfoundation.org
  
• Neuroleptic Malignant Syndrome Information Service. Hotline for health professionals (888) 667-8367. www.nmsis.org
  

Drug brand names

• Carbamazepine • Tegretol, Carbatrol
  
• Clonazepam • Klonopin
  
• Diazepam • Valium
  
• Lamotrigine • Lamictal
  
• Levetiracetam • Keppra
  
• Lithium carbonate • Lithobid, Eskalith CR
  
• Lorazepam • Ativan
  
• Phenobarbital • Luminal
  
• Phenytoin • Dilantin
  
• Tiagabine • Gabitril
  
• Topiramate • Topamax
  
• Valproic acid • Depakote
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in the article or with manufacturers of competing products.

Acknowledgment

Dr. Goveas was a geriatric psychiatry fellow, University of Pennsylvania, when he wrote this article in collaboration with his mentors, Drs. Caroff and Riggio.

Nonconvulsive status epilepticus (NCSE) is marked by neurobehavioral disturbances that resemble primary psychiatric disorders. Mistaken diagnosis and delayed treatment increase the risk of neurologic damage, so recognizing NCSE symptoms early is important.

To help you make a timely diagnosis, this article describes:

• neuropsychiatric manifestations of NCSE
  
• how to narrow the differential diagnosis by reviewing clinical symptoms and using electroencephalography (EEG)
  
• techniques used to rapidly halt ictal activity.
  

Box

Triggers, neurologic symptoms

NCSE is an acute but treatable medical emergency that calls for assessing and supporting cardiac and respiratory function, monitoring vital signs, temperature reduction, and fluid replacement. Prognosis is usually good unless NCSE is associated with a serious medical illness (Box).^1-11

Many metabolic, neurologic, pharmacologic, and medical abnormalities can precipitate NCSE (Table 1). The most common causes are hypoxia/anoxia, stroke, infection, subtherapeutic antiepileptic levels, alcohol and benzodiazepine intoxication/withdrawal, and metabolic abnormalities.^4,7,10,12

NCSE manifests as absence status epilepticus (ASE) or complex partial status epilepticus (CPSE). A generally accepted diagnostic definition is ≥30 minutes of behavioral change from baseline, with diagnostic EEG findings.^4,13 EEG is indispensable because the clinical manifestations of NCSE are predominantly behavioral, with minimal or no motor activity.

Table 1

Clinical factors that may precipitate NCSE

Medical	Recent infection, hyperventilation, trauma, menstruation, pregnancy, renal dialysis, postoperative period, sleep deprivation
Metabolic	Hypoparathyroidism, renal failure, hyper/hyponatremia, hyper/hypoglycemia, hypocalcemia
Neurologic	Mental retardation, dementia, stroke
Pharmacologic	Low serum levels or abrupt discontinuation of anticonvulsants, alcohol intoxication/withdrawal, benzodiazepine withdrawal lithium and neuroleptic use, psychotropic overdose
Source : References 9,10,12,16

ASE, a primary generalized process, is characterized by confusion or diminished responsiveness; it may be associated with occasional blinking or other minor motor activity and can last for hours to days. It usually occurs in patients with known epilepsy, particularly absence seizures.

ASE is reported primarily in children, although de novo cases have been described in elderly patients with no history of epilepsy.^10,14

CPSE is usually associated with a history of focal epilepsy and vascular disease. CPSE has a focal onset, with subsequent secondary generalization. Onset is usually temporal in origin but also can be extratemporal.

Patients with CPSE often cycle between an “epileptic twilight state” with confusion and complete unresponsiveness with stereotyped automatisms. It can present with marked behavioral fluctuation or a change in mental status and is generally followed by a prolonged postictal state.^4,7,13-15 Several NCSE cases have occurred in patients with no history of seizures.^9,10,16

Historically, CPSE was reported to be less common than ASE, but this misconception was most likely caused by failure to recognize CPSE’s clinical presentation and rapid generalization on EEG.^7,15

Neuropsychiatric features

Patients with NCSE may be referred for evaluation of an array of behavioral changes commonly seen in psychiatric practice. The differential diagnosis is extensive (Table 2) and includes neurologic and medical conditions often associated with catatonic syndrome.^17,18

In a retrospective study, Kaplan¹² assessed clinical presentations and reasons for diagnostic delay in 23 adults eventually diagnosed with NCSE. Presenting symptoms included:

• confusion, agitation, aggressive behavior
  
• lethargy, mutism, verbal perseveration, echolalia
  
• delirium, blinking, staring, chewing or picking behaviors
  
• tremulousness or myoclonus
  
• bizarre behavior (inappropriate laughing, crying, or singing)
  
• rigidity with waxy flexibility
  
• delusions, hallucinations.
  

Clinicians mistook hallucinations and mood lability for a primary psychiatric condition in 7 patients, presumed catalepsy was psychogenic in 3 patients, and thought obtundation was caused by alcohol or drug intoxication in 4 cases.

A prospective study of 22 patients with NCSE found that 7 had a history of psychotic depression, schizophrenia, self-mutilation, bipolar disorder, or episodic severe aggression; 12 of 18 with ASE had a history of epilepsy, and 3 of 4 with CPSE had experienced seizures associated with cerebrovascular accident, right cerebral embolus, and thiazide-induced hyponatremia, respectively.¹⁶

 

Table 2

Differential diagnosis of NCSE

Metabolic disorders	Hypo/hyperglycemia, hypercalcemia, Addison’s disease, Cushing’s disease, uremia
Neurologic disorders	Stroke, CNS tumors, closed head trauma, transient global amnesia, seizures, inflammatory and infectious encephalopathies
Psychiatric disorders	Schizophrenia, mood disorders, catatonia, malignant catatonia, somatoform disorders, conversion disorder, Asperger’s syndrome, malingering
Toxic disorders	Toxic encephalopathy, neuroleptic malignant syndrome, serotonin syndrome, alcohol and sedative-hypnotic withdrawal, drugs (lithium toxicity, tricyclics, baclofen, tiagabine, overdose)
Source: Reference 17,18

NCSE in the elderly can be difficult to diagnose, especially in patients with comorbid severe medical illnesses and other confusional states.⁴CPSE with possible generalization is more common than ASE in the elderly. Hyperreligiosity, intermittent agitation, motor perseveration, ictal fear, catatonic signs, delusional preoccupation, and auditory and visual hallucinations have been observed during NCSE in the elderly and misdiagnosed as primary psychiatric conditions.

Cerebrovascular disease, tumors, and trauma are the most common causes of late-life NCSE.^4,19 De novo NCSE occasionally presents:

• after benzodiazepine withdrawal
  
• with neuroleptic, tricyclic antidepressant, or lithium treatment^10,16
  
• with metabolic abnormalities and nonpsychotropic medications.¹⁰
  

Clinical symptoms

Clinical features of NCSE include cognitive changes, speech abnormalities, affective disturbances, psychosis, poor impulse control, and bizarre behaviors (Table 3). Some patients develop ictal phenomena resembling catatonia or clinical and EEG changes that mimic neuroleptic malignant syndrome (NMS).^20-23

Table 3

Clinical features that raise suspicion of NCSE

Domain	Features
Cognitive changes	Prolonged confusion, executive dysfunction, obtundation, attention/memory difficulties, lack of initiative, perseveration, stupor
Speech	Poverty of speech with monosyllabic answers, verbal perseveration, echolalia, palilalia, aphasia, paraphasic errors, confabulation, mutism
Affective	Prolonged fear, affective indifferent state with blank facial expression, hypomania, psychotic depression, inappropriate laughing and crying, anxiety states
Psychosis	Visual, auditory and cenesthetic hallucinations, delusions
Impulse control	Hostility, agitation, violence, groping, genital manipulation, picking, posturing
Others	Catatonic signs, autonomic disturbances
Source: References 5,7-9,12,15-17,20-23

Catatonia. Lim et al²⁴ described three patients with EEG-confirmed NCSE that manifested as ictal catatonia. A prolonged, trance-like, stuporous state during epilepsy has been reported, as has CPSE presenting with psychogenic unresponsiveness. Drury et al²⁵ described a patient who presented with catatonia and increased muscle tone but had prominent EEG abnormalities implicating an organic cause.

Among 29 patients with acute catatonic syndromes, epileptic activity was identified in 4. One patient with absence status was diagnosed with NMS during the catatonic period.²⁶ Conversely, the commonality of clinical features has led to misdiagnosis of psychogenic catatonia as NCSE. EEG is necessary to exclude NCSE in these cases.

NMS. Yoshino et al²⁷ described two patients taking neuroleptics who met criteria for NMS and had EEG changes consistent with NCSE. They later reported another patient with NCSE complicating NMS; the point at which NCSE developed was unknown, however, because EEG activity was not recorded at NMS onset.²⁸ Based on NMS diagnostic criteria proposed by Caroff et al,²⁹ these patients could have developed NCSE mimicking NMS.

EEG for diagnosis

Candidates. Because differentiating NCSE from similar conditions can be difficult, use EEG to confirm your clinical observations. No guidelines exist, but consider EEG when the patient’s history suggests NCSE. Ask the patient or family about:

• changes in mental status from baseline, especially new-onset catatonia or unexplained altered consciousness
  
• duration of events
  
• presence or absence of motor activity
  
• behavioral fluctuations
  
• presence or absence of automatisms or blinking.
  

List the patient’s medications, ask about illicit substance or alcohol use, and gather a comprehensive history of medical, neurologic, and psychiatric illnesses. Include NCSE in the differential diagnosis of elderly patients with acute prolonged confusion. Try to obtain EEG early to differentiate focal from secondary generalized seizures.

EEG patterns. Table 4 summarized NCSE diagnostic criteria. NCSE shows characteristic patterns in ASE and CPSE,^9,10,16,23 and EEG changes can be continuous or nearly continuous in both.

Table 4

EEG findings that support a clinical diagnosis of NCSE

Clear-cut criteria
Frequent or continuous focal seizures, with ictal patterns that wax and wane with change in amplitude, frequency, and/or spatial distribution
Frequent or continuous generalized spike wave discharges:
in patients without history of epilepsy in patients with epilepsy, when discharges show significant changes in intensity or frequency compared with baseline EEG
Periodic lateralized epileptiform discharges (“PLEDs”) or bilateral periodic epileptiform discharges (“biPEDs") occurring in patients with coma from generalized tonic-clonic status epilepticus (subtle SE)
Probable (equivocal) criteria
Patients with acute cerebral damage who also show frequent or continuous EEG abnormalities without previous similar findings
Patients with epilepsy who show frequent or continuous generalized EEG abnormalities and similar interictal EEG patterns but whose clinical symptoms suggest NCSE
Source: References 4,12-14,17

In ASE, a generalized, bilaterally synchronous, rhythmic, 3- to 3.5-second spike with a bifrontal maximum is seen in 40% of cases.³⁰ Also described in ASE are fragmented spike waves, multiple spikes and waves, and generalized bilateral discharges with focal predominance. This last pattern might suggest an underlying focal origin of the epileptic discharge with secondary generalization.

 

^31,32

In CPSE, less-synchronous epileptiform activity has been described, including rhythmical slow, rhythmic spikes, or rhythmic spike and slow waves. Two types of CPSE of frontal origin have been described:

• Type 1 presents clinically with mood disturbance and minimal confusion. EEG shows a frontal focus with a normal background.
  
• Type 2 presents clinically with confusion. EEG shows bilateral asymmetric frontal discharges.⁸
  

Not always clear. Making a clear distinction between primary and secondary generalization on EEG is not always possible.¹⁵ In a large series of NCSE cases,³¹ ictal discharges on EEG were:

• generalized in 69%
  
• diffuse with focal predominance in 18%
  
• focal in 13%.
  

Although most EEGs showed a generalized pattern, many cases probably started focally with immediate generalization. Morphologies seen—in descending order of frequency—were atypical spike and wave, multiple spike waves, rhythmic delta with intermittent spikes, and typical spike and wave patterns. Ictal discharge frequency also was variable and

Distinguish between ictal and interictal EEG findings with epileptiform activity, because only the former is diagnostic for NCSE. Intravenous benzodiazepines might be necessary during EEG to verify the diagnosis.³³

NCSE has developed after electroconvulsive therapy (ECT), but a cause-effect relationship is debatable. Interictal and abnormal EEG findings after ECT may be misdiagnosed as NCSE.³⁴

Neuroimaging has limited clinical value because of the need for patient cooperation and specialized equipment.⁴ Head CT or MRI can exclude structural abnormalities. PET and SPECT show increased metabolism and blood flow, respectively, in NCSE. MR spectroscopy shows elevated lactate and decreased N-acetyl aspartate.

Halting ictal activity

To rapidly stop ictal activity—the main goal of treatment—recognizing and correcting precipitant factors is vital:

• Consider discontinuing medications that could lower the seizure threshold.
  
• Order a complete blood count, serum electrolytes, calcium, arterial-blood gas, liver and renal function tests, urine toxicology screen, and serum antiepileptic drug concentrations.
  
• When possible, obtain neuroimaging and EEG in the emergency room for accurate diagnosis and prompt treatment.¹²
  

Medications. Benzodiazepines such as lorazepam, diazepam, and clonazepam are used most often to interrupt seizure activity. Use them cautiously in medically fragile patients, however, to prevent hypotension and respiratory depression.

Response to benzodiazepines might be transient, lasting only hours or days. For instance, diazepam’s anticonvulsant effect may last

Newer antiepileptics—such as lamotrigine, levetiracetam, or topiramate—have been used with varying results, and their role in first-line treatment of NCSE is evolving. Rarely, the antiepileptic tiagabine precipitates or worsens NCSE.^4,13,14

Related resources

• Epilepsy Foundation. www.epilepsyfoundation.org
  
• Neuroleptic Malignant Syndrome Information Service. Hotline for health professionals (888) 667-8367. www.nmsis.org
  

Drug brand names

• Carbamazepine • Tegretol, Carbatrol
  
• Clonazepam • Klonopin
  
• Diazepam • Valium
  
• Lamotrigine • Lamictal
  
• Levetiracetam • Keppra
  
• Lithium carbonate • Lithobid, Eskalith CR
  
• Lorazepam • Ativan
  
• Phenobarbital • Luminal
  
• Phenytoin • Dilantin
  
• Tiagabine • Gabitril
  
• Topiramate • Topamax
  
• Valproic acid • Depakote
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in the article or with manufacturers of competing products.

Acknowledgment

Dr. Goveas was a geriatric psychiatry fellow, University of Pennsylvania, when he wrote this article in collaboration with his mentors, Drs. Caroff and Riggio.

Nonconvulsive status epilepticus (NCSE) is marked by neurobehavioral disturbances that resemble primary psychiatric disorders. Mistaken diagnosis and delayed treatment increase the risk of neurologic damage, so recognizing NCSE symptoms early is important.

To help you make a timely diagnosis, this article describes:

• neuropsychiatric manifestations of NCSE
  
• how to narrow the differential diagnosis by reviewing clinical symptoms and using electroencephalography (EEG)
  
• techniques used to rapidly halt ictal activity.
  

Box

Triggers, neurologic symptoms

NCSE is an acute but treatable medical emergency that calls for assessing and supporting cardiac and respiratory function, monitoring vital signs, temperature reduction, and fluid replacement. Prognosis is usually good unless NCSE is associated with a serious medical illness (Box).^1-11

Many metabolic, neurologic, pharmacologic, and medical abnormalities can precipitate NCSE (Table 1). The most common causes are hypoxia/anoxia, stroke, infection, subtherapeutic antiepileptic levels, alcohol and benzodiazepine intoxication/withdrawal, and metabolic abnormalities.^4,7,10,12

NCSE manifests as absence status epilepticus (ASE) or complex partial status epilepticus (CPSE). A generally accepted diagnostic definition is ≥30 minutes of behavioral change from baseline, with diagnostic EEG findings.^4,13 EEG is indispensable because the clinical manifestations of NCSE are predominantly behavioral, with minimal or no motor activity.

Table 1

Clinical factors that may precipitate NCSE

Medical	Recent infection, hyperventilation, trauma, menstruation, pregnancy, renal dialysis, postoperative period, sleep deprivation
Metabolic	Hypoparathyroidism, renal failure, hyper/hyponatremia, hyper/hypoglycemia, hypocalcemia
Neurologic	Mental retardation, dementia, stroke
Pharmacologic	Low serum levels or abrupt discontinuation of anticonvulsants, alcohol intoxication/withdrawal, benzodiazepine withdrawal lithium and neuroleptic use, psychotropic overdose
Source : References 9,10,12,16

ASE, a primary generalized process, is characterized by confusion or diminished responsiveness; it may be associated with occasional blinking or other minor motor activity and can last for hours to days. It usually occurs in patients with known epilepsy, particularly absence seizures.

ASE is reported primarily in children, although de novo cases have been described in elderly patients with no history of epilepsy.^10,14

CPSE is usually associated with a history of focal epilepsy and vascular disease. CPSE has a focal onset, with subsequent secondary generalization. Onset is usually temporal in origin but also can be extratemporal.

Patients with CPSE often cycle between an “epileptic twilight state” with confusion and complete unresponsiveness with stereotyped automatisms. It can present with marked behavioral fluctuation or a change in mental status and is generally followed by a prolonged postictal state.^4,7,13-15 Several NCSE cases have occurred in patients with no history of seizures.^9,10,16

Historically, CPSE was reported to be less common than ASE, but this misconception was most likely caused by failure to recognize CPSE’s clinical presentation and rapid generalization on EEG.^7,15

Neuropsychiatric features

Patients with NCSE may be referred for evaluation of an array of behavioral changes commonly seen in psychiatric practice. The differential diagnosis is extensive (Table 2) and includes neurologic and medical conditions often associated with catatonic syndrome.^17,18

In a retrospective study, Kaplan¹² assessed clinical presentations and reasons for diagnostic delay in 23 adults eventually diagnosed with NCSE. Presenting symptoms included:

• confusion, agitation, aggressive behavior
  
• lethargy, mutism, verbal perseveration, echolalia
  
• delirium, blinking, staring, chewing or picking behaviors
  
• tremulousness or myoclonus
  
• bizarre behavior (inappropriate laughing, crying, or singing)
  
• rigidity with waxy flexibility
  
• delusions, hallucinations.
  

Clinicians mistook hallucinations and mood lability for a primary psychiatric condition in 7 patients, presumed catalepsy was psychogenic in 3 patients, and thought obtundation was caused by alcohol or drug intoxication in 4 cases.

A prospective study of 22 patients with NCSE found that 7 had a history of psychotic depression, schizophrenia, self-mutilation, bipolar disorder, or episodic severe aggression; 12 of 18 with ASE had a history of epilepsy, and 3 of 4 with CPSE had experienced seizures associated with cerebrovascular accident, right cerebral embolus, and thiazide-induced hyponatremia, respectively.¹⁶

 

Table 2

Differential diagnosis of NCSE

Metabolic disorders	Hypo/hyperglycemia, hypercalcemia, Addison’s disease, Cushing’s disease, uremia
Neurologic disorders	Stroke, CNS tumors, closed head trauma, transient global amnesia, seizures, inflammatory and infectious encephalopathies
Psychiatric disorders	Schizophrenia, mood disorders, catatonia, malignant catatonia, somatoform disorders, conversion disorder, Asperger’s syndrome, malingering
Toxic disorders	Toxic encephalopathy, neuroleptic malignant syndrome, serotonin syndrome, alcohol and sedative-hypnotic withdrawal, drugs (lithium toxicity, tricyclics, baclofen, tiagabine, overdose)
Source: Reference 17,18

NCSE in the elderly can be difficult to diagnose, especially in patients with comorbid severe medical illnesses and other confusional states.⁴CPSE with possible generalization is more common than ASE in the elderly. Hyperreligiosity, intermittent agitation, motor perseveration, ictal fear, catatonic signs, delusional preoccupation, and auditory and visual hallucinations have been observed during NCSE in the elderly and misdiagnosed as primary psychiatric conditions.

Cerebrovascular disease, tumors, and trauma are the most common causes of late-life NCSE.^4,19 De novo NCSE occasionally presents:

• after benzodiazepine withdrawal
  
• with neuroleptic, tricyclic antidepressant, or lithium treatment^10,16
  
• with metabolic abnormalities and nonpsychotropic medications.¹⁰
  

Clinical symptoms

Clinical features of NCSE include cognitive changes, speech abnormalities, affective disturbances, psychosis, poor impulse control, and bizarre behaviors (Table 3). Some patients develop ictal phenomena resembling catatonia or clinical and EEG changes that mimic neuroleptic malignant syndrome (NMS).^20-23

Table 3

Clinical features that raise suspicion of NCSE

Domain	Features
Cognitive changes	Prolonged confusion, executive dysfunction, obtundation, attention/memory difficulties, lack of initiative, perseveration, stupor
Speech	Poverty of speech with monosyllabic answers, verbal perseveration, echolalia, palilalia, aphasia, paraphasic errors, confabulation, mutism
Affective	Prolonged fear, affective indifferent state with blank facial expression, hypomania, psychotic depression, inappropriate laughing and crying, anxiety states
Psychosis	Visual, auditory and cenesthetic hallucinations, delusions
Impulse control	Hostility, agitation, violence, groping, genital manipulation, picking, posturing
Others	Catatonic signs, autonomic disturbances
Source: References 5,7-9,12,15-17,20-23

Catatonia. Lim et al²⁴ described three patients with EEG-confirmed NCSE that manifested as ictal catatonia. A prolonged, trance-like, stuporous state during epilepsy has been reported, as has CPSE presenting with psychogenic unresponsiveness. Drury et al²⁵ described a patient who presented with catatonia and increased muscle tone but had prominent EEG abnormalities implicating an organic cause.

Among 29 patients with acute catatonic syndromes, epileptic activity was identified in 4. One patient with absence status was diagnosed with NMS during the catatonic period.²⁶ Conversely, the commonality of clinical features has led to misdiagnosis of psychogenic catatonia as NCSE. EEG is necessary to exclude NCSE in these cases.

NMS. Yoshino et al²⁷ described two patients taking neuroleptics who met criteria for NMS and had EEG changes consistent with NCSE. They later reported another patient with NCSE complicating NMS; the point at which NCSE developed was unknown, however, because EEG activity was not recorded at NMS onset.²⁸ Based on NMS diagnostic criteria proposed by Caroff et al,²⁹ these patients could have developed NCSE mimicking NMS.

EEG for diagnosis

Candidates. Because differentiating NCSE from similar conditions can be difficult, use EEG to confirm your clinical observations. No guidelines exist, but consider EEG when the patient’s history suggests NCSE. Ask the patient or family about:

• changes in mental status from baseline, especially new-onset catatonia or unexplained altered consciousness
  
• duration of events
  
• presence or absence of motor activity
  
• behavioral fluctuations
  
• presence or absence of automatisms or blinking.
  

List the patient’s medications, ask about illicit substance or alcohol use, and gather a comprehensive history of medical, neurologic, and psychiatric illnesses. Include NCSE in the differential diagnosis of elderly patients with acute prolonged confusion. Try to obtain EEG early to differentiate focal from secondary generalized seizures.

EEG patterns. Table 4 summarized NCSE diagnostic criteria. NCSE shows characteristic patterns in ASE and CPSE,^9,10,16,23 and EEG changes can be continuous or nearly continuous in both.

Table 4

EEG findings that support a clinical diagnosis of NCSE

Clear-cut criteria
Frequent or continuous focal seizures, with ictal patterns that wax and wane with change in amplitude, frequency, and/or spatial distribution
Frequent or continuous generalized spike wave discharges:
in patients without history of epilepsy in patients with epilepsy, when discharges show significant changes in intensity or frequency compared with baseline EEG
Periodic lateralized epileptiform discharges (“PLEDs”) or bilateral periodic epileptiform discharges (“biPEDs") occurring in patients with coma from generalized tonic-clonic status epilepticus (subtle SE)
Probable (equivocal) criteria
Patients with acute cerebral damage who also show frequent or continuous EEG abnormalities without previous similar findings
Patients with epilepsy who show frequent or continuous generalized EEG abnormalities and similar interictal EEG patterns but whose clinical symptoms suggest NCSE
Source: References 4,12-14,17

In ASE, a generalized, bilaterally synchronous, rhythmic, 3- to 3.5-second spike with a bifrontal maximum is seen in 40% of cases.³⁰ Also described in ASE are fragmented spike waves, multiple spikes and waves, and generalized bilateral discharges with focal predominance. This last pattern might suggest an underlying focal origin of the epileptic discharge with secondary generalization.

 

^31,32

In CPSE, less-synchronous epileptiform activity has been described, including rhythmical slow, rhythmic spikes, or rhythmic spike and slow waves. Two types of CPSE of frontal origin have been described:

• Type 1 presents clinically with mood disturbance and minimal confusion. EEG shows a frontal focus with a normal background.
  
• Type 2 presents clinically with confusion. EEG shows bilateral asymmetric frontal discharges.⁸
  

Not always clear. Making a clear distinction between primary and secondary generalization on EEG is not always possible.¹⁵ In a large series of NCSE cases,³¹ ictal discharges on EEG were:

• generalized in 69%
  
• diffuse with focal predominance in 18%
  
• focal in 13%.
  

Although most EEGs showed a generalized pattern, many cases probably started focally with immediate generalization. Morphologies seen—in descending order of frequency—were atypical spike and wave, multiple spike waves, rhythmic delta with intermittent spikes, and typical spike and wave patterns. Ictal discharge frequency also was variable and

Distinguish between ictal and interictal EEG findings with epileptiform activity, because only the former is diagnostic for NCSE. Intravenous benzodiazepines might be necessary during EEG to verify the diagnosis.³³

NCSE has developed after electroconvulsive therapy (ECT), but a cause-effect relationship is debatable. Interictal and abnormal EEG findings after ECT may be misdiagnosed as NCSE.³⁴

Neuroimaging has limited clinical value because of the need for patient cooperation and specialized equipment.⁴ Head CT or MRI can exclude structural abnormalities. PET and SPECT show increased metabolism and blood flow, respectively, in NCSE. MR spectroscopy shows elevated lactate and decreased N-acetyl aspartate.

Halting ictal activity

To rapidly stop ictal activity—the main goal of treatment—recognizing and correcting precipitant factors is vital:

• Consider discontinuing medications that could lower the seizure threshold.
  
• Order a complete blood count, serum electrolytes, calcium, arterial-blood gas, liver and renal function tests, urine toxicology screen, and serum antiepileptic drug concentrations.
  
• When possible, obtain neuroimaging and EEG in the emergency room for accurate diagnosis and prompt treatment.¹²
  

Medications. Benzodiazepines such as lorazepam, diazepam, and clonazepam are used most often to interrupt seizure activity. Use them cautiously in medically fragile patients, however, to prevent hypotension and respiratory depression.

Response to benzodiazepines might be transient, lasting only hours or days. For instance, diazepam’s anticonvulsant effect may last

Newer antiepileptics—such as lamotrigine, levetiracetam, or topiramate—have been used with varying results, and their role in first-line treatment of NCSE is evolving. Rarely, the antiepileptic tiagabine precipitates or worsens NCSE.^4,13,14

Related resources

• Epilepsy Foundation. www.epilepsyfoundation.org
  
• Neuroleptic Malignant Syndrome Information Service. Hotline for health professionals (888) 667-8367. www.nmsis.org
  

Drug brand names

• Carbamazepine • Tegretol, Carbatrol
  
• Clonazepam • Klonopin
  
• Diazepam • Valium
  
• Lamotrigine • Lamictal
  
• Levetiracetam • Keppra
  
• Lithium carbonate • Lithobid, Eskalith CR
  
• Lorazepam • Ativan
  
• Phenobarbital • Luminal
  
• Phenytoin • Dilantin
  
• Tiagabine • Gabitril
  
• Topiramate • Topamax
  
• Valproic acid • Depakote
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in the article or with manufacturers of competing products.

Acknowledgment

Dr. Goveas was a geriatric psychiatry fellow, University of Pennsylvania, when he wrote this article in collaboration with his mentors, Drs. Caroff and Riggio.