Major neurocognitive disorder

Major neurocognitive disorder (dementia) is an acquired disorder of cognitive function that is commonly characterized by impairments in the memory, language, attention, executive function, social cognition, and/or perceptual-motor domains. Most forms are associated with older age. The most common causes of dementia are neurodegenerative (e.g., Alzheimer disease) and vascular disease. While all subtypes of dementia share impairments in cognition, other clinical features may differ depending on the dementia subtype. Initial diagnosis should focus on patient history and neurological examination, including a cognitive assessment. Additional laboratory tests and neuroimaging studies are often necessary to investigate specific causes. An important differential diagnosis is pseudodementia. In contrast to patients with dementia, individuals with pseudodementia often recall the onset of their cognitive impairments, overestimate their symptoms, and are responsive to treatment with antidepressants. In general, specific pharmacotherapy to slow the loss of cognitive function in dementia is of modest benefit; management should focus on nonpharmacological measures. Preventive interventions to reduce modifiable risk factors for dementia (e.g., control of ASCVD risk factors, treatment of hearing loss) may help prevent or slow cognitive decline, although studies assessing the efficacy of specific interventions are lacking. There are no universal screening recommendations for dementia, but clinicians should be vigilant for early signs of cognitive decline in all individuals to allow for early management, e.g., management of reversible causes, adjustment of other medical treatments.

Neurodegenerative brain diseases

• Alzheimer disease (> 50% of dementia cases)
• Parkinson disease
• Frontotemporal dementia
• Dementia with Lewy bodies
• Progressive supranuclear palsy
• Huntington disease

Additional causes

• Cerebrovascular disease (20% of dementia cases)
  • Multi-infarct dementia
  • Diffuse white matter disease (subcortical arteriosclerotic encephalopathy)
• Hypoxic brain damage
• Normal pressure hydrocephalus
• After head trauma, intracranial bleeding or brain tumors
• Drug/alcohol‑related (e.g., Wernicke‑Korsakoff syndrome)
• Wilson disease
• Vitamin deficiencies (thiamine, B₆, B₁₂, folate, niacin)
• Metabolic: exsiccosis, uremia, electrolyte imbalances
• Endocrine: hypothyroidism and hyperthyroidism, hypoparathyroidism and hyperparathyroidism
• Environmental toxins
• Inflammatory/infectious
  • Syphilis
  • Progressive multifocal leukoencephalopathy
  • HIV
  • Creutzfeldt-Jakob disease

Think DEMENTIAS for common etiologies of dementia: Degenerative (Alzheimer, Parkinson, Pick disease), Emotional (depression, psychosis), Metabolic (liver or kidney failure, toxins), Endocrine (hypothyroidism), Nutritional (vitamin deficiencies) or Neoplastic (carcinomatous meningitis), Traumatic (TBI), Infectious (syphilis, HIV, CJD), Autoimmune, Stroke.

References:^[1]

• General: memory impairment
• Additional cognitive impairment
  • Speech: aphasia, word-finding difficulties, semantic paraphasia
  • Intellectual capacities, reasoning, planning capabilities, and self-control
  • Spatial-temporal awareness (however, the awareness of oneself remains stable for a long time)
  • Apathy
• Changes in personality, mood, and behavior
  • Early stages: depression
  • Later stages: seemingly unconcerned mood and cognitive impairment is downplayed
• Dementia associated with CNS infections
  • Most types of CNS infections cause acute neurological or psychiatric symptoms rather than dementia.
  • Infections that may cause symptoms of dementia include:
    • Chronic meningitis
    • HIV and HIV-related opportunistic infections
    • Neurosyphilis

References:^[1]

Approach ^[2][3]

• Perform a comprehensive clinical evaluation, including:
  • Detailed history of cognitive decline
  • Evaluation for risk factors for and/or symptoms of specific types of dementia
  • Neurological examination, including a mental status examination and cognitive assessment
• Assess for reversible causes of cognitive impairment, including; delirium and pseudodementia.
  • See “Delirium vs. dementia.”
  • Review medications on the Beers Criteria.
  • Screen for major depressive disorder using PHQ-2.
• Confirm the diagnosis using DSM-5 diagnostic criteria for neurocognitive disorders.
• Obtain laboratory tests and neuroimaging to assess for underlying causes of major neurocognitive disorder.
• Refer patients with early-onset dementia, rapidly progressive dementia, or if more information is needed to guide management.
  • Neurology: specialized testing, including neuroimaging, CSF evaluation, EEG, or genetic testing
  • Geriatric psychiatry: full neuropsychological testing

The USPSTF has found insufficient evidence for or against screening for cognitive impairment in individuals with no symptoms; however, assessment for cognitive impairment is a routine part of the Medicare Annual Wellness Visit. ^[4]

Diagnostic criteria for neurocognitive disorders ^[2][5][6]

Diagnostic criteria for major neurocognitive disorder (dementia)

These criteria are in accordance with DSM-5. Unlike DSM-5, ICD-10 includes memory impairment as a diagnostic criterion.

Diagnostic criteria for mild neurocognitive disorder (mild cognitive impairment)

Diagnostic criteria are similar to dementia, with the following differences:

• Cognitive deficits are less severe, i.e., do not interfere with everyday life.
• Patients are typically aware of their deficits.

The defining difference between MCI and dementia is the degree of functional impairment and cognitive decline.

Initial evaluation of major neurocognitive disorder ^[2][3]

Obtain the following studies in all patients with suspected dementia to identify the cause of dementia and/or rule out other causes (e.g., delirium).

• Laboratory studies
  • Vitamin B₁₂ (cobalamin): assess for deficiency
  • TSH: hypothyroidism
  • CBC: anemia
  • CMP: kidney disease, liver disease, and hypoglycemia or hyperglycemia
  • Urinalysis: rule out infection
• Imaging ^[2][7][8][9]
  • Brain MRI is the preferred modality.
  • Obtain to detect reversible or structural causes of dementia.
  • Findings depend on the underlying disease and frequently include cortical atrophy.
  • See “Differential diagnosis of subtypes of dementia” for a comparison of imaging findings.

Additional studies ^[2][10]

Obtain as indicated under specialist guidance in patients with a rapidly progressive course of dementia, early-onset dementia (< 65 years), or symptoms, risk factors, or other findings suggestive of a specific type of dementia.

• Blood tests
  • CBC with differential
  • Folate (vitamin B₉) and homocysteine: ↓ folate and ↑ homocysteine associated with cognitive impairment ^[11]
  • ESR, CRP, ANA: inflammatory or autoimmune diseases
  • RPR: if there is clinical suspicion for neurosyphilis
  • Lyme titers: if there is clinical suspicion for chronic neuroborreliosis
  • HIV screening: to rule out HIV-associated neurocognitive disorder
  • Ceruloplasmin: to rule out Wilson disease
• Urine toxicology screen
• Lumbar puncture to: ^[10]
  • Assess for evidence of CNS inflammation (e.g., meningitis, encephalitis) or prion disease
  • Detect specific biomarkers (e.g., in Alzheimer disease)
  • Confirm normal pressure hydrocephalus (CSF tap test)
• PET scan or SPECT: to distinguish between specific neurodegenerative disorders
• Electroencephalogram (EEG): to evaluate for seizures, subcortical dementia, and frontal lobe degeneration ^[3][12]

General principles ^{[2][3][13][14]}

• Shorter screening tools (e.g., Mini-Cog) have adequate sensitivity and specificity for detecting dementia in most situations.
• Utilize a more extensive screening tool (e.g., Mini-Mental State Examination or Montreal Cognitive Assessment):
  • For diagnostic clarity
  • To assess the degree of cognitive impairment (e.g., MMSE < 24 suggests cognitive impairment)
• Factors such as education level, language, and illness can impact results.
• Repeat measurements to track disease progression over time.
• See “Mental status examination” for further details on cognitive domains.

Obtain neuropsychological testing if there is diagnostic uncertainty despite the use of extensive screening tools.

Overview of cognitive screening tools

Think VITAMINS for the most common causes of rapidly progressive dementia: Vascular, Infectious, Toxic-metabolic, Autoimmune, Metastases, Iatrogenic, Neurodegenerative, Systemic/Seizures/Structural.

The differential diagnoses listed here are not exhaustive.

Approach ^[3][28][29]

• Provide disease-specific treatment if available.
• Initiate supportive management and management of associated conditions.
• Arrange support for patients and their caregivers. ^[3][30][31]
• Consider referral to hospice for eligible patients. ^[32]

Behavioral problems (e.g., physical agitation) and fecal incontinence in patients with dementia are associated with caregiver burnout and poor outcomes for patients (e.g., emergency department visits and institutionalization). ^[3][29][33]

Pharmacological treatment of dementia ^[3][28][30]

• Antidementia medications may provide modest benefit for cognitive symptoms in some types of dementia.
• Cholinesterase inhibitors (donepezil, galantamine, rivastigmine)
  • Recommended for mild to moderate Alzheimer disease ^[30]
  • May be considered in patients with Parkinson dementia or Lewy body dementia
  • Discuss treatment goals and potential adverse effects before starting medication. ^[3][30][34]
  • Reevaluate patients 12 weeks after initiation. ^[34]
    • Ensure the benefits outweigh the adverse effects.
    • Discontinue if no beneficial cognitive effects are observed. ^[34][35]
• NMDA-receptor antagonist (memantine): recommended for moderate to severe Alzheimer disease
• See “Antidementia medications” in “Alzheimer disease” for more information.

Antidementia medications provide limited improvement of cognitive symptoms. Use shared decision-making to determine if pharmacotherapy is appropriate for the patient after discussing the risks, benefits, and alternatives. ^[28][31][34]

Discontinue cholinesterase inhibitors approximately 12 weeks after initiation if no beneficial cognitive effects are observed. ^[3][34]

Supportive management of patients with dementia ^[3][28][31]

• Regularly evaluate for associated medical, psychiatric, or behavioral conditions.
  • Manage risk factors (see “Prevention of dementia”).
  • Use delirium prevention strategies.
  • Treat hearing loss and vision loss if necessary.
• Periodically perform an assessment of care needs for older adults. ^[36]
  • Coordinate functional status assessments.
  • Offer psychoeducation.
  • Assess for caregiver burnout and provide referrals for assistance.
  • Encourage early advance care planning and financial planning.
• Recommend maintaining a:
  • Predictable schedule
  • Familiar home environment
• Encourage a healthy lifestyle, including:
  • Exercise
  • Recreational activities, e.g., social gatherings, art, puzzles, music, pet therapy
  • Mediterranean diet
  • Sleep hygiene, including a regular sleep schedule
  • Personal hygiene
• Consider cognitive interventions for patients with mild to moderate dementia. ^[37][38]
  • Cognitive training: may result in small gains in verbal fluency and global cognition ^[39]
  • Cognitive stimulation therapy: may improve cognitive function and reduce depression ^[40]

Cognitive training and cognitive stimulation therapy may modestly delay cognitive decline. However, these programs can lead to excessive frustration, which may exacerbate behavioral and neuropsychiatric symptoms. ^[28][31]

Patients with dementia are less likely to receive adequate pain management at the end of life. Consider using a nonverbal pain scale to assess pain, and follow a step-wise approach to analgesia.

Safety considerations

• Inform the patient and caregivers about increased risk of driving accidents.
• Consider referral for driving safety evaluation to assess for driving restrictions.
• Consider the need for interventions (e.g., supervision) to prevent wandering.
• Evaluate for risk of falls in older adults.

Advance care planning (ACP) ^[41]

• Discuss ACP at the time of diagnosis, or with changes in health status, residence, or financial situation.
• Document wishes and preferences, including a physician orders for life sustaining treatment, advance directive, and medical power of attorney.
• Consider a specific advance directive for dementia. ^[42]
• Assess decision-making capacity regularly.

Management of behavioral and psychological symptoms of dementia ^[3][32]

• Major depressive disorder and anxiety: Consider low dose of an SSRI (e.g., escitalopram or citalopram). ^[28][31]
  • Consider low dose of an SSRI (e.g., escitalopram or citalopram).
  • See “Depression in older adults.”
• Agitation and psychosis ^[31][43]
  • Avoid antipsychotic medications if possible.
  • Focus on delirium prevention and nonpharmacological deescalation. ^[43]
  • If other approaches have failed or the patient poses a substantial threat to themself or others, consider one of the following:
    • Citalopram ^[44]
    • Low dose of an antipsychotic ^[43]
  • If indicated, administer under medical supervision and in a time-limited fashion.
  • See “Delirium management” and “Management of the agitated patient.”
• Sleep disorders and disturbances ^[28]
  • Nonpharmacological measures are preferred, e.g.:
    • Sleep hygiene
    • Environmental restructuring
  • Address possible underlying causes (e.g., drug effects, nocturia, pain).
  • Consider pharmacotherapy for insomnia (e.g., trazodone) if other methods have failed and benefits are expected to outweigh the risks.
  • Avoid medications that increase the risk of delirium, disinhibition, daytime sedation, and/or falls.

Avoid drugs with strong anticholinergic effects (e.g., tricyclic antidepressants, diphenhydramine) and use the lowest effective dose of psychoactive drugs. ^[30]

Only consider using antipsychotics to treat psychobehavioral symptoms of dementia if nonpharmacological measures (e.g., deescalation techniques) have been unsuccessful or there is concern that the patient may pose a threat to themselves or others. ^[43]

Management of conditions in advanced dementia ^[3][32]

Malnutrition and weight loss ^[45]

• Screen for malnutrition in older adults every 3–6 months and monitor BMI.
• Assess for potential causes and initiate management accordingly.
• Ensure support to enable adequate food intake as needed.
• Avoid dietary restrictions and recommend providing food based on personal preference.
• Avoid appetite stimulants.
• Individualize decisions on artificial nutrition and hydration.
  • Consider time-limited use of a gastrointestinal tube in patients with mild to moderate dementia.
  • Provide oral feedings by hand instead of tube feedings in patients with severe dementia. ^[45][46][47]
  • Withholding nutrition and hydration at the end of life is not thought to affect patient comfort. ^[32]

Do not initiate tube feeding in patients with severe dementia. ^[34][45]

Fecal and urinary incontinence

• Evaluate for potentially reversible causes.
• Ensure adequate hygiene to avoid skin breakdown and infections.
• Use pharmacotherapy with caution; conservative management is preferred, e.g., prompted voiding.
• See “General treatment of urinary incontinence.”

Infections

• Focus on prevention.
  • Assess for aspiration risk factors.
  • Avoid indwelling urine catheters.
  • Monitor skin for pressure ulcers.
• Ensure antimicrobial treatment is only administered if patients meet indications. ^[48]
• If indicated, prescribe targeted antibiotic therapy in keeping with the patient's goals of care.

Primary prevention of dementia ^[38][49][50]

Modifiable risk factors

• Early interventions to reduce modifiable risk factors for dementia may help prevent or slow cognitive decline, although studies assessing the efficacy of specific interventions are lacking. ^[38][51]
• Some modifiable risk factors permanently increase the risk of dementia; preventive measures should be started in early life.
• Certain social determinants of health are modifiable risk factors and must be addressed at the population level, e.g.: ^[38]
  • Low level of education in early life ^[38]
  • Exposure to environmental pollution ^[38]

Reduction of all modifiable risk factors may prevent or delay approximately 40% of cases of dementia. ^[38]

Other interventions ^[38][49][50]

• Consider offering cognitive training to older adults for the prevention of dementia. ^[50]
• There is insufficient evidence to recommend the following interventions: ^[38][50]
  • Cognitive stimulation therapy
  • Dietary supplements (e.g., micronutrients, polyunsaturated fatty acids) ^[38][50]
  • Acetylcholinesterase inhibitors

Dietary supplements have not been found to prevent cognitive decline. ^[38][50][57]

Screening for dementia ^[4][58][59]

• Routine screening of asymptomatic older adults is not currently recommended in guidelines but is part of the Medicare annual wellness visit. ^[4]
• Perform screening if signs of dementia are observed during office visits or reported by friends or family members.
• See “Neuropsychological assessment in older adults” and “Cognitive assessment” for further information.

Physicians should remain vigilant for signs of cognitive decline, as early diagnosis may allow for the reduction of modifiable risk factors, mitigation of the impact of cognitive difficulties on other aspects of medical care, and anticipatory planning. ^[4]

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