Identifying the most common causes of reversible dementias
KEY POINTS
>> With life expectancy improving and the size of the population older than 65 years increasing, dementia will be a growing public health problem in the United States.
>> The precise frequency of treatable dementia has been difficult to determine; one meta-analysis found that 9% of dementias appear to be potentially reversible. Consequently, a precise diagnosis of the type of dementia and its cause is essential.
>> A reasonable screening battery of tests for the initial evaluation of a demented patient includes CBC, chemistry panel including electrolytes, vitamin B12, thiamine, free T4, thyroid-stimulating hormone, and VDRL synchronous fluorescent treponemal antibody-absorption (FTA-ABS).
>> In addition, patients should have neuroimaging, preferably noncontrast CT or MRI.
CME
Identifying the most common causes of reversible dementias: A review
Douglas J. Ladika, MEd, MPAS, PA-C, Samuel L. Gurevitz, PharmD, CGP
March 01, 2011
According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), dementia is defined as multiple cognitive deficits that include memory impairment and at least one of the following cognitive disturbances: aphasia, apraxia, agnosia, or a disturbance in executive functions. The cognitive impairment must be sufficiently severe to cause impairment in occupational or social functioning and must represent a decline from a previously higher level of functioning.1
Dementia is age related. With life expectancy improving2 and the size of the population older than 65 years increasing from 37 million people in 2006 to an estimated 71.5 million by 2030, dementia will be a growing public health problem in the United States.3 With the increasing number of elderly and the increase in the number of patients with dementia, greater attention to identifying potentially treatable and/or reversible causes is essential.
The precise frequency of treatable dementia has been difficult to determine. A meta-analysis published in 2003 found that 9% of dementias appear to be potentially reversible.4 It is also important to distinguish between delirium and dementia if appropriate interventions are to be initiated. Delirium is characterized by an acute, fluctuating change in mental status. Patients with delirium exhibit a cluster of symptoms, cognitive impairment, disorientation, and reduced ability to focus or maintain attention. Symptoms associated with dementia are insidious.5 This article reviews the etiologies, workup, and treatment of common, recognized reversible dementias.
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Learning Objectives
- Define dementia and its frequency
- Discuss the range of etiologies for reversible causes of dementia
- Describe laboraory testing and imaging studies used to diagnose reversible causes of dementia
- Explain treatments for common reversible causes of dementia
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ETIOLOGIES

Thyroid disorders
The thyroid hormones play an important role in the function of the brain. The CNS contains neuroregulators and neuromodulators.6 Although overt hypothyroidism is well-established as a common cause of reversible dementia and depression, evidence is increasing that subclinical hypothyroidism is associated with cognitive and behavior disturbances.7,8 This is particularly important to remember because dementia and hypothyroidism are common in the older patient. A history, physical examination, and testing to measure levels of thyroid-stimulating hormone (TSH) and free thyroxine (T4) are appropriate. 

Thyroid replacement therapy with synthetic levothyroxine is the treatment of choice for hypothyroidism.8 Follow-up testing with a thyroid panel is recommended in 6 to 8 weeks. It may take up to 3 months for thyroid levels to normalize. 

Vitamin B12 deficiency
Common in the elderly,9 vitamin B12 deficiency can manifest with hematological changes, neurologic impairments, mood changes, and cognitive impairment.10-12 B12 is required for the synthesis of S-adenosylmethionine, the main methyl-donor in the CNS for reactions involving neurotransmitters.11 Cognitive impairment should compel a neurologic (or neuropsychological) evaluation and testing for serum B12 value.

Even low-normal values of vitamin B12 can cause a cognitive decline in the elderly. Other laboratory assays such as measures of serum homocysteine and methylmalonic acid can be used to diagnose B12 deficiency even when the serum B12 level is normal. Both homocysteine and methylmalonic acid levels will be elevated when B12 deficiency is present.13 

The most common cause of B12 deficiency is malabsorption. Supplementation of vitamin B12 can be accomplished by the oral, nasal, or IM route. Most clinicians prefer the IM route, given that malabsorption is the most common cause. Treatment schedules for IM administration vary but usually involve initial loading doses followed by monthly maintenance injections. One regimen consists of injections of 1,000 mcg daily for 1 to 2 weeks, followed by a maintenance dosage of 1,000 mcg every 1 to 3 months.13 Recent studies have shown that high oral doses are as effective as IM treatment.14 The recommended oral dose is 2,000 mcg daily. Follow-up tests to measure vitamin B12 levels are necessary to ensure that replacement is adequate. 

Depression
The symptoms of this disorder frequently occur with dementia.15 Depression is characterized by sadness, negative thoughts, loss of interest, and disruptions in sleep, appetite, energy levels, and thinking. Depression is well-recognized to affect memory, attention, and cognitive function.16,17Pseudodementia is a term often applied to the cognitive impairment caused or exacerbated by depression. Some elderly persons are unaware of their mood state and may deny sadness and other typical symptoms of dysthymia. Thus clinicians must be doubly alert to recognize sadness, anxiety, and vegetative symptoms and signs to detect depression. The older patient presenting with depression should be fully evaluated for dementia.

Both pharmacologic and nonpharmacologic approaches to treating depression are helpful in reducing depressive symptoms in cognitive impairment and dementia. Antidepressants are frequently prescribed. The choice of agent is based on adverse effect profile and the characteristics of the individual patient. Selective serotonin reuptake inhibitors (for example, sertraline) may be preferred because they appear to be better tolerated than other antidepressants. Venlafaxine, bupropion, and mirtazapine may also be effective. Agents with substantial anticholinergic effects (such as amitriptyline) should be avoided. A trial of an antidepressant should include an adequate dosage and duration—8 to 12 weeks of treatment with at least 4 weeks at an adequate dosage. Treatment should continue until the patient not only responds but reaches remission.18
Medication-induced impairment
Risk factors for cognitive impairment in older patients resulting from medications include polypharmacy, comorbidities, and age-related pharmacokinetics and pharmacodynamic changes. Reduced hepatic and renal clearance are the most significant pharmacokinetic changes in the older patient.19 Many commonly prescribed medications, such as opioids, benzodiazepines, sleep aids, antipsychotics, and anticholinergics or any agent with anticholinergic properties, can lead to problems with mobility, falls, and cognition.20,21 Reversible cognitive dysfunction may involve drug-induced cognitive impairment or delirium. It is important to distinguish between the two if appropriate interventions are to be initiated.

The adverse effects of anticholinergic agents may not develop with one agent but rather as a cumulative effect of multiple agents with varying degrees of anticholinergic effects, called anticholinergic burden.20 Topiramate is an antiepileptic drug that is used in migraine prophylaxis and is increasingly used off label as a mood stabilizer. It has been reported to cause a reversible dementia in an older patient.22 Each patient's medication list should be screened for offending agents, and attempts should be made to eliminate or reduce dosages where possible. Medications should be eliminated or reduced in dosage gradually, over time.

Systemic inflammatory disorders
A number of inflammatory conditions are associated with vasculopathy of the CNS, by either inflammatory or coagulopathic mechanisms. This category includes Behcet disease, hypereosinophilic syndrome, celiac sprue, CNS vasculitis, Susac syndrome, lupus cerebritis, Sjögren syndrome, antiphospholipid antibody syndrome, and neurosarcoidosis.23 Vasculitis may have associated systemic symptoms, including fever, weight loss, rash, neuropathy, or other organ involvement.23 The workup for vasculitis includes the following tests: ESR,24 C-reactive protein, complement 3 and 4, reciprocal of the dilution of serum to lyse 50% of antibody-coated sheep RBCs (Ch-50), antinuclear antibody, rheumatoid factor, anti-Sjögren syndrome A, anti-Sjögren syndrome B, perinuclear antineutrophil cytoplasmic autoantibodies, classical antineutrophil cytoplasmic antibodies, and lupus anticoagulant. Celiac disease is diagnosed by testing for antigliadin antibody. MRI may reveal changes associated with lupus cerebritis. 

Normal pressure hydrocephalus
This condition may manifest with progressive impairment of gait and cognition in association with urinary incontinence.23,24 Half of cases are idiopathic, and the others occur secondary to head injury, subarachnoid hemorrhage, meningitis, or a neurosurgical procedure. In either instance, the flow of CSF is blocked.11 The pattern of gait disorder accompanied or followed by change in mentation with a subcortical pattern, plus an identifiable risk factor such as intracranial bleeding, indicates that the patient may respond to a shunt.10 The ventricular and cortical appearance on MRI is a helpful prognosticator as well (Figure 1).10,25 A patient questionnaire may help in the early detection of normal pressure hydrocephalus. Three or more Yes answers to the following questions suggest that normal pressure hydrocephalus should be in the differential diagnosis:26
* Do your feet feel stuck to the floor when you walk?

* Do you have trouble keeping your balance when walking or turning?

* Have you experienced sudden falls without loss of consciousness?

* Do you have difficulty maintaining attention?

* Have you experienced sudden urges in urinating?

* Have you had urinary accidents?

* Do you have trouble remembering things?26

Risk factors for normal pressure hydrocephalus include diabetes and hypertension. Gait abnormalities in patients with normal pressure hydrocephalus include a slightly backward lean, with normal arm swing.27
CNS infections
A history of sick contacts, blood transfusions, unsafe sexual practices, or IV drug use increases the risk for blood-borne diseases such as HIV infection,24 syphilis,24 and hepatitis. A history of immunodeficiency may point to unusual infections such as cryptococcal meningitis24 or other opportunistic infections.23 Travel to areas endemic for a particular disease, such as Lyme disease, may be revealing. Recent studies have found that CNS infections are not a significant cause of dementia in Western countries compared to other countries.24 Infectious causes of dementia are often discovered only incidentally.24
Physical examination of the skin may reveal signs of infection. Argyll Robertson pupil or some of its features may be present in cases of neurosyphillis.10 Reversible dementias tend to occur with a relatively normal to slightly impaired level of consciousness, and at the worst, a fluctuating level of consciousness. Attention is often impaired in these forms of dementias as well. Concentration requires further executive function, a role of the frontal lobes, to keep the patient on task and tracking. "Focality" on neurologic testing points away from systemic disease and, apart from abscess formation, mitigates the likelihood of infection as a cause. Cranial nerve palsies can be associated with tuberculosis. Whipple disease25,28 is a rare bacterial disease caused by Tropheryma whippelii, which should be considered when GI and joint symptoms are associated with dementia. In rare instances, neuroborreliosis may manifest as atypical normal pressure hydrocephalus.29

CSF offers the maximal amount of independent diagnostic information.24 Treatment is, of course, tailored to the discovered etiology. 

Intracranial masses
Tumors that may be surgically treatable can be considered a possible reversible cause of dementia.24 Chronic subdural hematomas may also act as space-occupying lesions and cause dementia in the older patient.30 Imaging may reveal an arteriovenous malformation, which may produce dementia secondary to ischemic neuronal dysfunction caused by the associated venous hypertension.31 Space-occupying lesions, particularly involving the parietal lobes, may cause clinical symptoms resembling Alzheimer disease.25 A thorough neurologic examination, including ophthalmoscopic examination for papilledema and/or the absence of venous pulsations, indicators of increased intracranial pressure, should be performed.

LABORATORY STUDIES AND IMAGING

When the clinical presentation points to a particular diagnosis, testing appropriate to that diagnosis should be performed.10 This section focuses on the laboratory and imaging studies that should be performed on all new patients presenting with dementia who do not have an obvious cause suggested by their clinical presentation.10

Screening laboratory testing
A reasonable screening battery of tests for the initial evaluation of a demented patient is as follows: CBC, chemistry panel including electrolytes, vitamin B12, thiamine, free T4, TSH, venereal disease research laboratory test (VDRL), and synchronous fluorescent treponemal antibody-absorption (FTA-ABS; 57% of patients with neurosyphilis will have a negative result on VDRL).25 In addition, patients should have neuroimaging with either noncontrast CT or MRI.10,25 More focused laboratory tests, depending on the clinical presentation, are listed in Table 1.
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Table 1. Focused laboratory testing
- Infectious causes: Lyme titer, HIV antibody, Cryptococcus antibody, polymerase chain reaction for Whipple disease
- Nutritional causes: vitamin B3 (niacin), vitamin B6, vitamin E, vitamin D, vitamin A, folate
- Electrolyte abnormalities: sodium, calcium, magnesium, phosphorus
- Metabolic causes: serum ammonia
- Hormonal causes: Free T4, appropriate antithyroid antibodies if basic thyroid function is abnormal, serum cortisol levels
- Abnormal proteins and systemic inflammatory disorders: serum protein electrophoresis, urine protein electrophoresis, ESR, antinuclear antibody
- Autoimmune causes: antistreptolysin antibody, ESR, rheumatoid factor, antinuclear antibody, lupus anticoagulant assay (tissue thromboplastin inhibition, anticardiolipin antibody, IgG, IgM), anti-Ro antibody, C3 complement, C4 complement, perinuclear antineutrophil cytoplasmic autoantibodies, classical antineutrophil cytoplasmic antibodies
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Other testing
Lumbar puncture is considered in atypical, primarily attentional or frontal-temporal syndromes to evaluate for infectious, neoplastic, or inflammatory causes.25

Imaging
Use of MRI of the brain is supported by the Canadian and American Academies of Neurology.10,24,25 In a study by Walstra and colleagues, CT and EEG were never diagnostically helpful when not considered clinically indicated.32 The Canadian Consensus Conference indications for neuroimaging in the evaluation of dementia include age younger than 60 years; use of anticoagulants; recent head trauma; history of cancer; unexplained neurologic symptoms; rapid, unexplained decline in symptoms or function; duration of dementia less than 2 years; history of gait disturbance or urinary incontinence early in the course; unusual or atypical cognitive, behavioral, or neuropsychological presentation; localizing signs; and gait ataxia.33 The American Academy of Neurology now says that "structural imaging with either a noncontrast CT or MRI scan in the routine initial evaluation of patients with dementia is appropriate."34

CONCLUSION

With increased awareness of common reversible causes of dementia, the screening studies to order, and the initial management of these disorders, the PA becomes well-placed to positively change the course of the patient's life (Table 2). It may not be possible to completely reverse cognitive impairment, but it is frequently possible to produce improvement or stabilization.
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Table 2. Clinical pearls
- The presence of normal arm swing differentiates normal pressure hydrocephalus from the gait of Parkinson disease.
- Hypothyroidism is common in the geriatric population.
- Normal vitamin B12 does not rule out deficiency; tests for homocysteine and methylmalonic acid levels are helpful.
- A diagnosis of pseudodementia may be facilitated by an empiric trial of antidepressant therapy for 8 to 12 weeks at therapeutic dosages.
- It is important to discover all medications and/or supplements that a patient is taking.
- With CNS infections, the only certainty is the variability in presentation with fluctuating cognitive impairment.
- Focal neurologic findings on examination warrant a search for intracranial masses and lesions.
- MRI and recommended screening laboratory tests should be done in all patients with the initial manifestation of a dementiform illness.
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Douglas Ladika and Samuel Gurevitz are assistant professors in the PA program at the College of Pharmacy and Health Sciences, Butler University, Indianapolis, Indiana. The authors have indicated no relationships to disclose relating to the content of this article.

DRUGS MENTIONED

Amitriptyline (Vanatrip, generics)

Bupropion (Aplenzin, Wellbutrin, generics)

Levothyroxine

Mirtazapine (Remeron, generics)

Sertraline (Zoloft, generics)

Topiramate (Topamax, generics)

Venlafaxine (Effexor, generics)


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