WORKUP	Section 5 of 11
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Lab Studies:

• As for any dementia evaluation, initial workup includes a vitamin B-12 level, thyroid function studies, fluorescent treponemal antibody testing for syphilis, and antinuclear antibodies (Nadeau, 1991).

• Rapid plasma reagent (RPR) and the Venereal Disease Research Laboratory (VDRL) test can be falsely negative in patients who are older than 65 years. Thus, a fluorescent treponemal antibody, which very rarely, if ever, produces false-negative results, should be performed instead.

• If prominent inattention is observed, the patient may have a toxic and/or metabolic encephalopathy rather than a true dementia. In such patients, obtain a urine toxicology screen, serum chemistry panel, complete blood count and differential count, liver function tests, ammonia level, and erythrocyte sedimentation rate.

• If the patient has parkinsonism or a movement disorder, the following tests can be added:
  • Ceruloplasmin (serum) and serum or urinary copper to exclude Wilson disease

  • Manual peripheral blood smear for acanthocytes

  • Genetic testing (consider for Huntington disease)

• Second-line workup includes cerebrospinal fluid examination (for chronic meningitis or elevated pressure) and HIV serology.

• If prominent inattention is present, obtain a metastatic cancer workup, electroencephalogram (EEG), and Lyme disease serology.

• Consider consultation by a social worker, geriatric case manager, or nurse practitioner.

• Third-line workup includes the following:

• Obtain evaluation by neuropsychologist, behavioral neurologist, or neuropsychiatrist.

• Consider and discuss brain biopsy in very select patients.

Imaging Studies:

• Brain computed tomography (CT) or magnetic resonance imaging (MRI)

• Order CT scan if MRI is contraindicated for the patient (eg, the patient has a pacemaker or metallic ocular implants).

• Otherwise check an MRI. Metastatic lesions and subcortical infarction (eg, caudate, thalamic) easily can be missed on CT scan.

• Functional brain image (eg, single-photon emission computed tomography [SPECT] scan) or physiologic imaging with positron emission tomography (PET scan) may be appropriate in some patients.

• In some patients with relatively isolated social-behavioral dysfunction, employers or others may require evidence of a medical disorder. Such patients may appear cognitively normal on objective neuropsychological tests, yet may be unable to function due to acquired brain disease.

• A SPECT scan may demonstrate relative hypometabolism in frontal and temporal areas (when other neuroimaging is normal), thus providing evidence of brain dysfunction.

Procedures:

• Lumbar puncture (cerebrospinal fluid examination) may be appropriate. Some memory disorder specialists perform this examination in every patient with frontal lobe or atypical dementia.

• Check pressure, cultures, cryptococcal antigen, and large-volume tap for cytology or acid-fast bacillus (AFB) if the clinical situation warrants such testing. If Alzheimer disease is suspected, tau protein or A-Beta 42 level may be ordered from the spinal fluid, although the exact sensitivity and specificity of these tests have not been established, and the tests should be ordered only if pretest and posttest counseling is available. Markers for Creutzfeldt-Jakob disease, CNS Whipple disease, progressive multifocal leukoencephalopathy (PML), and herpes encephalitis also can be ordered from the spinal fluid. Reports document that evaluating tau and amyloid protein in the CSF can distinguish Pick complex disorders from Alzheimer disease and nonpathologic states, but this has not been found to be a useful test, as it appears to be less sensitive than an informed clinical examination.

• Brain biopsy may be considered in exceptional circumstances if the diagnosis is in doubt and a treatment depends on the results. Occasionally, spinal fluid markers can obviate the need for a brain biopsy, even in these patients. Some of the factors mitigating for a brain biopsy include the following:
  • If diagnosis is in doubt (eg, faced with second- or third-line autoimmune therapy for neurosarcoidosis)

  • If a familial frontotemporal dementia is suspected

  • If the family desires

  • If treatment with significant adverse effects is being considered

Histologic Findings: See

	TREATMENT	Section 6 of 11
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Medical Care:

• On first evaluation, discontinue medications that can impair memory or cause confusion (eg, anticholinergic drugs, sedatives, benzodiazepines).

• Consider empiric treatment for symptoms that are consistent with depression and/or sleep disorders.

• Consider empiric treatment for herpes simplex encephalitis, if the onset is acute, especially if fever and seizures are also present.

• Consider administering thiamine empirically (100-300 mg IV/IM).

• On second evaluation, treat any systemic conditions that were identified and discuss performing a lumbar puncture and HIV testing with the patient and family.

• If prominent inattention is present and epilepsy is considered, consider further second-line workup, including EEG or an empiric trial of an anticonvulsant.

• Consider referral to a case manager, geriatric nurse practitioner, or other dementia resource person or group for social-family issues.

• On third evaluation, perform a lumbar puncture, treat any conditions identified on testing, and consider consultation with a behavioral neurologist or geriatric psychiatrist.

• Share dementia information and reading material with the family.

• Consider a brain biopsy if the diagnosis is in doubt or if substantial benefit results for the patient and/or family with a tissue diagnosis.

Activity: No restrictions on activity are necessary.

	MEDICATION	Section 7 of 11
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Unfortunately, no available drugs arrest or reverse the condition. Currently, practitioners use a combination of neuroprotective and symptomatic therapies.

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs) -- These agents act as neuroprotective agents that may prevent or delay the onset of degenerative dementias, according to several retrospective studies.

Drug Name	Ibuprofen (Ibuprin, Motrin, Advil) -- Inhibits inflammatory reactions and pain, probably by decreasing activity of the enzyme cyclooxygenase, which results in inhibition of prostaglandin synthesis. Other NSAIDs also may be helpful. No clear dosage recommendations are available based on existing literature.
Adult Dose	200-400 mg PO tid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; because of potential cross-sensitivity to other NSAIDs, do not administer to patients in whom aspirin, iodides, or other NSAIDs induce hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding
Interactions	Probenecid may increase concentrations and possibly toxicity of NSAIDs; may decrease effects of loop diuretics when administered concurrently; PT may increase when an NSAID is administered concurrently with anticoagulants; monitor for bleeding and obtain PT before administering an NSAID concomitantly with these types of medications; instruct patient to watch for signs and symptoms of bleeding; ibuprofen and other NSAIDs may increase serum lithium levels and risk of methotrexate toxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Category D in third trimester of pregnancy; caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in coagulation abnormalities or during anticoagulant therapy

Drug Category: Vitamins -- Cofactors necessary in metabolic reactions and essential for normal DNA synthesis, with some vitamins providing antioxidant effects.

Drug Name	Vitamin E (Vita-Plus E Softgels) -- May protect polyunsaturated acid in membranes from attack by free radicals.
Adult Dose	Although 1000 IU PO bid was used in a multicenter study showing potential effect to delay adverse events in Alzheimer disease, this dosage has not been compared with lower doses; recently, studies suggested that high doses of vitamin E may increase risk of death by other causes, and 200-400 IU daily is now a standard regimen for people with dementia.
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Anecdotal reports suggest addition of vitamin E causes increased INR in individuals taking Coumadin; in such patients, clinicians may wish to start at 800 IU and check INR after 4-5 d, adjust Coumadin as necessary, and then increase vitamin E by 800 IU until 2000 IU/d total dose is reached, monitoring INR
Pregnancy	A - Safe in pregnancy
Precautions	Large doses have been associated with a high incidence of necrotizing enterocolitis

Drug Name	Thiamine (Thiamilate) -- Essential coenzyme that combines with ATP to form thiamine pyrophosphate.
Adult Dose	100-300 mg IV/IM
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	A - Safe in pregnancy
Precautions	Sensitivity reactions can occur (intradermal test-dose recommended in suspected sensitivity); deaths have resulted from IV use; sudden onset or worsening of Wernicke encephalopathy, following glucose, may occur in thiamine-deficient patients; administer before or together with dextrose-containing fluids in suspected thiamine deficiency

Drug Category: Antidepressants -- Although SSRIs have been suggested for behavioral symptoms in these patients (eg, crave sweets, hypersexual) (Lebert, 2004; Litvan, 2001; Swartz, 1997), exercise care in using these agents in patients with parkinsonism, who may develop adverse effects of akathisia or dyskinesias.
Agents with mixed noradrenergic and serotonergic action may be helpful in treating patients with depression and frontal cognitive disorder.

Drug Name	Mirtazapine (Remeron) -- May be sedating, especially at the lower 15-mg dose, and may be useful for patients with agitation or disinhibition and depression.
Adult Dose	15 mg PO initially
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; MAOIs
Interactions	Increases sedative effects of alcohol, MAOIs, benzodiazepines, and other CNS depressants
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Exercise caution in patients with renal or hepatic dysfunction, seizure disorders, and in immunocompromised patients; inquire for symptoms of REM sleep behavior disorder, which may be triggered by SSRIs

Drug Name	Venlafaxine (Effexor) -- May be helpful for abulic patients who also have symptoms of depression or decreased initiative.
Adult Dose	37.5 mg PO bid initially
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; MAOIs within 14 d
Interactions	Cimetidine, MAOIs, sertraline, fluoxetine, class I-C antiarrhythmics, TCAs, and phenothiazine may increase effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Exercise caution in patients diagnosed with hepatic impairment, migraine, seizure disorders, cerebrovascular disorders, breast cancer, or thromboembolic disease; inquire for symptoms of REM sleep behavior disorder, which may be triggered by SSRIs

Drug Name	Trazodone (Desyrel) -- 5-HT2–receptor antagonist that inhibits reuptake of 5-HT. Negligible affinity for cholinergic, adrenergic, dopaminergic, or histaminic receptors. Good hypnotic properties. Effective in reducing agitation in patients with head trauma or dementia. Useful for sleep disturbances. Structurally unrelated to TCAs, tetracyclics, or MAOIs. Cardiac conduction effects of trazodone are qualitatively dissimilar and quantitatively less pronounced than TCAs and therefore are less toxic in overdose.
Adult Dose	50-75 mg PO qhs; increase to 200-300 mg PO qhs as tolerated
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May enhance response to alcohol, barbiturates, and other CNS depressants; digoxin and phenytoin serum levels may increase in patients receiving trazodone, concurrently; may decrease hypoprothrombinemic effects of warfarin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hypotension, including orthostatic hypotension and syncope, has occurred; may produce drowsiness, dizziness, or blurred vision; patients taking this medication should observe caution while driving or performing other tasks requiring alertness, coordination, or dexterity; inquire for symptoms of REM sleep behavior disorder, which may be triggered by SSRIs

Drug Category: Cholinergic agents -- Cholinergic therapy may be helpful for patients with aphasia (Tanaka, 1997), and preliminary studies indicate cholinesterase inhibitors may be useful for aphasia in Pick disease (Kertesz, 2005) and for other dementia-related symptoms in these patients (Lampl, 2004).

Drug Name	Donepezil (Aricept) -- Acetylcholinesterase inhibitor used in dementia of the Alzheimer type. Cholinergic stimulation may improve naming (Tanaka, 1997) and increase neuronal plasticity (Kilgard, 1998); thus, reasonable to attempt therapy in patients with primary progressive aphasia. Unfortunately, no clinical studies are available on the effect of donepezil in patients with Pick disease.
Adult Dose	5 mg PO qd initially
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; concurrent anticholinergic treatment, which is expected to nullify effect
Interactions	Effects of succinylcholine, cholinesterase inhibitors, or cholinergic agonists are increased when administered concurrently with donepezil
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Exercise caution in patients with seizures, asthma, sick sinus syndrome, or other supraventricular conduction abnormalities

Drug Category: Hormones -- May play beneficial role.

Drug Name	Conjugated estrogens (Premarin) -- Mode of action is unclear. May act to increase cerebral circulation as well as on neurotransmitter systems. In Alzheimer disease, estrogens administered from menopause may decrease incidence of disease. Unknown whether estrogen given later or in related conditions is beneficial.
Adult Dose	0.3-1.25 mg PO or more qd, depending on response of patient
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; male sex; some hormone-responsive tumors
Interactions	May reduce hypoprothrombinemic effect of anticoagulants; estrogen levels may be reduced with coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes; increase in corticosteroid levels may occur when administered concurrently with ethinyl estradiol; use of ethinyl estradiol with hydantoins may cause spotting, breakthrough bleeding, and pregnancy; increase in fluid retention caused by estrogen intake may reduce seizure control
Pregnancy	X - Contraindicated in pregnancy
Precautions	Estrogens must be cycled with progesterones; patient's primary medical doctor or gynecologist must monitor breast examinations and PAP smear

Drug Category: Dopaminergic agents -- Although these agents may worsen sexual or behavioral disinhibition, they may improve executive function, perseveration, and abulia (Imamura, 1998; McDowell, 1998; Drayton, 2004).

Drug Name	Bromocriptine (Parlodel) -- Semisynthetic ergot alkaloid derivative. Strong dopamine D2-receptor agonist. Partial dopamine D1-receptor agonist. Inhibits prolactin secretion with no effect on other pituitary hormones. May be given with food to minimize possibility of GI irritation. Approximately 28% absorbed from GI tract and metabolized in liver. Approximate elimination half-life is 50 h, with 85% excreted in feces and 3-6% eliminated in urine. Initiate at low dosage; slowly increase dosage to individualize therapy. Assess dosage titration every 2 wk. Gradually reduce dose in 2.5-mg decrements if severe adverse reactions occur.
Adult Dose	1.25 mg PO initially for 5-7 d, increase very slowly (over a month or more) to 2.5-5 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; ischemic heart disease; peripheral vascular disorders; psychosis; aggressiveness; violent behavior; uncontrolled hypertension; angina
Interactions	Toxicity may increase with ergot alkaloids; amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, reserpine; may decrease bromocriptine effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in renal or hepatic disease; rapid dose increase can be associated with nausea and vomiting; do not give after 6 pm (6 am/6 pm is a good schedule) as it will impair sleep and may be associated with vivid unpleasant dreams and disorganized nighttime behavior when taken at bedtime

Drug Name	Amantadine (Symmetrel) -- Inhibits N-methyl-D-aspartic acid (NMDA) receptor–mediated stimulation of acetylcholine release in rat striatum. May enhance dopamine release, inhibit dopamine reuptake, stimulate postsynaptic dopamine receptors, or enhance dopamine receptor sensitivity.
Adult Dose	100 mg PO qd; increase slowly over weeks to 100 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; renal failure
Interactions	Drugs with anticholinergic or CNS stimulant activity increase amantadine toxicity; the concurrent administration of hydrochlorothiazide plus triamterene with amantadine may increase plasma concentrations of amantadine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in liver disease, uncontrolled psychosis, eczematoid dermatitis, and seizures and in those receiving CNS stimulant drugs; reduce dose in renal disease when treating Parkinson disease; do not discontinue this medication abruptly; give second dose no later than 6 pm; may produce peripheral edema or delirium (discontinue if these symptoms are noted); livedo reticularis may be associated with this medication

	FOLLOW-UP	Section 8 of 11
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Further Inpatient Care:

• The second and third steps of the 3-step dementia workup also can be accomplished as an inpatient procedure.

• This is completed over 2 days with initial contact made by a case manager.

• It is particularly useful if the diagnosis is unclear, since referral for brain biopsy may be expedited.

Further Outpatient Care:

• Periodic follow-up care is indicated to manage problem behaviors or clinical problems of the patient, to support the caregiver, or to re-evaluate the diagnosis if it is in doubt.

• If paranoia, depression, or other behavioral problems manifest, pharmacologic treatments can be tailored to address these problems.

Complications:

• After diagnostic lumbar puncture, some patients with Pick disease and cerebral atrophy can develop a subdural hematoma.

• Observe for headache or change in mental status for several days after this procedure (some physicians admit for 23-h observation). If a subdural hematoma is suspected, perform a CT scan with and without contrast or an MRI scan with contrast.

Prognosis:

• Like most dementias, Pick disease is slowly progressive, leading to increased vocational and personal disability.

• Some patients can progress slowly over extremely long periods.

• Some may develop artistic or other talents during the course of their dementia, perhaps related to disinhibition of "creative" brain areas. Musical or artistic tastes also may change (eg, sudden interest in music intended for much younger listeners).

• Some may be capable of acquiring new knowledge or skills such as learning to use a computer-assisted simple communication system.

Patient Education:

• For excellent patient education resources, visit eMedicine's Dementia Center. Also, see eMedicine's patient education articles Pick Disease and Dementia Medication Overview.

	MISCELLANEOUS	Section 9 of 11
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Medical/Legal Pitfalls:

• Patients with progressive dementia should undergo neuroimaging sensitive enough to detect a structural lesion (eg, MRI in most patients, rather than a CT scan). Serologic testing for syphilis also should be strongly considered. Interim progression of these potentially treatable disorders can result in legal culpability.

Special Concerns:

• Consultation with a nurse practitioner or case manager experienced with dementia is indicated. If needed, such a person can be located through a local chapter of the Alzheimer's Association or the state Department of Aging.

• While the patient is able to participate, a family contact (eg, durable power of attorney) can be designated to decide care-giving and/or end-of-life issues.

• The nurse or case manager also can assist caregivers with stress management, teach behavioral techniques, refer to day programs, and assess a patient who may need to be admitted for short- or long-term management of behavioral problems.

• In situations where a strong family history of frontotemporal dementia or Pick disease is present, unaffected family members may desire genetic testing. It cannot be overstressed that this should only be performed after informed genetic counseling, preferably in a specialty center familiar with the genetics of dementing disorders. In this setting, testing may be of benefit (Steinbart, 2001).

	PICTURES	Section 10 of 11
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Caption: Picture 1. Motor perseveration in a patient with Pick disease. The patient is asked to copy the loops (as demonstrated by the examiner in the first line).
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Picture Type: Image

	BIBLIOGRAPHY	Section 11 of 11
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Pick Disease excerpt