Online newspaper of professor Yasser Metwally

The author: Professor Yasser Metwally

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INTRODUCTION

Background:

• Pick disease (Friedel Pick) is a progressive dementia that is defined by clinical and pathologic criteria.

• Unlike Alzheimer’s disease and other dementias that present with cognitive deficits localized to the posterior (parietal) cortex, Pick disease typically affects the frontal and/or temporal lobes.

• First described in 1892, Pick disease is now considered by some to be part of a “complex” of neurodegenerative disorders with similar or related histopathological and clinical features (Kertesz, 1994 and 1997).

• Nomenclature history:

  • Frontotemporal dementia (of which Pick disease is an example) is a broader term including Pick disease.

  • Frontal lobe dementia is a term signifying neuropsychological features localizing to the frontal lobes.

  • Clinically, Pick disease may be identical or very similar to “Frontal lobe degeneration” (Miller, 1991).

  • Some cases diagnosed premorbidly as “Pick” are shown pathologically to be progressive subcortical gliosis (Neumann and Cohn, 1967).

  • Other cases may be diagnosed pathologically as dementia lacking distinctive histopathology (Knopman, 1990)

  • A clinical/genetic nosology includes frontotemporal dementia linked to chromosome 17 (Foster, 1997)

  • Primary progressive aphasia (Weintraub, 1990) is a “focal atrophy” syndrome that may be associated with Pick, Alzheimer, or other pathology; clinically the deficit appears restricted to the frontal and/or temporal lobes.

Pathophysiology:

• Pick disease is defined pathologically by severe atrophy, neuronal loss, and gliosis. Swollen (ballooned) neurons (Pick cells) and argentophilic neuronal inclusions known as Pick bodies (Jellinger, 1995; Jackson and Lowe, 1996) disproportionally affect the frontal and temporal cortical regions.

Figure 1. A, Pick’s disease with the gross appearance of lobar atrophy is seen here involving the frontal lobe. Note the “knife like” gyri. B, Pick’s disease is demonstrated grossly in this coronal section in which there is marked atrophy with ex vacuo ventricular dilation. (Click to magnify figure)

Frequency:

• In the US:

  • Ten to 15 percent of demented individuals have clinical characteristics suggestive of Pick disease.

  • Pick disease is the third most common neurodegenerative cortical dementia after Alzheimer’s disease and diffuse Lewy Body disease (Neary, 1998), and the fourth most common if non-neurodegenerative (vascular) dementia is included (Roman, 1993).

  • After death, only about 5-7% of people meeting clinical criteria for the diagnosis of Pick Disease will meet strict neuropathological criteria for the diagnosis (Litvan, 1997)

  • In some clinical settings, the majority of patients with autopsy-confirmed Pick disease have been diagnosed during life as having Alzheimer’s disease or another neurodegenerative illness (Litvan, 1997).

• Internationally: Familial forms of this disease may occur more frequently in Europe (particularly in Scandinavian nations). In a recent study in the Netherlands, the prevalence was only 28 per 100,000 persons (Stevens, 1998).

Mortality/Morbidity:

• The disorder is progressive and invariably leads to increasing disability.

• In some individuals whose main symptoms are a disturbance of speech and language (primary progressive aphasia), the clinical course can be slow. The patient’s ability to function at home may be spared for ten or more years post-onset.

Race:

• Familial forms of Pick-complex dementias, linked to chromosome 17q, may be particularly common in people of Scandinavian origin/descent.

• It may represent up to 17% of dementias in these populations.

Sex: No gender preponderance

Age:

• Pick disease occurs in a younger age group than dementia of the Alzheimer type.

• Peak incidence occurs between 55-65 years of age and in most cases Pick disease often presents before 70 years of age.

CLINICAL PICTURE

History:

• The onset of behavioral and cognitive dysfunction is insidious.

• The primary impairment in cognition does not normally involve an abnormal level of consciousness or distractibility. Such a finding is more consistent with an attentional dementia (Nadeau, 1991) or a confusional state/dementia.

• Clinical course during the first 2 years:

  • Psychiatric abnormalities that seem to respect the pattern of the classical frontal lobe syndromes (Gregory and Hodges, 1996).

    • Patients with orbitofrontal dysfunction become aggressive and socially inappropriate. They may steal or demonstrate obsessive or repetitive, stereotyped behaviors.

    • Patients with dorsomedial or dorsolateral frontal may demonstrate a lack of concern, apathy or decreased spontaneity.

    • Patients may be depressed early in the disease.

    • These mood changes can predate amnesia.

  • Speech and language abnormalities often begin early and progress rapidly.

    • Patients usually have relatively little limb apraxia and/or visuospatial dysfunction, thus distinguishing them from patients with diffuse bihemispheric impairment.

    • Even memory impairment is relatively less severe than speech/language and behavioral changes.

  • Incontinence can occur early. In contrast, continence is generally preserved in mild to moderate Alzheimer’s disease.

  • Parkinsonism with its concomitant history of rigidity and gait impairment can occur.

    • Severe Parkinsonism suggests an alternate diagnosis such as corticobasal ganglionic degeneration, diffuse Lewy Body disease, or progressive supranuclear palsy.

Physical: The general physical often shows the patient to be unkempt at an earlier stage than in comparably impaired Alzheimer’s patients.

• Abnormal spontaneous behaviors observed during examination may include the following:

  • “Witzelsucht” or inappropriate jocularity

  • Echolalia (repeating the examiner’s words), echopraxia (imitating the examiner’s gestures: Lhermitte, 1983, Shimomura and Mori, 1998) and other disinhibited approach or utilization behaviors.

• General neurological examination may include some of the following abnormalities:

  • Primitive reflexes such as grasp, suck, snout (Sjogren, 1997)

  • Motor examination: akinesia, plastic rigidity or paratonia (Beversdorf and Heilman, 1998).

  • Resting tremor is uncommon and its presence suggests Parkinsons Disease or a Parkinson-Plus syndrome.

• Mental status/neuropsychological examination:

  • Verbal output is often nonfluent.

    • Most patients have difficulty in naming common objects or pictures (anomia).

    • Spontaneous speech can be sparse yet “fluent” in character, with preserved grammar (logopenia).

  • Perseveration (cognitive and motor: see picture below for an example of motor perseveration)

  • Relatively preserved visuospatial and visual orientation skills

Causes:

• The specific cause is unknown.

• In families with an inherited frontal lobe dementia (some of which pathologically or clinically were indistinguishable from Pick disease), linkage to markers on chromosome 17q21-22 has been reported (Lynch, 1994; Foster, 1997).

  • These familial disorders are heterogenous in different family members. Some members may present primarily with amyotrophy, others with primary supranuclear gaze palsy, Parkinsonism, schizophrenia-like thought disorder, or progressive aphasia/ apraxia.

WORK-UP

Lab Studies:

• Initial workup includes, as for any dementia evaluation, a B12 level, thyroid function studies, fluorescent treponemal antibody testing for syphilis, and antinuclear antibodies (Nadeau, 1991)

  • RPR, VDRL can be falsely negative in patients who are over 65 years of age. Thus, a fluorescent treponemal antibody, which very rarely, if ever, is false negative, should be performed instead.

  • If prominent inattention is seen, the patient may have a toxic /metabolic encephalopathy rather than a true dementia. Such patients should receive 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’s disease

    • Manual peripheral blood smear for acanthocytes

    • Consider genetic testing for Huntington disease

• Second line workup: Cerebrospinal fluid examination (for chronic meningitis or elevated pressure), HIV serology. If prominent inattention, check the following:

  • Metastatic cancer workup

  • Electroencephalogram (EEG)

  • Lyme disease serology

  • Consultation by social worker or geriatric case manager, nurse practitioner

• Third line workup:

  • Evaluation by neuropsychologist, behavioral neurologist, or neuropsychiatrist

  • Consider and discuss brain biopsy in very select cases

Imaging Studies:

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

  • Order CT if MRI is contraindicated for that patient, for example, if they have a pacemaker or metallic ocular implants.

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

Figure 2. A case with Picks dementia showing central and cortical atrophy associated with fronto-temporal signal changes on the MRI T2 images (Click to magnify figure)

• Functional brain image (eg, single photon emission computerized tomography (SPECT) scan) or physiological imaging with emission tomography (PET scan) may be appropriate in some cases.

  • 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 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:

• Spinal tap (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, large-volume tap for cytology or AFB if clinical situation warrants. If Alzheimer’s disease is suspected, tau protein or A-Beta 42 level may be ordered from the spinal fluid, though the exact sensitivity and specificity of these tests has not been established, and the tests should be ordered only if pre and post test counseling is available. Markers for Creutzfeldt-Jacob disease, CNS Whipple disease, PML, and Herpes encephalitis can also be ordered from the spinal fluid.

  • Brain biopsy may be considered in exceptional circumstances if the diagnosis is in doubt and a treatment hangs in the balance. Occasionally spinal fluid markers can obviate the need for a brain biopsy even in these cases. Some of the factors mitigating for a brain biopsy include:

  • If diagnosis is in doubt (eg, faced with second- or third-line autoimmune therapy for neurosarcoidosis)

  • If a familial frontal-temporal dementia is suspected

  • If the family desires

  • If treatment with significant side effects is being considered

Histologic Findings: See pathophysiology.

MANAGEMENT

Medical Care:

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

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

  • Consider empirical 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 IM/IV.

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

  • If there is prominent inattention and epilepsy is considered, consider further second line work-up, including electroencephalography (EEG) or an empirical 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 spinal tap, 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 there will be substantial benefit to the patient and/or family with a tissue diagnosis.

Consultations:

• Geriatric or Psychiatric Case Manager (Social Worker) or Nurse Practitioner

• Neuropsychologist, Behavioral Neurologist, Geriatric- or Neuro-psychiatrist

• For patients with progressive aphasia: speech pathologist for family and patient education and, in rare cases, referral for a computerized communication assistive device

Diet: High sugar content foods may need to be restricted in some patients with carbohydrate craving, which may indicate the Klüver-Bucy syndrome.

Activity: No restrictions

MEDICATION

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

Drug Category: Antidepressants – Although selective serotonin reuptake inhibitors (SSRIs) have been suggested for patients with evidence of serotonergic deficiency (crave sweets, hypersexual), care should be exercised in using these agents in patients with Parkinsonism, who may develop the side-effects of akathisia or dyskinesias.

FOLLOW-UP

Further Inpatient Care:

• The second and third steps of the 3-step dementia work-up can also 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 is indicated, to manage problem behaviors or clinical problems of the patient, to support the caregiver, or to re-evaluate the diagnosis is it was ever in doubt.

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

Complications:

• After diagnostic lumbar puncture (LP), 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-hour observation). If a subdural hematoma is suspected, a CT scan with and without contrast or an MRI scan with contrast should be performed.

Prognosis:

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

• Some patients can slowly progress 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.

• Some may acquire new knowledge or skills such as learning to use a computer-assisted, simple communication system.

References

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