Don't forget non-Alzheimer dementias
ABSTRACTDementia is commonly encountered in the elderly, with prevalence increasing with age. Although Alzheimer disease is the most recognized form of dementia, other types have distinct clinical features and are often overlooked. Proper identification aids patients, caregivers, and physicians in planning and management.
KEY POINTS
- Vascular dementia presents as a sudden, stepwise progression of cognitive deficits.
- Lewy body dementia often involves prominent visual hallucinations.
- Progressive supranuclear palsy starts with gait and balance problems caused by downward-gaze palsy.
- Many neurodegenerative conditions involve parkinsonism, but unlike Parkinson disease, they do not tend to respond well to levodopa, and dementia develops early.
- Corticobasal degeneration involves markedly asymmetric parkinsonism.
- Frontotemporal dementia involves dramatic behavior changes, including inappropriate impulsivity and complete apathy.
- Patients with rapidly progressive dementia should be evaluated for a treatable condition such as antibody-mediated encephalitis.
FRONTOTEMPORAL DEMENTIA
Frontotemporal dementia frequently starts before age 65 and accounts for 20% to 50% of dementias in this age group.52 Recognition of the condition in older patients is also growing.53 Frontotemporal dementia encompasses a spectrum of dementias, including behavioral variant frontotemporal dementia, semantic dementia, and progressive nonfluent aphasia.54
Gradual onset of uncharacteristic behaviors
Accepted diagnostic criteria include core features of gradual onset, early decline in social and interpersonal conduct, early impairment of self-regulation, emotional blunting, and loss of insight. Many patients are diagnosed with psychiatric conditions. Changes reported by family and caregivers typically deviate substantially from the person’s usual behavior, such as impulsive and inappropriate behaviors or complete withdrawal and apathy.
Language sometimes affected in frontotemporal dementia
Language impairment may be present in some variants. Behavioral and language changes often accompany other forms of dementia (Alzheimer disease, vascular dementia, primary progressive aphasia), making diagnosis more challenging. Office-based testing often does not reveal any deficits, although the Frontal Behavioral Inventory may help.55 A referral to a clinical neuropsychologist may help identify and quantify cognitive impairments.
MRI shows frontotemporal lobes affected
Structural neuroimaging may not reveal abnormalities initially, but with progression, atrophy may be seen in the frontal and temporal lobes. Functional neuroimaging (positron emission tomography, brain SPECT, functional MRI) show hypometabolism in the same areas.
Treat symptoms
There are no specific FDA-approved therapies for frontotemporal dementia. Acetylcholinesterase inhibitors can help progressive nonfluent aphasia in some cases. Selective serotonin reuptake inhibitors may alleviate depressive symptoms, and low doses of atypical antipsychotic medications may help with impulsivity, disinhibition, and aggressive or disruptive behaviors.56
PRIMARY PROGRESSIVE APHASIA
Language impairment predominates
Primary progressive aphasia is a rare form of dementia in which symptoms typically develop around age 60. Pathology is varied. In a study of 60 patients with initial clinical symptoms of primary progressive aphasia, postmortem histology of brain tissue revealed various findings, including those consistent with Alzheimer pathology and motor neuron diseasetype inclusions.57
Patients typically present with expressive language problems as the primary deficit for the first 2 years of the disease, with preservation in other cognitive areas such as memory, visuospatial skills, and executive function.58 Office-based testing may overstate the severity of the dementia, given the dependence of performance on intact language.
It is important to distinguish primary progressive aphasia from other dementias that also affect language. In the frontal variant of frontotemporal dementia, the primary language problem is anomia (inability to name objects) or diminished speech output, which may be accompanied by behavioral problems. Semantic dementia affects word recognition as well as comprehension. In Alzheimer disease, language may be affected along with memory and other areas of cognitive function.
Imaging shows focal degeneration in the left hemisphere
Structural neuroimaging does not initially reveal any deficits, but later it may reveal atrophy in the frontal, perisylvian complex, and temporal areas of the left hemisphere, reflecting the focal nature of the degeneration.59 Functional neuroimaging (positron emission tomography, SPECT) may reveal hypometabolism or diminished blood flow in these areas prior to changes in structural neuroimaging.60
Other communication methods may help
There are no FDA-approved therapies for primary progressive aphasia. Off-label use of some agents (eg, selective serotonin reuptake inhibitors and small doses of antipsychotic medications) has been found useful in small trials.56 Patients may benefit from learning other forms of communication, such as using sign language, laminated cards with printed words or pictures, or artificial voice synthesizers, to express their needs.
NORMAL-PRESSURE HYDROCEPHALUS
Classic triad: Gait, cognition, incontinence
With the onset of symptoms in the sixth or seventh decade, normal-pressure hydrocephalus affects less than 1% of people age 65 and older. It represents up to 5% of dementias, although estimates are influenced by the varied criteria for diagnosis.61 It is characterized by the classic triad of gait impairment, cognitive impairment, and urinary frequency or incontinence.62
Symptoms progress over a period of years, with gait impairment often predominating. As this triad is common in the geriatric population, identifying other explanations is important. Gait impairment caused by spinal stenosis, peripheral neuropathy, or parkinsonism should be explored. Cognitive impairment could be due to depression, Alzheimer disease, or other forms of dementia. Urinary symptoms may be related to detrusor instability or an enlarged prostate.
Gait impairment initially manifests as slowing of gait, but progresses to difficulty with gait initiation. Gait tends to be wide-based (stance more than 1 foot wide).
Cognitive impairment is typically subcortical, manifested as slowed processing speed and impaired executive function. Recall and working memory may be impaired.
Enlarged ventricles seen on imaging in normal-pressure hydrocephalus
Structural neuroimaging reveals enlarged ventricles (Evan’s ratio > 0.358). This can be difficult to distinguish from ventriculomegaly due to cerebral atrophy; assessing the callosal angle on MRI may distinguish the two.63,64 Diagnosis of normal-pressure hydrocephalus can be confirmed using a cerebrospinal fluid infusion test to assess resistance of fluid to resorption.65
Treat with cerebrospinal fluid drainage
Specific tests should be performed to determine candidacy for surgery. These include a high-volume lumbar puncture (40 to 50 mL) or a trial of external lumbar drainage (10 mL per hour for 48 to 72 hours).65 Definitive treatment is surgical placement of a shunt to allow cerebrospinal fluid to drain into the atria or peritoneal cavity.
Surgery may improve gait, but cognitive symptoms often remain,66 and clinical decline may occur after the shunt is placed. Once gait dysfunction is resolved, other explanations for cognitive impairment or residual gait impairment should be considered. An underlying reason for progression of normal-pressure hydrocephalus symptoms after surgical intervention should be identified.67
RAPIDLY PROGRESSIVE DEMENTIAS
Rapidly progressive dementias are among the most challenging of dementing illnesses. They are characterized by a subacute course and an accelerated rate of decline, developing in less than 2 years. Evaluation should typically be more comprehensive than for other types of dementia. The main goal is to diagnose potentially treatable conditions, such as Hashimoto encephalopathy or paraneoplastic limbic encephalitis, and to distinguish these conditions from diseases with a very poor prognosis, such as Creutzfeldt-Jakob disease.
Creutzfeldt-Jakob disease
Creutzfeldt-Jakob disease is a fatal prion-related neurodegenerative illness. Sporadic disease is most common, but variant, familial, and iatrogenic types have been reported. The most common initial symptoms in sporadic disease are cognitive (39%), cerebellar (21%), behavioral (20%), constitutional (20%), sensory (11%), motor (9%), and visual (7%).68
Chronic neurodegenerative diseases can be misdiagnosed as Creutzfeldt-Jakob disease because of an atypical time course and multi-system neurologic findings.
The US Centers for Disease Control and Prevention has adopted criteria for diagnosing probable Creutzfeldt-Jakob disease (Table 3). Routine investigations should also not suggest an alternative diagnosis.69
Autoimmune diseases
Autoimmune conditions may present as a rapidly progressive dementia, including Hashimoto encephalopathy and antibody-mediated limbic encephalitis, either associated with cancer (paraneoplastic) or without cancer (nonparaneoplastic).
Paraneoplastic limbic encephalitis is a group of inflammatory conditions involving antibodies produced within the cerebrospinal fluid and serum resulting in neurologic symptoms. These antibodies react against proteins expressed mostly by a tumor somewhere else in the body.70
Hashimoto encephalitis is a subacute to chronic encephalopathy that may present as dementia with abnormally high levels of thyroid antibodies. The symptoms can vary from confusion to psychosis. There are two main presentations: one involves a relapsing-remitting course with stroke-like episodes (27% of patients) and the second consists of insidious onset of seizures (66% of patients).
Diagnosis involves testing for elevated anti-thyroid peroxidase and thyroglobulin antibodies. MRI findings are nonspecific. Hashimoto encephalitis responds to treatment with corticosteroids, plasmapheresis, or immunosuppressive therapy.71
