The Non-Alzheimer Dementias:
An Approach to Evaluation and Management

THE CASE: A 72-year-old farmer is brought by his daughter for a comprehensive geriatric assessment. His previous history is unremarkable. The patient reports that he has had vivid visual hallucinations, which he calls "visitors." He becomes frightened and hostile when these incidents occur; on several occasions, he has exhibited violent behavior as persons around him tried to calm him. Although the patient was able to recall each episode in detail, he felt as if he had watched it from a distance and had not been an active participant. The patient also has experienced dizziness on standing and repeated falls. He is depressed because he is unable to participate in previous activities, such as driving and gardening. His daughter describes fluctuations in cognition that result in "good" and "bad" days. She feels he is having a "good" day at the time of his evaluation. Examination reveals orthostatic hypotension with no change in pulse on standing. Cardiovascular examination is otherwise unremarkable. Neurologic examination results are normal. Folstein Mini-Mental State Examination score is 20/30. Most notable are deficits in visuospatial ability out of proportion to other cognitive deficits. The patient completed only a 4th-grade education and is unable to spell "world" or write a sentence. He misses 1 of 3 items on delayed recall. He is unable to organize a clock drawing. What is the differential diagnosis for this pattern of cognitive impairment? Alzheimer dementia (AD) is the most common type of dementia; it affects 50% to 70% of patients with dementia. This is followed by vascular dementia (VaD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD), which affect 10% to 20%, 10% to 15%, and 5% to 15% of dementia patients, respectively. Although there is no cure for dementia, it is a chronic disease process like many others-such as diabetes and heart failure-in which a clinician's guidance can have profound impact on a patient's symptomatology and quality of life. Early detection is important because pharmacologic and nonpharmacologic measures can slow disease progression. However, unlike other medical illnesses, dementia is often not detected and addressed until its later stages. Because dementia affects activities of daily living, patients can present with medical noncompliance and malnutrition long before physicians and family are aware of the presence of dementia. The diagnosis and treatment of AD were reviewed in an earlier article in this series (Consultant, March 2004, page 388). The focus of this article is the non-Alzheimer dementias: their diagnosis, treatment, and prognosis. The field of non-AD research is evolving. Consensus groups from the fields of internal medicine, family practice, geriatrics, psychiatry, and neurology agree that dementia may be described as progressive decline in 2 or more areas of cognition to the point of impairment in social or occupational functioning. There is also agreement on the symptoms of AD. However, there is no consensus on the criteria for non-Alzheimer dementias. Evidencebased reviews show that current clinical criteria are inadequate, because most lack sensitivity and/or specificity compared with autopsy data. This article is based on current clinical guidelines and provides common language and definitionsfor use in the diagnosis and management of dementia. VASCULAR DEMENTIA
This broad category includes many vascular diseases that can lead to dementia (Table 1). Multi-infarct dementia is no longer classified as a major type of dementia; it is now considered one type of VaD. Neuroimaging studies complicate the diagnosis because of the high prevalence of white matter changes seen in these studies. These changes are not necessarily pathologic, nor are they always associated with clinical symptoms, but their presence may lead some clinicians to overdiagnose VaD. It is more likely that vascular disease in general contributes to the clinical outcomes of dementia. This conclusion is based on the results of the Nun Study, which showed that lacunar infarcts increased the risk of clinical dementia 20-fold, and that patients with VaD had fewer senile plaques and neurofibrillary tangles than patients with AD before signs of dementia appeared. ¹ History. Diagnosing VaD is straightforward when patients have cognitive deficits after an obvious cerebrovascular event. However, the diagnosis is more challenging when multiple silent cerebral infarctions have led to cognitive impairment. In fact, current guidelines do not include this condition under the broad category of VaD, even though many clinicians use this criterion in practice. The controversy surrounding this question continues to evolve. Urinary dysfunction and gait disturbance have been suggested as early markers of VaD.² Diagnosis. The National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria are still widely used as a tool for the diagnosis of VaD, even though they lack sensitivity (Table 2). Because memory may be only minimally affected, it is important to measure other areas of cognitive function, such as language, visuospatial ability, praxis, and executive function. The pattern of cognitive deficits depends on the location of the cerebral injury. Gait impairment often presents as short, shuffling steps similar to those seen in patients with Parkinson disease. Patients are more apathetic than those with AD. Treatment. Regardless of the diagnosis, vascular risk factors-such as diabetes and hypertension-should be controlled to prevent ischemic damage, especially in those with VaD resulting from ischemia. Progression of the disease is highly variable. Some evidence suggests that cholinesterase inhibitors slow disease progression.³ DEMENTIA WITH LEWY BODIES
Although the criteria for DLB (Table 3) lack the sensitivity and specificity of criteria for AD, it is important that a diagnosis be made- not only for family education but for prognosis and other clinical implications as well. History. Families often report prominent behavioral and neuropsychiatric changes before the onset of short-term memory loss. However, the order of symptom onset varies and may depend on the cortical location of the Lewy bodies. Patients may also exhibit substantial fluctuations in alertness or cognition. A history of repeated falls, syncope, and neuroleptic sensitivity suggests DLB. Patients tend to be more apathetic than those with AD. Many patients with DLB have rapid eye movement (REM) sleep disorders.^4-6 Diagnosis. On mental status examination, patients with DLB typically show prominent behavioral changes, executive dysfunction, and visuospatial dysfunction out of proportion to memory loss. Heightened sensitivity to neuroleptic agents predicts a greater likelihood of extrapyramidal side effects. Parkinsonism may or may not be present at the time of evaluation. Rigidity is seen in about 75% of patients; tremor is atypical. Neuroimaging is usually part of the workup. Treatment. The recommended approach involves management of the prominent symptoms. Some evidence suggests that treatment with cholinesterase inhibitors is associated with diminished hallucinations and improvements in behavior and cognition. 7 Antiparkinsonian medications, such as levodopa(Drug information on levodopa), which may be necessary to treat prominent motor symptoms, usually exacerbate hallucinations and confusion. To manage psychotic symptoms, it is best to reduce or eliminate the antiparkinsonian medications first. However, in order to avoid neuroleptic sensitivity, psychotic symptoms should be treated only if they are disturbing to the patient. Neuroleptic medications such as quetiapine(Drug information on quetiapine), which are less likely to cause extrapyramidal side effects, may also be helpful in mitigating psychotic symptoms. If a REM sleep disorder is present, low-dose clonazepam(Drug information on clonazepam) can be helpful. Selective serotonin reuptake inhibitors (SSRIs) are the agents of choice for anxiety or depression. DLB usually progresses more rapidly than AD; however, the duration varies greatly. The average is 6.4 years. Patients' insight into their deficits can make it difficult for families to implement a care plan that may decrease patients' independence. The fluctuations in cognition can also make caregiving extremely difficult because of the unpredictable nature of the disease process. FRONTOTEMPORAL DEMENTIA
Pick disease was the initial prototype for this category of dementia, but several similar clinical syndromes have been identified that do not have the same pathologic changes seen in Pick disease. These are now subsumed under the rubric of FTD. History. Patients typically present with prominent frontal lobe changes, such as personality and language disturbances (Table 4).The hallmark behavioral change is poor judgment. In addition, patients usually demonstrate either disinhibition or apathy. Families often report socially inappropriate actions or language. Drastic personality changes may occur long before memory impairment becomes apparent. Executive dysfunction and prominent language abnormalities are also reported. Diagnosis. Because FTD is uncommon, it has been more difficult to evaluate the diagnostic criteria. In research, functional imaging with single-photon emission CT and positron emission tomography can increase confidence in a clinical diagnosis; however, these tools have limited use in office practice. Neuropsychological testing and sometimes geropsychiatric evaluation may be considered for patients with suspected FTD. Treatment. The course is progressive and tends to be more rapid than that of AD. No treatment is currently available. CREUTZFELDT-JAKOB DISEASE
History. Patients present with a rapidly progressive dementia. Diagnosis. The classic triad of CJD involves dementia, myoclonus, and a distinctive periodic discharge pattern on electroencephalography. At least 2 of the following motor disturbances must be present for the diagnosis: myoclonus, extraocular or cerebellar disturbance, pyramidal/extrapyramidal dysfunction, and akinetic mutism. A positive 14-3-3 assay for cerebrospinal fluid is included in the diagnostic criteria; however, a negative assay does not rule out CJD. vCJD has atypical clinical features: the presence of prominent psychiatric or sensory symptoms at the time of clinical presentation or early in the course of the illness, delayed onset of neurologic abnormalities, duration of illness of at least 6 months, and a diffusely abnormal nondiagnostic electroencephalogram. Treatment. No treatment is currently available. OTHER DEMENTIAS
Other causes of dementia are found in fewer than 1% of patients with dementia (Table 5). RESOURCES FOR SUPPORT Although current treatments for dementia do not affect the underlying disease process, a clinician's knowledge of the various types of dementia and their key features can assist families and patients in their understanding of certain behaviors. If the diagnosis is made early enough, understanding the disease helps patients participate in planning for future care. As the diseases progresses, family members can benefit from understanding how dementia affects cognitive function. Although making the correct diagnosis and providing appropriate treatment are important, providing the caregiver with guidance and support is even more challenging and more critical. Most primary care clinicians are not able to provide ongoing support. However, a number of local and national organizations offer this help. The National Association of Area Agencies on Aging (www.n4a.org or 800-677-1116) and the Alzheimer's Association (www.alzheimers.org or 800-272-3900) are excellent places to start. The Alzheimer's Association assists caregivers of patients with AD as well as those with other types of memory loss. In some areas, local geriatric assessment centers are equipped with the resources for ongoing caregiver support. OUTCOME OF THIS CASE
A diagnosis of DLB was made. The patient's CT scan and laboratory data were unremarkable. The patient was given quetiapine to help manage his hallucinations and to help limit neuroleptic sensitivity. With weekly dosage increases, the hallucinations were eventually controlled. Donepezil(Drug information on donepezil) was initiated on the return visit. The patient's depression improved withthe addition of an SSRI. A safety check was done in the patient’s home to prevent falls. He was instructed to rise slowly from a seated position and pump his fists and legs before rising to prevent orthostatic hypotension. Both measures helped when the patient remembered to do them. One year later, the patient was still living at home and was able to function independently. Visual hallucinations persisted but were no longer threatening. The violent outbursts have not recurred.