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

THE CASE: A 72-year-old farmer is brought by his daughter for a comprehensivegeriatric assessment. His previous history is unremarkable. The patientreports that he has had vivid visual hallucinations, which he calls "visitors." He becomes frightenedand hostile when these incidents occur; on several occasions, he has exhibited violent behavioras persons around him tried to calm him. Although the patient was able to recall each episode indetail, 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 depressedbecause he is unable to participate in previous activities, such as driving and gardening. Hisdaughter describes fluctuations in cognition that result in "good" and "bad" days. She feels he ishaving a "good" day at the time of his evaluation.Examination reveals orthostatic hypotension with no change in pulse on standing. Cardiovascularexamination is otherwise unremarkable. Neurologic examination results are normal.Folstein Mini-Mental State Examination score is 20/30. Most notable are deficits in visuospatialability out of proportion to other cognitive deficits. The patient completed only a 4th-grade educationand 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 patternof cognitive impairment?Alzheimer dementia (AD) is themost common type of dementia; it affects50% to 70% of patients with dementia.This is followed by vasculardementia (VaD), dementia with Lewybodies (DLB) and frontotemporal dementia(FTD), which affect 10% to20%, 10% to 15%, and 5% to 15% of dementiapatients, respectively.Although there is no cure for dementia,it is a chronic disease processlike many others-such as diabetesand heart failure-in which a clinician'sguidance can have profoundimpact on a patient's symptomatologyand quality of life. Early detection isimportant because pharmacologicand nonpharmacologic measures canslow disease progression. However,unlike other medical illnesses, dementiais often not detected and addresseduntil its later stages. Becausedementia affects activities of daily living,patients can present with medicalnoncompliance and malnutrition longbefore physicians and family areaware of the presence of dementia.The diagnosis and treatment ofAD were reviewed in an earlier articlein this series (Consultant, March2004, page 388). The focus of thisarticle is the non-Alzheimer dementias:their diagnosis, treatment, andprognosis.The field of non-AD researchis evolving. Consensus groups fromthe fields of internal medicine, familypractice, geriatrics, psychiatry,and neurology agree that dementiamay be described as progressivedecline in 2 or more areas of cognitionto the point of impairmentin social or occupational functioning.There is also agreement on thesymptoms of AD. However, there isno consensus on the criteria fornon-Alzheimer dementias. Evidencebasedreviews show that currentclinical criteria are inadequate, becausemost lack sensitivity and/orspecificity compared with autopsydata. This article is based on currentclinical guidelines and providescommon language and definitionsfor use in the diagnosis and managementof dementia.VASCULAR DEMENTIA
This broad category includesmany vascular diseases that can leadto dementia (Table 1). Multi-infarctdementia is no longer classified as amajor type of dementia; it is now consideredone type of VaD.Neuroimaging studies complicatethe diagnosis because of thehigh prevalence of white matterchanges seen in these studies.These changes are not necessarilypathologic, nor are they always associatedwith clinical symptoms, buttheir presence may lead some cliniciansto overdiagnose VaD. It ismore likely that vascular disease ingeneral contributes to the clinicaloutcomes of dementia. This conclusionis based on the results of theNun Study, which showed that lacunarinfarcts increased the risk of clinicaldementia 20-fold, and that patientswith VaD had fewer senileplaques and neurofibrillary tanglesthan patients with AD before signsof dementia appeared. ¹History. Diagnosing VaD isstraightforward when patients havecognitive deficits after an obviouscerebrovascular event. However, thediagnosis is more challenging whenmultiple silent cerebral infarctionshave led to cognitive impairment. Infact, current guidelines do not includethis condition under the broad categoryof VaD, even though many cliniciansuse this criterion in practice.The controversy surrounding thisquestion continues to evolve. Urinarydysfunction and gait disturbance havebeen suggested as early markers ofVaD.²Diagnosis. The National Instituteof Neurological Disorders andStroke-Association Internationalepour la Recherche et l'Enseignementen Neurosciences (NINDS-AIREN)criteria are still widely used as a toolfor the diagnosis of VaD, even thoughthey lack sensitivity (Table 2). Becausememory may be only minimallyaffected, it is important to measureother areas of cognitive function,such as language, visuospatial ability,praxis, and executive function. Thepattern of cognitive deficits dependson the location of the cerebral injury.Gait impairment often presents asshort, shuffling steps similar to thoseseen in patients with Parkinson disease.Patients are more apatheticthan those with AD.Treatment. Regardless of the diagnosis,vascular risk factors-suchas diabetes and hypertension-shouldbe controlled to prevent ischemicdamage, especially in those with VaDresulting from ischemia. Progressionof the disease is highly variable. Someevidence suggests that cholinesteraseinhibitors slow disease progression.³DEMENTIA WITH LEWY BODIES
Although the criteria for DLB (Table 3) lack the sensitivity andspecificity of criteria for AD, it is importantthat a diagnosis be made-not only for family education but forprognosis and other clinical implicationsas well.History. Families often reportprominent behavioral and neuropsychiatricchanges before the onset ofshort-term memory loss. However,the order of symptom onset variesand may depend on the cortical locationof the Lewy bodies. Patients may also exhibit substantial fluctuations inalertness or cognition. A history ofrepeated falls, syncope, and neurolepticsensitivity suggests DLB. Patientstend to be more apathetic than thosewith AD. Many patients with DLBhave rapid eye movement (REM)sleep disorders.^4-6Diagnosis. On mental status examination,patients with DLB typicallyshow prominent behavioral changes,executive dysfunction, and visuospatialdysfunction out of proportion tomemory loss. Heightened sensitivityto neuroleptic agents predicts agreater likelihood of extrapyramidalside effects. Parkinsonism may ormay not be present at the time of evaluation.Rigidity is seen in about 75% ofpatients; tremor is atypical. Neuroimagingis usually part of the workup.Treatment. The recommendedapproach involves management of theprominent symptoms. Some evidencesuggests that treatment with cholinesteraseinhibitors is associated withdiminished hallucinations and improvementsin behavior and cognition.7 Antiparkinsonian medications,such as levodopa, which may be necessaryto treat prominent motorsymptoms, usually exacerbate hallucinationsand confusion. To managepsychotic symptoms, it is best to reduceor eliminate the antiparkinsonianmedications first. However, in order toavoid neuroleptic sensitivity, psychoticsymptoms should be treated only ifthey are disturbing to the patient.Neuroleptic medications such as quetiapine,which are less likely to causeextrapyramidal side effects, may alsobe helpful in mitigating psychoticsymptoms. If a REM sleep disorder ispresent, low-dose clonazepam can behelpful. Selective serotonin reuptakeinhibitors (SSRIs) are the agents ofchoice for anxiety or depression.DLB usually progresses morerapidly than AD; however, the durationvaries greatly. The average is 6.4years. Patients' insight into theirdeficits can make it difficult for familiesto implement a care plan thatmay decrease patients' independence.The fluctuations in cognition can alsomake caregiving extremely difficultbecause of the unpredictable natureof the disease process.FRONTOTEMPORAL DEMENTIA
Pick disease was the initial prototypefor this category of dementia,but several similar clinical syndromeshave been identified that do not havethe same pathologic changes seen inPick disease. These are now subsumedunder the rubric of FTD.History. Patients typically presentwith prominent frontal lobechanges, such as personality and languagedisturbances (Table 4).Thehallmark behavioral change is poorjudgment. In addition, patients usuallydemonstrate either disinhibition orapathy. Families often report sociallyinappropriate actions or language.Drastic personality changes mayoccur long before memory impairmentbecomes apparent. Executivedysfunction and prominent languageabnormalities are also reported.Diagnosis. Because FTD is uncommon,it has been more difficultto evaluate the diagnostic criteria. Inresearch, functional imaging withsingle-photon emission CT andpositron emission tomography canincrease confidence in a clinical diagnosis;however, these tools havelimited use in office practice. Neuropsychologicaltesting and sometimesgeropsychiatric evaluation may beconsidered for patients with suspectedFTD.Treatment. The course is progressiveand tends to be more rapidthan that of AD. No treatment is currentlyavailable.CREUTZFELDT-JAKOB DISEASE