Correspondence
Correction
Evaluation of Suspected Dementia
N Engl J Med 1996; 335:1996-1998December 26, 1996
- Article
To the Editor:
In their review of the evaluation of dementia (Aug. 1 issue),1 Geldmacher and Whitehouse expressed their “opinion . . . that apolipoprotein E testing will not be ready for clinical use as either a predictive or a diagnostic test until better population-based estimates of risk and appropriate genetic counseling are available.” There is virtual unanimity regarding the lack of support for apolipoprotein E genotyping in the prediction of asymptomatic persons — whether or not they have relatives with Alzheimer's disease.2 No apolipoprotein E genotype predicts accurately whether or when Alzheimer's disease will develop. However, the rationale for using apolipoprotein E genotyping for diagnosis is quite different.2,3
Four separate studies have found that the positive predictive value of carrying an apolipoprotein E ε4 allele is 96 to 100 percent, despite different strategies of ascertainment3-5 (and Welsh-Bohmer KA, et al.: unpublished data). More autopsy-confirmed series are needed to establish the confidence limits, but any diagnostic test that can accurately predict the eventual neuropathologic diagnosis with a positive predictive value of more than 95 percent cannot be ignored.
Given that diagnostic resources are no longer considered unlimited, can we justify not using a highly specific, relatively inexpensive, diagnostic adjunct that has useful positive predictive value for more than half the patients? The current routine evaluation of dementia, especially the use of low-yield imaging studies, is designed to find uncommon causes. Now, with genetic information, it may be time to modify the paradigm. A standard diagnostic evaluation consisting of a structured history taking, reliable and complete neurologic examination, blood chemistry evaluation, thyroid-function tests, and the like, along with apolipoprotein E genotyping would seem to be appropriate initially. Computed tomography and magnetic resonance imaging could be considered on the basis of the history and physical examination, rather than scheduled routinely for every patient.
5 ReferencesAllen D. Roses, M.D.
Ann M. Saunders, Ph.D.
Duke University Medical Center, Durham, NC 277101
Geldmacher DS ,Whitehouse PJ . Evaluation of dementia. N Engl J Med 1996;335:330-336
Full Text | Web of Science | Medline2
National Institute on Aging/Alzheimer's Association Working Group
Web of Science | Medline3
Saunders AM ,Hulette O ,Welsh-Bohmer KA , et al. Specificity, sensitivity, and predictive value of apolipoprotein-E genotyping for sporadic Alzheimer's disease. Lancet 1996;348:90-93
CrossRef | Web of Science | Medline4
Kakulas BA ,Wilton SD ,Fabian VA ,Jones TM . Apolipoprotein-E genotyping in diagnosis of Alzheimer's disease. Lancet 1996;348:483-483
CrossRef | Web of Science | Medline5
Smith AD ,Jobst KA ,Johnston C ,Joachim C ,Nagy Z . Apolipoprotein-E genotyping in diagnosis of Alzheimer's disease. Lancet 1996;348:483-484
CrossRef | Web of Science | Medline
To the Editor:
The excellent, succinct review of dementia by Drs. Geldmacher and Whitehouse omitted one important condition associated with dementia — alcoholism. Some cognitive dysfunction can be measured in 50 to 70 percent of alcoholics, and 10 percent of alcoholics have severe cognitive impairment requiring institutional care.1 Alcohol-related dementia was identified in 24 percent of cognitively impaired residents of a long-term care facility, ranking second only to Alzheimer's disease as a cause of dementia.2 The cause of dementia in alcoholics is multifactorial.3 Wernicke's encephalopathy, which is caused by thiamine deficiency, is a relatively common disorder in alcoholics and results in both selective memory loss (Korsakoff's syndrome) and global cognitive changes that may be indistinguishable from those due to Alzheimer's disease.4 Autopsy studies indicate that the diagnosis of acute and chronic Wernicke's encephalopathy is frequently overlooked.3 Alcoholics are subject to a variety of nutritional deficiencies, traumatic brain injury, hepatocerebral degeneration, alcohol neurotoxicity, and Marchiafava–Bignami syndrome; alone or in combination, these may contribute to dementia. A history of alcoholism should be carefully elicited from patients with cognitive dysfunction. Abstinence from alcohol and nutritional therapy may lead in some patients to stabilization or even improvement of cognitive function.
4 ReferencesMichael E. Charness, M.D.
Veterans Affairs Medical Center, West Roxbury, MA 021321
Eckardt MJ ,Martin PR . Clinical assessment of cognition in alcoholism. Alcohol Clin Exp Res 1986;10:123-127
CrossRef | Web of Science | Medline2
Carlen PL ,McAndrews MP ,Weiss RT , et al. Alcohol-related dementia in the institutionalized elderly. Alcohol Clin Exp Res 1994;18:1330-1334
CrossRef | Web of Science | Medline3
Charness ME ,Simon RP ,Greenberg DA . Ethanol and the nervous system. N Engl J Med 1989;321:442-454
Full Text | Web of Science | Medline4
Torvik A ,Lindboe CF ,Rogde S . Brain lesions in alcoholics: a neuropathological study with clinical correlations. J Neurol Sci 1982;56:233-248
CrossRef | Web of Science | Medline
To the Editor:
We were surprised that functional imaging of the brain with single-photon-emission computed tomography (SPECT) was not discussed in the review of the evaluation of dementia. SPECT has been used for over a decade and typically shows decreased perfusion in the bilateral posterior temporoparietal cortex in Alzheimer's disease, frontal hypoperfusion in Pick's disease, multiple asymmetric perfusion defects in vascular dementia, multifocal abnormalities in AIDS dementia complex, and a normal pattern in pseudo-dementia (depression).1 Although not entirely specific, a finding of bilateral posterior temporoparietal hypoperfusion in a patient with cognitive deficits is highly suggestive of Alzheimer's disease. In mild Alzheimer's disease (patients with a score of 20 to 24 on the Mini–Mental State Examination), SPECT still has a sensitivity of more than 80 percent. Conversely, a normal pattern of perfusion in patients with memory loss has a high negative predictive value and, in the appropriate clinical settings, favors the diagnosis of depressive disorder rather than early Alzheimer's disease.2 On the basis of the evidence from several well-designed clinical studies and clinicopathological series, SPECT is considered an established technique to support the clinical diagnosis of Alzheimer's disease.3
3 ReferencesMichel Rubinstein, M.D.
Roger Denays, M.D.
Andréa Collier, M.D.
Association Hospitalière Etterbeek-Ixelles, B-1050 Brussels, Belgium1
Holman BL ,Devous MD . Functional brain SPECT: the emergence of a powerful clinical method. J Nucl Med 1992;33:1888-1904
Web of Science | Medline2
Holman BL ,Johnson KA ,Gerada B ,Carvalho PA ,Satlin A . The scintigraphic appearance of Alzheimer's disease: a prospective study using technetium-99m-HMPAO SPECT. J Nucl Med 1992;33:181-185[Erratum, J Nucl Med 1992;33:484.]
Web of Science | Medline3
Assessment of brain SPECT: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology
Web of Science | Medline
To the Editor:
In their excellent review on the evaluation of dementia, Geldmacher and Whitehouse suggest that the diagnosis of normal-pressure hydrocephalus might be confirmed by radioisotope-diffusion studies. Although this test may confirm the presence of communicating hydrocephalus, it will not assist clinicians in managing cases of presumed normal-pressure hydrocephalus. The value of isotope cisternography for predicting the postsurgical clinical outcome is no higher than that of combined clinical and CT data.1 Since isotope cisternography is invasive, expensive, and time-consuming, performing this test in patients with presumed normal-pressure hydrocephalus should be discouraged.
1 ReferencesJan Vanneste, M.D.
Sint Lucas Andreas Ziekenhuis, 1061 AF Amsterdam, the Netherlands1
Vanneste J ,Augustijn P ,Davies GAG ,Dirven C ,Tan WF . Normal-pressure hydrocephalus: is cisternography still useful in selecting patients for a shunt? Arch Neurol 1992;49:366-370
Web of Science | Medline
To the Editor:
Geldmacher and Whitehouse state that the annual incidence of Creutzfeldt–Jakob disease in the United States is 1 per 167,000 population. This is the incidence for a subgroup of the population that is 70 to 74 years of age. The study to which the authors refer, an epidemiologic analysis of national mortality data by Holman et al.,1 reports an “average annual age-adjusted mortality rate of 0.9 deaths per million persons, a rate consistent with published estimates of the crude incidence worldwide of 1 case per million persons.” The study by Masters et al.2 to which Holman et al. refer states, “In the United States, the average annual mortality rate is used by epidemiologists to estimate annual disease incidence due to the rapidly fatal course of the disease for most patients with CJD [Creutzfeldt–Jakob disease].”
2 ReferencesElizabeth W. Lazzara, M.D.
College of Physicians and Surgeons of Columbia University, New York, NY 100321
Holman RC ,Khan AS ,Kent J ,Strine TW ,Schonberger LB . Epidemiology of Creutzfeldt-Jakob disease in the United States, 1979-1990: analysis of national mortality data. Neuroepidemiology 1995;14:174-181
CrossRef | Web of Science | Medline2
Masters CL ,Harris JO ,Gajdusek DC ,Gibbs CJ Jr ,Bernoulli C ,Asher DM . Creutzfeldt-Jakob disease: patterns of worldwide occurrence and the significance of familial and sporadic clustering. Ann Neurol 1979;5:177-188
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Charness correctly notes alcoholism as an important potential contributor to dementia. We agree that it deserves emphasis, and we presumed, perhaps unwisely, that practitioners routinely assess alcohol use by their patients.
Rubinstein et al. identify the strong points of SPECT in prototypical cases, but its value in atypical, and therefore diagnostically challenging, cases of dementia is less clear. We agree with Vanneste that although some clinicians continue to use isotope cisternography, its cost effectiveness is questionable.
Lazzara correctly notes that we misstate the incidence of Creutzfeldt–Jakob disease. The overall incidence in the United States is 0.9 per million. The figure of 1 per 167,000 cited in our article, however, is probably appropriate for the older groups that are frequently assessed for dementia.
In response to Roses and Saunders, we appreciate the new information concerning apolipoprotein E genotype testing in dementia and restate our view that in clinical practice asymptomatic persons should not be tested. They would receive far less information than persons with symptoms requiring diagnosis.1 The predictive values in selected autopsy populations do not necessarily reflect those in clinical populations. Knowing the apolipoprotein E status does supply more information about the likelihood of certain diagnoses, but the usefulness of the information in the routine evaluation of patients with dementia is uncertain.
We agree with Roses and Saunders that imaging studies might be conducted more selectively, but they do not specify where apolipoprotein E fits in their decision tree. It remains uncertain whether apolipoprotein E testing will really alter our use of imaging and other diagnostic tests and save money.
Not addressed by Roses and Saunders is another major issue raised by the literature2 as to how people use complex diagnostic and genetic-risk data. Current efforts to teach physicians, patients, and their families how to interpret the results of apolipoprotein E genotyping are inadequate. If they were more adequate, we think that fewer persons would opt to be tested.
Clinical-research use of apolipoprotein E, building on the exciting basic-science discoveries, should be encouraged, but at present clinical use should be highly discretionary. In the future, apolipoprotein E genotyping may prove useful in decisions about brain biopsy and about shunting in cases of possible normal-pressure hydrocephalus, and in other situations,3 but it does require further study. Fortunately, many agree with us, and such studies are under way.4
4 ReferencesPeter J. Whitehouse, M.D., Ph.D.
David S. Geldmacher, M.D.
University Hospitals of Cleveland, Cleveland, OH 441061
Breitner JC . APOE genotyping and Alzheimer's disease. Lancet 1996;347:1184-1185
CrossRef | Web of Science | Medline2
National Institute on Aging/Alzheimer's Association Working Group
Web of Science | Medline3
Andrews LB, Fullarton JE, Holtzman NA, Motulsky AG, eds. Assessing genetic risks: implications for health and social policy. Washington, D.C.: National Academy Press, 1994.
4
American College of Medical Genetics/American Society of Human Genetics Working Group on APOE and Alzheimer Disease
CrossRef | Web of Science
