Advertisement
Mayo Clinic Proceedings Home

The Eyes Don't Have It in Alzheimer's Disease

  • Nancy J. Newman
    Correspondence
    Address reprint requests to Dr. N. J. Newman, Neuro-Ophthalmology Unit, Emory Eye Center, Suite 3505, 1365-B Clifton Road NE, Atlanta, GA 30322
    Affiliations
    Departments of Ophthalmology, Neurology, and Neurosurgery Emory University School of Medicine Atlanta, Georgia
    Search for articles by this author
      In 1994, Scinto and colleagues
      • Scinto LFM
      • Daffner KR
      • Dressler D
      • Ransil BI
      • Rentz D
      • Weintraub S
      • et al.
      A potential noninvasive neurobiological test for Alzheimer's disease.
      proposed that pupillary responses to dilute tropicamide, a cholinergic antagonist, could be used as a noninvasive diagnostic test for Alzheimer's disease (AD). In an article in Science that generated a flurry of media excitement, the authors reported a pronounced hypersensitivity of pupil dilatation to dilute tropicamide in their patients with clinically diagnosed or suspected AD but not in a group of healthy elderly control subjects. The difference in pupillary responses between the groups was robust enough to distinguish among individuals. AD is the most common cause of dementia; although the accuracy of clinical diagnosis of AD has improved, definitive diagnosis still necessitates histopathologic confirmation. The possibility of a noninvasive, sensitive, specific, and easily performed diagnostic test for early AD was greeted enthusiastically.
      Two subsequent tropicamide studies reported in letters to Science
      • Marx JL
      • Kumar SR
      • Thach AB
      • Kiat-Winarko T
      • Frambach DA
      Detecting Alzheimer's disease [letter].
      • Treloar A
      • Assin M
      • Macdonald A
      Detecting Alzheimer's disease [letter].
      did not support the findings of Scinto and associates.
      • Scinto LFM
      • Daffner KR
      • Dressler D
      • Ransil BI
      • Rentz D
      • Weintraub S
      • et al.
      A potential noninvasive neurobiological test for Alzheimer's disease.
      Marx and coworkers
      • Marx JL
      • Kumar SR
      • Thach AB
      • Kiat-Winarko T
      • Frambach DA
      Detecting Alzheimer's disease [letter].
      reported that 13 young healthy subjects showed as much dilatation to dilute tropicamide as the patients with AD in the study by Scinto and colleagues,
      • Scinto LFM
      • Daffner KR
      • Dressler D
      • Ransil BI
      • Rentz D
      • Weintraub S
      • et al.
      A potential noninvasive neurobiological test for Alzheimer's disease.
      and Treloar and associates
      • Treloar A
      • Assin M
      • Macdonald A
      Detecting Alzheimer's disease [letter].
      were unable to distinguish patients with AD from those with other causes of dementia by their pupillary responses. Loupe and coworkers
      • Loupe DN
      • Newman NJ
      • Green RC
      • Lynn MJ
      • Williams KK
      • Geis TC
      • et al.
      Pupillary response to tropicamide in patients with Alzheimer disease.
      studied the pupillary responses to dilute tropicamide in four groups: 9 patients with AD, 10 patients with AD treated orally with an acetylcholinesterase inhibitor (tacrine), 11 older control subjects, and 10 young control subjects. The mean change in anisocoria was not significantly different among the groups, and the pupillary responses could not distinguish individual patients with AD from young or older control subjects.
      Subsequent publications, in general, have confirmed the lack of specificity, reproducibility, and reliability of pupillary responses to tropicamide as a diagnostic test for AD.
      • Arai H
      • Terajima M
      • Nakagawa T
      • Higuchi S
      • Mochizuki H
      • Sasaki H
      Pupil dilatation assay by tropicamide is modulated by apolipoprotein E e4 alíele dosage in Alzheimer's disease.
      • Reitner A
      • Baumgartner I
      • Thuile C
      • Baradaran Dilmaghani R
      • Ergun E
      • Kaminski S
      • et al.
      The mydriatic effect of tropicamide and its diagnostic use in Alzheimer's disease.
      • Litvan I
      • FitzGibbon EJ
      Can tropicamide eye drop response differentiate patients with progressive supranuclear palsy and Alzheimer's disease from healthy control subjects?.
      • Gomez-Tortosa E
      • del Barrio A
      • Jimenez-Alfaro I
      Pupil response to tropicamide in Alzheimer's disease and other neurodegenerative disorders.
      • FitzSimon JS
      • Waring SC
      • Kokmen E
      • McLaren JW
      • Brubaker RF
      Response of the pupil to tropicamide is not a reliable test for Alzheimer disease.
      • Kono K
      • Miyao M
      • Ishihara S
      • Takagi A
      • Ikari H
      • Suzuki Y
      • et al.
      Hypersensitivity in the pupil dilation response to a cholin-ergic antagonist in patients with Alzheimer's disease and Down's syndrome.
      • Robles A
      • Tourino R
      • Sesar A
      • Suarez P
      • Noya M
      Experiencia con el test pupilar de tropicamida en la enfermedad de Alzheimer.
      Although some studies suggested a trend for greater pupillary dilatation among the patients with AD,
      • Arai H
      • Terajima M
      • Nakagawa T
      • Higuchi S
      • Mochizuki H
      • Sasaki H
      Pupil dilatation assay by tropicamide is modulated by apolipoprotein E e4 alíele dosage in Alzheimer's disease.
      • Reitner A
      • Baumgartner I
      • Thuile C
      • Baradaran Dilmaghani R
      • Ergun E
      • Kaminski S
      • et al.
      The mydriatic effect of tropicamide and its diagnostic use in Alzheimer's disease.
      • Gomez-Tortosa E
      • del Barrio A
      • Jimenez-Alfaro I
      Pupil response to tropicamide in Alzheimer's disease and other neurodegenerative disorders.
      • Kono K
      • Miyao M
      • Ishihara S
      • Takagi A
      • Ikari H
      • Suzuki Y
      • et al.
      Hypersensitivity in the pupil dilation response to a cholin-ergic antagonist in patients with Alzheimer's disease and Down's syndrome.
      • Robles A
      • Tourino R
      • Sesar A
      • Suarez P
      • Noya M
      Experiencia con el test pupilar de tropicamida en la enfermedad de Alzheimer.
      all investigations reported considerable overlap among individuals; thus, the test has proved essentially useless for diagnostic purposes.
      In the article by Graff-Radford and colleagues in this issue of the Mayo Clinic Proceedings (pages 495 to 504), a controlled, masked study once again refutes the findings reported by Scinto and coworkers
      • Scinto LFM
      • Daffner KR
      • Dressler D
      • Ransil BI
      • Rentz D
      • Weintraub S
      • et al.
      A potential noninvasive neurobiological test for Alzheimer's disease.
      and demonstrates that the dilute tropicamide eyedrop test is neither reliable nor reproducible for determining the presence of AD. The authors performed pupillography over time, averaging pupil size on each measurement during a 1-minute period, in 23 patients with probable AD, 22 age-matched normal control subjects, 4 patients with isolated memory difficulty, and 6 patients with non-AD dementia. As in the study by Loupe and associates,
      • Loupe DN
      • Newman NJ
      • Green RC
      • Lynn MJ
      • Williams KK
      • Geis TC
      • et al.
      Pupillary response to tropicamide in patients with Alzheimer disease.
      they made use of the size of the pupil in the unmedicated eye (that is, the degree of anisocoria) as an internal control. No significant difference was noted in pupillary dilatation among normal subjects, patients with AD, and patients with non-AD dementia. Furthermore, on readministration of the test in the same patients, more than half the subjects changed from a group above or below 13% dilatation (a cutoff point reported by Scinto and colleagues to distinguish patients with AD from normal subjects) to the opposite group.
      Many problems are inherent in pupillary drug studies.
      • Loewenfeld IE
      Iris color may have a role in pupillary drug response, although studies about this issue have reported conflicting results.
      • Loewenfeld IE
      Increased corneal permeability can enhance topically applied drug effects,
      • Mishima S
      Clinical pharmacokinetics of the eye: Proctor lecture.
      and corneal permeability may be affected by several variables, including dry eyes, eyelid hygiene, blink rate, corneal sensation, tear production, and genetic factors. In one study,
      • FitzSimon JS
      • Waring SC
      • Kokmen E
      • McLaren JW
      • Brubaker RF
      Response of the pupil to tropicamide is not a reliable test for Alzheimer disease.
      ocular penetration by the eyedrops was assessed by using fluorophotometry after 2%fluorescein sodium was topically applied as a tracer. No statistically significant difference was found between patients with AD and control subjects in the rate of penetration by fluorescein into the aqueous humor. In the same study, the average blink rate was not significantly different between the groups. Finally, the fluctuation of pupil size bilaterally in relationship to a subject's physiologic and psychologic state is a well-established fact.
      • Loewenfeld IE
      Both pupils will dilate with agitation and distress; both will constrict with fatigue. If only change from baseline size of the treated pupil is measured (the variable reported in the study by Scinto and coworkers
      • Scinto LFM
      • Daffner KR
      • Dressler D
      • Ransil BI
      • Rentz D
      • Weintraub S
      • et al.
      A potential noninvasive neurobiological test for Alzheimer's disease.
      ), it may reflect a subject's autonomic or psychologic state at two points in time rather than a true response to the drug. Only the change in anisocoria should be accepted as a drug-induced effect.
      Because of the results of the currently reported study in this journal and similar previous studies during the past year, pupillary testing after instillation of tropicamide clearly cannot be used as a reliable diagnostic test for AD. The test lacks specificity, and the test-retest reliability is question- able. As new therapies for AD emerge that might be most efficacious if begun at an early or presymptomatic stage of the disease, a biologic marker is desperately needed for accurate early diagnosis. Unfortunately, the eyes don't have it.

      REFERENCES

        • Scinto LFM
        • Daffner KR
        • Dressler D
        • Ransil BI
        • Rentz D
        • Weintraub S
        • et al.
        A potential noninvasive neurobiological test for Alzheimer's disease.
        Science. 1994; 266: 1051-1054
        • Marx JL
        • Kumar SR
        • Thach AB
        • Kiat-Winarko T
        • Frambach DA
        Detecting Alzheimer's disease [letter].
        Science. 1995; 267: 1577
        • Treloar A
        • Assin M
        • Macdonald A
        Detecting Alzheimer's disease [letter].
        Science. 1995; 267: 1578
        • Loupe DN
        • Newman NJ
        • Green RC
        • Lynn MJ
        • Williams KK
        • Geis TC
        • et al.
        Pupillary response to tropicamide in patients with Alzheimer disease.
        Ophthalmology. 1996; 103: 495-503
        • Arai H
        • Terajima M
        • Nakagawa T
        • Higuchi S
        • Mochizuki H
        • Sasaki H
        Pupil dilatation assay by tropicamide is modulated by apolipoprotein E e4 alíele dosage in Alzheimer's disease.
        Neuroreport. 1996; 7: 918-920
        • Reitner A
        • Baumgartner I
        • Thuile C
        • Baradaran Dilmaghani R
        • Ergun E
        • Kaminski S
        • et al.
        The mydriatic effect of tropicamide and its diagnostic use in Alzheimer's disease.
        Vision Res. 1997; 37: 165-168
        • Litvan I
        • FitzGibbon EJ
        Can tropicamide eye drop response differentiate patients with progressive supranuclear palsy and Alzheimer's disease from healthy control subjects?.
        Neurology. 1996; 47: 1324-1326
        • Gomez-Tortosa E
        • del Barrio A
        • Jimenez-Alfaro I
        Pupil response to tropicamide in Alzheimer's disease and other neurodegenerative disorders.
        Acta Neurol Scand. 1996; 94: 104-109
        • FitzSimon JS
        • Waring SC
        • Kokmen E
        • McLaren JW
        • Brubaker RF
        Response of the pupil to tropicamide is not a reliable test for Alzheimer disease.
        Arch Neurol. 1997; 54: 155-159
        • Kono K
        • Miyao M
        • Ishihara S
        • Takagi A
        • Ikari H
        • Suzuki Y
        • et al.
        Hypersensitivity in the pupil dilation response to a cholin-ergic antagonist in patients with Alzheimer's disease and Down's syndrome.
        Nippon Ronen Igakkai Zasshi. 1996; 33: 829-834
        • Robles A
        • Tourino R
        • Sesar A
        • Suarez P
        • Noya M
        Experiencia con el test pupilar de tropicamida en la enfermedad de Alzheimer.
        Rev Neurol. 1996; 24: 65-68
        • Loewenfeld IE
        The Pupil: Anatomy, Physiology, and Clinical Applications. Vol 1. Iowa State University Press, Ames (I A)1993: 797-826
        • Mishima S
        Clinical pharmacokinetics of the eye: Proctor lecture.
        Invest Ophthalmol Vis Sei. 1981; 21: 504-541