Are Multiple Cerebral Infarcts Synergistic? Nicola Wolfe, PhD; Viken L. Babikian, MD; Richard T. Linn, PhD; Janice E. Knoefel, MD; Mark D'Esposito, MD; Martin L. Albert, MD Objective: goal of this study was to character- The ize the cumulative effects of multiple strokes on cognition. Design: We conducted a prospective, longitudinal case study with neuropsychological, neurological, and radio- logical evaluations. Setting: Research was conducted at the Boston (Mass) Veterans Administration Medical Center, Neurology Service, on successive inpatient hospital admissions. Patient: We followed up a 66-year-old right-handed man with multiple subcortical lacunae during a 3.5-year period during which he suffered two additional cortical infarctions. Main Outcome Measures: Each evaluation included approximately 3 hours of neuropsychological testing spanning a range of cognitive domains (attention, language, memory, visuospatial functions, response inhibition, and mental flexibility), full neurological examination, and com- puted tomographic scan. From the Department of Neurology, University of California at Davis, School of Medicine, and the Northern California Alzheimer's Disease Center, Berkeley (Dr Wolfe); Department of Neurology, Boston (Mass) University School of Medicine and Boston Veterans Administration Medical Center (Drs Babikian, Knoefel, D'Esposito, and Albert); and the Department of Psychiatry, State University of New York at Buffalo, School of Medicine (Dr Linn). The Results: The patient's stepwise cognitive decline was characterized by unexpected exacerbation of "frontal" neurobehavioral features following the occurrence of two posterior cortical lesions. At initial evaluation, the computed tomographic scan showed bilateral subcortical lacunae in basal ganglia and periventricular white matter, and symptoms included dysarthria and perseveration. The second evaluation, following a left posterior parietal lesion, revealed a range of new frontal features, including impulsivity, pull-to-stimulus, and difficulty shifting set. Following a subsequent right occipital infarct, further frontal lobe impairments emerged: forced grasp reflex and incontinence. Conclusions: We hypothesize that the cumulative effects of infarcts were synergistic. That is, the posterior cortical infarcts elicited frontal features that would not be expected from a simple sum of these lesions' effects. (Arch Neurol. 1994;51:211-215) cumulative effects of multiple strokes on cogni¬ tion have proved difficult to characterize. While single infarctions have been clearly associated with specific neurobehavioral syn¬ dromes, ' cases of multiple lesions have been more difficult to describe due to individual differences in the number, the extent, and the location of lesions. Hachinski2 has noted that although the effects of multiple lesions on mental function depend on size, site, num¬ ber, and nature of lesions, their cumulative effects seem not to be simply additive. To characterize the longitudinal course of cognitive decline with multiple infarcts, we conducted a prospective, longitudinal study of a 66-year-old, right-handed man with multiple subcortical lacunae during a 3.5- Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 05/26/2015 year period in which he suffered two addi¬ tional cortical infarctions. REPORT OF A CASE The patient, a retired postal worker with a seventh-grade education, was first seen at age 66 years after a Veterans Adminis¬ tration Medical Center admission for sud¬ den onset of light-headedness, slurred speech, and unsteady gait. The medical his¬ tory was significant for hypertension and METHODS The patient was followed up at the Boston (Mass) Veterans Administration Medical Center's Neurology Service with neuropsychological evaluations on May 6,1987; August 9, 1989; and November 20, 1990 (periods 1 through 3, re¬ spectively). Research neuropsychological evaluations were conducted using a battery specifically developed for a study of multi-infarct dementia and have been described previ¬ ously.3 Each evaluation included approximately 3 hours of neuropsychological testing spanning a range of cogni¬ tive domains, including the following: attention/con¬ centration, language, memory, visuospatial functions, re¬ sponse inhibition, and mental flexibility. Tests of attention included an Auditory Continuous Performance Test4 and Digit Span (from the Wechsler Adult Intelligence ScaleRevised5). Memory testing included the California Verbal Learning Test (nine-word dementia version)6; visuoconstructional tasks included drawing of clock, daisy, and cube mild hyperlipidemia, but the patient was not diabetic. The CT scan for period 1 in April 1987 is shown in Figure 1. It revealed evidence of four subcortical lacunar infarcts in the following locations: right periventricular white mat¬ ter, left periventricular white matter, left external capsule/ head of caudate, and right border of putamen and globus pallidus. In addition, the ventricles were moderately enlarged bilaterally, but radionuclide cisternogram (March 1989) for normal pressure hydrocephalus was negative. Figure 1. Computed tomographic scan for period 1, April 1987. copy7; and language evaluations in¬ cluded the Boston Naming Test ( 15-item version)8 and the Controlled Oral Word Association Test." Measures of re¬ sponse inhibition included Reciprocal Motor Programs10 and the Stroop Test.11 Ability to shift mental set was as¬ sessed using the Visual-Verbal Test (10-item version).12 The Center for Epidemiologie Study of Depression Scale13 was used to measure depressive symptoms. The Mini-Mental State examination14 and the Barthel Functioning Index15 were indexes of overall cognitive functioning and daily func¬ tioning, respectively. Full neurologic examinations were also performed at each period. to command and to Computed tomographic (CT) scans were performed as part of the patient's clinical evaluation and preceded neuro¬ psychological testing by 1 to 4 months. Thus, the subject was not tested during the short-term recovery period following a stroke. Approximately twelve 7-mm thick slices were obtained per CT. Lacunae were defined as small (<2 cm in maximum diameter), well-circumscribed, subcortical areas of low attenuation consistent with cerebral infarction.16 Throughout the follow-up period, findings from the car¬ diac examination remained unremarkable. Electrocar¬ diogram showed regular pulse with a left bundle branch block. An echocardiogram and an electroencephalo¬ graphic study were within normal limits. Noninvasive studies of the carotid arteries showed findings consis¬ tent with less than 50% stenosis bilaterally in April 1987 and April 1988. During the 3.5-year follow-up, the patient was re¬ admitted to the hospital with clinical symptoms of two further incidents of cerebral infarction. The CT scan for period 2 was performed in April 1989 (Figure 2). In ad¬ dition to the multiple subcortical lacunae, it showed a left cortical parietal area oflow attenuation with deep white matter extension. Figure 3 shows the CT scan for pe¬ riod 3, performed in July 1990. In addition to the four subcortical lacunae and the left parietal cortical lesion, a new right-sided occipital polar lesion of moderate size was present. Progression of ventricular enlargement, cor¬ tical atrophy, and white matter changes was also ob¬ served. A summary of neuropsychological results over three periods is shown in the Table. Although cognitive decline covered a broad range of domains, including attention, language, memory, and visuospatial functions, the most salient change was the emergence of "frontal" features in periods 2 and 3. The course of cognitive decline was stepwise, paralleling clini¬ cal symptoms of infarction. After the left parietal infarct, notable increases were seen in impulsivity. The number of impulsive errors on auditory continuous perfor¬ mance test (tapping after X alone on auditory XIs) in¬ creased from 1 to 13. Also at period 2, the patient dem¬ onstrated pull-to-stimulus, for example, drawing on top Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 05/26/2015 teria for probable ischemie vascular dementia.17 Follow¬ ing the additional occipital cortical lesion, period 3, fur¬ ther deterioration included a return of forced grasp reflex and urinary and fecal incontinence. Depressive symp¬ toms, as measured by the Center for Epidemiologie Study of Depression Scale, were less pronounced in periods 2 and 3 than in period 1. COMMENT Figure 2. Computed tomographic scan for period 2, April 1989. Figure 3. Computed tomographic scan for period 3, July 1990. of figures to be copied. Poor response inhibition was noted on the Stroop Test color-interference condition where his score declined from 38 to 10. Also, on reciprocal motor programs, errors of imitation increased from 2 to 33. He exhibited difficulty shifting mental set on the VisualVerbal Test, with the score declining from 100% shifted to only 28% shifted. It was at period 2 that the patient dropped below the dementia cutoff score of 24 on the Mini-Mental State examination and also met research cri- This patient suffered multifocal cognitive decline, with the emergence of frontal symptoms following additional posterior cortical lesions. It is this unexpected pattern that leads us to suggest the hypothesis that multiple in¬ farcts may have a "synergistic" effect. The term synergy is used here to mean that the combined effect of lesions yields a pattern of deficits different from that which would be predicted by simply summing individual lesion ef¬ fects. Specifically, the posterior cortical infarcts were as¬ sociated with development of frontal neurobehavioral features. This phenomenon, which we are labeling "synergistic," has been noted by other investigators. Hachinski,2 for example, noted the following: "In gen¬ eral, the effect of additional lesions of the brain increases with the number of lesions already present, so that defi¬ cits in the brain do not merely add up, they multiply." Interpretation of this case must also consider alter¬ native neuropathological and neuropsychological expla¬ nations. In addition to posterior cortical lesions, the CT scans reveal progression of cortical atrophy, ventricular enlargement, and mild leukoaraiosis suggestive of a more diffuse degenerative process. The progression of periven¬ tricular white matter abnormalities, including frontal white matter, could in part explain the emergence of frontal be¬ haviors. Although some investigators have noted leuko¬ araiosis on CT scans to be associated with increased de¬ mentia,18 leukoaraiosis is not necessarily associated with neuropsychological deficits.19 The severity of dementia in this patient and the time course that corresponds with subsequent cortical infarctions suggest that more than white matter abnormality is involved. Progressive enlargement of ventricles seen in this patient is unlikely to represent normal pressure hydrocephalus. The radionuclide cisternogram at period 2 was negative, and the clinical profile of normal pressure hydrocephalus (cognitive impairment, incontinence, and gait disturbance) was not present until period 3. More likely, this hydrocephalus ex vacuo was associated with tissue loss secondary to recurrent cerebral infarction. Some investigators20 have observed a correlation between ven¬ tricular enlargement and cognitive impairment. Al¬ though such a relationship may contribute to cognitive decline seen in this patient, it does not explain the se¬ verity or the stepwise pattern of cognitive decline. An alternative explanation is that following each in¬ farction, some recovery of function occurs through respe- Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 05/26/2015 Neuropsychology Testing Results* Period 1 2 3 (5/87) (8/89) (11/90) 6 5 22 3 3 11 01 2 12 7 11 6 28 3 42 1 Yes 11 8 15 8 Yes 01 01 1 No 2 38 13 Yes 33 10 10 Yes 26 Yes Yes Yes Yes Yes Yes 7/7 2/7 o/ot No No No No No No No No No No Yes Yes 27 100 11 85 10 35 39 20 18 Attention Digit span (forward) Digit span (backward) Auditory CPT (Xls) (No. correct /26)1 Memory California Verbal Learning Test (CVLT) (9-word dementia version) Maximum correct/9 (trials 1-5) 3 1 7 7 7 1 1 2 Immediate free recall 20-minute delayed free recall Total perseverations (trials 1-5) Total intrusions (trials 1-5) Total semantic clusters (trials 1-5) Visuospatial functions Drawing to copy (clock, daisy, cube) /15 Drawing to command (clock, daisy, cube) /15 13 Language Boston Naming Test (15-item version) No. correctly named /15 13 Phonemic paraphasias Verbal fluency (Controlled Oral Word Association Test) Phonemic (total FAS words correct) Perseverative repetitions on FAS Categories (total: animals, fruits and vegetables, first names) Perseverative repetition on categories Dysarthria Response inhibition Impulsivity (tapping prior to X on CPT Xls) Pull-to-stimulus (drawing on top of figure to be copied) Reciprocal motor programs (errors of imitation, maximum 40) Stroop test (No. correct: color-interference condition) Perseveration Continuous perseveration (m n m ) Continuous perseveration (multiple loops) Shifting mental set Visual-Verbal Test (No. of cards correctly shifted/No. correct first trial) Behavioral observations Sudden onset laughing or crying Apathy during testing Urinary and fecal Incontinence Forced grasp reflex Overall cognitive functioning Mini-Mental State examination Barthel Functioning Index Mood Center for Epidemiologie Study of Depression Scale (CES-D) /60 10 8 Yes 01 'FAS indicates Controlled Oral Word Association Test; CPT, Continuous Performance Test: and CES-D, Center for Epidemiologie Study of Depression Scale. tPatient was not able to initiate the mental set for this test. tNumber after virgule indicates the maximum score possible on this test. cialization of intact neural tissue. Subsequent infarction in that respecialized area could yield behavioral impair¬ ments not usually seen following a single lesion in that area. It is considered highly unlikely, however, in this particu- lar case, that respecialization of infarcted regions could explain the emergence of "frontal lobe" features. An alternative explanation is the presence of a de¬ generative disorder such as Alzheimer's disease in addi- Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 05/26/2015 tion to multiple infarctions. The pattern of neuropsy¬ chological findings is more characteristic of a frontal lobe dementia than the degeneration of Alzheimer's disease. Although the stepwise course in this case would be un¬ characteristic of Alzheimer's disease, this cause cannot be completely ruled out. In addition, it could be argued that the neuropsycho¬ logical impairments that emerged are not restricted to the frontal lobes. Difficulties shifting set, impulsivity, and pullto-stimulus were salient features; however, there was also global cognitive decline. Some functions such as confron¬ tation naming or mood did not decline with time, but de¬ terioration was not entirely restricted to frontal tasks. Localization of so-called frontal features specifically to the frontal lobes has been increasingly challenged. Re¬ cent publications have shown these frontal lobe behav¬ iors to emerge following lesions to a number of areas: left medial thalamus,21 paramedian thalamus,22 and head of caudate.23"25 We have noted previously,3 as did Ishii et al,26 that multiple subcortical lacunae could produce a behav¬ ioral profile characteristic of frontal damage. Thus, it may be more appropriate to attribute these symptoms to "fron¬ tal systems" damage. Bilateral lacunae in basal ganglia and periventricular white matter could be considered to have interfered with a frontal-subcortical system.27 In this pa¬ tient, however, the subcortical lacunae were present al¬ ready in period 1 and cannot explain the progression of frontal neuropsychological findings in periods 2 and 3. The idea that multiple infarcts combine synergistically is consistent with the model by Mesulam28 ofneuronal net¬ works and parallel distributed processing. He has suggested that "complex behavior is mapped at the level of multifo¬ cal neural systems rather than specific anatomical sites, giv¬ ing rise to brain behavior relationships that are both local¬ ized and distributed. Although it could be argued that this neuronal network model could explain many unexpected associations between lesions and cognition, the model, nev¬ ertheless, provides an anatomic basis for our clinical obser¬ vation that individual lesion effects do not simply add up but can be synergistic. This case suggests that functions of¬ ten associated with the frontal lobes, such as response in¬ hibition or complex executive functions, maybe emergent properties relying on the intact functioning of widely in¬ terconnected systems of neurons, rather than being rigidly localized to the frontal lobes. " Accepted for publication January 7, 1993. This research was supported in part by training grant NSO7239-04from the National Institutes of Health, Bethesda, Md, the Veterans Administration Medical Research Service, Washington, DC, and the Seidel Fund for Research on De¬ mentia at the Boston (Mass) University School of Medicine. Edith Kaplan, PhD, Boston, played a significant role in the development of the neuropsychological test battery used in this study, and William J. Jagust, MD, Berkeley, Calif, reviewed the manuscript. Reprint requests to University of California, Davis- Northern California Alzheimer's Disease Center, Alta Bates Medical Center, 2001 Dwight Way, Berkeley, CA 94704 (Dr Wolfe). REFERENCES 1. Damasio H, Damasio AR. Lesion Analysis in Neuropsychology. New York, NY: Oxford University Press Inc; 1989. 2. Hachinski V. Multi-infarct dementia. Neurol Clin. 1983;1:27-36. 3. Wolfe N, Linn R, Babikian VL. Knoefel JE, Albert ML. Frontal systems impairment following multiple lacunar infarcts. Arch Neurol. 1990;47:129-132. 4. Rosvold HE, Mirsky AF, Sarason I, Bransome ED Jr, Beck LH. A continuous performance test of brain damage. J Consult Clin Psychol. 1956;20:343-347. 5. Wechsler D. Wechsler Adult Intelligence Scale-Revised. New York, NY: The Psychological Corporation; 1981. 6. Delis DC, Kramer JH, Kaplan E, Ober BA. CVLT: The California Verbal Learning Test: Manual. New York, NY: The Psychological Corporation; 1987. 7. Goodglass H. Kaplan E. The Assessment of Aphasia and Related Disorders. 2nd ed. Philadelphia, Pa: Lea & Febiger; 1983. 8. Kaplan EF, Goodglass H, Weintraub S. The Boston Naming Test. Philadelphia, Pa: Lea & Febiger; 1983. 9. Spreen 0, Benton AL. Neurosensory Center Comprehensive Examination for Aphasia. Victoria. British Columbia: Neuropsychological Laboratory, Department of Psychology, University of Victoria; 1969. 10. Luria AR. Disturbance of higher cortical function with lesions of the frontal region. Higher Cortical Functions in Man. New York, NY: Basic Books Inc Publishers; 1966:218-292. 11. Stroop JR. Studies of interference in serial verbal reaction. J Exp Psychol. 1935; 18:643-662. 12. Feldman MJ, Drasgow J. The Visual-Verbal Test. Los Angeles, Calif: Western Psychological Services; 1959. 13. Radloff LS. The CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Meas. 1977;1:385-401. 14. Folstein MF, Folstein SE, McHugh PR. 'Mini-Mental State': a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198. 15. BarthelDW, Mahoney FI. Functional evaluation: Barthel Index. Md Med J. 1965; 14:61-65. 16. Weisberg LA. Lacunar infarcts: clinical and computed tomographic correlations. Arch Neurol. 1982;39:37-40. 17. Chui HC, Victoroff JI, Margolin D, Jagust W, Chankle R, Katzman R. Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer's Disease Diagnostic and Treatment Centers. Neurology. 1992; 42:473-480. 18. Steingart A, Hachinski VC, Lau C, et al. Cognitive and neurologic findings in demented patients with diffuse white matter lucencies on computed tomographic scan (leukoaraiosis). Arch Neurol. 1987;44:36-39. 19. Rao SM, Mittenberg W, Bernardin L, Haughton V, Leo GJ. Neuropsychological test findings in subjects with leukoaraiosis. Arch Neurol. 1989;46:40-44. 20. Aharon-Peretz J, Cummings JL, Hill MA. Vascular dementia and dementia of the Alzheimer type: cognition, ventricular size, and leukoaraiosis. Arch Neurol. 1988;45:719-721. 21. Sandson TA, Daffner KR, Carvalho PA, Mesulam M. Frontal lobe dysfunction following infarction of the left-sided medial thalamus. Arch Neurol. 1991;48: 1300-1303. 22. Eslinger PJ, Warner GC, Grattan LM, Easton JD. 'Frontal lobe' utilization behavior associated with paramedian thalamic infarction. Neurology. 1991;41: 450-452. 23. Richfield EK, Rwyman R, Berent S. Neurological syndrome following bilateral damage to the head of the caudate nuclei. Ann Neurol. 1987;22:768-771. 24. Mendez MF, Adams NL, Lewandowski KS. Neurobehavioral changes associated with caudate lesions. Neurology. 1989;39:349-354. 25. Caplan LR, Schmahmann JD, Kase CS, et al. Caudate infarcts. Arch Neurol. 1990;47:133-143. 26. Ishii N, Nishihara Y, Imamura T. Why do frontal lobe symptoms predominate in vascular dementia with lacunes? Neurology. 1986;36:340-345. 27. Rosvold HE. The frontal lobe system: cortical-subcortical interrelationships. Acta Neurobiol Exp. 1972;32:257-270. 28. Mesulam MM. Large-scale neurocognitive networks and distributed processing for attention, language and memory. Ann Neurol. 1990;28:597-613. Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 05/26/2015