Neuropsychological Studies

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Although a number of studies that have attempted to define the relationship between positive serology, CNS infection, and cognitive dysfunction, few have used neuropsychological testing to characterize the nature of the cognitive deficits. Neuropsychological tests have an advantage over even comprehensive bedside mental status examinations in detecting cognitive dysfunction associated with LE because the deficits are often subtle. For most neuropsychological procedures, the presence or absence of functional impairment is made on a statistical basis. Ideally, performance on a given test is interpreted in comparison to normative data appropriate to the patient's age, sex, and education. Probable impairment on a specific cognitive test is inferred when performance falls below a designated cutoff score, usually two standard deviations below the normative mean. Whether or not a particular test will discriminate between normal and abnormal function for either individuals or clinical populations depends on a number of critical factors. Reliability and validity data are essential for understanding the limits of a given test. Additionally, the ability of a test to discriminate between groups depends on the purpose and population for which the test was developed. For example, tests such as the Mini-Mental State Examination that were developed to screen for dementia in elderly populations are relatively insensitive to cognitive deficits in patients with Lyme disease.

The traditional approach in neuropsychological assessment used to define cognitive deficits associated

Figure 2 Quantitative SPECT analysis of nine patients with LE (mean data). Axial slices ascend from lowest (top left) to highest brain levels (bottom right). Macrovoxels whose mean perfusion is reduced at the p< 0.001 level below the mean of normal subjects (n = 53) are shown in white. The dark areas correspond to lower and the light areas to higher perfusion.

Figure 2 Quantitative SPECT analysis of nine patients with LE (mean data). Axial slices ascend from lowest (top left) to highest brain levels (bottom right). Macrovoxels whose mean perfusion is reduced at the p< 0.001 level below the mean of normal subjects (n = 53) are shown in white. The dark areas correspond to lower and the light areas to higher perfusion.

with brain disease is to administer a battery of tests. Often, differences in cognitive performance between two clinical populations, such as those with LE and those with depression alone, are best appreciated when the evaluation is based on an analysis of test score patterns. A pattern of scores not only indicates what is wrong with the patient but also what is right with the patient. The test battery usually includes both tests of general intellectual abilities, such as the Wechsler Scales, and tests developed to assess specific areas of cognitive dysfunction, such as attention, visual perception, construction, fine motor control, language, memory, and executive functioning. Test batteries also usually include measures of psychopathology in order to assess the patient's emotional state. The latter are often useful in interpreting other test results because psychological states such as anxiety and depression can impact a patient's cognitive abilities, particularly motivation and the ability to maintain and sustain attention. The importance of this cannot be overstated because although the sensitivity of neuropsychological tests in identifying brain dysfunction is quite high (between 80 and 90%), the specificity may be considerably lower. For example, a memory test that discriminates traumatic brain-injured patients from normal subjects does not indicate how important variables such as attention or affective states may impact performance. It is also incumbent upon the clinician or researcher to interpret neuropsychological test data in the context of the patients' medical and psychosocial history as well as psychiatric status. Table I provides a list of neuropsychological tests that have frequently been used in assessing cognitive deficits in Lyme disease patients.

In comparison to other more well-known brain disorders such as Alzheimer's disease, for which there are large neuropsychological databases, the number of neuropsychological studies in LE is relatively limited. The following discussion presents the neuropsycholo-gical test data in considerable detail in an attempt to

Table I

Neuropsychological Tests Frequently Used to Assess Deficits in Lyme Disease

Tested domain or function

General cognitive abilities


Short-term auditory attention Sustained attention

Interference Learning and memory

Language and verbal output Naming Verbal fluency

Executive functions

Set maintenance and shifting Abstraction and set shifting Distractibility Problem solving Motor dexterity

Neuropsychiatric symptoms Mood


Anxiety Fatigue

Neuropsychological test

Wechsler Intellignece Scales Shipley Institute of Living Scale

Digit Span Test Stroop Test (Word and Color) Continuous Performance Tests Symbol Digit Substitution Test Stroop Test (Color/Word) California Verbal Learning Test Selective Reminding Test Rey-Osterrieth Complex Figure Test

Wechsler Memory Scale

Boston Naming Test Controlled Word Association Test

Trails A and B Wisconsin Card Sorting Stroop Test

Halstead Category Test Finger Tapping Grooved Peg Board

Beck Depression Inventory

Center for Epidemiologic Studies Depression Scale

State Trait Anxiety Scale Minnesota Multiphasic Personality Inventory State Trait Anxiety Scale Fatigue Severity Scale demonstrate the nature and extent of cognitive dysfunction in LE.

In 1988, Halperin and colleagues published one of the earliest studies that included neuropsychological testing. They studied 17 Lyme patients before and after antibiotic treatment. All initially complained of memory deficits; however, only 4 had evidence of other neurological involvement and only 1 had abnormal CSF. The evaluation included tests of memory, visual spatial organization, conceptual thinking, and psy-chomotor and perceptual motor skills. The pretreat-ment results are difficult to interpret in part because these investigators failed to include a normal comparison group and also because there was no indication of the number of patients whose performance statistically fell outside the normal range. However, the authors report that there were pretreatment cognitive deficits in almost every area examined. Significant improvements following treatment were found on measures of recall memory on the California Verbal Learning Test (CVLT) as well as on tests of attention, concentration and motor speed, abstract problem solving, fine motor dexterity, and visual spatial organization. Improvement, however, was not evident on all tests. Patients' performances were unchanged on measures of tracking and sequencing, verbal fluency, auditory attention span, and recognition memory. Patients were also administered the Beck Depression Inventory (BDI), a self-administered questionnaire that measures the presence and severity of symptoms associated with depression. There was no evidence of significant depression either before or after treatment. However, the average score on the BDI, which reflects the overall severity of depression, was almost halved following treatment.

In a 1990 report, investigators at the New England Medical Center in Boston described 27 patients with chronic neurological abnormalities of at least 3 months duration following well-recognized manifestations of Lyme disease. Twenty-two of the 27 patients reported memory loss and 18 had CSF protein, evidence of intrathecal antibody to B. burgdorferi, or both. Each underwent a neuropsychological test battery consisting of tests of general cognitive abilities, memory, visual perception, construction, executive function, language, and fine motor dexterity. The patients were also administered the Minnesota Multi-phasic Personality Inventory (MMPI) to assess emotional status. Standard scores were calculated from published, age-corrected normative data, and scores that were two standard deviations below the mean were considered as evidence of impairment on a particular test. Memory impairment was defined as two standard deviations below average on any one test or one standard deviation below average on two tests, according to a previously described system. All patients had IQ scores that were calculated or estimated to be average or above average. Twelve of the 22 patients reporting memory difficulty met the criteria for memory impairment, as did 2 patients who denied memory problems. Only 1 patient had a below average

Recall Delayed Recognition

Figure 3 A comparison of memory scores for patients with LE, fibromyalgia, and depression on the CVLT.

Recall Delayed Recognition

Figure 3 A comparison of memory scores for patients with LE, fibromyalgia, and depression on the CVLT.

performance on a test of abstract problem solving, the Wisconsin Card Sorting test, and 1 patient did poorly on a naming test. No patient had a below average performance on any of the other cognitive tests. Nine patients produced MMPI profiles consistent with depression. Of the 12 patients with objective evidence of memory impairment, 9 had abnormal CSF findings; however, it should be noted that 9 of 10 patients with normal memory scores also had abnormal CSF. The 4 of 24 patients with abnormal MRI scans, which were characterized as small round lesions in the periventricular white matter, all had impaired memory and 3 of the 4 had abnormal CSF.

In contrast to the earlier study by Halperin and colleagues that described a wide range of cognitive impairment, the only significant deficits in this study were in the area of memory impairment. However, unlike the patients in Halperin's study, more than half of the patients in this study had been treated with one or more courses of antibiotic treatment prior to testing. It is therefore possible that the discrepancy in results between the two studies reflects partial recovery.

Many of the symptoms of LE are similar to those reported by patients with depression. These include irritability, fatigue, emotional liability, poor concentration, impaired sleep, and memory disturbance. Depression is also common in late-stage Lyme disease. To examine the impact of psychological factors—par-ticularly somatic concerns, depression, and anxiety

—on memory impairment in LE patients, my colleagues and I compared 20 patients with well-documented Lyme disease to patients with fibromyalgia and patients with mild to moderate depression. The rationale for comparing fibromyalgia and depressed patients with LE patients was that the cognitive symptoms in these illnesses are similar. Thirteen of the 20 Lyme patients had abnormal CSF and 2 had abnormal MRI scans. Memory was assessed using the three standardized memory instruments—the CVLT, the Wechsler Memory Scale (WMS), and the Rey-Osterrieth Complex Figure. Indices of psychopathol-ogy were obtained from the MMPI and BDI. The depression and fibromyalgia groups performed significantly better than the LE group on both the CVLT (Fig. 3) and a WMS visual memory subtest, whereas recognition memory on the CVLT did not differ. The depression group also performed better than the Lyme group on the WMS Verbal Paired Associate Learning test, another verbal learning test. In contrast, both the fibromyalgia and depressed groups showed greater evidence of psychopathology. On the MMPI, the Lyme group had significantly lower scores on the scales most sensitive to depression and anxiety compared to those of the depression group and significantly lower scores on scales sensitive to the somatic concerns compared to those of the fibromyalgia group (Fig. 4). The Lyme group also had lower BDI scores, but this did not reach statistical significance. These data strongly suggest that memory impairment in LE

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