Isolated U-fiber involvement in MS

Several studies have attempted to associate the physical and cognitive disabilities of MS patients with a particular gross anatomic distribution of plaque burden.^1-11 However, the results of these studies have been less than consistent or successful, possibly because a plaque within the deep white matter partially compromises a variable set of projections connecting a heterogeneous set of brain regions. In the present study we used a new, far more precise technique to quantify the demyelinating or edematous nature of an MS plaque, and we examined the effect of these plaques on a narrowly defined set of anatomic projections; namely, U-fibers(figure 1). In the past, MS lesions partially involving U-fibers have been studied using MRI.¹⁰ To our knowledge, however, isolated U-fiber MS lesions have not been described in detail. In this investigation we studied the frequency and sites of isolated U-fiber lesions in MS patients using MRI, and correlated these findings with physical disabilities and neuropsychological impairments. In particular, cognitive impairment is one of the major symptoms in MS, and this lessens the quality of life of the patients.¹² Many authors have associated the cognitive impairment in MS with subcortical plaques.^11,13,14 The present study is a preliminary test of the hypothesis that a specific distribution of plaque burden contributes to the cognitive difficulty of MS patients.

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Figure 1. Schema of patterns of MS lesion involvement of the U-fiber. (a) A lesion involving only the U-fibers(isolated U-fiber lesion). (b) A lesion involving the cortex and U-fibers.(c) A lesion involving the U-fibers and deep white matter. (d) A lesion involving the cortex, U-fibers, and deep white matter.

Methods. Fifty-three MR studies of 53 patients (35 women and 18 men), age 21 to 62 years (mean, 39.5 years) with clinically definite MS as defined by the Poser criteria¹⁵ were evaluated. Thirty-four patients had relapsing-remitting (RR) MS and 19 patients had chronic progressive (CP) MS as determined prior to entry into the study. Patients were assessed by a neurologist (DLK) specializing in the care of MS patients. Patients treated with immunosuppressants, or cytotoxic or immunomodulatory drugs were excluded, other than those subjected to brief courses of pulsed corticosteroids for exacerbations that have little effect on cognitive functioning. Written informed consent was obtained from the patients.

Patient motor disability was scored according to the Expanded Disability Status Scale (EDSS) and Ambulation Index (AI).^16,17 A battery of standardized neuropsychological tests with excellent test-retest reliability (table) was performed on each patient.¹⁸ This battery was selected to examine a broad range of cognitive functions known to be compromised in MS patients and thought to be related to lesion burden,^1-5 particularly including tests that reflect performance in memory and executive functioning that have been reported to be impaired in MS.^19,20

Images were obtained on a 1.5-T scanner (Signa, GE Medical Systems, Milwaukee, WI) with a quadrature head coil. The imaging protocol included interleaved, contiguous 3-mm-thick axial T2-weighted fast spin-echo imaging(TR, 2,500 msec; TE, 18 and 90 msec; echo space, 18 ms; echo train length, 8; number of excitations [NEX], 1; matrix size, 192 × 256; and field of view [FOV], 22 cm), and postgadolinium contiguous 3-mm-thick T1-weighted imaging (TR, 600 msec; TE, 27 msec; NEX, 1; matrix size, 192 × 256; FOV, 22 cm; with flow compensation). The postgadolinium images were obtained immediately after gadopentetate dimeglumine was given at a dose of 0.1 mmole/kg body weight.

An internal version of the 3DVIEWNIX software system (Medical Image Processing Group, Department of Radiology, HUP, Philadelphia, PA) was used to detect, delineate, and quantitate lesions on the T2-weighted images using fuzzy connectedness principles.^21-23 This method has been shown to have low intra- and interobserver variability with a coefficient of variation of 0.9% for total lesion volume, and high sensitivity with a false-negative volume fraction of 1.3%. Various aspects of the theory, and algorithms used for lesion detection are described in detail elsewhere.^21-23 A neuroradiologist verified whether every lesion involving the U-fiber region was isolated to the U-fibers or not.

Patients were divided into two groups-those without any or with only one isolated U-fiber lesion and those with more than one isolated U-fiber lesions-based on the assumption that multiple U-fiber lesions were needed to demonstrate an effect on cognitive functioning. Wilcoxon's rank sum test (two tailed) was used to determine the differences in EDSS, AI, and neuropsychological tests between these two groups. Student's t-test (two tailed) was used to determine if there is a significant difference in volume of the lesions on the T2-weighted images between the two groups.

Results. Forty-two arcuate hyperintensities along the U-fibers were detected by the software in 28 patients (53%; figures 2 and 3). Eighteen of the 34 RR patients (53%) and 10 of the 19 CP patients (53%) had at least one U-fiber lesion. Twenty patients(37.7%; 12 RR, 8 CP) had one U-fiber lesion, two patients (3.8%; 2 RR, 0 CP) had two U-fiber lesions, and six patients (11.3%; 4 RR, 2 CP) had three U-fiber lesions (figure 4). Among these 42 lesions, 27 (64.3%) were seen in the frontal lobe, eight (19.0%) in the temporal lobe, three (7.1%) in the parietal lobe, three (7.1%) in the occipital lobe, and one (2.4%) in both frontal and parietal lobes(figure 5). Among the lesions involving the frontal lobe, 12 (44%) were seen in the superior frontal gyrus (seefigure 2). Four lesions (9.5%) showed gadolinium enhancement. Seventeen lesions (40%) were hypointense on the T1-weighted image.

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Figure 2. A T2-weighted axial image shows an arcuate hyperintensity involving only the U-fiber of the right superior frontal gyrus (arrow).

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Figure 3. (A) An isolated U-fiber lesion is present in the left frontal lobe (arrow); however, this lesion might have been missed by human readers because its shape and intensity are similar to those of the CSF in the sulci (arrowheads). (B) The 3DVIEWNIX software system detects and delineates this lesion (yellow color). Note that the software system shows lesions one by one to the operator.

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Figure 4. Chart shows percentages of patients with different numbers of isolated U-fiber lesions.

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Figure 5. Chart shows percentages of locations of isolated U-fiber lesions.

Scores of three neuropsychological tests (Rey Auditory Verbal Learning Test [recall after interference], Sentence Repetition Test, and Controlled Oral Word Association Test) were significantly different between the patient group with more than one U-fiber lesion and the patient group without any or with only one U-fiber lesion (p = 0.03, p = 0.04, and p = 0.03 respectively; see table). Scores of three additional neuropsychological tests demonstrated nearly significant differences between the two groups (0.05 ≤ p < 0.1; seetable). All the neuropsychological tests that showed significant or nearly significant differences were tests reflecting performance in memory or executive control. EDSS and AI were not significantly different between the two groups (p = 0.68 and p = 0.95, respectively). Total lesion volume on the T2-weighted images was not significantly different between the two groups of patients with different numbers of isolated U-fiber lesions (t = 0.90, p = 0.37), indicating that differences in total plaque burden cannot fully account for differences in neuropsychological performance between the two groups. Discussion. MRI has established itself as the "gold standard" in identifying MS lesions in the white matter with superb sensitivity.²⁴ It is well known that subcortical U-fiber is one of the predilection sites for MS lesions.^25,26 However, it has not been well recognized that some lesions may involve only the U-fibers and may extend along the fibers (seefigure 1A). Although MR images illustrating such lesions have been shown,^26,27 to our knowledge there is no literature on their detection and quantification or on describing the frequency, signal intensity characteristics, or detailed relationship with the degree of neurologic impairment.

Our study demonstrated that about half of MS patients showed at least one lesion that affected only the U-fibers, regardless of their clinical classification. Three of the 11 executive control and memory tests showed statistically significant differences between the 45 patients with zero or one U-fiber involvement compared with the eight patients with multiple U-fiber lesions, which may suggest that U-fiber involvement contributes to deficits in memory and executive control. This preliminary and exploratory observation requires further confirmation, because the findings are not very strong in terms of number of the patients and the statistics. The total volumes of lesions on the T2-weighted images were not significantly different between these two patient groups, which excluded the possibility that a difference in the lesion volume in other white matter regions has produced the significant differences in the neuropsychological tests.

The U-fiber is a short-association fiber that connects adjacent gyri and is involved in higher functions of the brain.²⁸ A pathologic study revealed that the junction of the cortex and white matter, where the U-fibers run, is one of the predilection sites for MS plaques.²⁵ Paskavitz et al.²⁹ reported a case of acute demyelinating encephalopathy with isolated U-fiber lesions. In their patient, T2-weighted and postgadolinium MR images showed arcuate lesions along the U-fibers. Their neuropsychological tests showed decreased full-scale IQ, verbal IQ, and performance IQ. Pathologic examination revealed perivascular inflammation and demyelination along the U-fibers.

Four lesions (9.5%) were hyperintense and 17 lesions (40%) were hypointense on the postgadolinium T1-weighted images of our study. Active MS lesions enhance on postgadolinium images,^30,31 and hypointense lesions on the T1-weighted images likely represent demyelination with varying amounts of associated axonal loss.^32,33 Isolated U-fiber lesions thus may have variously evolving pathologic stages. However, the mechanism of evolution of isolated U-fiber lesions is undetermined. Since MS lesions usually do not develop along the nerve fibers in the brain, but rather tend to develop along the vessels,^34,35 we hypothesize that lymphocytic infiltration around vessels coursing through the U-fibers^36-39 may play a role in the development of isolated U-fiber lesions.

We used an internal version of the 3DVIEWNIX software system²¹ to detect MS lesions using a fuzzy connectedness method.^22,23 These methods have been shown to have high sensitivity and low intra- and interobserver variability in detecting MS lesions of the brain demonstrated on T2-weighted MR images.²³ Although this approach was originally developed for determining total MS lesion volume in the brain, we used it to detect isolated U-fiber lesions because of its superb sensitivity and constancy for lesion detection. Some isolated U-fiber lesions might have been missed on a conventional or fast spin-echo sequence by human readers because most of the lesions are small and very close to the CSF in the sulci, making human recognition difficult (see figure 3). A fluid-attenuated inversion recovery sequence may demonstrate better conspicuity of these lesions, because the intensity of CSF is nulled on this sequence.^40-43

Neurocognitive impairment is one of the major symptoms in MS. Cognitive deficits in MS most often include compromised executive control¹⁹ and memory.²⁰ Current estimates set the frequency of cognitive deficits in MS at 30 to 70%,^6,13,44-46 and these impairments can become so severe that they result in a "subcortical" dementia.⁴⁷

Our study demonstrated that scores of three neuropsychological tests (Rey Auditory Verbal Learning Test [recall after interference], Sentence Repetition Test, and Controlled Oral Word Association Test) differed significantly, and three other neuropsychological tests (Paced Auditory Serial Addition Test 16, Reading Comprehension Test, and Digit Span Test[backward]) were nearly significantly different between groups of MS patients with differing levels of isolated U-fiber lesion burden. All the neuropsychological tests that showed statistical significance were tests representing executive control or memory. A large proportion of the U-fiber lesions were located in the frontal lobes, and several of these neuropsychological measures are thought to be crucially dependent on frontal lobe function.^48-50 Previous pathologic²⁵ and MR imaging¹¹ findings have found that MS lesions are most frequently seen in the frontal lobes. U-fibers are probably an important component of the neural nets thought to play such a crucial role in cognitive function, and their interruption may contribute to the cognitive impairment of MS patients. In summary, our preliminary observations support the hypothesis that U-fiber lesions contribute to neurocognitive impairment in MS.

There was no significant difference in EDSS or AI between the two patient groups differing in their U-fiber lesion burden. EDSS and AI are most sensitive to motor and sensory dysfunction, presumably caused by plaque accumulation in discrete brain areas, including the pyramidal tracts, cerebellum, brainstem, and/or spinal cord. The probability of a sensorimotor deficit resulting from an isolated U-fiber lesion thus would be distinctly low. U-fiber involvement also did not appear to covary with measures of depression or fatigue.¹⁸ These findings suggest that some other mechanism contributes to the depression and fatigue that are common clinical complaints among MS patients.

In conclusion, isolated U-fiber involvement is an underappreciated MR finding in MS. Our preliminary and exploratory observation may lead the hypothesis that this may contribute to neuropsychological impairment, especially executive control and memory, although our observation requires further study and confirmation.