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Observation
April 2011

Childhood-Onset Multiple Sclerosis With Progressive Dementia and Pathological Cortical Demyelination

Author Affiliations

Author Affiliations: Departments of Neurology (Drs Bunyan, Popescu, and Lucchinetti) and Laboratory Medicine and Pathology (Dr Parisi), Mayo Clinic, College of Medicine, Rochester, Minnesota; and Department of Neurology, Mayo Clinic, Scottsdale, Arizona (Drs Carter and Caselli).

Arch Neurol. 2011;68(4):525-528. doi:10.1001/archneurol.2011.50
Abstract

Objective  To describe a case of childhood-onset progressive multiple sclerosis with dementia and evidence of extensive cortical demyelination from brain biopsy specimen.

Design  Case report.

Setting  Mayo Clinic, Rochester, Minnesota.

Patient  A 26-year-old man with a history of behavioral changes starting at the age of 13 years followed by progressive dementia.

Interventions  Neurological examination, magnetic resonance imaging, cerebrospinal fluid studies, neuropsychological testing, and brain biopsy.

Results  Magnetic resonance imaging scans showed numerous T2-weighted hyperintensities throughout the central nervous system not associated with contrast enhancement. Brain biopsy specimens showed cortical and subcortical demyelination. All 3 types of cortical demyelinating lesions were observed: leukocortical, intracortical, and subpial. Lesions were associated with profound microglial activation. The patient continued to progress despite attempts to treat with multiple sclerosis disease–modifying therapies.

Conclusions  Multiple sclerosis should be considered in the diagnosis of progressive dementia in children and young adults. Cortical demyelination may contribute to cognitive decline in patients with dementia due to multiple sclerosis.

Cognitive impairment in multiple sclerosis (MS) has been reported in 40% to 65% of patients, with double inversion recovery magnetic resonance imaging (MRI) studies demonstrating significant correlation between the burden of cortical lesion and the decline of cognitive function.1 However, dominant cognitive impairment due to MS is uncommon in childhood-onset MS.2 Furthermore, a primary progressive course in pediatric MS is rare.3,4 We present a case of progressive dementia in childhood-onset MS associated with evidence of extensive cortical demyelination (CDM) from brain biopsy specimen.

REPORT OF A CASE

A 26-year-old man first developed behavioral symptoms at age 13 years. These symptom were characterized by inattention and personality change, and he was diagnosed with attention-deficit disorder. His academic performance progressively declined, with grades dropping from Bs in middle school to Cs and Ds in high school. By age 17 years, he developed a subtle gait and sphincter difficulties, although his progressive cognitive symptoms predominated. He graduated high school and attended community college with difficulty. Over the subsequent years, he became increasingly apathetic with reduced motivation. At the age of 25 years, he had his first brain MRI, which revealed global brain atrophy and numerous T2-weighted hyperintense and T1-weighted hypointense periventricular, subcortical, juxtacortical, brainstem, and spinal cord lesions (Figure, A-C). The lesions did not enhance with contrast. Diagnostic workup included complete blood count, comprehensive metabolic panel, Lyme serology, and testing for C-reactive protein level, thyroid function, antinuclear antibodies, vitamin B12 level, vitamin D level, human immunodeficiency virus, lipid profile, and homocysteine level; all of the results were normal. Cerebrospinal fluid studies showed a white blood cell count of 16/μL (to convert to ×109/L, multiply by 0.001), a red blood cell count of 0 × 106/μL (to convert to ×1012/L, multiply by 1.0), a glucose level of 61 mg/dL (to convert to millimoles per liter, multiply by 0.0555), a total cerebrospinal fluid protein level of 68.9 mg/dL, 20 oligoclonal bands, an IgG index of 1.07, and an IgG synthesis rate of 28.1 mg/dL. The results of the patient's cerebrospinal fluid VDRL test, Lyme polymerase chain reaction, and cytology were all negative. Neuropsychological testing demonstrated evidence of severe impairment in multiple modalities, including intellectual function, language, executive function, sensorimotor function, visual-spacial abilities, processing speed, attention and concentration, and memory. His performance was in the dementia range. He had relative preservation of academic performance (reading, comprehension, and math). He also met criteria for major depression and generalized anxiety. He was diagnosed with MS. Despite the absence of relapses, he was treated with several courses of steroids, glatiramer acetate, monthly intravenous immunoglobulin, and natalizumab without response. Neurological examination at age 26 years revealed a score of 20/36 on the Kokmen Mini-Mental Status Examination. Other pertinent positive results included the following: saccadic, smooth pursuits; a left extensor plantar response; and moderate difficulty on tandem gait. Given the prominent cortical atrophy and dominant cognitive presentation, a diagnostic right frontal brain biopsy was performed to exclude a superimposed primary neurodegenerative disorder.

Figure.
A and C, Axial and sagittal fluid-attenuated inversion recovery magnetic resonance imaging (MRI) scans showing typical periventricular lesions of high signal. Some lesions appear to involve the cortical gray matter (arrows). B, Axial T1-weighted MRI scan with gadolinium showing absence of enhancing lesions. D, Subpial lesion showing loss of myelin that extends in the subcortical white matter (proteolipid protein [PLP]; scale bar, 1.6 mm). E, Cortical edge of the subpial lesion showing lack of active demyelination (PLP; scale bar, 50 μm). F, White matter border of the subpial lesion is mostly inactive, but rare macrophages containing myelin degradation products within their cytoplasm (inset) are still present (PLP; scale bar, 50 μm; inset scale bar, 10 μm). G, Intersecting subpial and leukocortical lesions; the subpial lesion bordered by a rim of microglia appears to expand toward subcortical white matter (black arrows), whereas a leukocortical lesion revealed by profound macrophage activation appears to extend toward the pial surface (white arrows) (KiM1P; scale bar, 1.6 mm). H, The subpial lesion is bordered by a rim of microglia, and some microglia are seen in close apposition to neurons (inset) (KiM1P; scale bar, 100 μm; inset scale bar, 20 μm). I, Macrophages are the predominant cells in the leukocortical lesion (KiM1P; scale bar, 100 μm). J, The white matter located in the intersection zone of the subpial and leukocortical plaques shows a destructive area; the inset shows a reactive astrocyte located in the proximity of a macrophage (hematoxylin-eosin; scale bar, 500 μm; inset scale bar, 20 μm). The parenchymal and perivascular CD3+ lymphocytes (CD3; scale bar, 100 μm) (K) and the parenchymal and perivascular CD8+ lymphocytes (CD8; scale bar, 100 μm) (L) are components of the inflammatory infiltrates located in the demyelinated white matter of the subpial and/or leukocortical lesion. The perivascular meningeal CD3+ lymphocytes (CD3; scale bar, 200 μm) (M) and the perivascular meningeal CD8+ lymphocytes (CD8; scale bar, 200 μm) (N) are components of the meningeal inflammatory infiltrates. O, Intracortical lesion (PLP; scale bar, 200 μm).

A and C, Axial and sagittal fluid-attenuated inversion recovery magnetic resonance imaging (MRI) scans showing typical periventricular lesions of high signal. Some lesions appear to involve the cortical gray matter (arrows). B, Axial T1-weighted MRI scan with gadolinium showing absence of enhancing lesions. D, Subpial lesion showing loss of myelin that extends in the subcortical white matter (proteolipid protein [PLP]; scale bar, 1.6 mm). E, Cortical edge of the subpial lesion showing lack of active demyelination (PLP; scale bar, 50 μm). F, White matter border of the subpial lesion is mostly inactive, but rare macrophages containing myelin degradation products within their cytoplasm (inset) are still present (PLP; scale bar, 50 μm; inset scale bar, 10 μm). G, Intersecting subpial and leukocortical lesions; the subpial lesion bordered by a rim of microglia appears to expand toward subcortical white matter (black arrows), whereas a leukocortical lesion revealed by profound macrophage activation appears to extend toward the pial surface (white arrows) (KiM1P; scale bar, 1.6 mm). H, The subpial lesion is bordered by a rim of microglia, and some microglia are seen in close apposition to neurons (inset) (KiM1P; scale bar, 100 μm; inset scale bar, 20 μm). I, Macrophages are the predominant cells in the leukocortical lesion (KiM1P; scale bar, 100 μm). J, The white matter located in the intersection zone of the subpial and leukocortical plaques shows a destructive area; the inset shows a reactive astrocyte located in the proximity of a macrophage (hematoxylin-eosin; scale bar, 500 μm; inset scale bar, 20 μm). The parenchymal and perivascular CD3+ lymphocytes (CD3; scale bar, 100 μm) (K) and the parenchymal and perivascular CD8+ lymphocytes (CD8; scale bar, 100 μm) (L) are components of the inflammatory infiltrates located in the demyelinated white matter of the subpial and/or leukocortical lesion. The perivascular meningeal CD3+ lymphocytes (CD3; scale bar, 200 μm) (M) and the perivascular meningeal CD8+ lymphocytes (CD8; scale bar, 200 μm) (N) are components of the meningeal inflammatory infiltrates. O, Intracortical lesion (PLP; scale bar, 200 μm).

Neuropathological analysis included routine staining and immunocytochemistry techniques that were performed according to previously published protocols5 and using the following markers: hematoxylin-eosin, Luxol fast blue and proteolipid protein (for myelin), glial fibrillary acidic protein (for astrocytes), neurofilament (for axons), KiM1P for macrophages, and CD3 and CD8 for T cells. All 3 cortical MS plaque types were observed and included subpial (Figure, D-I), intracortical (Figure, O), and leukocortical lesions (data not shown). Subpial and leukocortical lesions were sharply demarcated (Figure, D) and surrounded by a rim of microglia (Figure, G and H). As previously reported for chronic MS,6,7 active demyelination was absent in the cortical gray matter (Figure, E); however, myelin-laden macrophages were rarely present in the underlying white matter (Figure, F [inset] and I). Profound microglial activation was present within cortical lesions, with occasional microglia in close apposition to neurons (Figure, H [inset]). The white vs gray matter component of the lesions was more destructive (Figure, J) and contained parenchymal and perivascular CD3+ (Figure, K) and CD8+ (Figure, L) lymphocytic infiltrates. Reactive astrocytosis was present (Figure, J [inset]). Marked diffuse and perivascular meningeal inflammation composed of CD3+ (Figure, M) and CD8+ (Figure, N) lymphocytes was present, but it was not topographically associated with areas of CDM. Interestingly, whereas the myelin stain showed a subpial lesion extending into the subcortical white matter (Figure, D), the macrophage-microglial stain indicated the intersection of both a subpial and a leukocortical lesion, which appeared to advance in opposite directions (Figure, G).

COMMENT

To our knowledge, this is the first study to describe pathological evidence of CDM in the setting of childhood-onset progressive MS presenting with dominant cognitive impairment. The lack of a clear history of relapses suggests a primary progressive disease course, which is rare in children; only 4% of childhood-onset MS cases develop a secondary progressive course during childhood.3,4 Cognitive impairment as the predominant presentation of MS is also uncommon and has been previously described in a cohort of 23 adults with relapsing-remitting or progressive MS, 14 of whom had progressive dementia.2 Although our patient had an established diagnosis of MS prior to brain biopsy, the atypical presentation, coupled with pronounced cortical atrophy, raised concerns for an alternative or superimposed explanation for the progressive dementia. Nevertheless, among young adults presenting with progressive dementia, MS has been reported to be the sole cause in 11% of cases.8 Amato et al9 conducted a 6-month serial cognitive study of a cohort of patients aged 10.9 to 20.6 years with relapsing-remitting MS compared with healthy controls. Cognitive impairment was found in 57% of patients who were younger than 15 years of age and in 70% of patients who were 15 years age or older. Of these patients, 75% had deterioration in cognitive function with time. This did not correlate with disease duration, use of disease-modifying therapy, or the Expanded Disability Status Scale. An earlier study by MacAllister et al10 reported cognitive impairment among 35% of 37 children with clinically definite MS. Interestingly, similar to our case, one of the included cases had attention-deficit/hyperactivity disorder; however, the cognitive test result was otherwise normal. Our case underscores the importance of considering MS in the differential diagnosis of pediatric patients presenting with progressive cognitive decline. This case also demonstrates the challenges in the clinical diagnosis of childhood behavioral and cognitive abnormalities.

Pathological and imaging studies indicate that CDM is extensive in patients with progressive MS.11 Subpial cortical lesions have a predilection for anatomical regions involved in cognitive functions, including the cingulate, temporal, insular, and cerebellar cortexes.11 However, the precise contribution of CDM to clinical signs is difficult to determine, particularly in the setting of the burden of extensive white matter lesions, as was observed in our patient. There are, however, several case reports of cognitive-dominant MS associated with widespread subpial CDM in the complete absence of white matter lesions, which suggests that CDM may be an important pathological substrate for cognitive decline in some patients with MS.6 Previous pathological studies describing extensive CDM in MS were based on chronic autopsy archival material. Whereas analysis of MS brain biopsy specimens offers the advantage of evaluating tissue pathology from earlier disease phases, there are several inherent limitations to this approach, including selection and sampling bias. Although none of the sampled cortical regions in our patient's biopsy specimens were normal, the extent of CDM and the relative burden of cortical disease cannot be reliably determined by biopsy alone. Furthermore, the absence of cortical demyelination in biopsy specimens does not exclude the presence of CDM in another cortical region. Nevertheless, the pathological evidence demonstrating all 3 cortical plaque types in our case, as well as the presence of severe cortical atrophy and numerous cortical and juxtacortical lesions on MRI scans, suggests that CDM may have contributed to the predominant cognitive clinical manifestations observed in this case.

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Article Information

Correspondence: Claudia F. Lucchinetti, MD, Department of Neurology, Mayo Clinic, College of Medicine, 200 First St SW, Rochester, MN 55905 (lucchinetti.claudia@mayo.edu).

Accepted for Publication: November 29, 2010.

Author Contributions:Study concept and design: Lucchinetti. Acquisition of data: Bunyan, Popescu, Carter, Caselli, and Lucchinetti. Analysis and interpretation of data: Bunyan, Popescu, Carter, Parisi, and Lucchinetti. Drafting of the manuscript: Bunyan, Popescu, and Lucchinetti. Critical revision of the manuscript for important intellectual content: Bunyan, Carter, Caselli, Parisi, and Lucchinetti. Obtained funding: Lucchinetti. Administrative, technical, and material support: Caselli. Study supervision: Lucchinetti.

Financial Disclosure: Dr Lucchinetti receives royalties from the publication of Blue Books of Neurology: Multiple Sclerosis 3 (Saunders Elsevier, 2010) and research support from the National Institutes of Health (grant NS49577-R01 [principal investigator]) and the National Multiple Sclerosis Society (grant RG 3185-B-3 [principal investigator]). Dr Parisi serves on scientific advisory boards for the US Government Defense Health Board and the Subcommittee for Laboratory Services and Pathology; he also serves as a section editor for the journal Neurology and receives royalties from the publication of Principles and Practice of Neuropathology, 2nd ed. (Oxford University Press, 2003) and research support from the National Institutes of Health (grant NS32352-13 [coinvestigator]).

Funding/Support: This study was supported by grant RO1-NS049577-01-A2 from the National Institutes of Health and grant NMSS RG 3185-B-3 from the National Multiple Sclerosis Society (both to Dr Lucchinetti).

Additional Contributions: We thank Patricia Ziemer, BA, for her expert technical assistance.

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