Perivenous demyelination: association with clinically defined acute disseminated encephalomyelitis and comparison with pathologically confirmed multiple sclerosis

Abstract

Distinction between acute disseminated encephalomyelitis and acute multiple sclerosis is often clinically difficult. Perivenous demyelination is the pathological hallmark of acute disseminated encephalomyelitis, whereas confluent demyelination is the hallmark of acute multiple sclerosis. We investigated whether perivenous demyelination versus confluent demyelination distinguishes acute disseminated encephalomyelitis from multiple sclerosis. Patients with perivenous demyelination (n = 13; median age 43 years, range 5-67) on brain biopsy and/or autopsy, ascertained retrospectively, were compared with a cohort with confluent demyelination only (n = 91; 84% multiple sclerosis, 16% isolated syndrome at follow-up; median age 39 years, range 10-69). Clinical presentation, course and the International Paediatric Multiple Sclerosis Study Group clinical criteria for acute disseminated encephalomyelitis were assessed in both cohorts. Among the perivenous demyelination cohort, 10 patients had only perivenous demyelination and three also had confluent demyelination. All but one patient with perivenous demyelination only had a monophasic course, whereas two of three with both types had a relapsing course. The perivenous demyelination cohort was more likely than the confluent demyelination cohort to present with encephalopathy (P < 0.001), depressed level of consciousness (P < 0.001), headache (P < 0.001), meningismus (P = 0.04), cerebrospinal fluid pleocytosis (P = 0.04) or multifocal enhancing magnetic resonance imaging lesions (P < 0.001). A distinct pattern of cortical microglial activation and aggregation without associated cortical demyelination was found among six perivenous demyelination patients, all of whom had encephalopathy and four of whom had depressed level of consciousness. This pattern of cortical pathology was not observed in the confluent demyelination cohort, even in one patient with depressed level of consciousness. Clinical criteria were 80% sensitive and 91% specific for pathologically defined acute disseminated encephalomyelitis (perivenous demyelination), but misdiagnosed acute disseminated encephalomyelitis among 9% of patients with confluent demyelination and multiple sclerosis diagnosis at last follow-up. Perivenous demyelination is associated with meningoencephalopathic presentations and a monophasic course. Depressed level of consciousness is a more specific clinical criterion for pathologically confirmed acute disseminated encephalomyelitis than encephalopathy, which over-diagnosed acute disseminated encephalomyelitis among multiple sclerosis patients. A distinct pattern of cortical microglial activation without cortical demyelination may be the pathological correlate of depressed level of consciousness in acute disseminated encephalomyelitis. Although pathological evidence of perivenous demyelination may be superior to clinical criteria for diagnosing acute disseminated encephalomyelitis, the co-occurrence of perivenous and confluent demyelination in some individuals suggests pathogenic overlap between acute disseminated encephalomyelitis and multiple sclerosis and misclassification even with biopsy.

Figure 1

Case ascertainment.

Figure 2

Representative brain biopsies illustrating the observed patterns of demyelination. (A) Perivenous sleeve of inflammation and demyelination (20×); (B) three coalescing perivenous lesions (60×); and (C) extensive region of confluent demyelination with areas of perivenous demyelination in the periplaque white matter (4×). Luxol-fast blue periodic acid-Schiff myelin stain (A–C).

Figure 3

Patterns of cortical pathology in perivenous demyelination cohort. (A) Perivenous intracortical demyelinated lesion (20×); (B) subpial demyelination (arrows) (4×); (C) multifocal aggregates of cortical migroglial activation (4×); (D) macrophage/microglial activation concentrated in cortical layer 3 (arrows) (4×). Immunocytochemistry for proteolipid protein (A/B) and KiM1P (C/D).

Figure 4

Magnetic resonance imaging correlates of perivenous demyelination. (A) Coronal fluid attenuated inversion recovery (FLAIR): multifocal large ill-defined supratentorial and brainstem lesions without enhancement; (B) axial T₂: large ill-defined non-enhancing uni-hemispheric lesion; (C) T₁ with gadolinium: single large open ring enhancing mass with surrounding oedema; (D) axial FLAIR: large brainstem lesion with (H) punctate central and peripheral rim of enhancement; (E and F) sagittal FLAIR: numerous multifocal bilateral non-enhancing T₂ lesions in subcortical white matter, basal ganglion, cerebellum; (G) coronal T₁ with gadolinium: numerous bilateral enhancing subcortical white matter lesions; (I) T₁ with gadolinium: faint rim of enhancement of large ill-defined lesion with mass effect; (J) coronal FLAIR; residual confluent signal change crossing the corpus callosum; (K) axial FLAIR: residual signal change oriented perpendicular to corpus callosum becoming confluent; (L) new non-enhancing periventricular white matter lesions in patient with both perivenous demyelination and confluent demyelination.