Diagnostic utility of aquaporin-4 in the analysis of active demyelinating lesions.

OBJECTIVE: To assess, in a surgical biopsy cohort of active demyelinating lesions, the diagnostic utility of aquaporin-4 (AQP4) immunohistochemistry in identifying neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD) and describe pathologic features that should prompt AQP4 immunohistochemical analysis and AQP4-immunoglobulin G (IgG) serologic testing. METHODS: This was a neuropathologic cohort study of 20 surgical biopsies (19 patients; 11 cord/9 brain), performed because of diagnostic uncertainty, interpreted as active demyelinating disease and containing 2 or more of the following additional features: tissue vacuolation, granulocytic infiltrates, or astrocyte injury. RESULTS: AQP4 immunoreactivity was lost in 18 biopsies and increased in 2. Immunopathologic features of the AQP4 loss cohort were myelin vacuolation (18), dystrophic astrocytes and granulocytes (17), vascular hyalinization (16), macrophages containing glial fibrillary acid protein (GFAP)-positive debris (14), and Creutzfeldt-Peters cells (0). All 14 cases with available serum tested positive for AQP4-IgG after biopsy. Diagnosis at last follow-up was NMO/NMOSD (15) and longitudinally extensive transverse myelitis (1 each relapsing and single). Immunopathologic features of the AQP4 increased cohort were macrophages containing GFAP-positive debris and granulocytes (2), myelin vacuolation (1), dystrophic astrocytes (1), Creutzfeldt-Peters cells (1), and vascular hyalinization (1). Diagnosis at last follow-up was multiple sclerosis (MS) and both tested AQP4-IgG seronegative after biopsy. CONCLUSIONS: AQP4 immunohistochemistry with subsequent AQP4-IgG testing has diagnostic utility in identifying cases of NMO/NMOSD. This study highlights the importance of considering NMOSD in the differential diagnosis of tumefactive brain or spinal cord lesions. AQP4-IgG testing may avert biopsy and avoid ineffective therapies if these patients are erroneously treated for MS.

Early and widespread injury of astrocytes in the absence of demyelination in acute haemorrhagic leukoencephalitis.

Acute hemorrhagic leukoencephalitis (AHL) is a fulminant demyelinating disease of unknown etiology. Most cases are fatal within one week from onset. AHL pathology varies with the acuteness of disease. Hemorrhages, vessel fibrinoid necrosis, perivascular fibrin exudation, edema and neutrophilic inflammation are early features, while perivascular demyelination, microglial foci and myelin-laden macrophages appear later. Reactive astrocytosis is not present in early hemorrhagic non-demyelinated lesions, but is seen in older lesions. This case report presents the pathology of an AHL case with fulminant course and fatal outcome within 48 hours from presentation. Severe hemorrhages, edema and neutrophilic inflammation in the absence of circumscribed perivascular demyelination affected the temporal neocortex and white matter, hippocampus, cerebellar cortex and white matter, optic chiasm, mammillary bodies, brainstem, cranial nerve roots and leptomeninges. Perivascular end-feet and parenchymal processes of astrocytes exhibited impressive swelling in haemorrhagic but non-demyelinated white matter regions. Astrocytes were dystrophic and displayed degenerating processes. Astrocytic swellings and remnants were immunoreactive for aquaporin-4, aquaporin-1 and glial fibrillary acidic protein. These morphological changes of astrocytes consistent with injury were also observed in haemorrhagic and normal appearing cortex. Our findings reinforce that perivascular demyelination is not present early in AHL. This is the first study that highlights the early and widespread astrocytic injury in the absence of demyelination in AHL, suggesting that, similarly to neuromyelitis optica and central pontine myelinolysis, demyelination in AHL is secondary to astrocyte injury.

Pathologic heterogeneity persists in early active multiple sclerosis lesions.

OBJECTIVE: Multiple sclerosis (MS) lesions demonstrate immunopathological heterogeneity in patterns of demyelination. Previous cross-sectional studies reported immunopatterns of demyelination were identical among multiple active demyelinating lesions from the same individual, but differed between individuals, leading to the hypothesis of intraindividual pathological homogeneity and interindividual heterogeneity. Other groups suggested a time-dependent heterogeneity of lesions. The objective of our present study was to analyze tissue samples collected longitudinally to determine whether patterns of demyelination persist over time within a given patient. METHODS: Archival tissue samples derived from patients with pathologically confirmed central nervous system inflammatory demyelinating disease who had undergone either diagnostic serial biopsy or biopsy followed by autopsy were analyzed immunohistochemically. The inclusion criteria consisted of the presence of early active demyelinating lesions--required for immunopattern classification--obtained from the same patient at 2 or more time points. RESULTS: Among 1,321 surgical biopsies consistent with MS, 22 cases met the study inclusion criteria. Twenty-one patients (95%) showed a persistence of immunopathological patterns in tissue sampled from different time points. This persistence was demonstrated for all major patterns of demyelination. A single patient showed features suggestive of both pattern II and pattern III on biopsy, but only pattern II among all active lesions examined at autopsy. INTERPRETATION: These findings continue to support the concept of patient-dependent immunopathological heterogeneity in early MS and suggest that the mechanisms and targets of tissue injury may differ among patient subgroups. These observations have potentially significant implications for individualized therapeutic approaches.

Inflammatory cortical demyelination in early multiple sclerosis.

BACKGROUND: Cortical disease has emerged as a critical aspect of the pathogenesis of multiple sclerosis, being associated with disease progression and cognitive impairment. Most studies of cortical lesions have focused on autopsy findings in patients with long-standing, chronic, progressive multiple sclerosis, and the noninflammatory nature of these lesions has been emphasized. Magnetic resonance imaging studies indicate that cortical damage occurs early in the disease. METHODS: We evaluated the prevalence and character of demyelinating cortical lesions in patients with multiple sclerosis. Cortical tissues were obtained in passing during biopsy sampling of white-matter lesions. In most cases, biopsy was done with the use of stereotactic procedures to diagnose suspected tumors. Patients with sufficient cortex (138 of 563 patients screened) were evaluated for cortical demyelination. Using immunohistochemistry, we characterized cortical lesions with respect to demyelinating activity, inflammatory infiltrates, the presence of meningeal inflammation, and a topographic association between cortical demyelination and meningeal inflammation. Diagnoses were ascertained in a subgroup of 77 patients (56%) at the last follow-up visit (at a median of 3.5 years). RESULTS: Cortical demyelination was present in 53 patients (38%) (104 lesions and 222 tissue blocks) and was absent in 85 patients (121 tissue blocks). Twenty-five patients with cortical demyelination had definite multiple sclerosis (81% of 31 patients who underwent long-term follow-up), as did 33 patients without cortical demyelination (72% of 46 patients who underwent long-term follow-up). In representative tissues, 58 of 71 lesions (82%) showed CD3+ T-cell infiltrates, and 32 of 78 lesions (41%) showed macrophage-associated demyelination. Meningeal inflammation was topographically associated with cortical demyelination in patients who had sufficient meningeal tissue for study. CONCLUSIONS: In this cohort of patients with early-stage multiple sclerosis, cortical demyelinating lesions were frequent, inflammatory, and strongly associated with meningeal inflammation. (Funded by the National Multiple Sclerosis Society and the National Institutes of Health.).