John W. Prineas

Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion.

The study describes the clinical and pathological findings in 12 patients with relapsing and remitting multiple sclerosis, who died during or shortly after the onset of a relapse. Pathological changes not previously associated with the formation of new symptomatic lesions were observed in seven cases, namely, extensive oligodendrocyte apoptosis and microglial activation in myelinated tissue containing few or no lymphocytes or myelin phagocytes. No current laboratory model of multiple sclerosis, in particular, experimental allergic encephalomyelitis, is known with these features, which raises the possibility of some novel process underlying new lesion formation in multiple sclerosis. Ann Neurol 2004;55:000–000

Chronic relapsing polyneuritis

Clinical, electrophysiological and pathological findings in 23 patients with subacute and relapsing idiopathic demyelinating polyneuropathies are described. In 17 patients with relapsing polyneuropathy, the neurological illness was unaccompanied by any systemic disturbances. The term preferred for the neuropathy in this group of patients is chronic relapsing polyneuritis. The findings in this group suggest that the common form of this syndrome is due to a single disease entity. Chronic relapsing polyneuritis differs from acute idiopathic polyneuritis chiefly in regard to the rate of evolution and the severity of the initial episode of polyneuropathy. If these two polyneuropathies have the same pathogenesis, the factor which determines whether the disease is acute and self-limiting or chronically relapsing is often present at the time of onset of the disease. The relationship of chronic relapsing polyneuritis to relapsing hypertrophic polyneuropathy and progressive hypertrophic polyneuropathy is also discussed and it is concluded that these diseases may constitute a spectrum of pathogenetically related disorders. In chronic relapsing polyneuritis, as in other demyelinating polyneuropathies, a marked segmental reduction in axon diameter accompanies demyelination. This corresponds to a more than 50% reduction in the volume of the affected region of the axon and it is associated with increased packing of axoplasmic organelles and wrinkling of the axolemma. It is suggested that in the normal myelinated nerve fibre, the Schwann cell and myelin sheath maintain fluid locally within the axon.

Immunopathology of secondary-progressive multiple sclerosis

Twenty‐three plaques obtained at early autopsy from 2 patients with secondary‐progressive multiple sclerosis were examined immunohistochemically for microglia/macrophages, and for immunoglobulins and components of activated complement. Most of the lesions examined in both cases exhibited evidence of low‐grade active demyelination of an unusual type (frustrated phagocytosis) in periplaque white matter. This included linear groups of microglia engaging short segments of disrupted myelin that were associated with deposits of C3d, an opsonin formed during complement activation. Similar microglia/C3d/myelin profiles were not observed in newly forming lesions in cases of acute multiple sclerosis or other central white matter diseases. As C3d coupling is known to increase the immunogenicity of potential antigens enormously, present findings point to disrupted myelin close to plaques as a possible source of the putative multiple sclerosis antigen. Ongoing myelin destruction found in a high proportion of old, established plaques was surprising. It suggests that slowly expanding lesions (progressive plaques), in which ongoing myelin breakdown occurs in the absence of florid perivascular cell cuffing or other histological signs of acute inflammation, contribute to disease progression in cases of secondary‐progressive multiple sclerosis.

Multiple sclerosis: Distribution of inflammatory cells in newly forming lesions†

CD4 T‐cell–dependent macrophage activation directed against a myelin or oligodendrocyte antigen is generally thought to be the mechanism causing myelin destruction in multiple sclerosis (MS). However, areas within expanding MS lesions may exhibit prominent oligodendrocyte loss and apoptosis in the absence of infiltrating lymphocytes. The present study was designed to further investigate the inflammatory profile of different regions within rapidly expanding MS lesions.

Immunopathology of multiple sclerosis: report on an international meeting held at the Institute of Neurology of the University of Vienna.

H. Lassmann , C.S. Raine , J. Antel , J.W. Prineas d a Institute of Neurology, UniÕersity of Vienna, Schwarzspanierstrasse 17, A-1090 Vienna, Austria b ( ) Department of Pathology Neuropathology , K433 Albert Einstein College of Medicine of YeshiÕa UniÕersity 1300 Morris Park AÕenue, Bronx, NY 10461, USA c Montreal Neurological Institute, Montreal, Canada d Dept. Veterans Affairs, Medical Center, East Orange, NJ, USA

The fine structure of chronically active multiple sclerosis plaques.

Materials and methods. Seventeen typical, old spinal and cerebral plaques, in tissue fured for electronmicroscopy by in situ perfusion with 3 percent glutaraldehyde within 20 minutes of death, were studied in two MS patients. The clinical features in each case and the fixation method are reported elsewhere.lS2 One-pm-thick epoxy embedded sections, stained with toluidine blue, were used extensively for light microscopy and to select areas for electronmicroscopy. Most of the lesions examined were also studied using frozen sections obtained from mirror blocks and stained with oil red 0 and hematoxylin. Axon diameters were measures in electronmicrographs printed at a final magnification of 14,000 x , the diameter of each axon being taken as the mean of the longest diameter and the diameter at right angles to this a t its midpoint. Distinguishing nonmyelinated axons from astroglial processes of the same size was not a problem, since the latter usually contained glycogen granules, tight bundles of filaments, and relatively few or no microtubules, whereas small axons contained numerous tubules, a few loosely arranged filaments, and no glycogen. All nonmyelinated axonal profiles that were measured were classified as unmyelinated fibers without allowing for the fact that some of these were nodal sections of myelinated fibers.

Pathology of the early lesion in multiple sclerosis

Ideas concerning the nature of multiple sclerosis continue to be strongly influenced by the unusual morphology of the disease. A review of classic histology studies, however, reveals that there is less agreement than might be supposed concerning several important histiological features of the early lesion. Electron microscopy of brain biopsies, of immersion fixed autopsy tissue and of autopsy tissue fixed by early in situ brain perfusion suggests that the mechanism of demyelination in multiple sclerosis may be an unusual one that involves a progressive reduction in the number of myelin lamellae around nerve fibers in the vicinity of cells of uncertain origin that contain filamentous and multilamellated cytoplasmic inclusions unlike the usual pleomorphic inclusions seen in myelin phagocytes. Lymphocytes are not directly involved in this process but are observed to contact the inclusion material following its delivery to the Virchow-Robin spaces. The putative neurogenic or viral antigen in multiple sclerosis may be contained in this material. The occurrence of filamentous nuclei in early lesions fixed by immersion is an unrelated phenomenon, which may be an autolytic or drug induced artifact although this has not yet been established.

Blood-Brain Barrier Abnormalities in Longstanding Multiple Sclerosis Lesions. An Immunohistochemical Study

Abstract. Thirty-five randomly selected plaques from five patients with longstanding multiple sclerosis were examined immunohistochemically for evidence of extravascular serum proteins. One lesion showed histological evidence of active demyelination and 34 were inactive. In the one active lesion and in 26 of the 34 inactive lesions, serum proteins were detected outside blood vessels in a distribution consistent with leakage during life. The findings suggest that the blood-brain barrier (BBS) is permanently damaged in many old plaques, although to a degree not often detectable by current gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA)-enhanced magnetic resonance imaging (MRI). The findings also suggest that in patients with multiple sclerosis, a breached BBB is not by itself sufficient to induce active demyelination. Continuous exposure of demyelinated axons and glia to cytokines, antibody or other factors present in the circulation might be important, however, in preventing oligodendrocyte regeneration and new myelin formation in longstanding lesions.

Paramyxovirus-Like Particles Associated with Acute Demyelination in Chronic Relapsing Multiple Sclerosis

Electron microscopy of small perivenous demyelinating lesions in a formalin-fixed brain of a multiple sclerosis subject revealed nuclear and cytoplasmic particles resembling paramyxovirus nucleocapsids. These particles, 18 to 20 nanometers in diameter, were found in mononuclear cells related to the central vein and infiltrating the zone of active demyelination. It is suggested that multiple sclerosis lesions may be initiated by seeding of lymphocytes bearing latent paramyxovirus to white matter of the central nervous system.

Adrenomyeloneuropathy A probable variant of adrenoleukodystrophy: II. General pathologic, neuropathologic, and biochemical aspects

Histopathologic features were studied in postmortem examination of two men with adrenomyeloneuropathy, and biochemical studies were performed on one of these individuals. The histopathologic picture of one case included dying-back features in the nervous system and lamellar cytoplasmic inclusions in the brain, adrenal gland, and testis similar to those in adrenoleukodystrophy. Biochemical studies of the cerebral white matter of this individual revealed increased amounts of long-chain saturated fatty acids in cholesterol esters, an abnormality characteristic of adrenoleukodystrophy. Despite differences in clinical presentation and neuropathology, adrenomyeloneuropathy probably represents a distinct variant of adrenoleukodystrophy.