In this review, we emphasize neuropathologic and neurobehavioral aspects of central pontine and extrapontine myelinolysis (CPM/EPM), also known as the osmotic demyelination syndrome. The literature is reviewed from the time of the initial report in 1959 and from key developments that have occurred more recently. Particular consideration is given to pathogenic mechanisms as revealed by recent animal studies. The role of white matter pathology in neurobehavioral dysfunction is also considered. The “then” and “now” of CPM and EPM tell 2 different stories. Yet, in many respects, this expansion of information over the past nearly 50 years simply represents a continuum, as well as recognition, of the vast gaps that still persist in our understanding of this disorder.
Alcoholism, Central pontine myelinolysis, Extrapontine myelinolysis, Hyponatremia, Lateral pontine myelinolysis, Osmotic demyelination, Pathogenesis, White matter
Several excellent reviews have recently appeared in the internal medicine and neurology literature on central pontine and extrapontine myelinolysis (CPM/EPM), also known as osmotic demyelination syndrome, and have provided concise overviews on the topic from a clinical perspective. These studies have focused on historical aspects and updates on treatment of hyponatremia (1), refutation of the role of factors other than correction of hyponatremia in the causation of CPM (2), delineation of clinical features related to pontine and extrapontine lesions (3, 4), and changes in underlying medical disorders associated with CPM (5). A study of 44 patients with CPM published in 1999 documented a significantly more favorable clinical outcome than many earlier clinical studies had suggested (6). Most clinically symptomatic patients survive if secondary complications common to all debilitated patients can be controlled such as aspiration pneumonia, septicemia, deep venous thromboses, and pulmonary emboli (6); in this study, one third of survivors recovered completely, one third had some deficits but were independent, and one third had more significant neurologic deficits (6). Several new etiologic mechanisms have been proposed for CPM/EPM, including apoptosis (7, 8). In this issue of the Journal of Neuropathology & Experimental Neurology, an original study describing the role of myoinositol and possible pathogenic osmotic mechanisms appears (9).
In the process of developing the content for this review, the question “can more be said on CPM/EPM?” was certainly raised. Although historical, clinical, and neuroradiologic perspectives have often been covered by others, certain issues still remain even within these categories. Neurobehavioral changes have rarely been discussed, and more recent considerations of possible pathogenic mechanisms merit further discussion.
The seminal paper of Adams et al from 1959 that first recognized CPM as a new disorder is familiar to most neuropathologists (10). Based on their puzzling clinical experience with 2 patients and detailed autopsy study of 2 additional asymptomatic cases identified from review of a 10-year period of autopsies at Massachusetts General Hospital, these authors identified a lesion of sharply outlined myelin loss that seemed to suffuse out from the midline, within the rostral, central pons (10). The strikingly unique features of CPM on detailed histologic examination indicated that the disease could hardly have been present, but otherwise overlooked, by earlier neuropathologists. The authors were “unable to discover any reference to a disease of this type in the medical literature of the past 75 years” (10).
The pontine involvement in all 4 cases was stereotypic in shape, location, and symmetry. The authors predicted that “the nature and location of the disease favor either an exogenous or an endogenous intoxication, or a deficiency of some essential substance” (10). Vascular diseases, Wernicke encephalopathy, Marchiafava-Bignami disease, and multiple sclerosis were all carefully considered, discussed, and excluded. Serum electrolyte abnormalities were not suspected in the original report because values were not routinely measured in those years (1950–1959). Instead, the original authors focused their attention on malnutrition (one of 4 of the original patients) or alcoholism (3 of the 4 original patients) as causative factors (10).
Less well known is that, in a 1979 paper, Wright et al identified a 1932 German-language report by Luthy of demyelination in the basis pontis in a patient with Wilson disease, which they felt to be a credible example of CPM (11). This report antedates the original paper of Adams et al (10) by 27 years (11). Although Wright et al do not reproduce the figure from Luthy's paper, we were successful in finding the 1932 volume and have reproduced the original figure for this review (Fig. 1A). This CPM case can be compared with one of our CPM cases that shows the classic batwing configuration of midline myelin loss, suffusing out from the midline in symmetric fashion at the level of the fifth cranial nerve (Fig. 1B). We morphologists need the visual image to be fully convinced, and this illustration was convincing.
(A) A 1932 example of central pontine myelinolysis (CPM) reproduced from a German-language article by Luthy on hepatocerebral degeneration (Luthy F. Uber die hepato-lentikulare degeneration. Deutsche Zeitschrift fur Nervenheilkunde 1932;123:101-56; used with permission from Springer Verlag). Myelin stain. (B) This typical example of chronic active CPM with early cavitation demonstrates the well-demarcated, batwing area of myelin loss suffusing out from the midline at the level of the fifth cranial nerve. This case is taken from our files and nicely parallels the historical example seen in (A). Whole-mount section stained with Luxol fast blue-periodic acid Schiff stain for myelin. (C) In contrast to the large typical example in (B), small CPM lesions such as this one may be easily overlooked grossly and even microscopically, particularly if they are subacute and not yet cavitated, as in this example. Small lesions such as this one would not be expected to produce clinical symptoms, and this case was discovered only at autopsy. Whole-mount section stained with Luxol fast blue-periodic acid Schiff stain for myelin. (D, E) This pair of corresponding gross (D) and whole-mount sections (E) from the same patient with a subacute CPM lesion come from a patient who was diagnosed with CPM premortem. Patient 2 in the Table is illustrated. (E) Whole-mount section stained with Luxol fast blue-periodic acid Schiff stain for myelin. (F, G) The most difficult lesions to recognize grossly and microscopically are those in lateral pontine (F, patient 3 in the Table is illustrated; most subtle areas circled) and extrapontine (patient 2 in the Table is illustrated) sites. The lateral geniculate is one of the most frequently, and often the only, extrapontine site involved in a case (G, arrow). (H) All 3 of our acute or subacute examples of CPM showed axonal swellings within their lesions. Modified Bielschowsky stain for axons, 600×. (Pontine lesion from patient 2 in the Table is illustrated.) (I) Occasionally, large lesions may be associated with a mild perivascular lymphocytic infiltrate, which does not negate the diagnosis of CPM. These lymphocytes are usually T cells and may represent a response to extensive tissue injury. Hematoxylin and eosin, 600×. (Lesion from patient 4 from the Table with active CPM is illustrated.)
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