Article abstract
A 46-year-oldman with nontropicalsprue had anemia and hypoproteinemiaforseveral years, until his condition was diagnosed and treated with dietary measures. Within a year after the diagnosis, progressive multifocal leukoencephalopathy developed, and the patient had a slightly fluctuating chronic downhill course until he died 10 years later. It is postulatedthat this patient's immune deficiency was related to his malabsorption syndrome and hypoglobulinemia, and the course became unusually protracted (longest reported course in the American literature) because of restoration of plasma protein levels. Autopsy showed the classic findings of progressive multifocal leukoencephalopathy, with much tissue loss of subcorticalwhite matter and active perivascularinflammatoryfoci with numerous eosinophilic granulocytes. On electron microscopy, oligodendrocyte nuclei and cytoplasm were crowded with virions, but many myelin sheaths invested by severely infected oligodendrocytic processes were remarkably well preserved. This fact would argue against a direct cause-and-effect relationship between infection of oligodendrocytes and myelin breakdown in progressive multifocal leukoencephalopathy.The likelihood of an autoimmunemechansim at work in this disease is suggested, and the role of eosinophils and other cells in such process is considered.
Progressive multifocal leukoencephalopathy with 1O-year survival in a patient with nontropical sprue Report of a case with unusual light and electron microscopic features JOHN J. KEPES, M.D., SAMUEL M. CHOU, M.D., and LAURANCE W. PRICE, JR., M.D.
E
ver since i s t r d m , Mancall, and Richardson] reported the first cases of progressive multifocal leukoencephalopathy (PML), it has been recognized that the overwhelming majority of these patients have an underlying systemic disease that in one way or another alters their immune defenses. Malignant lymphomas (particularly Hodgkin's disease) and leukemias are most often seen, but sarcoidosis, carcinomatosis, chronic infections such as extensive tuberculosis, and old age with severe debilitation also have been found as the underlying condition. Ellison3 provided laboratory documentation From the Department of Pathology and Oncology, University of Kansas Medical Center, Kansas City, Kansas (Dr. Kepes); the Department of Pathology, West Virginia University Medical Center, Morgantown, West Virginia (Dr. Chou); and the Department of Pathology, Lawrence Memorial Hospital, Lawrence, Kansas (Dr. Price). Received for publication March 28, 1975. Dr. Kepes' address is Departmentof Pathology and Oncology, University of Kansas Medical Center, Rainbow Blvd. at 39th, Kansas City, KS 66103.
1008 NEUROLOGY 25: 1006-1012. November 1975
of immunologic hypoactivity for the delayed type of hypersensitivity and for antibody formation in a case of lymphosarcoma complicated by PML. There have been very few reports of patients dying of PML who at autopsy did not show evidence of underlying disease."* In patients who have an underiying disease, the very nature of that disease is likely to cause a permanent alteration in immune mechanisms. In patients with a partial or transient alteration in the immune mechanisms, the clinical course may be unusually protracted, and the white matter wasting may be strikingly extensive. This report describes such a patient, in whom nontropical sprue with a documented temporary hypoglobulinemia was diagnosed, followed within a year by clinical signs and symptoms suggestive of PML. The patient lived another 10 years (twice as long as the previously reported longest course in the American literatureg), with progressive neurologic deficits despite the clinical recovery from the state of malnutrition and anemia after dietary therapy.
Histologic and electron microscopic findings in the brain raised some intriguing questions relating to the pathogenesis of PML. Case report. A man was admitted to Kansas University Medical
Center three times. He was first admitted to the Medicine Service in December 1963, when he was 46 years old. His chief complaint was swollen ankles and diarrhea. He had had light-colored stools “for many years.” He had a big appetite, but was unable to gain weight. On yearly physical examinations, his private physician had found that he was anemic and had given him iron on each occasion. On admission, the patient was thin. He was 6 ft 2 in. in height and weighed 143 lb; his blood pressure was 96/60 mm Hg. Results of physical examination, including neurologic examination, were within normal limits. Laboratory findings included a hematocrit of 35 and a hemoglobin of 9.9 gm. Total protein was 5.6 gm, serum albumin 3.4 gm, and serum globulin 2.2 gm. Fat uptake was below normal limits. A D-xylose test revealed excretion of 120 gm of xylose in 5 hours (normal 6.5 gm in 5 hours). Barium meal showed multiple areas of segmentation and clumping in the small bowel. Pancreatic studies were normal. The discharge diagnosis was nontropical sprue with steatorrhea and hypochromic microcytic anemia (caused by deficient absorption of iron). He was placed on a gluten-free diet with water-soluble vitamins. Within 2 months after his discharge, he gained 12 Ib and the diarrhea stopped. About 9 months following dismissal, the patient experienced gradual onset of difficulty in controlling his left leg and closing his right hand, followed by numbness on the left side of the mouth and chin, and was again admitted to Kansas University Medical Center. He had nystagmus to right lateral gaze, but otherwise intact cranial nerves. Gait was normal. Strength was decreased in the left hand and foot. There was ataxia on finger-to-nose and heel-to-knee tests on the left side. A positive palmomental reflex was elicited on the right hand. Spinal fluid and a r i g h t c a r o t i d a n g i o g r a m w e r e n o r m a l . An electroencephalogram revealed asymmetrical rhythmic activity, more prominent on the left, and a pneumoencephalogram showed moderate cerebral atrophy. By the time the patient was admitted for the third time, a year and a half later (in 1966), he was confused and seizures had developed, starting with tremor of the left hand and followed by generalized tonic-clonic type-seizures. His mental functions (penmanship, calculation, dressing ability) had deteriorated. He had staggering gait and decreased vibratory and position sense on the left. Brain scan and spinal fluid, including the India ink test, were negative. During this hospitalization, he became more alert and was less confused. He was discharged with the diagnosis of generalized cortical atrophy. Subsequently, the patient was repeatedly seen at Kansas University Medical Center as an outpatient. On many occasions, he and his wife claimed subjective improvement of his condition, but the observers noted an overall tendency toward decline. The patient also was admitted three times to Lawrence Memorial Hospital in Lawrence, Kansas, first in 1971 for an episode of thrombophlebitis of the lower limbs. He was believed at that time to have a pulmonary embolus. He was described as considerably disabled by his neurologic disease, and had a spastic gait, hyperactive reflexes, and a left Babinski sign. He was on a gluten-free diet because of a past diagnosis of nontropical sprue, and was taking diphenylhydantoin (Dilantin@)and phenobarbital for a seizure disorder. After being treated for thrombophlebitis and pulmonary embolism, he was discharged improved. He returned to the Lawrence Memorial Hospital in 1973 for
evaluation. At this time, he had a marked problem with speech and could not be understood. He had generalized muscle weakness and spasticity and had difficulty in swallowing. He was unable to stand or walk, and he had a fixed expression. He was still on a gluten-free diet and also was taking anticonvulsants and crystalline sodium warfarin (Coumadin@). On the patient’s final admission, in April 1974, his condition appeared critical. He was unable to communicate, although he was awake. He had difficulty in breathing because of accumulation of secretions in his posterior pharynx. There was no bowel or bladder control. He was emaciated, with marked atrophy of all muscles. During the short survival in the hospital, his major problem was breathing, which eventually became quite irregular, with periodic apnea. Cyanosis developed and he died.
A u t o p s y f i n d i n g s . General. Autopsy showed generalized emaciation with severe atrophy of the musculature, atherosclerosis of the aorta and coronary arteries, and acute bronchopneumonia in the lower lobes of both lungs. Postmortem autolysis prevented detailed examination of small intestinal mucosa, but some fusion of the stroma of villi could still be observed in the duodenum and jejunum. Brain. The brain was submitted in the formol-fixed state to Kansas University Medical Center for examination. It weighed 1,410 gm. The leptomeninges were greatly thickened, were gray-white in color, and had lost their translucency. There were fibrous adhesions between the medial surfaces of the frontal lobes. The arteries of the circle of Willis showed only minimal scattered atherosclerotic changes. The external configuration of the hemispheres was symmetrical, with massive atrophy of the cortex that was better appreciated after the leptomeninges were stripped from the surface (figure 1). The substance of the brain stem and cerebellum was much better preserved. Coronal sections of the brain showed markedly dilated lateral and third ventricles. The cerebral cortex was atrophic, but more severe changes were seen in the immediate subcortical white matter, which showed grumous and mushy softening consisting of small foci that in many areas became confluent and created the pattern of ribbonlike zones of necrosis and cavitation. The changes were more severe in the dorsal aspects of the hemispheres (figure 2 ) . Subcortical softening could be followed through the parietal and occipital lobes, whereas the temporal lobes, while grossly atrophic, showed multiple small punctate gray lesions in the white matter with less confluence. Altogether, the areas of gross demyelination varied from pinpoint size to areas reaching diameters of 1.5 cm. In general, the lesions closer to the convexities appeared older and more likely to be cavitated; the lesions of the frontobasal area and of the temporal lobes were smaller and showed no cavity formation. Similarchanges, i.e., elementary small lesions and confluent larger ones, were seen in the external and internal capsules, upper brain stem and cerebellar white matter, where some of the folia had completely lost their myelin contingent. The lower brain stem and the spinal cord were not remarkable on gross examination.
NEUROLOGY November 1975 1007
Leukoencephalopathy with nontropical sprue
Figure 1. Brain shows massive cortical atrophy, better seen on side stripped of meninges.
Figure 2. Coronal section slightly behind genu corporis callosi. Massive cortical atrophy dorsolaterally, with mushy disintegration of subcortical white matter. Basal cortex and white matter are relatively spared. Lateral ventricles show hydrocephalus ex vacuo.
Figure 3. Patchy and confluent demyelination in hemispheric cerebellar white matter and in middle cerebellar peduncle (left). Weil-Weigert stain.
1008 NEUROLOGY November 1975
Figure 4. Right parietal white matter. Marked perivascular round cell infiltration in area of demyelination. Hematoxylin and eosin. x80.
Microscopic findings. Sections of the cortex showed moderate cell loss of thcneuronal population but no other pathognomonic changes. The grossly observed lesions of the cerebral and cerebellar white matter showed patchy demyelination on Weil-Weigert stain (figure 3). On hematoxylin and eosin-stained sections, many blood vessels in the white matter were surrounded by lymphocytes, an occasional plasma cell, and a surprisingly large number of eosinophilic granulocytes (figures 4 and 5). In the areas of demyelination, there were also large numbers of fat-filled macrophages as well as nodules of proliferating slender microglial cells. The nuclei of oligodendrocytes showed replacement of normal chromatin by a smudgy dark basophilic substance. In several a s t r o c y t e s , t h e nuclei were b i z a r r e , hyperchromatic, and greatly enlarged, reminiscent of neoplastic alterations (figure 6), but mitotic activity was not noted, In and around older foci, there was mostly astrocytic gliosis, with marked glial fiber formation and more moderate pleomorphism of nuclei. The diagnosis was advanced PML. Electron microscopy was performed at the University of West Virginia. Portions of wet brain tissue were afterfixed with glutaraldehyde and osmic acid, embedded in Epon@,and sectioned. Electron microscopy showed that large proportions (20 to 40 percent) of perivascular inflammatory cells were eosinophils (figure 7). The
Figure 5. In some of the infiltrates a large number of eosinophils are observed. Hematoxylin and eosin, x 400.
Figure 6. Bizarre, hypertrophic astrocytic nucleus in areaof recent demyelination. Hematoxylin and eosin, x 480.
NEUROLOGY November 1975 1009
Leukoencephalopathy with nontropical sprue
Figure 7. Perivascular mononuclear cell infiltrate, predominantly of eosinoInset: Intraphils. ~2,600. nuclear fibrillar inclusions i n each eosinophif. x 14,300.
Figure 8 . Papova-virion packed oligodendroglial nucleuswith jagged nuclear outline. The myelin sheaths (arrows), probably invested by this oligodendroglia, are surprisingly well preserved. Original magnification, x 14,400.
majority of the eosinophilic nuclei contained fibrillar material or “rodlets” of unknown significance (figure 7, inset). Unlike the spheroid and distended oligodendroglial nuclei containing papova virions previously described, the oligodendroglial nuclei with papova virions in this patient were irregular in shape and jagged in contour 1010 NEUROLOGY November 1975
(figure 8). The intranuclear virions were ultrastructurally typical of the papova virions that have been described in cases; they measured 40 nm in diameter and were occasionally mixed with tubular particles. NO virions forming crystalline arrays were seen. Despite inadequate fixation and postmortem autolysis, the cytoplasm and the
myelin sheaths invested by the infected oligodendroglia were remarkably well preserved (figures 8 and 9, arrows). Occasionally, the oligodendroglial cytoplasm was crowded with the virions that were either enveloped (70 to 80 nm in diameter, figure 9, inset, arrows) or unenveloped, (figure 9); yet, the myelin sheaths invested by the process full of the virions appeared relatively intact and showed no signs of myelin destruction (figure 9, inset). Discussion. This case raises several theoretical questions and considerations regarding PML. Long survival time. It would be tempting to speculate that persons without permanent immune deficiency or without any apparent underlying predisposing disease would live longer because they are able to “put up a longer fight” against the virus. Indeed, the patient with the longest recorded course of PML ( 19years) reported by Stam,’** had no debilitating disease clinically or at autopsy. Stam’s report did not include demonstration of viruses by electron microscopy or cultures, but the classic neuropathologic findings, i.e., the triad of multifocal demyelination; dense, basophilic, swollen oligodendroglial nuclei; and bizarre astrocytes, were well documented. Our patient, who we believe had only a temporary deficiency of plasma proteins, corrected later by dietary measures, lived for 10 years, thus becoming the second longest survivor in the literature. Nevertheless,
Hedley-Whyte and co-workers’g patient had a remitting course for 5 years; yet, this patient had lymphosarcoma all along. On the other hand, two patients with PML, who by clinical history and autopsy had no evidence of underlying immune deficiency, lived only 18 months and 7 months, respectively, after the clinical onset of the di~ease.~J’ Another patient with apparent “spontaneous” PML, had a total course of 3 years, 2 monthss Perivascular lymphocytic cuffs were described in all of four previously reported patients with PML without evidence of underlying predisposing disease,”’ and plasma cell infiltrates were found in three of these patients, the exception being the patient reported by Bolton and Rozdilsky .6 Malabsorption syndrome underlying PML. Our patient had nontropical sprue for several years; the diagnosis had been well established by x-ray and laboratory methods. We postulated that his poor nutritional state, combined with the low serum protein levels, may well have facilitated the entry of the viruses. We found only one similar case in the literature, in a patient with Whipple’s disease who was reported by Hecker and Reid.Io This patient, however, received steroids for the underlying disease (60 mg prednisolone daily), with subsequent extensive moniliasis of the gastrointestinal tract, and this treatment may have played a significant role in altering the immune responses. A remarkably high incidence of
Figure9. Oligodendroglialcytoplasmcrowdedwith virions, both enveloped and unenveloped, with normal-appearing myelin sheaths (arrows) attached to the plasma membrane. x 15,600. Inset: Higher magnification of the squared area showing an enveloped virion (arrows) and the intact myelin sheath invested by the process that is packed with virions. x 49,500. NEUROLOGY November 1975 1011
Leukoencephalopathy with nontropical sprue
lymphoma and carcinoma in patients with nontropical sprue tends to suggest a certain fundamental defect in the immune mechanisms common to other patients with PML. Deficiency in macroglobulin (IgM) levels has been reported in 37 percent of 75 adult patients with untreated celiac disease.ll It is of great interest that the patient with PML reported by Ellison3 showed no detectable IgM. Change in spec8c gruviy of bruin after long-lusting PML. In our patient, there was a striking contrast between the apparent severe atrophy of the brain (marked gym1 shrinkage, hydrocephalus ex vacuo) and the brain weight of 1,450 gm. Hedley-Whyte and associates’Ypatient, who lived for 5 years, also had marked gross cerebral atrophy, yet the brain weighed 1,550 gm. The loss of white matter and concomitant fibrous gliosis was probably responsible for this increase in the density of brain tissue. (The brain weight was not indicated in Stam’s’ report of the patient who lived for 19 years.) Pathogenesis of PML. Before Zu Rhein and Choul* discovered viral particles in glial cells on electron microscopy, investigators considered a possible autoimmune mechanism in the demyelinating process in PML.I3 The discovery of viral particles in oligodendrocytes, i.e., the glial cells responsible for the production and probably the maintenance of central nervous system myelin, seemed to indicate that myelin destruction is the direct consequence of virus-induced necrosis or at least degeneration of oligodendroglial cells. Chou and c o - w o r k e r ~ ,however, ’~ in the first biopsy study with the electron microscope, demonstrated good preservation of the cytoplasm of infected oligodendroglial cells, thus refuting a direct cytolytic effect by the virus. They suggested instead that a basic protein, as a by-product of viral synthesis, may become a myelinotoxic a n t i g e n by t r i g g e r i n g a n i m m u n e r e s p o n s e o f lymphocytes. In the present patient, many myelin sheaths with essentially intact fine structure were seen in conjunction with the plasma membranes of oligodendrocytes whose cytoplasm and nuclei were crowded with viral particles. Instead of spheroidal oligodendroglial nuclei distended with the harbored virions, which are among the most characteristic findings in P M L , many infected oligodendrocytes displayed nondistended nuclei with jagged outlines. This finding suggests the likelihood that viral multiplication was in part suppressed or dormant. This may have been due to an immune response, which, however, seemed unable to completely neutralize the viral agents. An autoimmune process can be postulated where damage to myelin sheaths has occurred; at least in our patient, the presence of large numbers of eosinophils in the penvascular infiltrates suggests this. An insidious, slow but active viral infection of 10 years’ duration could certainly lead to an immune response, with ensuing local deposits of antigen-antibody complexes. These in turn might have subsequently stimulated local eosinophilic infiltration as suggested by Litt.15 Although “the allergist may have been premature in considering the eosinophil its own special ce11,”16 it is an accepted fact that an 1012 NEUROLOGY November 1975
eosinophil chemotactic factor dependent on serum complement emerges from the effects of some antigen-antibody reactions, and a precursor substance (ECF) is believed to be elaborated by antigenstimulated leukocytes to explain eosinophilia accompanying some autoimmune and collagen diseases. The antigen-antibody complexes also may have triggered the unusual “effector” cell response that eventually induces demyelination, as proposed by Allison,” since it is generally believed that most PML cases occur against a background of the delayed-type immunologic defect. If an autoimmune mechanism should cause the demyelination, the cytotoxic cells involved should not be T or B lymphocytes; instead, a third type of “effector” cells would then provide a plausible immunopathic mechanism in PML. Other cells also may be involved. It is of interest that Richardson and Johnsoni8 recently reported a few patients with PML who had massive plasma cell infiltrates. However, rather than considering these as part of the pathogenesis for the demyelinating lesions, these authors suggested that the plasma cell infiltrates possibly represented unusually strong host resistance to the disease. The possibility that the eosinophils in our patient also had a certain defensive role cannot, of course, be ruled out and the solution to this problem will have to await further studies. REFERENCES 1.Astr~mKE, Mancall EL, Richardson EP Jr: Progressive multifocal encephalopathy: A hitherto unrecognized complication of chronic lymphatic leukemia and Hodgkin’s disease. Brain 81:93111,1958 2.Richardson EP Jr: Progressive muitifocal leukoencephalopathy. N Engl J Med 265:815-833,1961 3.Ellison GW: Progressive multifccal leukoencephalopathy (PML). I. Investigationof the immunologic status of a patientwith lymphosarcoma and PML. J Neuropathol Exp Neurol 28501-506,1969 4.Silverman L, Rubinstein LJ: Electron microscopic observations on a case of progressive multifocalleukoencephalopathy. Acta Neuropathol (Berl) 5x215-224,1965 5. Fermaglich J, Hardman JM, Earle KM: Spontaneous progressive multifocal leukoencephalopathy. Neurology (Minneap) 20:479-484,
1970 6.Bolton CF, Rozdilsky 8: Primary progressive multifocal leukoencephalopathy. Neurology (Minneap) 21 :72-77, 1971 7.Stam FC: Multifocal leukoencephalopathy with slow progression and very long survival. Psychiatr Neurol Neurochir 69:453459,1966 8. Stam FC: Personal Communication 9.Hedley-Whyte TE, Smith BP, T y l e r R, e t al: Multifocal leukoencephalopathy with remission and five year survival. J Neuropathol Exp Neurol 25107-116,1966 10. Hecker R, Reid RTW: Cerebral demyelination in Whipple’s disease. Med J Aust 49(1):211-212, 1962 11. Hobbs JR, Hepner GW: Deficiency of M-globulin in coeliac disease. Lancet 1:217-220, 1968 12.Zu Rhein GM, Chou SM: Particles resembling papovavirusesin human cerebral demyelinating disease. Science 148:1477-I 479,1965 13.Cavanagh JB, Greanbaurn D, Marshall AHE, e l al: Cerebral demyelination associated with disorders of the reticuloendothelial system. Lancet 2524-529,1959 14.Chou SM, Oguchi K, Holden EM, etal: Unusualultrastructuralfindings in PML (progressive multifocal leukoencephalopathy). Presented at the 50th annual meeting of the American Association of Neuropatblogists, Boston, Mass, 1974 15.Litt M: Eosinophils and antigen-antibody reactions. Ann NY Acad Sci 116:964-985, 1964 16. Cohen SG:The eosinophil and eosinophilia. (Editorial) N Engl J Med 290:457-459, 1974 17.Allison AC: Immunity and immunopathology in virus infections. Ann lnst Pasteur (Paris) 123:585-608, 1972 18. Richardson EP Jr, Johnson PC: Atypical progressive multifocal
leukoencephalopathy with plasma cell infiltrates. Symposium on malignant lymphomas of the nervous system. Vienna, 1974, Acta Neuropathol, Suppl VI, 247-250,1975
Progressive multifocal leukoencephalopathy with 10−year survival in a patient with nontropical sprue: Report of a case with unusual light and electron microscopic features JOHN J. KEPES, SAMUEL M. CHOU and LAURANCE W. PRICE, JR. Neurology 1975;25;1007 DOI 10.1212/WNL.25.11.1007 This information is current as of November 1, 1975 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1975 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
A 46-year-oldman with nontropicalsprue had anemia and hypoproteinemiaforseveral years, until his condition was diagnosed and treated with dietary measures. Within a year after the diagnosis, progressive multifocal leukoencephalopathy developed, and the patient had a slightly fluctuating chronic downhill course until he died 10 years later. It is postulatedthat this patient's immune deficiency was related to his malabsorption syndrome and hypoglobulinemia, and the course became unusually protracted (longest reported course in the American literature) because of restoration of plasma protein levels. Autopsy showed the classic findings of progressive multifocal leukoencephalopathy, with much tissue loss of subcorticalwhite matter and active perivascularinflammatoryfoci with numerous eosinophilic granulocytes. On electron microscopy, oligodendrocyte nuclei and cytoplasm were crowded with virions, but many myelin sheaths invested by severely infected oligodendrocytic processes were remarkably well preserved. This fact would argue against a direct cause-and-effect relationship between infection of oligodendrocytes and myelin breakdown in progressive multifocal leukoencephalopathy.The likelihood of an autoimmunemechansim at work in this disease is suggested, and the role of eosinophils and other cells in such process is considered.
Progressive multifocal leukoencephalopathy with 1O-year survival in a patient with nontropical sprue Report of a case with unusual light and electron microscopic features JOHN J. KEPES, M.D., SAMUEL M. CHOU, M.D., and LAURANCE W. PRICE, JR., M.D.
E
ver since i s t r d m , Mancall, and Richardson] reported the first cases of progressive multifocal leukoencephalopathy (PML), it has been recognized that the overwhelming majority of these patients have an underlying systemic disease that in one way or another alters their immune defenses. Malignant lymphomas (particularly Hodgkin's disease) and leukemias are most often seen, but sarcoidosis, carcinomatosis, chronic infections such as extensive tuberculosis, and old age with severe debilitation also have been found as the underlying condition. Ellison3 provided laboratory documentation From the Department of Pathology and Oncology, University of Kansas Medical Center, Kansas City, Kansas (Dr. Kepes); the Department of Pathology, West Virginia University Medical Center, Morgantown, West Virginia (Dr. Chou); and the Department of Pathology, Lawrence Memorial Hospital, Lawrence, Kansas (Dr. Price). Received for publication March 28, 1975. Dr. Kepes' address is Departmentof Pathology and Oncology, University of Kansas Medical Center, Rainbow Blvd. at 39th, Kansas City, KS 66103.
1008 NEUROLOGY 25: 1006-1012. November 1975
of immunologic hypoactivity for the delayed type of hypersensitivity and for antibody formation in a case of lymphosarcoma complicated by PML. There have been very few reports of patients dying of PML who at autopsy did not show evidence of underlying disease."* In patients who have an underiying disease, the very nature of that disease is likely to cause a permanent alteration in immune mechanisms. In patients with a partial or transient alteration in the immune mechanisms, the clinical course may be unusually protracted, and the white matter wasting may be strikingly extensive. This report describes such a patient, in whom nontropical sprue with a documented temporary hypoglobulinemia was diagnosed, followed within a year by clinical signs and symptoms suggestive of PML. The patient lived another 10 years (twice as long as the previously reported longest course in the American literatureg), with progressive neurologic deficits despite the clinical recovery from the state of malnutrition and anemia after dietary therapy.
Histologic and electron microscopic findings in the brain raised some intriguing questions relating to the pathogenesis of PML. Case report. A man was admitted to Kansas University Medical
Center three times. He was first admitted to the Medicine Service in December 1963, when he was 46 years old. His chief complaint was swollen ankles and diarrhea. He had had light-colored stools “for many years.” He had a big appetite, but was unable to gain weight. On yearly physical examinations, his private physician had found that he was anemic and had given him iron on each occasion. On admission, the patient was thin. He was 6 ft 2 in. in height and weighed 143 lb; his blood pressure was 96/60 mm Hg. Results of physical examination, including neurologic examination, were within normal limits. Laboratory findings included a hematocrit of 35 and a hemoglobin of 9.9 gm. Total protein was 5.6 gm, serum albumin 3.4 gm, and serum globulin 2.2 gm. Fat uptake was below normal limits. A D-xylose test revealed excretion of 120 gm of xylose in 5 hours (normal 6.5 gm in 5 hours). Barium meal showed multiple areas of segmentation and clumping in the small bowel. Pancreatic studies were normal. The discharge diagnosis was nontropical sprue with steatorrhea and hypochromic microcytic anemia (caused by deficient absorption of iron). He was placed on a gluten-free diet with water-soluble vitamins. Within 2 months after his discharge, he gained 12 Ib and the diarrhea stopped. About 9 months following dismissal, the patient experienced gradual onset of difficulty in controlling his left leg and closing his right hand, followed by numbness on the left side of the mouth and chin, and was again admitted to Kansas University Medical Center. He had nystagmus to right lateral gaze, but otherwise intact cranial nerves. Gait was normal. Strength was decreased in the left hand and foot. There was ataxia on finger-to-nose and heel-to-knee tests on the left side. A positive palmomental reflex was elicited on the right hand. Spinal fluid and a r i g h t c a r o t i d a n g i o g r a m w e r e n o r m a l . An electroencephalogram revealed asymmetrical rhythmic activity, more prominent on the left, and a pneumoencephalogram showed moderate cerebral atrophy. By the time the patient was admitted for the third time, a year and a half later (in 1966), he was confused and seizures had developed, starting with tremor of the left hand and followed by generalized tonic-clonic type-seizures. His mental functions (penmanship, calculation, dressing ability) had deteriorated. He had staggering gait and decreased vibratory and position sense on the left. Brain scan and spinal fluid, including the India ink test, were negative. During this hospitalization, he became more alert and was less confused. He was discharged with the diagnosis of generalized cortical atrophy. Subsequently, the patient was repeatedly seen at Kansas University Medical Center as an outpatient. On many occasions, he and his wife claimed subjective improvement of his condition, but the observers noted an overall tendency toward decline. The patient also was admitted three times to Lawrence Memorial Hospital in Lawrence, Kansas, first in 1971 for an episode of thrombophlebitis of the lower limbs. He was believed at that time to have a pulmonary embolus. He was described as considerably disabled by his neurologic disease, and had a spastic gait, hyperactive reflexes, and a left Babinski sign. He was on a gluten-free diet because of a past diagnosis of nontropical sprue, and was taking diphenylhydantoin (Dilantin@)and phenobarbital for a seizure disorder. After being treated for thrombophlebitis and pulmonary embolism, he was discharged improved. He returned to the Lawrence Memorial Hospital in 1973 for
evaluation. At this time, he had a marked problem with speech and could not be understood. He had generalized muscle weakness and spasticity and had difficulty in swallowing. He was unable to stand or walk, and he had a fixed expression. He was still on a gluten-free diet and also was taking anticonvulsants and crystalline sodium warfarin (Coumadin@). On the patient’s final admission, in April 1974, his condition appeared critical. He was unable to communicate, although he was awake. He had difficulty in breathing because of accumulation of secretions in his posterior pharynx. There was no bowel or bladder control. He was emaciated, with marked atrophy of all muscles. During the short survival in the hospital, his major problem was breathing, which eventually became quite irregular, with periodic apnea. Cyanosis developed and he died.
A u t o p s y f i n d i n g s . General. Autopsy showed generalized emaciation with severe atrophy of the musculature, atherosclerosis of the aorta and coronary arteries, and acute bronchopneumonia in the lower lobes of both lungs. Postmortem autolysis prevented detailed examination of small intestinal mucosa, but some fusion of the stroma of villi could still be observed in the duodenum and jejunum. Brain. The brain was submitted in the formol-fixed state to Kansas University Medical Center for examination. It weighed 1,410 gm. The leptomeninges were greatly thickened, were gray-white in color, and had lost their translucency. There were fibrous adhesions between the medial surfaces of the frontal lobes. The arteries of the circle of Willis showed only minimal scattered atherosclerotic changes. The external configuration of the hemispheres was symmetrical, with massive atrophy of the cortex that was better appreciated after the leptomeninges were stripped from the surface (figure 1). The substance of the brain stem and cerebellum was much better preserved. Coronal sections of the brain showed markedly dilated lateral and third ventricles. The cerebral cortex was atrophic, but more severe changes were seen in the immediate subcortical white matter, which showed grumous and mushy softening consisting of small foci that in many areas became confluent and created the pattern of ribbonlike zones of necrosis and cavitation. The changes were more severe in the dorsal aspects of the hemispheres (figure 2 ) . Subcortical softening could be followed through the parietal and occipital lobes, whereas the temporal lobes, while grossly atrophic, showed multiple small punctate gray lesions in the white matter with less confluence. Altogether, the areas of gross demyelination varied from pinpoint size to areas reaching diameters of 1.5 cm. In general, the lesions closer to the convexities appeared older and more likely to be cavitated; the lesions of the frontobasal area and of the temporal lobes were smaller and showed no cavity formation. Similarchanges, i.e., elementary small lesions and confluent larger ones, were seen in the external and internal capsules, upper brain stem and cerebellar white matter, where some of the folia had completely lost their myelin contingent. The lower brain stem and the spinal cord were not remarkable on gross examination.
NEUROLOGY November 1975 1007
Leukoencephalopathy with nontropical sprue
Figure 1. Brain shows massive cortical atrophy, better seen on side stripped of meninges.
Figure 2. Coronal section slightly behind genu corporis callosi. Massive cortical atrophy dorsolaterally, with mushy disintegration of subcortical white matter. Basal cortex and white matter are relatively spared. Lateral ventricles show hydrocephalus ex vacuo.
Figure 3. Patchy and confluent demyelination in hemispheric cerebellar white matter and in middle cerebellar peduncle (left). Weil-Weigert stain.
1008 NEUROLOGY November 1975
Figure 4. Right parietal white matter. Marked perivascular round cell infiltration in area of demyelination. Hematoxylin and eosin. x80.
Microscopic findings. Sections of the cortex showed moderate cell loss of thcneuronal population but no other pathognomonic changes. The grossly observed lesions of the cerebral and cerebellar white matter showed patchy demyelination on Weil-Weigert stain (figure 3). On hematoxylin and eosin-stained sections, many blood vessels in the white matter were surrounded by lymphocytes, an occasional plasma cell, and a surprisingly large number of eosinophilic granulocytes (figures 4 and 5). In the areas of demyelination, there were also large numbers of fat-filled macrophages as well as nodules of proliferating slender microglial cells. The nuclei of oligodendrocytes showed replacement of normal chromatin by a smudgy dark basophilic substance. In several a s t r o c y t e s , t h e nuclei were b i z a r r e , hyperchromatic, and greatly enlarged, reminiscent of neoplastic alterations (figure 6), but mitotic activity was not noted, In and around older foci, there was mostly astrocytic gliosis, with marked glial fiber formation and more moderate pleomorphism of nuclei. The diagnosis was advanced PML. Electron microscopy was performed at the University of West Virginia. Portions of wet brain tissue were afterfixed with glutaraldehyde and osmic acid, embedded in Epon@,and sectioned. Electron microscopy showed that large proportions (20 to 40 percent) of perivascular inflammatory cells were eosinophils (figure 7). The
Figure 5. In some of the infiltrates a large number of eosinophils are observed. Hematoxylin and eosin, x 400.
Figure 6. Bizarre, hypertrophic astrocytic nucleus in areaof recent demyelination. Hematoxylin and eosin, x 480.
NEUROLOGY November 1975 1009
Leukoencephalopathy with nontropical sprue
Figure 7. Perivascular mononuclear cell infiltrate, predominantly of eosinoInset: Intraphils. ~2,600. nuclear fibrillar inclusions i n each eosinophif. x 14,300.
Figure 8 . Papova-virion packed oligodendroglial nucleuswith jagged nuclear outline. The myelin sheaths (arrows), probably invested by this oligodendroglia, are surprisingly well preserved. Original magnification, x 14,400.
majority of the eosinophilic nuclei contained fibrillar material or “rodlets” of unknown significance (figure 7, inset). Unlike the spheroid and distended oligodendroglial nuclei containing papova virions previously described, the oligodendroglial nuclei with papova virions in this patient were irregular in shape and jagged in contour 1010 NEUROLOGY November 1975
(figure 8). The intranuclear virions were ultrastructurally typical of the papova virions that have been described in cases; they measured 40 nm in diameter and were occasionally mixed with tubular particles. NO virions forming crystalline arrays were seen. Despite inadequate fixation and postmortem autolysis, the cytoplasm and the
myelin sheaths invested by the infected oligodendroglia were remarkably well preserved (figures 8 and 9, arrows). Occasionally, the oligodendroglial cytoplasm was crowded with the virions that were either enveloped (70 to 80 nm in diameter, figure 9, inset, arrows) or unenveloped, (figure 9); yet, the myelin sheaths invested by the process full of the virions appeared relatively intact and showed no signs of myelin destruction (figure 9, inset). Discussion. This case raises several theoretical questions and considerations regarding PML. Long survival time. It would be tempting to speculate that persons without permanent immune deficiency or without any apparent underlying predisposing disease would live longer because they are able to “put up a longer fight” against the virus. Indeed, the patient with the longest recorded course of PML ( 19years) reported by Stam,’** had no debilitating disease clinically or at autopsy. Stam’s report did not include demonstration of viruses by electron microscopy or cultures, but the classic neuropathologic findings, i.e., the triad of multifocal demyelination; dense, basophilic, swollen oligodendroglial nuclei; and bizarre astrocytes, were well documented. Our patient, who we believe had only a temporary deficiency of plasma proteins, corrected later by dietary measures, lived for 10 years, thus becoming the second longest survivor in the literature. Nevertheless,
Hedley-Whyte and co-workers’g patient had a remitting course for 5 years; yet, this patient had lymphosarcoma all along. On the other hand, two patients with PML, who by clinical history and autopsy had no evidence of underlying immune deficiency, lived only 18 months and 7 months, respectively, after the clinical onset of the di~ease.~J’ Another patient with apparent “spontaneous” PML, had a total course of 3 years, 2 monthss Perivascular lymphocytic cuffs were described in all of four previously reported patients with PML without evidence of underlying predisposing disease,”’ and plasma cell infiltrates were found in three of these patients, the exception being the patient reported by Bolton and Rozdilsky .6 Malabsorption syndrome underlying PML. Our patient had nontropical sprue for several years; the diagnosis had been well established by x-ray and laboratory methods. We postulated that his poor nutritional state, combined with the low serum protein levels, may well have facilitated the entry of the viruses. We found only one similar case in the literature, in a patient with Whipple’s disease who was reported by Hecker and Reid.Io This patient, however, received steroids for the underlying disease (60 mg prednisolone daily), with subsequent extensive moniliasis of the gastrointestinal tract, and this treatment may have played a significant role in altering the immune responses. A remarkably high incidence of
Figure9. Oligodendroglialcytoplasmcrowdedwith virions, both enveloped and unenveloped, with normal-appearing myelin sheaths (arrows) attached to the plasma membrane. x 15,600. Inset: Higher magnification of the squared area showing an enveloped virion (arrows) and the intact myelin sheath invested by the process that is packed with virions. x 49,500. NEUROLOGY November 1975 1011
Leukoencephalopathy with nontropical sprue
lymphoma and carcinoma in patients with nontropical sprue tends to suggest a certain fundamental defect in the immune mechanisms common to other patients with PML. Deficiency in macroglobulin (IgM) levels has been reported in 37 percent of 75 adult patients with untreated celiac disease.ll It is of great interest that the patient with PML reported by Ellison3 showed no detectable IgM. Change in spec8c gruviy of bruin after long-lusting PML. In our patient, there was a striking contrast between the apparent severe atrophy of the brain (marked gym1 shrinkage, hydrocephalus ex vacuo) and the brain weight of 1,450 gm. Hedley-Whyte and associates’Ypatient, who lived for 5 years, also had marked gross cerebral atrophy, yet the brain weighed 1,550 gm. The loss of white matter and concomitant fibrous gliosis was probably responsible for this increase in the density of brain tissue. (The brain weight was not indicated in Stam’s’ report of the patient who lived for 19 years.) Pathogenesis of PML. Before Zu Rhein and Choul* discovered viral particles in glial cells on electron microscopy, investigators considered a possible autoimmune mechanism in the demyelinating process in PML.I3 The discovery of viral particles in oligodendrocytes, i.e., the glial cells responsible for the production and probably the maintenance of central nervous system myelin, seemed to indicate that myelin destruction is the direct consequence of virus-induced necrosis or at least degeneration of oligodendroglial cells. Chou and c o - w o r k e r ~ ,however, ’~ in the first biopsy study with the electron microscope, demonstrated good preservation of the cytoplasm of infected oligodendroglial cells, thus refuting a direct cytolytic effect by the virus. They suggested instead that a basic protein, as a by-product of viral synthesis, may become a myelinotoxic a n t i g e n by t r i g g e r i n g a n i m m u n e r e s p o n s e o f lymphocytes. In the present patient, many myelin sheaths with essentially intact fine structure were seen in conjunction with the plasma membranes of oligodendrocytes whose cytoplasm and nuclei were crowded with viral particles. Instead of spheroidal oligodendroglial nuclei distended with the harbored virions, which are among the most characteristic findings in P M L , many infected oligodendrocytes displayed nondistended nuclei with jagged outlines. This finding suggests the likelihood that viral multiplication was in part suppressed or dormant. This may have been due to an immune response, which, however, seemed unable to completely neutralize the viral agents. An autoimmune process can be postulated where damage to myelin sheaths has occurred; at least in our patient, the presence of large numbers of eosinophils in the penvascular infiltrates suggests this. An insidious, slow but active viral infection of 10 years’ duration could certainly lead to an immune response, with ensuing local deposits of antigen-antibody complexes. These in turn might have subsequently stimulated local eosinophilic infiltration as suggested by Litt.15 Although “the allergist may have been premature in considering the eosinophil its own special ce11,”16 it is an accepted fact that an 1012 NEUROLOGY November 1975
eosinophil chemotactic factor dependent on serum complement emerges from the effects of some antigen-antibody reactions, and a precursor substance (ECF) is believed to be elaborated by antigenstimulated leukocytes to explain eosinophilia accompanying some autoimmune and collagen diseases. The antigen-antibody complexes also may have triggered the unusual “effector” cell response that eventually induces demyelination, as proposed by Allison,” since it is generally believed that most PML cases occur against a background of the delayed-type immunologic defect. If an autoimmune mechanism should cause the demyelination, the cytotoxic cells involved should not be T or B lymphocytes; instead, a third type of “effector” cells would then provide a plausible immunopathic mechanism in PML. Other cells also may be involved. It is of interest that Richardson and Johnsoni8 recently reported a few patients with PML who had massive plasma cell infiltrates. However, rather than considering these as part of the pathogenesis for the demyelinating lesions, these authors suggested that the plasma cell infiltrates possibly represented unusually strong host resistance to the disease. The possibility that the eosinophils in our patient also had a certain defensive role cannot, of course, be ruled out and the solution to this problem will have to await further studies. REFERENCES 1.Astr~mKE, Mancall EL, Richardson EP Jr: Progressive multifocal encephalopathy: A hitherto unrecognized complication of chronic lymphatic leukemia and Hodgkin’s disease. Brain 81:93111,1958 2.Richardson EP Jr: Progressive muitifocal leukoencephalopathy. N Engl J Med 265:815-833,1961 3.Ellison GW: Progressive multifccal leukoencephalopathy (PML). I. Investigationof the immunologic status of a patientwith lymphosarcoma and PML. J Neuropathol Exp Neurol 28501-506,1969 4.Silverman L, Rubinstein LJ: Electron microscopic observations on a case of progressive multifocalleukoencephalopathy. Acta Neuropathol (Berl) 5x215-224,1965 5. Fermaglich J, Hardman JM, Earle KM: Spontaneous progressive multifocal leukoencephalopathy. Neurology (Minneap) 20:479-484,
1970 6.Bolton CF, Rozdilsky 8: Primary progressive multifocal leukoencephalopathy. Neurology (Minneap) 21 :72-77, 1971 7.Stam FC: Multifocal leukoencephalopathy with slow progression and very long survival. Psychiatr Neurol Neurochir 69:453459,1966 8. Stam FC: Personal Communication 9.Hedley-Whyte TE, Smith BP, T y l e r R, e t al: Multifocal leukoencephalopathy with remission and five year survival. J Neuropathol Exp Neurol 25107-116,1966 10. Hecker R, Reid RTW: Cerebral demyelination in Whipple’s disease. Med J Aust 49(1):211-212, 1962 11. Hobbs JR, Hepner GW: Deficiency of M-globulin in coeliac disease. Lancet 1:217-220, 1968 12.Zu Rhein GM, Chou SM: Particles resembling papovavirusesin human cerebral demyelinating disease. Science 148:1477-I 479,1965 13.Cavanagh JB, Greanbaurn D, Marshall AHE, e l al: Cerebral demyelination associated with disorders of the reticuloendothelial system. Lancet 2524-529,1959 14.Chou SM, Oguchi K, Holden EM, etal: Unusualultrastructuralfindings in PML (progressive multifocal leukoencephalopathy). Presented at the 50th annual meeting of the American Association of Neuropatblogists, Boston, Mass, 1974 15.Litt M: Eosinophils and antigen-antibody reactions. Ann NY Acad Sci 116:964-985, 1964 16. Cohen SG:The eosinophil and eosinophilia. (Editorial) N Engl J Med 290:457-459, 1974 17.Allison AC: Immunity and immunopathology in virus infections. Ann lnst Pasteur (Paris) 123:585-608, 1972 18. Richardson EP Jr, Johnson PC: Atypical progressive multifocal
leukoencephalopathy with plasma cell infiltrates. Symposium on malignant lymphomas of the nervous system. Vienna, 1974, Acta Neuropathol, Suppl VI, 247-250,1975
Progressive multifocal leukoencephalopathy with 10−year survival in a patient with nontropical sprue: Report of a case with unusual light and electron microscopic features JOHN J. KEPES, SAMUEL M. CHOU and LAURANCE W. PRICE, JR. Neurology 1975;25;1007 DOI 10.1212/WNL.25.11.1007 This information is current as of November 1, 1975 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1975 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
