Refer to: Canning B, Kobayashi RM, Kaplan CG, et al: Progressive multifocal leukoencephalopathy-Neurologic Clinicopathologic Conference, University of California, San Diego, and University Hospital, San Diego (Specialty Conference). West J Med 125:364-369, Nov 1976


Progressive Multifocal Leu koencephalopathy

Taken from a Neurologic Clinicopathologic Conference held at the University Hospital, University of California, San Diego on August 29, 1975.

BRENDAN CANNING, MD: * A 76-year-old man was first admitted in December 1974 with complaint of progressive fatigue, easy bruising and a 40pound weight loss over two to three months. On physical examination, pallor, scattered ecchymoses and hepatosplenomegaly were noted. There was impaired appreciation of vibratory sense, pin prick and touch below the knees; results of neurological examination were otherwise unremarkable. Laboratory studies gave the following values: hematocrit reading, 24 percent; platelet count, 35,000 to 58,000 per cu mm; leukocyte count, 138,000 per cu mm, with 98 percent mature lymphocytes. A diagnosis of chronic lymphocytic leukemia was made and treatment carried out with transfusion, administration of allopurinal for hyperuricemia and a two-month regimen of cyclo-

phosphamide (Cytoxan®). The patient was readmitted in January 1975 with an apparent infection on the floor of his mouth. This responded to administration of antibiotics and local treatment. Findings on lumbar puncture were normal. The patient was first evaluated by the neurology service on June 4, 1975 for two to three months of poor balance and occasional falls. One month before, he had been briefly stunned but not knocked out from a fall. Since then he had become irascible. The patient said that he had not had headaches but that he had had difficulty with reading. He was alert, with normal speech and *Resident, Department of Neurosciences, University of California, San Diego, School of Medicine. Reprint requests to: Ronald M. Kobayashi, MD, Neurology Service, 664/180, Veterans Administration Hospital, 3350 La Jolla Village Drive, San Diego, CA 92161.


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intact mental status. He had difficulty switching lines while reading a newspaper with either eye and with both eyes at the same time. Bilateral cataracts and macular change with visual acuity of 20/30 in the right eye and 20/60 in the left eye were present. Extraocular movements were normal, as was motor performance. Reflexes were normal except for absent ankle jerks bilaterally. Vibratory sense was absent below the knees. There was slight unsteadiness on heel to toe walking with a positive Romberg sign. On July 9, 1975 the patient was admitted because of periods of confusion, increasing irritability with inappropriate behavior, and sleeping during the day. His wife stated his vision had deteriorated in the previous four weeks, and he had become unable to dress or feed himself in the preceding week. He became disoriented and could not find the bathroom. He was intermittently alert, oriented to person, place, date, but not time. Calculations such as serial subtraction of sevens were performed well and he remembered three of five objects after five minutes. Speech was clear and judgment appeared to be intact. He was unable to see well enough to read or write. He could not count fingers at 6 inches, but could distinguish light from dark. A left homonymous hemianopsia was present. The pupils were equal, reactive to light and accommodation. Fundi were normal. Extraocular movements were intact with mild nystagamus on lateral gaze. There was a left lower facial weakness with forehead sparing. Lower cranial nerves were intact. A mild to moderate left hemiparesis was present, with a left Babinski sign. Ankle jerks were absent bilaterally. Results of sensory examination were


normal in the upper extremities but were inconsistent in the lower extremities. Gait was unsteady, and the patient was unable to tandem walk. The Romberg sign was positive. The hematocrit reading was 38 percent; leukocyte count was 22,400 per cu mm, with 94 percent lymphocytes; platelet count was 47,000 per cu mm. A random blood glucose value was 152 mg per 100 ml. The blood urea nitrogen level was 43 mg and the creatinine level was 1.9 mg per 100 ml. Findings on studies of serum electrolytes, calcium, bilirubin, lactic dehydrogenase and alkaline phosphatase were all within normal limits. The serum cholesterol value was 174 mg and triglycerides were 163 mg per 100 ml. Findings on analysis of urine and on electrocardiogram were within normal limits. On an x-ray film of the skull, a small bone island was noted in the left parietal region. Brain scan showed normal flow with suggestion of increased uptake in the left parieto-occipital region (possibly in bone). On electroencephalogram there was dysrhythmia Grade I generalized, maximal in left temporal region. The patient became intermittently resistive, agitated and confused; chlordiazepoxide and haloperidol were given. On the third hospital day, his sensorium was improved, and he could now read letters. On the fourth hospital day he fell out of bed and sustained a small laceration on the left occipital area. Results of neurological examination showed no changes. No fracture was seen on an x-ray film of the skull. On the fifth hospital day he was found to be lethargic but arousable, and had a stiff neck. He had a temperature of 100.8 to 102.3°F with Cheyne-Stokes respirations; on an x-ray film of the chest no acute changes were seen. Findings on studies of sputum showed many polymorphonuclear leukocytes and Gram-positive cocci. On lumbar puncture there was an opening pressure of 75 mm with initially clear fluid that subsequently became streaked with blood. In the first tube there were 1,700 erythrocytes and 60 leukocytes (all mononuclears). In the third tube there were 26,150 erythrocytes and 420 leukocytes (all mononuclears). The supernatant fluid was colorless. Protein was 51 mg per 100 ml and sugar 84 mg per 100 ml. Spinal fluid cultures were negative. With hydration, the fever subsided and the patient's condition improved without antibiotic therapy. On the sixth hospital day his temperature rose to 102°F. The patient became increasingly lethargic, but was

able to follow two-part commands and repeat, and at one point was said to be alert. Lumbar puncture was repeated, and after several attempts bloody cerebrospinal fluid was obtained. In the second tube were 3,000 erythrocytes and 111 leukocytes (all mononuclears). The protein was 61 mg per 100 ml. On the eighth hospital day, his temperature rose to 104°F and the patient became hypotensive. Administration of penicillin and gentamicin was begun, but the patient died later that day.

Differential Diagnosis RONALD M. KOBAYASHI, MD:* The illness in this 76-year-old man evolved in two phases. The first phase was recognized eight months before death when chronic lymphocytic leukemia was diagnosed. This diagnosis is straightforward and unequivocal. The second phase of this illness was neurological and began four to six months after the diagnosis of chronic lymphocytic leukemia was made. The initial symptoms consisted of poor balance resulting in falls, behavioral change and some reading disability. The findings of decreased perception of vibration, pin prick and touch in the lower legs, absent ankle jerks, unsteady gait and positive Romberg's sign with normal motor power indicate the presence of a sensory polyneuropathy. The deficits of a sensory polyneuropathy may be partially compensated by visual cueing. In the presence of diminished visual acuity accompanied by cataracts and macular change, however, visual compensation may be impaired. This may be sufficient explanation for the poor balance and falls. In fact, diminished sensation in the legs was observed during the December 1974 admission, but the patient was apparently asymptomatic at that time. That is evidence suggestive of a progressive neuropathy. The possible explanations for this sensory polyneuropathy are relatively few. Uremia secondary to hyperuricemia is unlikely with a blood urea nitrogen level of only 43 mg per 100 ml. Random studies of blood glucose showed slightly elevated levels, but this does not necessarily indicate that the neuropathy was of diabetic origin. If the patient were alcoholic, this would be a possible cause. Neuropathies, either sensory or sensorimotor, are among the most common of paraneoplastic processes, or remote effect of carcinoma, especially with carcinoma of the lung.' *Assistant Professor of Neurosciences, University of California, San Diego, School of Medicine, and Clinical Investigator, Veterans Administration Hospital, San Diego.




In the absence of other documented causes, I am left with the possibility that the neuropathy is a remote effect of the underlying malignancy. Frequent falls are of particular concern in a thrombocytopenic patient, but his alertness and intact mental status are evidence against a chronic subdural hematoma that could either arise spontaneously or as a consequence of head trauma from a fall. During the four weeks after the initial neurologic evaluation, the patient's condition progressively worsened and resulted in his final admission. The prominent symptoms may be summarized as progressive mental and personality deterioration accompanied by pronounced visual impairment. In the presence of normal pupillary responses and normal fundi, the localization of the bilateral blindness should be caudal to the lateral geniculate bodies and involve both sides. The left hemianopsia suggests more extensive involvement of the right visual pathway. The left hemiparesis with reflex asymmetry and a Babinski response along with the facial palsy of central origin are consistent with a subcortical lesion on the right. Fluctuating mental status is relatively common in patients with lesions of the nondominant hemi-

sphere. Laboratory tests of particular neurological interest are the skull x-ray, brain scan and electroencephalogram. If these show any abnormality at all, it was on the wrong side. The lumbar puncture findings raise some important considerations. First, the indications are rather clear-cut because the presence of fever and nuchal rigidity suggest meningitis, although one examiner ascribed the rigidity to osteoarthritis. Patients with chronic lymphocytic leukemia carry a high risk of infection. The results obtained from the lumbar puncture, however, are more confusing than clarifying. The lumbar puncture was apparently traumatic since the fluid was initially clear and then became streaked with blood. This observation is corroborated by the rise in red blood cells from the first to the third tube. Intracranial bleeding in chronic lymphocytic leukemia is primarily subarachnoid and secondary to thrombocytopenia. If there had been major intracranial bleeding, the expected findings would include increased cerebrospinal fluid pressure, xanthochromia and elevation of the protein level. These findings are absent. Of more concern is the apparent increase of leukocytes for the amount of red cells present. Since bacterial, fungal or tuberculous in366

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fection should elevate the cerebrospinal fluid protein level and lower the glucose level (at least in bacterial infection), this appears unlikely. Are these mononuclear cells actually lymphocytes which are present in increased number due to his underlying leukemia? Cytology was not done, but might have been useful in this differential. The repeat spinal tap on the next day also appeared to be traumatic. It should be mentioned that spinal taps in patients with thrombocytopenia carry the risk of subdural or epidural hematoma at the puncture site and should be done only with clear indications and with great caution.2 Following this evaluation, the patient made some unsustained improvement, became febrile and died on the eighth hospital day. To summarize, the neurological problem was characterized by progressive mental change, pronounced bilateral visual impairment, left hemiparesis and left hemianopsia superimposed on chronic lymphocytic leukemia and sensory polyneuropathy. The disease involves both sides of the brain and is largely supratentorial in location. What disease process or processes are responsible? Are these manifestations related to his underlying leukemia or are they independent? Of the unlikely considerations, I should briefly mention metabolic disorders, leukemic infiltration with or without hydrocephalus, infections, central pontine myelinolysis, limbic encephalitis, subdural hematoma and vascular disease. Metabolic disturbances such as hypercalcemia, hyponatremia, hypoglycemia, failure of the kidneys, liver or lung, and drug intoxications have either been excluded by normal laboratory values or are not adequate explanations for the neurologic features. Leukemic infiltration and meningeal implants usually occur with acute rather than chronic leukemia. The infiltrations cause mental changes in 80 percent and headaches in 50 percent of patients and have a very different spinal fluid profile consisting of elevated pressure, protein levels and cells, diminished glucose and positive cytology. Hydrocephalus may result from these meningeal implants. This condition appears unlikely. Bacterial and fungal infections, while occurring with greater frequency in chronic lymphocytic leukemia, are unlikely in view of the spinal fluid profile and negative cultures. Central nervous system bacterial infection in leukemia, moreover, is usually associated with leukopenia as indicated by a recent report from the Sloan Kettering Cancer Institute.3 Viral encephalitis is far less frequent than bacte-


rial or fungal encephalitis. Central pontine myelinolysis occurs in malnourished alcoholics, but has also been reported with leukemia. Different clinical features are present consisting of quadriparesis, ocular palsies, pupillary abnormalities and bulbar signs. This diagnosis is unlikely. Limbic encephalitis is another paraneoplastic complication, and it characteristically produces memory impairment, dementia and seizures with a more insidious time course than seen in this patient.4 Subdural hematoma is not usually associated with hemianopsia and often causes xanthochromia of the cerebrospinal fluid. Although the thrombocytopenia may be a predisposing condition, I doubt that a subdural hematoma was a significant factor. The most difficult diagnosis to exclude is that of cerebral vascular disease. Against this diagnosis is a lack of predisposing conditions and concomitants, such as evidence of vascular disease in other organs, history of transient ischemic attacks or signs of carotid disease, hypertension, diabetes, or elevated cholesterol or triglycerides or both. Bilateral central retinal artery occlusion is unlikely to produce the visual loss without a history that the loss was sudden, and changes in the fundi would be expected. Furthermore, the temporal profile is not typical of cerebral vascular disease.

It is possible that the left hemiparesis and hemianopsia occurred without the patient's awareness at any point in the month preceding his final admission because patients with nondominant hemisphere lesions may be unaware of the deficit. It may, therefore, not be possible to document the temporal profile. During the month following a, stroke, however, electroencephalograms and brain scans would be expected to show the abnormality. Furthermore, bilateral lesions would be required to explain the visual symptoms and mental changes. If vascular in nature, the process is more likely multifocal emboli than thrombotic infarction, because the involvement is bilateral and asymmetrical. Findings on the neurological studies also do not support the presence of discrete large infarcts. If embolic, what is the source? Marantic or nonbacterial endocarditis is usually associated with adenocarcinomas. There is no evidence of emboli to other organs such as spleen, kidney or lung. I favor the diagnosis of progressive multifocal leukoencephalopathy (PML), which is rare by contrast to vascular disease, but adheres to the a A.

40 a

4Yk *

,i |a

Figure 1.-Focus of demyelination in the parietal cortex. An affected oligodendrocyte with an enlarged nucleus is present in the center of the field. Tissue stained with H & E. Scale bar is 30 Am. The inset shows an affected oligodendrocyte that is pos'itive for JC virions when examined by indirect immunofluorescence. The small bright objects are normal autofluorescence. The scale bar is 15 Asm.






Figure 2.-Papovavirus in the cytoplasm of an affected oligodendrocyte. The scale bar is 200 nm. The inset shows that the virus in the cytoplasm of the affected oligodendrocytes is positively stained by antiserum to JC virions using indirect immunofluorescence. The scale bar is 30 /im and the small bright spots are autofluorescence.




principle of parsimony. This diagnosis adequately explains the clinical findings and course, and relates these to the underlying leukemia. The usual conditions for PML are met in this case. First, PML is usually associated with an underlying malignancy or chronic disease. Of these underlying diseases, chronic lymphocytic leukemia is second only to Hodgkin's disease, having been observed in 18 percent of the first 83 cases reviewed pathologically by Richardson.5 Other cases of PML have been related to tuberculosis, sarcoidosis, systemic lupus erythematosis, renal transplantation and nontropical sprue. Second, this case is consistent with the clinical principles that in PML asymmetrical involvement is the rule and cerebral manifestations predominate, although brain stem, cerebellar and spinal involvement may occur. Typical initial manifestations are monoparesis or hemiparesis with altered mental state, personality changes and visual loss. As the disease progresses over its usual three to six month course, there is pronounced deterioration of mental function, vision and motor performance. It is to be emphasized that this is a diagnosis based on these characteristic clinical features. The laboratory studies, such as cerebrospinal fluid examination, brain scan and radiology offer only negative results. Findings on an electroencephalogram are usually abnormal, but in no way specific. The basic process appears to be caused by a papovavirus infection in immunodeficient patients.6 The clinical diagnosis may be confirmed by biopsy study of the brain, utilizing light and electron microscopy, and by rapid immunofluorescence techniques.6 Treatment with the antideoxyviral agents cytarabine and idoxiuridine has been unsuccessful ex-

4~~~~~x,1 j n

cept for a single case which remitted after treatment with cytarabine.7 My diagnoses are: (1) chronic lymphocytic leukemia; (2) progressive multifocal leukoencephalopathy; (3) sensory polyneuropathy, possibly with a paraneoplastic cause, and (4) terminal infection, either pneumonia or septicemia.

Pathological Features CYNTHIA G. KAPLAN, MD:* An acute necrotizing pneumonia due to Escherichia coli and Staphylococcus aureus resulted in septicemia and the patient's death. Three pathologic entities were present in the brain: ((1) chronic lymphocytic leukemia, (2) cystic infarct and (3) progressive multifocal leukoencephalopathy. Chronic lymphocytic leukemia of the brain was documented by diffuse perivascular cuffing with small lymphocytes having a relatively uniform, mature morphology. The brain parenchyma was not infiltrated. The meninges were free of cellular infiltrates. A small healed cystic infarct was present in the right putamen. The most important entity was progressive multifocal leukoencephalopathy. This disease was manifested morphologically by multiple asymmetrically located foci of demyelination with some axonal loss. These foci contained macrophages filled with myelin fragments, oligodendrocytes with enlarged circular nuclei (Figure 1) and astrocytes with enlarged bizarre nuclei. These foci were not related to blood vessels and did not contain any polymorphonuclear or mononuclear cellular infiltrates other than macrophages. These lesions were shown to be present in the frontal cortex, parietal cortex, left visual cortex, cerebellum, basal ganglia and medulla. Only mild atherosclerotic changes were present in the cerebral vessels. There was no cerebral edema, uncal or cerebellar herniation; meningitis; cortical trauma, or subdural or epidural hematoma formation. Peripheral nerves were normal.

Clinical Pathological Correlation JAMES A. ROBB, MD:t The terminal event in this patient was septicemia secondary to acute necrotizing pneumonia caused by E. coli and S. aureus. Findings on examination of lymph nodes and bone marrow documented the chronic lymphocytic leukemia. The neurological problems in this patient

Figure 3.-Papovavirus in the extracellular space between myelin sheaths. The scale bar is 1 00 lAm. The virus particles are approximately 35 nm in diameter. 368

NOVEMBER 1976 * 125 * 5

*Resident, Department of Pathology, University of California, San Diego, School of Medicine. tAssistant Professor of Pathology, University of California, San Diego, School of Medicine.


were primarily related to the progressive multifocal leukoencephalopathy and not to the mild leukemic infiltrates in the cerebral perivascular spaces or to the small healed infarct in the right putamen. The progressive sensory polyneuropathy was most likely paraneoplastic, secondary to the chronic leukemia. Direct invasion of peripheral nerves by leukemic cells, however, was not observed in several independent sections of peripheral nerves. Progressive multifocal leukoencephalopathy (PML) is still relatively rare and occurs in patients with an altered immune response, primarily in patients with lymphoma, iatrogenic immunosuppression and sarcoid. The cause of the disease is believed to be an activation of a latent infection by a human papovavirus called JC virus after the patient's initials from whom the first isolate was made8 after ZuRhein observed the virus in the patient's brain by electron microscopy.9 Humans are quite commonly infected at a young age (50 percent of 3 year olds have neutralizing antibody to JC virus) by this virus and another human papovavirus, BK virus. BK virus is not associated with PML. A simian virus 40 (SV40)-like virus was also isolated from a patient with PML.10 These viruses probably remain associated with cells in various organs for life. JC virus appears to have a predilection for brain cells whereas BK virus has a predilection for kidney cells. BK virus has been isolated in the urine of renal transplant patients. In our case, a papovavirus was shown in the enlarged nuclei and cytoplasm (Figure 2) of affected oligodendrocytes. In these cells, virus replication occurred and killed the cell producing primary demyelination. No virus particles were observed in the affected astrocytes. The virus was identified as JC virus by indirect immunofluorescence using antisera supplied by Dr. Kenneth Takemoto of the National Institutes of Health. The infected oligodendrocytes stained positively with antiserum specific for JC virus, but did not stain with antiserum specific to BK virus or simian virus 40 (SV40) (Figures 1 and 2). Many of the affected oligodendrocytes had JC virus particles in their cytoplasm (Figure 2) indicating the beginning of cell lysis. Virus particles in the extracellular space were also present next to myelin sheaths (Figure 3). The JC virus genome deoxyribonucleic acid (DNA) is thought to be incorporated into the DNA of the abnormal oligodendrocytes and astrocytes in the demyelinated foci and to function as if it

were a cellular gene. The virus is activated to reproduce itself in at least some of the oligodendrocytes and kills them. The reasons for the virus activation are presently unknown, but are presumably due to the altered immune state of the patient. The virus, acting like a cellular gene in affected astrocytes, causes "transformation" of the astrocytes into bizarre cells with enlarged nuclei, but no virus is produced. These "transformed" astrocytes that do not produce virus are analogous to the cells that are "transformed" in test tubes by these viruses and other oncogenic papovaviruses such as SV40 and the mouse polyoma virus. The "transformed" astrocytes probably have the in vivo oncogenic potential of the JC virus although no direct evidence is yet available that the human papovaviruses produce cerebral tumors. SV40 causes cerebral tumors in young hamsters when inoculated intracerebrally. When JC virus infects cells in test tubes, a viruscoded antigen appears in the nuclei called tumor (T) antigen. This same antigen appears in the nuclei of cells in animal tumors produced by JC virus. This antigen is thought to regulate the growth of the tumor cells. The T antigen of JC, BK and SV40 viruses all cross-react immunologically. The nuclei in "transformed" astrocytes in our patient's parietal lobe, however, did not fluoresce when the cells were stained with antiserum specific for SV40 T antigen. The interactions between JC virus infected cells and the human immune system producing progressive multifocal leukoencephalopathy, may provide a framework for understanding the possible roles of viruses in other central and peripheral nervous system diseases in humans such as multiple sclerosis, amyotrophic lateral sclerosis and subacute sclerosing panencephalitis. 1. Croft PB, Urich H, Wilkinson M: Peripheral neuropathy of sensorimotor type associated with malignant disease. Brain 90:3166, 1967 2. Edelson RN, Chernik NL, Posner JB: Spinal subdural hematomas complicating lumbar puncture. Arch Neurol 31:134-137, 1974 3. Chemik NL, Armstrong D, Posner JB: Central nervous system infections in patients with cancer. Med 52:563-581, 1973 4. Corsellis JAN, Goldberg GJ, Norton AR: "Limbic encephalitis" and its association with carcinoma. Brain 91:481-496, 1968 5. Richardson EP: Progressive multifocal leukoencephalopathy, In Vinken PJ and Bruyn GW (Eds): Handbook of Clinical Neurology. Amsterdam, No-Holland Publ Co, 1970, pp 485-499 6. Narayan 0, Penney JB, Johnson RT, et al: Etiology of progressive multifocal leukoencephalopathy-Identification of papovavirus. N Engl J Med 289:1278-1282, 1973 7. Bauer WR, Turel AP, Johnison KP: Progressive multifocal leukoencephalopathy and cytarabine-Remission with treatment. JAMA 226:174-176, 1973 8. Padgett BL, Walker DL, ZuRhein GM, et al: Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet 1:1257-1260, 1971 9. ZuRhein GM, Chou M: Particles resembling papovaviruses in human cerebral demyelinating disease. Science 148:1477-1479, 1965 10. Martin MA, Gelb LD, Garon C, et al: Characterization of "heavy" and "light" SV40-like particles from a patient with PML. Virology 59:179-189, 1974



Progressive multifocal leukoencephalopathy.

Refer to: Canning B, Kobayashi RM, Kaplan CG, et al: Progressive multifocal leukoencephalopathy-Neurologic Clinicopathologic Conference, University of...
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