Case 14-2004 — A 66-Year-Old Man with Progressive Neurologic Deficits
http://www.100md.com
《新英格兰医药杂志》
Presentation of Case
A 66-year-old, right-handed man was admitted to the hospital because of progressive left-sided weakness.
Nineteen years before admission, the patient had received a renal transplant from a living related donor because of end-stage renal failure due to nephrolithiasis. He had alcoholic cirrhosis, which resulted in variceal bleeding and recurrent ascites requiring intermittent paracentesis. Other problems included type 1 diabetes mellitus, cholelithiasis, osteoarthritis (for which bilateral hip replacements had been performed), and coronary artery disease.
Two months before admission, weakness of the left side of the face and left hand developed. A cranial magnetic resonance imaging (MRI) study (Figure 1) showed a nonenhancing lesion in the right centrum semiovale and frontal subcortical white matter, with mass effect; the mass was hyperintense on T2-weighted images and hyperintense on apparent-diffusion-coefficient imaging maps. Other scattered, hyperintense white-matter foci were also present on T2-weighted images. The major intracranial flow voids were normal. During the three weeks before admission, the weakness worsened, and the left leg also became weak. The patient had no headaches, visual problems, or fever. He was admitted to this hospital.
Figure 1. MRI Scan Obtained Two Months before the First Hospital Admission.
The fluid-attenuated inversion recovery (FLAIR) image at the level of the frontal lobes (Panel A, arrow) shows a T2-weighted hyperintense lesion in the posterior aspect of the right frontal lobe; the lesion predominantly involves white matter in a subcortical location, spares the cortex, and has no enhancement (not shown) or mass effect. On the apparent-diffusion-coefficient map (Panel B), the lesion (white oval) does not show restricted diffusion but rather shows hyperintensity that is more consistent with chronic changes than with acute infarction.
The patient was a retired administrator. He had smoked one pack of cigarettes daily for 15 years but had stopped 15 years before admission. He had drunk a six-pack of beer daily for 20 years but had stopped 19 years before admission. He did not use illicit drugs and had not been out of the United States in the previous 10 years. A test for antibodies to the human immunodeficiency virus (HIV) had been negative 10 years earlier. His medications and supplements were a neutral protamine Hagedorn preparation of insulin, insulin lispro, azathioprine, prednisone, pantoprazole, vitamin B12, folic acid, vitamin B6, vitamin C, multivitamins, gabapentin, quetiapine, spironolactone, lactulose, and lorazepam.
The neurologic examination showed a normal mental status, fluent speech, and mild dysarthria. There was no neglect, and the patient correctly copied diagrams of a clock and a complex geometric shape. The cranial-nerve examination revealed full visual fields with no extinction; a left-sided facial droop with an upper-motor-neuron pattern was detected. The left arm and leg were weak, with motor power graded as follows: deltoids, biceps, and triceps, 4/5; wrist extensors, 3/5; wrist flexors, 4/5; finger extensors, 1/5; finger flexors, 4/5; interossei, 0/5; and iliopsoas, 4/5. Strength was full in the remainder of the left leg and in the right arm and leg. Sensation was intact except for extinction of light touch in the left arm on bilateral simultaneous stimulation. The deep-tendon reflexes were ++ bilaterally in the triceps, biceps, brachioradialis, and patella; the ankle jerks were absent. There was no clonus, but a left Babinski reflex was present. Cerebellar examination with the use of finger-to-nose testing on the right side was normal. The gait was limited by the weakness of the left leg.
The urine was normal. The levels of calcium, phosphorus, magnesium, aspartate aminotransferase, alanine aminotransferase, fibrinogen, vitamin B12, and vitamin B6 were normal. The results of other laboratory tests are shown in Table 1, Table 2, and Table 3. An electrocardiogram showed a normal rhythm and pattern.
Table 1. Hematologic Laboratory Data.
Table 2. Coagulation Test Results.
Table 3. Blood Chemical Values.
A chest radiograph was clear. A cranial MRI study (Figure 2A), performed without the administration of gadolinium, revealed that the right frontal lesion had enlarged. There was no mass effect. On T2-weighted images there were several small, hyperintense foci in the left frontal lobe that had not been present on the previous study. Magnetic resonance angiographic examination of the head and neck disclosed no stenosis. Ultrasonographic examination of the right and left carotid arteries showed minimal disease in the arterial bifurcations. A transcranial Doppler study showed normal flow in the distal internal carotid arteries and in the cerebral artery stems.
Figure 2. MRI Study Showing Progression of the Lesion over Time.
Two FLAIR images through the plane of the frontal lobes at the time of the first hospital admission (Panel A) and one month later, on the day after the second admission (Panel B), show the growth of the original lesion in the right frontal lobe (arrows in both panels) into the corpus callosum. An additional focus of disease is seen in the left frontal lobe (Panel B, arrowhead). An image through the plane of the temporal lobes (Panel C) shows the development of multiple additional foci of disease (arrows) in the right pons and at two sites in the right temporal lobe.
Because of the patient's hepatic disease, no anticoagulation therapy was given. Folic acid, multivitamins, and vitamins B12 and B6 were administered. The neurologic findings remained stable, and on the fifth hospital day he was discharged to a rehabilitation hospital.
During the ensuing month, the patient progressively lost motor function on the left side, became unable to stand without assistance, and became unable to move his left hand. His right arm and both legs also became progressively weaker, and he began to have difficulty swallowing liquids and occasionally aspirated them. Twenty-three days after his discharge, computed tomographic (CT) scanning of the brain, performed without the intravenous administration of contrast material, revealed a hypodense focus in the subcortical white matter of the left frontal lobe that appeared more prominent than on the most recent MRI study; the right-sided lesion was unchanged. A cranial MRI examination (Figure 2B and Figure 2C) three days later showed enlargement of the right frontal lesion with extension into the posterior limb of the right internal capsule, cerebral peduncle, pons, and right forceps major. The left frontal lesion had increased in size, and there were new lesions in the body of the corpus callosum and the right brain stem. There was no mass effect or abnormal enhancement. The patient was readmitted to the hospital one month after discharge.
The temperature was 36.5°C, the pulse was 80 beats per minute, and the respiratory rate was 18 breaths per minute. The blood pressure was 90/70 mm Hg. The patient appeared cachectic but not acutely ill. There were numerous ecchymoses. The carotid pulses were normal, without bruits. The lungs were clear. A grade 1 systolic murmur was present at the cardiac apex. The abdomen was distended, and there was evidence of ascites. A surgical scar was present over the right lower quadrant. The liver edge descended 3.5 cm below the right costal margin; the spleen was not felt. Rectal examination revealed no abnormalities.
On neurologic examination, the patient was alert and oriented. He misspelled "world" backward and had difficulty making calculations but was able to recall three objects. His speech was fluent except for difficulty with guttural sounds. He drew a diagram of a clock with complete numbers and correct hand positions, but the size of the hands was inappropriate. He wrote a complex sentence and correctly identified objects. The left lower facial droop persisted; the strength of the sternocleidomastoid was weaker on the left side. The tongue deviated to the right. The remaining cranial-nerve functions were intact.
There was diffuse bilateral muscle atrophy, with cogwheeling. Muscle strength on the left was as follows: 0/5 in the left biceps, triceps, interossei, and wrist flexors and in hip extension, plantar flexion, and dorsiflexion; 4–/5 in the left shoulder shrug; and 1/5 in right hip flexion. Muscle strength on the right was as follows: right biceps, 4–/5; triceps, 4–/5; shoulder shrug, 4–/5; interossei, 4/5; wrist extensors 4–/5; wrist flexors, 4/5; hip extensors, 4–/5; hip flexors, 4–/5; plantar flexors, 4/5, and dorsiflexors, 4/5. The deep-tendon reflexes were 2+ throughout, except that the ankle jerks were 1+ bilaterally. There were 13 beats of clonus in the right ankle and 12 beats in the left ankle; the left Babinski reflex persisted. The sensations of light touch and pinprick were decreased in the left arm. There was decreased vibratory sensation in the right arm and leg. The sense of position was inconsistent. Coordination, tested only on the right side, evoked past pointing. Gait was not assessed.
The urine was normal. The levels of magnesium, phosphorus, serum aspartate aminotransferase, serum alanine aminotransferase, and fibrinogen were normal. The results of other laboratory tests are shown in Table 1, Table 2, and Table 3. An electrocardiogram showed a normal rhythm at a rate of 81 beats per minute. A magnetic resonance spectroscopic study (Figure 3) revealed marked elevation in the choline-to-creatine ratio and depression of the N-acetyl aspartate peak.
Figure 3. Findings on Magnetic Resonance Spectroscopy.
Spectroscopy was performed with the use of a multivoxel chemical-shift technique, with selection of the anterior portion of the lesion in the right frontal lobe as the region of interest (Panel A, rectangle with numbers). The spectra reveal substantial abnormalities of cerebral metabolism (Panel B). The N-acetyl aspartate peak is greatly reduced (arrow), a finding indicative of neuronal loss or malfunction, and there is a lactate doublet (arrowhead), a finding indicating anaerobic metabolism. The elevated ratio of choline to creatine (white oval) is often seen in the setting of increased membrane turnover.
A lumbar puncture yielded clear, colorless cerebrospinal fluid that contained 540 red cells and 1 white cell per cubic millimeter in the fourth tube. A stained smear contained 37 percent neutrophils, 53 percent lymphocytes, 7 percent monocytes, and 3 percent nonhematic cells. The glucose level was 63 mg per deciliter (3.5 mmol per liter), and the total protein level 35 mg per deciliter.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Igor J. Koralnik: This patient had many factors that predisposed him to central nervous system disease, including long-term immunosuppressive therapy, multiple cerebrovascular risk factors, and alcoholic cirrhosis of the liver. Since he initially presented with a left facial droop and hand weakness, followed by weakness of the left leg, without changes in his mental function or sensation, the lesion responsible for his left-sided hemiparesis was interrupting the corticospinal or corticobulbar tract fibers below the cortex of the right frontal lobe and above the medulla. The time course of the neurologic presentation is critical: a gradual worsening over a period of three weeks is too slow for a vascular event and too fast for a tumor, but it is compatible with a metabolic, inflammatory, or infectious process.
May we review the imaging studies of the brain?
Dr. Dawid Schellingerhout: The fluid-attenuated inversion recovery (FLAIR) image from his first MRI scan (Figure 1A) shows a lesion in the posterior aspect of the right frontal lobe involving subcortical white matter and sparing the cortex, with no mass effect or enhancement. The apparent-diffusion-coefficient imaging map (Figure 1B) shows only T2-weighted hyperintensity, which is a feature that is consistent with the presence of chronic, rather than acute, infarction. Restricted diffusion, a feature of acute infarction, was not noted.
The second MRI scan (Figure 2A) shows that the lesion has enlarged, extending posteriorly into the frontal lobe and involving the corpus callosum. There are a few small foci of T2-weighted hyperintensity in the left frontal lobe that were not present on the previous study. The apparent-diffusion-coefficient imaging maps show no sign of restricted diffusion. Again, these findings are most consistent with a chronic or slowly progressive process, rather than acute infarction.
The third MRI scan shows progression of the disease (Figure 2B and Figure 2C). The lesion in the posterior right frontal lobe extends into the corpus callosum and has progressed medially, anteriorly, and posteriorly. The lesion in the left anterior frontal lobe has enlarged, and there is a new focus of involvement in the right brain stem and pons, extending into the internal capsule on the right side.
Magnetic resonance spectroscopy (Figure 3) performed with the use of a multivoxel chemical-shift technique over the right frontal lobe shows an elevated choline-to-creatine ratio, a reduced N-acetyl aspartate peak, and a small inverted lactate doublet. The reduced N-acetyl aspartate peak indicates decreased neuronal mass or metabolism due to neuronal distress or loss. The elevated choline-to-creatine ratio is typical of cancer and other conditions involving increased membrane turnover. The lactate doublet is an indication of anaerobic metabolism, with accumulation of lactate, a metabolic product of glycolysis that is consumed during normal metabolism.
In summary, although some of the initial radiologic findings might have been consistent with the presence of an infarction, the changes over time do not support this diagnosis. Cancer is a consideration, but the lack of a mass effect and enhancement and the rapid course argue against that possibility. A progressive demyelinating condition would best fit the imaging findings.
Dr. Koralnik: The initial MRI scans confirm the presence of a right hemispheric lesion and provide additional important information: the lesion is restricted to the white matter and does not involve the cortex or the basal ganglia. The absence of enhancement and of a mass effect indicates that the blood–brain barrier is intact and rules out inflammation. The topographic features of the lesion do not correspond to a specific vascular territory. The lesion is hyperintense on images based on the apparent diffusion coefficient, indicating increased diffusion of water within the brain parenchyma, which occurs when there is damage to cell membranes. This is the opposite of what occurs in acute stroke,1 which is characterized by lesions that are initially hypointense on apparent-diffusion-coefficient images because of restricted diffusion of water within the damaged area.
The neurologic examination at the time of the patient's first hospitalization revealed a left pyramidal syndrome but also extinction of the sensation of light touch on double simultaneous stimulation of the left arm. In the absence of left-sided neglect, this finding indicates a posterior extension of the lesion toward the thalamocortical projections of the right parietal lobe, rather than involvement of the right parietal cortex itself.
Other salient features of the patient's presentation include his normal mental status and the absence of fever, meningismus, or signs of increased intracranial pressure. In an immunocompetent person, these findings would usually rule out a bacterial or fungal infection. However, because this patient was immunosuppressed and lymphopenic, the inflammatory reaction to an infectious agent could be less than that in an immunocompetent person. Moreover, the differential diagnosis needs to be extended to include conditions that occur more often in the setting of a depressed immune system.
A worsening of the patient's neurologic condition prompted his second hospitalization. At that time, two months after the onset of his symptoms, the neurologic examination revealed mild inattention and impairment of visuospatial skills, a bilateral pyramidal syndrome, bilateral sensory deficits, and evidence of brain-stem dysfunction, indicating that the disease now involved the frontal and parietal lobes of both hemispheres and extended downward to the pons.
The CT scan and the third MRI scan of the brain confirm the presence of new lesions. In addition, the results of proton magnetic resonance spectroscopy constitute valuable metabolic information, providing evidence of either neoplasia or demyelination but not infarction. N-acetyl aspartate is a neuronal marker, choline is a component of cell membranes, and creatine serves as a measure of baseline metabolism. Therefore, a decreased N-acetyl aspartate peak in the white matter indicates axonal damage, whereas elevation of the choline-to-creatine ratio is consistent either with neoplasia or with demyelination but not with acute brain infarction. Finally, all lesions have the same appearance and are restricted to the cerebral white matter. Hence, this disorder is a leukoencephalopathy. The conditions associated with leukoencephalopathy in adults are summarized in Table 4.
Table 4. Causes of Leukoencephalopathy in Adults.
Causes of Leukoencephalopathy
Vascular Causes
Although this patient had multiple cerebrovascular risk factors, the absence of stepwise progression and the appearance and topographic features of the lesions on the apparent-diffusion-coefficient MRI scan and the proton magnetic resonance spectroscopic study argue against subcortical arteriosclerotic encephalopathy, also known as Binswanger's disease. The same reasoning applies to cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL) and to isolated central nervous system vasculitis. The normal erythrocyte sedimentation rate, the normal protein level in the cerebrospinal fluid, and the normal cellularity of the cerebrospinal fluid, as well as the absence of cortical involvement, argue against the latter disorder.
Toxic and Metabolic Causes
The patient did not have a history of exposure to toxic substances, and except for hepatic dysfunction, he did not have metabolic problems. The use of alcohol has been associated with Marchiafava–Bignami disease, or selective demyelination of the corpus callosum, but the patient had discontinued his use of alcohol 19 years before admission. His immunosuppressive regimen did not include cyclosporine or tacrolimus, which cause an acute and reversible leukoencephalopathy in 1 to 6 percent of treated patients.2
Hereditary Causes
Hereditary leukodystrophies, resulting from enzymatic disorders that can occur in late adulthood, include X-linked cerebral adrenoleukodystrophy and metachromatic leukodystrophy. Adult X-linked cerebral adrenoleukodystrophy is caused by a deficiency of a peroxisomal acyl coenzyme A synthetase, which leads to the accumulation of very-long-chain fatty acids; metachromatic leukodystrophy is secondary to a deficiency of arylsulfatase A, which results in the accumulation of sulfated sphingolipids. Both usually occur in adults with dementia or psychiatric disturbances, which this patient did not have.
Autoimmune and Inflammatory Causes
A group of conditions that affect the white matter of the central nervous system, such as multiple sclerosis and acute demyelinating encephalomyelitis, which are autoimmune or inflammatory in nature, needs to be considered. However, these conditions have been described only rarely in immunosuppressed persons.3 Furthermore, an inflammatory component was conspicuously absent in this patient. Other entities, such as systemic lupus erythematosus, can be ruled out by the absence of systemic symptoms, the normal erythrocyte sedimentation rate, and the normal white-cell count and protein concentration in the cerebrospinal fluid.
Tumoral Causes
Primary central nervous system lymphoma deserves special consideration, since it is associated with immunosuppression and can be manifested as a subacute, multifocal infiltration of the central nervous system white matter.4 In HIV-positive patients with primary central nervous system lymphoma, analysis of the cerebrospinal fluid for Epstein–Barr virus with the use of the polymerase chain reaction (PCR) has a sensitivity of 83 to 100 percent and a specificity of 93 to 100 percent,5,6 and thallium-201, single-photon-emission CT has 92 percent sensitivity and 89 percent specificity. However, the usefulness of thallium-201 depends on the resolution of the images, and appropriate instruments may not be available in every center. Cytologic examination of the cerebrospinal fluid and testing for Epstein–Barr virus should be considered in this patient.
Intravascular lymphoma7 and lymphomatoid granulomatosis8 are rare entities that may be restricted to the central nervous system and that may appear as a leukoencephalopathy on an MRI scan. However, the lesions usually show contrast enhancement.
Gliomatosis cerebri is a rare, diffusely infiltrative tumor that is characterized by the absence of contrast enhancement in 70 percent of patients. However, a mass effect is present in most cases, and involvement is usually not restricted to the white matter.9
Infectious Causes
Infections that may be manifested as a leukoencephalopathy, such as Lyme neuroborreliosis, neurosyphilis, and tuberculosis, are highly unlikely in this case because of the patient's normal cerebrospinal fluid and the absence of systemic symptoms. Encephalitis due to toxoplasma is almost always associated with the appearance of ring-enhancing lesions. Small-vessel encephalitis associated with varicella–zoster virus10 affects the central nervous system white matter in elderly and immunosuppressed persons and can also be ruled out in this case because of the absence of inflammation in the cerebrospinal fluid and the appearance of the lesions on diffusion-weighted imaging and the proton magnetic resonance spectroscopic study.
The result of a serologic test for HIV infection in this patient 10 years earlier was negative. Since central nervous system disorders in people with the acquired immunodeficiency syndrome (AIDS) and such disorders in organ-transplant recipients often overlap, a repeated serologic test for HIV seems justified. A positive result would have tremendous implications for the management of this patient's disease. HIV encephalopathy,11 or the newly recognized demyelinating HIV-associated leukoencephalopathy,12 may be manifested as localized, hyperintense, white-matter lesions on T2-weighted MRI examination, but the lesions are usually symmetric and are not associated with focal neurologic deficits. In addition, signs of a cognitive disorder would be expected in HIV encephalopathy.
Progressive Multifocal Leukoencephalopathy
None of the entities I have reviewed entirely fit the clinical and neuroradiologic presentation of this patient. A purely descriptive characterization of this patient's disease would be a leukoencephalopathy that is multifocal and progressive. An entity with these features was recognized in 193013 and was given the name progressive multifocal leukoencephalopathy by Astrom and colleagues at this hospital in 1958, on the basis of their examination of pathological specimens from patients with lymphomas.14 In 1965, polyomavirus particles were detected in the nuclei of oligodendrocytes on electron microscopy.15 Polyomavirus JC was isolated from the brain of a patient with progressive multifocal leukoencephalopathy in 1971 and was named with the patient's initials.16
Asymptomatic infection with the JC virus occurs in childhood; 80 to 90 percent of healthy adults are seropositive for the virus,17 which is excreted in the urine and commonly found in sewer samples.18 The virus remains quiescent in the tubular epithelial cells of the kidneys and in lymphoid organs but may be reactivated in the setting of severe cellular immune deficiency. Progressive multifocal leukoencephalopathy emerged as a major opportunistic infection at the beginning of the epidemic of HIV infection, occurring in up to 5 percent of patients with AIDS. It is also diagnosed in 0.07 percent of patients who are immunosuppressed because of hematologic cancer,19 and it has been described as a fatal complication of organ transplantation both in the early post-transplantation period20 and more than 10 years after the procedure.21 In an autopsy study of liver-transplant recipients, 1 of 132 patients (0.8 percent) had progressive multifocal leukoencephalopathy.22 Of the 61 patients with this disorder enrolled in our clinical studies after 1995, 48 had AIDS, 8 had a hematologic cancer, 3 were recipients of a bone marrow transplant, 1 had a history of a thymoma, and 1 had dermatomyositis.
During the past decade, detection of JC virus DNA in the cerebrospinal fluid with the use of polymerase chain reaction (PCR) was found to have a sensitivity of 72 to 93 percent and a specificity of 92 to 100 percent for the diagnosis of progressive multifocal leukoencephalopathy in HIV-positive persons.5,23,24 It has a similarly high sensitivity and specificity in HIV-negative subjects.24 Therefore, it is now accepted as a diagnostic test for progressive multifocal leukoencephalopathy.25,26
In this HIV-negative patient, treatment of progressive multifocal leukoencephalopathy should include, if possible, a reduction or interruption of immunosuppressive therapy. Treatment with cytosine arabinoside was associated with the stabilization of disease in 7 of 19 patients (37 percent) in a retrospective study.27 Unfortunately, patients who survive do not recover neurologic function and are often left with devastating sequelae, and most die within one year after the onset of symptoms.27 Factors associated with a good prognosis include evidence of an inflammatory response such as a lymphoplasmacytic infiltrate in the lesions,28,29 faint contrast enhancement on brain imaging studies,30 and detectable cytotoxic T lymphocytes specific for polyomavirus JC in the blood.31,32
In immunosuppressed patients with multiple brain lesions, more than one disease may be present, and therefore a positive result on PCR assay or a histologic finding on examination of a brain-biopsy specimen may not provide all the answers. In the case under discussion, however, the clinical presentation, the homogeneity of the lesions on the MRI scans, and the results of apparent-diffusion-coefficient MRI and proton magnetic resonance spectroscopy33 all point to the presence of a single entity.
Dr. Nancy Lee Harris (Pathology): Dr. Buonanno, what was your impression of this patient during the course of his illness and before the diagnostic procedure was performed?
Dr. Ferdinando Buonanno (Neurology): When this patient first came to my office, he had had an episode of left-sided hemiparesis, which was improving. For this reason, we suspected that his illness had a vascular cause. Later, the progressive nature of the illness started to emerge, and we strongly suspected progressive multifocal leukoencephalopathy. We performed a brain biopsy to establish the diagnosis.
Clinical Diagnosis
Progressive multifocal leukoencephalopathy.
Dr. Igor J. Koralnik's Diagnosis
Progressive multifocal leukoencephalopathy.
Pathological Discussion
Dr. Matthew P. Frosch: Smear preparations of the stereotactic brain-biopsy specimen, made during an intraoperative consultation, showed oligodendrocytes with enlarged, glassy, smudged nuclei (Figure 4A). Similar oligodendrocytes, with nuclei up to four times as large as normal nuclei, were evident on paraffin-embedded sections (Figure 4B). Since oligodendrocytes produce the myelin sheath, damage to these cells causes loss of myelin with relative preservation of axons, as seen by comparing stains for axons (an immunostain for neurofilament proteins) and myelin (Figure 4C and Figure 4D). There was no inflammatory response associated with this demyelination. No enlarged or bizarre astrocytes were present in the biopsy specimens.
Figure 4. Specimen from a Stereotactic Brain Biopsy.
Four high-power microscopical fields from the intraoperative smear preparation (Panel A; hematoxylin and eosin, x750) show round, enlarged nuclei with indistinct chromatin (arrows) in the oligodendrocytes. In each field, there is also an oligodendrocyte that appears normal in size and that has more distinct chromatin (arrowheads). A paraffin-embedded section (Panel B; hematoxylin and eosin, x250) shows multiple enlarged oligodendrocyte nuclei with abnormal chromatin (arrows). Sections stained for myelin (Panel C, x125) and immunostained with antibodies for neurofilament proteins (Panel D; immunoperoxidase, x125) show loss of myelin (clear areas with loss of blue in center, Panel C) and preservation of axons (brown areas, Panel D).
The etiologic agent of progressive multifocal leukoencephalopathy, JC virus, was identified by immunostaining for the large T antigen (Figure 5A), in the infected oligodendrocytes. The lesions grow as the infected cell enters the lytic stage, releasing viral particles that infect other cells. The number of infected cells varies according to the age of the lesion and the area of the lesion that is examined. This biopsy specimen appears to have come from an area of relatively recent involvement. Electron microscopy showed that viral particles were present (Figure 5B).
Figure 5. Identification of Polyomavirus JC in a Biopsy Specimen of the Brain.
Immunostaining with antibodies against the large T antigen of JC virus shows numerous infected cells (Panel A; immunoperoxidase, x250). An electron micrograph of an oligodendrocyte (Panel B, x8800) shows abundant viral particles concentrated in the center of the nucleus; these are seen at higher magnification in the inset (x38,100). The scale bar represents 0.44 μm.
The combination of abnormal nuclei in the oligodendrocytes and evidence of demyelination, supported by the identification of the virus by ultrastructural and immunologic studies, confirms the diagnosis of progressive multifocal leukoencephalopathy. After the biopsy was performed, samples of cerebrospinal fluid analyzed by the PCR JC virus were reported to be positive.
Dr. Harris: Dr. Black-Schaffer, you cared for this patient at the rehabilitation hospital. Could you give us your thoughts about his course before the diagnostic procedure?
Dr. Randie M. Black-Schaffer (Physiatry): The patient came to us with a diagnosis of stroke. His endurance and overall functional status gradually declined. In the third week, a specific focal increase in his left hemiparesis appeared, first in the arm, and then, within a few days, in the leg. The CT and MRI studies were performed, and he was referred back to the hospital for a biopsy.
Dr. Harris: Dr. Buonanno, what was the outcome?
Dr. Buonanno: He had progressive neurologic deterioration and died in hospice care soon after the biopsy. No autopsy was performed.
Anatomical Diagnosis
Progressive multifocal leukoencephalopathy.
Supported in part by grants from the National Institutes of Health (2PO1CA6924605 and 1-R24-CA92782-01), the Radiologic Society of North America, and the American Brain Tumor Association (to Dr. Schellingerhout) and by grants from the National Institutes of Health (R01NS/AI 41198, R01 NS 047029, R21 NS 046243, and P30-AI 28691) and the Harvard Center for Neurodegeneration and Repair (to Dr. Koralnik).
Source Information
From the Departments of Neurology and Medicine, Beth Israel Deaconess Medical Center (I.J.K.); the Departments of Radiology (D.S.) and Pathology (M.P.F.), Massachusetts General Hospital; and the Departments of Neurology (I.J.K.), Radiology (D.S.), and Pathology (M.P.F.), Harvard Medical School — all in Boston.
References
Warach S, Dashe JF, Edelman RR. Clinical outcome in ischemic stroke predicted by early diffusion-weighted and perfusion magnetic resonance imaging: a preliminary analysis. J Cereb Blood Flow Metab 1996;16:53-59.
Singh N, Bonham A, Fukui M. Immunosuppressive-associated leukoencephalopathy in organ transplant recipients. Transplantation 2000;69:467-472.
Berger JR, Sheremata WA, Resnick L, Atherton S, Fletcher MA, Norenberg M. Multiple sclerosis-like illness occurring with human immunodeficiency virus infection. Neurology 1989;39:324-329.
Phan TG, O'Neill BP, Kurtin PJ. Posttransplant primary CNS lymphoma. Neuro-oncology 2000;2:229-38.
Cinque P, Vago L, Dahl H, et al. Polymerase chain reaction on cerebrospinal fluid for diagnosis of virus-associated opportunistic diseases of the central nervous system in HIV-infected patients. AIDS 1996;10:951-958.
Antinori A, Ammassari A, De Luca A, et al. Diagnosis of AIDS-related focal brain lesions: a decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF. Neurology 1997;48:687-694.
Moussouttas M. Intravascular lymphomatosis presenting as posterior leukoencephalopathy. Arch Neurol 2002;59:640-641.
Tateishi U, Terae S, Ogata A, et al. MR imaging of the brain in lymphomatoid granulomatosis. AJNR Am J Neuroradiol 2001;22:1283-1290.
Herrlinger U, Felsberg J, Kuker W, et al. Gliomatosis cerebri: molecular pathology and clinical course. Ann Neurol 2002;52:390-399.
Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, Mahalingam R, Cohrs RJ. Neurologic complications of the reactivation of varicella-zoster virus. N Engl J Med 2000;342:635-645.
Post MJ, Tate LG, Quencer RM, et al. CT, MR, and pathology in HIV encephalitis and meningitis. AJR Am J Roentgenol 1988;151:373-380.
Langford TD, Letendre SL, Marcotte TD, et al. Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy. AIDS 2002;16:1019-1029.
Hallervorden J. Eigerartige und nicht rubrizierbare Prozesse. In: Bumke O, ed. Handbuch der Geiteskrankheiten. Vol. 2. Berlin: Springer, 1930:1063-107.
Astrom KE, Mancall EL, Richardson EP Jr. Progressive multifocal leuko-encephalopathy: a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin's disease. Brain 1958;81:93-127.
ZuRhein GM, Chou S-M. Particles resembling papova viruses in human cerebral demyelinating disease. Science 1965;148:1477-1479.
Padgett BL, Walker DL, ZuRhein GM, Eckroade RJ, Dessel BH. Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet 1971;1:1257-1260.
Weber T, Trebst C, Frye S, et al. Analysis of the systemic and intrathecal humoral immune response in progressive multifocal leukoencephalopathy. J Infect Dis 1997;176:250-254.
Bofill-Mas S, Girones R. Excretion and transmission of JCV in human populations. J Neurovirol 2001;7:345-349.
Power C, Gladden JG, Halliday W, et al. AIDS- and non-AIDS-related PML association with distinct p53 polymorphism. Neurology 2000;54:743-746.
Manz HJ, Dinsdale HB, Morrin PA. Progressive multifocal leukoencephalopathy after renal transplantation: demonstration of papova-like virions. Ann Intern Med 1971;75:77-81.
Berner B, Krieter DH, Rumpf KW, et al. Progressive multifocal leukoencephalopathy in a renal transplant patient diagnosed by JCV-specific DNA amplification and an intrathecal humoral immune response to recombinant virus protein 1. Nephrol Dial Transplant 1999;14:462-465.
Martinez AJ, Ahdab-Barmada M. The neuropathology of liver transplantation: comparison of main complications in children and adults. Mod Pathol 1993;6:25-32.
Weber T, Turner RW, Frye S, et al. Progressive multifocal leukoencephalopathy diagnosed by amplification of JC virus-specific DNA from cerebrospinal fluid. AIDS 1994;8:49-57.
Koralnik IJ, Boden D, Mai VX, Lord CI, Letvin NL. JC virus DNA load in patients with and without progressive multifocal leukoencephalopathy. Neurology 1999;52:253-260.
Cinque P, Koralnik IJ, Clifford DB. The evolving face of human immunodeficiency virus-related progressive multifocal leukoencephalopathy: defining a consensus for terminology definition. J Neurovirol 2003;9:Suppl 1:88-92.
Marra CM, Rajicic N, Barker DE, et al. A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS. AIDS 2002;16:1791-1797.
Aksamit AJ. Treatment of non-AIDS progressive multifocal leukoencephalopathy with cytosine arabinoside. J Neurovirol 2001;7:386-390.
Du Pasquier RA, Koralnik IJ. Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol 2003;9:Suppl 1:25-31.
Richardson EP Jr, Johnson PC. Atypical progressive multifocal leukoencephalopathy with plasma-cell infiltrates. Acta Neuropathol (Berl) 1975;6:247-250.
Berger JR, Levy RM, Flomenhoft D, Dobbs M. Predictive factors for prolonged survival in acquired immunodeficiency syndrome-associated progressive multifocal leukoencephalopathy. Ann Neurol 1998;44:341-349.
Koralnik IJ, Du Pasquier RA, Kuroda MJ, et al. Association of prolonged survival in HLA-A2+ progressive multifocal leukoencephalopathy patients with a CTL re-sponse specific for a commonly recognized JC virus epitope. J Immunol 2002;168:499-504.
Du Pasquier RA, Kuroda M, Schmitz JE, et al. Low frequency of cytotoxic T lymphocytes against the novel HLA A*0201-restricted JC virus epitope VP1p36 in patients with proven or possible progressive multifocal leukoencephalopathy. J Virol 2003;77:11918-11926.
Chang L, Ernst T, Tornatore C, et al. Metabolite abnormalities in progressive multifocal leukoencephalopathy by proton magnetic resonance spectroscopy. Neurology 1997;48:836-845.(Igor J. Koralnik, M.D., D)
A 66-year-old, right-handed man was admitted to the hospital because of progressive left-sided weakness.
Nineteen years before admission, the patient had received a renal transplant from a living related donor because of end-stage renal failure due to nephrolithiasis. He had alcoholic cirrhosis, which resulted in variceal bleeding and recurrent ascites requiring intermittent paracentesis. Other problems included type 1 diabetes mellitus, cholelithiasis, osteoarthritis (for which bilateral hip replacements had been performed), and coronary artery disease.
Two months before admission, weakness of the left side of the face and left hand developed. A cranial magnetic resonance imaging (MRI) study (Figure 1) showed a nonenhancing lesion in the right centrum semiovale and frontal subcortical white matter, with mass effect; the mass was hyperintense on T2-weighted images and hyperintense on apparent-diffusion-coefficient imaging maps. Other scattered, hyperintense white-matter foci were also present on T2-weighted images. The major intracranial flow voids were normal. During the three weeks before admission, the weakness worsened, and the left leg also became weak. The patient had no headaches, visual problems, or fever. He was admitted to this hospital.
Figure 1. MRI Scan Obtained Two Months before the First Hospital Admission.
The fluid-attenuated inversion recovery (FLAIR) image at the level of the frontal lobes (Panel A, arrow) shows a T2-weighted hyperintense lesion in the posterior aspect of the right frontal lobe; the lesion predominantly involves white matter in a subcortical location, spares the cortex, and has no enhancement (not shown) or mass effect. On the apparent-diffusion-coefficient map (Panel B), the lesion (white oval) does not show restricted diffusion but rather shows hyperintensity that is more consistent with chronic changes than with acute infarction.
The patient was a retired administrator. He had smoked one pack of cigarettes daily for 15 years but had stopped 15 years before admission. He had drunk a six-pack of beer daily for 20 years but had stopped 19 years before admission. He did not use illicit drugs and had not been out of the United States in the previous 10 years. A test for antibodies to the human immunodeficiency virus (HIV) had been negative 10 years earlier. His medications and supplements were a neutral protamine Hagedorn preparation of insulin, insulin lispro, azathioprine, prednisone, pantoprazole, vitamin B12, folic acid, vitamin B6, vitamin C, multivitamins, gabapentin, quetiapine, spironolactone, lactulose, and lorazepam.
The neurologic examination showed a normal mental status, fluent speech, and mild dysarthria. There was no neglect, and the patient correctly copied diagrams of a clock and a complex geometric shape. The cranial-nerve examination revealed full visual fields with no extinction; a left-sided facial droop with an upper-motor-neuron pattern was detected. The left arm and leg were weak, with motor power graded as follows: deltoids, biceps, and triceps, 4/5; wrist extensors, 3/5; wrist flexors, 4/5; finger extensors, 1/5; finger flexors, 4/5; interossei, 0/5; and iliopsoas, 4/5. Strength was full in the remainder of the left leg and in the right arm and leg. Sensation was intact except for extinction of light touch in the left arm on bilateral simultaneous stimulation. The deep-tendon reflexes were ++ bilaterally in the triceps, biceps, brachioradialis, and patella; the ankle jerks were absent. There was no clonus, but a left Babinski reflex was present. Cerebellar examination with the use of finger-to-nose testing on the right side was normal. The gait was limited by the weakness of the left leg.
The urine was normal. The levels of calcium, phosphorus, magnesium, aspartate aminotransferase, alanine aminotransferase, fibrinogen, vitamin B12, and vitamin B6 were normal. The results of other laboratory tests are shown in Table 1, Table 2, and Table 3. An electrocardiogram showed a normal rhythm and pattern.
Table 1. Hematologic Laboratory Data.
Table 2. Coagulation Test Results.
Table 3. Blood Chemical Values.
A chest radiograph was clear. A cranial MRI study (Figure 2A), performed without the administration of gadolinium, revealed that the right frontal lesion had enlarged. There was no mass effect. On T2-weighted images there were several small, hyperintense foci in the left frontal lobe that had not been present on the previous study. Magnetic resonance angiographic examination of the head and neck disclosed no stenosis. Ultrasonographic examination of the right and left carotid arteries showed minimal disease in the arterial bifurcations. A transcranial Doppler study showed normal flow in the distal internal carotid arteries and in the cerebral artery stems.
Figure 2. MRI Study Showing Progression of the Lesion over Time.
Two FLAIR images through the plane of the frontal lobes at the time of the first hospital admission (Panel A) and one month later, on the day after the second admission (Panel B), show the growth of the original lesion in the right frontal lobe (arrows in both panels) into the corpus callosum. An additional focus of disease is seen in the left frontal lobe (Panel B, arrowhead). An image through the plane of the temporal lobes (Panel C) shows the development of multiple additional foci of disease (arrows) in the right pons and at two sites in the right temporal lobe.
Because of the patient's hepatic disease, no anticoagulation therapy was given. Folic acid, multivitamins, and vitamins B12 and B6 were administered. The neurologic findings remained stable, and on the fifth hospital day he was discharged to a rehabilitation hospital.
During the ensuing month, the patient progressively lost motor function on the left side, became unable to stand without assistance, and became unable to move his left hand. His right arm and both legs also became progressively weaker, and he began to have difficulty swallowing liquids and occasionally aspirated them. Twenty-three days after his discharge, computed tomographic (CT) scanning of the brain, performed without the intravenous administration of contrast material, revealed a hypodense focus in the subcortical white matter of the left frontal lobe that appeared more prominent than on the most recent MRI study; the right-sided lesion was unchanged. A cranial MRI examination (Figure 2B and Figure 2C) three days later showed enlargement of the right frontal lesion with extension into the posterior limb of the right internal capsule, cerebral peduncle, pons, and right forceps major. The left frontal lesion had increased in size, and there were new lesions in the body of the corpus callosum and the right brain stem. There was no mass effect or abnormal enhancement. The patient was readmitted to the hospital one month after discharge.
The temperature was 36.5°C, the pulse was 80 beats per minute, and the respiratory rate was 18 breaths per minute. The blood pressure was 90/70 mm Hg. The patient appeared cachectic but not acutely ill. There were numerous ecchymoses. The carotid pulses were normal, without bruits. The lungs were clear. A grade 1 systolic murmur was present at the cardiac apex. The abdomen was distended, and there was evidence of ascites. A surgical scar was present over the right lower quadrant. The liver edge descended 3.5 cm below the right costal margin; the spleen was not felt. Rectal examination revealed no abnormalities.
On neurologic examination, the patient was alert and oriented. He misspelled "world" backward and had difficulty making calculations but was able to recall three objects. His speech was fluent except for difficulty with guttural sounds. He drew a diagram of a clock with complete numbers and correct hand positions, but the size of the hands was inappropriate. He wrote a complex sentence and correctly identified objects. The left lower facial droop persisted; the strength of the sternocleidomastoid was weaker on the left side. The tongue deviated to the right. The remaining cranial-nerve functions were intact.
There was diffuse bilateral muscle atrophy, with cogwheeling. Muscle strength on the left was as follows: 0/5 in the left biceps, triceps, interossei, and wrist flexors and in hip extension, plantar flexion, and dorsiflexion; 4–/5 in the left shoulder shrug; and 1/5 in right hip flexion. Muscle strength on the right was as follows: right biceps, 4–/5; triceps, 4–/5; shoulder shrug, 4–/5; interossei, 4/5; wrist extensors 4–/5; wrist flexors, 4/5; hip extensors, 4–/5; hip flexors, 4–/5; plantar flexors, 4/5, and dorsiflexors, 4/5. The deep-tendon reflexes were 2+ throughout, except that the ankle jerks were 1+ bilaterally. There were 13 beats of clonus in the right ankle and 12 beats in the left ankle; the left Babinski reflex persisted. The sensations of light touch and pinprick were decreased in the left arm. There was decreased vibratory sensation in the right arm and leg. The sense of position was inconsistent. Coordination, tested only on the right side, evoked past pointing. Gait was not assessed.
The urine was normal. The levels of magnesium, phosphorus, serum aspartate aminotransferase, serum alanine aminotransferase, and fibrinogen were normal. The results of other laboratory tests are shown in Table 1, Table 2, and Table 3. An electrocardiogram showed a normal rhythm at a rate of 81 beats per minute. A magnetic resonance spectroscopic study (Figure 3) revealed marked elevation in the choline-to-creatine ratio and depression of the N-acetyl aspartate peak.
Figure 3. Findings on Magnetic Resonance Spectroscopy.
Spectroscopy was performed with the use of a multivoxel chemical-shift technique, with selection of the anterior portion of the lesion in the right frontal lobe as the region of interest (Panel A, rectangle with numbers). The spectra reveal substantial abnormalities of cerebral metabolism (Panel B). The N-acetyl aspartate peak is greatly reduced (arrow), a finding indicative of neuronal loss or malfunction, and there is a lactate doublet (arrowhead), a finding indicating anaerobic metabolism. The elevated ratio of choline to creatine (white oval) is often seen in the setting of increased membrane turnover.
A lumbar puncture yielded clear, colorless cerebrospinal fluid that contained 540 red cells and 1 white cell per cubic millimeter in the fourth tube. A stained smear contained 37 percent neutrophils, 53 percent lymphocytes, 7 percent monocytes, and 3 percent nonhematic cells. The glucose level was 63 mg per deciliter (3.5 mmol per liter), and the total protein level 35 mg per deciliter.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Igor J. Koralnik: This patient had many factors that predisposed him to central nervous system disease, including long-term immunosuppressive therapy, multiple cerebrovascular risk factors, and alcoholic cirrhosis of the liver. Since he initially presented with a left facial droop and hand weakness, followed by weakness of the left leg, without changes in his mental function or sensation, the lesion responsible for his left-sided hemiparesis was interrupting the corticospinal or corticobulbar tract fibers below the cortex of the right frontal lobe and above the medulla. The time course of the neurologic presentation is critical: a gradual worsening over a period of three weeks is too slow for a vascular event and too fast for a tumor, but it is compatible with a metabolic, inflammatory, or infectious process.
May we review the imaging studies of the brain?
Dr. Dawid Schellingerhout: The fluid-attenuated inversion recovery (FLAIR) image from his first MRI scan (Figure 1A) shows a lesion in the posterior aspect of the right frontal lobe involving subcortical white matter and sparing the cortex, with no mass effect or enhancement. The apparent-diffusion-coefficient imaging map (Figure 1B) shows only T2-weighted hyperintensity, which is a feature that is consistent with the presence of chronic, rather than acute, infarction. Restricted diffusion, a feature of acute infarction, was not noted.
The second MRI scan (Figure 2A) shows that the lesion has enlarged, extending posteriorly into the frontal lobe and involving the corpus callosum. There are a few small foci of T2-weighted hyperintensity in the left frontal lobe that were not present on the previous study. The apparent-diffusion-coefficient imaging maps show no sign of restricted diffusion. Again, these findings are most consistent with a chronic or slowly progressive process, rather than acute infarction.
The third MRI scan shows progression of the disease (Figure 2B and Figure 2C). The lesion in the posterior right frontal lobe extends into the corpus callosum and has progressed medially, anteriorly, and posteriorly. The lesion in the left anterior frontal lobe has enlarged, and there is a new focus of involvement in the right brain stem and pons, extending into the internal capsule on the right side.
Magnetic resonance spectroscopy (Figure 3) performed with the use of a multivoxel chemical-shift technique over the right frontal lobe shows an elevated choline-to-creatine ratio, a reduced N-acetyl aspartate peak, and a small inverted lactate doublet. The reduced N-acetyl aspartate peak indicates decreased neuronal mass or metabolism due to neuronal distress or loss. The elevated choline-to-creatine ratio is typical of cancer and other conditions involving increased membrane turnover. The lactate doublet is an indication of anaerobic metabolism, with accumulation of lactate, a metabolic product of glycolysis that is consumed during normal metabolism.
In summary, although some of the initial radiologic findings might have been consistent with the presence of an infarction, the changes over time do not support this diagnosis. Cancer is a consideration, but the lack of a mass effect and enhancement and the rapid course argue against that possibility. A progressive demyelinating condition would best fit the imaging findings.
Dr. Koralnik: The initial MRI scans confirm the presence of a right hemispheric lesion and provide additional important information: the lesion is restricted to the white matter and does not involve the cortex or the basal ganglia. The absence of enhancement and of a mass effect indicates that the blood–brain barrier is intact and rules out inflammation. The topographic features of the lesion do not correspond to a specific vascular territory. The lesion is hyperintense on images based on the apparent diffusion coefficient, indicating increased diffusion of water within the brain parenchyma, which occurs when there is damage to cell membranes. This is the opposite of what occurs in acute stroke,1 which is characterized by lesions that are initially hypointense on apparent-diffusion-coefficient images because of restricted diffusion of water within the damaged area.
The neurologic examination at the time of the patient's first hospitalization revealed a left pyramidal syndrome but also extinction of the sensation of light touch on double simultaneous stimulation of the left arm. In the absence of left-sided neglect, this finding indicates a posterior extension of the lesion toward the thalamocortical projections of the right parietal lobe, rather than involvement of the right parietal cortex itself.
Other salient features of the patient's presentation include his normal mental status and the absence of fever, meningismus, or signs of increased intracranial pressure. In an immunocompetent person, these findings would usually rule out a bacterial or fungal infection. However, because this patient was immunosuppressed and lymphopenic, the inflammatory reaction to an infectious agent could be less than that in an immunocompetent person. Moreover, the differential diagnosis needs to be extended to include conditions that occur more often in the setting of a depressed immune system.
A worsening of the patient's neurologic condition prompted his second hospitalization. At that time, two months after the onset of his symptoms, the neurologic examination revealed mild inattention and impairment of visuospatial skills, a bilateral pyramidal syndrome, bilateral sensory deficits, and evidence of brain-stem dysfunction, indicating that the disease now involved the frontal and parietal lobes of both hemispheres and extended downward to the pons.
The CT scan and the third MRI scan of the brain confirm the presence of new lesions. In addition, the results of proton magnetic resonance spectroscopy constitute valuable metabolic information, providing evidence of either neoplasia or demyelination but not infarction. N-acetyl aspartate is a neuronal marker, choline is a component of cell membranes, and creatine serves as a measure of baseline metabolism. Therefore, a decreased N-acetyl aspartate peak in the white matter indicates axonal damage, whereas elevation of the choline-to-creatine ratio is consistent either with neoplasia or with demyelination but not with acute brain infarction. Finally, all lesions have the same appearance and are restricted to the cerebral white matter. Hence, this disorder is a leukoencephalopathy. The conditions associated with leukoencephalopathy in adults are summarized in Table 4.
Table 4. Causes of Leukoencephalopathy in Adults.
Causes of Leukoencephalopathy
Vascular Causes
Although this patient had multiple cerebrovascular risk factors, the absence of stepwise progression and the appearance and topographic features of the lesions on the apparent-diffusion-coefficient MRI scan and the proton magnetic resonance spectroscopic study argue against subcortical arteriosclerotic encephalopathy, also known as Binswanger's disease. The same reasoning applies to cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL) and to isolated central nervous system vasculitis. The normal erythrocyte sedimentation rate, the normal protein level in the cerebrospinal fluid, and the normal cellularity of the cerebrospinal fluid, as well as the absence of cortical involvement, argue against the latter disorder.
Toxic and Metabolic Causes
The patient did not have a history of exposure to toxic substances, and except for hepatic dysfunction, he did not have metabolic problems. The use of alcohol has been associated with Marchiafava–Bignami disease, or selective demyelination of the corpus callosum, but the patient had discontinued his use of alcohol 19 years before admission. His immunosuppressive regimen did not include cyclosporine or tacrolimus, which cause an acute and reversible leukoencephalopathy in 1 to 6 percent of treated patients.2
Hereditary Causes
Hereditary leukodystrophies, resulting from enzymatic disorders that can occur in late adulthood, include X-linked cerebral adrenoleukodystrophy and metachromatic leukodystrophy. Adult X-linked cerebral adrenoleukodystrophy is caused by a deficiency of a peroxisomal acyl coenzyme A synthetase, which leads to the accumulation of very-long-chain fatty acids; metachromatic leukodystrophy is secondary to a deficiency of arylsulfatase A, which results in the accumulation of sulfated sphingolipids. Both usually occur in adults with dementia or psychiatric disturbances, which this patient did not have.
Autoimmune and Inflammatory Causes
A group of conditions that affect the white matter of the central nervous system, such as multiple sclerosis and acute demyelinating encephalomyelitis, which are autoimmune or inflammatory in nature, needs to be considered. However, these conditions have been described only rarely in immunosuppressed persons.3 Furthermore, an inflammatory component was conspicuously absent in this patient. Other entities, such as systemic lupus erythematosus, can be ruled out by the absence of systemic symptoms, the normal erythrocyte sedimentation rate, and the normal white-cell count and protein concentration in the cerebrospinal fluid.
Tumoral Causes
Primary central nervous system lymphoma deserves special consideration, since it is associated with immunosuppression and can be manifested as a subacute, multifocal infiltration of the central nervous system white matter.4 In HIV-positive patients with primary central nervous system lymphoma, analysis of the cerebrospinal fluid for Epstein–Barr virus with the use of the polymerase chain reaction (PCR) has a sensitivity of 83 to 100 percent and a specificity of 93 to 100 percent,5,6 and thallium-201, single-photon-emission CT has 92 percent sensitivity and 89 percent specificity. However, the usefulness of thallium-201 depends on the resolution of the images, and appropriate instruments may not be available in every center. Cytologic examination of the cerebrospinal fluid and testing for Epstein–Barr virus should be considered in this patient.
Intravascular lymphoma7 and lymphomatoid granulomatosis8 are rare entities that may be restricted to the central nervous system and that may appear as a leukoencephalopathy on an MRI scan. However, the lesions usually show contrast enhancement.
Gliomatosis cerebri is a rare, diffusely infiltrative tumor that is characterized by the absence of contrast enhancement in 70 percent of patients. However, a mass effect is present in most cases, and involvement is usually not restricted to the white matter.9
Infectious Causes
Infections that may be manifested as a leukoencephalopathy, such as Lyme neuroborreliosis, neurosyphilis, and tuberculosis, are highly unlikely in this case because of the patient's normal cerebrospinal fluid and the absence of systemic symptoms. Encephalitis due to toxoplasma is almost always associated with the appearance of ring-enhancing lesions. Small-vessel encephalitis associated with varicella–zoster virus10 affects the central nervous system white matter in elderly and immunosuppressed persons and can also be ruled out in this case because of the absence of inflammation in the cerebrospinal fluid and the appearance of the lesions on diffusion-weighted imaging and the proton magnetic resonance spectroscopic study.
The result of a serologic test for HIV infection in this patient 10 years earlier was negative. Since central nervous system disorders in people with the acquired immunodeficiency syndrome (AIDS) and such disorders in organ-transplant recipients often overlap, a repeated serologic test for HIV seems justified. A positive result would have tremendous implications for the management of this patient's disease. HIV encephalopathy,11 or the newly recognized demyelinating HIV-associated leukoencephalopathy,12 may be manifested as localized, hyperintense, white-matter lesions on T2-weighted MRI examination, but the lesions are usually symmetric and are not associated with focal neurologic deficits. In addition, signs of a cognitive disorder would be expected in HIV encephalopathy.
Progressive Multifocal Leukoencephalopathy
None of the entities I have reviewed entirely fit the clinical and neuroradiologic presentation of this patient. A purely descriptive characterization of this patient's disease would be a leukoencephalopathy that is multifocal and progressive. An entity with these features was recognized in 193013 and was given the name progressive multifocal leukoencephalopathy by Astrom and colleagues at this hospital in 1958, on the basis of their examination of pathological specimens from patients with lymphomas.14 In 1965, polyomavirus particles were detected in the nuclei of oligodendrocytes on electron microscopy.15 Polyomavirus JC was isolated from the brain of a patient with progressive multifocal leukoencephalopathy in 1971 and was named with the patient's initials.16
Asymptomatic infection with the JC virus occurs in childhood; 80 to 90 percent of healthy adults are seropositive for the virus,17 which is excreted in the urine and commonly found in sewer samples.18 The virus remains quiescent in the tubular epithelial cells of the kidneys and in lymphoid organs but may be reactivated in the setting of severe cellular immune deficiency. Progressive multifocal leukoencephalopathy emerged as a major opportunistic infection at the beginning of the epidemic of HIV infection, occurring in up to 5 percent of patients with AIDS. It is also diagnosed in 0.07 percent of patients who are immunosuppressed because of hematologic cancer,19 and it has been described as a fatal complication of organ transplantation both in the early post-transplantation period20 and more than 10 years after the procedure.21 In an autopsy study of liver-transplant recipients, 1 of 132 patients (0.8 percent) had progressive multifocal leukoencephalopathy.22 Of the 61 patients with this disorder enrolled in our clinical studies after 1995, 48 had AIDS, 8 had a hematologic cancer, 3 were recipients of a bone marrow transplant, 1 had a history of a thymoma, and 1 had dermatomyositis.
During the past decade, detection of JC virus DNA in the cerebrospinal fluid with the use of polymerase chain reaction (PCR) was found to have a sensitivity of 72 to 93 percent and a specificity of 92 to 100 percent for the diagnosis of progressive multifocal leukoencephalopathy in HIV-positive persons.5,23,24 It has a similarly high sensitivity and specificity in HIV-negative subjects.24 Therefore, it is now accepted as a diagnostic test for progressive multifocal leukoencephalopathy.25,26
In this HIV-negative patient, treatment of progressive multifocal leukoencephalopathy should include, if possible, a reduction or interruption of immunosuppressive therapy. Treatment with cytosine arabinoside was associated with the stabilization of disease in 7 of 19 patients (37 percent) in a retrospective study.27 Unfortunately, patients who survive do not recover neurologic function and are often left with devastating sequelae, and most die within one year after the onset of symptoms.27 Factors associated with a good prognosis include evidence of an inflammatory response such as a lymphoplasmacytic infiltrate in the lesions,28,29 faint contrast enhancement on brain imaging studies,30 and detectable cytotoxic T lymphocytes specific for polyomavirus JC in the blood.31,32
In immunosuppressed patients with multiple brain lesions, more than one disease may be present, and therefore a positive result on PCR assay or a histologic finding on examination of a brain-biopsy specimen may not provide all the answers. In the case under discussion, however, the clinical presentation, the homogeneity of the lesions on the MRI scans, and the results of apparent-diffusion-coefficient MRI and proton magnetic resonance spectroscopy33 all point to the presence of a single entity.
Dr. Nancy Lee Harris (Pathology): Dr. Buonanno, what was your impression of this patient during the course of his illness and before the diagnostic procedure was performed?
Dr. Ferdinando Buonanno (Neurology): When this patient first came to my office, he had had an episode of left-sided hemiparesis, which was improving. For this reason, we suspected that his illness had a vascular cause. Later, the progressive nature of the illness started to emerge, and we strongly suspected progressive multifocal leukoencephalopathy. We performed a brain biopsy to establish the diagnosis.
Clinical Diagnosis
Progressive multifocal leukoencephalopathy.
Dr. Igor J. Koralnik's Diagnosis
Progressive multifocal leukoencephalopathy.
Pathological Discussion
Dr. Matthew P. Frosch: Smear preparations of the stereotactic brain-biopsy specimen, made during an intraoperative consultation, showed oligodendrocytes with enlarged, glassy, smudged nuclei (Figure 4A). Similar oligodendrocytes, with nuclei up to four times as large as normal nuclei, were evident on paraffin-embedded sections (Figure 4B). Since oligodendrocytes produce the myelin sheath, damage to these cells causes loss of myelin with relative preservation of axons, as seen by comparing stains for axons (an immunostain for neurofilament proteins) and myelin (Figure 4C and Figure 4D). There was no inflammatory response associated with this demyelination. No enlarged or bizarre astrocytes were present in the biopsy specimens.
Figure 4. Specimen from a Stereotactic Brain Biopsy.
Four high-power microscopical fields from the intraoperative smear preparation (Panel A; hematoxylin and eosin, x750) show round, enlarged nuclei with indistinct chromatin (arrows) in the oligodendrocytes. In each field, there is also an oligodendrocyte that appears normal in size and that has more distinct chromatin (arrowheads). A paraffin-embedded section (Panel B; hematoxylin and eosin, x250) shows multiple enlarged oligodendrocyte nuclei with abnormal chromatin (arrows). Sections stained for myelin (Panel C, x125) and immunostained with antibodies for neurofilament proteins (Panel D; immunoperoxidase, x125) show loss of myelin (clear areas with loss of blue in center, Panel C) and preservation of axons (brown areas, Panel D).
The etiologic agent of progressive multifocal leukoencephalopathy, JC virus, was identified by immunostaining for the large T antigen (Figure 5A), in the infected oligodendrocytes. The lesions grow as the infected cell enters the lytic stage, releasing viral particles that infect other cells. The number of infected cells varies according to the age of the lesion and the area of the lesion that is examined. This biopsy specimen appears to have come from an area of relatively recent involvement. Electron microscopy showed that viral particles were present (Figure 5B).
Figure 5. Identification of Polyomavirus JC in a Biopsy Specimen of the Brain.
Immunostaining with antibodies against the large T antigen of JC virus shows numerous infected cells (Panel A; immunoperoxidase, x250). An electron micrograph of an oligodendrocyte (Panel B, x8800) shows abundant viral particles concentrated in the center of the nucleus; these are seen at higher magnification in the inset (x38,100). The scale bar represents 0.44 μm.
The combination of abnormal nuclei in the oligodendrocytes and evidence of demyelination, supported by the identification of the virus by ultrastructural and immunologic studies, confirms the diagnosis of progressive multifocal leukoencephalopathy. After the biopsy was performed, samples of cerebrospinal fluid analyzed by the PCR JC virus were reported to be positive.
Dr. Harris: Dr. Black-Schaffer, you cared for this patient at the rehabilitation hospital. Could you give us your thoughts about his course before the diagnostic procedure?
Dr. Randie M. Black-Schaffer (Physiatry): The patient came to us with a diagnosis of stroke. His endurance and overall functional status gradually declined. In the third week, a specific focal increase in his left hemiparesis appeared, first in the arm, and then, within a few days, in the leg. The CT and MRI studies were performed, and he was referred back to the hospital for a biopsy.
Dr. Harris: Dr. Buonanno, what was the outcome?
Dr. Buonanno: He had progressive neurologic deterioration and died in hospice care soon after the biopsy. No autopsy was performed.
Anatomical Diagnosis
Progressive multifocal leukoencephalopathy.
Supported in part by grants from the National Institutes of Health (2PO1CA6924605 and 1-R24-CA92782-01), the Radiologic Society of North America, and the American Brain Tumor Association (to Dr. Schellingerhout) and by grants from the National Institutes of Health (R01NS/AI 41198, R01 NS 047029, R21 NS 046243, and P30-AI 28691) and the Harvard Center for Neurodegeneration and Repair (to Dr. Koralnik).
Source Information
From the Departments of Neurology and Medicine, Beth Israel Deaconess Medical Center (I.J.K.); the Departments of Radiology (D.S.) and Pathology (M.P.F.), Massachusetts General Hospital; and the Departments of Neurology (I.J.K.), Radiology (D.S.), and Pathology (M.P.F.), Harvard Medical School — all in Boston.
References
Warach S, Dashe JF, Edelman RR. Clinical outcome in ischemic stroke predicted by early diffusion-weighted and perfusion magnetic resonance imaging: a preliminary analysis. J Cereb Blood Flow Metab 1996;16:53-59.
Singh N, Bonham A, Fukui M. Immunosuppressive-associated leukoencephalopathy in organ transplant recipients. Transplantation 2000;69:467-472.
Berger JR, Sheremata WA, Resnick L, Atherton S, Fletcher MA, Norenberg M. Multiple sclerosis-like illness occurring with human immunodeficiency virus infection. Neurology 1989;39:324-329.
Phan TG, O'Neill BP, Kurtin PJ. Posttransplant primary CNS lymphoma. Neuro-oncology 2000;2:229-38.
Cinque P, Vago L, Dahl H, et al. Polymerase chain reaction on cerebrospinal fluid for diagnosis of virus-associated opportunistic diseases of the central nervous system in HIV-infected patients. AIDS 1996;10:951-958.
Antinori A, Ammassari A, De Luca A, et al. Diagnosis of AIDS-related focal brain lesions: a decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF. Neurology 1997;48:687-694.
Moussouttas M. Intravascular lymphomatosis presenting as posterior leukoencephalopathy. Arch Neurol 2002;59:640-641.
Tateishi U, Terae S, Ogata A, et al. MR imaging of the brain in lymphomatoid granulomatosis. AJNR Am J Neuroradiol 2001;22:1283-1290.
Herrlinger U, Felsberg J, Kuker W, et al. Gliomatosis cerebri: molecular pathology and clinical course. Ann Neurol 2002;52:390-399.
Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, Mahalingam R, Cohrs RJ. Neurologic complications of the reactivation of varicella-zoster virus. N Engl J Med 2000;342:635-645.
Post MJ, Tate LG, Quencer RM, et al. CT, MR, and pathology in HIV encephalitis and meningitis. AJR Am J Roentgenol 1988;151:373-380.
Langford TD, Letendre SL, Marcotte TD, et al. Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy. AIDS 2002;16:1019-1029.
Hallervorden J. Eigerartige und nicht rubrizierbare Prozesse. In: Bumke O, ed. Handbuch der Geiteskrankheiten. Vol. 2. Berlin: Springer, 1930:1063-107.
Astrom KE, Mancall EL, Richardson EP Jr. Progressive multifocal leuko-encephalopathy: a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin's disease. Brain 1958;81:93-127.
ZuRhein GM, Chou S-M. Particles resembling papova viruses in human cerebral demyelinating disease. Science 1965;148:1477-1479.
Padgett BL, Walker DL, ZuRhein GM, Eckroade RJ, Dessel BH. Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet 1971;1:1257-1260.
Weber T, Trebst C, Frye S, et al. Analysis of the systemic and intrathecal humoral immune response in progressive multifocal leukoencephalopathy. J Infect Dis 1997;176:250-254.
Bofill-Mas S, Girones R. Excretion and transmission of JCV in human populations. J Neurovirol 2001;7:345-349.
Power C, Gladden JG, Halliday W, et al. AIDS- and non-AIDS-related PML association with distinct p53 polymorphism. Neurology 2000;54:743-746.
Manz HJ, Dinsdale HB, Morrin PA. Progressive multifocal leukoencephalopathy after renal transplantation: demonstration of papova-like virions. Ann Intern Med 1971;75:77-81.
Berner B, Krieter DH, Rumpf KW, et al. Progressive multifocal leukoencephalopathy in a renal transplant patient diagnosed by JCV-specific DNA amplification and an intrathecal humoral immune response to recombinant virus protein 1. Nephrol Dial Transplant 1999;14:462-465.
Martinez AJ, Ahdab-Barmada M. The neuropathology of liver transplantation: comparison of main complications in children and adults. Mod Pathol 1993;6:25-32.
Weber T, Turner RW, Frye S, et al. Progressive multifocal leukoencephalopathy diagnosed by amplification of JC virus-specific DNA from cerebrospinal fluid. AIDS 1994;8:49-57.
Koralnik IJ, Boden D, Mai VX, Lord CI, Letvin NL. JC virus DNA load in patients with and without progressive multifocal leukoencephalopathy. Neurology 1999;52:253-260.
Cinque P, Koralnik IJ, Clifford DB. The evolving face of human immunodeficiency virus-related progressive multifocal leukoencephalopathy: defining a consensus for terminology definition. J Neurovirol 2003;9:Suppl 1:88-92.
Marra CM, Rajicic N, Barker DE, et al. A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS. AIDS 2002;16:1791-1797.
Aksamit AJ. Treatment of non-AIDS progressive multifocal leukoencephalopathy with cytosine arabinoside. J Neurovirol 2001;7:386-390.
Du Pasquier RA, Koralnik IJ. Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol 2003;9:Suppl 1:25-31.
Richardson EP Jr, Johnson PC. Atypical progressive multifocal leukoencephalopathy with plasma-cell infiltrates. Acta Neuropathol (Berl) 1975;6:247-250.
Berger JR, Levy RM, Flomenhoft D, Dobbs M. Predictive factors for prolonged survival in acquired immunodeficiency syndrome-associated progressive multifocal leukoencephalopathy. Ann Neurol 1998;44:341-349.
Koralnik IJ, Du Pasquier RA, Kuroda MJ, et al. Association of prolonged survival in HLA-A2+ progressive multifocal leukoencephalopathy patients with a CTL re-sponse specific for a commonly recognized JC virus epitope. J Immunol 2002;168:499-504.
Du Pasquier RA, Kuroda M, Schmitz JE, et al. Low frequency of cytotoxic T lymphocytes against the novel HLA A*0201-restricted JC virus epitope VP1p36 in patients with proven or possible progressive multifocal leukoencephalopathy. J Virol 2003;77:11918-11926.
Chang L, Ernst T, Tornatore C, et al. Metabolite abnormalities in progressive multifocal leukoencephalopathy by proton magnetic resonance spectroscopy. Neurology 1997;48:836-845.(Igor J. Koralnik, M.D., D)