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case records of the massachusetts general hospital


Founded by Richard C. Cabot Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor

Case 9-2010: A 37-Year-Old Woman with Paresthesias and Ataxia


Misha L. Pless, M.D., Yi-Bin Chen, M.D., William A. Copen, M.D., and Matthew P. Frosch, M.D., Ph.D.

Pr e sen tat ion of C a se


Dr. Mikael L. Rinne (Neurology): A 37-year-old right-handed woman was admitted to this hospital because of intermittent paresthesias, slurred speech, ataxia, and abnormalities on brain imaging. The patient had been well until 7 months earlier, when numbness and tingling developed while she was lying in bed first in the right foot and leg, and then in the face and right arm and resolved completely within 20 minutes. She went to another hospital. She reported having had a tick bite on her right hand 1 month earlier, without associated symptoms. Results of routine laboratory tests were normal, and testing for Lyme disease was negative. One month later, an episode of nausea, left-sided numbness, and slurred speech occurred, followed 2 hours later by right-sided numbness and aphasia. The episode resolved within 1 hour but was followed by a diffuse headache (rated 8 on a scale of 1 to 10, where 10 is the most severe), nausea, photophobia, and phonophobia. The patient was admitted to a second hospital. Computed tomography (CT) of the head without the administration of contrast material and CT angiography (CTA) of the head and neck were reportedly normal. Magnetic resonance imaging (MRI) without contrast material showed T2-weighted hyperintense lesions in the left centrum semiovale and in the subcortical white matter of the left frontoparietal region, with increased signal on diffusion-weighted images but no evidence of a mass effect, intracranial hemorrhage, or restricted water diffusion. She was discharged and referred to a neurologist. Neurologic examination and electroencephalography (EEG) 2 weeks later were normal. Prednisone was administered for 14 days, and topiramate and eletriptan were begun; topiramate was stopped because the patient reported grogginess. Daily headaches and episodes of numbness and tingling continued. Five months before this evaluation, MRI of the brain after the administration of a gadolinium-based contrast agent showed evolution of the lesions in the supratentorial white matter and two new, small, linear regions of T2-weighted hyperintensity with restricted water diffusion and heterogeneous enhancement in the left cerebellar hemisphere. A lumbar puncture was performed; results of cerebrospinal fluid analysis are shown in Table 1. A chest radiograph and transesophageal echocardiogram were reportedly normal.
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From the Department of Neurology (M.L.P.), the Division of Hematology and Oncology (Y.-B.C.), and the Departments of Radiology (W.A.C.) and Pathology (M.P.F.), Massachusetts General Hospital; and the Departments of Neurology (M.L.P.), Medicine (Y.-B.C.), Radiology (W.A.C.), and Pathology (M.P.F.), Harvard Medical School. N Engl J Med 2010;362:1129-38.
Copyright 2010 Massachusetts Medical Society.

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Table 1. Cerebrospinal Fluid Analysis.* Reference Range, Adults Colorless Clear None 0 0 0 to 5 0 to 5 0 0 0 5 to 55 11.0 to 50.9 50 to 75 57 4 (ref 15) <2.0 (ref 0 to 4.0) 0.0 to 8.0 6.3 (ref 0.8 to 7.7) +7.1 (ref 9.9 to 3.3) 0.52 (ref <0.66) No banding in CSF concentrated 80 One band in CSF concentrated <31 15.0 97 3 53 86 13 89 (ref 15 to 45) 57.2 (ref 8.0 to 42.0) 64 233 3 12 7 5 275 Other Hospital, 5 Mo before Admission Colorless Clear Another Hospital, 3 Days before Admission This Hospital, 2nd Day Faint pink Slight Yes 1760 1540 18 23 9 68 23 260 118.0 57

Variable Color Turbidity Xanthochromia Red cells (per mm3) Tube 1 Tube 4 White cells (per mm3) Tube 1 Tube 4 Differential count (%) Neutrophils Lymphocytes Monocytes Protein (mg/dl) Albumin (mg/dl) Glucose (mg/dl) Angiotensin-converting enzyme (U/liter) Myelin basic protein (g/liter) IgG (mg/dl) Rate of IgG synthesis (mg/24 hr) IgG index Protein electrophoresis

* CSF denotes cerebrospinal fluid, and ref the reference range at the other hospitals. To convert the values for glucose to millimoles per liter, multiply by 0.05551. Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients. The differential count totals 99% because one cell was large and binucleated and not included in the count.

During the next 5 months, the patient had episodes of dizziness, loss of balance, nausea, vomiting, and facial droop. Relatives noted cognitive problems, with confusion and inappropriate dressing. Four months before this evaluation, she saw another neurologist. The level of vanilmandelic acid in the urine was normal. Verapamil was begun, and prednisone was resumed, with no improvement. Three months before this evaluation, MRI of the brain showed new, widespread, patchy T2-weighted hyperintensity in the supratentorial white matter, without associated enhancement. The previously seen T2-weighted hyperintense lesions in the left cerebellar hemisphere had increased in size. A cerebral angiogram reportedly
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showed mild focal narrowing of the left anterior cerebral artery but was otherwise normal. Azathioprine (50 mg daily) was begun. Three weeks before admission, gait imbalance, unsteadiness, and visual hallucinations developed. An EEG reportedly showed asymmetric slowing. The patient was admitted to a psychiatric hospital for 1 week, with a diagnosis of depression; citalopram and outpatient psychiatric treatment were begun. Four days before admission, slurred speech, numbness of the right hand, aphasia, a choking sensation, ataxia, and joint pain developed, and a rash appeared on her legs. The patient was admitted to another hospital. She did not have fever,

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double vision, abnormalities of smell or taste, loss of consciousness, seizure, bowel or bladder symptoms, night sweats, weight loss, joint swelling, or a history of head injury; she also had no heart, lung, or kidney problems. On examination by a neurologist, she was anxious, with a depressed affect. The vital signs were normal. There was a slightly raised, red rash above both ankles. Her speech was dysarthric. Deep-tendon reflexes were 3+ and brisk throughout, and plantar responses were flexor. There was a tremor on finger-to-nose testing, a wide-based gait, and weakness in the right arm and leg. The remainder of the examination was normal. A screening test for toxins in the urine was positive for cocaine. An electrocardiogram was reportedly normal; an EEG showed mild relative slowness in the left temporoparietal region. Magnetic resonance angiography (MRA) of the head and neck reportedly showed subtle focal narrowing in the left anterior cerebral artery. MRI of the brain showed new enhancement in the previously seen white-matter lesions. The left cere bellar lesions extended to the cerebellar cortex. Multiple new lesions, many of which enhanced, were present in both cerebellar hemispheres. The patient was discharged on the fifth day and referred to the neurology clinic of this hospital. She had been healthy before this illness. She was married, lived with her husband and children, and worked with children. She owned a parrot, had used cocaine as a teenager, and did not smoke, drink alcohol, or use illicit drugs. Her father had had depression and was deceased, her mother had had cervical cancer, two aunts had breast cancer, a brother was well, and her two children were healthy. There was a family history of hypertension, coronary artery disease, asthma, and lung cancer and no history of multiple sclerosis or clotting disorders. She had no allergies. Medications included azathioprine, prednisone, verap amil, citalopram, diazepam, acetaminophen, and aspirin. On examination, the patient was in a wheelchair. The vital signs were normal. There were multiple ecchymoses on the skin, which she attributed to falling, and scaly plaques on the medial aspects of both lower legs. She was oriented and aware of current events but responded slowly. Tests of attention, concentration, and recent and remote memory were normal. There was a left afferent pupillary defect (less constriction of the pupils when a light was shone in the left eye than

in the right eye). Disk margins were pale, more so on the left than on the right, and peripheral and central vision in the left eye was diminished. There was normal saccadic pursuit, with no Horners syndrome or ptosis. Speech was dysarthric. There was increased tone in all limbs, with normal strength. The reflexes were 3+ in the arms and legs, and plantar responses were flexor bilaterally. A tremor was present during finger-to-nose testing in both arms, and heel-to-shin testing showed dysmetria; rapid alternating movements were impaired. The gait was slightly wide-based; the patient was unable to walk with a tandem gait. The remainder of the general and neurologic examinations was normal. She was admitted to this hospital. The level of alkaline phosphatase was 277 U per liter (reference range, 30 to 100), aspartate aminotransferase 245 U per liter (reference range, 9 to 32), and alanine aminotransferase 327 U per liter (reference range, 7 to 30). Results were normal for the erythrocyte sedimentation rate; levels of serum electrolytes, glucose, bilirubin, angiotensin-converting enzyme, lipoprotein A, vitamin B12, folic acid, C-reactive protein, immunoglobulins, and thyrotropin; tests of renal function and coagulation; hypercoagulability screening; serum protein electrophoresis; and urinalysis. Testing was negative for Lyme disease; syphilis; antimitochondrial antibodies; antineutrophil cytoplasmic antibodies; antinuclear antibodies; antibodies against double-stranded DNA, Ro antigen, La antigen, and Sm antigen; rheumatoid factor; the human immunodeficiency virus (HIV); hepatitis A, B, and C viruses; and hepatitis B e antigen, as was nucleicacid testing for hepatitis B, C, and D viruses. Toxicology screening of the blood revealed the presence of diazepam, nordazepam, verapamil, and norverapamil and was otherwise negative. Azathioprine and prednisone were stopped, and citalopram, verapamil, enoxaparin, diazepam, and aspirin were given. On the second day, a lumbar puncture was performed. The opening pressure was 6 cm of water; needle manipulation caused the spinal fluid to become blood-tinged. Results of the cerebrospinal fluid analysis are shown in Table 1. CTA of the brain and neck revealed a hypodensity in the left cerebellar hemisphere and associated tissue loss; the vessels appeared normal. MRI of the brain showed extensive T2-weighted hyperintense lesions in the supratentorial and infratentorial
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white matter, many of which showed enhancement and no mass effect. There was no decreased diffusion to suggest recent infarction, although there were findings suggesting chronic infarcts in the left cerebellar hemisphere, where leptomeningeal enhancement was also present. MRI of the cervical and thoracic spine showed degenerative disk disease, with no intrinsic spinal cord lesions. CT of the abdomen and pelvis showed right-sided sacroiliitis and no evidence of intraabdominal mass lesions or lymphadenopathy. Ultrasonography of the abdomen showed fatty changes of the liver. On the fifth day, a diagnostic procedure was performed.

Differ en t i a l Di agnosis
Dr. Misha L. Pless: May we review the imaging studies? Dr. William A. Copen: Axial T2-weighted fluidattenuated inversion recovery images of the brain, obtained between 5 months before and 2 days after admission to this hospital (Fig. 1A through 1D), showed T2-weighted hyperintense lesions in the supratentorial white matter that progressed slowly at first but at an accelerating pace later. The presence of such white-matter lesions in a young woman suggests multiple sclerosis. However, when viewed over time, several findings argue against that diagnosis. First, although the white-matter lesions initially did not enhance after the administration of contrast material (Fig. 1E and 1F), many of them, including lesions that had been present for months, began to enhance at approximately the same time, 5 days before admission (Fig. 1G). When the lesions of multiple sclerosis enhance, they tend to do so transiently, often at the time of their first appearance, rather than all at once, as in this case. Second, although the patients white-matter disease was fairly widespread, there was no involvement of the corpus callosum, which is often disproportionately involved in cases of multiple sclerosis. Third, the appearance of the two T2weighted hyperintense lesions in the left cerebellar hemisphere (Fig. 2) was quite unusual for multiple sclerosis. The lesions appeared to spare the cerebellar white matter and involve the gray matter with a linear, radially oriented appearance suggestive of infarction in the territory of a small artery. Therefore, the primary diagnostic considerations included diseases diffusely affecting the
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small arteries of the brain. These include primary central nervous system (CNS) angiitis and other autoimmune, infectious, or drug-induced vasculopathies. One of the cerebellar lesions (Fig. 2A and 2B) showed associated faint parenchymal or leptome ningeal enhancement, which appeared to spread gradually over the undersurface of the cerebellum (Fig. 2C and 2D), rather than resolving, as would be expected for an infarct. A sagittal T1weighted image obtained 2 days after admission (Fig. 2E) confirmed the presence of leptomeningeal enhancement, which may be seen in a variety of infectious or inflammatory vasculitides, as well as in neoplastic processes that spread over the brains surface and result in occlusion of small vessels, typically as a result of leptomeningeal carcinomatosis or lymphomatosis. Dr. Pless: I cared for this patient and am aware of the diagnosis. This complex case exemplifies the importance of the history in the neurologic differential diagnosis. This previously healthy woman had dramatic, diverse, and changing neurologic symptoms during a period of 7 months. Neurologic dysfunction was disseminated in both space and time, meaning that neurologic signs and symptoms appeared over time, with intervening remissions, and that these signs and symptoms spread to diverse regions of the brain and spinal cord. This patients symptoms show initial involvement of the following regions: sensory pathways serving the left hemibody, with subsequent involvement of the language regions of the dominant hemisphere, and possibly the left parietal lobe. Subsequent symptoms reflect involvement of the brain stem, specifically around the fourth ventricle, as suggested by nausea and vomiting. Later, symptoms of right parietal and cerebellar dysfunction developed in rapid succession. Finally, her recent imbalance, bradyphrenia, inattention, confusion, depression, and hyperreflexia suggest a holocerebral or diffuse pattern of dysfunction, which would suggest participation of nearly every component of the CNS. A few neurologic diseases tend to behave in this specific manner and constitute the bulk of the differential diagnosis in this case.
Multiple sclerosis

Multiple sclerosis is probably the most common disease seen by neurologists and internists that has the classic features of dissemination of time and space.1 It is thus not surprising that this pa-

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Figure 1. MRI Scans of the Supratentorial Brain. Axial T2 -weighted fluid-attenuated inversion recovery images of the brain (Panels A through D) and T1-weighted imRETAKE 1st obtained 5 months before ages of the brain after the administration of contrast material (Panels E, F, and G) were Pless AUTHOR ICM 2nd REG before F FIGURE admission (Panels A and E), 3 months admission admission (Panels C and 1a-g (Panels B and F), 5 days before 3rd CASE G), and 2 days after admission (Panel D). Multiple T2 -weighted supratentorial white-matter lesions progressed slowTITLE Revised EMail ly at first and then at an accelerating rate, with enhancement first visible Line 4-C 5 days before admission (Panel G, arrows).
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Figure has been redrawnnosis and type has been reset. tient was initially diagnosed and treated for mulof neuroborreliosis. Seronegativity for syphPlease check carefully. tiple sclerosis. However, there is a cautionary tale ilis and HIV essentially rules out lues and AIDS, in the analysis of this patients initial course and two conditions that may have protean neurologic JOB: 36212 ISSUE: 3-25-10 subsequent rapid progression. The initial few clin- presentations. ical manifestations had features that suggested a vascular cause rapid progression, evolution, Rheumatologic diseases and resolution which argued against demyeli- A group of disorders to be considered in this case nating disease, which usually has a slower onset are neurorheumatologic diseases, such as systemic and resolution. Additional red flags include the lupus erythematosus (SLE) and Sjgrens syndrome. very rapid dissemination in time and space. Most SLE can present with CNS involvement either important, features such as aphasia, apraxia, and lupus cerebritis or lupus cerebral vasculopathy confusion, which suggest gray-matter and corti- and in this case is an important contender.2-4 Lucal lesions, are not characteristic of multiple scle- pus cerebritis may cause clinical findings similar rosis. Finally, the presence of cortical cerebellar to those in this patient, including dissemination lesions is atypical of multiple sclerosis. in space and time, spontaneous remission, and vascular-type events involving mainly small-toInfectious diseases medium-size vessels. However, CNS involvement Neuroborreliosis was considered because of the that progresses to the extent seen in this patient patients history of a tick bite, but she did not have over a period of 7 months, without any other sysconstitutional and rheumatologic symptoms sug- temic rheumatic manifestations, would be rare. gestive of Lyme disease. Neuroborreliosis may pro- Moreover, several negative antinuclear-antibody duce neurologic symptoms that wax and wane tests argue against this diagnosis. Similarly, over time and in rare cases remit spontaneously. Sjgrens syndrome affecting the spinal cord or the Four negative antibody titers ruled out the diag- brain, without sicca symptoms or classic rheuma-

AUTHOR, PLEASE NOTE:

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Figure 2. MRI Scans of the Cerebellum. Five months before admission, axial T2 -weighted fluid-attenuated inversion recovery images (Panel A) and T1-weighted images obtained after the administration of contrast material (Panel B) showed a small, enhancing, RETAKE 1st arterial infarction, rather than Pless its appearance AUTHOR ICM cortical gray-matter lesion in the left cerebellar hemisphere; suggested 2nd REG F 2a-e FIGURE multiple sclerosis (arrows). Three months before admission, the lesion was larger in similar fluid-attenuated inver3rd CASE sion recovery images (Panel C, arrow) andTITLE T1-weighted images obtained after the administration of contrast material Revised EMail 4-C obtained after the administration of conLine (Panel D, arrows). Two days after admission, a sagittal T1-weighted image SIZE Enon ARTIST: mst H/T H/T trast material (Panel E) confirmed the presence of leptomeningeal enhancement (arrows).
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AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset. Please check carefully. is a mitochondrial (MELAS) tologic manifestations, is rare, and at least one or

two appropriate antibodies must be present, which JOB: 36212 were conspicuously absent in this case. Related conditions such as the antiphospholipid-antibody syndrome, Sneddons syndrome, and thromboembolic events associated with lupus anticoagulant are rare, but they may affect the brain and spinal cord in ways that mimic multiple sclerosis. Thus, a hypercoagulability workup was important and appropriate in this case, and it was negative.3
Genetic Diseases

Two genetic conditions that confer a predisposition to strokelike events in the brain warrant consideration. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike symptoms
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disorder that may present with dissemination in time and space. AlISSUE: 3-25-10 though the features of the clinical presentation in this patient are suggestive of MELAS, the MRI findings are atypical for MELAS.5 MELAS is characterized by supratentorial strokelike lesions involving large areas of brain territory, which do not correspond to the large arterial territories of largevessel stroke. In addition, the infratentorial lesions that are so prominent in this patient are seldom seen in MELAS. The other disease that merits mention is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which can present with strokelike lesions involving the temporal lobe and other regions of the brain.6 Typically, there is a strong family history of migraine and early death. This

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ers are negative, but this is a false assumption. CNS vasculitis may produce only nonspecific white-matter lesions, similar to those in multiple sclerosis. MRA, CTA, or catheter angiography may be diagnostic if vascular lesions are evident but negative in cases of biopsy-proven CNS vasculitis. Cocaine abuse The most reliable method of diagnosis is tissue The patient had used cocaine in her youth, and biopsy, but the sensitivity of this test is not always one of the toxicology screenings showed cocaine. sufficiently high to justify the possible complicaAlthough she vehemently denied current cocaine tions of the procedure. use, it is nonetheless important to consider. Cocaine administered transnasally, intravenously, Lymphoma or orally has been linked to severe cerebrovascular Certain features of the imaging suggested a madisorders, including intracranial hemorrhage; co- lignant tumor of the CNS in particular, the caine-related vasculopathy, with small-vessel or development of enhancement in the lesions and large-vessel strokes; and even an allergic vasculitic the involvement of the leptomeninges near one of process that may closely mimic this patients pre- the lesions. Such multifocal involvement of the sentation. In general, patients with cerebrovascu- CNS would be unusual in most malignant tumors; lar disease due to cocaine are engaged in heavy and the one exception is lymphoma. Primary lymphoongoing use of the drug, and if this patient was mas of the CNS usually present as mass lesions, recently exposed, the exposure appears to have either single or multiple, in the white matter; this been minimal.7 patients imaging studies did not show the presThus, we must finally zero in on vascular dis- ence of mass effect associated with the lesions. orders of the brain that may disseminate in time In addition, the slow pace and remitting characand space. This leaves us with only a few disorders: ter of this patients disease would be unlikely for isolated angiitis of the CNS and malignant tumors CNS lymphoma, which is usually of the rapidly that may spread through vessels to the brain. growing diffuse large-B-cell type. Intravascular large-B-cell lymphoma is a rare form of lymphoCentral Nervous System Vasculitis ma that often presents in the CNS; in this disCNS vasculitis is suggested by this patients clin- ease, the lymphoma cells are present within the ical presentation, including involvement of many lumina of small blood vessels instead of forming regions of the brain, fluctuating symptoms, stroke- solid masses.12,13 Symptoms are due to occlusion like events, cortical symptoms, confusion, severe of the vascular lumina and compromise of blood headache, and involvement of the white matter and flow and thus may mimic those of vasculitis. In gray matter, as well as supratentorial and infraten- addition, symptoms, unlike those of most lymphotorial brain regions.8,9 The presence of skin le- mas, may wax and wane over a period of weeks sions could suggest the presence of peripheral to months, as in this case.14,15 vasculitis, and a biopsy of one of these might have been diagnostic. The presence of irregularities in Summary the vessels of the brain that were seen on MRA We considered CNS vasculitis to be the most likely and catheter angiography is strongly suggestive diagnosis in this young woman with progressive neurologic symptoms, including headache, conof CNS vasculitis. There is no classic presentation of CNS vascu- fusion, white-matter and gray-matter findings, and litis, and many other conditions may mimic vas- an inexorable course of deterioration due to mulculitis.10 Most patients with vasculitis present with tifocal brain involvement. The main differential confusion and fluctuating headaches. Dissemina- diagnosis would be lymphoma, particularly intration of symptoms in space and time is seen in this vascular lymphoma. We thought that a tissue bidisorder more often than not, by virtue of the mul- opsy was essential to establish a diagnosis. tifocal lesions noted. There is no site of predilection in the brain. There is no laboratory value that Dr . Mish a L . Pl e sss Di agnosis is specific or helpful, and neuroimaging is not always helpful.11 Physicians may think that CNS Central nervous system vasculitis; rule out lymvasculitis is unlikely when the rheumatology mark- phoma.
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patient did indeed have severe headaches. Rare cases of CADASIL may be due to new mutations of the NOTCH3 gene and lack a family history. However, the appearance of this patients lesions on MRI argues strongly against this diagnosis.

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Pathol o gic a l Discussion


Dr. Matthew P. Frosch: A stereotactic biopsy of the right frontal lobe of the brain was performed. Pathological examination of the biopsy specimen revealed that the cortical gray matter was of normal cellularity, with no evidence of glioma or other infiltrative processes. Instead, large atypical cells with prominent nucleoli and moderate amounts of cytoplasm were located within the intracortical blood vessels (Fig. 3A). Immunohistochemical staining revealed reactivity for the B-cell antigen CD20 (Fig. 3B). CD3-positive T cells were present around the vessels (Fig. 3C). The large tumor cells expressed CD5 but not CD10, a common finding in intravascular large-B-cell lymphoma, and cytoplasmic kappa light chain (as seen with the use of in situ hybridization) (Fig. 3D). This combination of features is diagnostic of intravascular large-B-cell lymphoma.16 There was no evidence of infarction, ischemia, or vasculitis. Intravascular large-B-cell lymphoma is an aggressive tumor that occurs in adults and typically presents with organ involvement (often skin or brain) but is sparing of lymph nodes. The tumor cells are primarily found within the capillary beds of the affected organs, sometimes extending into venules and small arterioles. Direct extension into the perivascular tissue can be observed but is usually limited. The property of restriction to the intravascular space has been attributed to the absent or reduced expression of molecules such as intercellular adhesion molecule 1 and 1 integrin, as well as of matrix metalloproteinases, all of which are necessary for endothelial adhesion and trafficking of the lymphoid cells.17-19 It is likely that the interaction between the tissue-specific endothelial cells and the surface antigens on the tumor cells results in the different patterns of disease distribution.

Discussion of M a nagemen t
Dr. Yi-Bin Chen: Systemic staging with whole-body positron-emission tomography (PET) and CT showed no evidence of disease outside the CNS, and cytologic analysis of cerebrospinal fluid obtained by means of lumbar puncture was negative for malignant cells. Neuro-ophthalmologic examination disclosed no intraocular involvement. A dermatologist concluded that the skin lesions on the leg were consistent with eczema or contact dermatitis and not suggestive of lymphoma.
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In determining the management for this patients disease, we considered management of intravascular lymphoma and management of lymphoma that involves the CNS at the time of presentation. Since both of these situations are rare, there were no prospective clinical trials to guide us, and our recommendations were based on retrospective comparisons, phase 2 single-center series, and consensus opinions. Although early reports of cases of intravascular lymphoma indicated a very poor survival rate, more recent case series suggest that those who are able to receive combination anthracycline-based therapy such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) have a response rate and disease-free survival rate similar to the rates among patients with high-risk diffuse large-B-cell lymphoma of other sites.20 Rituximab (an anti-CD20 monoclonal antibody) has improved the survival of patients with diffuse large-B-cell lymphoma and is effectively distributed in the intravascular compartment; retrospective comparisons have suggested a dramatic benefit for patients with intravascular lymphoma, with 2-year progression-free and overall survival rates of 56% and 66%, respectively, in one large series, as compared with 27% and 45% for those treated with chemotherapy alone.21-23 Consequently, rituximab with CHOP-like chemotherapy (R-CHOP) is our initial regimen for patients with intravascular lymphoma. Although the intravascular component of this patients lymphoma was systemic, since it was outside the bloodbrain barrier, it was likely that at least some tumor cells were present around the blood vessels within the brain parenchyma.24 Some practitioners have recommended that intravascular lymphoma with CNS involvement should be treated in the same way as systemic diffuse large-B-cell lymphoma with concurrent CNS disease,15 and I tend to agree. Treatment of patients with concurrent CNS disease has been modeled somewhat on the treatment of primary CNS lymphoma; it has evolved from a radiation-based approach to an increasingly chemotherapy-based regimen, specifically involving high doses of intravenous methotrexate, which crosses the blood brain barrier.25,26 Consolidation with high-dose therapy and autologous stem-cell rescue, in hopes of being able to effectively deliver therapeutic concentrations of multiple cytotoxic agents across the bloodbrain barrier, has shown promising results.27-30

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Figure 3. Biopsy Specimen of the Right Frontal Lobe of the Brain. Malignant lymphoid cells are present within intracortical vessels (Panel A, hematoxylin and eosin). The malignant cells are immunoreactive for CD20 (Panel B, immunoperoxidase), whereas the benign perivascular cells are immunoreactive for CD3 (Panel C, in situ hybridization). malignant lymphoma cells express kappa light-chain mRNA RETAKE 1st Pless AUTHOR The ICM 2nd (Panel D, in situ hybridization) but REG notFlambda light-chain 3a-d mRNA (inset, immunoperoxidase). FIGURE
CASE EMail Enon

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On the basis of these considerations, this paand aminotransferasFILL tient was treated with two cycles of high-dose es were AUTHOR, PLEASE NOTE:elevated. Was this evidence of liver inFigure has been redrawn and type has been reset. methotrexate therapy, followed by six cycles of volvement? Please check carefully. R-CHOP-M, which consisted of standard R-CHOP Dr. Chen: At the time, it was suspected that the given every 3 weeks, with the addition of metho- abnormal tests were due to azathio3-25-10 JOB: 36212 ISSUE: liver-function trexate on day 14 of each cycle. The regimen had prine therapy, which had been started for treatan acceptable side-effect profile, and the patients ment of presumed multiple sclerosis. While the symptoms and imaging studies showed improve- patient was in the hospital and before treatment ment. She then underwent consolidation therapy for lymphoma was initiated, the levels began to with high-dose chemotherapy that consisted of fall. Although the PET scans were normal, PET thiotepa, busulfan, and cyclophosphamide fol- scans are not very sensitive for detecting diffuse lowed by autologous stem-cell rescue. Her course liver disease. Therefore, we cannot rule out the was complicated by fevers and mucositis. Approxi- possibility that the liver was involved. mately 100 days after stem-cell rescue, an MRI showed no evidence of active disease. Her neuA nat omic a l Di agnosis rologic symptoms resolved completely. Currently, 19 months after completion of treatment, she Intravascular large-B-cell lymphoma. has no symptoms and is back at work. This case was presented at the Medical Case Conference, JanuDr. Hasan Bazari (Medicine): Initially, the lev- ary 9, 2009.
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Dr. Pless reports receiving consulting fees from Bayer, EMD Serono, Pfizer, and Teva Neuroscience; honoraria from Bayer, EMD Serono, Novartis, Pfizer, and Teva Neuroscience; and grant support from EMD Serono; and Dr. Frosch, receiving honoraria References
1. Rolak LA, Fleming JO. The differen-

from Elsevier. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

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