CASE REPORT/CASE SERIES
A Unique Case of Intravascular Lymphoma Mimicking Encephalomyeloradiculoneuropathy Pavan Bhargava, MD,* Fazeel Siddiqui, MD,* Brajesh Aggarwal, MD,* Brian E. Moore, MD,w and Rodger J. Elble, MD, PhD*
Introduction: Angiotropic lymphoma is a rare large B-cell lymphoma involving the intravascular compartment without local tissue or vessel wall infiltration. Case Report: A 48-year-old male presented with 8 months of progressive paraparesis and bowel and bladder incontinence. Initial cerebrospinal fluid analysis showed high protein, lymphocytic pleocytosis, high IgG synthesis, but no oligoclonal bands. Brain imaging at presentation was unrevealing. Electromyography revealed evidence of bilateral lumbosacral radiculoplexopathy [R > L]. A trial of intravenous solumedrol resulted in significant improvement in weakness. He had multiple hospital admissions for worsening lower extremity weakness, altered mental status, and new-onset upper extremity weakness. Magnetic resonance imaging of the spine revealed abnormal hyperintense T2 signal at T7-T8 level. Visual-evoked potentials revealed significant slowing of conduction in both optic nerves. Repeat electromyography showed a moderate to severe motor axonal polyneuropathy with secondary demyelination in the upper and lower extremities. A working diagnosis of encephalomyeloradiculoneuritis was made because of signs of polyradiculopathy, peripheral neuropathy and myelopathy. Patient had 3 trials of intravenous solumedrol with transient improvement in symptoms. The magnetic resonance imaging brain on his sixth hospital admission revealed multiple areas of restricted diffusion throughout the brain parenchyma. The patient underwent a right frontal lobe biopsy, which showed large CD-20 + neoplastic lymphocytes within small arteries, veins, and capillaries with no extension to surrounding brain parenchyma. The findings were consistent with intravascular large B-cell lymphoma. Conclusion: Angiotropic lymphoma is a rare disease with frequent involvement of central nervous system and skin that can present with neurological involvement of both the peripheral and central nervous system. Key Words: intravascular lymphoma, encephalomyeloradiculoneuropathy, angiotropic lymphoma
(The Neurologist 2015;20:18–21)
I
ntravascular lymphoma (IVL) is a rare type of extranodal non-Hodgkin lymphoma. It is a variant of diffuse large B-cell lymphoma and has been recognized as a separate entity by the World Health Organization in its classification of lymphomas.1 Although it is most commonly of B-cell origin, cases of T cell as well as natural killer cell origin have been described.2,3 The
From the *Department of Neurology, Southern Illinois University School of Medicine; and wMemorial Medical Center, Springfield, IL. The authors declare no conflict of interest. Reprints: Pavan Bhargava, MD, Department of Neurology, Southern Illinois University School of Medicine, 751 N Rutledge Street, Suite 3100, P.O. Box 19643, Springfield, IL 62794-9643. E-mail: bhargava.pavan@ gmail.com. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1074-7931/15/2001-0018 DOI: 10.1097/NRL.0000000000000042
disease manifests as proliferation of lymphomatous cells in the lumina of small vessels, particularly capillaries, whereas the parenchyma of the involved organs are generally spared.4 It presents most commonly with nervous system and skin symptoms and has generally been a challenge to diagnose because of the variety of possible presentations and lack of noninvasive markers. The term encephalomyeloradiculoneuropathy has been used traditionally to describe demyelinating disorders causing affectation of both the central and peripheral nervous systems.5 Most commonly, this involves autoimmune conditions, postviral demyelination, and connective tissue disorders.6,7 To the best of our knowledge, this syndrome has not hitherto been attributed to IVL. We describe a case of IVL that had a unique pattern of neurological involvement mimicking encephalomyeloradiculoneuropathy. This is a novel presentation of IVL and stresses the need to include IVL in the differential diagnosis of patients with encephalomyeloradiculoneuropathy. Our case is also unique in that the diagnosis was made antemortem, and the patient has survived for >60 months. Given the poor prognosis usually associated with this disease and the chances of near-complete remission with early diagnosis and appropriate treatment, it is essential that neurologists be aware of this disease and its various manifestations. We review here the major manifestations, diagnostic challenges, and treatment options of IVL.
CASE A 48-year-old male presented with an 8-month history of progressive neurological deterioration, first noted as urinary and bowel incontinence, vertigo, and gait ataxia. Two weeks later, he developed progressive bilateral lower extremity weakness. His neurological examination on first encounter revealed severe weakness in the right lower extremity, proximally as well as distally with the strength of only 1/5 associated with significant hypotonia. He had slightly better strength in the left lower extremity with some effort against gravity. Bilateral ankle and knee reflexes were absent. Babinski reflex was absent on the left and equivocal on the right side. He had impaired vibration, pinprick, and proprioception below the knee in both the lower extremities. There was no involvement of the upper extremities or cranial nerves. Initial cerebrospinal fluid analysis showed a protein of 81 mg/dL, white blood cell count of 5, elevated IgG synthesis, high myelin basic protein but undetectable oligoclonal bands. Initial magnetic resonance imaging (MRI) brain showed scattered areas of T2 hyperintensities in the subcortical white matter, which were consistent with small vessel disease. A whole spine MRI showed mild to moderate degenerative changes There was no postcontrast enhancement. Somatosensory-evoked potential of posterior tibial nerves showed normal central conduction but bilateral prolongation of the lumbar potential reflecting peripheral nerve conduction delay. An electromyography/nerve conduction study was done which showed electrophysiological evidence of significant active ongoing denervation of bilateral lower extremity muscles with asymmetric changes (more axonal denervation changes seen in the right lower extremity). This, in combination with normal sensory and motor routine nerve conduction
18 | www.theneurologist.org The Neurologist Volume 20, Number 1, July 2015 Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
The Neurologist
Volume 20, Number 1, July 2015
studies but absent right peroneal F wave latency and prolongation of the right tibial H reflex response latency along with presence of positive sharp waves and fibrillation potential in lumbar paraspinal and lower extremity muscles indicated a possibility of bilateral lower lumbosacral radiculopathy, more severe on the right. Patient received a trial of intravenous (IV) solumedrol 1 g for 3 days and showed significant improvement in weakness. Patient had 5 subsequent hospital admissions for fluctuating lower extremity weakness, altered mental status, and new-onset of upper extremity weakness. He became completely wheel chair bound 2 months after his first admission. A series of tests were performed to identify possible hormonal and nutritional deficiencies, as well as connective tissue disease, all of which were negative. He had positive serology for hepatitis C, but undetectable viral counts. Tests for antinuclear antibodies and antineutrophil cytoplasmic autoantibodies (p-ANCA and c-ANCA) were negative as well. Infectious serologies were also negative (human Immunodeficiency virus, Varicella zoster virus, human T-cell lymphotropic virus, cytomegalo virus, Epstein-Barr virus, borrelia, mycoplasma, Treponema pallidum haemagglutination/Venereal diseases research laboratory). His second MRI spine revealed an abnormal hyperintense T2 signal at T7-T8 level. An MRI brain showed a new focal area of hyperintensity on T2 and fluid attenuated inversion recovery (FLAIR) in the splenium of corpus callosum. A repeat cerebrospinal fluid analysis showed protein of 99 mg/dL and white blood cell count 13, elevated IgG synthesis, and negative oligoclonal bands. A visual-evoked potential examination revealed significant slowing of conduction in both the optic nerves. Upper and lower extremity evoked potentials (somatosensory-evoked potential) showed significant peripheral and central slowing of conduction. His second electromyography/nerve conduction study showed a moderate to severe motor axonal peripheral polyneuropathy with secondary demyelinating process in the upper and lower extremities and right distal median neuropathy at the wrist This conclusion was supported by the findings of significantly reduced compound muscle action potential or absence of motor responses, prolonged distal motor latencies, and H reflex latencies as well as slowed motor conduction velocities with relatively normal sensory study in the right upper and bilateral lower extremities. A working diagnosis of encephalomyeloradiculoneuropathy was made because of signs of polyradiculopathy, peripheral neuropathy, and myelopathy. Patient had 3 trials of intravenous solumedrol. Initially, he had marked improvement in his symptoms. He also received IVIG and methotrexate with variable response. His fourth MRI of the brain on his sixth admission to hospital revealed multiple areas of diffusion restriction throughout the brain parenchyma without contrast enhancement. On the basis of new MRI findings, the patient finally received a right frontal lobe biopsy, which showed large CD-20 + neoplastic lymphocytes within small arteries, veins, and capillaries with no extension to surrounding brain parenchyma. The findings were consistent with intravascular large B-cell (angiotropic) lymphoma (Fig. 1). He was subsequently treated with the de-Angelis regimen (5 cycles of highdose IV methotrexate, vincristine, and oral procarbazine) in addition to high-dose IV rituximab. This was followed by 6-monthly maintenance treatment with IV rituximab and intrathecal methotrexate for 3 years. Patient has been in remission for 5 years. His paraplegia and bladder symptoms, however, have not improved.
DISCUSSION IVL was first described by Pfleger and Tappeiner in 1959 as “angioendotheliomatosis proliferans systemisata” in a young female patient with cutaneous manifestation of systemic endotheliomatosis.8 The disorder has been known by several names. The disorder has recently been included in the World Health Organization classification as a separate entity.1 Initially, the proliferating cells were believed to be of endothelial origin as they were limited to the vascular lumen.9 Immunohistochemical studies have subsequently shown that the cells are of B-cell or T-cell lineage, more commonly B cell.10 IVL usually occurs in middle-aged to elderly people with no sex preference. The most commonly affected organs are the skin and the nervous system.11 However, involvement of Copyright
r
Unique Case of Intravascular Lymphoma
adrenal glands, kidney, heart, lungs, liver, spleen, gut has been described.12–14 In some cases, involvement of the bone marrow has been documented. In the majority of cases, diagnosis is made at autopsy. It is a disorder that has a myriad of presentations, including fever of unknown origin, single system involvement of skin or central nervous system (CNS), and multisystemic disease.15 Dementia, stroke-like episodes, conus medullaris lesions, and peripheral neuropathy have been described.16–19 The plethora of neurological signs and symptoms in cases of IVL and the rarity of this disease makes it a great imitator that is extremely hard to diagnose. In a previous series, the neurological presentations fell into 4 main categories: progressive multifocal cerebrovascular events, spinal cord and nerve root vascular syndromes, subacute encephalopathy, and peripheral or cranial neuropathies.20 The lack of specific laboratory tests and imaging features make IVL a challenging diagnosis. Commonly described laboratory abnormalities include an elevated lactate dehydrogenase, elevated erythrocyte sedimentation rate, and mild anemia. In cases with hemophagocytic syndrome (a subset of IVL primarily described in Asia), pancytopenia and liver function abnormalities may be detected.21 Thrombophilia has also been described in patients with IVL, and in our patient, 1 episode of hospitalization was necessitated by lower extremity DVT. Cases with presence of antiphospholipid antibody in conjunction with IVL have been described, and this may be a factor contributing to thrombophilia. Florid disseminated intravascular coagulation may also occur. Brain and spinal MRI are the imaging modalities most commonly used in the evaluation of these patients. In 1 series, 3 of 5 patients had scattered MRI abnormalities in the cerebral hemispheres.22 Brain stem, spinal cord, and cerebellum were less frequently involved. Most cases had hyperintense lesions on DWI, suggestive of ischemia. These lesions subsequently were identifiable as hyperintense areas on FLAIR sequences suggesting glial scarring. Three of the patients also presented initially with lesions with contrast enhancement.22 Liow et al23 also described 2 cases with linear, punctuate, and patchy gadolinium enhancement on brain MRI. FDG-PET has been helpful in identifying sites for biopsy in cases of IVL presenting as fever of unknown origin. FDGPET may also be useful in monitoring of disease during chemotherapy.24 Diagnosis is made only by biopsy of an involved organ. The organs most commonly biopsied are the skin, brain, or lungs.25,26 Biopsy of visceral organs is usually preferable to brain biopsy, so computed tomography of the chest, abdomen, and pelvis should be undertaken to a target for biopsy in the adrenal glands, kidney, liver, spleen, lymph node, or muscle.27–30 Muscle biopsy was found diagnostic in two thirds of patients with neurogenic weakness in the lower limbs.31 In the Asian variant, the bone marrow is commonly involved, and a bone marrow biopsy may be diagnostic.24 Cerebral biopsies can be falsely negative, even when areas of MRI abnormality are biopsied. There are no controlled studies or guidelines for treatment of IVL. The International Extranodal Lymphoma Study Group reviewed data on 35 patients with IVL and found that 22 were treated with chemotherapy with a response rate of 59%. The 3year event-free and survival rates were 27% and 33%, respectively.32 This series, however, included 7 patients with cutaneous limited variant, and these patients have been shown to have better response to chemotherapy. The overall survival time for disseminated IVL was
A Unique Case of Intravascular Lymphoma Mimicking Encephalomyeloradiculoneuropathy Pavan Bhargava, MD,* Fazeel Siddiqui, MD,* Brajesh Aggarwal, MD,* Brian E. Moore, MD,w and Rodger J. Elble, MD, PhD*
Introduction: Angiotropic lymphoma is a rare large B-cell lymphoma involving the intravascular compartment without local tissue or vessel wall infiltration. Case Report: A 48-year-old male presented with 8 months of progressive paraparesis and bowel and bladder incontinence. Initial cerebrospinal fluid analysis showed high protein, lymphocytic pleocytosis, high IgG synthesis, but no oligoclonal bands. Brain imaging at presentation was unrevealing. Electromyography revealed evidence of bilateral lumbosacral radiculoplexopathy [R > L]. A trial of intravenous solumedrol resulted in significant improvement in weakness. He had multiple hospital admissions for worsening lower extremity weakness, altered mental status, and new-onset upper extremity weakness. Magnetic resonance imaging of the spine revealed abnormal hyperintense T2 signal at T7-T8 level. Visual-evoked potentials revealed significant slowing of conduction in both optic nerves. Repeat electromyography showed a moderate to severe motor axonal polyneuropathy with secondary demyelination in the upper and lower extremities. A working diagnosis of encephalomyeloradiculoneuritis was made because of signs of polyradiculopathy, peripheral neuropathy and myelopathy. Patient had 3 trials of intravenous solumedrol with transient improvement in symptoms. The magnetic resonance imaging brain on his sixth hospital admission revealed multiple areas of restricted diffusion throughout the brain parenchyma. The patient underwent a right frontal lobe biopsy, which showed large CD-20 + neoplastic lymphocytes within small arteries, veins, and capillaries with no extension to surrounding brain parenchyma. The findings were consistent with intravascular large B-cell lymphoma. Conclusion: Angiotropic lymphoma is a rare disease with frequent involvement of central nervous system and skin that can present with neurological involvement of both the peripheral and central nervous system. Key Words: intravascular lymphoma, encephalomyeloradiculoneuropathy, angiotropic lymphoma
(The Neurologist 2015;20:18–21)
I
ntravascular lymphoma (IVL) is a rare type of extranodal non-Hodgkin lymphoma. It is a variant of diffuse large B-cell lymphoma and has been recognized as a separate entity by the World Health Organization in its classification of lymphomas.1 Although it is most commonly of B-cell origin, cases of T cell as well as natural killer cell origin have been described.2,3 The
From the *Department of Neurology, Southern Illinois University School of Medicine; and wMemorial Medical Center, Springfield, IL. The authors declare no conflict of interest. Reprints: Pavan Bhargava, MD, Department of Neurology, Southern Illinois University School of Medicine, 751 N Rutledge Street, Suite 3100, P.O. Box 19643, Springfield, IL 62794-9643. E-mail: bhargava.pavan@ gmail.com. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1074-7931/15/2001-0018 DOI: 10.1097/NRL.0000000000000042
disease manifests as proliferation of lymphomatous cells in the lumina of small vessels, particularly capillaries, whereas the parenchyma of the involved organs are generally spared.4 It presents most commonly with nervous system and skin symptoms and has generally been a challenge to diagnose because of the variety of possible presentations and lack of noninvasive markers. The term encephalomyeloradiculoneuropathy has been used traditionally to describe demyelinating disorders causing affectation of both the central and peripheral nervous systems.5 Most commonly, this involves autoimmune conditions, postviral demyelination, and connective tissue disorders.6,7 To the best of our knowledge, this syndrome has not hitherto been attributed to IVL. We describe a case of IVL that had a unique pattern of neurological involvement mimicking encephalomyeloradiculoneuropathy. This is a novel presentation of IVL and stresses the need to include IVL in the differential diagnosis of patients with encephalomyeloradiculoneuropathy. Our case is also unique in that the diagnosis was made antemortem, and the patient has survived for >60 months. Given the poor prognosis usually associated with this disease and the chances of near-complete remission with early diagnosis and appropriate treatment, it is essential that neurologists be aware of this disease and its various manifestations. We review here the major manifestations, diagnostic challenges, and treatment options of IVL.
CASE A 48-year-old male presented with an 8-month history of progressive neurological deterioration, first noted as urinary and bowel incontinence, vertigo, and gait ataxia. Two weeks later, he developed progressive bilateral lower extremity weakness. His neurological examination on first encounter revealed severe weakness in the right lower extremity, proximally as well as distally with the strength of only 1/5 associated with significant hypotonia. He had slightly better strength in the left lower extremity with some effort against gravity. Bilateral ankle and knee reflexes were absent. Babinski reflex was absent on the left and equivocal on the right side. He had impaired vibration, pinprick, and proprioception below the knee in both the lower extremities. There was no involvement of the upper extremities or cranial nerves. Initial cerebrospinal fluid analysis showed a protein of 81 mg/dL, white blood cell count of 5, elevated IgG synthesis, high myelin basic protein but undetectable oligoclonal bands. Initial magnetic resonance imaging (MRI) brain showed scattered areas of T2 hyperintensities in the subcortical white matter, which were consistent with small vessel disease. A whole spine MRI showed mild to moderate degenerative changes There was no postcontrast enhancement. Somatosensory-evoked potential of posterior tibial nerves showed normal central conduction but bilateral prolongation of the lumbar potential reflecting peripheral nerve conduction delay. An electromyography/nerve conduction study was done which showed electrophysiological evidence of significant active ongoing denervation of bilateral lower extremity muscles with asymmetric changes (more axonal denervation changes seen in the right lower extremity). This, in combination with normal sensory and motor routine nerve conduction
18 | www.theneurologist.org The Neurologist Volume 20, Number 1, July 2015 Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
The Neurologist
Volume 20, Number 1, July 2015
studies but absent right peroneal F wave latency and prolongation of the right tibial H reflex response latency along with presence of positive sharp waves and fibrillation potential in lumbar paraspinal and lower extremity muscles indicated a possibility of bilateral lower lumbosacral radiculopathy, more severe on the right. Patient received a trial of intravenous (IV) solumedrol 1 g for 3 days and showed significant improvement in weakness. Patient had 5 subsequent hospital admissions for fluctuating lower extremity weakness, altered mental status, and new-onset of upper extremity weakness. He became completely wheel chair bound 2 months after his first admission. A series of tests were performed to identify possible hormonal and nutritional deficiencies, as well as connective tissue disease, all of which were negative. He had positive serology for hepatitis C, but undetectable viral counts. Tests for antinuclear antibodies and antineutrophil cytoplasmic autoantibodies (p-ANCA and c-ANCA) were negative as well. Infectious serologies were also negative (human Immunodeficiency virus, Varicella zoster virus, human T-cell lymphotropic virus, cytomegalo virus, Epstein-Barr virus, borrelia, mycoplasma, Treponema pallidum haemagglutination/Venereal diseases research laboratory). His second MRI spine revealed an abnormal hyperintense T2 signal at T7-T8 level. An MRI brain showed a new focal area of hyperintensity on T2 and fluid attenuated inversion recovery (FLAIR) in the splenium of corpus callosum. A repeat cerebrospinal fluid analysis showed protein of 99 mg/dL and white blood cell count 13, elevated IgG synthesis, and negative oligoclonal bands. A visual-evoked potential examination revealed significant slowing of conduction in both the optic nerves. Upper and lower extremity evoked potentials (somatosensory-evoked potential) showed significant peripheral and central slowing of conduction. His second electromyography/nerve conduction study showed a moderate to severe motor axonal peripheral polyneuropathy with secondary demyelinating process in the upper and lower extremities and right distal median neuropathy at the wrist This conclusion was supported by the findings of significantly reduced compound muscle action potential or absence of motor responses, prolonged distal motor latencies, and H reflex latencies as well as slowed motor conduction velocities with relatively normal sensory study in the right upper and bilateral lower extremities. A working diagnosis of encephalomyeloradiculoneuropathy was made because of signs of polyradiculopathy, peripheral neuropathy, and myelopathy. Patient had 3 trials of intravenous solumedrol. Initially, he had marked improvement in his symptoms. He also received IVIG and methotrexate with variable response. His fourth MRI of the brain on his sixth admission to hospital revealed multiple areas of diffusion restriction throughout the brain parenchyma without contrast enhancement. On the basis of new MRI findings, the patient finally received a right frontal lobe biopsy, which showed large CD-20 + neoplastic lymphocytes within small arteries, veins, and capillaries with no extension to surrounding brain parenchyma. The findings were consistent with intravascular large B-cell (angiotropic) lymphoma (Fig. 1). He was subsequently treated with the de-Angelis regimen (5 cycles of highdose IV methotrexate, vincristine, and oral procarbazine) in addition to high-dose IV rituximab. This was followed by 6-monthly maintenance treatment with IV rituximab and intrathecal methotrexate for 3 years. Patient has been in remission for 5 years. His paraplegia and bladder symptoms, however, have not improved.
DISCUSSION IVL was first described by Pfleger and Tappeiner in 1959 as “angioendotheliomatosis proliferans systemisata” in a young female patient with cutaneous manifestation of systemic endotheliomatosis.8 The disorder has been known by several names. The disorder has recently been included in the World Health Organization classification as a separate entity.1 Initially, the proliferating cells were believed to be of endothelial origin as they were limited to the vascular lumen.9 Immunohistochemical studies have subsequently shown that the cells are of B-cell or T-cell lineage, more commonly B cell.10 IVL usually occurs in middle-aged to elderly people with no sex preference. The most commonly affected organs are the skin and the nervous system.11 However, involvement of Copyright
r
Unique Case of Intravascular Lymphoma
adrenal glands, kidney, heart, lungs, liver, spleen, gut has been described.12–14 In some cases, involvement of the bone marrow has been documented. In the majority of cases, diagnosis is made at autopsy. It is a disorder that has a myriad of presentations, including fever of unknown origin, single system involvement of skin or central nervous system (CNS), and multisystemic disease.15 Dementia, stroke-like episodes, conus medullaris lesions, and peripheral neuropathy have been described.16–19 The plethora of neurological signs and symptoms in cases of IVL and the rarity of this disease makes it a great imitator that is extremely hard to diagnose. In a previous series, the neurological presentations fell into 4 main categories: progressive multifocal cerebrovascular events, spinal cord and nerve root vascular syndromes, subacute encephalopathy, and peripheral or cranial neuropathies.20 The lack of specific laboratory tests and imaging features make IVL a challenging diagnosis. Commonly described laboratory abnormalities include an elevated lactate dehydrogenase, elevated erythrocyte sedimentation rate, and mild anemia. In cases with hemophagocytic syndrome (a subset of IVL primarily described in Asia), pancytopenia and liver function abnormalities may be detected.21 Thrombophilia has also been described in patients with IVL, and in our patient, 1 episode of hospitalization was necessitated by lower extremity DVT. Cases with presence of antiphospholipid antibody in conjunction with IVL have been described, and this may be a factor contributing to thrombophilia. Florid disseminated intravascular coagulation may also occur. Brain and spinal MRI are the imaging modalities most commonly used in the evaluation of these patients. In 1 series, 3 of 5 patients had scattered MRI abnormalities in the cerebral hemispheres.22 Brain stem, spinal cord, and cerebellum were less frequently involved. Most cases had hyperintense lesions on DWI, suggestive of ischemia. These lesions subsequently were identifiable as hyperintense areas on FLAIR sequences suggesting glial scarring. Three of the patients also presented initially with lesions with contrast enhancement.22 Liow et al23 also described 2 cases with linear, punctuate, and patchy gadolinium enhancement on brain MRI. FDG-PET has been helpful in identifying sites for biopsy in cases of IVL presenting as fever of unknown origin. FDGPET may also be useful in monitoring of disease during chemotherapy.24 Diagnosis is made only by biopsy of an involved organ. The organs most commonly biopsied are the skin, brain, or lungs.25,26 Biopsy of visceral organs is usually preferable to brain biopsy, so computed tomography of the chest, abdomen, and pelvis should be undertaken to a target for biopsy in the adrenal glands, kidney, liver, spleen, lymph node, or muscle.27–30 Muscle biopsy was found diagnostic in two thirds of patients with neurogenic weakness in the lower limbs.31 In the Asian variant, the bone marrow is commonly involved, and a bone marrow biopsy may be diagnostic.24 Cerebral biopsies can be falsely negative, even when areas of MRI abnormality are biopsied. There are no controlled studies or guidelines for treatment of IVL. The International Extranodal Lymphoma Study Group reviewed data on 35 patients with IVL and found that 22 were treated with chemotherapy with a response rate of 59%. The 3year event-free and survival rates were 27% and 33%, respectively.32 This series, however, included 7 patients with cutaneous limited variant, and these patients have been shown to have better response to chemotherapy. The overall survival time for disseminated IVL was
