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A confusing case of multiple sclerosis and central nervous system graft versus host disease

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The neurologic manifestations observed in allogeneic stem cell transplantation (allo-SCT) recipients are related to infections, metabolic abnormalities, and relapse of malignant disease in the central nervous system (CNS)... Several reports have described that GVHD affects the CNS ; however, CNS-GVHD is a rare finding and remains controversial... Confounding factors, including infections, drugs, and autoimmune manifestations can make the diagnosis challenging... We experienced a case in which the symptoms mimicked those of CNS-GVHD after allo-SCT but were ultimately considered a newly developed case of multiple sclerosis (MS)... He also described progressive difficulty climbing stairs and walking... He did not complain of visual disturbances, dizziness, or headache... A sensory examination revealed decreases in all modalities below the T6 dermatome... Normal results were observed on the mini-mental state examination, as well as on cranial nerve and cerebellar function tests... The patient received high dose intravenous methylprednisolone for 5 days followed by oral prednisolone (60 mg)... Despite this treatment, his symptoms failed to improve... The pathological analysis of the brain biopsy was more compatible with a CNS demyelinating disease than with CNS-GVHD... Second, GI-GVHD affects only the CNS and does not involve other organs for approximately 5 years after onset... Immunotherapies, such as cyclophosphamide, mitoxantrone, chemotherapy, and allo-SCT have been evaluated to assess their efficacy for treating refractory MS, which affects only a small portion of patients with MS... In contrast, our patient was a case of newly developed MS after allo-SCT... Furthermore, both CNS-GVHD and MS are rare in a clinical setting.

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Histology of the brain biopsy. (A) The lesion shows a large number of gitter cells (foamy macrophages) infiltrating with a relatively sharp border with the normal area (H&E, ×50). (B) Normal area shows intact myelinated nerve fibers on Luxol fast blue (LFB) staining (×200). (C) The lesion shows near-complete loss of myelinated nerve fibers with heavy macrophage infiltration compared to the normal area (LFB stain, ×200). (D) Neurofilament stain (×100) of the lesion shows relatively intact axons.
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f2-kjim-2015-065: Histology of the brain biopsy. (A) The lesion shows a large number of gitter cells (foamy macrophages) infiltrating with a relatively sharp border with the normal area (H&E, ×50). (B) Normal area shows intact myelinated nerve fibers on Luxol fast blue (LFB) staining (×200). (C) The lesion shows near-complete loss of myelinated nerve fibers with heavy macrophage infiltration compared to the normal area (LFB stain, ×200). (D) Neurofilament stain (×100) of the lesion shows relatively intact axons.

Mentions: A 36-year-old man with no history of demyelinating disease or any other specific illness was diagnosed with acute lymphoblastic leukemia. The patient underwent matched related allo-SCT. Cyclosporin-A followed by tacrolimus were administered for GVHD prophylaxis. Approximately 8 months after allo-SCT, he was admitted to our hospital complaining of watery diarrhea. An endoscopic biopsy of the colon revealed multiple apoptotic bodies in the crypts and increased lymphoplasma cell infiltration in lamina propria, and he was diagnosed with gastrointestinal GVHD (GI-GVHD). High-dose oral steroids were administered and improved his symptoms. No eventful or GVHD-related disease was observed for 1 year after allo-SCT. Additionally, his bone marrow showed normal blood cells and complete donor chimerism. The patient presented 2 years after allo-SCT with a progressive tingling sensation below the abdomen and weakness in both legs. He also described progressive difficulty climbing stairs and walking. He did not complain of visual disturbances, dizziness, or headache. A neurological examination demonstrated symmetrical muscle weakness in both legs (Medical Research Council [MRC] grade 3) and increased deep tendon reflexes during induced knee and ankle reflexes. A sensory examination revealed decreases in all modalities below the T6 dermatome. Normal results were observed on the mini-mental state examination, as well as on cranial nerve and cerebellar function tests. No Babinski sign or ankle clonus were observed. Brain and spinal magnetic resonance imaging (MRI) revealed high T2 signal intensity lesions at T3 level of the spinal cord and of the corpus callosum and right temporal subcortex (Fig. 1). These lesions were enhanced with gadolinium. Cerebrospinal fluid (CSF) was clear and showed no pleocytosis, oligoclonal bands, or increased protein. Serum and CSF viral studies were negative for Epstein-Barr virus (EBV), cytomegalovirus, and the John Cunningham virus. There was no evidence of a CNS infection or leukemia relapse in the CNS. Furthermore, he had a GI-GVHD history; thus, we diagnosed probable CNS-GVHD. The patient received high dose intravenous methylprednisolone for 5 days followed by oral prednisolone (60 mg). Despite this treatment, his symptoms failed to improve. A stereotactic brain biopsy (right temporal lobe) revealed gitter cells (foamy macrophages) and loss of myelinated nerve fibers without leukemic infiltration (Fig. 2). An excision biopsy of the thoracic spinal cord revealed only fibrosis. His symptoms had improved gradually 3 weeks later. Strength in the lower extremities was MRC 4 and sensory numbness showed steady improvement. The patient was discharged and could ambulate independently. Oral prednisolone was tapered by 15 mg every other day over 8 months. The patient redeveloped a tingling sensation and weakness in all extremities approximately 3 years after allo-SCT. Neurological signs indicated weakness in bilateral arms (MRC grade 3) and legs (MRC grade 2) and decreased sensory responses below the T1 spinal cord level, and increased bilateral deep tendon reflexes in the upper and lower extremities. A spinal MRI revealed partially enhanced C1–2 lesions in the spinal cord (Fig. 3). Anti-nuclear antibody, anti-neutrophil cytoplasmic antibody, rheumatoid factor, anti-Ro, anti-La, cryoglobulin antibody, and anti-aquaporin-4 antibody were not detected. Both P100 latencies were delayed (right, 120 ms; left, 125 ms) in a visual evoked study. Furthermore, electrophysiologic evidence suggested central conduction delays in bilateral median and posterior tibial nerve evoked potentials. He was treated with high doses of intravenous methylprednisolone, and his symptoms improved gradually. Arm and leg weakness had become MRC 5 1 month later. We initially considered CNS-GVHD as a possible diagnosis based on the CNS characteristics. We could have also considered a CNS demyelinating disease, which can cause relapsing myelopathy, such as relapsing and remitting MS, as another possible diagnosis. The patient was started on subcutaneous injections of interferon β (IFN-β) in addition to oral prednisolone (10 mg). No eventful symptoms were detected that indicated a relapse during a 36-month observation period.


A confusing case of multiple sclerosis and central nervous system graft versus host disease
Histology of the brain biopsy. (A) The lesion shows a large number of gitter cells (foamy macrophages) infiltrating with a relatively sharp border with the normal area (H&E, ×50). (B) Normal area shows intact myelinated nerve fibers on Luxol fast blue (LFB) staining (×200). (C) The lesion shows near-complete loss of myelinated nerve fibers with heavy macrophage infiltration compared to the normal area (LFB stain, ×200). (D) Neurofilament stain (×100) of the lesion shows relatively intact axons.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5016275&req=5

f2-kjim-2015-065: Histology of the brain biopsy. (A) The lesion shows a large number of gitter cells (foamy macrophages) infiltrating with a relatively sharp border with the normal area (H&E, ×50). (B) Normal area shows intact myelinated nerve fibers on Luxol fast blue (LFB) staining (×200). (C) The lesion shows near-complete loss of myelinated nerve fibers with heavy macrophage infiltration compared to the normal area (LFB stain, ×200). (D) Neurofilament stain (×100) of the lesion shows relatively intact axons.
Mentions: A 36-year-old man with no history of demyelinating disease or any other specific illness was diagnosed with acute lymphoblastic leukemia. The patient underwent matched related allo-SCT. Cyclosporin-A followed by tacrolimus were administered for GVHD prophylaxis. Approximately 8 months after allo-SCT, he was admitted to our hospital complaining of watery diarrhea. An endoscopic biopsy of the colon revealed multiple apoptotic bodies in the crypts and increased lymphoplasma cell infiltration in lamina propria, and he was diagnosed with gastrointestinal GVHD (GI-GVHD). High-dose oral steroids were administered and improved his symptoms. No eventful or GVHD-related disease was observed for 1 year after allo-SCT. Additionally, his bone marrow showed normal blood cells and complete donor chimerism. The patient presented 2 years after allo-SCT with a progressive tingling sensation below the abdomen and weakness in both legs. He also described progressive difficulty climbing stairs and walking. He did not complain of visual disturbances, dizziness, or headache. A neurological examination demonstrated symmetrical muscle weakness in both legs (Medical Research Council [MRC] grade 3) and increased deep tendon reflexes during induced knee and ankle reflexes. A sensory examination revealed decreases in all modalities below the T6 dermatome. Normal results were observed on the mini-mental state examination, as well as on cranial nerve and cerebellar function tests. No Babinski sign or ankle clonus were observed. Brain and spinal magnetic resonance imaging (MRI) revealed high T2 signal intensity lesions at T3 level of the spinal cord and of the corpus callosum and right temporal subcortex (Fig. 1). These lesions were enhanced with gadolinium. Cerebrospinal fluid (CSF) was clear and showed no pleocytosis, oligoclonal bands, or increased protein. Serum and CSF viral studies were negative for Epstein-Barr virus (EBV), cytomegalovirus, and the John Cunningham virus. There was no evidence of a CNS infection or leukemia relapse in the CNS. Furthermore, he had a GI-GVHD history; thus, we diagnosed probable CNS-GVHD. The patient received high dose intravenous methylprednisolone for 5 days followed by oral prednisolone (60 mg). Despite this treatment, his symptoms failed to improve. A stereotactic brain biopsy (right temporal lobe) revealed gitter cells (foamy macrophages) and loss of myelinated nerve fibers without leukemic infiltration (Fig. 2). An excision biopsy of the thoracic spinal cord revealed only fibrosis. His symptoms had improved gradually 3 weeks later. Strength in the lower extremities was MRC 4 and sensory numbness showed steady improvement. The patient was discharged and could ambulate independently. Oral prednisolone was tapered by 15 mg every other day over 8 months. The patient redeveloped a tingling sensation and weakness in all extremities approximately 3 years after allo-SCT. Neurological signs indicated weakness in bilateral arms (MRC grade 3) and legs (MRC grade 2) and decreased sensory responses below the T1 spinal cord level, and increased bilateral deep tendon reflexes in the upper and lower extremities. A spinal MRI revealed partially enhanced C1–2 lesions in the spinal cord (Fig. 3). Anti-nuclear antibody, anti-neutrophil cytoplasmic antibody, rheumatoid factor, anti-Ro, anti-La, cryoglobulin antibody, and anti-aquaporin-4 antibody were not detected. Both P100 latencies were delayed (right, 120 ms; left, 125 ms) in a visual evoked study. Furthermore, electrophysiologic evidence suggested central conduction delays in bilateral median and posterior tibial nerve evoked potentials. He was treated with high doses of intravenous methylprednisolone, and his symptoms improved gradually. Arm and leg weakness had become MRC 5 1 month later. We initially considered CNS-GVHD as a possible diagnosis based on the CNS characteristics. We could have also considered a CNS demyelinating disease, which can cause relapsing myelopathy, such as relapsing and remitting MS, as another possible diagnosis. The patient was started on subcutaneous injections of interferon β (IFN-β) in addition to oral prednisolone (10 mg). No eventful symptoms were detected that indicated a relapse during a 36-month observation period.

View Article: PubMed Central - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

The neurologic manifestations observed in allogeneic stem cell transplantation (allo-SCT) recipients are related to infections, metabolic abnormalities, and relapse of malignant disease in the central nervous system (CNS)... Several reports have described that GVHD affects the CNS ; however, CNS-GVHD is a rare finding and remains controversial... Confounding factors, including infections, drugs, and autoimmune manifestations can make the diagnosis challenging... We experienced a case in which the symptoms mimicked those of CNS-GVHD after allo-SCT but were ultimately considered a newly developed case of multiple sclerosis (MS)... He also described progressive difficulty climbing stairs and walking... He did not complain of visual disturbances, dizziness, or headache... A sensory examination revealed decreases in all modalities below the T6 dermatome... Normal results were observed on the mini-mental state examination, as well as on cranial nerve and cerebellar function tests... The patient received high dose intravenous methylprednisolone for 5 days followed by oral prednisolone (60 mg)... Despite this treatment, his symptoms failed to improve... The pathological analysis of the brain biopsy was more compatible with a CNS demyelinating disease than with CNS-GVHD... Second, GI-GVHD affects only the CNS and does not involve other organs for approximately 5 years after onset... Immunotherapies, such as cyclophosphamide, mitoxantrone, chemotherapy, and allo-SCT have been evaluated to assess their efficacy for treating refractory MS, which affects only a small portion of patients with MS... In contrast, our patient was a case of newly developed MS after allo-SCT... Furthermore, both CNS-GVHD and MS are rare in a clinical setting.

No MeSH data available.