A 52-Year-Old Man With Progressive Weakness and Incontinence

Abstract

Here we report a challenging case of a 52-year-old man presenting with subacute constipation, urinary retention, impotence, absent Achilles reflexes, and hypoesthesia in S2-S5 dermatomes. We review the clinical decision-making as the symptoms evolved and diagnostic testing changed over time. Once the diagnosis is settled, we discuss the sign and symptoms, additional diagnostic tools, treatment options and prognosis.

A 52-year-old man presented to the hospital with progressive constipation, urinary retention and impotence for 2 months. His vitals were stable on admission. He did not have a significant past medical history and the family history was noncontributory. On physical examination, the patient was cognitively intact and had no cranial nerve involvement or weakness. Deep tendon reflexes were normoactive throughout except for bilaterally absent Achilles reflexes. He had hypoesthesia in the S2-S5 dermatomes. A preliminary diagnosis of conus medullaris syndrome was considered.

Our patient’s initial presentation pointed toward a pathology in either conus medullaris or cauda equina in the setting of bowel and bladder involvement. The most common cause for both conditions is compression of the lumbar or sacral spine due to disc herniation or by a neoplasm. ¹ Our patient’s MRI of the spine with contrast showed spinal canal stenosis secondary to multiple disc protrusions, most notably in the L4-5 and L5-S1, and no gadolinium-enhancing lesions. The discopathies and spinal canal stenosis prompted a neurosurgery consult. It was concluded that the patient’s signs and symptoms could not be justified by the findings on imaging. Given the presenting symptoms and initial MRI findings, differential diagnoses shifted towards subacute infectious, inflammatory, vascular processes.

His cranial magnetic resonance imaging (MRI) with contrast revealed one gadolinium (Gd)-enhancing acute lesion in the periventricular white matter in the parietal lobe and 2 partially Gd-enhancing subacute frontal lobe lesions. There were also multiple small white matter changes indicative of small vessel ischemia. MR angiography of the brain and spinal cord was unyielding. Laboratory workup showed an erythrocyte sedimentation rate of 36mm/h, negative results for HIV and syphilis serologies. The cerebrospinal fluid (CSF) investigation was normal. An extensive meningitis-encephalitis work up in the CSF for Escherichia Coli., Haemophilus Influenzae, Listeria Monocytogenes, Neisseria Meningitides, Streptococcus Pneumonia, Cytomegalovirus, Enterovirus, Herpes Simplex 1-2 Viruses (HSV), Human Herpes Virus 6, Human Parvovirus, Varicella Zoster and Cryptococcus Neoformans were all negative. Another panel using immune electrophoresis for Borrelia DNA culture, Borrelia specific IgM and IgG, autoimmune and paraneoplastic encephalitides, and Brucella serology were unremarkable. A cardiac workup was done due to concern for stroke given the ischemic findings on the MRI. Transthoracic echocardiography revealed a relatively big patent foramen ovale and degenerative changes in the aortic and mitral valves. 48-hour Holter monitor did not show any rhythm abnormalities. Hypercoagulability workup was unrevealing.

After possible infectious and vascular etiologies are ruled out, the possibility of alternative underlying causes including malignancy and paraneoplastic processes should be investigated. A hematological/oncological workup can be considered if there is particular concern for a neoplasm with age, exposures, family and social history increasing the risk. Lymphoma is an important consideration given that it can present as extranodal disease in the absence of overt nodal involvement, making it a challenging diagnosis.

Hematology was consulted due to concern for lymphoma. As part of the hematological workup, lactate dehydrogenase enzyme was found to be elevated up to 275 U/L. CSF flow cytometry was unrevealing. Serum immunofixation electrophoresis showed only a mild increase in kappa and lambda light chains. Urine immune electrophoresis was normal. A whole-body Positron emission tomography (PET)- computerized tomography (CT) scan showed hypermetabolic nodular enlargement of the bilateral adrenal glands. However, adrenocorticotrophic hormone (ACTH), cortisol and parathyroid hormone (PTH) levels were within normal limits. Ten days after admission, MR angiography was repeated and diffusion weighted sequences revealed new lesions in the deep white matter, cortical and juxtacortical areas in the right frontal and parietal lobes. Due to concern for embolic showering from a cardiac source, transesophageal echocardiography (TEE) was done which showed no thrombus and only calcific changes in the aortic valve. Repeat MRI of the lumbar region demonstrated contrast enhancement of the S1 nerve fibers.

The patient was started on empiric acyclovir 10 mg/kg IV 3 times daily for a working diagnosis of Elsberg syndrome (ES). This is a condition which presents as acute or subacute lumbosacral radiculitis, often with myelitis secondary to HSV-2 reactivation as its most likely cause. ² Undiagnostic CSF studies are commonly seen in patients with ES; therefore the negative CSF infectious workup did not rule out this diagnosis for our patient. ³ Nevertheless, a repeat lumbar puncture (LP) was performed and the CSF studies resulted negative for Borrelia Burgdorferi, Varicella Zoster virus, Cytomegalovirus and Ebstein-Barr viruses.

On the seventh day of acyclovir treatment, our patient’s perianal hypoesthesia and bowel incontinence started to improve. However due to insufficient response to acyclovir, he was started on intravenous methyl prednisolone (IVMP) therapy (1000mg/day). While on IVMP, he had further improvement of the sensory and bladder functions. After seven days of IVMP treatment, the steroid regimen was switched to weekly dosing. Unfortunately after the second weekly dose, he presented to the emergency department due to sudden onset severe pain and mild weakness in the left lower extremity. Repeat MRI with contrast of the spine showed resolution of the prior contrast-enhancing lesions in the spinal cord. However new contrast enhancing areas were seen in the sacral regions and conus medullaris (Figure 1F). Cranial MRI revealed a new tumefactive lesion in the left temporal lobe with minimal contrast enhancement that developed within 4 weeks while the patient was on IVMP (Figure 1A-D). Our patient was readmitted for further workup.

Figure 1.

(A) The FLAIR sequence done in January 2019, showing multiple hyperintense lesions in cerebral white matter, the most prominent lesion being in the left frontal lobe. Frontal lobe lesion showing a patchy enhancement after IV gadolinium injection on postcontrast VIBE sequencing (B). (C-D) diffusion restriction on b1000 diffusion weighted image and ADC sequencing. (E-F) sagittal pre-contrast (E) and post-contrast (F) T1 weighted MRI image of lumbar region showing enhancement of the conus medullaris. (G-H) FLAIR and post-contrast images after treatment (March 2019) with near to complete resolution of the frontal lobe lesion.

A thorough investigation for inflammatory etiologies is warranted in case of progression or development of new white matter lesions. Studies to be sent include but are not limited to routine analysis, oligoclonal bands, cytology, a multiple sclerosis panel and a paraneoplastic panel. If all studies are inconclusive, a more aggressive approach with consideration of tissue biopsy is most likely the next step. In our case, routine CSF analysis was unremarkable. CSF studies were negative for oligoclonal bands, serum myelin oligodendrocyte protein and aquaporin-4 autoantibodies. Ultimately, a decision was made to pursue stereotactic brain biopsy for definitive tissue diagnosis (Figure 2).

Figure 2.

Microscopic images of the brain biopsy with higher powers of magnification with different staining. A, Complete specimen, red arrow showing the area with foamy macrophages, black arrow showing the area with reactive changes. B, Foamy macrophages with red blood cells. C, Neurofilament protein staining of the infiltrative region on the right and the preserved area on the left. D, Reactive changes with a few intravascular atypical cells (circle). E, CD20 staining with CD20+ intravascular cells (circle). F, Ki-67 staining with ki-67+ positive cells (circle).

The frozen section biopsy specimen was reported as free of malignancy and the histopathological findings were consistent with demyelination. The day after the brain biopsy, the patient developed severe paraparesis with loss of deep tendon reflexes and urinary incontinence. Lumbar MRI with contrast showed enhancement of the distal sacral fibers. With the acute clinical deterioration and the frozen section report, it was deemed the most rational for the patient to be started on intravenous immunoglobulin (IVIG) empirically. His symptoms continued to worsen with transient confusion periods after 4 days of IVIG. MRI brain with contrast was repeated which showed persistent cranial and sacral lesions. After a 5-day course of IVIG was completed without clinical or radiological improvement, patient was restarted on IVMP 1000mg/day for 7 days. Minimal improvement of the motor and sensory functions of the lower extremities was achieved.

The diagnostic evaluation of the biopsied tissue is quite valuable as it enables the use of a variety of immunohistochemical techniques to identify cytopathological changes that may point to the diagnosis. In our case, the biopsy specimen showed an infiltration of the tissue by foamy macrophages and red blood cells. Cytoplasm of the macrophages did not reveal myelin breakdown products with Luxol fast blue stain. Neurofilament protein immunostaining was positive for axonal loss. These 2 findings are suggestive of a reperfusion and neovascularization process.

Further examination of the biopsy specimen revealed a number of large intravascular atypical cells. They were found to be ki-67 positive and CD20 positive, leading to a diagnosis of diffuse large B cell intravascular lymphoma. It was concluded that the multiple infarcts seen on imaging and microscopy were secondary to the occlusion of the brain vessel lumina by neoplastic cells.

In intravascular lymphoma cases, neoplastic lymphocytes grow selectively within the lumen of small vessels, leading to the occlusion of the lumina of vessels resulting in ischemia and thrombosis. ⁴ Usually no neoplastic cells are found in circulation or as nodal or extranodal masses, which makes it a difficult disease to diagnose. ⁴ Our patient had several clinical features that broadened the differential diagnosis for the initial symptoms and workup findings. The multifocal ischemic lesions on the brain MRI pointed to a possibly subacute infectious, inflammatory or neoplastic process. However, the CSF studies came back negative and no malignant cells were detected in the CSF. As the symptoms progressed despite empiric antiviral treatment and IVIG, a diagnosis of CNS malignancy was reconsidered. Therefore, it is prudent to reconsider possible etiologies that were initially ruled out in patients with progressive neurologic symptoms.

After the diagnosis of stage IV intravascular B cell lymphoma was made, CSF flow cytometry was repeated with the addition of bone marrow flow cytometry. Interestingly, both of the tests were undiagnostic, and showed no bone marrow involvement. He was started on chemotherapy with 1 cycle of R-MPV regimen (rituximab, methotrexate, procarbazine and vincristine) followed by 5 cycles of R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and 6 cycles of high dose methotrexate. Follow-up PET/CT was negative for FDG uptake while the cranial MRI revealed complete resolution of the previously seen lesions. However, MRI of the spine had residual contrast enhancing areas in the cauda equina even after the treatment course was completed. The patient received 2.5 Gy/fraction of radiotherapy directed at T11-L3 for 30 days due to remaining lesions in cauda equina. Post chemo-radiotherapy brain and spinal MRI showed near to complete remission (Figure 1G-H).

Most cases of IVL warrant the need for systematic treatment due to the delay from disease onset to diagnosis when the disease is at advanced stage. It has a rapidly progressive course, and remission rates are low despite chemotherapy with a relapse in half of treated patients.^5-7 Indications of a better prognosis include single small cutaneous lesions, good performance status and low tumor burden.^5,6 The most common treatment regimen is R-CHOP, (cyclophosphamide, doxorubicin, vincristine and prednisone combined with rituximab). Studies show that anthracycline comprises the cornerstone of the IVL treatment, as the response rate in regimens without this drug is dramatically low.^5,8 Despite the presence of response to this chemotherapy, the search for drugs with better CNS bioavailability is still ongoing.

Two months following the completion of chemotherapy, the patient presented with hoarseness of voice. A head and neck PET-CT showed hypermetabolic lymphadenopathy posterolateral to the internal carotid artery within the carotid sheath likely in the setting of relapse. A biopsy was not pursued due to unfavorable anatomy. As salvage therapy, he received 3 cycles of R-ICE regimen (rituximab, ifosfamide, carboplatin, etoposide). He was considered as a candidate for autologous stem cell transplantation. Pre-transplant PET showed complete remission. He was maintained on conditioning regimen with TEAM (thiotepa, etoposide, cytarabine, and melphalan) which was chosen because of the central nervous system (CNS) involvement. Thirteen months after his diagnosis, he remained in remission on his follow up evaluation.

This case highlights the importance of considering intravascular lymphoma (IVL) in the differential diagnosis for patients presenting with spinal cord involvement. IVL is a rare and aggressive form of Non-Hodgkin lymphoma and a specific subtype of extra nodal diffuse large B cell lymphoma with unknown pathophysiology, as established by the 2008 World Health Organization (WHO) classification. ⁹ It can involve all organs, but there is a geographical predilection in terms of more common presentations. In Western countries, patients present more with CNS and skin involvement. On the contrary, in Asian patients CNS and skin symptoms are seen less, whereas the more common symptoms include fever, thrombocytopenia, hepatosplenomegaly and bone marrow invasion.^10,5 They constitute “hemaphagocytic syndrome.” There is also a cutaneous variant of IVL where the symptoms are limited to the skin. Neurologic manifestations are the presenting symptoms in one-third of the cases, ⁶ which include delirium, dementia, encephalopathy, seizures, cerebrovascular accidents, cranial neuropathy, transverse myelitis, radiculopathy, peripheral neuropathy and myopathy.^11,12

Interestingly, an investigation of abnormalities in the adrenal glands may yield additional clues for the diagnosis of IVL (Figure 3). In our case, a PET scan detected bilaterally hypermetabolic and enlarged nodules in the adrenals. Unilateral and bilateral adrenal enlargement in cases of IVL were reported in the literature.^13,14 Adrenal involvement may actually be more common than reported, as adrenal infiltration was seen in 60% of autopsy cases. ¹⁴ It is advisable to include an abdominal CT scan as part of the workup, and a follow up of abnormal findings with adrenal biopsy can provide a more preferable alternative to brain biopsy to justify the IVL diagnosis. Another consideration for an alternative diagnostic tool is open muscle biopsy as demonstrated by a few case series. ¹⁵

Figure 3.

Timeline of diagnostic procedures and treatment until the diagnosis of IVL.

In conclusion, IVL is a rare form of lymphoma which should be included in the differential diagnosis of myelopathy. IVL mimics myelitis, radiculitis or vasculitis, among other neurologic syndromes. The delay in an accurate diagnosis may preclude the chance for timely treatment. Tissue biopsy is often warranted for confirmation of the diagnosis.