2025 Volume 12 Pages 249-254
Neurolymphomatosis is a rare lymphoma infiltrating cranial nerves, peripheral nerves, and spinal nerve roots. We present a unique case of neurolymphomatosis involving the central nervous system, initially resembling polyneuropathy in Sjögren's syndrome. A 79-year-old woman experienced dry eye symptoms for 2 years before presenting with left facial nerve palsy and lumbar pain to her previous physician. Brain magnetic resonance imaging revealed high signal intensity on diffusion-weighted imaging solely in the left peripheral facial nerve and lower cranial nerves. Initially diagnosed with Sjögren's syndrome-associated polyneuritis, she underwent treatment with high-dose steroid pulse therapy and intravenous immunoglobulin. Despite treatment, her symptoms progressed, leading to referral to our hospital with multiple peripheral nerve palsies and severe lumbar pain. Subsequent brain magnetic resonance imaging demonstrated gadolinium enhancement in the bilateral caudate nucleus heads and the left facial and lower cranial nerves. Stereotactic brain tumor biopsy-confirmed diffuse large B-cell lymphoma upon pathological analysis. Treatment with rituximab, high-dose methotrexate significantly improved her symptoms, with no recurrence observed for 12 months. These findings underscore the diagnosis of neurolymphomatosis involving the central nervous system, initially masquerading as Sjögren's syndrome. Neurolymphomatosis should be considered in cases of refractory Sjögren's syndrome presenting with multiple nerve palsies.
Neurolymphomatosis (NL) is defined as primary or secondary lymphoma affecting the peripheral nervous system.1) Nearly all cases of NL are non-Hodgkin lymphomas, with the most common subtype of being diffuse large B-cell lymphoma (DLBCL).1,2) Although NL may be secondary to idiopathic autoimmune diseases, the relationship between NL and primary lymphoma in the peripheral nerves remains poorly understood.1) NL is frequently misdiagnosed as polyneuropathy based on symptoms and imaging findings. In such cases, steroid pulse therapy and intravenous immunoglobulin (IVIG) may be attempted but may prove ineffective, delaying the initiation of systemic chemotherapy. Here, we report a rare case of primary NL that mimicked multiple mononeuropathies in Sjögren's syndrome (SS), diagnosed through cerebrospinal fluid (CSF) examination and a navigation-guided biopsy, and successfully treated with methotrexate-based chemotherapy.
A 79-year-old woman presented to another hospital with progressively worsening left facial paralysis and an inability to walk. She had a two-year history of dry eyes and reduced salivary secretion (xerostomia). Neurologic examination revealed left facial nerve palsy (House-Blackman grade IV), left soft palate paralysis, and hoarseness, although swallowing function was preserved. She also exhibited lower limb weakness (manual muscle testing 3/5) in the gastrocnemius, quadriceps, hamstring, and tibialis anterior muscles. Additionally, she had right-sided allodynia and dysesthesia, along with severe lumbar pain, but no deep sensory disturbance or thermal sensation disorder.
Laboratory tests showed no abnormalities in blood chemistry or complete blood count, but elevated levels of anti-SS-A antibody (>1,200 U/mL), anti-SS-B antibody (55.2 U/mL), antinuclear antibody (640×), and serum soluble interleukin-2 receptor (sIL-2R; 508 U/mL). The Schirmer test was positive, and a labial minor salivary gland biopsy revealed lymphocytic and plasma cell infiltrates, confirming a diagnosis of SS.
CSF examination revealed normal initial spinal fluid pressure (120 mm), mild protein elevation (134 mg/dL), and normal glucose levels (37 mg/dL). The CSF cell count was 72 cell/μL, with all cells being mononuclear. CSF sIL-2R levels were not measured, and CSF cytology was not performed. Thoracoabdominal plain computed tomography revealed no significant findings. Cervicothoracic magnetic resonance imaging (MRI) showed no obvious abnormalities. Brain MRI revealed high signal intensity on diffusion-weighted imaging (DWI) in the left peripheral facial nerve and lower cranial nerves (Fig. 1A-C), with no high signal intensity in other areas of the central nervous system (CNS) (Fig. 1D). Constructive interference in steady-state (CISS) MRI showed enlargement of the left lower cranial nerve in the jugular foramen (Fig. 1E). However, contrast-enhanced MRI was not performed at that time. Furthermore, lumbar spine MRI could not be conducted due to severe lumbar pain, which restricted the patient's ability to extend her lower back. Fluorodeoxyglucose positron emission tomography (FDG-PET) was also not performed. Nerve conduction studies revealed severe peripheral lower limb sensory and motor neuropathy.
A: Brain MRI before steroid pulse therapy and IVIG shows high signal intensity on DWI in the left lower cranial nerve passing through the left jugular foramen (white arrowhead). B: Brain MRI before steroid pulse therapy and IVIG shows high signal intensity on DWI in the left facial nerve peripheral to the brainstem (white arrowhead). C: Brain MRI before steroid pulse therapy and IVIG shows high signal intensity on DWI in the peripheral portion of the left lower cranial nerves (white arrowhead). D: Brain MRI before steroid pulse therapy and IVIG show no high signal intensity on DWI in the bilateral caudate nucleus or other areas of the central nervous system. E: Constructive interference in steady-state MRI shows an enlargement of the lower cranial nerve in the left jugular foramen.
DWI: diffusion-weighted imaging; IVIG: intravenous immunoglobulin; MRI: magnetic resonance imaging
Her previous neurologists treated her for multiple neuropathies secondary to SS, and she underwent 5 cycles of plasmapheresis. In addition, her prior physician started high-dose methylprednisolone (1,000 mg/day) for 3 days and IVIG (400 mg/kg/day) for 5 days, followed by a second course of steroid pulse therapy (methylprednisolone 1,000 mg/day for 3 days). Afterward, she was prescribed oral prednisolone (0.5 mg/kg/day). While lower limb motor function temporarily improved, it worsened again, and swallowing function deteriorated within 2 weeks. A second brain MRI, performed 2 months after the first, revealed a more prominent and larger high signal intensity on DWI than before steroid pulse therapy and IVIG, in the same nerve regions as previously (Fig. 2A-C), with no high-intensity lesions on DWI in other CNS areas (Fig. 2D). CISS MRI also showed increased enlargement of the lower cranial nerves in the left jugular foramen compared to the first CISS MRI (Fig. 2E).
A, B, and C: Brain MRI after steroid pulse therapy and IVIG shows much more obvious and larger high signal intensity on DWI than before steroid pulse therapy and IVIG in the same portion of the nerves before treatment (white arrowheads). D: Brain MRI after steroid pulse therapy and IVIG shows no high signal intensity on DWI in the bilateral caudate nucleus and another area of the central nervous system. E: CISS MRI shows that the lower cranial nerves in the left jugular foramen are more enlarged in comparison with the first CISS MRI.
CISS: Constructive interference in steady state; DWI: diffusion-weighted imaging; IVIG: intravenous immunoglobulin; MRI: magnetic resonance imaging
A third course of steroid pulse therapy (methylprednisolone 1,000 mg/day for 3 days) and a second course of IVIG (400 mg/kg/day for 5 days) were administered for refractory SS. However, swallowing function worsened, leading to a gastrostomy. Her symptoms progressively worsened. Four months after her first visit to her prior physician, she was transferred to our hospital with multiple peripheral nerve palsies, impaired consciousness, and severe lumbar pain.
A third brain MRI, conducted at our hospital 4 months after the first MRI, revealed high signal intensity on DWI in the head of the caudate nucleus bilaterally (Fig. 3A) and the largest and most prominent high signal intensity on DWI in the peripheral portion of the left lower cranial nerves (Fig. 3B). Additionally, brain MRI showed gadolinium (Gd) enhancement in the head of the caudate nucleus bilaterally (Fig. 3C), the left facial nerve in the internal auditory canal (Fig. 3D) and facial canal (Fig. 3E and F), and the left lower cranial nerve. Laboratory tests revealed elevated anti-SS-A antibody (597 U/mL), elevated antinuclear antibody (160x), and elevated sIL-2 (1,080 U/mL), while all other lab values were normal. CSF analysis showed normal initial spinal fluid pressure (60 mm), mild elevation in protein (97 mg/dL), mild elevation in sugar (97 mg/dL), slightly elevated cell count (38 cell/μL, all mononuclear cells), high β2-microglobulin (5,417 mg/L), high sIL-2R (426.5 U/mL), and high interleukin-10 (509 pg/mL). No malignant cells were detected in CSF cytology. These findings suggested DLBCL, and she underwent navigation-guided brain tumor biopsy. Tissue samples were taken from the left caudate nucleus. Pathological analysis revealed diffuse proliferation of large lymphoma cells (Fig. 4A), and immunohistochemistry showed that tumor cells were positive for CD20 (Fig. 4B). The Ki-67 staining index was approximately 80% (Fig. 4C). The final histopathological diagnosis was DLBCL.
A: Preoperative brain MRI shows high signal intensity on DWI in the head of the caudate nucleus bilaterally (white arrowhead). B: Preoperative MRI on DWI shows the most obvious and largest high signal intensity in the clinical course of the peripheral portion of the left lower cranial nerves (white arrowhead). C: Preoperative contrast-enhanced MRI shows gadolinium enhancement in the head of the caudate nucleus bilaterally (white arrowhead). D: Preoperative contrast-enhanced MRI shows gadolinium enhancement in the left facial nerve in the internal auditory canal (white arrowhead). E and F: Axial and coronal contrast-enhanced MRI shows gadolinium enhancement in the left facial nerve in the facial canal (white arrowhead).
DWI: diffusion-weighted imaging; MRI: magnetic resonance imaging
A: Hematoxylin and eosin-stained diffuse proliferation of large atypical cells. B: Immunostaining for CD20 is positive. C: The Ki-67 staining index was approximately 80%. Original magnification ×400 (A, B, and C). D: Lumbar axial spinal MRI shows T2/gadolinium enhancement in the right L4 nerve root (white arrowhead). E: Lumbar axial spinal MRI shows slightly high signal intensity on T1-weighted images in the right erector spinae muscle (white arrowheads).
MRI: magnetic resonance imaging
She underwent 6 cycles of R-MTX (rituximab, high-dose methotrexate), with rituximab (375 mg/kg) administered intravenously on day 1 and high-dose methotrexate (1,750 mg/kg) administered intravenously on day 2 of a 14-day cycle. After 6 cycles of R-MTX therapy, left facial nerve function improved to House Brackmann grade II. Lumbar pain also improved, and she regained the ability to extend her lower back. However, fiber laryngoscopy revealed left vocal cord paralysis, and dysphagia persisted. Brain MRI showed that the Gd-enhancing lesion in the head of the left caudate nucleus had resolved, but Gd enhancement remained in the left facial ganglion, left facial nerve in the facial canal, and left lower cranial nerve. Lumbar spinal MRI revealed Gd enhancement in the right L4 nerve root and slightly increased signal intensity on T-weighted images in the right erector spinae muscle (Fig. 4D and E). These findings suggested the presence of NL in the right L4 nerve root and fatty degeneration of the right erector spinae muscle due to damage to the right L4 nerve root. She has shown no evidence of recurrence for 12 months. Based on these findings, we diagnosed primary NL invading the CNS, rather than refractory SS.
This case was initially diagnosed as multiple mononeuropathies of the facial and lower cranial nerve secondary to SS. However, based on the response to R-MTX treatment rather than steroid pulse therapy and IVIG, we believe this case to be a primary NL invading the CNS, which mimicked SS neuropathy. Baehring et al.1) reported CNS complications in 26% of NL cases, many of which were diagnosed concurrently with NL. Similarly, a report documented primary NL of the trigeminal nerve invading the CNS, with DLBCL diagnosed through a biopsy of an intracranial lesion.3)
On MRI, DWI is widely recognized as useful in diagnosing primary CNS lymphoma (PCNSL).4,5) In this case, intracranial contrast-enhanced MRI was not performed during the initial presentation of peripheral neurological symptoms. However, the right facial and lower cranial nerves showed high signal intensity on DWI, with no intracranial lesions displaying high signal intensity prior to steroid pulse therapy and IVIG. This supports the hypothesis that primary NL invaded the CNS during the disease course.
NL is rarely localized to a single nerve. In cranial nerve NL, involvement of the trigeminal nerves is more common than the facial nerve, as seen in our patient.1-3) We could not find any reports of dysphagia due to NL invading the lower cranial nerves, as in this case. For spinal nerves, the sciatic nerve is more commonly involved than other nerves, as it is relatively thick and long.1,6) However, there have been reports of NL invading the lumbosacral nerves, where patients experienced dyskinesia and pain in the lower limbs, as in this case.1,6)
NL tends to present as multiple mononeuropathies, making it difficult to differentiate from inflammatory neuropathy, sarcoid neuropathy, and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).2) As in this case, treatment with steroids may lead to temporary improvement, but there is a risk of early re-exacerbation. While distinguishing NL from neuropathies associated with the aforementioned diseases is challenging, an association between NL and autoimmune diseases has been suggested, including CIDP, Guillain-Barré syndrome, and SS.1,7,8) In SS patients, polyclonal lymphocytic infiltration of the salivary and lacrimal glands leads to chronic antigen stimulation, which then evolves into monoclonal lymphocytic proliferation, mucosa-associated lymphoid tissue lymphoma, and eventually DLBCL in other organs.9-11) Epidemiological data linking SS and NL may emerge as more cases are documented.
In this case, brain MRI showed Gd enhancement in the head of the caudate nucleus bilaterally and in the left facial and lower cranial nerves. We biopsied an intracranial lesion rather than a peripheral nerve to ensure a safer and easier procedure from the left caudate nucleus. However, a limitation of this case was the inability to perform an accurate diagnosis of NL via direct peripheral nerve biopsy. Several reports have indicated that 70-80% of NL cases show Gd enhancement and nerve swelling, although these findings are not specific to NL and may resemble those of various inflammatory diseases. The sensitivity of MRI for diagnosing NL is relatively low (about 40%).1,12) The diagnostic sensitivity of direct nerve biopsy for NL is estimated at 80%, but depending on the location, obtaining a sufficient specimen volume for diagnosis can be challenging.1,12,13) Some studies suggest that if PCNSL has been diagnosed by intracranial biopsy, a peripheral nerve biopsy may not be necessary to diagnose NL, and early treatment initiation can improve prognosis.1)
Additionally, FDG-PET, which was not performed in this case, could be a valuable diagnostic tool for patients with suspected NL when other diagnostic methods are inconclusive. Recent reports have shown that FDG-PET scans for NL diagnosis have a sensitivity of 89%-100% and a specificity of 72%-95%.1,12,14,15) However, FDG-PET also accumulates in neuroinflammatory lesions, making it difficult to distinguish NL from neuroinflammation.16) FDG-PET may be useful not only in diagnosing NL, but also in selecting the target for peripheral nerve biopsy and assessing treatment efficacy.
In this case, repeated steroid pulse therapy and IVIG were ineffective. After the diagnosis of NL, treatment with R-MTX was performed, resulting in a marked improvement in the patient's neurological symptoms. The effectiveness of this treatment suggests that this case is more likely to be primary NL rather than severe peripheral neuropathy in SS. Several reports have shown a significant response of NL to R-MTX or R-MPV (rituximab, methotrexate, procarbazine, and vincristine), while other reports have indicated that R-MTX or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with intrathecal methotrexate or radiotherapy was less effective.1,12,14) Therefore, the optimal treatment for NL has not yet been established. Some reports have suggested that the median survival for patients with primary NL is 20 months, compared to 8 months for those with secondary NL, while other reports have indicated shorter survival outcomes.12-14)
ConclusionNL should be suspected in cases of refractory SS presenting with multiple nerve palsies. Although NL has a poor prognosis, establishing an early and reliable diagnosis may improve outcomes.
The authors would like to thank ThinkSCIENCE, Ltd. (https://www.thinkscience.co.jp) for their English language editing.
The necessary patient informed consent was obtained in this study.
All authors have no conflict of interest.
