Lumbosacral plexopathy associated with monoclonal gammopathy of clinical (neurological) significance

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Introduction

Lumbosacral plexopathy (LSP) is a peripheral nervous system disorder characterized by damage to the lumbar and/or sacral plexuses, manifesting as asymmetric limb weakness, reduced or absent knee and/or Achilles reflexes, sensory disturbances, and neuropathic pain in the innervation areas of the affected segments [1–3]. The clinical presentation is heterogeneous and depends on the involvement of specific lumbosacral plexus branches [2, 3]. In lumbar plexopathy involving L1–L4, sensory disturbances and pain are localized to the anterolateral and medial thigh, whereas weakness affects the quadriceps femoris, hip flexors, and hip adductors, with the knee reflex being diminished or absent. In sacral plexopathy involving L5–S1, motor and sensory deficits affect the posterior thigh, lower leg, and foot, and the Achilles reflex is absent. In total or subtotal LSP involvement, the symptoms overlap. The most common cause of LSP is diabetes mellitus. The incidence of diabetes-associated LSP is reported to be 4.2 per 100,000 person-years, and it is diagnosed in 0.8% of diabetes patients [1, 4]. Other causes of LSP include immune-mediated and neoplastic processes, high-dose radiation therapy, pelvic trauma, and compression due to retroperitoneal hematomas, abscesses, and space-occupying lesions, among others [5–10].

Monoclonal gammopathy (MG) of undetermined or clinical significance, as well as MG in the context of lymphoproliferative disease (LPD), is most often accompanied by symmetric motor and sensory polyneuritic disorders, classified as paraproteinemic demyelinating polyneuropathies (PDP) [11–14]. PDP have been well studied to date, and diagnostic criteria for this group of chronic dysimmune neuropathies have been developed [15]. However, in clinical practice, other neurological manifestations of MG are encountered, including LSP. The Center for Peripheral Nervous System Diseases of the Russian Center of Neurology and Neurosciences (RCNN) has accumulated experience in diagnosing such conditions.

The aim of the publication is to demonstrate a case series of LSP associated with MG of clinical and undetermined significance (MGUS).

Clinical case 1

Patient A., a 35-year-old male with no significant medical history, first presented to RCNN in May 2020 with complaints of progressive asymmetric weakness and muscle wasting in the limbs, and gait disturbance, which had been worsening over the preceding 6 months. On examination, lower flaccid distal asymmetric paraparesis (in the foot extensors: right side to 1 point, left side to 0 points; in the foot flexors to 2 points bilaterally) with gait disturbance (bilateral steppage gait, walking without support) were found, as well as asymmetric hypotrophy of the muscles of the lower third of the thighs, shins, and feet, absence of knee and Achilles tendon reflexes. There were no sensory disturbances. Lumbosacral spine MRI ruled out vertebrogenic causes of the neurological disorders and revealed a space-occupying lesion of the right iliac bone of unclear origin. Electroneuromyography was performed to rule involvement of peripheral motor neurons and polyneuritic changes. Clinical and neurophysiological established the diagnosis of bilateral LSP. There was no obvious cause for such a contellation of neurological symptoms in a young patient. As part of the differential workup, serum protein electrophoresis with immunofixation was recommended for the first time, which revealed paraproteinemia IgA-lambda (6.2 g/L). The patient was consulted at the National Medical Research Center for Hematology. The examination findings allowed diagnosing multiple myeloma, presenting with secretion of IgA-lambda, a space-occupying lesion of the right iliac bone, and involvement of the peripheral nervous system. Polychemotherapy and radiation therapy were administered, resulting in remission.

Patient A. returned to RCNN for follow-up in 2021, 2022, and 2023. Given the stabilization of the underlying disease and the slow regression of neurological symptoms, it was decided to refrain from additional immunomodulatory therapy; continued follow-up with an hematologic oncologist and rehabilitation were recommended.

Thus, this clinical case demonstrates the potential LPD onset (multiple myeloma) manifesting as bilateral LSP in the absence of other clinical and laboratory manifestations. This led the patient to seek initial medical care from a neurologist. Timely identification of the neurological disorder cause resulted in the prompt initiation of pathogenetic therapy with subsequent regression and stabilization of the main symptoms.

Clinical case 2

Patient M., 66 years old, first presented to RCNN in July 2024 with complaints of progressive asymmetric (D > S) weakness and numbness in the limbs, as well as gait impairment. The onset of neurological symptoms was noted in the autumn of 2023, with slow progression over time. The patient was referred with a diagnosis of idiopathic polyneuropathy (PNP). Prior to the visit to the RCNN, at the patient’s local residence, dysimmune, deficiency, infectious, paraneoplastic, and toxic etiologies of peripheral nervous system involvement had been ruled out; transthyretin familial amyloid PNP was also excluded. Serum protein electrophoresis with immunofixation was performed before the visit to the RCNN, and the results revealed a trace secretion of IgM-kappa paraprotein; however, these findings were overlooked. Neurological examination revealed lower asymmetric distal flaccid paraparesis D > S (in the flexor and extensor muscles of the feet up to 1 point) with gait impairment (bilateral steppage, ataxia, walking with support, wearing ankle-foot orthoses); a positive Trendelenburg sign on the right; hypotrophy of the leg and foot muscles; hyperactive knee tendon reflexes (L2–L4) and absent Achilles reflexes; polysegmental sensory impairment in the limbs and severe sensory ataxia. During the clinical and neurophysiological examination, the diagnosis was revised, and bilateral LSP was confirmed. Additionally, an MRI of lumbosacral plexus was performed, which revealed increased MR signal intensity from the anterior branches of the right L5 and S1 spinal nerves, and T1-weighted coronal images showed intense enhancement of the cauda equina roots and the anterior branch of the right L5 spinal nerve (see Fig. 1).

 

Fig. 1. Lumbosacral plexus MRI of patient 2. T2-weighted sagittal images show a tortuous pattern and mild thickening of the cauda equina roots. STIR coronal images reveal a mild increase in MR signal intensity from the anterior branches of the right L5 and S1 spinal nerves (arrows). Post-contrast T1-weighted coronal images demonstrate intense enhancement of the cauda equina roots and the anterior branch of the right L5 spinal nerve (arrows). Figure and description provided by S.N. Morozova, Cand. Sci. (Med.), an employee of the Department of Radiology, RCNN.

 

The patient was first referred for consultation with an hematologic oncologist. Examination findings at the National Medical Research Center for Hematology showed no evidence of LPD, and a diagnosis of monoclonal gammopathy of clinical significance was established; therapy with rituximab was recommended. During the follow up at the RCNN in November 2024, immunomodulatory therapy was recommended according to the following regimen: Stage 1 — high-volume plasmapheresis with total plasma removal of at least 6 L; Stage 2 — administration of rituximab at a dose of 750 mg once weekly for 4 doses; upon completion — restorative and rehabilitative treatment.

Following therapy, at the examination in November 2025, clear improvement was observed: a mild increase in strength in the lower extremities and significant improvement in stability (near-complete regression of sensory ataxia). It was recommended to continue restorative therapy, and the need for an additional course of immunomodulatory therapy should be considered over time.

This case demonstrates the importance of laboratory testing for MG (serum protein electrophoresis with immunofixation) in patients with polyneuropathy or bilateral plexopathy. Even trace secretion may have clinical significance and requires verification by an hematologic oncologist. Immunosuppressive therapy, justified by the high probability of a link between the secretion of pathological protein and progressive disabling neurological symptoms, resulted in an improved patient’s condition.

Clinical case 3

Patient A., a 62-year-old female, first presented to RCNN in November 2022 with complaints of weakness in the right leg, difficulty walking, and asymmetric (D > S) numbness in the limbs. The onset of neurological symptoms was noted in 2019; over the course of 3 years, she was followed up with a diagnosis of drug-induced peripheral neuropathy and right sciatic neuropathy. Neurological examination revealed lower distal asymmetric flaccid paraparesis D > S (in the hip extensors and knee flexors on the right, up to 3.5–4.0 points; in the foot and toe extensors on the right/left, up to 2 and 4 points, respectively; in the foot and toe flexors on the right/left, up to 2 and 3 points, respectively) with gait impairment; hypotrophy and hypotonia of the thigh and foot muscles; reduced knee reflexes and absent Achilles tendon reflexes; sensory ataxia and a polysegmental pattern of sensory disturbances in the L4–L5–S1 dermatomes. Based on the results of clinical and neurophysiological examination at the RCNN, a primary bilateral, asymmetric D > S lesion of the lumbosacral plexus was first suspected. Further diagnostic follow-up was recommended.

MRI of lumbosacarl plexus revealed right-sided lumbar plexopathy (L5–S1): at the L5–S1 level, the nerve roots and trunks were thickened (up to 6–7 mm), more pronounced on the right, with slightly increased signal intensity from the right roots and the subsequent nerve trunk at this level compared to the contralateral side on T2 and T2 fat-saturated sequences. After contrast administration, more intense homogeneous enhancement of the roots and nerve trunk at the L5–S1 level was observed. Serum protein electrophoresis with immunofixation revealed IgM-kappa paraproteinemia with a secretion level of 5.4 g/L. Oncological screening revealed no abnormalities; consultation with a hematologic oncologist at the patient’s place of residence showed no evidence of LPD.

Based on all the data, the diagnosis was confirmed: progressive bilateral lumbosacral plexopathy, right > left (4-year follow-up), associated with monoclonal IgM-kappa secretion (monoclonal gammopathy of clinical significance), asymmetric lower flaccid distal paraparesis. As the first step, glucocorticosteroid (GCS) therapy was initiated on an alternating regimen of 48/24 mg for 1 month, during which a positive trend was observed withincreased strength in the foot extensors. However, the patient subjectively reported worsening of symptoms, and GCS side effects were also observed. During the follow-up at the RCNNin August 2023, with a reduction in the GCS dose, ambiguous changes were noted: on one hand, increased strength in some muscle groups; on the other, worsening sensory disturbances and instability when walking, leading to a recommendation for high-dose intravenous immunoglobulin (IVIG) at a total dose of 2 g per 1 kg of body weight, which stabilized the condition. At the same time, it was decided to repeat the consultation and examination with a hematologic oncologist at a specialized center. In March 2024, at the National Medical Research Center for Hematology, after further evaluation, the patient was diagnosed with Waldenström’s macroglobulinemia. Comination chemotherapy (rituximab + bendamustine) was recommended. The patient continues follow-up with a hematologic oncologist and remains neurologically stable.

In the presented case, the clinical pattern revealed pronounced asymmetry of leg weakness, which initially led to a diagnosis of sciatic mononeuropathy. Comprehensive clinical and instrumental evaluation prompted revision of the suspected level of involvement and lead to a diagnosis of bilateral asymmetric LSP. Following a differential diagnostic algorithm for the LSP causes revealed monoclonal secretion in the absence of other hematologic manifestations. Initial therapy based on the diagnosis of monoclonal gammopathy of clinical significance did not result in clear improvement, providing further justification for re-evaluation by a hematologic oncologist, ultimately resulting in a revised diagnosis of LPD. This, in turn, fundamentally altered the treatment approach and enabled stabilization of the patient’s neurological status.

Clinical case 4

Patient M., a 55-year-old woman, initially presented to the RCNN in the summer of 2022 with complaints of clumsiness in the left leg, gait disturbance, and burning sensation in the feet. Her medical history demonstrated that in December 2008, during evaluation as a bone marrow donor, the patient was found to have monoclonal IgG-kappa secretion (5.9 g/L), and a diagnosis of MGUS was established. In subsequent years follow-up was maintained, and serial immunochemical analyses showed a gradual increase in secretion levels to 13.8 g/L. In 2014, a follow-up hematological examination was performed, which revealed no evidence of LPD. During further studies, the level of monoclonal secretion gradually increased, reaching 19.7 g/L by 2020, when the patient first noted the above complaints. Before referral to the RCNN, the following examinations were performed:

• Brain MRI (2022): mild replacement hydrocephalus, single vascular foci;
• MRI of the cervical, thoracic, and lumbosacral spine (2022): degenerative-dystrophic changes, mild stenosis at C4–C6, herniated intervertebral discs at L3–S1 without signs of neural compression.

Thus, at the patient’s place of residence, a vertebrogenic origin of the neurological disorders was ruled out, and the patient was referred to the RCNN with a diagnosis of polyneuropathy of unspecified origin.

Neurological examination revealed lower asymmetric paraparesis: on the right — paresis of the flexor muscles of the foot and toes to 4 points (on the right, difficulty standing on tiptoe), on the left — paresis of the extensor and flexor muscles of the foot and toes to 3 points (on the left, difficulty standing on the heel, unable to stand on tiptoe); hypotrophy of the thigh, leg, and foot muscles on the left, steppage gait on the left during walking, diffuse reduction of tendon reflexes (knee D > S, Achilles — absent); polysegmental sensory disturbance in the limbs.

Based on clinical data from the initial examination, a diagnosis of bilateral asymmetric LSP was established. Given the absence of other causes for neurological impairments, a relationship between monoclonal secretion and progressive neurological symptoms was first hypothesized. A repeat consultation with hematologic oncologist was recommended for further evaluation and revision of the primary diagnosis (probable transformation of MGUS into LPD). Additional laboratory testing was performed for the hematological profile:

• immunochemical study of serum proteins: IgG-kappa secretion — 25.6 g/L;
• vascular endothelial growth factor level — 340.2 pg/mL (reference range 0–691 IU/mL);
• myelogram — 3.6% plasma cells; immunophenotyping of bone marrow cells: 1.40% plasma cells with aberrant immunophenotype of CD38⁺CD138⁺CD319⁺CD19^–CD45^–CD56highCD27^–/+CD81^–CD20^–CD269^–/+;
• histology of bone marrow trephine biopsy: pronounced focal-interstitial inter- and paratrabecular infiltration by mature plasma cells.

Additional instrumental examinations were also performed:

• electroneurography of peripheral nerves and electromyography of limb muscles: neurophysiological signs of the proximal segments L2–L3–L4 < L5–S1 involved on the left; no neurophysiological evidence of peripheral motor neuron damage at the examined segmental levels; the conduction in the examined long nerves of the left leg in the distal segments was not impaired;
• PET–CT: a metabolically active osteolytic lesion measuring 12 × 6 mm with cortical thinning was detected in the manubrium of the sternum;
• whole-body MRI: evidence of diffuse focal bone marrow infiltration of the skeletal bones with focal lesions in the L1 vertebral body and the manubrium of the sternum.

In March 2023, based on the examination at the National Medical Research Center for Hematology, the following diagnosis was established: Multiple myeloma, transformation from MGUS, with secretion of IgG-kappa, widespread osteodestructive process; high cytogenetic risk; stage IIA according to Durie–Salmon. Starting in April 2023, courses of combination chemotherapy (bortezomib, cyclophosphamide, dexamethasone) were administered, achieving a very good partial response (trace paraprotein secretion). In September 2023, autologous stem cell transplantation was performed. In April 2024, maintenance therapy with lenalidomide (15 mg on days 1–21) was initiated; after 2 courses, complete remission was achieved.

Despite stabilization of the underlying disease, the patient’s neurological symptoms worsened: weakness in the left limb increased, and a burning sensation appeared in the feet. During a repeat consultation at the RCNN in February 2024, given the worseniong neurological status, it was recommended to discuss with the hematologic oncologist the administration of IVIG. In March 2024, at the patient’s place of residence, IVIG was administered at a total course dose of 2 g per 1 kg of body weight, followed by 5 repeat courses of IVIG at a total course dose of 1 g/kg of body weight once a month. During this period, the patient’s condition remained stable, and the effect of IVIG was assessed as satisfactory.

On a follow-up immunochemical study of serum proteins in September 2024, no monoclonal secretion was detected; the hematologic oncologist recommended continuing maintenance therapy with lenalidomide. For her neurological deficit, the patient continues to receive maintenance IVIG every 8 weeks, at a total course dose of 1 g/kg body weight; she is followed at the RCNN with the diagnosis: Chronic bilateral asymmetric LSP on the right < left (follow-up 4 years), associated with LPD (multiple myeloma, IgG-kappa paraproteinemia), stabilized on maintenance IVIG; lower flaccid distal asymmetric paraparesis with impaired gait function; concomitant chemotherapy-induced symmetric sensory painful polyneuropathy; cramp syndrome.

This clinical case demonstrates the transformation of MGUS, which debuted in 2008, into monoclonal gammopathy of clinical (neurological) significance with bilateral asymmetric LSP after 12 years. The latter progressed alongside an increase in paraprotein secretion levels, in the absence of immunosuppressive therapy. After 3 years, LPD (multiple myeloma) was diagnosed. Combination chemotherapy did not fully manage the neurological symptoms. Adding IVIG to the treatment course led to stabilization of the condition.

Thus, patients with bilateral asymmetric LSP in the context of clinically significant MG (Case2) and LPD (Cases 1, 3, and 4) are currently under follow-up at the RCNN.

Discussion

Despite a large body of literature on the diagnosis and management of patients with PDPs associated with MGUS and LPD, paraproteinemic LSP has been described only in isolated reports and represents an atypical pattern of peripheral nervous system involvement in monoclonal secretion [16–21].

R. Gadot et al. described a clinical case of paraproteinemic LSP in a 59-year-old female patient with stage 3 multiple myeloma accompanied by IgG-lambda secretion [18]. Neurological examination revealed lower flaccid paraparesis with symmetric proximal and asymmetric distal weakness in the lower extremities, bilateral asymmetric hypotrophy of the thigh and leg muscles, areflexia, and a polyneuritic type of sensory disturbances in the limbs. Based on clinical, neurophysiological, and neuroimaging findings, the patient was diagnosed with paraproteinemic asymmetric (L2–S1 on the right, L5–S1 on the left) LSP. The patient improved after high-volume plasmapheresis.

L. Cerrahoglu et al. described a case of LPD with idiopathic brachial plexopathy. A 59-year-old patient presented with clinical, historical, and paraclinical findings characteristic of neuralgic amyotrophy (Parsonage–Turner syndrome). Examination revealed anemia, hypercalcemia, laboratory signs of renal failure, and radiographic evidence of an extensive osteolytic lesion of the humerus. Serum protein electrophoresis with immunofixation detected IgG-kappa secretion [19]. Cases of neuralgic amyotrophy have also been described by other authors in patients with an already established diagnosis of POEMS syndrome [20].

Additionally, several reports include clinical cases of malignant infiltration of plexus trunks and peripheral nerves by plasma cells in patients with multiple myeloma [16, 17, 21].

We present for the first time a case series of bilateral asymmetric LSP occurring in the context of monoclonal secretion. A similar clinical pattern may be seen in length-independent small fiber neuropathy-ganglionopathy, but the latter is not characterized by clinical and neurophysiological signs of involvement of thick myelinated motor and sensory fibers [22–24], as well as multiple mononeuropathy. As has been shown, bilateral asymmetric LSP is often misdiagnosed by neurologists as PNP. In the vast majority of cases, PNP is symmetric in nature. Therefore, asymmetric symptoms should alert physicians to a different level of peripheral nervous system involvement.

The potential of neurophysiological examination in LSP is significantly limited. At this level of lesion, electroneuromyography is performed primarily for differential diagnostic purposes and to exclude other phenotypically similar diseases (motor neuron disease, multiple mononeuropathy, PNP, radiculopathy, etc.). The leading instrumental method for assessing lumboscaral plexus structures and verifying LSP is MRI (see Fig. 1). According to international criteria, the study should be performed in orthogonal projections through oblique planes of the plexus (in sagittal, coronal, and axial planes) using T1-weighted, T2-weighted, T2-weighted fat-suppressed sequences or short tau inversion recovery sequences, and may include post-contrast T1-weighted sequences, with T2-weighted images being of particular interest. In plexopathy, thickening of the roots, increased signal intensity on T2-weighted and T2 fat-saturated sequences, and contrast enhancement are detected [25]. The high cost and low availability of the study limit its widespread use.

As in paraproteinemic demyelinating polyneuropathies, an immune-mediated pathogenesis is presumed for the development of LSP in MGUS of clinical significance and LPD. In this regard, despite the absence of generally accepted management recommendations for this category of patients, immunosuppressive and/or immunomodulatory therapy is recommended, which can stabilize the condition and, in some cases, lead to clinical improvement.

However, the most important finding in the analysis of this case series is that it is the responsibility of the neurologist to conduct a differential diagnosis of these conditions with hematologic causes, since patients initially present to neurologist. The only reliable diagnostic tool is serum protein electrophoresis with immunofixation, and the detection of even trace secretion is a warning sign that warrants referral of the patient to an hematologic oncologist for a complete examination. In 3 out of 4 cases, the cause of LSP was LPD (multiple myeloma, Waldenström’s macroglobulinemia), and in one patient, transformation from MGUS through MG of clinical (neurological) significance to LPD was demonstrated.

Conclusion

One possible cause of bilateral progressive asymmetric LSP is MG of clinical (neurologic) significance, including within the framework of LPD. Establishing the precise diagnosis can lead to improvement of neurologic status with subsequent stabiliztion of the patient’s condition.

About the authors

Anna M. Narbut

Russian Center of Neurology and Neurosciences

Author for correspondence.
Email: narbut.anna.m@gmail.com
ORCID iD: 0000-0003-2026-5199

neurologist, functional diagnostics physician, Center for peripheral nervous system diseases, Institute of Clinical and Preventive Neurology

Russian Federation, Moscow

Daria A. Grishinа

Russian Center of Neurology and Neurosciences

Email: shevchuk.d.v@neurology.ru
ORCID iD: 0000-0002-7924-3405

D. Sci. (Med.), Head, Center for peripheral nervous system diseases, Institute of Clinical and Preventive Neurology

Russian Federation, Moscow

Natalia A. Suponeva

Russian Center of Neurology and Neurosciences

Email: slotina@neurology.ru
ORCID iD: 0000-0003-3956-6362

Dr. Sci. (Med.), Corr. Member of RAS, Director, Institute of Neurorehabilitation

Russian Federation, Moscow

Alexander E. Grachev

National Medical Research Center for Hematology

Email: gra4al@yandex.ru
ORCID iD: 0000-0003-4950-523X

Cand. Sci. (Med.), hematologist, Department of chemotherapy of hematological diseases

Russian Federation, Moscow

References

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