Successful Treatment of Multifocal Demyelinating Sensory-Motor Neuropathy (Lewis-Sumner Syndrome) With Rituximab: A Case Report

Introduction

Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), also known as Lewis-Sumner syndrome (LSS) [1], is recognized as a variant of chronic inflammatory demyelinating polyneuropathy (CIDP) [2]. CIDP is a rare disease with prevalence rates that vary across different geographical regions [3], ranging from 0.67 to 10.3 per 100 000 people [4], with asymmetric variants comprising 8% to 15% of CIDP patients [4]. MADSAM is primarily characterized by multifocal sensory loss and muscle weakness, which are often asymmetrical and predominantly affect the upper limbs, while lower-limb involvement is less common [5]. Most MADSAM cases exbibit a chronic progressive course, while the remaining cases demonstrate a relapsing-remitting pattern. Approximately 17.3% of patients experience cranial nerve involvement, with the oculomotor, trigeminal, facial, vagus, and hypoglossal nerves being more frequently affected than in other CIDP forms [2,5]. Unilateral vocal cord paralysis and laryngeal muscle tremors are also noted as rare manifestations of MADSAM [6]. Due to the rarity and diverse manifestations of this disease, diagnosis can be challenging in some cases, often resulting in significant delays in treatment. In this report, we present a case of MADSAM in which the lower limbs were primarily affected, accompanied by successive involvement of the facial and hypoglossal nerves.

Case Report

A 27-year-old woman was admitted on December 28, 2022, presenting with “repeated numbness and weakness in the left lower limb for 3 years, recurrent for over 3 months”. At the end of 2019, she experienced numbness and weakness in the left lower limb, accompanied by facial paralysis. These symptoms improved following treatment with corticosteroids and rehabilitation therapy at another facility. In March 2022, she had a recurrence of numbness and weakness in the left lower limb, along with an abnormal gait and reduced grip strength in her left hand. This condition improved after a short-term outpatient oral steroid treatment. In August 2022, she had a third episode, characterized predominantly by weakness in the left lower limb, numbness in the left foot, and an abnormal walking posture. No abnormal signals were observed in the head MRI, cervical MRI, thoracic MRI, or lumbar MRI. Her symptoms progressively worsened, resulting in difficulties in walking, numbness in the left foot ascending to the knee, hypersensitivity to temperature perception, and abnormal sweating. Concurrently, she reported pain in her lower limbs. She presented at our hospital in December 2022. Throughout the course of the illness, she did not experience fever, bowel or bladder dysfunction, or cognitive dysfunction. Her medical history included thyroid nodules, with no family history of similar diseases. Her growth and development history were normal, and her menstrual cycles were regular.

Upon admission, the physical examination identified an abnormal gait characterized with foot drop, atrophy of the tongue muscles, and a leftward deviation of the tongue. Vision acuity was normal. Muscle strength in the right limbs was assessed at 5/5, whereas in the left upper limb, proximal muscle strength was 4/5 and distal strength was 3/5. In the left lower limb, proximal muscle strength was recorded at 3–/5, and distal strength was 0. Both superficial and deep sensation were diminished in the left lower limb. Decreased muscle tone was observed in the left limbs, accompanied by reduced tendon reflexes. Neither meningeal signs nor Brudzinski’s sign were observed. The Inflammatory Neuropathy Cause and Treatment Disability Score (INCAT) was 4. The Medical Research Council Muscle Strength Score (MRC) was 45, and the Inflammatory Rasch-built Overall Disability Scale (I-RODS) was 23 (Figure 1).

Following admission, serological assessments, including complete blood count, blood biochemistry, folic acid, vitamin B12, rheumatology panel, ANCA, rheumatoid factor, and M-proteins, revealed no abnormalities. The lumbar puncture pressure was within normal limits, and the cerebrospinal fluid (CSF) analysis, encompassing routine examination, biochemistry, immunology, and IgG index, was unremarkable. The total protein in the CSF was 226 mg/L, which falls within the normal range of 150–450 mg/L, and oligoclonal bands (OB) were absent. Both serum and CSF anti-ganglioside antibodies (including those related to autoimmune nodopathy), anti-myelin antibodies, and anti-oncological antibodies were tested negative. The electrocardiogram indicated a heart rate of 109 beats per minute. Tumor screening was normal yielded normal results. A subsequent MRI of the head and neck revealed no abnormalities, with negative findings in the enhancement head MRI, SWI, and thoracic MRI. Nerve conduction studies (NCS) indicated demyelination of the motor and sensory nerves in the left lower limb, as evidenced by delayed distal motor latency (DML) and reduced motor nerve conduction velocity (MCV) in the left tibial nerve and peroneal nerve, while the compound muscle action potential (CMAP) amplitude remained normal (Figure 2A, 2B). F-waves results were normal. However, the sensory nerve conduction velocity (SCV) of the left superficial peroneal nerve and sural nerve was reduced, while the sensory nerve action potential amplitude (SNAP) remained within the normal limits (Figure 2C, 2D). Despite mild weakness in the distal left upper limb, no abnormalities were defected in the nerve conduction of the left upper limb at this time. Nerve conduction in both the right upper and lower limbs was within normal parameters. Lumbosacral plexus MRI (Figure 3) revealed a small area of high signal intensity on T2-weighted MRI sequences in the left L5 nerve root exit zone. MRI of the lower-limb nerves showed no significant abnormalities in the bilateral sciatic nerves, tibial nerves, and peroneal nerves. Based on the multiple sensory and motor nerve demyelination changes in the lower limbs and hypoglossal nerve involvement, along with a history of left facial palsy, the diagnosis considered was multifocal sensory and motor neuropathy.

As the patient’s CSF and serological tests showed no abnormalities, the etiology of the condition remained unclear. However, given her history of recurrent-relieving episodes and reliance on corticosteroid treatment, an immune-mediated etiology was considered. Subsequently, immunotherapy with oral corticosteroids (0.75 mg/kg) and tacrolimus (3 mg/d) was initiated, and she was discharged.

She returned 2 months later with exacerbated symptoms. At this time, NCS studies revealed demyelinated lesions also present in the sensory nerves of the right lower limb (Figure 4). A subsequent biopsy of left sural nerve showed a mild reduction in myelinated nerve fibers within the nerve bundles, with demyelination changes and axonal degeneration. Some axons had slightly increased diameters, with the formation of medullary globules. No obvious onion bulb-like changes were observed (Figure 5). Therefore, multifocal acquired demyelinating sensory-motor neuropathy (MADSAM) was ultimately considered. The immunotherapy was continued. She was followed up monthly, and her symptoms gradually improved. After nearly 6 months of immunotherapy (at the 42nd month of the disease), she underwent a follow-up NCS. Aside from the left sural nerve showing a slowed SCV and reduced SNAP due to the biopsy, all other NCS results returned to normal. Concurrently, her clinical symptoms also significantly improved. The dosage of corticosteroids was tapered to 10 mg/d, and tacrolimus treatment was continued for maintenance.

Her fourth relapse occurred in August 2023 (44 months into the disease), with worsening weakness in the left upper limb, difficulty holding objects, trouble climbing stairs, and difficulty standing after squatting. The INCAT score was 4 points, and the MRC score was 41 points (Figure 1). Subsequently, a high-dose pulse corticosteroid treatment (1g/d for 5 days, then gradually tapered to an oral dosage) was administered. Following this, the limb weakness symptoms improved, and the involvement of the hypoglossal nerve showed signs of recovery, as evidenced by a centered tongue position. In light of previous reports indicating the limited efficacy of immunoglobulin for MADSAM and the patient’ reluctance to use it, the B-cell depleting agent rituximab (RTX, 200 mg, first injection) was subsequently employed to manage the disease. The CD19 B-cell count was consistently monitored during treatment, with therapy resuming when the count exceeded 10/μL.

Over the subsequent 1-year follow-up, the patient’s symptoms showed continuous improvement without any recurrence. She discontinued corticosteroid therapy in July 2024 and commenced RTX maintenance treatment (300 mg, second injection). By September 2024 (the 45th month of the disease course), she had slight weakness in the distal upper limbs, along with mild limitations in stair climbing and squatting. The INCAT score was 2 points, and the MRC score was 52 points (Figure 1). Follow-up MRI of the left lower limb continued to show swelling and thickening of the left sciatic nerve, tibial nerve, and common peroneal nerve (Figure 6), necessitating ongoing immunotherapy (RTX, 300 mg, third injection) and treatment follow-up.

Discussion

The primary characteristic of this case was multifocal peripheral nerve damage amid relapsing remission, with simultaneous involvement of both the left upper and lower limbs, predominantly affecting the lower limbs. This was successively accompanied by involvement of the facial nerve and hypoglossal nerve, along with pain and autonomic dysfunction. As the condition progresses, electromyography and imaging reveal gradual involvement of both lower limbs. Corticosteroid treatment was effective but followed a dosage-dependent pattern. In this case, RTX also demonstrated efficacy.

Differential diagnosis of multifocal mononeuropathy is challenging. In young women, vasculitis should be initially considered. However, our patient had no history of systemic disease, and laboratory tests yielded no positive findings. Additionally, the demyelinating features observed in NCS and sural nerve biopsy sharply contrast with the significant axonal degeneration characteristic of vasculitic mononeuritis, rendering a diagnosis of vasculitis less likely. Furthermore, given the patient’s prominent sensory symptoms and electrophysiological evidence of sensory demyelinating damage, multifocal motor neuropathy was readily excluded. Hereditary neuropathy with liability to pressure palsies (HNPP) often presents with a family history, and the most frequently affected nerves are those crossing common sites of trauma or entrapment. The peripheral myelin protein-22 (PMP22) gene testing can assist in differentiation in most cases [7]. Another condition to consider is spinal muscular atrophy. However, in this case, the patient primarily presented with lower-limb involvement along with sensory-motor demyelinating damage, making this diagnosis unlikely.

Our patient had a 38-month delay in diagnosis, primarily due to the condition’s insidious onset, atypical early symptoms, and its characteristic pattern of relapse and remission. The first 2 relapses briefly responded to steroid treatment, resulting in oversight by both the patient and doctors. Additionally, the rarity of this disease and insufficient recognition contributed to the delay. Diagnostic delays are common in patients with CIDP, with an average delay of 21.3 months (ranging from 2 to 132 months), primarily due to misdiagnosis (68.3%) [8,9].

In most reported MADSAM cases initially presenting with an asymmetric pure upper-limb form, lower-limb involvement is less common. A review of 38 cases revealed that most (85.7%) eventually exhibited progressive transition and spread to initially unaffected limbs, manifesting as asymmetric lower-limb or mixed, simultaneous upper- and lower-limb onset. Furthermore, patients with lower-limb involvement are more prone to spreading to other limbs compared to those with upper-limb involvement [5]. Although our case primarily presented with symptoms in the left lower limb, the progression of the disease, as evidenced by electrophysiological studies and MRI of the lower-limb nerves, indicated lesions extending to the contralateral leg. The transition from atypical CIDP, including MADSAM, to classic CIDP is not uncommon, although the average conversion time is relatively long. Within 5 years, 36% of MADSAM cases had progressed to typical CIDP; this figure increased to 63% at 10 years [10]. Cranial involvement was observed in 27.8% of MADSAM cases [5]. A recent CIDP nationwide survey conducted in Japan [11] noted that cranial nerve involvement is more prevalent in multifocal variants. However, no previous reports have documented a case similar to ours, characterized by sequential involvement of the facial and hypoglossal nerves. Two head MRI scans revealed no abnormal signals, and CSF results were normal, thereby excluding central nervous damage. Furthermore, patients with typical CIDP exhibit a higher level of disability and impairment compared to those with MADSAM [10].

In MADSAM cases, elevated CSF protein is less common than in CIDP [12], with 38% of patients exhibiting increased CSF protein and a mean level of 82 mg/dL (range 61–146) [10], which is consistent with our case. These findings may suggest a relatively low likelihood of affected nerve roots in such MADSAM cases, as lumbosacral plexus MRIs in our patient did not demonstrate significant nerve root thickening or T2-weighted high-intensity signals. Conduction block (CB) is a common electrophysiological characteristic in MADSAM, occurring more frequently at proximal than distal sites [5], and it is a typical feature of demyelination. In MADSAM, CB can persist for months or years and remains localized. The persistent presence of local conduction block may also be related to the ongoing disruption of the blood-nerve barrier in that area. In our patient, we did not observe CB in the distal extremities; the diagnosis of demyelination was based on the slowed MCV and delayed DML in motor nerves, as well as delayed SCV in sensory nerves. Since we did not assess proximal nerve conduction, we cannot exclude the possibility of missing proximal CBs.

Corticosteroids, plasma exchange, and intravenous or subcutaneous immunoglobulins are well-established treatments for CIDP [2]. In our MADSAM case, immunotherapy was effective, with corticosteroids and RTX significantly ameliorating symptoms. It is reported that patients with MADSAM are less likely to respond to immunoglobulin than those with typical CIDP, and 67% improved with steroid treatment [10]. However, recent research indicated that, compared to CIDP, the MADSAM group demonstrated a less favorable therapeutic response rate and long-term outcomes, as well as a challenging weaning process [12], suggesting the need for more prolonged and effective treatment. Consistent with previous studies [13,14], our MADSAM case responded well to rituximab after the patient did not respond to conventional immunosuppressants. These data suggest that rituximab is a potential therapeutic option for MADSAM patients unresponsive to first- and second-line treatments.

Conclusions

We have documented a rare case of MADSAM, primarily affecting the lower limbs, which showed improvement following immunotherapy. MADSAM is an uncommon disorder with varied manifestations, complicating its diagnosis and differential diagnosis. Therapeutically, corticosteroids, plasma exchange, and immunoglobulins have been reported as effective treatments for MADSAM. Our patient initially responded well to corticosteroids and immunosuppressants; however, the efficacy diminished in the later stages. Rituximab was subsequently administered and demonstrated significant efficacy without adverse events. This case supports the consideration of rituximab as alternative therapeutic intervention in MADSAM. Further studies are warranted to explore the role of rituximab in the treatment of MADSAM.