Delayed treatment and diagnostic challenges in differentiating multifocal acquired demyelinating sensory and motor neuropathy from lupus: a case report and literature review
Highlight box
Key findings
• The case highlights the importance of understanding the various causes of weakness and neuropathy, particularly with an atypical presentation, to pursue the correct diagnostic tests and treatment. The case particularly focuses on the difference between Lewis-Sumner syndrome, also known as multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), and systemic lupus erythematosus (SLE). There is significant clinical overlap between the two, and a misdiagnosis can delay effective treatment and worsen outcomes by allowing progression to more debilitating stages of the illness.
What is known and what is new?
• MADSAM is a rare autoimmune-mediated inflammatory response with negative antibodies which causes demyelination of multiple peripheral nerves in an asymmetric distribution with both motor and sensory deficits. MADSAM is typically asymmetric, demyelinating, and limited to peripheral nerves, whereas SLE is systemic, more commonly axonal, and has vasculitic features. SLE is treated with steroids and immunosuppressants while MADSAM is treated with intravenous immunoglobulin, steroids, or plasmapheresis. There is a good short-term prognosis for MADSAM with early treatment, but prognosis can worsen with delayed or inappropriate therapy.
• MADSAM can be clinically challenging to diagnose. Diagnosis for MADSAM relies on a combination of clinical and electrodiagnostic studies, and symptoms can overlap with other neurological conditions such as SLE.
What is the implication, and what should change now?
• Early and accurate differentiation between MADSAM and SLE is critical to prevent misdiagnosis and delayed treatment. Clinicians should consider MADSAM in atypical neuropathy presentations and use targeted electrodiagnostic testing. Earlier use of electromyography and nerve conductions studies can improve prognosis by ensuring timely, appropriate therapy tailored to the specific underlying condition.
Introduction
Lewis-Sumner syndrome, also known as multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), is a rare and atypical variant of chronic inflammatory demyelinating polyneuropathy (CIDP). It is an inflammatory process which causes demyelination of multiple peripheral nerves and has a typical age of onset in the early 50s (1,2). It is typically asymmetric with both motor and sensory signs in different nerve distributions, and patients frequently present with weakness in the hand or wrist (1-3). This appears similar to other mononeuropathies and can be mistaken for various compressive conditions, such as carpal tunnel syndrome (1). MADSAM should be suspected in patients with weakness and sensory loss in one limb which progresses to other areas over several months to years (4).
We describe the case of a patient who was misdiagnosed with systemic lupus erythematosus (SLE) prior to admission. The patient presented with progressive generalized weakness, weight loss, muscle atrophy, paresthesia, and numbness despite several months of treatment with hydroxychloroquine. She underwent extensive autoimmune testing, neuroimaging studies, nerve conduction studies, and electromyography (EMG) findings to ultimately be diagnosed with MADSAM. She was subsequently treated with intravenous immunoglobulin (IVIG) and showed significant improvement. This highlights the need for proper diagnosis to facilitate the correct treatment and prevent the morbidity associated with MADSAM.
The patient was presumably diagnosed with SLE because it can also affect the central and peripheral nervous system with patterns resembling mononeuropathy, polyneuropathy, plexopathy, and small fiber neuropathy (5,6). Clinicians should be cautious of diagnosing SLE when there is involvement of the peripheral nervous system without other associated clinical presentations, especially in the absence of specific serologies. About one-third of SLE cases with peripheral neuropathies are later recognized to have a non-SLE etiology (5). Additionally, SLE treatment options do not completely overlap with MADSAM and can result in worsening debility. SLE is typically treated with steroids and immunosuppressant agents, but these treatments may not be optimal for other demyelinating neuropathies. MADSAM should be treated with IVIG, plasmapheresis, or steroids (7,8). Treatment aids in suppressing the inflammatory process and should be initiated quickly. Treatment delays from misdiagnosis can lead to further deterioration and irreversible nerve damage.
This case illustrates how overlapping features in autoimmune disorders can obscure the true diagnosis, especially if clinicians anchor on clinical findings without correlating with electrophysiology or nerve biopsy. Electrophysiological and nerve conduction studies are critical to diagnosing MADSAM (3,4) but may not be performed if clinicians attribute symptoms to SLE early on. Such cases support the development of diagnostic algorithms that incorporate nerve conduction studies early in autoimmune disease workups when neuropathy is asymmetric or progressive. While SLE with peripheral neuropathy is well-documented, misdiagnosis with CIDP variants is rarely described in the literature. This may suggest that SLE-related neuropathies are over-diagnosed in certain cases where the real diagnosis is a neuropathic CIDP variant. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-82/rc).
Case presentation
A Caucasian female in her 50s with a 1-year diagnosis of SLE presented for evaluation of progressive generalized weakness and weight loss. She reported having diffuse weakness, pain, and numbness. One year prior, she was exposed to an unspecified respiratory illness and subsequently developed bilateral lower extremity weakness. Over several weeks her weakness progressed to the point where she was unable to ambulate without the assistance of a walker. She saw a rheumatologist and was given a provisional diagnosis of SLE following an extensive work-up. She was started on hydroxychloroquine 200 mg but her symptoms continued to worsen, with weakness ascending from her lower extremities to upper extremities. She lost approximately 13.5 kilograms over 6 months. Prior to this she had an unremarkable medical history.
On evaluation she was unable to stand, had significant muscle loss, and appeared cachectic. There was significant proximal muscle weakness against gravity in all limbs, resulting in impaired ambulation. She had significantly reduced grip strength bilaterally and her hands were noted to be disfigured due to intrinsic muscle loss. There was diminished strength in multiple muscle regions. She displayed dysmetria on finger-to-nose. Vibratory sensation, pinprick sensation, and deep tendon reflexes were bilaterally diminished. There was no visual field deficit, and bowel and bladder function were intact.
Serum and cerebrospinal fluid (CSF) autoimmune laboratory results were either negative or within normal limits (as seen in Table 1). CSF cultures demonstrated no growth. There was initial concern for paraneoplastic syndrome considering her weight loss over 6 months. However, it was ruled unlikely after an abdominal and pelvic computed tomography (CT) scan showed no obvious signs of a metastatic process. A magnetic resonance imaging (MRI) scan of her lumbar spine and thoracic spine did not show explanatory cord lesions. Brain MRI was also unremarkable. SLE was considered to be unlikely due to negative serological studies and lack of physical signs such as synovitis, dactylitis, Raynaud’s phenomenon, dermatitis, or mucocutaneous ulcers.
Table 1
| Parameters | Patient result | Reference range |
|---|---|---|
| Erythrocyte sedimentation rate (mm/hour) | 3 | 0–30 |
| C-reactive protein (mg/L) | 1.6 | 0.00–5.00 |
| Complements (mg/dL) | C3: 123 | C3: 75–175 |
| C4: 33.8 | C4: 15–45 | |
| Quantitative immunoglobulins (mg/dL) | IgG: 1,083 | IgG: 700–1,600 |
| IgA: 69 | IgA: 69–517 | |
| IgM: 44 | IgM: 33–293 | |
| Rheumatoid factor | Negative | Negative |
| Sjogren’s antibodies | SSA: <0.9 | 0–0.9 Ab index |
| SSB: <0.2 | ||
| Double-stranded DNA antibodies | Negative | Negative |
| Antinuclear antibodies | Negative | Negative |
| Ganglioside GM-1 antibodies | Negative | Negative |
| Anti-RNP antibodies | Negative | Negative |
| Anti-SM antibodies | Negative | Negative |
| Cyclic citrullinated peptide | Negative | Negative |
| CSF paraneoplastic antibodies (amphiphysin, AChR ganglionic neuronal antibody, AGNA-1, ANNA-1, ANNA-2, ANNA-3, CRMP-5-IgG, neuronal K+ channel antibody, N-type calcium channel antibody, P/Q-type calcium channel antibody, PCA-Tr, PCA-1, PCA-2, striational muscle antibody) | Negative | Negative |
| Immunofixation electrophoresis | Within normal limits for monoclonal IgG lambda and kappa | – |
AChR, acetylcholine receptor; AGNA-1, anti-glial nuclear antigen-1 antibodies; ANNA-1, anti-neuronal nuclear antigen-1; ANNA-2, anti-neuronal nuclear antigen-2; ANNA-3, anti-neuronal nuclear antigen-3; anti-RNP, anti-ribonucleoprotein; anti-SM, anti-Smith; C3, complement component 3; C4, complement component 4; CRMP-5, collapsin response mediator protein 5; CSF, cerebrospinal fluid; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; PCA-1, Purkinje cell cytoplasmic antibody type 1; PCA-2, Purkinje cell cytoplasmic antibody type 2; PCA-Tr, Purkinje cell cytoplasmic antibody type TR; SSA, Sjogren’s syndrome-related antigen A; SSB, Sjogren’s syndrome-related antigen B.
EMG and nerve conduction studies were conducted. Findings (as seen in Table 2) were consistent with an immune-mediated demyelinating neuropathy, such as Lewis-Sumner syndrome, which typically demonstrates absent sensory nerve action potentials (SNAPs) and decreased or prolonged compound motor action potentials (CMAPs) on nerve conduction studies, and increased motor unit action potentials (MUAPs) on EMG (9). The patient was then started on IVIG treatment (Privigen 70 g) every 4 weeks and responded favorably with rapid symptomatic improvement. A timeline of the patient’s symptoms and interventions can be seen in Figure 1.
Table 2
| Study | Method | Abnormal findings |
|---|---|---|
| Nerve conduction | Right median, ulnar, radial, sural, and superficial peroneal sensory studies were performed with surface electrodes. Right median, ulnar, peroneal, and tibial motor responses were obtained. Right median, ulnar, peroneal, and tibial F waves were acquired. Unless otherwise noted, upper extremity temperature was maintained at 320 ℃ or higher and lower extremity temperature was maintained at 300 ℃ or higher | (I) Absent right median, ulnar, and radial SNAPs |
| (II) Prolonged right median, ulnar, peroneal, and tibial CMAP distal latencies | ||
| (III) Decreased right median, ulnar, and tibial CMAP amplitudes | ||
| (IV) Significant decrease (>50%) in median, ulnar, and tibial CMAP amplitudes when stimulated proximally compared to the amplitude at distal stimulation site | ||
| (V) Decreased right median, ulnar, and tibial CMAP conduction velocities | ||
| (VI) Absent right median, ulnar, peroneal, and tibial F waves | ||
| EMG | EMG studies were performed of the right upper and lower extremities with concentric needle electrodes. Muscles tested included the right deltoid, triceps brachii, extensor digitorum communis, first dorsal interosseous, tibialis anterior, gastrocnemius (medial head), and vastus medialis | (I) Increased MUAPs amplitude in the right triceps brachii and gastrocnemius |
| (II) Increased incidence of long duration MUAPs in the right triceps brachii, tibialis anterior, gastrocnemius, and vastus medialis | ||
| (III) Increased incidence of PPP in the right extensor digitorum communis, first dorsal interosseous, and vastus medialis | ||
| (IV) Reduced recruitment of MUAPs in the right triceps brachii, extensor digitorum communis, first dorsal interosseous, tibialis anterior, gastrocnemius, and vastus medialis |
CMAP, compound motor action potential; EMG, electromyography; MUAPs, motor unit action potentials; PPP, polyphasic potential; SNAPs, sensory nerve action potentials.
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report. A copy of the written consent is available for review by the editorial office of this journal.
Discussion
Our patient was initially diagnosed with SLE, likely due to her physical exam findings and nonspecific symptoms of progressive weakness and numbness. Neurological symptoms are documented in up to 80% of patients with SLE, and can include encephalitis, hemiparesis, and demyelinating polyneuropathy (8). SLE can cause both polyneuropathy and mononeuropathy multiplex. Mononeuropathy refers to damage to a single nerve, whereas polyneuropathy refers to damage to multiple nerves. Polyneuropathies diffusely affect all nerves resulting in a symmetric presentation, while mononeuropathy multiplex affects one nerve at a time and spreads in an asymmetric manner. CIDP specifically affects peripheral nerves and nerve roots without affecting the brain or spinal cord, and can be associated with SLE (2,7,8,10,11).
We explored multiple causes for our patient’s neuropathy and ordered testing based on her clinical signs and history. There was mild suspicion for Amyotrophic Lateral Sclerosis (ALS) but it was considered unlikely as our patient had both sensory and motor symptoms, whereas ALS is a motor neuron disease that overwhelmingly causes motor weakness without a sensory component (12). Myasthenia gravis was considered unlikely as it also does not typically result in sensory symptoms, and deep tendon reflexes are usually preserved (13). Multiple sclerosis (MS) affects the central nervous system and can mimic various symptoms; however, neuroimaging was negative for signs of MS. Guillain-Barre syndrome (GBS) has both ascending numbness and weakness, and can follow a respiratory infection, but typically resolves on its own with symptomatic nadir at 2 to 4 weeks (14). GBS is considered a type of acute inflammatory demyelinating polyneuropathy (AIDP), so findings consistent with chronic processes such as muscle loss would not be expected. Transverse myelitis is spinal cord inflammation which causes numbness and weakness, but usually impacts a sensory level and has symptoms suggestive of spinal cord disease such as Lhermitte’s sign or genitourinary symptoms (15). Our patient’s clinical findings and the exclusion of other causes increased suspicion for CIDP.
Prevalence of CIDP ranges from 0.7 to 10.3 cases per 100,000 people (2). There is a male predominance with incidence increasing with age (2). Because it is chronic, there is progression over multiple months. There is loss of deep tendon reflexes due to lower motor damage. CSF demonstrates elevated proteins without pleocytosis, however this finding is also present in other conditions such as GBS (2,16). Evidence of demyelination on electroconductive studies or nerve biopsy is confirmatory (2,3,8,16). MRI findings that are sensitive for CIDP are enlargement and hyperintensity of nerve roots, nerve plexuses, or peripheral nerves (17). CIDP, like most polyneuropathies, is usually symmetric and causes weakness in both proximal and distal muscle weakness (3,7). It can also result in a sensory-predominant or asymmetric presentation (7). Common features of demyelination and response to immunotherapy are seen in both typical and atypical presentations of CIDP. In classic CIDP, there are symmetric proximal and distal weakness, sensory deficit in both upper and lower extremities and reduced deep tendon reflexes (3). When patients demonstrate progressive motor weakness and sensory deficits in more than one distal limb without exhibiting findings of compressive neuropathy in electroconductive studies, MADSAM should be considered (1). There are subtle differences in laboratory findings when comparing CIDP and MADSAM. CIDP includes elevated CSF protein, occasional presence of monoclonal proteins [immunoglobulin G (IgG) or immunoglobulin A (IgA)], and rare presence of anti-GM1 antibodies. In MADSAM there are usually elevated CSF proteins, rare presence of monoclonal proteins, and rare presence of anti-GM1 antibodies (4). There can also be a complete absence of autoimmune markers on antibody panels (18). Diagnostic criteria typically relies on a combination of clinical and electrodiagnostic studies (19). Because of the rare nature of MADSAM, there are cases of it being misdiagnosed as CTS, Guyon’s canal syndrome, anterior and posterior interosseous syndrome, and tardy ulnar neuropathy (1).
Conclusions
Clinician awareness of CIDP and other uncommon causes of weakness and neuropathy is essential in facilitating timely treatment. Although diagnoses like SLE overlap with many neuropathies, it is still crucial to obtain electrophysiological and nerve conduction studies early to facilitate timely and appropriate treatment. Both MADSAM and SLE can present with neuropathy, overlapping serological findings, and systemic symptoms. A misdiagnosis can delay effective treatment and worsen outcomes by allowing progression to more debilitating stages of the illness. The incidence of CIDP is roughly 1 in 100,000, with MADSAM accounting for approximately 5% of CIDP cases (19). Despite its rarity, MADSAM should be considered when patients demonstrate both progressive motor weakness and sensory deficits in more than one limb without findings of compressive neuropathy on electrophysiological or nerve conduction studies (1). Laboratory findings can include elevated CSF proteins, monoclonal proteins, and anti-GM1 antibodies (4). The insidious and relatively nonspecific nature of MADSAM may further contribute to difficulties in diagnosis. The rarity of conditions likes MADSAM also leads to limited literature directly comparing SLE-associated neuropathy to CIDP variants. Such cases of misdiagnosis can inform clinical teaching and guide future guideline updates.
Acknowledgments
None.
Footnote
Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-82/rc
Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-82/prf
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-82/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report. A copy of the written consent is available for review by the editorial office of this journal.
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Cite this article as: Khan S, Wennberg B, Hooda F, Witkowska M. Delayed treatment and diagnostic challenges in differentiating multifocal acquired demyelinating sensory and motor neuropathy from lupus: a case report and literature review. AME Case Rep 2025;9:111.
