Long‐Term Outcomes in Stiff Person Spectrum Disorder

ABSTRACT

Background

Long‐term outcome data for stiff person spectrum disorder (SPSD) remain limited and sustained response to treatment varies.

Methods

In this retrospective cohort study, we included patients with probable or definite SPSD (Mayo Clinic criteria), evaluated at Mayo Clinic (12/1995‐07/2024) with ≥ 5 years of follow‐up after diagnosis. Primary outcome measures included the modified Rankin scale (mRS) and use of gait aids.

Results

Fifty‐four patients were included, 41 (76%) were female; median age at onset was 45 years (16–78). Most were antibody‐positive (51 [94%]), with high‐titer (serum, ≥ 20 nmol/L) GAD65‐IgG in 45 (83%). Nine patients had a stiff‐limb presentation (17%). The median interval from onset to diagnosis was 2 years (0–34), and median follow‐up was 9 years (5–26). Most patients (46 [85%]) received immune therapy; 37 (82%) reported improvement. All patients had significant impairment (mRS ≥ 2) at nadir, with 31 (57%) losing functional independence (mRS ≥ 3) and 40 (75%) requiring bilateral gait assistance. The median time from onset to nadir was 6 years (0–39). At last follow‐up, most (37 [69%]) were functionally independent (mRS ≤ 2), including 8 (15%) with minimal restrictions (mRS ≤ 1). Bilateral gait assistance was needed in 22 (41%). Among 40 patients with ≥ 10 years of follow‐up, 22 (56%) had an mRS ≤ 2 and 25 (63%) required a gait aid at last follow‐up. Poor outcome in this population was associated with bilateral gait assistance at nadir and older age (p < 0.05).

Conclusions

Although over half of SPSD patients lose functional independence at disease nadir, many regain independence and achieve well‐controlled symptoms.

1. Introduction

Stiff person spectrum disorder (SPSD), first described in 1956 at Mayo Clinic, is a rare autoimmune condition marked by central nervous system hyperexcitability, leading to stiffness, spasms in the limbs and axial muscles, exaggerated startle responses, and falls [1, 2, 3, 4, 5].

SPSD is associated with antibodies specific for the glutamic acid decarboxylase 65 kDa isoform (GAD65), the α1‐subunit of the glycine receptor (GlyR), or amphiphysin [6]. In rare cases, other neural antibodies have been implicated; a small minority of cases still remain antibody‐negative [6]. High‐titer GAD65‐IgG is the most frequently detected neural antibody, and GAD65‐IgG‐associated SPSD can overlap with other manifestations of neurological autoimmunity, such as cerebellar ataxia and epilepsy, as well as autoimmunity of other organs [4, 6, 7, 8]. However, the presence of low‐titer GAD65‐IgG in serum lacks specificity for neurological manifestations and can be encountered in healthy adults [7].

SPSD is frequently misdiagnosed, leading to delayed treatment [9, 10, 11]. Conversely, other conditions, such as chronic pain syndromes and functional neurological disorders, can be incorrectly diagnosed as SPSD [10]. To enhance diagnostic accuracy, diagnostic criteria have been recently proposed, incorporating clinical, serological, and electrophysiological findings [10].

Current research on long‐term outcomes of SPSD patients remains limited, often involving heterogenous patient populations and short follow‐up periods, which restricts effective prognostication and development of clinical trial designs [2, 5, 6, 12, 13, 14]. Our aim for this study is to assess the long‐term outcomes of patients with SPSD, stratified by the serological findings.

2. Methods

2.1. Standard Protocol Approvals, Patient Consent and Data Availability

This retrospective study was approved by the Mayo Clinic Institutional Review Board (IRB# 24‐000388); patients included consented to research review of their records. Deidentified data will be available from the corresponding author upon reasonable request.

2.2. Study Population

We included adult patients identified through an electronic medical record search for SPS‐relevant diagnostic codes and cross‐referenced with Mayo Clinic Neuroimmunology Laboratory existing databases who met suggested diagnostic criteria for probable or definite SPSD [10] and were evaluated in the Mayo Clinic Neurology Department (12/1995‐07/2024) with a follow‐up duration ≥ 5 years from diagnosis. Patients with progressive encephalomyelitis with rigidity and myoclonus (PERM) were excluded due to their distinct clinical presentation that has a substantial impact on functional outcomes. GAD65‐IgG was assessed using a radioimmunoprecipitation assay, with a positive result defined as high‐titer antibodies in serum (≥ 20 nmol/L in our laboratory) or any positive result in the cerebrospinal fluid (CSF; > 0.02 nmol/L) [15]. Amphiphysin‐IgG was detected by mouse‐tissue‐based indirect immunofluorescence assay and confirmed by recombinant antigen‐specific blot, and GlyR‐IgG was tested by a live‐cell binding assay [16, 17]. Twenty‐two patients have been previously reported [2].

The modified Rankin scale (mRS) and need for gait assistive devices were retrospectively assessed as outcome measures at disease nadir, first and last Mayo Clinic visits, and at 5, 10, 15, and 20 years from symptom onset (or the nearest timepoint within 2.5 years). The maximal gait assistance required was recorded, even if only used intermittently (e.g., when walking in open spaces). Outcomes were separately analyzed for patients with and without GAD65‐IgG, given the high prevalence of GAD65‐IgG positive patients in this cohort. Since mRS does not directly account for gait aid use (only assistance from another person), we defined poor outcome as an mRS score ≥ 3 or the need for at least bilateral gait assistance at last follow‐up. Treatment responses were categorized based on the treating physician's documentation: no response (no or minimal improvement), moderate response (moderate improvement but with residual symptoms and functional impairment), or excellent response (marked improvement with no or minimal residual symptoms or functional impairment). Maximal response was assessed even if it was not sustained long‐term. Serum GAD65‐IgG titers were assessed longitudinally in patients with at least two samples, collected at least 3 months apart. Titers were stratified as: < 20 nmol/L, 20–99.9 nmol/L, and ≥ 100 nmol/L.

2.3. Statistical Analysis

Dichotomous variables were analyzed using Fisher's exact test; continuous variables were compared using the Mann–Whitney U test. A multivariable analysis was not performed because the limited sample size and number of events did not permit reliable multivariable modeling. p values < 0.05 were considered significant. Missing variables were excluded. Kaplan–Meier analysis was used to illustrate the cumulative probability of time from onset to disease nadir and first‐time need for bilateral assistance. Statistical analysis was performed using R version 4.3.0 (R Foundation for Statistical Computing).

3. Results

3.1. Patient Characteristics

We identified 54 patients with SPSD and follow‐up duration ≥ 5 years from diagnosis (definite, 25; probable, 29), Table 1. The cohort was predominantly female (41 [76%]), with a median age at onset of 45 years (range, 16–78). Thirty‐eight (70%) had co‐existent autoimmune disorders, with the most frequently encountered being thyroid autoimmunity (27 [50%]), diabetes mellitus type I (21 [39%]), pernicious anemia (7 [13%]), and vitiligo (5 [9%]). The median interval from symptom onset to diagnosis was 2 years (range, 0–34), and the median interval from diagnosis to last visit was 9 years (5–26). Most patients had at least two Mayo Clinic visits (46 [85%]). The vast majority (51 [94%]) were seropositive for SPSD‐associated neural autoantibodies. High‐titer GAD65‐IgG was identified in 45 patients (83%). All GAD65‐IgG‐positive patients had high serum titers, with 18/21 (86%) also testing positive in the CSF; no patients had isolated CSF positivity. GlyR‐IgG was detected in six patients (two with concurrent high‐titer GAD65‐IgG), while amphiphysin‐IgG was identified in two. No neural antibodies were detected in three patients; two of these patients had not been tested for GlyR‐IgG.

TABLE 1.

Patient characteristics (N = 54).

Female sex (%)	41/54 (76)
Age at SPSD onset, median (range), years	45 (16–78)
Time to diagnosis, median (range), years	2 (0–34)
Onset to immune therapy (range), years	2 (0–34) a
Disease phenotype
Definite SPSD (%)	25/54 (46)
Probable SPSD (%)	29/54 (54)
Alcohol overuse (%)	3/48 (6)
Co‐existent autoimmune disorder (%)	38/54 (70) b
Cancer diagnosis ≤ 2 years of SPSD symptom onset (%)	2/54 (4) c
Initially limited to one body area (%)	31/46 (67)
Stiff‐limb variant (%)	9/54 (17)
Ataxia (%)	7/54 (13) d
Exaggerated startle (%)	40/54 (74) e
Other trigger present (%)	49/54 (91) f
Follow‐up
Follow‐up from symptom onset, median (range), years	13 (6–40)
> 10 years of follow‐up (%)	40/53 (75)
Poor outcome (%)	22/54 (41)

Abbreviation: SPSD, stiff person syndrome spectrum disorder.

^a Two patients receiving immune treatment at baseline for other autoimmune disorders.

^b Thyroid disease, 27; Diabetes mellitus type I, 21; Pernicious anemia, 7; Vitiligo, 5; Rheumatoid arthritis, 2; Celiac disease, 1; Myasthenia Gravis, 1; Addison's disease, 1; Systemic Lupus Erythematosus, 1; Sjogren's syndrome, 1; Seronegative arthritis, 1.

^c Both patients with amphiphysin‐IgG autoimmunity and underlying breast adenocarcinoma.

^d Six patients were high‐titer GAD65‐IgG positive and one was amphiphysin‐IgG positive.

^e Induced by loud noises, 29; Induced by touch, 13; Induced by sudden visual stimuli, 1.

^f Exacerbation: emotional stress/anxiety, 23; walking in open spaces, 9; walking on concrete, 2; walking in dark environment, 1; cold environment, 8; hot environment, 1; exacerbation during nighttime, 9; exacerbation during morning, 6; infection, 4; full bladder, 1. Improvement: massage, 2, change with physical activity, 26.

3.2. Clinical Phenotypes and Treatment

Symptoms were described in only one body area at symptom onset in most patients (31/46 with sufficient data [67%]; lower limbs [involving either one or both limbs], 25; lower back, 4; abdomen, 1; upper limbs, 1) (Figure 1A,B). However, only nine patients (17%) continued to have limited involvement at last follow‐up (stiff‐limb variant). The frequency of body area involvement was similar between first and last visit. At last follow‐up, the lower extremities were involved in all patients, followed by the lower back (43 [80%]), abdomen (24 [44%]), upper extremities (19 [35%]), neck (12 [22%]), chest (11 [20%]), and face (3 [6%]). Additionally, episodes of whole‐body stiffness/spasms were reported during the disease course in 14 patients [26%].

FIGURE 1.

Summary of body region involvement and treatment. (A) Venn diagram of body region involvement at last visit. All patients had concurrent involvement of lower limbs (nine with stiff‐limb variant). (B) Barplot of body region involvement at first and last visit. (C) Symptomatic and immune therapies received throughout disease course. *One patient received methotrexate and hydroxychloroquine for possible rheumatoid arthritis, and one patient received glatiramer acetate for initial multiple sclerosis misdiagnosis. (D) Treatment response to symptomatic and immune therapies. The maximal response was assessed even if the effect was not sustained in the long‐term. ASM, anti‐seizure medication; GABA, gamma‐aminobutyric acid; IVIG, intravenous immunoglobulin; SCT, stem‐cell transplant.

Most patients reported at least one triggering/exacerbating factor for their spasms (49 [91%]), Table 1. Triggers included loud noises (29 [54%]), emotional stress or anxiety (23 [43%]), tactile stimuli (13 [24%]), walking in open spaces (9 [17%]), during nighttime (9 [17%]), and exposure to a cold environment (8 [15%]). Muscle activation and physical activity affected symptoms in half of the patients (26 [48%]), either exacerbating or ameliorating them. One female reported significant improvement of symptoms during pregnancy, while three patients reported catamenial worsening.

Benzodiazepines were used in most cases during the disease course (52 [96%]), with most patients experiencing at least partial improvement (45 of 49 with sufficient data [92%]) (Figure 1C,D). Some patients required exceptionally high doses, up to 250 mg of diazepam daily, with a median maximum dosage of 60 mg per day. Non‐benzodiazepine muscle relaxants (baclofen, tizanidine) were also frequently employed (39 [72%]), with most patients reporting some benefit (27 of 38 with sufficient data [71%]). Botox was used in 9 (17%) patients for symptomatic control. Notably, seven patients received an intrathecal baclofen pump, and all experienced symptom improvement. In one patient, however, the improvement was transient, leading to the eventual removal of the pump.

Most patients (46 [85%]) received immune therapy, within a median interval of 2 years from symptom onset (range, 0–34). The median number of agents tried was 2 (range, 0–6), with IVIG (37 [69%]), corticosteroids (24 [44%]), rituximab (15 [28%]), and azathioprine (13 [24%]) being the most common, Figure 1C. Most patients showed at least moderate maximal response to immune treatment (37/45 with available data [82%]), although the benefit was not always sustained in the long term (Figure 1D).

3.3. Outcomes of GAD65‐IgG‐Associated SPSD

Among 45 GAD65‐IgG‐positive patients, most (38 [84%]) received immune therapy during their disease course. Five patients developed cerebellar ataxia after SPSD onset (four within 3 years), while one patient developed SPSD 15 years after cerebellar ataxia onset. In contrast, three out of four patients with epilepsy experienced epilepsy onset before SPSD (range, 1–15 years), while in one patient, epilepsy began 3 years after SPSD onset.

All SPSD patients had significant impairment (mRS ≥ 2) at nadir, with approximately half losing functional independence (mRS ≥ 3; 26 [58%]) and most (33 of 44 with available data [75%]) requiring bilateral gait assistance (Figure 2). The median time from onset to disease nadir was 6 years (range, 0–39) (Figure 3). Almost half of the patients (20 [44%]) demonstrated an improvement in mRS of ≥ 1 point compared to their score at nadir. At last follow‐up, most were functionally independent (mRS ≤ 2; 30 [67%]; 3 with co‐existent ataxia), with 8 (18%) having minimal restrictions (mRS ≤ 1). The use of bilateral gait assistive device was needed in 19 (42%). The most common symptoms at last follow‐up were spasms (39 [87%]), gait instability (33 [73%]), pain (29 [65%]), anxiety (17 [38%]), fatigue (18 [40%]), and falls (15 [33%]), Table 2. The most common signs were persistent hypertonia (29 [64%]) and hyperlordosis (18 [40%]). Fractures were documented in 18 (40%) patients during their disease course.

FIGURE 2.

(A) Gait assistive devices needed at disease nadir, last visit, 5, 10, 15, 20 years (or closest timepoint within 2.5 years) from symptom onset. (B) Modified Rankin scale (mRS) scores at disease nadir, last visit, 5, 10, 15, 20 years (or closest timepoint within 2.5 years) from symptom onset. (C) Modified Rankin scale (mRS) scores at nadir and last visit stratified by serological phenotype.

FIGURE 3.

Kaplan–Meier analysis illustrating the cumulative probability for (A) time from onset to disease nadir (N = 49) and (B) time from onset to first‐time need for bilateral assistance (N = 45) within the first 20 years of disease.

TABLE 2.

Clinical phenotype at first and last visit (N = 54).

	First visit (%)	Last visit (%)
Symptoms
Spasms	46/46 (100)	45/54 (83)
Pain	35/46 (76)	35/54 (65)
Exaggerated startle	28/46 (61)	13/54 (24)
Fatigue	9/46 (20)	20/54 (37)
Dysarthria/Dysphagia/Dysphonia/Diplopia	9/46 (20)	9/54 (17)
Urinary frequency/urgency/incontinence	4/46 (9)	4/54 (7)
Cognitive impairment	2/46 (4)	4/54 (7)
Seizures	3/46 (7)	3/54 (6)
Anxiety	18/46 (39)	20/54 (37)
Fear of falling	17/46 (37)	16/54 (30)
Depression	10/46 (22)	8/54 (15)
Gait instability	37/46 (80)	40/54 (74)
Falls	28/46 (61)	19/54 (35)
Signs
Hypertonia	42/46 (91)	35/54 (65)
Hyperlordosis	24/46 (52)	19/54 (35)
Hyperreflexia	22/46 (48)	13/54 (24)
Exaggerated startle on exam	3/46 (7)	1/54 (2)
Nystagmus	2/46 (4)	3/54 (6)
Cerebellar ataxia	5/46 (11)	7/54 (13)
Treatment received
Benzodiazepines	28/46 (61)	49/54 (91)
Daily benzodiazepine dosage in diazepam equivalents, median (range), milligrams	22 (5–27)	30 (5–160)
Non‐benzodiazepine muscle relaxants	18/46 (39)	27/54 (50)
Intrathecal baclofen pump	3/46 (7)	6/54 (11)
GABAergic medication	6/46 (13)	8/54 (15)
Immune therapy	6/46 (13)	21/54 (39)
SSRI/SNRIs	12/46 (26)	16/54 (30)
Opioid analgesics	7/46 (15)	4/54 (7)

Abbreviations: GABA, gamma‐aminobutyric acid; SNRI, serotonin‐norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

Among GAD65‐IgG‐positive patients requiring bilateral gait assistance at their first Mayo Clinic visit, 61% developed a poor outcome (p = 0.006). Similarly, among those who required bilateral gait assistance at nadir, 55% developed a poor outcome (p = 0.01). Patients with poor outcome were more likely to have co‐existent dysarthria at last follow‐up (21% vs. 0%; p = 0.03). No associations were found with age, sex, use of immune therapy, or interval from onset to diagnosis or initiation of immune therapy.

Compared to GAD65‐IgG‐negative patients, those with GAD65‐IgG were more likely to have co‐existent type 1 diabetes mellitus (47% vs. 0%; p = 0.009) and thyroid disease (58% vs. 11%; p = 0.02), but less likely to have cancer (0% vs. 22%; p = 0.03). Additionally, GAD65‐IgG‐positive patients were more likely to report falls at first visit (68% vs. 25%; p = 0.04) and exhibit upper extremity involvement at first visit (13% vs. 50%; p = 0.04) but were less frequently receiving SSRI or SNRI medications at last follow‐up (22% vs. 67%; p = 0.01).

3.4. Outcomes of Non‐GAD65‐IgG‐Associated SPSD

Breast adenocarcinoma was detected within 2 years after SPSD symptom onset in both patients with amphiphysin‐IgG autoimmunity. Both patients underwent surgical resection and radiation therapy for the underlying tumor. One patient was additionally treated with aromatase inhibitors, corticosteroids, and IVIG, with no SPSD symptom improvement. The other patient reported improvement following chemotherapy (cyclophosphamide and adriamycin) with no additional benefit from immune therapies (corticosteroids, IVIG, rituximab). Ultimately, both patients experienced poor neurological outcomes, with additional multifocal neurological manifestations (cerebellar ataxia and myeloneuropathy) contributing to functional impairment in one (Figure 2).

Among the six GlyR‐IgG‐positive patients, two had co‐existent high‐titer GAD65‐IgG (with concurrent CSF positivity) and are described above. Of the remaining four, one presented with a stiff‐limb variant. Notably, all four patients had co‐morbid anxiety and/or depression at first visit. All received immune treatment and, despite remaining symptoms, had favorable neurological outcome at last visit, with an mRS score of 2; two required a gait assistive device at last follow‐up (Figure 2).

In the antibody‐negative group, comprising three patients, two received immune therapies. All had favorable outcomes, and one required a gait assistive device (cane) at last follow‐up (Figure 2).

3.5. Outcomes of Patients With Extended Follow‐Up (≥ 10 Years)

Among 40 patients with a follow‐up of ≥ 10 years from SPSD symptom onset, all remained symptomatic at last follow‐up, with 6 (15%) showing minimal symptoms (mRS = 1) (Figure 2). The majority (22 [56%]) were independent with some functional impairment (mRS = 2; one with co‐existent ataxia), while one‐third (12 [30%]) had significant functional limitations (mRS ≥ 3; two with co‐existent ataxia). Longitudinal mRS changes are shown in Figure 4A. Most patients eventually required a gait assistive device (25 [63%]), with half needing bilateral assistance (18 [45%]) (Figure 2). Factors associated with poor outcome included the need for a bilateral gait assistive device at first visit (63% poor outcome vs. 38% favorable outcome; p = 0.02) and at nadir (53% poor outcome vs. 47% favorable outcome; p = 0.01), ataxia at first visit (100% poor outcome vs. 0% favorable outcome; p = 0.047), and older age at diagnosis (median ages 54 vs. 46; p = 0.04).

FIGURE 4.

Longitudinal changes in modified Rankin Scale (mRS) score in patients with ≥ 10 years of follow‐up (N = 38) (A) and GAD65‐IgG serum titers (N = 30) (B). Only patients with data available at two or more timepoints are included. Only samples collected at least 3 months apart are shown. *Nine patients received immune therapy prior to the first sample collection.

3.6. Longitudinal Changes in Serum GAD65‐IgG Titers

The longitudinal changes in serum GAD65‐IgG titers are depicted in Figure 4B. Among 30 patients with at least two titers, 25 had titers > 100 nmol/L at their first sample, all maintaining high‐titer GAD65‐IgG throughout follow‐up, regardless of immune therapy. Of the four patients with titers 20–99.9 nmol/L at the initial sample, one patient's titer increased to > 100 nmol/L, one patient without prior immune therapy experienced a decrease to low‐titer after receiving corticosteroids, IVIG, and plasma exchange, and two patients with prior immune therapy (IVIG in one; IVIG and rituximab in the other) showed a decrease to low‐titer following azathioprine and stem cell transplantation, respectively. Additionally, one patient initially had low‐titer antibodies despite no prior immune therapy, with titers later increasing to 20–99.9 nmol/L before decreasing again following IVIG treatment.

4. Discussion

This study provides insights into the long‐term outcomes of Stiff Person Spectrum Disorder (SPSD), focusing on a cohort of 54 patients with follow‐up periods of at least 5 years from diagnosis, including 40 patients with more than 10 years of follow‐up from symptom onset. Unlike previous studies, our study emphasizes extended follow‐up from the time of diagnosis and thus possible intervention [5]. By examining longitudinal changes in functional outcomes (mRS, use of gait aids), our study contributes to a better understanding of the natural history of SPSD. Utilizing recently proposed diagnostic criteria and stratifying patients by antibody status, our study provides a detailed depiction of disease progression over time, rather than at last follow‐up alone.

Our cohort, predominantly GAD65‐IgG‐positive, aligns with previous studies in demonstrating the rarity of GlyR‐IgG‐ and amphiphysin‐IgG‐positive cases [6, 18]. The vast majority of GAD65‐IgG‐positive patients with high serum titers exhibited CSF positivity when both specimens were tested, and all positive CSF samples also demonstrated serum positivity, reinforcing prior findings on the CSF‐serum correlation in GAD65‐IgG‐associated neurological autoimmunity [7]. Antibody‐negative cases, requiring electrophysiological evidence for a probable diagnosis, were rare. This contrasts with recent findings [19], reflecting the more stringent diagnostic criteria employed in the current study to minimize SPSD misdiagnosis, which has been reported in up to 72% of patients referred to tertiary centers [10].

We observed considerable variability in the time from symptom onset to diagnosis, possibly reflecting differences in symptom presentation, progression rates, and occasional misdiagnoses. Symptoms in most patients initially appeared localized but often progressed to involve other body areas [5, 13]. Lower limb involvement, often accompanied by lower back stiffness, was nearly universal, while facial involvement was rare [5, 13].

Chronic pain and functional neurological symptoms also co‐exist in such patients [10]. In our cohort, chronic pain, fatigue, and psychiatric symptoms were prominent at last follow‐up, underscoring the need for comprehensive psychosocial evaluation and support in SPSD patients, in addition to pharmacological treatment.

SPSD management often required a combination of symptomatic and immune therapies. Most patients in our cohort received immune treatment, with the majority experiencing at least partial symptom relief, though sustained responses varied. IVIG was most commonly used and remains the only treatment supported by randomized controlled trials [20], although its effectiveness can diminish over time [14]. Benzodiazepines provided partial relief for most patients, with some requiring very high doses.

In this study, the rate of progression varied, with most patients reaching nadir after several years. While functional impairment was universal at nadir, about half of GAD65‐IgG‐positive patients improved by at least one mRS point with treatment. At last follow‐up, one‐fifth were minimally restricted, while one‐third were not fully functionally independent. Most patients required bilateral gait assistance at nadir, which predicted a poor outcome at last follow‐up.

GlyR‐IgG‐positive and antibody‐negative SPSD patients had better outcomes, maintaining functional independence, consistent with prior studies [6]. Amphiphysin‐IgG‐positive SPSD in our cohort was associated with breast adenocarcinoma, consistent with previous reports [17] and poor long‐term outcomes. All patients with over 10 years of follow‐up remained symptomatic at the last visit, with a small portion reporting minimal symptoms. Additionally, one‐third of patients were not functionally independent at last follow‐up. Notably, many patients eventually required a gait‐assistive device, with some needing bilateral assistance, emphasizing the progressive nature of the disease. Despite some patients achieving partial symptom relief, the need for ongoing support and treatment highlights the chronic, evolving course of SPSD and the necessity for novel therapeutic approaches [21].

Previous studies have shown varying degrees of functional decline in SPSD, reflecting differences in inclusion criteria, follow‐up duration, and outcome measures. Our study results align with an earlier study conducted by our group where 35 GAD65‐IgG‐positive patients had a median mRS of 2 at the last follow‐up, with one‐third unable to work due to SPSD [2]. Additionally, a previous study of 57 SPSD patients followed for up to 8 years reported that 80% lost independent ambulation during their disease course and 40% required bilateral assistance at last follow‐up, proportions similar to those observed in our cohort [13].

A separate study involving 75 SPSD patients with a median follow‐up of only 18 months reported a median mRS of 2 at the last follow‐up; half of the patients had an mRS ≥ 3 or showed no improvement from diagnosis [6]. In contrast, only 30% of our cohort had an mRS ≥ 3, likely reflecting the benefit of longer follow‐up. Another analysis of 227 patients, with a mean follow‐up of 10 years from symptom onset, showed that 70%–80% of patients required an assistive device at last follow‐up [5]. In comparison, fewer than 60% of our cohort needed an assistive device, likely due to differences in study design, including the inclusion of PERM, and shorter follow‐up durations in the other study.

Our longitudinal analysis of serum GAD65‐IgG titers demonstrated that most patients initially had very high titers (> 100 nmol/L) that persisted to be in the high‐level category throughout follow‐up, regardless of immune therapy. In contrast, patients with moderately high or low titers exhibited more variability, and some of them decreased below the neurological threshold of 20 nmol/L in the serum. This is consistent with a previous report in a limited number of patients [22].

The study has limitations inherent to its retrospective design, including reliance on clinical documentation, which may have led to underreporting of milder or subjective symptoms and limited the thorough assessment of treatment‐specific responses. Although the mRS is a valuable outcome measure widely used in clinical trials, it does not fully capture the impact of SPSD on patients' quality of life, and no specific questionnaires for quality of life assessment were available in these patients. Additionally, mRS scores were retrospectively assigned based on chart review, which may introduce assessment bias. The small sample size in the non‐GAD65‐IgG subgroup also limits the generalizability of findings for this population. Lastly, as SPSD is a rare disorder, this study was conducted at a tertiary referral center, which might have introduced selection bias toward more severe or atypical cases.

Despite these limitations, this study enhances our understanding of the clinical course and outcomes of SPSD. Our findings highlight the potential for functional improvement with optimized management, even in severe cases. Future research on SPSD outcomes should be prospective, focus on quality‐of‐life assessments and objective disease measures, and refine therapeutic strategies to improve outcomes for patients.

Author Contributions

James H. Bower: writing – review and editing. Andrew McKeon: writing – review and editing. Georgios Mangioris: conceptualization, investigation, writing – original draft, data curation, visualization, formal analysis. Anastasia Zekeridou: conceptualization, investigation, writing – review and editing, supervision. Divyanshu Dubey: writing – review and editing. Sean J. Pittock: writing – review and editing. Nisa Vorasoot: writing – review and editing. Eoin P. Flanagan: writing – review and editing.

Funding

The authors have nothing to report.

Conflicts of Interest

Andrew McKeon has patents issued for GFAP and MAP1B‐IgGs and patents pending for Septins‐5 and ‐7, PDE10A‐IgG, CAMKV‐IgG and KLCHL11‐IgGs; and has consulted for Roche pharmaceuticals, without personal compensation. James H. Bower has received research funding from Novartis and Amylyx pharmaceuticals not relevant to this study. Divyanshu Dubey has consulted for UCB, Immunovant, Argenx, Arialys, and Astellas pharmaceuticals. All compensation for consulting activities is paid directly to Mayo Clinic. He is a named inventor on a filed patent that relates to KLHL11 as a marker of autoimmunity and germ cell tumor. He has patents pending for LUZP4‐IgG, cavin‐4‐IgG, and SKOR2‐IgG as markers of neurological autoimmunity. He has received funding from the DOD (CA210208 & PR220430), David J. Tomassoni ALS Research Grant Program, and UCB. Eoin P. Flanagan has served on advisory boards for Alexion, Genentech, Horizon Therapeutics and UCB. He has received research support from UCB. He received royalties from UpToDate. Dr. Flanagan is a site principal investigator in a randomized clinical trial of Rozanolixizumab for relapsing myelin oligodendrocyte glycoprotein antibody‐associated disease run by UCB. Dr. Flanagan is a site principal investigator and a member of the steering committee for a clinical trial of satralizumab for relapsing myelin oligodendrocyte glycoprotein antibody‐associated disease run by Roche/Genentech. Dr. Flanagan is a Co‐Investigator on a study of ravulizumab for neuromyelitis optica spectrum disorder run by Alexion. Dr. Flanagan has given educational talks on neuromyelitis optica spectrum disorder funded by Alexion. Dr. Flanagan has received funding from the NIH (R01NS113828). Dr. Flanagan has received honoraria for editing and writing articles for The Continuum Lifelong Learning in Neurology Journal which is a publication of the American Academy of Neurology. Dr. Flanagan is a member of the medical advisory board of the MOG project. Dr. Flanagan is an editorial board member of Neurology, Neuroimmunology and Neuroinflammation, The Journal of the Neurological Sciences and Neuroimmunology Reports. A patent has been submitted on DACH1‐IgG as a biomarker of paraneoplastic autoimmunity. Sean J. Pittock has received personal compensation for serving on scientific advisory boards or data safety monitoring boards for F. Hoffman‐LaRoche AG, Genentech, Arialys and UCB. His institution has received compensation for serving as a consultant for Astellas, Alexion/AstraZeneka, and Viela Bio/MedImmune/Amgen. All compensation is paid to Mayo Clinic. He has received research support from Alexion/AstraZeneka, Viela Bio/MedImmune/Amgen, Roche/Genentech and Adimmune. He has a patent, Patent# 8,889,102 (Application#12‐678350, Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia)—issued; a patent, Patent# 9,891,219B2 (Application#12‐573942, Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin‐4 (AQP4)‐IgG Autoantibody positive)—issued and from which he has received royalties and a patent for GFAP‐IgG; Septin‐5‐IgG; MAP1B‐IgG; Kelch‐like protein 11; PDE10A pending. He is working as a consultant in the Mayo Clinic Neuroimmunology laboratory clinical service. The Mayo Clinic Neuroimmunology Laboratory commercially offers MOG‐IgG testing, but revenue accrued does not contribute to salary, research support, or personal income. Anastasia Zekeridou has patents submitted for DACH1‐IgG, PDE10A‐IgG, CAMKV‐IgG, Tenascin‐R‐IgG as biomarkers of neurological autoimmunity. She has received research funding from Roche/Genetech and Center for MS and Autoimmune Neurology at Mayo Clinic not relevant to this study. She has consulted without personal compensation for Alexion pharmaceuticals. She is a site PI and on the steering committee for the KYSA‐8 study for autologous CAR‐T‐19 treatment for SPS; no personal compensation. The other authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.