Long-term Effectiveness of IVIg Maintenance Therapy in 36 Patients With GAD Antibody–Positive Stiff-Person Syndrome

Demographics

The study included 36 patients, 29 women and 7 men, of median age 58 years (range 32–81 years). Time from symptom onset to SPS diagnosis ranged from 0 years (diagnosed the same year as symptom onset) to 26 years, with a median of 3.5 years. Time from symptom onset to treatment with IVIg ranged from 0 years (treated the same year as symptom onset) to 26 years with a median of 4 years. Thirty-two of the 36 patients were positive for GAD-65 antibodies with high titers, as previously specified^1,4,14,-,16; 4 patients were diagnosed with seronegative SPS based on all the other required criteria and exclusions^4,5 (Table 1, eTable 1, links.lww.com/NXI/A732). Five GAD-positive patients also had cerebellar involvement, as part of GAD-SPS spectrum disorder.^4,5,17

Overall Clinical Changes and Benefits From IVIg

Of the 36 patients, 24 (67%) had a clinically significant response to treatment with IVIg, similar to what was noted in our original short-term (3-month) controlled study,⁷ with benefit extended up to a median period of 40 months (Figure 1). Of the 4 patients with seronegative SPS, 2 improved with IVIg; 1 had complications and discontinued treatment after a single dose, and the fourth did not respond to IVIg. Subjectively, the responders reported the following overall long-term experience with IVIg: improved gait, improved daily functioning, improved balance, decreased dysarthria and faster speech, decreased stiffness, decreased painful spasms, improved energy, decreased startle response, improved posture, and improved facial expression (Table 1). Based on objective neurologic examinations, responders were noted to have decreased rigidity, improved gait, improved facial expression, decreased nystagmus, and decreased dysarthria (in the patients with SPS and cerebellar findings).

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Figure 1 Median Duration and Range of IVIg Treatment in 36 Patients With Stiff-Person Syndrome Categorized as IVIg Responders or Nonresponders

IVIg responders were subcategorized based on their response to long-term treatment—continued benefit over time, decreasing benefit over time, demonstration of a conditioning effect, not assessed with a dependency trial, or unable to assess due to premature discontinuation of therapy.

Among the 36 patients who received IVIg, 12 patients did not exhibit any benefit (as defined above), at any time during a median of 3 months (range 1–24 months) of IVIg treatment (Figure 1; eTable 1, links.lww.com/NXI/A732). No differences in the clinical phenotype, GAD Ab status, or symptomatology characteristics were noted between the responders and nonresponders.

Response Assessed by the Modified Rankin Scale Score

Of the 24 IVIg responders, 8 patients (33%) responded to the extent that their modified Rankin Scale score improved by 1 point (in 6 patients) or by 2 points (in 2 patients), most dramatically illustrated by the ability to walk without an assistive device after treatment. Specifically, 6 of these patients were using a wheelchair before starting IVIg but became able to walk independently (R2 and R16; Table 1) or with a cane or walker (R5, R11, R19, and R24; Table 1) several months after IVIg; 2 others who required a cane or a walker to walk pre-IVIg became able to walk without assistance after several IVIg courses (R4, R10; Table 1). The other 16 responders maintained the same mRS score after long-term IVIg treatments, demonstrating a stabilizing effect.

Duration of Long-term Benefit of IVIg and Dependency Tests

For the 24 IVIg responders, the duration of treatment ranged from 11 to 216 months, with a median of 40 months (Figure 1). Sixteen of the 24 responders underwent formal dependency trials or an equivalent. After holding their IVIg infusions, reducing the monthly IVIg dose from 2 g/kg to 1 g/kg or prolonging the frequency of the infusions, there was a clear symptom recurrence indicating that maintenance therapy was beneficial and still needed. One patient (R1; Table 1) who declined further when IVIg was held due to poor venous access exhibited a satisfactory clinical response with less side effects when switched to SCIg; in this patient, SCIg continues to ensure improvement and stability for the last 2 years. Eight of the 24 responders continued receiving treatment without undergoing a formal dependency test (Figure 2); 2 of these patients continued to experience clear benefit and were categorized in Table 1 in the responders with continued benefit subgroup; another prematurely discontinued therapy because of medical comorbidities and was categorized in Table 1 in the discontinued prematurely subgroup; the remaining 5 continued on IVIg for a median of 58 months (range 13–143 months) because it was felt to be beneficial and were categorized in Table 1 in the responders with no dependency trial subgroup.

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Figure 2 Relative Proportion of Patients With Stiff-Person Syndrome Who Responded to IVIg Therapy in Each Subcategory of Responders With the Median Duration and Range of Treatment for Each Category

Subgroup Analysis of Long-term Responders Based on Continuing Stability, Declined Benefit, Conditioning Effect, or Safety Issues

Of the 24 patients who benefited from IVIg with a high maintenance dose of 2 g/kg per month, 6 patients (25%) with active disease continued to experience and exhibit clinically meaningful benefit for a median duration of 40 months (range 13–62 months) (Figure 1). Seven other patients (29.1%) also exhibited clinically meaningful improvement based on dependency trials for a median of 39 months (range 16–121 months), but started to notice a decreasing relative treatment benefit after an estimated median of 31 months (range 19–50 months), despite receiving high-dose IVIg treatments (Figure 2 and Table 1).

Three of the 24 responders (12.5%) (Figure 2) who initially demonstrated clear benefit experienced decreasing benefit over time but were continued on maintenance therapy despite a lack of objective decline with dependency tests. These patients requested continuation of IVIg therapy, citing increased fatigue and pain without treatment and expressing fear that their functional status would decline if not continued on maintenance therapy, exhibiting a form of conditioning effect.^8,9 This patient subgroup remained on maintenance therapy for a median duration of 58 months (range 23–216 months) (Figure 2).

Of the 24 patients who benefited from IVIg, 3 patients (12.5%) prematurely discontinued treatment after a median period of 12 months (range 11–48 months) due to other medical comorbidities (Figures 1 and 2). One patient discontinued IVIg due to cardiac risk factors, another due to starting other immunotherapies for rheumatologic conditions, and the third as advised due to a prior intracerebral hemorrhage considered unrelated to IVIg. Overall, other than the common and mild infusion–related reactions,⁸ no major adverse events were observed with the chronic IVIg treatments.

GAD-Positive Patients With SPS With Cerebellar Involvement (GAD-SPS Spectrum)

Five GAD-positive patients with SPS also had cerebellar findings with ataxia and dysarthria, consistent with GAD-SD.^4,5,10 Three of these patients (R7, R11, and R13; Table 1) exhibited a beneficial response to IVIg with objective improvement in speech, balance, and nystagmus but with decreasing benefit over time. One patient (R11, Table 1) had a substantial response with improvement in the mRS score, going from being a wheelchair user before IVIg to being able to walk with a walker after IVIg; he gradually exhibited, however, decreasing benefit and switched to rituximab. Two other patients (NR3 and NR8; eTable 1, links.lww.com/NXI/A732) did not show convincing signs of improvement and were categorized as nonresponders, although 1 patient noted a mild but transient improvement in gait.