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

Yi, Jessica; Dalakas, Marinos C.

doi:10.1212/nxi.0000000000200011

Cited by 24 publications

(26 citation statements)

References 21 publications

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“…In this large cohort, 24 of the 36 patients (67%) had a clinically meaningful response over a median 3.3 (range 1-18) year period exhibiting improved gait, posture, and balance and also decreased stiffness, spasms, and startle response; some wheelchair-bound patients and those ambulating with devices walked unassisted. 47 Among the responders, 37.5% had longterm stability without disease progression for 4.3 (range 1-18) year period; the other 29.1%, however, although continued to experience improvement, they also exhibited diminishing benefits after a mean 3.3 year period due to disease progression highlighting the need for more effective long-term therapies. 47 Of interest, 12.5% exhibited a conditioning effect after 5 (range 2-18) years emphasizing the need to perform periodic dependency trials during chronic therapy to avoid overuse, as stressed in other neurologic disorders on chronic IVIG therapy.…”

Section: Intravenous Immunoglobulinmentioning

confidence: 93%

“…47 Among the responders, 37.5% had longterm stability without disease progression for 4.3 (range 1-18) year period; the other 29.1%, however, although continued to experience improvement, they also exhibited diminishing benefits after a mean 3.3 year period due to disease progression highlighting the need for more effective long-term therapies. 47 Of interest, 12.5% exhibited a conditioning effect after 5 (range 2-18) years emphasizing the need to perform periodic dependency trials during chronic therapy to avoid overuse, as stressed in other neurologic disorders on chronic IVIG therapy. 43 Based on these 2 large short-term and long-term studies, IVIg is effective in SPS and remains a key immunomodulatory therapy with proven benefit requiring, however, a judicious use for chronic maintenance to avoid overuse and conditioning effects.…”

Section: Intravenous Immunoglobulinmentioning

confidence: 93%

“…46 These issues have been recently addressed in a large study of 36 GAD-positive patients with SPS diagnosed and treated with monthly maintenance IVIg by the same neurologists who determined the long-term effects of IVIg over a 10-year period based on improvement in mRS scores, physician-assessed stiffness, balance, and gait. 47 Continuing benefit was objectively assessed based on performing dependency trials evaluating symptom recurrence after stopping IVIg, prolonging infusion frequency, decreasing monthly dose, or wearing-off effects in-between doses. In this large cohort, 24 of the 36 patients (67%) had a clinically meaningful response over a median 3.3 (range 1-18) year period exhibiting improved gait, posture, and balance and also decreased stiffness, spasms, and startle response; some wheelchair-bound patients and those ambulating with devices walked unassisted.…”

Section: Intravenous Immunoglobulinmentioning

confidence: 99%

“…The experience with long-term IVIG therapy has identified the need for more effective long-term therapies because IVIg-although still beneficial-cannot arrest disease progression in 30% of the patients after a mean period of 4 years. 47 There are arguably challenges in a future study design because in addition to the standard scales of Activities of Daily Living and "time to walk" as used in other autoimmune neurologic diseases, in SPS there is a need to include methods that statistically capture the frequency and severity of episodic spasms and stiffness and the task-specific phobias. The lack of objective laboratory studies of response to therapies, such as MRI imaging as used in patients with MS, is also a major issue because efficacy is essentially based on clinical assessments.…”

Section: Challenges On Therapies and Future Trial Designs In Spsmentioning

confidence: 99%

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Therapies in Stiff-Person Syndrome

Dalakas

2023

Neurol Neuroimmunol Neuroinflamm

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Among the glutamic acid decarboxylase (GAD)-antibody–spectrum disorders, the most common phenotypic subset is the stiff-person syndrome (SPS), caused by impaired GABAergic inhibitory neurotransmission and autoimmunity characterized by very high titers of GAD antibodies and increased GAD-IgG intrathecal synthesis. If not properly treated or untreated because of delayed diagnosis, SPS progresses leading to disability; it is therefore fundamental to apply the best therapeutic schemes from the outset. This article is focused on the rationale of specific therapeutic strategies based on the SPS pathophysiology targeting both the impaired reciprocal GABAergic inhibition to symptomatically improve the main clinical manifestations of stiffness in the truncal and proximal limb muscles, gait dysfunction, and episodic painful muscle spasms and the autoimmunity to enhance improvement and slow down disease progression. A practical, step-by-step therapeutic approach is provided, highlighting the importance of combination therapies with the preferred gamma-aminobutyric acid–enhancing antispasmodic drugs, such as baclofen, tizanidine, benzodiazepines, and gabapentin, that provide the first-line symptomatic therapy, while detailing the application of current immunotherapies with intravenous immunoglobulin (IVIg) plasmapheresis, and rituximab. The pitfalls and concerns of long-term therapies in different age groups, including children, women planning pregnancy, and especially the elderly considering their comorbidities are emphasized, also highlighting the challenges in distinguishing the conditioning effects or expectations of chronically applied therapies from objective meaningful clinical benefits. Finally, the need for future targeted immunotherapeutic options based on disease immunopathogenesis and the biologic basis of autoimmune hyperexcitability are discussed, pointing out the unique challenges in the design of future controlled clinical trials especially in quantifying the extend and severity of stiffness, episodic or startle-triggered muscle spasms, task-specific phobias, and excitability.

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Section: Intravenous Immunoglobulinmentioning

confidence: 93%

Section: Intravenous Immunoglobulinmentioning

confidence: 93%

Section: Intravenous Immunoglobulinmentioning

confidence: 99%

Section: Challenges On Therapies and Future Trial Designs In Spsmentioning

confidence: 99%

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Therapies in Stiff-Person Syndrome

Dalakas

2023

Neurol Neuroimmunol Neuroinflamm

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“…Her current functional status is overall improved from her nadir dysfunction with maintenance IVIg, and hence, this immune therapy will be continued in conjunction with her symptomatic interventions. In fact, a recent study demonstrated that maintenance IVIg can be a durable treatment for patients with SPS (17).…”

Section: Dr Newsome (Neuroimmunology)mentioning

confidence: 99%

Centripetal Nystagmus, Slow Saccades, Cerebellar Ataxia, and Parkinsonism in a Patient With Anti-GAD65-Associated Stiff Person Syndrome Spectrum Disorder

Hac¹,

Murphy²,

Butala³

et al. 2023

Journal of Neuro-Ophthalmology

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:A 68-year-old woman with positional dizziness and progressive imbalance presented for vestibular evaluation. Examination was notable for spontaneous downbeat nystagmus (DBN), horizontal and vertical gaze-evoked nystagmus (GEN) with centripetal and rebound nystagmus, and positional apogeotropic nystagmus. There was also mild–moderate slowing of saccades horizontally and vertically and poor fast phases with an optokinetic stimulus. Further consultation by a movement disorder specialist uncovered asymmetric decrementing bradykinesia and rigidity, masked facies, and a wide-based stance without camptocormia. Screening serum laboratory results for metabolic, rheumatologic, infectious, heavy metal, endocrine, or vitamin abnormalities was normal. Surveillance imaging for neoplasms was unremarkable, and cerebrospinal fluid (CSF) analysis was negative for 14-3-3 and real-time quaking-induced conversion (RT-QuIC). However, her anti-glutamic acid decarboxylase-65 (GAD65) immunoglobulin G (IgG) level was markedly elevated in serum to 426,202 IU/mL (reference range 0–5 IU/mL) and in CSF to 18.1 nmol/L (reference range <0.03 nmol/L). No other autoantibodies were identified on the expanded paraneoplastic panel. The patient was referred to neuroimmunology, where torso rigidity, spasticity, and significant paravertebral muscle spasms were noted. Overall, the clinical presentation, examination findings, and extensive workup were consistent with a diagnosis of anti-GAD65-associated stiff person syndrome-plus (musculoskeletal plus cerebellar and/or brainstem involvement). She was subsequently treated with intravenous immunoglobulin (IVIg) and has been stable since commencing this therapy. In patients with centripetal nystagmus, especially in association with other cerebellar findings, an autoimmune cerebellar workup should be considered.

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Stiff person spectrum disorder diagnosis, misdiagnosis, and suggested diagnostic criteria

Chia

McKeon

Dalakas

et al. 2023

Ann Clin Transl Neurol

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Background: Stiff person spectrum disorder (SPSD) is heterogeneous, and accurate diagnosis can be challenging. Methods: Patients referred for diagnosis/ suspicion of SPSD at the Mayo Autoimmune Neurology Clinic from July 01, 2016, to June 30, 2021, were retrospectively identified. SPSD diagnosis was defined as clinical SPSD manifestations confirmed by an autoimmune neurologist and seropositivity for high-titer GAD65-IgG (>20.0 nmol/L), glycinereceptor-IgG or amphiphysin-IgG, and/or confirmatory electrodiagnostic studies (essential if seronegative). Clinical presentation, examination, and ancillary testing were compared to differentiate SPSD from non-SPSD. Results: Of 173 cases, 48 (28%) were diagnosed with SPSD and 125 (72%) with non-SPSD. Most SPSD were seropositive (41/48: GAD65-IgG 28/41, glycine-receptor-IgG 12/41, amphiphysin-IgG 2/41). Pain syndromes or functional neurologic disorder were the most common non-SPSD diagnoses (81/125, 65%). SPSD patients more commonly reported exaggerated startle (81% vs. 56%, p = 0.02), unexplained falls (76% vs. 46%, p = 0.001), and other associated autoimmunity (50% vs. 27%, p = 0.005). SPSD more often had hypertonia (60% vs. 24%, p < 0.001), hyperreflexia (71% vs. 43%, p = 0.001), and lumbar hyperlordosis (67% vs. 9%, p < 0.001) and less likely functional neurologic signs (6% vs. 33%, p = 0.001). SPSD patients more frequently had electrodiagnostic abnormalities (74% vs. 17%, p < 0.001), and at least moderate symptomatic improvement with benzodiazepines (51% vs. 16%, p < 0.001) or immunotherapy (45% vs. 13% p < 0.001). Only 4/78 non-SPSD patients who received immunotherapy had alternative neurologic autoimmunity. Interpretation: Misdiagnosis was threefold more common than confirmed SPSD. Functional or non-neurologic disorders accounted for most misdiagnoses. Clinical and ancillary testing factors can reduce misdiagnosis and exposure to unnecessary treatments. SPSD diagnostic criteria are suggested.

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

Cited by 24 publications

References 21 publications

Therapies in Stiff-Person Syndrome

Therapies in Stiff-Person Syndrome

Centripetal Nystagmus, Slow Saccades, Cerebellar Ataxia, and Parkinsonism in a Patient With Anti-GAD65-Associated Stiff Person Syndrome Spectrum Disorder

Stiff person spectrum disorder diagnosis, misdiagnosis, and suggested diagnostic criteria

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