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

Chia, N.; McKeon, Andrew; Dalakas, Marinos C.; Flanagan, Eoin P.; Bower, James H.; Klassen, Bryan T.; Dubey, Divyanshu; Zalewski, Nicholas L.; Duffy, Dustin; Pittock, Sean J.; Ζεκερίδου, Αναστασία

doi:10.1002/acn3.51791

Cited by 18 publications

(13 citation statements)

References 37 publications

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“…A recent study from the Mayo Clinic also enhances the common SPS misdiagnoses highlighting that most of the patients referred as SPS actually had functional disorders, resulting in unnecessary and expensive therapies. 11 Another concern with IVIg therapy in the elderly is the frequent observation of a conditioning effect, seen more often with intravenous therapies. Even if IVIg is initially effective, older patients tend to exhibit earlier declining benefits and conditioning effects compared to their younger counterparts, requesting maintenance IVIg on a regular basis, even if there is no longer any significant benefit, due to their perception that it helps fatigue and pain but mostly reduces their fear that discontinuation will worsen the disease.…”

Section: Discussionmentioning

confidence: 99%

“…In summary, and in spite of the study limitations mostly related to a small number of patients with LOSPS, the data carefully dissected among the large number of SPS patients our group has been personally following, 11 clearly show that LOSPS is not only frequently missed due to low suspicion of the disease in the elderly because their complex symptomatology of painful spasms and anxiety-driven stiffness are easily attributed to other conditions, but also because of the need for multi-disciplined care to avoid rapidly evolving disability. It is essential therefore to coordinate their care with support from the family members and the other providers to properly address all their physical and psychological needs they face from the outset.…”

Section: Discussionmentioning

confidence: 99%

“…In a recent series of 173 patients, referred for SPS based on clinical presentation, symptom onset above the age 60 was not infrequent. 11 In our retrospective review of 36 patients (29 women and 7 men) treated by our group over the span of 12 years with maintenance Intravenous Immune globulin (IVIg), the median current age of patients was 58 years. 12 The cut-off limit above the age of 60 in defining LOSPS is therefore representative of a subgroup of patients outside the typical range at disease onset.…”

Section: Introductionmentioning

confidence: 99%

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Late-onset stiff-person syndrome: challenges in diagnosis and management

Dalakas,

2023

Ther Adv Neurol Disord

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Background: Stiff person syndrome (SPS) is a rare slowly progressive autoimmune neuronal hyperexcitability disease with very-high GAD-65 antibody titers that most commonly presents above the age of 20, with muscle stiffness, painful muscle spasms, slow gait, and falls leading to disability. In other autoimmune disorders, late-onset disease has different symptom-spectrum and outcomes, but there is no information regarding late-onset SPS (LOSPS). Objective: Highlight delayed diagnosis and poor tolerance or incomplete response to therapies of patients with LOSPS and outline how best to increase disease awareness early at onset. Design: A retrospective chart review.Methods: We reviewed GAD-positive SPS patients with symptom onset above age 60, identified among 54 SPS patients, examined, treated and followed-up by the same clinicians, focused on clinical presentation, misdiagnoses, response and tolerance to therapies, and evolved disability. Results: Nine patients had LOSPS with symptom onset at median age of 61 years (range 60–78), and current median age of 73. The median time from symptom onset to SPS diagnosis was 3 years; prior to diagnosis, five patients were treated for lumbosacral radiculopathies (one with laminectomy), two for Parkinson’s disease, one for multiple sclerosis, and another for cerebellar degeneration. Progressive decline occurred rapidly in all patients; at time of diagnosis, six patients were already using a cane or walker and two were wheelchair-bound. Tolerance and response to treatment were limited; two patients did not respond to IVIg, two discontinued IVIg despite early response due to comorbidities (cardiac disease, thrombosis), four others partially responded to IVIg and one to rituximab; several could not tolerate high doses of oral antispasmodics due to somnolence; and two patients died. Conclusions: LOSPS is almost always misdiagnosed for other similar conditions commonly seen in the elderly. Patients with LOSPS decline quickly to clinically severe disease due to delayed treatment initiation, poor response or tolerance, other comorbidities, and possibly immunosenescence. Increased awareness that SPS can occur in the elderly mimicking other disorders is important for early diagnosis and treatment, even necessitating earlier immunotherapy initiation, compared to their younger counterparts, to prevent faster-evolving severe disability.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Late-onset stiff-person syndrome: challenges in diagnosis and management

Dalakas,

2023

Ther Adv Neurol Disord

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“…Amphiphysin autoantibodies were reported to occur in 26 of 1816 (1.43%) schizophrenic patients and in 35 of 2391 (1.46%) of controls (Daguano Gastaldi et al, 2022). Amphiphysin antibodies are known to be associated with stiff person syndrome (Chia et al, 2023;Dalakas et al, 2022) or paraneoplastic neurological syndromes. However, their role in schizophrenia is completely unknown; it may be attributable to the effects of amphiphysin antibodies on synaptic vesicular transport dynamics via dynamin on nerve endings (David et al, 1996) that interfere with synaptic transmission.…”

Section: Amphiphysin Autoantibodiesmentioning

confidence: 99%

Current Findings on the Spectrum of Neuronal Autoantibodies Associated with Psychotic Disorders

Hansen

2023

J. Psychol. Psychother.Res

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Background: Neural autoantibodies are observed in a subtype of psychotic disorders ranging from first-episode psychosis to schizophrenia. The clinical spectrum has so far been incompletely described, as new neuronal autoantibodies are emerging in the context of psychosis. This review is dedicated to describing the current spectrum of neural autoantibodies associated with psychotic disorders. Methods: In our narrative review, we searched for neural autoantibodies addressed in the PubMed database in the last 15 years focusing on the last three years after publication of the international guidelines for autoimmune psychosis. We relied on small and large cohort studies and case series descriptions related to neural autoantibodies in psychotic disorders. Results: Mainly neural autoantibodies against membrane surface structures such as N-Methyl-D-aspartate receptors (NMDAR) and against intracellular targets are present in psychotic disorders, but also in healthy controls. There is current suspicion that these neuronal autoantibodies (ie., NMDAR autoantibodies) play a potentially relevant role in the development of brain pathologies in psychotic disorders, especially when detected in cerebrospinal fluid. Autoantibodies against cell adhesion molecules and synaptic proteins such as neuronal cell adhesion molecule 1 (NCAM1) and antigen neurexin 1 alpha (NRXN1)-alpha occur in schizophrenia, but not in controls, suggesting that these are highly disease-specific antibodies. These lines of evidence are further supported by animal-model evidence showing a role of these autoantibodies in brain pathology and the development of schizophrenia-like symptoms. Conclusions: In recent years, a new landscape of potentially relevant neural autoantibodies has emerged in a subtype of psychotic disorders. Their significance remains unclear. Large-scale investigations should particularly investigate what triggers the pathogenicity of these autoantibodies, as they probably do not cause the psychotic disorder per se, but might be involved as one factor in the immunopathophysiology. Psychotic disorders remain elusive, and differential diagnosis is required to determine the role neural autoantibodies play in the manifestation of psychoses.

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“…Relevant for SPSD in particular is the issue of low titer-positive GAD65 antibodies. Chia and colleagues reported GAD65 antibody positivity (mostly low titer) in 60% of patients misdiagnosed as having SPSD [ 33 ]. Low-titer GAD65 antibodies can occur as a non-specific finding, even in the healthy population [ 34 , 35 ].…”

Section: The Diagnosis—about Swallows Summers and Antibodiesmentioning

confidence: 99%

Stiff Person Spectrum Disorders—An Update and Outlook on Clinical, Pathophysiological and Treatment Perspectives

Vlad,

Wang,

Newsome

et al. 2023

Biomedicines

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Stiff person spectrum disorders (SPSD) are paradigm autoimmune movement disorders characterized by stiffness, spasms and hyperekplexia. Though rare, SPSD represent a not-to-miss diagnosis because of the associated disease burden and treatment implications. After decades as an enigmatic orphan disease, major advances in our understanding of the evolving spectrum of diseases have been made along with the identification of multiple associated autoantibodies. However, the most important recent developments relate to the recognition of a wider affection, beyond the classic core motor symptoms, and to further insights into immunomodulatory and symptomatic therapies. In this review, we summarize the recent literature on the clinical and paraclinical spectrum, current pathophysiological understanding, as well as current and possibly future therapeutic strategies.

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

Cited by 18 publications

References 37 publications

Late-onset stiff-person syndrome: challenges in diagnosis and management

Late-onset stiff-person syndrome: challenges in diagnosis and management

Current Findings on the Spectrum of Neuronal Autoantibodies Associated with Psychotic Disorders

Stiff Person Spectrum Disorders—An Update and Outlook on Clinical, Pathophysiological and Treatment Perspectives

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