Stiff-person Syndrome Research Articles

A Case of Stiff Person Syndrome Treated Using Intrathecal Baclofen

Introduction: Stiff Person Syndrome is a rare autoimmune neurological disorder with chronic muscle spasms leading to chronic pain and debilitation. Case Report: We describe a case of a 57-year-old man with the history of Diabetes mellitus type 1 diagnosed 15 years back with high-titer positive anti-GAD antibodies and poorly controlled blood sugar levels under highly dosed insulin treatment. Discussion: Intrathecal baclofen showed a marked improvement for the relief of spasticity with the choice of a baclofen pump for similar patients.

Early Neuroaxonal Damage in Neurologic Disorders Associated With GAD65 Antibodies.

Neurodegeneration is considered a relevant pathophysiologic feature in neurologic disorders associated with antibodies against glutamic acid decarboxylase 65 (GAD65). In this study, we investigate surrogates of neuroaxonal damage in relation to disease duration and clinical presentation. In a multicentric cohort of 50 patients, we measured serum neurofilament light chain (sNfL) in relation to disease duration and disease phenotypes, applied automated MRI volumetry, and analyzed clinical characteristics. In patients with neurologic disorders associated with GAD65 antibodies, we detected elevated sNfL levels early in the disease course. By contrast, this elevation of sNfL levels was less pronounced in patients with long-standing disease. Increased sNfL levels were observed in patients presenting with cerebellar ataxia and limbic encephalitis, but not in those with stiff person syndrome. Using MRI volumetry, we identified atrophy predominantly of the cerebellar cortex, cerebellar superior posterior lobe, and cerebral cortex with similar atrophy patterns throughout all clinical phenotypes. Together, our data provide evidence for early neuroaxonal damage and support the need for timely therapeutic interventions in GAD65 antibody-associated neurologic disorders.

H - 38 Neuropsychological Evaluation and Cognitive Profile of Stiff Person Syndrome (SPS) in a Predominantly Spanish-Speaking Older Adult: Is Cognition Really Affected?

Stiff Person Syndrome (SPS) is a rare autoimmune disorder that affects approximately one in every million people. It is characterized by progressive muscle rigidity and intense, episodic muscle spasms triggered by environmental and psychosocial (i.e., emotional stress) factors. While original diagnostic criteria for classical SPS included the absence of frank cognitive impairment (aside from what would be expected from seizures), more recent literature suggests a number of neurocognitive difficulties potentially associated with reduced GABA levels. The following case study presents a 73-year-old, predominantly Spanish-speaking man with 14years of education. His medical history is notable for over 20years with diagnosed SPS, hypertension well managed with medications, and the absence of other medical conditions that may contribute to cerebrovascular burden. He completed a comprehensive neuropsychological evaluation in Spanish. Overall, his profile was notable for mild inefficiencies in frontal-subcortical functions, with a relative weakness in rote learning and retention. He performed remarkably well relative to his level of motor compromise. There was no evidence of either a mild or major neurocognitive disorder, and his clinical interview and behavioral inventories were suspicious for a personality disorder. Recent literature proposes SPS is related to impairment in verbal learning, retention, fluency, processing speed, and attention. The present case corroborated, at most, mild inefficiencies in these previously documented areas. Careful consideration should be used in the evaluation of studies on SPS and cognition, particularly in determining whether samples had high degrees of comorbid conditions (i.e., cerebrovascular burden) that could help explain positive findings related to cognition.

The many faces of gastrointestinal dysfunction in stiff person syndrome spectrum disorders.

The effect of stiff person syndrome spectrum disorders (SPSD) on the gastrointestinal tract (GIT) is unknown. This case series aims to characterize the prevalence and types of GI dysfunction in individuals with SPSD. A retrospective chart review included individuals diagnosed with SPSD with descriptors of GI symptoms in their medical records. SPSD phenotypes, type of motility test performed, and dysmotility pattern (upper, lower, or diffuse) were assessed. Descriptive statistics and univariate chi-square analyses were utilized. Of 240 individuals with SPSD, 32% reported GI symptoms, most were female (83.1%), and white (74%), with a median age at time of GI symptom onset of 50 ± 13 years. Most common symptoms reported were dysphagia (45%), constipation (40%), and nausea/vomiting (23%). Most individuals had classic SPS (47%) followed by SPS-plus (29%) and 82.9% were positive for serum antiGAD65 antibodies. Of 36 patients that underwent at least one GI motility test, 26 had evidence of upper, lower, or diffuse GI dysmotility (44.4%, 17%, and 4%, respectively). The group who did not undergo testing had a higher proportion of patients with DM. There is a high prevalence of GI symptoms and transit abnormalities in patients with SPSD. Future prospective, longitudinal studies are warranted to further assess GI symptoms in the context of SPSD and to determine if individuals with GI symptoms differ in prognosis or treatment response from those without GI symptoms. In the meantime, there should be a low threshold for motility testing in patients with SPSD.

THU246 What’s The Importance of GAD Antibodies In Patients With Stiff Person Syndrome

Abstract Disclosure: A. Barnett: None. G. Elshimy: None. Introduction: Stiff Person Syndrome (SPS) has a strong autoimmune component with positive serology for GAD-65 antibody as one of the diagnostic criteria. GAD is an enzyme selectively concentrated in neurons secreting the neurotransmitter gamma-aminobutyric acid (GABA) but is also present in pancreatic beta cells. Hence, insulin-dependent diabetes mellitus (LADA) can develop in patients with SPS. We present two cases that highlight the importance of this association and the difference in the time of onset to ensure appropriate screening. Case: Our first case was a 46-year-old female with systemic sclerosis and SPS that was diagnosed with steroid-induced diabetes in 2012 with HbA1c 8.7% (4.3-6.1%). Her GAD-65 antibody was significantly elevated at 1971 (less than 2nmol/L). For almost 8 years, the patient only required insulin therapy while on high dose steroids, but eventually developed persistent hyperglycemia requiring insulin therapy. Her C-peptide was 0.49 (0.78-5.19ng/mL) with plasma glucose of 201 (74-106mg/dL), consistent with beta-cell dysfunction. The second case was a 60-year-old female with a 20-year history of SPS who was diagnosed with type 2 diabetes in 2014 after receiving high doses of steroids while undergoing chemotherapy for breast cancer. She was initially well-controlled on oral medications until 2 years after her initial diabetes diagnosis where her HbA1c increased rapidly to 8.1% (4.8-5.9%). At that time, she was started on insulin therapy and antibody testing was pursued which showed positive GAD-65 antibody greater than 250 (less than 5IU/mL) consistent with LADA. She had a negative IA-2 antibody undetectable. Due to other autoimmune associations, she was also screened for thyroid disease revealing an elevated TPO-antibody with a normal TSH 4.02 that is being monitored. Discussion: SPS is associated with autoantibodies and other autoimmune disorders including but not limited to type 1 diabetes, anti-thyroglobulin antibodies and anti-parietal cell antibodies. In both cases, the diagnosis of SPS preceded the onset of diabetes then with a latent “honeymoon” phase not requiring long-term insulin therapy for years, most consistent with LADA. However, there are exacerbating factors including high-dose steroids which could be misleading and result in diagnosing these patients with type 2 diabetes initially. It should be taken into consideration that there is variability in the time of onset of beta-cell dysfunction, which varied from 2 to 8 years in our patients. Hence, the recognition of the correlation of autoimmune-mediated diabetes and the variable time course to insulin deficiency is critical for the continued monitoring in patients with SPS. Physicians should be aware of the importance of screening patients with SPS for type 1 diabetes mellitus and differentiate it from steroid-induced type 2 diabetes to avoid developing diabetic ketoacidosis in these patients. Presentation: Thursday, June 15, 2023

THU356 Muscle Pain In A Diabetic: Think Outside The Box

Abstract Disclosure: R. Ellangovan: None. M. Rizk: None. V. Singh MD: None. C. Sherpa: None. Introduction: Stiff person syndrome (SPS) is a rare immunological disorder associated with GAD antibody-spectrum disorders and characterized by rigidity and painful muscle spasms. SPS has a prevalence of 1-2 cases per million and affects females more than men. We present a case of SPS who was admitted for progressive muscle pain and rigidity causing impaired ambulation. Case Presentation: A 60-year-old female with a two-year history of type 2 diabetes, Graves' disease was diagnosed with acral lentiginous melanoma of the left foot. One month after Nivolumab immunotherapy, she converted to type 1 diabetes with low C-peptide and positive GAD antibody. She was admitted with severe muscle pain and spasms in her lower extremities and trunk, debilitating enough to make her bedbound. Her muscle strength and sensory function were intact. MRI of thigh was concerning for myositis versus diabetic myonecrosis. She was initiated on NSAIDs with no improvement. Core muscle biopsy revealed necrosis and granulation tissue with no evidence of malignancy. Extensive work up including myositis panel and myasthenia gravis panel were negative. The presence of GAD antibodies and no improvement to NSAIDs, prompted suspicion for SPS. The patient declined lumbar puncture (LP) for further evaluation. Diazepam showed mild improvement. Due to persistent severe symptoms, she was treated with IVIG for 5 days that resulted in marked improvement. Discussion: There is no gold standard test for definitive diagnosis of SPS. Classic features of SPS include muscle spasms, pain, and rigidity typically involving the trunk and lower extremities. There are GAD antibodies in serum and CSF and glycine receptor or amphiphysin antibodies. EMG study will show continuous motor unit activity in affected muscles. A robust response to muscle relaxants like GABA agonists and exclusion of alternative neurological disorder favors SPS. LP or EMG was not performed on this patient, yet she met other criteria including the presence of other GAD disorders like type 1 diabetes. Current recommended therapy for symptomatic relief includes GABA agonists or baclofen. If no improvement is noted, IVIG can be considered. Plasmapheresis and rituximab have been used with variable efficacy. Prognosis is variable and many patients experience disability despite combining multiple therapies. Hence it is crucial to have a high index of suspicion in GAD spectrum disorders for early recognition and prompt treatment. Presentation: Thursday, June 15, 2023

An update on malignant tumor-related stiff person syndrome spectrum disorders: clinical mechanism, treatment, and outcomes.

Stiff person syndrome (SPS) is a rare central nervous system disorder associated with malignancies. In this review, we retrieved information from PubMed, up until August 2023, using various search terms and their combinations, including SPS, stiff person syndrome spectrum disorders (SPSSDs), paraneoplastic, cancer, and malignant tumor. Data from peer-reviewed journals printed in English were organized to explain the possible relationships between different carcinomas and SPSSD subtypes, as well as related autoantigens. From literature searching, it was revealed that breast cancer was the most prevalent carcinoma linked to SPSSDs, followed by lung cancer and lymphoma. Furthermore, classic SPS was the most common SPSSD subtype, followed by stiff limb syndrome and progressive encephalomyelitis with rigidity and myoclonus. GAD65 was the most common autoantigen in patients with cancer and SPSSDs, followed by amphiphysin and GlyR. Patients with cancer subtypes might have multiple SPSSD subtypes, and conversely, patients with SPSSD subtypes might have multiple carcinoma subtypes. The first aim of this review was to highlight the complex nature of the relationships among cancers, autoantigens, and SPSSDs as new information in this field continues to be generated globally. The adoption of an open-minded approach to updating information on new cancer subtypes, autoantigens, and SPSSDs is recommended to renew our database. The second aim of this review was to discuss SPS animal models, which will help us to understand the mechanisms underlying the pathogenesis of SPS. In future, elucidating the relationship among cancers, autoantigens, and SPSSDs is critical for the early prediction of cancer and discovery of new therapeutic modalities.

Successful treatment of stiff-person syndrome with plasmapheresis: case report and literature review

Stiff-person syndrome (SPS) is a rare neurologic disease, most often caused by autoimmune process during which antibodies against glutamic acid decarboxylase (anti-GAD65) are synthesised. The main clinical symptoms, among which are axial and proximal leg muscle stiffness and painful spasms, are often provoked by external triggers. In addition to those, the disease presents with anxiety, phobias, and other psychiatric symptoms. The most notable SPS comorbidities include temporal lobe epilepsy and type 1 diabetes mellitus. In this article, we present a clinical case of a patient illustrating the course of the disease, diagnostic difficulties, and treatment options, all of which are discussed in the literature review.

Stiff-Leg Syndrome Associated with Autoimmune Retinopathy and Its Treatment with IVIg-A Case Report and Review of the Literature.

Antibodies to glutamic acid decarboxylase (GAD) have been predominantly associated with stiff-person syndrome (SPS), which is often accompanied by organ-specific autoimmune diseases, such as late-onset type 1 diabetes. Autoimmune retinal pathology in SPS has recently been suggested to coexist in patients suffering from this disease; however, evidence reporting potential treatment options for the neurological and visual symptoms these patients experience remains scarce. We provide a review of the relevant literature, presenting a rare case of a middle-aged woman with autoimmune retinopathy (AIR) followed by stiff-leg syndrome who responded to intravenous immune globulin treatment (IVIg). Our report adds to previously reported data supporting the efficacy of IVIg in SPS spectrum disorders while also proposing the potential effect of IVIg in treating SPS spectrum patients with coexisting AIR.

Prevalence, Clinical Profiles, and Prognosis of Stiff-Person Syndrome in a Japanese Nationwide Survey.

To elucidate current epidemiologic, clinical, and immunologic profiles and treatments of stiff-person syndrome (SPS) in Japan. A nationwide mail survey was conducted using an established method. Data processing sheets were sent to randomly selected departments of internal medicine, neurology, pediatrics, psychiatry, and neurosurgery in hospitals and clinics throughout Japan to identify patients with SPS who were seen between January 2015 and December 2017. Thirty cases were identified as glutamic acid decarboxylase 65 (GAD65)-positive SPS cases on the basis of detailed clinical data of 55 cases. Four patients had α1 subunit of glycine receptor (GlyR) antibodies, and 1 patient had both GAD65 and GlyR antibodies. The total estimated number of patients with GAD65-positive SPS was 140, and the estimated prevalence was 0.11 per 100,000 population. The median age at onset was 51 years (range, 26-83 years), and 23 (76%) were female. Of these, 70% had classic SPS, and 30% had stiff-limb syndrome. The median time from symptom onset to diagnosis was significantly longer in the high-titer GAD65 antibody group than in the low-titer group (13 months vs 2.5 months, p = 0.01). The median modified Rankin Scale (mRS) at baseline was 4, and the median mRS at the last follow-up was 2. Among the 29 GAD65-positive patients with ≥1 year follow-up, 7 received only symptomatic treatment, 9 underwent immunotherapy without long-term immunotherapy, and 13 received long-term immunotherapy such as oral prednisolone. The coexistence of type 1 diabetes mellitus and the lack of long-term immunotherapy were independent risk factors for poor outcome (mRS ≥3) in the GAD65-positive patients (odds ratio, 15.0; 95% CI 2.6-131.6; p = 0.001; odds ratio, 19.8; 95% CI 3.2-191.5; p = 0.001, respectively). This study provides the current epidemiologic and clinical status of SPS in Japan. The symptom onset to the diagnosis of SPS was longer in patients with high-titer GAD65 antibodies than in those with low-titer GAD65 antibodies. The outcome of patients with SPS was generally favorable, but more aggressive immunotherapies are necessary for GAD65-positive patients with SPS.

Stiff Person Syndrome Mimicking as Atypical Parkinson’s Disease - A Diagnostic Dilemma

Stiff person syndrome (SPS) is a rare neurological disorder characterized by stiffness and spasm of the truncal muscles and subsequent postural deformities. In this report, we present a case of a woman in her early 60s who presented to us with muscle stiffness, back pain, and frequent falls. On examination, she was found to have increased muscle tone and mild tremors. Given her age and presentation, a provisional diagnosis of Atypical Parkinson’s was made. Patient was treated with Diazepam. Because of presence of autoimmune co-morbid conditions, anti-glutamic acid decarboxylase (GAD) antibodies were tested, which were positive, and thus, diagnosis of SPS was made. Treatment with Diazepam was continued, and her symptoms significantly improved. Even though SPS is a rare disorder, our case report highlights the need to keep it in differential diagnoses when an elderly patient presents with stiffness and postural instability, as treatment for SPS and atypical Parkinson’s vary considerably.

Efgartigimod beyond myasthenia gravis: the role of FcRn-targeting therapies in stiff-person syndrome.

Stiff-person syndrome (SPS) is a rare autoimmune neurological disorder characterized by high titers of antibodies against glutamic acid decarboxylase (GAD) causing impaired GABAergic inhibitory neurotransmission. To date, there is not a defined therapy for such condition, but immunomodulating therapies, such as plasma exchange, intravenous immunoglobulins, and rituximab, have been widely used in clinical practice. However, the efficacy and tolerability of these treatments is not well established. Efgartigimod, a new neonatal Fc receptor (FcRn) blocker, is a human IgG1 antibody Fc fragment engineered with increased affinity for FcRn binding, leadingto areduction in IgGs levels, includingpathogenic IgG autoantibody showing promising results in neurological autoimmune disorders and has been approved for the treatment of AChR-seropositive generalizedmyasthenia gravis (MG). In this study, we report and describe the first data on treatment with efgartigimod in three patients affected by both AChR-seropositive generalized MG and anti-GAD-seropositive SPS. Patients were followed since the start of efgartigimod and for the whole treatment period (12weeks). MG symptoms were assessed with the "MG activity of daily living score" and the Quantitative Myasthenia Gravis score, while SPS ones were assessed with the "SPS activity of daily living score"; muscle strength was assessed with the Medical Research Council Sum score; the overall disability from MG and SPS was assessed by the modified Rankin Scale. All patients showed an improvement in symptoms of both SPS and MG after 2 cycles of treatment. Our data suggest that efgartigimod may be considered as a candidate drug for SPS and other autoantibody-mediated neurological disorders.

Clinical presentation, comorbidities and treatment of GAD antibodies associated Stiff Person Syndrome

Clinical presentation, comorbidities and treatment of GAD antibodies associated Stiff Person Syndrome

Quality of Life of Patients with Stiff Person Syndrome

Aim: This study aimed to identify the factors that significantly affect the quality of life (QoL) of patients with Stiff-Person syndrome (SPS) by examining their physical, psychological, and social aspects using questionnaires. Methods: This cross-sectional study included 23 patients with SPS. Data were collected using several questionnaires. Patient QoL was quantified using the EuroQoL-5-Dimention 5-Level; sociodemographic characteristics and other relevant variables were examined. Results: QoL was poorer for patients with SPS than those with moderate to severe Alzheimer’s disease. Several important factors for patients’ QoL have been identified, including difficulty in breathing, pain, mobility issues leading to difficulty performing daily activities, depressive symptoms inherent to SPS, and insufficient social support. Conclusion: Factors that significantly influenced the QoL of patients with SPS were related to multiple aspects of their lives. We evaluated all previously used methods. A disease-specific evaluation form is required to assess these patients thoroughly.

Progressive Encephalomyelitis with Rigidity and Myoclonus with an Aggressive Presentation Mimicking Septic Shock: A Pediatric Case Report and Literature Review

AbstractProgressive encephalomyelitis with rigidity and myoclonus (PERM) is a relapsing–remitting neurological disorder that falls within the stiff person syndrome–spectrum disorders. We report a 16-year-old girl with PERM associated with an anti-glutamic acid decarboxylase (GAD) antibody. She had an aggressive initial presentation mimicking fulminant septic shock, followed by truncal and lower limb rigidity, stimulus-sensitive spasm, cognitive impairment, brainstem signs (hyperekplexia, nystagmus), and dysautonomia (urinary retention, constipation, facial flushing, blood pressure fluctuation). Cerebrospinal fluid, electroencephalography, and magnetic resonance imaging of the brain and spine showed features suggestive autoimmune encephalitis and myelitis. The serum anti-GAD antibody was positive, and the diagnosis of PERM was made. She had fluctuating clinical response despite intravenous immunoglobulin, steroids, plasmapheresis, and symptomatic medications. Eventually, in the fourth month since admission, she showed gradual and persistent clinical improvement after introducing rituximab. She was discharged after 6 months of hospitalization, and no relapse was observed in the first 3 years of follow-up.PERM is a rare and underrecognized condition in children. Contrary to previous reports, our case describes an aggressive and life-threatening presentation for PERM. Vague symptoms and the lack of gold diagnostic tests hinder a timely diagnosis. Our study also highlights the need for developing standardized diagnostic criteria and consensus in managing PERM.

Stiff-Person Syndrome

Stiff-person syndrome (SPS) is a rare autoimmune neurological disorder characterized by progressive axial muscle stiffness, central nervous system hyper-excitability, and painful stimulus-sensitive muscle spasms. SPS is classified into classic SPS and SPS variants, including stiff-limb syndrome (SLS) and progressive encephalomyelitis with rigidity and myoclonus (PERM), based on clinical presentation. SPS responds to immunotherapy, and several autoantigens have been identified. Most patients with SPS have high-titers of antibodies against glutamic acid decarboxylase (GAD), the rate-limiting enzyme for the synthesis of γ-aminobutyric acid (GABA), and up to 15% of the patients have antibodies against the glycine receptor α-subunit.

Quality of Life in Patients with Stiff-Person Syndrome: Evaluation Congruent with Patient Values using the Schedule-Direct Weighting Method

Patients with chronic progressive disease have a low health-related quality of life (HRQoL); however, various compensation mechanisms can improve and restore quality of life (QoL) even in cases of severe physical disability. In this study, we evaluate QoL according to patient value by individual QoL evaluation and identify QoL determinants in patients with stiff-person syndrome (SPS) to consider appropriate support measures. By 13 December 2020, SPS patients completed semi-structured interviews. For patients, the positive factors were "family support" and "parental care", while the negative factors were "physical symptoms" and "relationship with doctors". Parental care" was identified as the most important area, but satisfaction was low. Therefore, in each case, support is needed to ensure that the patient is satisfactory. In addition, "physical symptoms" are the strongest negative areas and can be alleviated with appropriate medical assistance. In addition, rehabilitation should work on pain relief caused by muscle spasms and stiffness.

Stiff-Person syndrome: A rare neurological disorder

The Stiff-person syndrome (SPS) is an uncommon disorder characterized by progressive rigidity, muscle stiffness, and spasm involving the axial muscles, resulting in severe impairment of ambulation. We present the case of a 49-year-old gentleman with recent onset of progressive asymmetric spastic ataxia, subsequently diagnosed with SPS.

N°368 – Non-neurologic diseases mimicking stiff person syndrome

In climate modelling, a critical issue is the accurate representation of urban areas in space and variation over time. Urban features may be parameterised through urban canopy parameters (UCPs), including the impervious surface area (ISA). One of the aims of the Consortium for Small-scale Modelling (COSMO) and the CLM-Community is to improve urban numerical weather prediction (NWP) and climate simulations by implementing the urban canopy scheme TERRA_URB in the ICOsahedral Nonhydrostatic (ICON) modelling framework. To harmonise and update the datasets adopted for the UCPs, the Consortium has launched the Priority Project “City Induced Temperature change Through A'dvanced modelling” (PP CITTÀ). Within this framework, the study explores recent and detailed land cover datasets to update ISA and harmonise it with datasets adopted for the UCPs. We identify and compare some relevant datasets at the pan-European level. The results show the benefits obtained by correlating the UCPs from urban Local Climate Zones taken from the ECOCLIMAP-Second Generation with the ISA depending on the imperviousness degree provided by the Copernicus Land Monitoring Service. These results will foster an updating of NWP and climate models with urban surface parameterisations to match urban features while avoiding inconsistencies consistently.

Stiff person syndrome revealing a LADA

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)