[A case of Stiff-person syndrome with muscle tonicity of the extremities and neck after use of Dulvalumab for lung adenocarcinoma].

A 74-year-old woman taking dulvalumab for lung adenocarcinoma developed muscle tonicity in the extremities and trunk. Painful paroxysmal muscle spasms with profuse sweating were frequently observed, and surface electromyography showed simultaneous contraction of the active and antagonist muscles. Blood tests were strongly positive for anti-amphiphysin antibodies, and stiff-person syndrome (SPS) was diagnosed. Intravenous immunoglobulin therapy and clonazepam were initiated, and the paroxysmal painful muscle spasms disappeared. As the primary tumor was under control, and the onset occurred approximately six weeks after the resumption of immune checkpoint inhibitors, we considered SPS to be an immune-related adverse event. Although extremely rare, it should be considered a neuromuscular disease that can occur in association with immune checkpoint inhibitors.

Axial dystonia as a manifestation of stiff-person syndrome in a paediatric patient.

Stiff-person syndrome (SPS) is a rare neurological condition that frequently affects adults, with the neurologist diagnosing only one or two cases during his or her career. Reports of paediatric SPS are exceedingly rare, with less than 20 cases described in the literature.The patient presented was initially diagnosed with a functional movement disorder then a genetic dystonia, with a poor response to treatment trials and negative genetic testing. Consideration of Wilson's disease was refuted with non-supportive investigations and assessments.We aim to present the long road to diagnosing our first paediatric patient with SPS, who presented in middle childhood.

Remimazolam and Remifentanil Anesthetics for an Adolescent Patient with Stiff-Person Syndrome: A Case Report.

Stiff-person syndrome (SPS) is a rare autoimmune disease characterized by fluctuating rigidity and stiffness of the axial muscles. There are no reports on the use of remimazolam in a patient with SPS. A 16-year-old Japanese woman with SPS was scheduled to undergo intrathecal baclofen pump exchange. General anesthesia was induced and maintained using remimazolam, remifentanil, and intermittent rocuronium bromide. No intraoperative mobility or significant autonomic symptoms were observed. Additionally, electroencephalographic signature showed sufficient anesthetic depth. The patient's emergence from general anesthesia was uneventful. In conclusion, remimazolam could be considered an effective anesthetic drug for patients with SPS.

A case report of integrating Chinese and Western medicine: A new era in the treatment of stiff person syndrome.

RATIONALE: At present, there are limitations to the treatment of stiff person syndrome (SPS). Current treatments are still ineffective or financially burdensome for some patients, so it is imperative to explore more appropriate treatments for patients. This is a case report of a SPS with a more significant effect of combined Chinese and Western medicine, which may provide new treatment ideas for other patients. PATIENT CONCERNS: This patient presented with episodes of stiffness and pain in the lower back and lower extremities. His electromyography shows continued activation of normal motor units in the paraspinal and abdominal muscles. However, relevant laboratory tests including glutamic acid decarboxylase antibody and Amphiphysin antibody were negative. After a period of treatment including clonazepam, baclofen, prednisone and intravenous immunoglobulin, this patient experiences a shortened maintenance period of medication, accompanied by symptoms such as emotional anxiety and cognitive decline, which severely affects his life. DIAGNOSES: This patient was diagnosed with SPS. INTERVENTIONS: In May 2022 the patient decided to combine Chinese medicine for simultaneous treatment. OUTCOMES: During the period of simultaneous treatment with Chinese and Western medicine, the patient experienced remission of clinical symptoms, reduction of concomitant symptoms and improved quality of life. CONCLUSION: A combination of Western and Chinese medicine was effective in relieving this patient pain and stiffness and reducing the patient anxiety. Combined Chinese and Western medicine treatment may be able to bring better results to more patients with stiff person syndrome.

Glycine Receptor ß-Targeting Autoantibodies Contribute to the Pathology of Autoimmune Diseases.

BACKGROUND AND OBJECTIVES: Stiff-person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM) are rare neurologic disorders of the CNS. Until now, exclusive GlyRα subunit-binding autoantibodies with subsequent changes in function and surface numbers were reported. GlyR autoantibodies have also been described in patients with focal epilepsy. Autoimmune reactivity against the GlyRß subunits has not yet been shown. Autoantibodies against GlyRα1 target the large extracellular N-terminal domain. This domain shares a high degree of sequence homology with GlyRß making it not unlikely that GlyRß-specific autoantibody (aAb) exist and contribute to the disease pathology. METHODS: In this study, we investigated serum samples from 58 patients for aAb specifically detecting GlyRß. Studies in microarray format, cell-based assays, and primary spinal cord neurons and spinal cord tissue immunohistochemistry were performed to determine specific GlyRß binding and define aAb binding to distinct protein regions. Preadsorption approaches of aAbs using living cells and the purified extracellular receptor domain were further used. Finally, functional consequences for inhibitory neurotransmission upon GlyRß aAb binding were resolved by whole-cell patch-clamp recordings. RESULTS: Among 58 samples investigated, cell-based assays, tissue analysis, and preadsorption approaches revealed 2 patients with high specificity for GlyRß aAb. Quantitative protein cluster analysis demonstrated aAb binding to synaptic GlyRß colocalized with the scaffold protein gephyrin independent of the presence of GlyRα1. At the functional level, binding of GlyRß aAb from both patients to its target impair glycine efficacy. DISCUSSION: Our study establishes GlyRß as novel target of aAb in patients with SPS/PERM. In contrast to exclusively GlyRα1-positive sera, which alter glycine potency, aAbs against GlyRß impair receptor efficacy for the neurotransmitter glycine. Imaging and functional analyses showed that GlyRß aAbs antagonize inhibitory neurotransmission by affecting receptor function rather than localization.

Successful Autologous Hematopoietic Stem Cell Transplant in Glycine Receptor Antibody-Positive Stiff Person Syndrome: A Case Report

BACKGROUND AND OBJECTIVES: To describe a case of glycine receptor (GlyR) antibody-positive stiff person syndrome (SPS) treated with autologous hematopoietic stem cell transplant (aHSCT). METHODS: This was a multicenter collaboration for the treatment of a single patient who underwent aHSCT as part of a clinical trial (NCT00716066). To objectively assess the response to transplantation, several clinical outcome measures were evaluated pretransplant and up to 18 months post-transplant, including modified Rankin Score (mRS), stiffness index, Hauser Ambulation Score (HAS), hypersensitivity index, timed 25-foot walk, and Montreal Cognitive Assessment. RESULTS: After transplant, the patient achieved sustained clinical improvement evidenced across various clinical scales, including mRS, stiffness index, HAS, and 25-foot walk time. DISCUSSION: aHSCT represents a promising treatment option for SPS, including for GlyR-positive patients. In addition, this case represents the need to validate and standardize best clinical outcome measures for patients with SPS. CLASSIFICATION OF EVIDENCE: Class IV; this is a single observational study without controls.

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, leading to a reduction in IgGs levels, including pathogenic IgG autoantibody showing promising results in neurological autoimmune disorders and has been approved for the treatment of AChR-seropositive generalized myasthenia 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 (12 weeks). 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.

Early Neuroaxonal Damage in Neurologic Disorders Associated With GAD65 Antibodies.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. DISCUSSION: Together, our data provide evidence for early neuroaxonal damage and support the need for timely therapeutic interventions in GAD65 antibody-associated neurologic disorders.

Severe Stiff-Person Syndrome After COVID: The First Video-Documented COVID Exacerbation and Viral Implications

OBJECTIVES: To describe a patient with mild GAD-positive stiff-leg syndrome (SLS) who developed severely disabling stiff-person syndrome (SPS) 1 week after mild COVID-19 and discuss the impact of viral implications. METHODS: Video-documented serial clinical observations at baseline, after acute COVID-19, and after IVIG treatments. RESULTS: A 39-year-old man with left-SLS was stable during a 2-year follow-up with low-dose antispasmodics, working fully and functioning normally, even able to run. One week after mild COVID-19, he started to experience generalized SPS symptomatology that steadily worsened the following 2-3 weeks, becoming unable to walk, requiring a walker, with significant thoracolumbar and bilateral leg stiffness and spasms. GAD ab were very high. After 3 monthly IVIg infusions he showed improvements, but his gait remains significantly stiff. All clinical changes, from baseline to post-Covid, and then post- IVIg have been video-documented. DISCUSSION: This is the first, clearly documented, severe GAD-positive SPS after COVID-19. Although viral or postviral causation can be incidental, the temporal connection with acute COVID-19, the severe disease worsening after symptom-onset, and the subsequent steady improvement after IVIg, suggest viral-triggered autoimmunity. Because COVID-19 reportedly can trigger or worsen GAD-associated diabetes type 1 through proinflammatory mediators, and SPS has been reportedly triggered by West Nile Virus, possibly through molecular mimicry, this case of acutely converting GAD-SLS to GAD-SPS suggest the need to explore viral etiologies in patients with GAD-SPS experiencing acute, long-lasting episodic exacerbations of stiffness and spasms.

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

BACKGROUND AND OBJECTIVES: To elucidate current epidemiologic, clinical, and immunologic profiles and treatments of stiff-person syndrome (SPS) in Japan. METHODS: 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. RESULTS: 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). DISCUSSION: 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.

Diabetes in stiff-person syndrome.

Anti-glutamic acid decarboxylase (GAD) autoantibodies are a hallmark of stiff-person syndrome (SPS) and insulin-dependent diabetes mellitus (IDDM). However, patients with concurrent IDDM and SPS often manifest insulin resistance, and SPS-associated IDDM probably has heterogeneous causes. Some patients manifest IDDM associated only with high titers of anti-GAD65 caused by SPS. By contrast, other patients develop IDDM only after being treated with high-dose corticosteroids or they progress to insulin dependency following their treatment with high-dose corticosteroids. The profile of autoantibodies differs markedly between type 1 diabetes mellitus (T1DM), late-onset diabetes mellitus, and SPS-associated IDDM. Therefore, as with new-onset diabetes after transplantation (NODAT), SPS-associated IDDM should be classified as a specific diabetes entity, the pathophysiology of which requires increased attention.

[Stiff person syndrome associated with thymoma]. / Síndrome de la persona rígida asociado a timoma.

Stiff-person syndrome is a rare neurological condition characterized by muscular rigidity of the trunk and extremities and muscle spasms triggered by sensory or emotional stimuli, which progresses towards prostration. It has a pathophysiogenic mechanism with an immunological basis, in which autoantibodies, such as antiGAD65, play a central role. Likewise, the detection of these antibodies corroborates the diagnosis in a patient with a suggestive clinical picture. Four to 6% of cases have underlying neoplasms. Treatment is based on symptomatic, immunomodulatory, and underlying disease management in paraneoplastic cases. We report a case of classic stiff person syndrome associated with thymoma and review the main characteristics of this entity.

El síndrome de persona rígida es un cuadro neurológico infrecuente caracterizado por rigidez muscular de tronco y extremidades y espasmos musculares gatillados por estímulos sensoriales o emocionales, que progresa hacia la postración. Cuenta con un mecanismo fisiopatogénico con base inmunológica, en el cual los autoanticuerpos, como el antiGAD65, cumplen un rol central. Asimismo, la detección de dichos anticuerpos corrobora el diagnóstico ante un paciente con cuadro clínico sugestivo. Un 4 a 6% de los casos tienen neoplasias subyacentes. El tratamiento se basa en el manejo sintomático, inmunomodulador y de la enfermedad de base en los casos paraneoplásicos. Reportamos un caso de síndrome de persona rígida clásico asociado a timoma y describimos las características principales de esta entidad.

[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.

Rare Association of Autoimmune Limbic Encephalitis and Stiff Person Syndrome.

Antibodies to Glutamic Acid Decarboxylase (GAD) have been implicated in the pathogenesis of both autoimmune Limbic Encephalitis (LE) and Stiff Person Syndrome (SPS). However, their association is quite rare. We present a case of a 48-year-old Caucasian female who presented with symptoms of recurrent severe headaches, behavioral and cognitive dysfunction, and an episode of seizure. She was found to have high titers of anti-GAD65 antibodies in both cerebrospinal fluid and serum. She was diagnosed with LE and SPS, and was started on immunosuppressive therapy with steroids and intravenous immunoglobulins (IVIG). The patient responded well to treatment with improvement in her symptoms.

Respiratory symptoms are common in stiff person syndrome spectrum disorders and are associated with number of body regions involved.

BACKGROUND AND PURPOSE: Stiff person syndrome (SPS) spectrum disorders (SPSSD) cause spasms and rigidity throughout different body regions and can be associated with apnea and acute respiratory failure. There are limited data on the prevalence and predictors of respiratory symptoms with spasms (RSwS) in SPSSD. We sought to characterize the spirometry patterns and the frequency and predictors of RSwS in a large SPSSD cohort. METHODS: Participants were recruited from the Johns Hopkins SPS Center between 1997 and 2021, as part of an ongoing, longitudinal observational study. Medical records were reviewed to assess demographics and clinical characteristics. Data were analyzed using descriptive statistics and multivariable logistic regression models. RESULTS: One-hundred ninety-nine participants (mean age = 53.4 ± 13.6 years, median time to diagnosis = 36 [IQR 66] months, 74.9% women, 69.8% White, 62.8% classic SPS phenotype) were included in final analyses; 35.2% of participants reported RSwS, of whom 24.3% underwent spirometry as part of routine clinical care. Obstructive (23.5%) and restrictive (23.5%) patterns were most commonly observed in those with SPSSD. An increasing number of body regions involved predicted the presence of RSwS (odds ratio [OR] = 1.95, 95% confidence interval [CI] = 1.50-2.53); those with ≥5 body regions involved (vs. ≤4) had higher odds (OR = 6.19, 95% CI = 2.81-13.62) of experiencing RSwS in adjusted models. Two patients died from SPSSD-associated respiratory compromise. CONCLUSIONS: RSwS are common in SPSSD and may be predicted by an increasing number of body regions involved by SPSSD. Close clinical monitoring and having a low threshold to obtain spirometry should be considered in people with SPSSD.

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

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), glycine-receptor-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.

A loss-of-function variant in canine GLRA1 associates with a neurological disorder resembling human hyperekplexia.

Hereditary hyperekplexia is a rare neuronal disorder characterized by an exaggerated startle response to sudden tactile or acoustic stimuli. In this study, we present a Miniature Australian Shepherd family showing clinical signs, which have genetic and phenotypic similarities with human hereditary hyperekplexia: episodes of muscle stiffness that could occasionally be triggered by acoustic stimuli. Whole genome sequence data analysis of two affected dogs revealed a 36-bp deletion spanning the exon-intron boundary in the glycine receptor alpha 1 (GLRA1) gene. Further validation in pedigree samples and an additional cohort of 127 Miniature Australian Shepherds, 45 Miniature American Shepherds and 74 Australian Shepherds demonstrated complete segregation of the variant with the disease, according to an autosomal recessive inheritance pattern. The protein encoded by GLRA1 is a subunit of the glycine receptor, which mediates postsynaptic inhibition in the brain stem and spinal cord. The canine GLRA1 deletion is located in the signal peptide and is predicted to cause exon skipping and subsequent premature stop codon resulting in a significant defect in glycine signaling. Variants in GLRA1 are known to cause hereditary hyperekplexia in humans; however, this is the first study to associate a variant in canine GLRA1 with the disorder, establishing a spontaneous large animal disease model for the human condition.