[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.

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.

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.

Therapies in Stiff-Person Syndrome: Advances and Future Prospects Based on Disease Pathophysiology.

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.

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

ABSTRACT: 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.

[Isolated ACTH deficiency clinically presented as stiff-person syndrome, successfully treated by hormonal replacement: a case report].

A 65-year-old man was admitted to our hospital with a 6-year history of painful muscle stiffness in his trunk and lower limbs, preventing him from walking. Stiff-person syndrome (SPS) was diagnosed because the patient had symptoms of painful muscle spasms elicited by tactile stimulation without joint contracture. Although SPS- related autoantibodies in the serum, including anti-glycine R, anti-amphiphysin, anti-glutamic acid decarboxylase (GAD), anti-dipeptidyl peptidase-like protein (DPPX) and anti-γ-aminobutyric acid-A (GABAA) R, were negative, the ACTH and cortisol levels were low. On the basis of additional loading tests for anterior pituitary function and ACTH, isolated ACTH deficiency (IAD) was diagnosed. Hormonal replacement therapy with hydrocortisone at 15 mg/day ameliorated the condition quickly, and the patient became asymptomatic after three months. Flexion contractures have been reported as musculoskeletal symptoms of IAD, but are not usually evident in patients with SPS. The present case illustrates that the painful muscle spasms elicited by tactile stimulation without joint contracture characteristic of SPS can also be symptoms of IAD.

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

BACKGROUND AND OBJECTIVES: IVIg has been the preferred immunotherapy in stiff-person syndrome (SPS) based on a 3-month controlled trial, but whether it is also effective in inducing long-term benefits or arresting disease progression is unknown. The information is needed because SPS is a progressively disabling disease and IVIg is liberally used as chronic therapy without efficacy data. The present study explores the long-term effects of IVIg in the largest cohort of well-characterized patients with SPS followed by the same clinicians over 10 years. METHODS: Data of 36 patients (32 glutamic acid decarboxylase [GAD] positive), diagnosed and treated with monthly maintenance IVIg by the same neurologists, were analyzed. Response was assessed by physician-observed changes, patients' reports of symptom improvement, modified Rankin Scale (mRS) scores, and dependency trials evaluating symptom recurrence after stopping IVIg, prolonging infusion frequency, decreasing monthly dose, or wearing-off effects in between doses. Clinically meaningful long-term response was defined by improved mRS scores, improvement in physician-assessed stiffness, balance and gait, and functional decline with dependency trials. RESULTS: Twenty-four of 36 (67%) patients had clinically meaningful response over a median 40-month period. Patients with improved mRS scores by 1-2 points manifested improved gait, posture, balance and decreased stiffness, spasms, and startle response; some patients using a wheelchair and those ambulating with devices walked unassisted. In 25% of responders, treatment benefit was sustained for a 40-month median period, but in 29.1%, it declined over a 39-month period; 12.5% exhibited a conditioning effect. Three of 5 patients with cerebellar GAD-SPS variant also improved over time. The 12 patients who did not respond the first 3 months remained unresponsive even if IVIg continued for several months. DISCUSSION: This is a large study in 36 patients with SPS demonstrating that monthly maintenance IVIg therapy offers long-term benefits in 67% of patients for a median 3.3-year period. Because 29.1% experienced diminishing benefit over time due to disease progression, the study highlights the need for more effective therapies.

Stiff-person Syndrome and GAD Antibody-spectrum Disorders: GABAergic Neuronal Excitability, Immunopathogenesis and Update on Antibody Therapies.

Although antibodies against Glutamic Acid Decarboxylase (GAD) were originally associated with Stiff Person Syndrome (SPS), they now denote the "GAD antibody-spectrum disorders (GAD-SD)" that include Cerebellar Ataxia, Autoimmune Epilepsy, Limbic Encephalitis, PERM and eye movement disorder. In spite of the unique clinical phenotype that each of these disorders has, there is significant overlapping symptomatology characterized by autoimmune neuronal excitability. In addition to GAD, three other autoantibodies, against glycine receptors, amphiphysin and gephyrin, are less frequently or rarely associated with SPS-SD. Very high serum anti-GAD antibody titers are a key diagnostic feature for all GAD-SD, commonly associated with the presence of GAD antibodies in the CSF, a reduced CSF GABA level and increased anti-GAD-specific IgG intrathecal synthesis denoting stimulation of B-cell clones in the CNS. Because anti-GAD antibodies from the various hyperexcitability syndromes recognize the same dominant GAD epitope, the clinical heterogeneity among GAD-SD patients remains unexplained. The paper highlights the biologic basis of autoimmune hyperexcitability connected with the phenomenon of reciprocal inhibition as the fundamental mechanism of the patients' muscle stiffness and spasms; addresses the importance of high-GAD antibody titers in diagnosis, pinpointing the diagnostic challenges in patients with low-GAD titers or their distinction from functional disorders; and discusses whether high GAD-antibodies are disease markers or pathogenic in the context of their association with reduced GABA level in the brain and CSF. Finally, it focuses on therapies providing details on symptomatic GABA-enhancing drugs and the currently available immunotherapies in a step-by-step approach. The prospects of future immunotherapeutic options with antibody therapies are also summarized.

Stiff-person syndrome: an atypical presentation and a review of the literature.

Introduction: Stiff-person syndrome (SPS) is a rare autoimmune neurological disorder associated with muscle rigidity and spasms. A number of antibodies have been associated with disorder, including anti-glutamic acid decarboxylase and anti-amphiphysin.Case report; In this report, we present a rare case of a 79-year-old woman who presented with bilateral lower extremity weakness who was ultimately diagnosed with stiff-limb syndrome, a rare variant of SPS. Extensive laboratory and CSF studies were unrevealing. Electromyography showed significant peroneal motor neuropathy and complex repetitive discharges in the left tibialis anterior muscle. Antibodies to glutamic acid decarboxylase were significantly elevated at 124 units/mL. She was subsequently started on oral diazepam with significant improvement in her symptoms.Conclusion: The presentation of SPS can vary based on epidemiologic factors, clinical symptoms, and associated disorders. These forms can have overlapping features which may make the categorization of patients into one of these forms challenging.

Subcutaneous Immunoglobulin Therapy with IgPro20 in Patients with Stiff Person Syndrome and Primary Immunodeficiency Disease.

Stiff Person Syndrome (SPS), a rare autoimmune neurologic disorder characterized by fluctuating muscle spasms and rigidity, is mediated by autoantibodies to glutamic acid decarboxylase (GAD) antibodies. Symptoms of SPS have been shown to improve after administration of intravenous immunoglobulin (IVIG) however, there is a paucity of information regarding use of SCIg in SPS. Four patients with Stiff Person Syndrome were treated with SCIgPro20 for a period between 31 to 101 months. Most reactions were local and mild. All patients reported improvement in spasticity, and 2 patients reported improvement in seizure frequency. SCIgPro20 was well tolerated in patients with SPS and was associated with improvement in symptoms.

Anti-amphiphysin positive stiff-person syndrome due to invasive ductal carcinoma in a male patient.

Stiff-person syndrome (SPS) is a rare progressive neurological disorder characterised by painful muscle spasms and progressive muscle rigidity, leading in some cases to impaired ambulation. Anti-amphiphysin positive SPS is a paraneoplastic variant, frequently associated with breast carcinomas and small cell lung cancers. We report the case of a 53-year-old patient who developed symptoms of anti-amphiphysin positive SPS 3 years before being diagnosed with invasive ductal carcinoma. Specifically, computed tomography (CT) of the chest, abdomen and pelvis, positron emission tomography-CT (PET-CT), mammogram, colonoscopy and magnetic resonance imaging (MRI) did not identify malignancy during the 3 years following the onset of symptoms. Following diagnosis of invasive ductal carcinoma and completion of curative-intent oncological treatment, the patient experienced improvement, though not complete resolution, in his SPS symptoms. This case highlights the importance of thorough oncological workup when clinical presentation and diagnostic testing are suggestive of anti-amphiphysin positive SPS.

Autologous Hematopoietic Stem Cell Transplantation for Stiff-Person Spectrum Disorder: A Clinical Trial.

OBJECTIVE: To test the hypothesis that autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) is safe and shows efficacy in the treatment of stiff-person spectrum disorder (SPSD). METHODS: Twenty-three participants were treated in a prospective open-label cohort study of safety and efficacy. After stem cell mobilization with cyclophosphamide (2 g/m2) and filgrastim (5-10 µg/kg/d), participants were treated with cyclophosphamide (200 mg/kg) divided as 50 mg/kg IV on day -5 to day -2; rabbit anti-thymocyte globulin (thymoglobulin) given intravenously at 0.5 mg/kg on day -5, 1 mg/kg on days -4 and -3, and 1.5 mg/kg on days -2, and -1 (total dose 5.5 mg/kg); and rituximab 500 mg IV on days -6 and +1. Unselected peripheral blood stem cells were infused on day 0. Safety was assessed by survival and National Cancer Institute common toxicity criteria for adverse events during HSCT. Outcome was assessed by ≥50% decrease or discontinuation of antispasmodic drugs and by quality of life instruments. RESULTS: There was no treatment-related mortality. One participant died 1 year after transplantation of disease progression. Of the 74% of participants who responded, 47% have stayed in remission for a mean of 3.5 years; 26% did not respond. Compared to nonresponders, responders were more likely to have pretransplantation intermittent muscle spasms (16 of 17 vs 0 of 6), normal reflexes (12 of 17 vs 0 of 6), and positive CSF anti-glutamic acid decarboxylase serology (12 of 14 vs 2 of 6). Compared to responders, nonresponders were more likely to have lead pipe rigidity (4 of 6 vs 0 of 17) and EMG-documented simultaneous contraction of agonist/antagonist limb muscles (4 of 6 vs 1 of 17). Pre-HSCT use of prescription serotonin selective receptor inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI) was more common in those who relapsed or never responded (9 of 12) compared to those responders who never relapsed (0 of 11). CONCLUSION: In this cohort, HSCT was safe, but the beneficial effect of HSCT was variable and confined predominately to participants with episodic spasms and normal tendon reflexes without simultaneous cocontraction of limb agonist/antagonist muscles who were not taking SSRI or SNRI antidepressants. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, for a subset of people with SPSD, autologous nonmyeloablative HSCT improves outcomes. CLINICALTRIALSGOV IDENTIFIER: NCT02282514.

Advanced Progression of Scoliosis After Intrathecal Baclofen in an Adult With Stiff Person Syndrome: A Case Report.

Stiff person syndrome is a neuroimmunological disorder characterized by progressive muscular rigidity and spasms that affect axial/limb muscles, resulting in severe pain and functional limitations. When refractory to conservative treatments, intrathecal baclofen is a viable option to treat the increased tone. Intrathecal baclofen has been shown to accelerate underlying neuromuscular scoliosis in the pediatric population with cerebral palsy. This adverse effect has never been reported in adults with stiff person syndrome. We report a case of an adult with stiff person syndrome and underlying scoliosis who experienced accelerated progression of scoliosis after initiation of intrathecal baclofen, subsequently requiring neurosurgical intervention.

Transient Neurological Symptoms Preceding Cerebellar Ataxia with Glutamic Acid Decarboxylase Antibodies.

A prompt diagnosis and treatment of patients with autoimmune cerebellar ataxia (CA) with antibodies against glutamic acid decarboxylase (GAD-Abs) may lead to a better prognosis. Herein, we report prodromal transient neurological symptoms that should raise clinical suspicion of CA with GAD-Abs. We initially identified a 70-year-old man who presented a first acute episode of vertigo, diplopia, and ataxia lasting 2 weeks. Two months later, he experienced a similar episode along with new-onset gaze-evoked nystagmus. After 4 months, downbeat nystagmus, left limb dysmetria, and gait ataxia progressively appeared, and an autoimmune CA was diagnosed based on the positivity of GAD-Abs in serum and cerebrospinal fluid (CSF). We searched retrospectively for similar presentations in a cohort of 31 patients diagnosed with CA and GAD-Abs. We found 11 (35.4%) patients (all women, median age 62 years; 8/11 [72.7%] with autoimmune comorbidities) with transient neurological symptoms antedating CA onset by a median of 3 months, including vertigo in 9 (81.8%; described as paroxysmal in 8) and fluctuating diplopia in 3 (27.3%) patients. The identification of transient neurological symptoms of unknown etiology, such as paroxysmal vertigo and fluctuating diplopia, should lead to GAD-Abs testing in serum and CSF, especially in patients with autoimmune comorbidities.

C.292G>A, a novel glycine receptor alpha 1 subunit gene (GLRA1) mutation found in a Chinese patient with hyperekplexia: A case report.

INTRODUCTION: Hyperekplexia is a rare hereditary neurological disorder; only 5 glycine receptor alpha 1 subunit gene (GLRA1) mutations have been reported in 5 Chinese patients. We report a Chinese infant with hyperekplexia and a novel mutation at c.292G > A. PATIENT CONCERNS: A Chinese infant with hyperekplexia and a novel mutation at c.292G > A. DIAGNOSIS: All exons of GLRA1 were sequenced in her parents and her, which revealed a mutation at c.1030C > T and another novel mutation at c.292G > A. Her diagnosis was confirmed as hereditary hyperekplexia with GlRA1 hybrid gene mutations based on the sequencing results. INTERVENTIONS: She was treated with clonazepam. OUTCOMES: Her muscle hypertonia recovered rapidly and the excessive startle reflex to unexpected stimuli was significantly reduced. CONCLUSION: Genetic DNA sequencing is a crucial method for diagnosing hyperekplexia-related gene mutation.

Neurologic syndromes related to anti-GAD65: Clinical and serologic response to treatment.

OBJECTIVE: Antibodies against glutamic acid decarboxylase 65 (anti-GAD65) are associated with a number of neurologic syndromes. However, their pathogenic role is controversial. Our objective was to describe clinical and paraclinical characteristics of anti-GAD65 patients and analyze their response to immunotherapy. METHODS: Retrospectively, we studied patients (n = 56) with positive anti-GAD65 and any neurologic symptom. We tested serum and CSF with ELISA, immunohistochemistry, and cell-based assay. Accordingly, we set a cutoff value of 10,000 IU/mL in serum by ELISA to group patients into high-concentration (n = 36) and low-concentration (n = 20) groups. We compared clinical and immunologic features and analyzed response to immunotherapy. RESULTS: Classical anti-GAD65-associated syndromes were seen in 34/36 patients with high concentration (94%): stiff-person syndrome (7), cerebellar ataxia (3), chronic epilepsy (9), limbic encephalitis (9), or an overlap of 2 or more of the former (6). Patients with low concentrations had a broad, heterogeneous symptom spectrum. Immunotherapy was effective in 19/27 treated patients (70%), although none of them completely recovered. Antibody concentration reduction occurred in 15/17 patients with available pre- and post-treatment samples (median reduction 69%; range 27%-99%), of which 14 improved clinically. The 2 patients with unchanged concentrations showed no clinical improvement. No differences in treatment responses were observed between specific syndromes. CONCLUSION: Most patients with high anti-GAD65 concentrations (>10,000 IU/mL) showed some improvement after immunotherapy, unfortunately without complete recovery. Serum antibody concentrations' course might be useful to monitor response. In patients with low anti-GAD65 concentrations, especially in those without typical clinical phenotypes, diagnostic alternatives are more likely.