Stiff-person Syndrome Research Articles

Therapeutic Plasma Exchange in the Management of Stiff Person Syndrome Spectrum Disorders: A Case Series and Review of the Literature (S25.008)

Therapeutic Plasma Exchange in the Management of Stiff Person Syndrome Spectrum Disorders: A Case Series and Review of the Literature (S25.008)

Paraneoplastic Stiff Person Syndrome: Persistence of Symptoms is Common Despite Treatment of Underlying Malignancy (P18-1.001)

Paraneoplastic Stiff Person Syndrome: Persistence of Symptoms is Common Despite Treatment of Underlying Malignancy (P18-1.001)

A patient with stiff-person syndrome with takotsubo cardiomyopathy requiring intensive care: A case report

A patient with stiff-person syndrome with takotsubo cardiomyopathy requiring intensive care: A case report

Rare diseases in the differential diagnosis of myalgia

Myalgia describes pain in the skeletal muscles. According to the current German clinical guidelines from 2020 (AWMF register number: 030/051), the initial diagnostic assessment consists of the anamnesis, clinical examination, electrophysiological examination and standard laboratory tests. Additional special examinations, such as molecular genetic investigations, special laboratory tests, medical imaging and muscle biopsy are only needed in certain cases. This article focuses on rare neurological diseases that are classically associated with myalgia. In this context etiologically different diseases are considered, whereby some genetically linked diseases (fascioscapulohumeral dystrophy, FSHD, dystrophia myotonica, McArdle's disease, Pompe's disease, limb girdle muscular dystrophy) are contrasted with diseases with an (auto)immune-related pathogenesis (stiff-person syndrome, Isaacs syndrome). The aspects relevant for the diagnosis are particularly highlighted. The therapeutic aspects of the diseases are not part of this article.

Coexisting Stiff Limb Syndrome, Myositis, and Myasthenia Gravis in a Patient with Thymoma.

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Peptide Antibody Reactivity to Homologous Regions in Glutamate Decarboxylase Isoforms and Coxsackievirus B4 P2C.

Two isoforms of the glutamate decarboxylase (GAD) enzyme exist, GAD65 and GAD67, which are associated with type 1 diabetes (T1D) and stiff-person syndrome (SPS), respectively. Interestingly, it has been reported that T1D patients seldom develop SPS, whereas patients with SPS occasionally develop T1D. In addition, coxsackievirus B4 (CVB4) has previously been proposed to be involved in the onset of T1D through molecular mimicry. On this basis, we aimed to examine antibody cross-reactivity between a specific region of GAD65 and GAD67, which has high sequence homology to the nonstructural P2C protein of CVB4 to determine potential correlations at antibody level. Monoclonal peptide antibodies generated in mice specific for a region with high similarity in all three proteins were screened for reactivity along with human sera in immunoassays. In total, six antibodies were generated. Two of the antibodies reacted to both GAD isoforms. However, none of the antibodies were cross-reactive to CVB, suggesting that antibody cross-reactivity between GAD65 and CVB, and GAD67 and CVB may not contribute to the onset of T1D and SPS, respectively.

Pediatric stiff limb syndrome with polyautoimmunity of anti-GAD-65, anti-islet cell, and thyroid peroxidase antibodies: A case report and review of literature

We report an early childhood onset Stiff Limb Syndrome (SLS) in association with unusual polyautoimmunity of GAD-65, anti-islet cell, and Thyroid Peroxidase (TPO) autoantibodies, who has achieved a nearly complete neurological recovery following combined immunotherapy, symptomatic and physical therapy. The patient had normal MRIs of the brain and spinal cord and a negative paraneoplastic work-up. Subsequently, she developed hypothyroidism requiring levothyroxine supplementation. We then conducted an extensive review of literature and identified 52 previously reported pediatric Stiff Man Syndrome (SMS)/Stiff Person Syndrome (SPS) or SLS cases, which has demonstrated a common association with other systemic autoimmune conditions. In the available literature, screening for concurrent autoimmunity has only been reported infrequently. We found that a paraneoplastic process is extremely rare in pediatric cases. Timely diagnosis and initiation of immunotherapy are critical to a favorable outcome. Therefore, we recommend to include SMS/SPS or SLS as an important differential diagnosis for MRI-negative myelopathy. Further clinical and research efforts should be focused on understanding the role of both genetic predisposition and environmental insults in the autoimmunity of pediatric SMS/SPS or SLS.

Are anti-glutamic acid decarboxylase 65-kDa isoform antibodies related to diabetes or brain tumor?

BackgroundAntibodies against the 65-kDa isoform of glutamic acid decarboxylase (GAD65) are biomarkers of autoimmune disorders and are more common in non-neurological autoimmune diseases than in neurological disorders. As for the central nervous system (CNS), it is well known that GAD65 is primarily associated with stiff-person syndrome, cerebellar ataxia, epilepsy, and paraneoplastic neurological syndrome. However, GAD65 antibodies have not been reported in patients with brain tumors.Case presentationThis study presents the case of a 62-year-old man who manifested rapidly progressive dizziness with gradually worsening physical disturbance and unstable gait in the 2 months prior to consultation. Antibodies against GAD65 were detected in his serum. Brain magnetic resonance imaging (MRI) showed abnormal signals in the corpus callosum, the semi-oval center in both hemispheres, and the area below the frontal cortex, along with enhanced intracranial lesions in the same regions. Positron emission tomography–computed tomography (PET–CT) showed high metabolism in the corpus callosum, which protruded into both ventricles. Due to signs of malignancy, the patient was diagnosed with a malignant glioma.ConclusionsThis case raises awareness on the fact that anti-GAD65 antibodies may be associated with CNS neoplastic lesions. Early recognition of anti-GAD antibodies could be of great importance for the early diagnosis and targeted treatment of neoplastic lesions, and could lead to better prognosis.

Pilomotor seizures in autoimmune limbic encephalitis: description of two GAD65 antibodies- related cases and literature review

BackgroundIctal piloerection (IP) is a rare manifestation of focal epilepsy. Autoimmune limbic encephalitis (LE) and malignant brain tumours are the most frequent recognized aetiologies. MethodsWe selected all patients diagnosed with LE in our Institute from 2004 to 2020 and manifesting with IP. We performed a literature review on LE patients presenting IP. ResultsOf 15 patients diagnosed with LE (13.3%), two manifested IP as prominent ictal feature. One of them also had stiff-limb syndrome. Video-EEG documented ictal discharges from the right temporal regions with concomitant sympathetic skin response (SSR) recording. Antibody testing showed elevated serum and CSF titres of GAD65 antibodies (Ab), in both cases. Despite a combination of several anti-seizure medications and first- and second-line immunotherapy, they showed a poor clinical outcome after 2 and 9 years of follow-up, respectively. The literature review yielded 13 papers reporting 26 LE cases with IP. LGI1 Ab were the most frequently associated (73.1%) followed by VGKC-complex (7.7%), GAD65 (7.7%), NMDAr (3.8%), Ma2 (3.8%) and Hu (3.8%) Ab. Cases with LGI1 Ab showed a good response to immunotherapy. Discussion and conclusionThe prevalence of IP in our LE cohort was of 13.3%, higher than expected. According to the literature review, most cases were associated with LGI1 Ab and showed a good response to immunotherapy. With the contribution of our cases, GAD65 emerged as the second most frequently detected Ab, showing a poor outcome. Our findings widen the spectrum of IP-associated Ab, with the respective prognostic implications.

Neuropsychiatric Manifestations of Autoimmune Encephalitis in a Tertiary Hospital: A Case Series and Current Perspectives.

Importance:Autoimmune encephalitis (AE) refers to a group of neuropsychiatric conditions associated with specific circulating autoantibodies directed against synaptic receptors, neuronal cell surface proteins, and intracellular targets. Increased recognition of these disorders is of value, as affected patients prominently display cognitive impairment, behavioral disturbances, and seizures requiring multidisciplinary teams, with early recognition often impacting prognosis.Observations: This case series is based on a retrospective record review of adult patients diagnosed with AE between January 1, 2010- January 1, 2020. Cases 1 and 2, demonstrating anti- N-methyl-d-aspartate receptor (NMDAR) encephalitis with initial manifestations of neurologic and psychiatric symptoms, correlate with the literature describing a higher prevalence of this condition in young women. Case 3, despite being seronegative, exhibited classic features of anti-NMDAR encephalitis. Case 4 demonstrates a classic presentation of anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis: a middle-aged male with psychosis, altered mentation, and epilepsy. Case 5 had a more indolent neuropsychiatric presentation with mild elevation of N-type voltage-gated potassium channel (VGKC) antibody. Case 6, with glutamic acid decarboxylase 65 (GAD65) antibody, was an elderly female with speech dysfunction and altered mentation, and case 7 was an elderly male with GAD65 antibody who had stiff-person syndrome, ataxia, cognitive decline, and thymoma.Conclusions: This retrospective case series describes the clinical details of 7 individuals with AE and overlapping neuropsychiatric symptoms. This series is limited in scope, with a small number of cases and observational findings, which prevents specific conclusions from being drawn. Despite this limitation, the present article explores the nuances of variable presentations of this disease to inform better interdisciplinary management and emphasize the gap areas that need rigorous research.

Impaired Verbal Memory Recall in Patients With Axonal Degeneration and Serum Glycine-Receptor Autoantibodies-Case Series.

BackgroundGlycine receptor antibody-associated neuropsychiatric disease is currently known to be dominated by the phenotypes stiff-person syndrome and progressive encephalomyelitis entailing rigidity and myoclonus. In our case series we aim to depict the less-often reported feature of cognitive impairment associated with glycine receptor antibodies.MethodsWe investigated five patients with cognitive impairment varying from mild cognitive impairment to dementia associated with serum glycine receptor antibodies. Mild and major neurocognitive disorders were diagnosed according to the DSM-5 (fifth edition of the Diagnostic and Statistical Manual of Mental Disorders). Neuropsychology via Consortium to Establish a Registry for Alzheimer's Disease (CERAD) testing results, psychopathology data via the Manual for the Assessment and Documentation of Psychopathology in Psychiatry (AMDP), cerebrospinal fluid analysis and magnetic resonance imaging data were retrospectively analyzed from patient files.ResultsWe identified five patients with cognitive impairment as the main neuropsychiatric feature associated with serum glycine receptor antibodies. One patient also presented akinetic rigidity syndrome. The psychopathology comprised disorders of attention and memory, orientation, formal thought, and affect. In addition to suffering deficits in verbal memory function, figural recall, phonematic fluency, and globally deteriorated cognitive function, these patients presented seriously impaired memory recall in particular. Tau protein and phosphorylated tau protein 181 were elevated in 75% of patients.ConclusionsOur results suggest that axonal neurodegeneration and especially impaired verbal memory recall in addition to deficits in verbal and figural memory characterize patients with progressive cognitive impairment associated with glycine receptor antibodies. This unresolved issue should be clarified by researchers to discover whether axonal degeneration is merely an age-related phenomenon or one related to glycine-receptor autoantibodies in old age. Cognitive impairment as a neuropsychiatric syndrome of glycine-receptor antibody disease is a potential, conceivable, but so far unproven additional feature requiring deeper large-scale investigations and consideration during differential diagnosis in memory clinics.

Case Report: Multisystem Autoimmune and Overlapping GAD65-Antibody-Associated Neurological Disorders With Beneficial Effect of Epilepsy Surgery and Rituximab Treatment

Glutamic acid decarboxylase (GAD) antibodies are associated with disabling conditions such as stiff person syndrome, temporal lobe epilepsy (TLE), limbic encephalitis, cerebellar ataxia (CA), and ocular movement disorders, which are usually chronic and difficult to treat. GAD-related TLE has poor response to anti-seizure medications and immune therapies, and epilepsy surgery is rarely successful. We report on a 47-year-old female with history of migraine, autoimmune thyroid disease, ankylosing spondylitis, and drug-resistant TLE. A video electroencephalography recorded frequent seizures with temporo-insular semiology, correlating to left temporal epileptiform activity and left mesiotemporal hyperintensity on magnetic resonance imaging. GAD autoimmunity was confirmed by very high GAD antibody titers in serum and cerebrospinal fluid. Steroids, immunoglobulins, and cyclophosphamide had no effect, and selective left amygdalectomy was performed based on very restricted hypermetabolism on positron-emission tomography. After transient seizure freedom, significant epilepsy improvement was observed in spite of memory decline. Transient worsening was noted 1 year later during diabetes mellitus manifestation and 5 years later during presentation of progressive CA, which stabilized on rituximab treatment. We believe this case illustrates the diversity and the frequent overlap of GAD-associated disorders, the need of early and aggressive immunotherapy in severe patients, as well as the possible benefit from epilepsy surgery in some GAD-TLE.

“Undiagnosed Neurodegenerative Syndrome – A Case Study”

Introduction: Due to advancement in medical services, life span of individual has increased. Increased age also increases neurodegenerative problems generally in geriatric population. Neurodegenerative disorders affect many individuals across the world by increasing their disability. Aim: Aim of the study was to evaluate undiagnosed neurodegenerative disorder in details to understand and gain insight into the selected case. Case Report: Here reported case is affected by undiagnosed neurodegenerative syndrome at early age of 34 years. Patient was also invited by National Institute of Health, US under Undiagnosed Program for further investigations. Patient was managed by combined approach of allopathy, physiotherapy and naturotherapy. Discussion: Patient was also suspected for diagnosis of Bipyramidal syndrome, Stiff man syndrome, Motor Neuron Disease, Neimann pick disease type C, Krebbee’s disease, Chediak Higashi disease affecting the central nervous system by Neurophysician. The patient represents a rarest of rare case of Undiagnosed Neurodegenerative Program. Conclusion: Patient can be benefited in symptoms by combined approach of medicine and physiotherapy in case of undiagnosed neurodegenerative.

A review of the neurological complications of breast cancer.

Conducting broad assessments of the main burden of breast cancer is the core factor for improving overdiagnosis and overtreatment of breast cancer patients as well as their survival rates. Breast cancer patients may experience neurological complications that cause devastating effects on them. Chemotherapy-induced peripheral neuropathy (CIPN) and neuropathic pain are two of the most reported complications. Objective: This study aims to review the neurological complications of breast cancer and the ways to control and treat them. Comprehensive searches were carried out about the keywords of Breast Cancer, Neurological Complications, and Breast Cancer Consequences. These keywords were searched through the most well-known databases of MEDLINE, PUBMED, Cochrane Library, Best Evidence, CancerLit, HealthSTAR, and LegalTrac. In this regard, 83 articles were chosen to be included in this study from 2010 to 2021. The identification and treatment process of neurologic syndromes are not easy. The main neurologic syndromes which the breast cancer patients face are opsoclonus myoclonus syndrome (OMS), encephalitis, sensorimotor neuropathy, retinopathy, cerebellar degeneration, and stiff-person's syndrome. CIPN and neuropathic pain are among the most prevalent side effects which are categorized as neurological complications and mainly seen 1 year after the management of breast cancer. Aiming to minimize the burden following the treatment of breast cancer, these complications should be diagnosed and treated accurately.

Immunological, Physical, and Psychological Interventions in Young-Onset Stiff-Person Syndrome.

Immunological, Physical, and Psychological Interventions in Young-Onset Stiff-Person Syndrome.

Successful management of dyspnea in a patient with stiff person syndrome with noninvasive positive-pressure ventilation: A case report

Approximately half of patients with stiff person syndrome experienced dyspnea due to the involvement of the respiratory muscles. If these muscles are severely affected, respiratory failure can occur. Here, we describe a patient with stiff person syndrome whose nighttime dyspnea was successfully controlled by noninvasive positive-pressure ventilation (NIPPV). A 38-year-old female patient visited the emergency room due to nighttime dyspnea. Her O2 saturation was 93%, and PaCO2 increased to 53.4 mmHg on arterial blood gas analysis. No specific lesion was found on the chest radiograph. We considered that her dyspnea was caused by respiratory muscle stiffness following SPS. For the management of nighttime hypercapnia, we applied NIPPV with volume-targeted assist-control ventilation mode using an oronasal mask interface during sleep. After such treatment, PaCO2 was normalized, and nighttime dyspnea disappeared. We think that NIPPV would be a useful therapeutic option for managing dyspnea induced by stiff person syndrome.

Outpatient Based Autologous Hematopoietic Stem Cell Transplantation Is a Feasible Therapeutic Option for Patients with Chronic Inflammatory Demyelinating Polyneuropathy: The Mexican Experience

IntroductionSeveral autoimmune disorders such as multiple sclerosis, Stiff man syndrome or chronic inflammatory demyelinating polyneuropathy (CIDP) can benefit from autologous hematopoietic stem cell transplantation (HSCT) due to its immunomodulatory effects at short- and long-term. Here we present the results from the conduction of an outpatient HSCT procedures in 16 patients with CIDP.MethodsProspective study of HSCT in persons with CIDP recruited since 2015. Patients with and without previous immunomodulatory therapy were enrolled and a 3-month wash-out period was recquired; previous or current use of walking support was not a contraindication. All patients signed a consent before starting the study and the study protocol was approved by Clínica Ruiz IRB. Before the conditioning, all participants underwent a comprehensive evaluation. On day -11 and -10, patients received cyclophosphamide (Cy) at 50 mg/kg, followed by a 7-day course of G-CSF previous to cell collection (day -2) through apheresis using a Mahurkar catheter. Then, on day -2 and -1 a second round of Cy at 50 mg/kg was given (Figure 1). Transfusions and antimicrobial prophylaxis were administered per local protocol. Upon hematological recovery (>500 ANC) all patients received a rituximab infusion at 1000 mg.ResultsSixteen patients with CIDP underwent screening for transplantation clearance and all of them proceeded to HSCT. Of those, 8 (50%) patients were male. Median age at transplantation was found to be 44 years (SD 10.5). Walking support was employed at the time of HSCT by 7 (44%) patients and most frequent previous therapy was intravenous immunoglobulin in 4 (25%) patients. On average a mean 8.5x10 6/kg (SD 4.2) of CD34 + cells were infused. The mean nadir neutropenia was found to be 0.11x10 9/L (SD 0.13) and the median time of granulocytes recovery was 7.0 days (SD 2.9) while median time of platelet recovery was 5.5 days (SD 3.0). One (6%) patient was admitted to hospital due to febrile neutropenia and 4 (25%) patients required red-blood cell and platelet transfusion support. In 3 of 5 persons the need of walking support reverted.ConclusionsOur experience suggests that people with CIDP may undergo HSCT with no major complications on an outpatient basis. Hospital admissions, hematological recovery, and infectious complications seem to be relatively low-severity complications that could be manage with standard protocols. [Display omitted] DisclosuresGomez-Almaguer: Bristol-Myers-Squibb: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau.

Stiff-person syndrome with sensorimotor polyneuropathy – case report

Stiff-person syndrome (SPS) is a rare disorder with an estimated prevalence in the general population of 1–2 cases/1,000,000. It is 2–3 times more common in females, with symptom onset at the age of 20–50 years in most cases. Although stiff-person syndrome is associated with antibodies against glutamic acid decarboxylase and amphiphysin, their presence is not necessary for the diagnosis. The treatment should be multidirectional and include immunomodulation, symptomatic treatment as well as monitoring and treatment of overlapping autoimmune, and surgery. We present a case report of a patient diagnosed with stiff-person syndrome overlapping with axonal and demyelinating sensorimotor polyneuropathy. The diagnostic workup indicated diabetes-related polyneuropathy. About 30% of patients diagnosed with stiff-person syndrome also have diabetes. Polyneuropathy alone is rarely reported to overlap with the disorder. In our opinion, polyneuropathy may have a beneficial effect on the clinical presentation of stiff-person syndrome.

Clinical presentation, comorbidities and treatment of GAD antibodies associated stiff person syndrome

Stiff Person Syndrome (SPS) is a rare autoimmune neurological disorder, characterized by axial and limb muscular stiffness and spasms, due to a loss of physiological GABAergic CNS inhibition. In 60%–80% of patients with classic SPS phenotype antibodies against glutamic acid decarboxylase (GAD) enzyme can be detected.

Update on Intravenous Immunoglobulin in Neurology: Modulating Neuro-autoimmunity, Evolving Factors on Efficacy and Dosing and Challenges on Stopping Chronic IVIg Therapy

In the last 25 years, intravenous immunoglobulin (IVIg) has had a major impact in the successful treatment of previously untreatable or poorly controlled autoimmune neurological disorders. Derived from thousands of healthy donors, IVIg contains IgG1 isotypes of idiotypic antibodies that have the potential to bind pathogenic autoantibodies or cross-react with various antigenic peptides, including proteins conserved among the “common cold”-pre-pandemic coronaviruses; as a result, after IVIg infusions, some of the patients’ sera may transiently become positive for various neuronal antibodies, even for anti-SARS-CoV-2, necessitating caution in separating antibodies derived from the infused IVIg or acquired humoral immunity. IVIg exerts multiple effects on the immunoregulatory network by variably affecting autoantibodies, complement activation, FcRn saturation, FcγRIIb receptors, cytokines, and inflammatory mediators. Based on randomized controlled trials, IVIg is approved for the treatment of GBS, CIDP, MMN and dermatomyositis; has been effective in, myasthenia gravis exacerbations, and stiff-person syndrome; and exhibits convincing efficacy in autoimmune epilepsy, neuromyelitis, and autoimmune encephalitis. Recent evidence suggests that polymorphisms in the genes encoding FcRn and FcγRIIB may influence the catabolism of infused IgG or its anti-inflammatory effects, impacting on individualized dosing or efficacy. For chronic maintenance therapy, IVIg and subcutaneous IgG are effective in controlled studies only in CIDP and MMN preventing relapses and axonal loss up to 48 weeks; in practice, however, IVIg is continuously used for years in all the aforementioned neurological conditions, like is a “forever necessary therapy” for maintaining stability, generating challenges on when and how to stop it. Because about 35-40% of patients on chronic therapy do not exhibit objective neurological signs of worsening after stopping IVIg but express subjective symptoms of fatigue, pains, spasms, or a feeling of generalized weakness, a conditioning effect combined with fear that discontinuing chronic therapy may destabilize a multi-year stability status is likely. The dilemmas of continuing chronic therapy, the importance of adjusting dosing and scheduling or periodically stopping IVIg to objectively assess necessity, and concerns in accurately interpreting IVIg-dependency are discussed. Finally, the merit of subcutaneous IgG, the ineffectiveness of IVIg in IgG4-neurological autoimmunities, and genetic factors affecting IVIg dosing and efficacy are addressed.