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Marinos C Dalakas - One of the best experts on this subject based on the ideXlab platform.
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Quantitative clinical and autoimmune assessments in Stiff Person Syndrome: evidence for a progressive disorder
BMC Neurology, 2019Co-Authors: Goran Rakocevic, Harry Alexopoulos, Marinos C DalakasAbstract:Background Stiff Person Syndrome (SPS) is an under-diagnosed disorder that affects mobility and the quality of life of affected patients. The aim of the study is to describe the natural history of SPS, the extent of accumulated disability and the associated clinical and immunological features in patients followed for up to 8 years in a single center. Methods Our collective cohort included 57 SPS patients. Additionally, 32 of these patients were examined every 6 months for a two-year period in a longitudinal study protocol, to assess disease progression using quantitative measures of Stiffness and heightened sensitivity. Results The most frequent initial symptom was leg Stiffness, followed by paraspinal muscle rigidity and painful spasms in 95% of the patients. Although none of the patients required assistance for ambulation during the first 2 years of disease onset, 46 patients (80%) lost the ability to walk independently during our follow-up, despite symptomatic medications. In the longitudinal cohort, the number of Stiff areas increased ( p
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treatment of Stiff Person Syndrome
2019Co-Authors: Marinos C DalakasAbstract:Stiff-Person Syndrome (SPS) is characterized by (1) Stiffness of truncal and limb muscles due to continuous co-contracture of agonist and antagonist muscles resulting in hyperlordosis, difficulty bending or turning, and slow, wide-based gait, (2) sudden spasms precipitated by unexpected noises and tactile or visual stimuli, and (3) overt anxiety with task-specific phobias. The symptoms vary in severity and can be fluctuating or fixed leading to disability in up to 65% of patients. SPS is an autoimmune disease with antibodies against (a) GAD-65, the enzyme responsible for synthesis of GABA, the brain’s main inhibitory neurotransmitter, (b) anti-glycine receptor, and (c) amphiphysin when paraneoplastic. The treatment begins with GABA-enhancing drugs such as diazepam, baclofen, and gabapentin, followed by immunotherapy. IVIg, proven effective in a controlled trial, is the first-in-line immunotherapy followed by rituximab and plasmapheresis.
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glycine receptor antibodies in Stiff Person Syndrome and other gad positive cns disorders
Neurology, 2013Co-Authors: Harry Alexopoulos, Sofia Akrivou, Marinos C DalakasAbstract:Stiff-Person Syndrome (SPS) is characterized by Stiffness in trunk and limb muscles, phobic anxiety, and sudden spasms. A disturbance in inhibitory GABAergic pathways, presumably by autoantibodies against GAD (the main GABA-synthesizing enzyme), is considered fundamental for SPS pathogenesis.1 As the precise role of anti-GAD antibodies in SPS remains unclear,2,3 several other candidate disease-specific autoantibodies associated with inhibitory pathways have been explored3,4 or are actively pursued. Recently, McKeon et al.5 described anti-glycine-α1 receptor (GlyR) antibodies in a subset of patients with SPS. Glycine is a neurotransmitter in spinal inhibitory interneurons and GlyR are primarily expressed in the spinal cord, brainstem, and cerebellum. Anti-GlyR antibodies have been associated with progressive encephalomyelitis with rigidity and myoclonus (PERM), a Syndrome resembling SPS.6 Our aims were to search for GlyR antibodies in a large number of patients with well-characterized SPS and other CNS autoimmune controls and other GAD-positive disorders; and to correlate anti-GlyR titers with clinical symptomatology using quantitative scales of Stiffness and spasms.7 The authors thank Dr. Goran Rakocevic and Beverly McElroy, RN, for helping with the care of patients studied at the NIH under Dr. Dalakas's protocols.
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immunology of Stiff Person Syndrome and other gad associated neurological disorders
Expert Review of Clinical Immunology, 2013Co-Authors: Harry Alexopoulos, Marinos C DalakasAbstract:Antibodies against glutamic acid decarboxylase (GAD), the rate-limiting enzyme for the synthesis of GABA, are associated with an array of distinct, mostly autoimmune, neurological conditions. In all associated Syndromes, namely Stiff Person Syndrome, cerebellar ataxia, epilepsy, limbic encephalitis or abnormal eye movements, anti-GAD antibodies are detected at high titers and play a fundamental role in diagnosis, but do not correlate with disease severity, diversity of symptomatology or response to therapies. Despite considerable efforts, including in vitro (enzymatic assays) and in vivo (animal models) systems, the pathogenicity of anti-GAD antibodies has not been unequivocally proven for any specific condition. The search for the responsible autoantigen has revealed a few other antigenic targets, particularly for SPS, localized in the pre- or post-synaptic inhibitory neuronal synapses. Cumulative clinical and laboratory evidence indicates that anti-GAD and related antibodies define a novel group of Syndromes, collectively known as 'hyperexcitability disorders'.
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a critical update on the immunopathogenesis of Stiff Person Syndrome
European Journal of Clinical Investigation, 2010Co-Authors: Harry Alexopoulos, Marinos C DalakasAbstract:Eur J Clin Invest 2010; 40 (11): 1018–1025 Abstract Background Stiff Person Syndrome (SPS) is a relatively rare but often overlooked autoimmune neurological disorder that targets antigens within the brain’s inhibitory pathways resulting in incapacitating Stiffness and spasms that impact on the patients’ quality of life. Although a number of immunomodulating therapies significantly improve the patients’ symptoms, the exact pathogenic mechanisms remain unclear. Materials and methods The current literature on SPS was reviewed and combined with the authors' experience with many patients and various laboratory studies. The majority of the patients have high-titre anti-GAD (Glutamic Acid Decarboxylase) antibodies in the sera and CSF suggesting dysfunction of the GABAergic neurotransmission. These antibodies are excellent disease markers but their pathogenic role remains uncertain. Conclusions This review provides a critical assessment on the immunobiology of SPS, describes the identification of anti-GABARAP antibodies as a new antigenic target in the GABAergic synapse and identifies the areas for future research.
Christian Geis - One of the best experts on this subject based on the ideXlab platform.
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Stiff Person-Syndrome IgG affects presynaptic GABAergic release mechanisms
Journal of Neural Transmission, 2015Co-Authors: Christian Werner, Holger Haselmann, Andreas Weishaupt, Klaus V. Toyka, Claudia Sommer, Christian GeisAbstract:The majority of patients with Stiff Person-Syndrome (SPS) are characterized by autoantibodies to glutamate decarboxylase 65 (GAD65). In previous passive-transfer studies, SPS immunoglobulin G (IgG) induced SPS core symptoms. We here provide evidence that SPS-IgG causes a higher frequency of spontaneous vesicle fusions. Sustained GABAergic transmission and presynaptic GABAergic vesicle pool size remained unchanged. Since these findings cannot be attributed to anti-GAD65 autoantibodies alone, we propose that additional autoantibodies with so far undefined antigen specificity might affect presynaptic release mechanisms.
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human Stiff Person Syndrome igg induces anxious behavior in rats
PLOS ONE, 2011Co-Authors: Christian Geis, Andreas Weishaupt, Benedikt Grunewald, Thomas Wultsch, Andreas Reif, Daniela Perani, Manfred Gerlach, Ronald Dirkx, Michele Solimena, Manfred HeckmannAbstract:Background Anxiety is a heterogeneous behavioral domain playing a role in a variety of neuropsychiatric diseases. While anxiety is the cardinal symptom in disorders such as panic disorder, co-morbid anxious behavior can occur in a variety of diseases. Stiff Person Syndrome (SPS) is a CNS disorder characterized by increased muscle tone and prominent agoraphobia and anxiety. Most patients have high-titer antibodies against glutamate decarboxylase (GAD) 65. The pathogenic role of these autoantibodies is unclear.
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the immunological basis for treatment of Stiff Person Syndrome
Journal of Neuroimmunology, 2011Co-Authors: Trygve Holmoy, Christian GeisAbstract:Antibodies against autoantigens involved in GABAergic neurotransmission are a shared feature of the different subtypes of Stiff Person Syndrome (SPS). The autoantigens can be either presynaptic such as the smaller isoform of glutamic acid decarboxylase (GAD65), postsynaptic such as GABA-A receptor-associated protein and gephyrin, or located at the pre- and postsynaptic side such as amphiphysin. Most of these autoantigens are intracellular, and antibodies against GAD65 also occur in diabetes mellitus type 1 as well as other neurological diseases. Their pathogenic role has therefore been questioned. We here discuss the role of autoantibodies and T cells in SPS.
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Stiff Person Syndrome associated autoantibodies to amphiphysin mediate reduced gabaergic inhibition
Brain, 2010Co-Authors: Christian Geis, Andreas Weishaupt, Stefan Hallermann, Benedikt Grunewald, Carsten Wessig, Thomas Wultsch, Andreas Reif, Nadiya Byts, Marcus BeckAbstract:Synaptic inhibition is a central factor in the fine tuning of neuronal activity in the central nervous system. Symptoms consistent with reduced inhibition such as Stiffness, spasms and anxiety occur in paraneoplastic Stiff Person Syndrome with autoantibodies against the intracellular synaptic protein amphiphysin. Here we show that intrathecal application of purified anti-amphiphysin immunoglobulin G antibodies induces Stiff Person Syndrome-like symptoms in rats, including Stiffness and muscle spasms. Using in vivo recordings of Hoffmann reflexes and dorsal root potentials, we identified reduced presynaptic GABAergic inhibition as an underlying mechanism. Anti-amphiphysin immunoglobulin G was internalized into neurons by an epitope-specific mechanism and colocalized in vivo with presynaptic vesicular proteins, as shown by stimulation emission depletion microscopy. Neurons from amphiphysin deficient mice that did not internalize the immunoglobulin provided additional evidence of the specificity in antibody uptake. GABAergic synapses appeared more vulnerable than glutamatergic synapses to defective endocytosis induced by anti-amphiphysin immunoglobulin G, as shown by increased clustering of the endocytic protein AP180 and by defective loading of FM 1-43, a styryl dye used to label cell membranes. Incubation of cultured neurons with anti-amphiphysin immunoglobulin G reduced basal and stimulated release of γ-aminobutyric acid substantially more than that of glutamate. By whole-cell patch-clamp analysis of GABAergic inhibitory transmission in hippocampus granule cells we showed a faster, activity-dependent decrease of the amplitude of evoked inhibitory postsynaptic currents in brain slices treated with antibodies against amphiphysin. We suggest that these findings may explain the pathophysiology of the core signs of Stiff Person Syndrome at the molecular level and show that autoantibodies can alter the function of inhibitory synapses in vivo upon binding to an intraneuronal key protein by disturbing vesicular endocytosis.
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Stiff Person Syndrome associated anti amphiphysin antibodies reduce gaba associated ca2 i rise in embryonic motoneurons
Neurobiology of Disease, 2009Co-Authors: Christian Geis, Andreas Weishaupt, Marcus Beck, K V Toyka, Sibylle Jablonka, Michael Sendtner, Claudia SommerAbstract:Abstract Autoantibodies to the synaptic protein amphiphysin play a crucial pathogenic role in paraneoplastic Stiff-Person Syndrome. Impairment of GABAergic inhibition is the presumed pathophysiological mechanism by which these autoantibodies become pathogenic. Here we used calcium imaging on rat embryonic motor neurons to investigate whether antibodies to amphiphysin directly hinder GABAergic signaling. We found that the immunoglobulin G fraction from a patient with Stiff-Person Syndrome, containing high titer antibodies to amphiphysin and inducing Stiffness in rats upon passive transfer, reduced GABA-induced calcium influx in embryonic motor neurons. Depletion of the anti-amphiphysin fraction from the patient's IgG by selective affinity chromatography abolished this effect, showing its specificity for amphiphysin. Quantification of the surface expression of the Na + /K + /2Cl 2− cotransporter revealed a reduction after incubation with anti-amphiphysin IgG, which is concordant with a lower intracellular chloride concentration and thus impairment of GABA mediated calcium influx. Thus, anti-amphiphysin antibodies exert a direct effect on GABA signaling, which is likely to contribute to the pathogenesis of SPS.
Scott D. Newsome - One of the best experts on this subject based on the ideXlab platform.
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use of subcutaneous immunoglobulin in Stiff Person Syndrome case series
Medicine, 2021Co-Authors: Salman Aljarallah, Scott D. NewsomeAbstract:Introduction Intravenous immunoglobulin (IVIG) has been shown to be effective for the treatment of Stiff Person Syndrome (SPS). However, some patients might not tolerate it. We report the tolerability profile of subcutaneous immunoglobulin (SCIg) in patients with SPS who did not tolerate IVIG. To our knowledge, the use of SCIg in SPS has not been reported before in a case series. Patient concerns The five patients included in this case series presented with various combinations of symptoms of spasms, axial and limb Stiffness, and exaggerated responses to outside stimuli. These symptoms often lead to gait and functional impairment. Diagnosis Patients were diagnosed with classic SPS as they met the clinical criteria, which require the presence of spasms, axial rigidity, and hyperexcitability. Interventions Subcutaneous immunoglobulin infusion. Outcomes Five patients were identified that were treated with SCIg. Three tested positive for serum anti-glutamic acid decarboxylase 65 antibodies prior to any treatment. The mean age at SCIg initiation was 33 years (range: 22-47). The mean duration of SPS prior to SCIg initiation was 5.9 years (range: 2.5-7). All patients used IVIG for at least two months (up to 18 months) but switched to SCIg due to IVIG side effects. Duration of SCIg use ranged from 4 months to 6 years (mean, 19.2 months). Upon switching to SCIg, the SPS symptoms remained stable. SCIg was well-tolerated in most as only one patient discontinued SCIg due to side effects. Conclusion This case series highlights that SCIg could be a treatment option for patients with SPS, especially when IVIG is not feasible. Injection site reactions might be a limiting factor in some patients treated with SCIg. Prospective controlled studies are needed to confirm SCIg treatment durability and efficacy.
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improvement of Stiff Person Syndrome symptoms in pregnancy case series and literature review
Neuroimmunology and Neuroinflammation, 2020Co-Authors: Megan Esch, Scott D. NewsomeAbstract:Objective To describe 2 cases from a single academic institution of improvement in Stiff-Person Syndrome (SPS) symptoms during pregnancy and to review the clinical outcomes of SPS in 6 additional pregnancies described in the literature. Methods Evaluation of clinical symptoms and treatment changes of disease state during pregnancy. Results Seven patients with 9 pregnancies are described in women with a diagnosis of SPS. Six of 7 (86%) women were positive for glutamic acid decarboxylase (GAD65) antibody. In 5 of 9 (56%) pregnancies, symptomatic medications (antispasmodics) were significantly reduced with stabilization or improvement in symptoms through pregnancy. Nine live, healthy pregnancies resulted. All 7 (100%) women experienced worsening of symptoms after the birth of their children, and symptomatic therapies were resumed and/or increased. Conclusions The immune pathogenesis of SPS continues to be explored. Immunomodulatory shifts during pregnancy may influence changes of clinical SPS symptoms and provide insight into the unique pathogenesis of SPS. Some women with SPS may be able to reduce symptomatic medications related to clinical improvement during pregnancy. Women with SPS may safely carry pregnancies to term, delivering healthy and unaffected babies.
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use of subcutaneous immunoglobulin in Stiff Person Syndrome 327
Neurology, 2020Co-Authors: Salman Aljarallah, Scott D. NewsomeAbstract:Objective: To describe our experience with subcutaneous immunoglobulin (SCIg) treatment in patients with Stiff Person Syndrome (SPS). Background: SPS is a rare immune-mediated neurologic disorder. Multiple treatments are used for the treatment of SPS, although, to date, intravenous immunoglobulin (IVIG) remains the primary immunomodulating therapy in those who have inadequate responses to symptomatic therapies. However, in some patients, IVIG might not be tolerable or logistically difficult to administer. SCIg has emerged as an alternative to IVIG in certain disorders but to our knowledge, the use of SCIg has not been reported in SPS. Design/Methods: This is a descriptive case series of patients with SPS who were treated with SCIg at Johns Hopkins. Review of medical records was from 1997 to 2019. Patients were included if they fulfilled clinical criteria for SPS and were exposed to SCIg. Patients were excluded if their symptoms were explained by another neurological disorder. Results: We identified five SPS patients that were treated with SCIg. Three patients tested positive for serum anti-GAD65 antibodies prior to any treatment. Mean age at SCIg initiation was 33 years (range:22–47). Mean duration of SPS prior to SCIg initiation was 5.9 years (range:2.5–7). All patients used IVIG for at least 2 months (up to 18 months) but switched to SCIg due to IVIG side effects. Duration of SCIg use ranged from 4 months to 6 years (mean,19.2 months). SCIg dose ranged from 0.4g–1g/kg/month. SCIg lead to sustained symptom improvement or stabilization in four patients (80%). The remaining patients had transient improvement. One patient developed mild-moderate injection site reactions. Conclusions: This case series highlights that SCIg is a reasonable and safe immune-treatment option for SPS patients especially in whom IVIG is not feasible. Injection site reactions might be a limiting factor in some patients and future studies are needed to assess long-term safety/efficacy. Disclosure: Dr. Aljarallah has nothing to disclose. Dr. Newsome has received Personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Celgene, EMD Serono, Genentech, medDay Pharmaceuticals, and Gerson Lehrman Group.. Dr. Newsome has received research support from Biogen, Genentech.
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Retinal pathology occurs in Stiff-Person Syndrome
Neurology, 2020Co-Authors: Jeffrey Lambe, Shiv Saidha, Peter A. Calabresi, Alissa Rothman, Jerry L. Prince, Scott D. NewsomeAbstract:Objective To evaluate whether structural and functional changes occur in the afferent visual system of patients with Stiff-Person Syndrome (SPS) and whether these changes correlate with disease burden, given the high concentration of γ-aminobutyric acid receptors, which are generally thought to be involved in SPS pathogenesis, in the retina. Methods In this single-center, cross-sectional study, patients with SPS and healthy controls (HCs) underwent optical coherence tomography (OCT), with a subset undergoing high- and low-contrast visual acuity (VA) assessments. Burden of disease was assessed via the number of body regions affected. Individuals with uncontrolled hypertension or comorbid neurologic or ophthalmologic disorders were excluded. Statistical analyses were performed using mixed-effects linear regression models. Results Thirty-five patients with SPS and 40 age- and sex-matched HCs underwent OCT. A subset of 23 patients with SPS and 28 HCs underwent VA assessments. Relative to HCs, patients with SPS had lower ganglion cell + inner plexiform layer (GCIPL) thicknesses (SPS: 74.36 µm [SD 5.7]; HCs: 76.33 µm [SD 4.2]; p = 0.005), inner nuclear layer thicknesses (SPS: 44.37 µm [SD 2.7]; HCs: 45.18 µm [SD 2.2]; p = 0.042), and 100% (SPS: 53 [SD 9.6]; HCs: 57.5 [SD 6.1]; p = 0.005), 2.5% (SPS: 24.35 [SD 10.1]; HCs: 30.16 [SD 7.7]; p = 0.006), and 1.25% contrast (SPS: 16.41 [SD 10.6]; HCs: 20.84 [SD 8.6]; p = 0.034) letter acuity scores. GCIPL thicknesses correlated with the number of body regions affected in SPS (decrease of 1.25 µm [95% confidence interval, −2.2 to −0.3 µm; p = 0.008] per additional body region affected). Conclusions Retinal neuronal pathology can occur in SPS. OCT may have utility as a biomarker of disease burden in SPS.
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Stiff Person Syndrome masquerading as multiple sclerosis
Journal of the Neurological Sciences, 2017Co-Authors: Joseph J Sabatino, Scott D. NewsomeAbstract:Abstract Background Stiff Person Syndrome (SPS) is a rare neuroimmunological disorder presenting with a wide variety of signs and symptoms that mimic neuro-inflammatory diseases, such as multiple sclerosis (MS), thus delaying diagnosis. Methods We performed a retrospective chart review of over 100 patients with SPS who were treated at Johns Hopkins Hospital and identified five patients previously diagnosed with MS. Results Patients were female with a mean age of 53 years old (range 43–64). Mean time to SPS diagnosis was 5.5 years. They presented with typical SPS features (axial/leg spasms, torso rigidity, hyperlordosis, and gait instability) as well as atypical features (hemiparesis, hemisensory dysfunction, fine motor impairment) and were all initially given a diagnosis of MS. In all patients, brain MRI demonstrated non-specific white matter lesions and CSF was negative for intrathecal antibodies in the 4 out of 5 patients who underwent lumbar puncture. SPS diagnosis was supported by elevated anti-glutamic acid decarboxylase (GAD65) antibodies in each patient. Two patients were treated with disease-modifying therapies for MS before being diagnosed with SPS. Following diagnosis with SPS, the patients were treated with varying combinations of immunosuppressants and symptomatic therapies resulting in stabilization or improvement in four of the patients. Conclusion We present five patients with SPS, who were initially thought to have MS, including one patient treated with three different MS therapies due to “disease progression”. These cases demonstrate the need to consider less common neuroimmunological disorders, such as SPS, especially in patients with atypical features for MS.
Claudia Sommer - One of the best experts on this subject based on the ideXlab platform.
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Stiff Person-Syndrome IgG affects presynaptic GABAergic release mechanisms
Journal of Neural Transmission, 2015Co-Authors: Christian Werner, Holger Haselmann, Andreas Weishaupt, Klaus V. Toyka, Claudia Sommer, Christian GeisAbstract:The majority of patients with Stiff Person-Syndrome (SPS) are characterized by autoantibodies to glutamate decarboxylase 65 (GAD65). In previous passive-transfer studies, SPS immunoglobulin G (IgG) induced SPS core symptoms. We here provide evidence that SPS-IgG causes a higher frequency of spontaneous vesicle fusions. Sustained GABAergic transmission and presynaptic GABAergic vesicle pool size remained unchanged. Since these findings cannot be attributed to anti-GAD65 autoantibodies alone, we propose that additional autoantibodies with so far undefined antigen specificity might affect presynaptic release mechanisms.
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Stiff Person Syndrome associated anti amphiphysin antibodies reduce gaba associated ca2 i rise in embryonic motoneurons
Neurobiology of Disease, 2009Co-Authors: Christian Geis, Andreas Weishaupt, Marcus Beck, K V Toyka, Sibylle Jablonka, Michael Sendtner, Claudia SommerAbstract:Abstract Autoantibodies to the synaptic protein amphiphysin play a crucial pathogenic role in paraneoplastic Stiff-Person Syndrome. Impairment of GABAergic inhibition is the presumed pathophysiological mechanism by which these autoantibodies become pathogenic. Here we used calcium imaging on rat embryonic motor neurons to investigate whether antibodies to amphiphysin directly hinder GABAergic signaling. We found that the immunoglobulin G fraction from a patient with Stiff-Person Syndrome, containing high titer antibodies to amphiphysin and inducing Stiffness in rats upon passive transfer, reduced GABA-induced calcium influx in embryonic motor neurons. Depletion of the anti-amphiphysin fraction from the patient's IgG by selective affinity chromatography abolished this effect, showing its specificity for amphiphysin. Quantification of the surface expression of the Na + /K + /2Cl 2− cotransporter revealed a reduction after incubation with anti-amphiphysin IgG, which is concordant with a lower intracellular chloride concentration and thus impairment of GABA mediated calcium influx. Thus, anti-amphiphysin antibodies exert a direct effect on GABA signaling, which is likely to contribute to the pathogenesis of SPS.
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neuropathology and binding studies in anti amphiphysin associated Stiff Person Syndrome
Neurology, 2003Co-Authors: Carsten Wessig, R Klein, M F Schneider, K V Toyka, Markus Naumann, Claudia SommerAbstract:The authors report a 71-year-old woman with amphiphysin-associated paraneoplastic Stiff-Person Syndrome, opsoclonus, and encephalopathy. The patient's symptoms temporarily responded to plasmapheresis in parallel with a decline of serum anti-amphiphysin antibody titers. Later, the encephalopathy progressed rapidly and the patient died. Binding studies and the detection of autoantibodies in the patient's CNS as well as the treatment response suggest a pathogenic role of the anti-amphiphysin antibodies.
Mary Kay Floeter - One of the best experts on this subject based on the ideXlab platform.
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autoimmune Stiff Person Syndrome and related myelopathies understanding of electrophysiological and immunological processes
Muscle & Nerve, 2012Co-Authors: Goran Rakocevic, Mary Kay FloeterAbstract:Stiff Person Syndrome (SPS) is a disabling autoimmune central nervous system disorder characterized by progressive muscle rigidity and gait impairment with superimposed painful spasms that involve axial and limb musculature, triggered by heightened sensitivity to external stimuli. Impaired synaptic GABAergic inhibition resulting from intrathecal B-cell-mediated clonal synthesis of autoantibodies against various presynaptic and synaptic proteins in the inhibitory neurons of the brain and spinal cord is believed to be an underlying pathogenic mechanism. SPS is most often idiopathic, but it can occur as a paraneoplastic condition. Despite evidence that anti-GAD and related autoantibodies impair GABA synthesis, the exact pathogenic mechanism of SPS is not fully elucidated. The strong association with several MHC-II alleles and improvement of symptoms with immune-modulating therapies support an autoimmune etiology of SPS. In this review, we discuss the clinical spectrum, neurophysiological mechanisms, and therapeutic options, including a rationale for agents that modulate B-cell function in SPS.
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motor cortex excitability in Stiff Person Syndrome
Brain, 2000Co-Authors: Friedhelm Sandbrink, Marinos C Dalakas, Mavis Fujii, Nadir Ali Syed, Mary Kay FloeterAbstract:Muscle Stiffness in Stiff-Person Syndrome (SPS) is produced by continuous, involuntary firing of motor units that is thought to be caused by an autoimmune mediated dysfunction of GABA-ergic inhibitory neurones. We have postulated that the loss of GABA-ergic inputs from spinal interneurones alone is insufficient to produce tonic firing of motor neurones and that excessive supraspinal excitation could also play a role. To determine whether SPS is associated with dysfunction in supraspinal GABA-ergic neurones, we assessed the excitability of the motor cortex with transcranial magnetic stimulation (TMS) in seven SPS patients and seven age-matched healthy volunteers. SPS patients had normal central motor conduction times, normal thresholds for motor evoked potentials (MEPs) in leg muscles, and a normal MEP stimulus versus response recruitment curve with increasing TMS intensities in resting hand and leg muscles. Cortical silent periods were shortened in leg muscles. Intracortical inhibition and excitation were assessed while recording from the abductor pollicis brevis, using a paired pulse TMS paradigm with subthreshold conditioning stimuli. Patients had decreased inhibition and markedly increased facilitation at short intervals. Using paired suprathreshold TMS, patients exhibited increased facilitation at 20- and 40-ms intervals. These results point to a hyperexcitability of the motor cortex in SPS, which could be explained by impairment of supraspinal GABA-ergic neurones, leading to an impaired balance between inhibitory and excitatory intracortical circuitry.
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the Stiff Person Syndrome an autoimmune disorder affecting neurotransmission of gamma aminobutyric acid
Annals of Internal Medicine, 1999Co-Authors: Lucien M Levy, Marinos C Dalakas, Mary Kay FloeterAbstract:The Stiff-Person Syndrome, a rare and disabling disorder, is characterized by muscle rigidity and episodic spasms that involve axial and limb musculature. Continuous contraction of agonist and antagonist muscles caused by involuntary motor-unit firing at rest are the hallmark clinical and electrophysiologic signs of the disease. Except for global muscle Stiffness, results of neurologic examination are usually normal. Results of conventional computed tomography and magnetic resonance imaging of the brain are also normal. The cause of the Stiff-Person Syndrome is unknown; however, an autoimmune pathogenesis is suspected because of 1) the presence of antibodies against glutamic acid decarboxylase (GAD), the rate-limiting enzyme for the synthesis of the inhibitory neurotransmitter g-aminobutyric acid (GABA); 2) the association of the disease with other autoimmune conditions; 3) the presence of various autoantibodies; and 4) a strong immunogenetic association. Anti-GAD antibodies, which are found in high titers in most patients, seem to be directed against conformational forms of GAD. New evidence suggests that these antibodies may be pathogenic because they interfere with the synthesis of GABA. In addition, a reduction in brain levels of GABA, which is prominent in the motor cortex, has been demonstrated with magnetic resonance spectroscopy in patients with the Stiff-Person Syndrome. The Stiff-Person Syndrome is clinically elusive but potentially treatable and should be considered in patients with unexplained Stiffness and spasms. Drugs that enhance GABA neurotransmission, such as diazepam, vigabatrin, and baclofen, provide mild to modest relief of clinical symptoms. Immunomodulatory agents, such as steroids, plasmapheresis, and intravenous immunoglobulin, seem to offer substantial improvement. Results of an ongoing controlled trial will elucidate the role of these agents in the treatment of the disease. Ann Intern Med. 1999;131:522-530.
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physiologic studies of spinal inhibitory circuits in patients with Stiff Person Syndrome
Neurology, 1998Co-Authors: Mary Kay Floeter, Josep Vallssole, Camilo Toro, D Jacobowitz, M HallettAbstract:Objective: To test inhibitory spinal circuits in patients with Stiff-Person Syndrome(SPS). Background: Patients with SPS have fluctuating muscle Stiffness and spasms, and most have antibodies against GABAergic neurons. We predicted they would also have abnormalities of spinal GABAergic circuits. Design/Methods: Physiologic methods using H-reflexes were used to test reciprocal inhibition in the forearm and thigh, vibration-induced inhibition of flexor carpi radialis and soleus H-reflexes, recurrent inhibition, and nonreciprocal(1b) inhibition of soleus H-reflexes. Results: Vibration-induced inhibition of H-reflexes was diminished in eight of nine patients tested, but the presynaptic period of reciprocal inhibition was normal in most patients. Both circuits are presumed to involve presynaptic inhibition and GABAergic interneurons. Presumed glycinergic circuits, including the first period of reciprocal inhibition and nonreciprocal (1b) inhibition, showed occasional abnormalities. Recurrent inhibition was normal in all five patients tested. Conclusion: Differences between the two presumptive GABAergic circuits may indicate that not all populations of GABAergic neurons are uniformly affected in SPS. The involvement of presumptive glycinergic circuits in some patients could point to impairment of nonGABAergic neurons, unrecognized involvement of GABAergic neurons in these inhibitory circuits, or, more likely, alterations of supraspinal systems that exert descending control over spinal circuits.