Stiff Person Syndrome Patients Research Articles

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

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

Late-onset stiff-person syndrome: challenges in diagnosis and management.

Stiff person syndrome (SPS) is a rare slowly progressive autoimmune neuronal hyperexcitability disease with very-high GAD-65 antibody titers that most commonly presents above the age of 20, with muscle stiffness, painful muscle spasms, slow gait, and falls leading to disability. In other autoimmune disorders, late-onset disease has different symptom-spectrum and outcomes, but there is no information regarding late-onset SPS (LOSPS). Highlight delayed diagnosis and poor tolerance or incomplete response to therapies of patients with LOSPS and outline how best to increase disease awareness early at onset. We reviewed GAD-positive SPS patients with symptom onset above age 60, identified among 54 SPS patients, examined, treated and followed-up by the same clinicians, focused on clinical presentation, misdiagnoses, response and tolerance to therapies, and evolved disability. Nine patients had LOSPS with symptom onset at median age of 61 years (range 60-78), and current median age of 73. The median time from symptom onset to SPS diagnosis was 3 years; prior to diagnosis, five patients were treated for lumbosacral radiculopathies (one with laminectomy), two for Parkinson's disease, one for multiple sclerosis, and another for cerebellar degeneration. Progressive decline occurred rapidly in all patients; at time of diagnosis, six patients were already using a cane or walker and two were wheelchair-bound. Tolerance and response to treatment were limited; two patients did not respond to IVIg, two discontinued IVIg despite early response due to comorbidities (cardiac disease, thrombosis), four others partially responded to IVIg and one to rituximab; several could not tolerate high doses of oral antispasmodics due to somnolence; and two patients died. LOSPS is almost always misdiagnosed for other similar conditions commonly seen in the elderly. Patients with LOSPS decline quickly to clinically severe disease due to delayed treatment initiation, poor response or tolerance, other comorbidities, and possibly immunosenescence. Increased awareness that SPS can occur in the elderly mimicking other disorders is important for early diagnosis and treatment, even necessitating earlier immunotherapy initiation, compared to their younger counterparts, to prevent faster-evolving severe disability.

Stiff Person Syndrome Misdiagnosis: Clinical and Ancillary Testing Characteristics

Objective To assess stiff person syndrome (SPS) misdiagnosis and identify factors differentiating SPS from non-SPS. Background SPS is a heterogeneous immune-mediated central hyperexcitability disorder that is challenging to differentiate from alternative diagnoses. Design/Methods Patients referred to the Mayo Autoimmune Neurology Clinic for SPS (01-Jul-2016 to 30-Jun-2021) were included. SPS diagnosis was defined as compatible clinical syndrome confirmed by an autoimmune neurologist and either serum positivity for high-titer GAD65-IgG (>20.0 nmol/L), glycine-receptor-IgG or amphiphysin-IgG (seropositive cases), or confirmatory electrodiagnostic studies (seronegative cases). Seven patients were excluded (diagnostic uncertainty). Patients were compared for clinical presentation, examination findings, laboratory and electrodiagnostic testing, and treatment responses. Results Of 173 cases, 48 (28%) were diagnosed with SPS and 125 (72%) with non-SPS. Age and sex did not significantly differ in the two groups. Most SPS patients were seropositive (41/48 total: GAD65-IgG 27/41, glycine-receptor-IgG 12/41 and amphiphysin-IgG 2/41). Fibromyalgia/chronic pain syndrome or functional neurological disorder were the most common non-SPS diagnoses (81/125, 65%). True SPS patients more commonly had a history of exaggerated startle (81% vs 56%, p = 0.02), unexplained falls (76% vs 46%, p = 0.001) and prior autoimmunity (50% vs 27%, p = 0.005). On examination, SPS patients more often had hypertonia (60% vs 24%, p < 0.001), hyperreflexia (71% vs 43%, p = 0.001) and exaggerated lumbar lordosis (67% vs 9%, p < 0.001) but less likely had functional signs (6% vs 33%, p = 0.001). SPS patients more often had abnormal electrodiagnostic studies (74% vs 17%, p < 0.001), and at least moderate symptomatic improvement was more likely with benzodiazepines (51% vs 16%, p < 0.001) or immunotherapy (45% vs 13% p < 0.001). Seventy-one non-SPS patients received immunotherapy; only 4 had an autoimmune neurological condition. Conclusions SPS misdiagnosis is common and most alternative diagnoses were non-neurologic. Misdiagnosis may be reduced by considering clinical and paraclinical factors; improved diagnostic accuracy will reduce exposure to unnecessary treatments and health care costs.

Involuntary movement in stiff-person syndrome with amphiphysin antibodies: A case report.

Rationale:Stiff-person syndrome (SPS) is a rare neurological immune disorder characterized by progressive axial and proximal limb muscle rigidity, stiffness, and painful muscle spasms. Amphiphysin antibodies are positive in approximately 5% of SPS patients. To date, there have been no relevant reports on involuntary movement in cases of SPS with amphiphysin antibodies.Patient concerns:We describe the case of a 69-year-old man with a 2-year history of progressive stiffness in the neck, bilateral shoulders, and chest muscles, and a more-than-a-year history of dyspnea accompanied by mandibular involuntary movement. The patient was a vegetarian and had good health in the past. The family's medical history was unremarkable.Diagnoses:He was diagnosed with SPS based on the progressive muscle stiffness, the amphiphysin antibody seropositivity, the continuous motor activity on electromyography, and the effective treatment with benzodiazepines.Interventions:The patient was orally administered clonazepam and baclofen, and corticosteroid IV followed by prednisone orally.Outcomes:In the hospital, after treatment with methylprednisolone, clonazepam, and baclofen, the patient's rigidity, stiffness, and dyspnea significantly improved. The involuntary movement of the mandible persisted throughout the treatment process. Currently, under oral treatment with baclofen and clonazepam, the patient's symptoms of muscle stiffness and dyspnea exist, and follow-up is continued.Lessons:We report a rare and novel case of involuntary movement in SPS with amphiphysin antibodies. The present report explores the relationship between SPS and involuntary movement and expands the spectrum of clinical manifestations of SPS.

Association of stiff-person syndrome with autoimmune endocrine diseases.

BACKGROUNDStiff-person syndrome (SPS) and its subtype, stiff limb syndrome (SLS), are rare neurological disorders characterized by progressive muscular rigidity and spasms. Glutamic acid decarboxylase (GAD) is the enzyme that catalyzes the production of γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter of the central nervous system. SPS is an autoimmune disease triggered by anti-glutamic acid decarboxylase antibody (anti-GAD Ab). Clinically, anti-GAD Ab is associated with SPS, type 1 diabetes mellitus (T1DM), and other autoimmune diseases.AIMTo investigate the link of autoimmune endocrine disorders with anti-GAD Ab in SPS subjects.METHODSThis retrospective study was approved by the Institutional Review Board of Chang Gung Memorial Hospital, Taiwan. We collected the patients with SPS from January 2001 to June 2018. By reviewing 14 patients from medical records, we analyzed the clinical findings with coexisting autoimmune diseases, particularly diabetes mellitus and thyroid disease, which are associated with anti-GAD antibody titers or other immunological test results (anti-thyroid peroxidase and anti-nuclear antibodies). We also evaluated malignancies, major complications, and reported treatment to improve symptoms. Anti-GAD antibodies were measured using radioimmunoassay and enzyme-linked immunosorbent assay (ELISA). The cut-off values of these tests are < 1 U/mL and < 5 U/mL, respectively.RESULTSThe median age of all patients was 39.3 (range, 28.0-54.0) years with a median follow-up period of 6.0 (2.7-13.3) years. Five (35.7%) patients were female; twelve (85.7%) were diagnosed with classic SPS and two (14.3%) with SLS. The median age of onset of symptoms was 35.0 (26.0-56.0) years with a median follow-up duration of 9.0 (2.1-14.9) years in the classic SPS group; the SLS group had a median age of onset of 46.7 years and a shorter follow-up duration of 4.3 years. Among nine classic SPS patients who underwent the anti-GAD Ab test, three were anti-GAD Ab seropositive and each of these three patients also had T1DM, latent autoimmune diabetes in adults, and autoimmune thyroid disease, respectively. In contrast, other rare autoimmune diseases co-existed in six anti-GAD Ab seronegative SPS patients. None of the SLS patients had additional autoimmune diseases.CONCLUSIONWhile typical clinical symptoms are crucial for the diagnosis of SPS, the presence of anti-GAD autoantibody may consolidate the diagnosis and predict the association with other autoimmune diseases.

O-35 The Stiff Person Syndrome. Neurophysiological findings

Background Stiff Person Syndrome (SPS) an encephalomyelitis, is an immune-mediated disorder characterized by rigidity of the axial and proximal limb muscles with painful spasThis rare disease responds to immunotherapies and is frequently associated with other autoimmune diseases. More than 80% of SPS patients have autoantibodies to GAD65 and up to 15% have antibodies to glycinereceptor. Neurophysiological studies can help in the diagnosis by demonstrating the presence of continuous motor unit activity at rest, that the patient cannot voluntarily suppress. Material and methods We present a male patient 28 y/o with a history of weight loss, abdominal pain, ortostathic hypotension, ptosis and babinski sign, whith stiffness and painful spasms in both cuadriceps, tibialis anterior, gastronemius, rectus abdominis, thoracic and lumbar paraspinal muscles. Results EMG showed continuous, involuntary activity of normal motor unit potentials. Painful spasms of involuntary muscle activity, were also detected. No other abnormal spontaneus activity such as fibrilations, positive waves, miokimias, high frequency nor myotonic or neuromyotonic discharges were recorded. The SSR was absent en both hands. The Silent period was normal. ENG and SFEMG were normal. Antibodies to glycinereceptors were positive. After treatment with IvIg and plasma exchange the patient had moderate improvement and at present he is on baclofen, diazepam, methylprednisone and levetirazetam, with persistence of fluctuating stiffness and spas. Conclusions The neurophysiological studies play an important role in the differential diagnosis of the diseases associated with excess motor unit activity, leading in this patient to the diagnosis of encephalomyelitis with rigidity, variant of SPS.

Stiff person syndrome with Anti-GAD65 antibodies within the national veterans affairs health administration.

Stiff person syndrome (SPS) is a neurological disorder characterized by muscle rigidity primarily in the truncal muscles, commonly associated with autoantibodies to the glutamic acid-decarboxylase 65 kD receptor (GAD65). There is limited epidemiological information on patients with SPS. We performed a retrospective case review using the National United States Veterans Affairs Health Administration electronic medical record system. We analyzed prevalence, demographics, disease characteristics, and treatment outcomes in SPS patients who were anti-GAD65 antibody positive. Fifteen patients met our criteria. Point prevalence was 2.06 per million, and period prevalence was 2.71 per million. Men to women ratio was 14:1. All patients benefitted from treatment with symptomatic antispasmodic agents. Ten of 15 patients received intravenous immunoglobulin, with a majority demonstrating stable or improved modified Rankin scores. This investigation was a large North American epidemiological study of SPS with predominantly male patients. Symptomatic therapy was beneficial for most patients, with less clear sustained benefit of immunotherapy. Muscle Nerve 58:801-804, 2018.

F59. Spasmodic reflex myoclonus-an characteristic electrophysiological manifestation for the diagnosis of Stiff-person syndrome

Introduction Stiff person syndrome (SPS) is a rare disease entity and the pivotal clinical features contain progressive course of fluctuating stiffness of the low back and lower limbs. Progressive encephalomyelitis with rigidity and myoclonus (PERM) is one of the unique variants of stiff person syndrome, and it was characterized with rigidity, stimulus-sensitive spasms, myoclonus, autonomic disturbance, and brainstem signs. These features resemble those of hyperekplexia. The accurate diagnosis of SPS is difficult but is crucial for the in time intervention with immunotherapy for life saving. In addition to the detection of responsible antibody, clinical electrophysiological manifestation, spasmodic reflex myoclonus, would be of great help in establishing the diagnosis. Methods Multichannel surface electromyogram (sEMG) and accelerometer recordings were conducted over the lumbar paraspinalis, rectus abdominalis, quadriceps, and hamstring muscles. Stimulus sensitive phenomenon was illustrated with accelerometer tapped over the pinprick. The signals were processed and digitized with CED power1401 with Spike2. The band pass for sEMG was set from 80 Hz to 1000 Hz. Results The results demonstrated that episodes of spontaneous onset of spasm of the low trunk and legs lasted about seconds to minutes. Stimuli with nose tip tapping, would elicit vigorous jerks with dissemination of long lasting muscle spasm of the neck, paraspinal muscle, rectus abdominalis muscle, to quadriceps and hamstring muscles in a descending spreading pattern. The unique electrophysiological manifestations illustrate the characteristic feature of spasmodic reflex myoclonus. The surface EMG recording also showed the phenomena of habituation, in which a trend of amplitude decrescendo from the first toward the third EMG responses were observed during consecutive auditory stimulus. The serum levels of anti-glutamic acid decarboxylase 65 antibodies was 164 IU. Conclusion The unique EMG pattern can help identify SPS. The clinical features of spasmodic reflex myoclonus are similar to hyperekplexia. However, there are some differences between the two phenomena. Unlike hyperekplexia, the spasmodic reflex myoclonus can be habituated after repetitive stimulation in the SPS patient. Furthermore, the initial myoclonic bursts of spasmodic reflex myoclonus were not present in hyperekplexia and the EMG burst duration was much shorter of the hyperekplexia as compared with that of spasmodic reflex myoclonus. These neurophysiological features discern spasmodic reflex myoclonus from hyperekplexia and are helpful in making diagnosis of SPS.

GAD65 autoantibody characteristics in patients with co-occurring type 1 diabetes and epilepsy may help identify underlying epilepsy etiologies

BackgroundAutoantibodies against the smaller isoform of glutamate decarboxylase (GAD65Ab) reflect autoimmune etiologies in Type 1 diabetes (T1D) and several neurological disorders, including Stiff Person Syndrome (SPS). GAD65Ab are also reported in cases of epilepsy, indicating an autoimmune component. GAD65Ab in patients with co-occurring T1D, epilepsy or SPS may be part of either autoimmune pathogenesis. To dissect the etiologies associated with GAD65Ab, we analyzed GAD65Ab titer, epitope specificity and enzyme inhibition in GAD65Ab-positive patients diagnosed with epilepsy (n = 28), patients with epilepsy and T1D (n = 10), patients with SPS (n = 20), and patients with T1D (n = 42).ResultsGAD65Ab epitope pattern in epilepsy differed from T1D and SPS patients. Four of 10 patients with co-occurring T1D and epilepsy showed GAD65Ab profiles similar to T1D patients, while lacking GAD65Ab characteristics found in GAD65Ab-positive epilepsy patients. One of these patients responded well to anti-epileptic drugs (AEDs), while another patient did not require medication for seizure control. The third patient was refractory due to a diagnosis of meningioma. The response of the remaining patient to AEDs was unknown. GAD65Ab in the remaining six patients with T1D and epilepsy showed profiles similar to those in epilepsy patients.ConclusionsDifferent autoimmune responses associated with T1D, epilepsy and SPS are reflected by disease-specific GAD65Ab patterns. Moreover, the epileptic etiology in patients diagnosed with both T1D and epilepsy may present two different etiologies regarding their epileptic condition. In one group T1D co-occurs with non-autoimmune epilepsy. In the other group GAD65Ab are part of an autoimmune epileptic condition.

A double-blind, placebo-controlled study of rituximab in patients with stiff person syndrome.

In stiff person syndrome (SPS), an antibody-mediated impaired γ-aminobutyric acidergic (GABAergic) neurotransmission is believed to cause muscle stiffness and spasms. Most patients improve with GABA-enhancing drugs and intravenous immunoglobulin, but some respond poorly and remain disabled. The need for more effective therapy prompted a trial with the anti-CD20 monoclonal antibody rituximab. This was a placebo-controlled randomized trial of rituximab (2 biweekly infusions of 1g each). The primary outcome was a change in stiffness scores at 6 months. Secondary outcomes were changes in heightened-sensitivity and quality of life scores. Enrolling 24 patients was calculated to detect 50% change in stiffness scores. Randomization was balanced for age, sex, disease duration, and glutamic acid decarboxylase autoantibody titers. No significant changes were noted at 6 months after treatment in all outcomes. Specifically, no differences were noted in the stiffness index, the primary outcome, or sensitivity scores, the secondary outcome, at 3 or 6 months. Quality of life scores improved significantly (p < 0.01) at 3 months in both groups, but not at 6 months, denoting an early placebo effect. Blinded self-assessment rating of the overall stiffness for individual patients revealed improvement in 4 patients in each group. At 6 months, improvement persisted in 1 patient in the placebo group versus 3 of 4 in the rituximab group, where these meaningful improvements were also captured by video recordings. This is the largest controlled trial conducted in SPS patients and demonstrates no statistically significant difference in the efficacy measures between rituximab and placebo. Rituximab's lack of efficacy could be due to a considerable placebo effect; insensitivity of scales to quantify stiffness, especially in the less severely affected patients; or drug effectiveness in only a small patient subset. Ann Neurol 2017;82:271-277.

両下肢痛の診断に難渋したStiff-person syndromeの1例

両下肢痛の診断に難渋したStiff-person syndromeの1例

Elevated Serum GAD65 and GAD65-GADA Immune Complexes in Stiff Person Syndrome.

Glutamic acid decarboxylase 65 (GAD65) and autoantibodies specific for GAD65 (GADA) are associated with autoimmune diseases including Stiff Person Syndrome (SPS) and Type 1 diabetes (T1D). GADA is recognized as a biomarker of value for clinical diagnosis and prognostication in these diseases. Nonetheless, it remains medically interesting to develop sensitive and specific assays to detect GAD65 preceding GADA emergence, and to monitor GADA-GAD65 immune complexes in blood samples. In the present study, we developed a highly sensitive proximity ligation assay to measure serum GAD65. This novel assay allowed detection of as little as 0.65 pg/ml GAD65. We were also able to detect immune complexes involving GAD65 and GADA. Both free GAD65 and GAD65-GADA levels were significantly higher in serum samples from SPS patients compared to healthy controls. The proximity ligation assays applied for detection of GAD65 and its immune complexes may thus enable improved diagnosis and better understanding of SPS.

Characterization of continuous B-cell epitopes in the N-terminus of glutamate decarboxylase67 using monoclonal antibodies.

Glutamate decarboxylase (GAD) is an autoantigen associated with the autoimmune disorders Type-1 diabetes (T1D) and stiff-person syndrome (SPS). The protein, being an essential enzyme involved in the production of the inhibitory neurotransmitter γ-aminobutyric acid, exists in two isoforms, GAD67 and GAD65. Both isoforms may be targeted by autoantibodies in SPS and T1D patients, although SPS primarily is associated with the presence of GAD67 autoantibodies, whereas T1D mainly is associated with the presence of GAD65 autoantibodies. In this study, we describe antibody reactivity to overlapping GAD67 peptides covering the complete protein sequence by modified peptide enzyme-linked immunosorbent assay in order to identify potential GAD67 epitopes using two monoclonal antibodies (mAbs). Both GAD67 mAbs showed reactivity to linear epitopes located at the N-terminal end of GAD67. The epitopes of GAD mAb 1 and 2 were identified as the amino acid sequences NAGADPNTTN and TETDFSNLF, respectively, corresponding to amino acids 14-23 and 91-99. Fine mapping of the epitopes revealed that antibody reactivity was related to amino acid side-chain functionality, rather than amino acid side-chain specificity. Additionally, results suggested that non-contact amino acids in the epitope structure were essential for antibody reactivity. The exact role of these amino acids remains to be determined, but they are thought to be involved in backbone hydrogen bonds or stabilization of the epitope structure. As only limited knowledge is available in relation to antigenic regions of GAD67, this study contributes to characterization of GAD67 epitopes and may be a first step in the development of peptide-based therapeutics against SPS.

DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients.

To describe the detection frequency and clinical associations of immunoglobulin G (IgG) targeting dipeptidyl-peptidase-like protein-6 (DPPX), a regulatory subunit of neuronal Kv4.2 potassium channels. Specimens from 20 patients evaluated on a service basis by tissue-based immunofluorescence yielded a synaptic immunostaining pattern consistent with DPPX-IgG (serum, 20; CSF, all 7 available). Transfected HEK293 cell-based assay confirmed DPPX specificity in all specimens. Sixty-nine patients with stiff-person syndrome and related disorders were also evaluated by DPPX-IgG cell-based assay. Of 20 seropositive patients, 12 were men; median symptom onset age was 53 years (range, 13-75). Symptom onset was insidious in 15 and subacute in 5. Twelve patients reported prodromal weight loss. Neurologic disorders were multifocal. All had one or more brain or brainstem manifestations: amnesia (16), delirium (8), psychosis (4), depression (4), seizures (2), and brainstem disorders (15; eye movement disturbances [8], ataxia [7], dysphagia [6], dysarthria [4], respiratory failure [3]). Nine patients reported sleep disturbance. Manifestations of central hyperexcitability included myoclonus (8), exaggerated startle (6), diffuse rigidity (6), and hyperreflexia (6). Dysautonomia involved the gastrointestinal tract (9; diarrhea [6], gastroparesis, and constipation [3]), bladder (7), cardiac conduction system (3), and thermoregulation (1). Two patients had B-cell neoplasms: gastrointestinal lymphoma (1), and chronic lymphocytic leukemia (1). Substantial neurologic improvements followed immunotherapy in 7 of 11 patients with available treatment data. DPPX-IgG was not detected in any of the stiff-person syndrome patients. DPPX-IgG is a biomarker for an immunotherapy-responsive multifocal neurologic disorder of the central and autonomic nervous systems.

Characteristics ofin-vitrophenotypes of glutamic acid decarboxylase 65 autoantibodies in high-titre individuals

Previous studies have indicated phenotypical differences in glutamic acid decarboxylase 65 autoantibodies (GADA) found in type 1 diabetes (T1D) patients, individuals at risk of developing T1D and stiff-person syndrome (SPS) patients. In a Phase II trial using aluminium-formulated GAD(65) (GAD-alum) as an immunomodulator in T1D, several patients responded with high GADA titres after treatment, raising concerns as to whether GAD-alum could induce GADA with SPS-associated phenotypes. This study aimed to analyse GADA levels, immunoglobulin (Ig)G1-4 subclass frequencies, b78- and b96·11-defined epitope distribution and GAD(65) enzyme activity in sera from four cohorts with very high GADA titres: T1D patients (n = 7), GAD-alum-treated T1D patients (n = 9), T1D high-risk individuals (n = 6) and SPS patients (n = 12). SPS patients showed significantly higher GADA levels and inhibited the in-vitro GAD(65) enzyme activity more strongly compared to the other groups. A higher binding frequency to the b78-defined epitope was found in the SPS group compared to T1D and GAD-alum individuals, whereas no differences were detected for the b96·11-defined epitope. GADA IgG1-4 subclass levels did not differ between the groups, but SPS patients had higher IgG2 and lower IgG4 distribution more frequently. In conclusion, the in-vitro GADA phenotypes from SPS patients differed from the T1D- and high-risk groups, and GAD-alum treatment did not induce SPS-associated phenotypes. However, occasional overlap between the groups exists, and caution is indicated when drawing conclusions to health or disease status.

Trialing of Intrathecal Baclofen Therapy for Refractory Stiff-Person Syndrome

Stiff-person syndrome (SPS) is a rare disorder of the central nervous system characterized by stiffness and muscle spasms that may be progressive in nature. When oral medication is inadequate to control muscle spasticity, intrathecal baclofen may be used. We report a patient with severe SPS and glutamate decarboxylase negative [GAD(-)] (note: GAD(-) indicates the patient has no antibodies to GAD), refractory to oral standard therapies. The patient was effectively trialed with an intrathecal catheter and subsequently treated with chronic intrathecal baclofen, which provided significant relief of spasticity symptoms. A 48-year-old white man with a history consistent with SPS presented to the clinic. His previous history showed that he met several diagnostic criteria for GAD(-) SPS and had a muscle biopsy positive for myositis. Oral medications were unable to control his muscle spasticity, preventing him from working. The patient received an intrathecal trial using a lumbar approach for placement of a thoracic catheter with an initial baclofen dose of 50 μg/d. Gradual titration to symptom relief was performed up to 150 μg/d. Functional evaluation by our physical therapist showed improved motor function, the temporary catheter was removed, and a permanent intrathecal pump placed for intrathecal baclofen infusion. The patient reported excellent symptom relief over the next 6 months and improved activity. Refractory SPS is difficult to treat and has few therapeutic options. We report a GAD(-) patient with SPS and resulting debilitating spasticity that was refractory to oral medications who underwent successful continuous intrathecal catheter trial of baclofen over 4 days and subsequently went on to implantation of intrathecal pump. The literature reports only 5 cases of GAD(-) SPS patients treated with intrathecal baclofen therapy, and these resulted in poor long-term success. Our patient completed a 4-day trial of intrathecal baclofen titrated to effect before pump implantation. We advocate continuous intrathecal trialing, as opposed to single-injection technique, to possibly better determine the effective therapeutic dose and ensure posttrialing successful therapy.

Human Stiff person syndrome IgG-containing high-titer anti-GAD65 autoantibodies induce motor dysfunction in rats

Stiff person syndrome (SPS) is an autoimmune CNS disorder characterized by muscle rigidity, spasms and anxiety. The majority of patients have high-titer autoantibodies (ab) against glutamate decarboxylase (GAD65). A pathogenic role of SPS-associated IgG with ab against GAD65 has been shown for anxiety-like behavior but not for the core motor signs.We repetitively injected the purified IgG fraction of an SPS patient with severe motor impairment but without anxious comorbidity containing high titers of anti-GAD65 ab (SPS-IgG) into the lateral ventricle (i.c.v.) or intrathecally (i.th.) at the spinal level in experimental rats. We analyzed the effects on motor and anxiety-like behavior. Non-SPS human IgG fractions served as controls.Animals injected i.c.v. with SPS-IgG showed stiffness-like behavior with impaired walking ability and reduced grip strength of the upper limbs as well as postural and sensorimotor dysfunction. Testing for anxiety-like behavior revealed no significant differences between SPS and control IgG-treated rats. IgG deposits were found only in rats treated with SPS-IgG and were localized predominantly in CNS structures involved in motor control including globus pallidus, internal capsule, striatum and anterior thalamus. Double immunofluorescence staining revealed that predominantly GABAergic interneurons were positive for i.c.v. injected SPS-IgG. Rats injected i.th. with SPS-IgG did not present obvious motor symptoms and had a normal synaptic transmission at the spinal level.We conclude that SPS-like motor dysfunction can be induced in rats by passive transfer of IgG from an SPS-patient with high titer of anti-GAD65 ab. GABAergic dysfunction in supraspinal motor pathways rather than in the spinal cord may lead to motor deficits observed in the rats contrasting observations made in SPS with amphiphysin antibodies.

Cannabis derivatives therapy for a seronegative stiff-person syndrome: a case report

Stiff-person syndrome (SPS) is an uncommon and disabling disorder characterized by progressive rigidity and episodic painful spasms involving axial and limb musculature. SPS treatment is mostly based on benzodiazepines, baclofen, immunosuppressants and intravenous immunoglobulin. Cannabis derivatives [tetrahydrocannabinol (THC) and cannabidiol (CBD)] are available as an oromucosal spray (Sativex(®)), indicated as add-on treatment, for symptom improvement in patients with moderate to severe spasticity because of multiple sclerosis (MS). Our objective is to report a case of seronegative SPS successfully treated with THC-CBD oromucosal spray. We report a case of a 40-year-old man presenting with progressive muscle stiffness and intermittent spasms for 6-years. The diagnosis of stiff-person syndrome was based on the clinical features and neuroelectrophysiologic findings of continuous motor unit activity. Glutamic acid decarboxylase autoantibodies was absent in our patient, in both serum and cerebrospinal fluid (CSF). Cannabis derivatives oromucosal spray was introduced after a series of unsatisfactory traditional medical treatments. After 14 months treated with THC-CBD oromucosal spray, improvement was verified in the eight dimensions of the scale of SF-36 quality of life questionnaire. Clinical experience with cannabis derivatives in patients with multiple sclerosis is accumulating steadily, but there is no current literature about its efficacy for SPS. Because MS and SPS share some neurological symptoms such as spasticity and rigidity, it is thought that THC-CBC can be an option for SPS patient. Our case report suggests that THC-CBD oromucosal spray is an alternative treatment for patients with refractory SPS, and further validation is appropriate.

Efficacy of pregabalin in a case of stiff-person syndrome: Clinical and neurophysiological evidence

Symptomatic treatment of stiff-person syndrome (SPS) might be challenging and a significant improvement of stiffness and rigidity is generally reached with high doses of benzodiazepines or baclofen causing side effects.A 71-year old woman diagnosed with SPS complained of marked stiffness of trunk and lower limb muscles with sudden painful spasms. She was unable to walk and she could not lean on her right leg. Cortical silent period (CSP) duration evaluated from right abductor pollicis brevis (APB) with transcranial magnetic stimulation was shortened. Polygraphic electromyographic (EMG) evaluation from paraspinal and leg muscles disclosed continuous motor unit activity at rest with interference muscular pattern. Symptomatic treatment with diazepam was withdrawn because of excessive sedation. In order to relieve the intense lumbar pain, she was prescribed pregabalin; since the day after, rigidity and painful spasms dramatically improved and she could walk without assistance. The clinical benefit persisted at 3months follow-up and was paralleled by almost complete disappearance of EMG activity at rest and prolongation of CSP. The clinical and electrophysiological data in this SPS patient suggest the possible efficacy of pregabalin as symptomatic treatment without any significant side effects, which needs to be replicated in larger case series.

Human Stiff-Person Syndrome IgG Induces Anxious Behavior in Rats

BackgroundAnxiety 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.Methodology/Principal FindingsWe re-investigated a 53 year old woman with SPS and profound anxiety for GABA-A receptor binding in the amygdala with (11)C-flumazenil PET scan and studied the potential pathogenic role of purified IgG from her plasma filtrates containing high-titer antibodies against GAD 65. We passively transferred the IgG fraction intrathecally into rats and analyzed the effects using behavioral and in vivo electrophysiological methods. In cell culture, we measured the effect of patient IgG on GABA release from hippocampal neurons. Repetitive intrathecal application of purified patient IgG in rats resulted in an anxious phenotype resembling the core symptoms of the patient. Patient IgG selectively bound to rat amygdala, hippocampus, and frontal cortical areas. In cultured rat hippocampal neurons, patient IgG inhibited GABA release. In line with these experimental results, the GABA-A receptor binding potential was reduced in the patient's amygdala/hippocampus complex. No motor abnormalities were found in recipient rats.Conclusion/SignificanceThe observations in rats after passive transfer lead us to propose that anxiety-like behavior can be induced in rats by passive transfer of IgG from a SPS patient positive for anti-GAD 65 antibodies. Anxiety, in this case, thus may be an antibody-mediated phenomenon with consecutive disturbance of GABAergic signaling in the amygdala region.