Spinal cord stimulation for the symptomatic treatment of rigidity and painful spasm in a case of stiff person syndrome.

BACKGROUND: Stiff person syndrome (SPS) is a rare neuroimmunological disorder characterized by rigidity and painful spasm primarily affecting the truncal and paraspinal musculature due to autoimmune-mediated neuronal hyperexcitability. Spinal cord stimulation (SCS) is an approved therapy for managing painful neuropathic conditions, including diabetic peripheral neuropathy and refractory angina pectoris. We describe the novel use of SCS for the treatment of spasm and rigidity in a 49-year-old man with seropositive stiff person syndrome (SPS). The patient was treated with intravenous immunoglobulin (IVIG) and oral medications over a 13-month period with minimal improvement, prompting consideration of SCS. To our knowledge, this is the first report of the successful use of SCS in SPS with the demonstration of multifaceted clinical improvement. METHODS: Following a successful temporary SCS trial, permanent implantation was performed. Spasm/stiffness (Distribution of Stiffness Index; Heightened Sensitivity Scale; Penn Spasm Frequency Scale, PSFS), disability (Oswestry Disability Index, ODI; Pain Disability Index, PDI), depression (Patient Health Questionnaire-9, PHQ-9), sleep (Pittsburgh Sleep Quality Index, PSQI), fatigue (Fatigue Severity Scale, FSS), pain (Numerical Pain Rating Scale, NPRS), quality of life (EuroQoL 5 Dimension 5 Level, EQ-5D-5L), and medication usage were assessed at baseline, 6-month, and 10-month postimplantation. RESULTS: ODI, PHQ-9, FSS, NPRS, PSQI, and EQ-5D-5L scores showed a notable change from baseline and surpassed the defined minimal clinically important difference (MCID) at 6-month and 10-month follow-up. Oral medication dosages were reduced. CONCLUSIONS: The novel use of SCS therapy in seropositive SPS resulted in functional improvement and attenuation of symptoms. We present possible mechanisms by which SCS may produce clinical response in patients with SPS and aim to demonstrate proof-of-concept for a future comprehensive pilot study evaluating SCS-mediated response in SPS.

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

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

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

ABSTRACT: A 68-year-old woman with positional dizziness and progressive imbalance presented for vestibular evaluation. Examination was notable for spontaneous downbeat nystagmus (DBN), horizontal and vertical gaze-evoked nystagmus (GEN) with centripetal and rebound nystagmus, and positional apogeotropic nystagmus. There was also mild-moderate slowing of saccades horizontally and vertically and poor fast phases with an optokinetic stimulus. Further consultation by a movement disorder specialist uncovered asymmetric decrementing bradykinesia and rigidity, masked facies, and a wide-based stance without camptocormia. Screening serum laboratory results for metabolic, rheumatologic, infectious, heavy metal, endocrine, or vitamin abnormalities was normal. Surveillance imaging for neoplasms was unremarkable, and cerebrospinal fluid (CSF) analysis was negative for 14-3-3 and real-time quaking-induced conversion (RT-QuIC). However, her anti-glutamic acid decarboxylase-65 (GAD65) immunoglobulin G (IgG) level was markedly elevated in serum to 426,202 IU/mL (reference range 0-5 IU/mL) and in CSF to 18.1 nmol/L (reference range <0.03 nmol/L). No other autoantibodies were identified on the expanded paraneoplastic panel. The patient was referred to neuroimmunology, where torso rigidity, spasticity, and significant paravertebral muscle spasms were noted. Overall, the clinical presentation, examination findings, and extensive workup were consistent with a diagnosis of anti-GAD65-associated stiff person syndrome-plus (musculoskeletal plus cerebellar and/or brainstem involvement). She was subsequently treated with intravenous immunoglobulin (IVIg) and has been stable since commencing this therapy. In patients with centripetal nystagmus, especially in association with other cerebellar findings, an autoimmune cerebellar workup should be considered.

Stiff Person Syndrome and Encephalitis with GAD Antibodies with Severe Anterograde Amnesia in an Adolescent: A Case Study and Literature Review.

Antiglutamic acid decarboxylase (GAD65) encephalitis is rare and few pediatric cases have been reported, with variable clinical presentations. A 14-year-old female adolescent was managed in our department. She had been treated for several months for drug-resistant temporal lobe epilepsy and gradually presented major anterograde amnesia with confusion. Upon her arrival at the University Hospital Centre, she showed a classical form of stiff person syndrome. The brain magnetic resonance imaging showed bitemporal hyperintensities and hypertrophy of the amygdala. The blood and cerebrospinal fluid were positive for GAD65 antibodies. At 2 years of immunosuppressive treatment and rehabilitation, the course showed partial improvement of the memory and neuropsychiatric impairment, and epilepsy that continued to be active. GAD65 antibodies are associated with various neurological syndromes, and this presentation combining limbic encephalitis and stiff person syndrome is the first pediatric form published to date; there are also few cases described in adults.

Postoperative hypotonia in a patient with stiff person syndrome: a case report and literature review.

PURPOSE: Stiff person syndrome (SPS), an autoimmune disease that manifests with episodic muscle rigidity and spasms, has anesthetic considerations because postoperative hypotonia may occur. This hypotonia has been linked to muscle relaxants and volatile anesthetics and may persist in spite of neostigmine administration and train-of-four (TOF) monitoring suggesting full reversal. We present a patient with SPS who experienced hypotonia following total intravenous anesthesia (TIVA), which was promptly reversed with sugammadex. These observations are considered in light of the relevant medical literature. CLINICAL FEATURES: A 46-yr-old female patient with SPS underwent breast lumpectomy and sentinel node biopsy. Anesthesia consisted of TIVA (propofol/remifentanil) with adjunctive administration of rocuronium 20 mg to obtain adequate intubating conditions. Despite return of the TOF ratio to 100% within 30 min, hypotonia was clinically evident at conclusion of surgery two hours later. Sugammadex 250 mg reversed residual muscle relaxation permitting uneventful extubation. A literature review identified six instances of postoperative hypotonia (TIVA, n = 3; volatile anesthetics, n = 3) in spite of neostigmine administration (n = 2) and TOF monitoring suggesting full reversal (n = 4). CONCLUSIONS: Patients with SPS may show hypotonia regardless of general anesthetic technique (TIVA vs inhalational anesthesia), which can persist despite recovery of the TOF ratio and may be more effectively reversed by a chelating agent than with an anticholinesterase. If general anesthesia is required, we suggest a cautious approach to administering muscle relaxants including using the smallest dose necessary, considering the importance of clinical assessment of muscle strength recovery in addition to TOF monitoring, and discussing postoperative ventilation risk with the patient prior to surgery.

RéSUMé: OBJECTIF: Le syndrome de la personne raide (SPR), une maladie auto-immune qui se manifeste par une rigidité musculaire et des spasmes épisodiques, requiert certaines considérations anesthésiques en raison du risque d'hypotonie postopératoire. Cette hypotonie a été liée à des myorelaxants et à des anesthésiques volatils et peut persister malgré l'administration de néostigmine et un monitorage du train-de-quatre (TDQ) suggérant une neutralisation complète. Nous présentons le cas d'une patiente atteinte de SPR qui a souffert d'hypotonie après une anesthésie intraveineuse totale (TIVA), laquelle a été rapidement neutralisée à l'aide de sugammadex. Ces observations sont examinées à la lumière de la littérature médicale pertinente. CARACTéRISTIQUES CLINIQUES: Une patiente de 46 ans atteinte de SPR a bénéficié d'une tumorectomie mammaire et d'une biopsie du ganglion sentinelle. L'anesthésie consistait en une TIVA (propofol/rémifentanil) avec administration d'appoint de 20 mg de rocuronium pour atteindre des conditions d'intubation adéquates. Malgré le retour du ratio de TdQ à 100 % dans les 30 minutes, l'hypotonie était cliniquement évidente à la fin de la chirurgie deux heures plus tard. L'administration de 250 mg de sugammadex a neutralisé la relaxation musculaire résiduelle, permettant une extubation sans incident. Une revue de la littérature a identifié six cas d'hypotonie postopératoire (TIVA, n = 3; anesthésiques volatils, n = 3) malgré l'administration de néostigmine (n = 2) et le monitorage du TdQ suggérant une neutralisation complète (n = 4). CONCLUSION: Les patients atteints de SPR peuvent présenter une hypotonie quelle que soit la technique d'anesthésie générale utilisée (TIVA vs anesthésie par inhalation), laquelle peut persister malgré la récupération du rapport de TdQ; cette hypotonie peut être plus efficacement neutralisée par un agent chélateur qu'avec un anticholinestérasique. Si une anesthésie générale est nécessaire, nous suggérons une approche prudente pour l'administration de myorelaxants, y compris l'utilisation de la plus petite dose nécessaire, la prise en compte de l'importance de l'évaluation clinique de la récupération de la force musculaire en plus du monitorage du TdQ, et la communication du risque de ventilation postopératoire au patient avant la chirurgie.

Progressive encephalomyelitis with rigidity and myoclonus (PERM).

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a subtype of stiff-person syndrome (formerly stiff-man syndrome). It is rare and disabling, and characterised by brainstem symptoms, muscle stiffness, breathing issues and autonomic dysfunction. We describe a 65-year-old man who presented with odynophagia together with tongue and neck swelling, followed by multiple cranial nerve palsies culminating in bilateral vocal cord paralysis with acute stridor. He subsequently developed progressive generalised hypertonia and painful limb spasms. Serum antiglycine receptor antibody was strongly positive, but antiglutamic acid decarboxylase and other antibodies relating to stiff-person syndrome were negative. We diagnosed PERM and gave intravenous corticosteroids and immunoglobulins without benefit; however, following plasma exchange he has made a sustained improvement.

Neurological Causes of Chest Pain.

PURPOSE OF REVIEW: Chest pain is a very common presenting complaint among patients in the hospital, a large proportion of whom have non-cardiac chest pain (NCCP). Neurological causes of NCCP have not been previously reviewed although several causes have been identified. RECENT FINDINGS: Chest pain has been reported as a symptom of multiple neurological conditions such as migraine, epilepsy, and multiple sclerosis, with varying clinical presentations. The affected patients are often not formally diagnosed for long periods of time due to difficulties in recognizing the symptoms as part of neurological disease processes. This paper will briefly summarize well-known etiologies of chest pain and, then, review neurological causes of NCCP, providing an overview of current literature and possible pathophysiologic mechanisms.

Ocular Motor and Vestibular Characteristics of Antiglutamic Acid Decarboxylase-Associated Neurologic Disorders.

BACKGROUND: Antiglutamic acid decarboxylase (GAD)-associated neurologic disorders are rare, with varied presentations, including stiff-person syndrome (SPS) and cerebellar ataxia (CA). Vestibular and ocular motor (VOM) dysfunction can be the main presentation in a subset of patients. METHODS: Retrospective review of the Johns Hopkins Hospital medical records from 1997 to 2018 identified a total of 22 patients with a diagnosis of anti-GAD-associated SPS or CA who had detailed VOM assessments. Eight had prominent VOM dysfunction at the initial symptom onset and were referred to neurology from ophthalmology or otolaryngology ("early dominant"). Fourteen patients had VOM dysfunction that was not their dominant presentation and were referred later in their disease course from neurology to neuro-ophthalmology ("nondominant"). We reviewed clinical history, immunological profiles, and VOM findings, including available video-oculography. RESULTS: In the 8 patients with early dominant VOM dysfunction, the average age of symptom onset was 53 years, and 5 were men. The most common symptom was dizziness, followed by diplopia. Seven had features of CA, and 4 had additional features of SPS. None had a structural lesion on brain MRI accounting for their symptoms. The most common VOM abnormalities were downbeating and gaze-evoked nystagmus and saccadic pursuit. All received immune therapy and most received symptomatic therapy. Most experienced improvement in clinical outcome measures (modified Rankin scale and/or timed 25-foot walk test) or VOM function. By contrast, in the 14 patients in whom VOM dysfunction was nondominant, most had an SPS phenotype and were women. VOM abnormalities, when present, were more subtle, although mostly still consistent with cerebellar and/or brainstem dysfunction. CONCLUSIONS: Individuals with anti-GAD-associated neurologic disorders may present with prominent VOM abnormalities at the initial symptom onset that localize to the cerebellum and/or brainstem. In our cohort, immune and symptomatic therapies improved clinical outcomes and symptomatology.

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

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

Stiff-Person Syndrome Associated with Anti-Glutamic Acid Decarboxylase Autoimmune Encephalitis in a Young Woman: A Case Report.

A 34-year-old female with stiff-person syndrome (SPS) is reported in this paper. She experienced short-term memory impairment and was diagnosed with anti-glutamic acid decarboxylase (GAD) autoimmune encephalitis (AE) at the local hospital. However, after the treatment with intravenous immunoglobulin and high-dose glucocorticoids, her symptoms unchanged. Two months later, she was admitted to our hospital due to an unstable gait and persistent leg stiffness, at which point she was diagnosed as anti-GAD AE concomitant with SPS. Her clinical symptoms improved with an increased dose of ?-aminobutyric acid (GABA)-enhancing drug and plasma exchange. Anti-GAD antibody-associated AE combined with SPS is extremely rare. Treatment with GABA-enhancing drugs and appropriate immunotherapy can improve the neurological function of patients suffering from the combination of SPS and limbic encephalitis.

Chronic intestinal pseudo-obstruction with dilated biliary tract as a spectrum of stiff person syndrome in a nondiabetic patient.

Stiff person syndrome (SPS) is a rare and challenging neuromuscular junction disorder with typical musculoskeletal manifestations associated with anti-GAD65 antibodies, extra rheumatological manifestations, including neuropsychiatric symptoms and severe dysautonomic troubles. Chronic intestinal pseudo-obstruction (CIPO) is also a rare condition corresponding to a sub-occlusive syndrome, resulting from the functional or structural impairment of smooth neuromuscular tissues of the intestinal tract. In the clinical spectrum of SPS, CIPO has rarely been described and dilated biliary tract has never been described. This present report is therefore the first in the context of anti-GAD65 antibodies with the additional involvement of the biliary tract. Here, we report the case of a 44-year-old woman hospitalized for a rapidly progressive CIPO associated with dilated biliary tract, revealing a typical SPS with slowly progressive rheumatologic complaints relegated to the background. The concomitant improvement of the neuromuscular function on skeletal, intestinal and biliary tree systems with the good outcomes of anti-GAD65 titer under immunosuppressant drugs, allowed us to link all three organic involvements to the antibody pathogenicity on the respective neuromuscular junctions. Therefore, we discussed their common pathogeny based on our patient's treatment outcome.

Case report of a woman with anti amphiphysin positive stiff person syndrome.

Stiff person syndrome is a rare neuroimmunological disease, characterized by severe, involuntary stiffness with superimposed painful muscle spasms, which are worsened by external stimuli. The classical form is associated with high levels of antibodies against glutamic acid decarboxylase. One of the variant forms is associated with antibodies against amphiphysin. This entity is a paraneoplastic syndrome, caused primarily by breast cancer, secondarily by lung cancer. Symptomatic therapy of anti amphiphysin positive stiff person syndrome includes treatment with benzodiazepines and baclofen (including intrathecal baclofen therapy). The effect of immunological therapies is controversial. Treatment of the underlying cancer may be very effective. In this report, we describe a 68 year old female presenting with an unusally rapidly developing anti amphiphysin positive stiff person syndrome, which was associated with breast cancer. Her painful spasms abolished after intrathecal baclofen treatment was initiated. Her condition improved spontaneously and significantly after cancer treatment, which enabled to start her complex rehabilitation and the simultaneous dose reduction of the intrathecal baclofen. The bedridden patient improved to using a rollator walker and the baclofen pump could be removed 18 monthes after breast surgery. This highlights the importance of cancer screening and treatment in anti amphiphysin positive stiff person syndrome cases.

Apraxia in anti-glutamic acid decarboxylase-associated stiff person syndrome: link to corticobasal degeneration?

Corticobasal syndrome (CBS) is associated with asymmetrical rigidity as well as asymmetrical limb-kinetic and ideomotor apraxia. Stiff person syndrome (SPS) is characterized by muscle stiffness and gait difficulties. Whereas patients with CBS have several forms of pathology, many patients with SPS have glutamic acid decarboxylase antibodies (GAD-ab), but these 2 disorders have not been reported to coexist. We report 2 patients with GAD-ab-positive SPS who also had signs suggestive of CBS, including asymmetrical limb rigidity associated with both asymmetrical limb-kinetic and ideomotor apraxia. Future studies should evaluate patients with CBS for GAD-ab and people with SPS for signs of CBS.

Presynaptic neuromuscular transmission defect in the stiff person syndrome.

BACKGROUND: The stiff person syndrome (SPS) is a rare disorder characterized by muscular rigidity and stiffness. CASE PRESENTATIONS: We describe an SPS patient presenting with longstanding fatigue and electrophysiological evidence of presynaptic neuromuscular transmission defect, who responded to administration of pyridostigmine. In contrast, no electrophysiolgical evidence of neuromuscular transmission defect was demonstrated in 2 other SPS patients without fatigue symptoms. CONCLUSIONS: Our findings suggest that glutamic acid decarboxylase (GAD) antibodies may play a role in presynaptic neuromuscular transmission defect of SPS patients with fatigue.

Acute Respiratory Failure in a Patient with Stiff-Person Syndrome.

BACKGROUND: Stiff-person syndrome (SPS) is a rare disorder characterized by progressive muscle stiffness, rigidity, and spasms involving the axial muscles. Acute respiratory distress has rarely been reported in this condition. METHODS: We report a case of a 49-year-old woman with autoimmune SPS diagnosed during an episode of acute respiratory failure secondary to repetitive episodes of apnea, requiring intensive care. RESULTS: Acute respiratory failure manifesting with apneic episodes is a life-threatening and unpredictable complication of SPS. Its pathophysiology is not well known. The two suggested mechanisms are as follows: (1) apnea due to muscle rigidity and paroxysmal muscle spasms, and (2) paroxysmal autonomic hyperactivity. Sudden and unexpected deaths have been reported in SPS, and all described cases have been associated with apnea. Thus, the onset of apnea during SPS should be considered a criterion of high severity and should lead to intensive care unit (ICU) admission for continuous monitoring. In patients with severe disease who are unresponsive to symptomatic treatment with benzodiazepines and baclofen, or in patients with life-threatening complications, early immunotherapy by intravenous immunoglobulins should be considered. CONCLUSION: Onset of apneas during SPS should be considered as a signal of possible progression toward acute respiratory failure and sudden death, and should lead to ICU admission for continuous monitoring. Early immunotherapy should be started in such situations, including intravenous immunoglobulins as the first-line treatment.

Extremely rare coincidence of non-radiographic axial spondyloarthropathy HLA-B27 positive and Stiff Person Syndrome--rheumatologist point of view.

Stiff Person Syndrome (SPS) is a rare autoimmune neurological disorder characterized by progressive stiffness and rigidity of truncal muscles accompanied with co-contraction of agonist-antagonist muscles. Our 51-year-old female patient was presented for the first time to physiatrists in 2006 and diagnosed with axial-spondyloarthropathy (SpA) HLA-B27 positive. SPS was diagnosed 7 years after initial symptoms. SPS should be taken into consideration in HLA-B27 positive patients if stiffness of paravertebral and abdominal muscles progresses during SpA therapy.

LADA type diabetes, celiac diasease, cerebellar ataxia and stiff person syndrome. A rare association of autoimmune disorders.

Celiac disease--in its typical form--is a chronic immune-mediated enteropathy with typical clinical symptoms that develops against gliadin content of cereal grains, and is often associated with other autoimmune diseases. In cases of atypical manifestation classic symptoms may be absent or mild, and extra-intestinal symptoms or associated syndromes dominate clinical picture. The authors present a longitudinal follow-up of such a case. A 63-years old woman was diagnosed with epilepsy at the age of 19, and with progressive limb ataxia at the age of 36, which was initially thought to be caused by cerebellar atrophy, later probably by stiff person syndrome. At the age 59, her diabetes mellitus manifested with type 2 diabetic phenotype, but based on GAD positivity later was reclassified as type 1 diabetes. Only the last check-up discovered the celiac disease, retrospectively explaining the entire disease course and neurological symptoms. By presenting this case, the authors would like to draw attention to the fact that one should think of the possibility of celiac disease when cerebellar ataxia, progressive neurological symptoms and diabetes are present at the same time. An early diagnosis may help to delay the progression of disease and help better treatment.

Progressive Encephalomyelitis With Rigidity and Myoclonus With Glycine Receptor and GAD65 Antibodies: Case Report and Potential Mechanisms.

OBJECTIVES: Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a severe form of stiff-person spectrum disorder that can be associated with antibodies against surface antigens (glycine receptor (GlyR), dipeptidyl-peptidase-like-protein-6) and intracellular antigens (glutamate decarboxylase (GAD65), amphiphysin). METHODS: We report clinico-pathologic findings of a PERM patient with coexisting GlyR and GAD65 antibodies. RESULTS: A 75-year-old man presented with myoclonus and pain of the legs, subsequently developed severe motor symptoms, hyperekplexia, a pronounced startle reflex, hallucinations, dysautonomia, and died 10 months after onset despite extensive immunotherapy, symptomatic treatment, and continuous intensive care support. Immunotherapy comprised corticosteroids, IVIG, plasmapheresis, immunoadsorption, cyclophosphamide, and bortezomib. Intensive care treatment and permanent isoflurane sedation was required for more than 20 weeks. CNS tissue revealed neuronal loss, astrogliosis and microgliosis, representing a pallido-nigro-dentato-bulbar-spinal degeneration pattern, specifically along GlyR and GAD expression sites. Neurons showed pSTAT1, MHC class I, and GRP78 upregulation. Inflammation was moderate and characterized by CD8+ T cells and single CD20+/CD79a+ B/plasma cells. Focal tau-positive thread-like deposits were detected in gliotic brainstem areas. In the spinal cord, GlyR, glycine transporter-2, and GAD67 expression were strongly reduced. DISCUSSION: A possible potentiating effect of pathogenic GlyR antibodies together with T cells directed against neurons may have led to the severe and progressive clinical course.

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

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