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

The study demonstrates that maintenance therapy with IVIg continues to be effective over a median of 3.3 years in 67% of patients with typical SPS, improving daily functioning, gait, balance, painful spasms, posture, and facial expression with a demonstrable effect in decreasing stiffness, spasms and startle response. Although uncontrolled due to disease rarity and clinical ethics to give placebo over 2–3 years, this is a long-term study in a large group of patients with SPS seen over time by the same experienced clinicians that documents continued IVIg efficacy based on a combination of mRS scores, dependency tests, and objective clinical observations. The results complement the conclusions from the original short-term 3-month controlled study that the same investigators conducted 20 years ago with a much smaller number of enrolled patients.7 The present analysis, however, highlights several additional observations of increased clinical and practical importance that is reviewed in the ‘Discussion’ section at the end.

Complement activation contributes to GAD antibody-associated encephalitis

Our data indicate that, in addition to cell-mediated immunity, complement deposition contributes to the pathology of GAD Ab-associated AE.

Clinical Heterogeneity in Acute Symptomatic Seizures due to Autoimmune Encephalitis Related to GAD65 Antibodies

This study aimed to explore the diversity and clinical features of acute symptomatic seizures due to autoimmune encephalitis related to anti-glutamate decarboxylase (GAD) 65 antibodies in a series of 6 patients. 

Clinical features of acute symptomatic seizures related to GAD65 antibodies are diverse, and early and continuous immunotherapy is necessary for patients.

Treatment of Anti-GAD65 Autoimmune Encephalitis With Methylprednisolone

This case illustrates the importance of considering a diagnosis of autoimmune encephalitis for patients with rapidly deteriorating mental status. Unless contraindicated, treatment with high-dose glucocorticoids can be successful for these patients. This case also shows a potential association between hypothyroidism and anti-GAD65 antibodies.

Quantitative brain imaging analysis of neurological syndromes associated with anti-GAD antibodies

Highlights

The pattern of cortical atrophy is present throughout all anti-GAD phenotypes.

The radiomic features correctly classify anti-GAD patients versus healthy subjects.

The different neurological anti-GAD phenotypes should be considered as a continuum.

How Much GAD65 Do You Have? High Levels of GAD65 Antibodies in Autoimmune Encephalitis

Objective: Antibodies against glutamic acid decarboxylase 65 (anti-GAD65) are associated with a number of neurologic
syndromes. However, their pathogenic role is controversial. Our objective was to describe clinical and paraclinical characteristics of anti-GAD65 patients and analyze their response to immunotherapy.

Conclusion: Most patients with high anti-GAD65 concentrations (>10 000 IU/mL) showed some improvement after
immunotherapy, unfortunately without complete recovery. Serum antibody concentrations’ course might be useful to monitor
response. In patients with low anti-GAD65 concentrations, especially in those without typical clinical phenotypes, diagnostic
alternatives are more likely.

Case Report: Autoimmune Encephalitis Associated With Anti-glutamic Acid Decarboxylase Antibodies: A Pediatric Case Series

Pediatric cases are rare. This case report includes 3 cases. 

Conclusion: In addition to limbic encephalitis, extralimbic encephalitis is also an important phenotype in patients who are positive for anti-GAD65 antibodies. Early diagnosis and immunotherapy can improve the symptoms. However, patients with limbic encephalitis often have refractory epilepsy in the chronic phase and have a poor long-term outcome.

Musicogenic epilepsy: Expanding the spectrum of glutamic acid decarboxylase 65 neurological autoimmunity

The objective of this study was to describe serological association of musicogenic epilepsy and to evaluate clinical features and outcomes of seropositive cases.

16 patients with GAD65 all had temporal lobe epilepsy, and bitemporal epileptiform abnormalities were common. Right temporal lobe seizures were most frequently captured when seizures were induced by music on EEG (75%). Intravenous (IV) methylprednisolone and/or IV Ig (IVIG) was utilized in four patients, with one having greater than 50% reduction. Rituximab (n = 2) and mycophenolate (n = 1) were ineffective. Two patients underwent right temporal lobe resections but continued to have seizures. Vagus nerve stimulation was effective at reducing seizures in one patient by 50%, and an additional patient was seizure‐free by avoiding provoking music. Right temporal lobe epilepsy was more common among patients with musicogenic epilepsy when compared to nonmusicogenic GAD65 epilepsies (n = 71, 89% vs. 47%, p = .03). GAD65‐IgG should be tested in patients with musicogenic epilepsy, given implications for management and screening for comorbid autoimmune conditions

Clinical spectrum of high-titre GAD65 antibodies

Objective To determine clinical manifestations, immunotherapy responsiveness and outcomes of glutamic acid decarboxylase-65 (GAD65) neurological autoimmunity.

Methods We identified 323 Mayo Clinic patients with high-titre (>20 nmol/L in serum) GAD65 antibodies out of 380 514 submitted anti-GAD65 samples (2003–2018). Patients classified as having GAD65 neurological autoimmunity after chart review were analysed to determine disease manifestations, immunotherapy responsiveness and predictors of poor outcome (modified Rankin score >2).

Interpretation High-titre GAD65 antibodies were suggestive of, but not pathognomonic for GAD65 neurological autoimmunity, which has discrete core and secondary manifestations. SPSD was most likely to respond to immunotherapy, while epilepsy was least immunotherapy responsive. Complete immunotherapy response was rare. Serum GAD65 antibody titre >500 nmol/L and cerebellar ataxia predicted poor outcome.

Psychiatric symptoms in anti glutamic acid decarboxylase associated limbic encephalitis in adults: a systematic review

Highlights 

Anti Glutamic Acid Decarboxylase (GAD) antibodies have emerged as a cause of Limbic Encephalitis (LE). 

Limbic encephalitis associated to anti-GAD antibodies has atypical clinical presentation with psychiatric features. 

Median diagnostic delay appears delayed. 

Patients with association of neurological and psychiatric symptoms should be screened for anti-GAD antibodies.

Patients with anti-GAD LE can benefit from immunomodulatory treatment.

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

Conclusion: 

Most patients with high anti-GAD65 concentrations (>10,000 IU/mL) showed some improvement after immunotherapy, unfortunately without complete recovery. Serum antibody concentrations’ course might be useful to monitor response. In patients with low anti-GAD65 concentrations, especially in those without typical clinical phenotypes, diagnostic alternatives are more likely.

GAD antibodies in neurological disorders — insights and challenges

Key Points: 

  • The main neurological syndromes associated with high levels of antibodies to glutamic acid decarboxylase (GAD) include stiff-person syndrome, cerebellar ataxia and temporal lobe epilepsy.

  • Serum levels of GAD antibodies can be considered high when quantitative tests (radioimmunoassays or enzyme-linked immunosorbent assays) and qualitative tests (immunohistochemistry, cell-based assays or line-blot assays) are positive.

  • Cerebrospinal fluid levels and intrathecal synthesis of GAD antibodies should be determined in all patients with suspected CNS syndromes and high serum levels of GAD antibodies.

  • We propose that the diagnosis of probable or definite GAD antibody-associated syndrome must be based on the spectrum of symptoms, serum levels of GAD antibodies and demonstration of intrathecal antibody synthesis.

  • There is no clear evidence that GAD antibodies are pathogenic in any of the associated CNS syndromes (stiff-person syndrome, cerebellar ataxia, temporal lobe epilepsy or limbic encephalitis).

  • In general, immunotherapy has limited effects on the outcomes of neurological syndromes associated with GAD antibodies.

Multiplex family with GAD65-Abs neurologic syndromes

Objective: Neurologic autoimmune syndromes associated with anti–glutamate acid decarboxylase 65 antibodies (GAD65-Abs) are rare and mostly sporadic.

Results: The proband had cerebellar ataxia and probable limbic encephalitis features, whereas her niece had stiff-person syndrome. Both had a high titer of GAD65-Abs in serum and CSF and showed signs of inflammation in CSF. Both affected members carried the same rare recombinant DRB1*15:01:01∼DQA1*01:02:01∼DQB1*05:02:01 haplotype, which may or may not be involved in disease susceptibility. Of interest, other unaffected members of the family either had the same HLA haplotype but normal serum GAD65-Abs or had different HLA types but a high titer of serum GAD65-Abs without neurologic symptoms, suggesting cumulative effects.

Conclusions: This unique association strengthens the concept that hereditary factors, possibly including specific HLA haplotypes, play a role in neurologic syndromes associated with GAD65-Abs.

Gluten free diet useful for GAD 65 positive

GAD is the enzyme responsible for the production of y-aminobutyric acid (GABA), the most abundant inhibitory neurotransmitter in the central nervous system. Antibodies against GAD have been described in stiff person syndrome, insulin-dependent diabetes mellitus (IDDM), and autoimmune polyendocrine syndromes, as well as in some immune mediated ataxias. These antibodies are present in at least 60% of both patients with gluten ataxia and patients with CD and no neurological manifestations. Furthermore, the levels and positivity of these anti-GAD antibodies can be significantly reduced by the introduction of a gluten-free diet.

GAD antibody-spectrum disorders: progress in clinical phenotypes, immunopathogenesis and therapeutic interventions

Highly Recommended

Antibodies against glutamic acid decarboxylase (GAD), originally linked to stiff person syndrome (SPS), now denote the “GAD antibody-spectrum disorders” (GAD-SD). This review highlights that high-titer anti-GAD antibodies are associated with an array of distinct neurological syndromes including SPS, cerebellar ataxia, epilepsy, limbic encephalitis, abnormal eye movements. Although high anti-GAD antibodies in serum or their presence in CSF are important for diagnosis, the titers do not correlate with disease severity and do not generally predict response to immunotherapy. Despite considerable efforts, using both in vitro and in vivo preparations, the pathophysiological role of anti-GAD antibodies has not yet been clarified, suggesting that other autoantibodies affecting inhibitory neurotransmission might be of importance, because autoimmunity targeting inhibitory synaptic antigens point to a unifying theme of hyperexcitability as the underlying pathomechanism.

Collectively, the practicing neurologists need to be aware that anti-GAD antibody titers do matter: if high (>10,000 IU/mL), they are diagnostic for a true GAD-SD, necessitating immunotherapy; lower (<10,000 IU/mL) titers are associated with atypical or non-specific neurological disorders requiring further investigation, whereas very low titers (<2000 IU) are typically seen in DM-1 or are of unclear significance.74 Importantly, GAD-Abs can also be detected within the various IVIg preparations and anti-GAD antibodies can be detected in patients receiving IVIg.84 Most importantly, there is no association between GAD-Ab titer and disease severity or response to therapy without significant titer reduction after immunotherapies with either IVIg or rituximab based on two controlled studies we have performed.

GAD antibody-spectrum disorders: progress in clinical phenotypes, immunopathogenesis and therapeutic interventions

Highly Recommended

Antibodies against glutamic acid decarboxylase (GAD), originally linked to stiff person syndrome (SPS), now denote the “GAD antibody-spectrum disorders” (GAD-SD). This review highlights that high-titer anti-GAD antibodies are associated with an array of distinct neurological syndromes including SPS, cerebellar ataxia, epilepsy, limbic encephalitis, abnormal eye movements. Although high anti-GAD antibodies in serum or their presence in CSF are important for diagnosis, the titers do not correlate with disease severity and do not generally predict response to immunotherapy. Despite considerable efforts, using both in vitro and in vivo preparations, the pathophysiological role of anti-GAD antibodies has not yet been clarified, suggesting that other autoantibodies affecting inhibitory neurotransmission might be of importance, because autoimmunity targeting inhibitory synaptic antigens point to a unifying theme of hyperexcitability as the underlying pathomechanism.

Collectively, the practicing neurologists need to be aware that anti-GAD antibody titers do matter: if high (>10,000 IU/mL), they are diagnostic for a true GAD-SD, necessitating immunotherapy; lower (<10,000 IU/mL) titers are associated with atypical or non-specific neurological disorders requiring further investigation, whereas very low titers (<2000 IU) are typically seen in DM-1 or are of unclear significance.74 Importantly, GAD-Abs can also be detected within the various IVIg preparations and anti-GAD antibodies can be detected in patients receiving IVIg.84 Most importantly, there is no association between GAD-Ab titer and disease severity or response to therapy without significant titer reduction after immunotherapies with either IVIg or rituximab based on two controlled studies we have performed.

Pediatric autoimmune encephalitis associated with anti-glutamic acid decarboxylase 65 antibody: two cases report and literature review

Conclusions: Pediatric anti-GAD65 antibody-associated autoimmune encephalitis is a rare but treatable disease, including limbic encephalitis and extra limbic encephalitis. The most common clinical manifestations are seizures and memory impairment. Early diagnosis and immunotherapy can improve the symptoms in a short time. But patients with limbic encephalitis often had refractory epilepsy in the chronic phase, and have a poor long-term outcome.

Neurological Syndromes Associated with Anti-GAD Antibodies

Glutamic acid decarboxylase (GAD) is an intracellular enzyme whose physiologic function is the decarboxylation of glutamate to gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter within the central nervous system. GAD antibodies (Ab) have been associated with multiple neurological syndromes, including stiff-person syndrome, cerebellar ataxia, and limbic encephalitis, which are all considered to result from reduced GABAergic transmission. The pathogenic role of GAD Ab is still debated, and some evidence suggests that GAD autoimmunity might primarily be cell-mediated. Diagnosis relies on the detection of high titers of GAD Ab in serum and/or in the detection of GAD Ab in the cerebrospinal fluid. Due to the relative rarity of these syndromes, treatment schemes and predictors of response are poorly defined, highlighting the unmet need for multicentric prospective trials in this population.

 

Intravenous methylprednisolone or immunoglobulin for anti-glutamic acid decarboxylase 65 antibody autoimmune encephalitis: which is better?

Patients positive for anti-glutamic acid decarboxylase 65 (GAD65) antibodies have attracted increasing attention. Their clinical manifestations are highly heterogeneous and can be comorbid with tumors. Currently, there is no consensus on the therapeutic regimen for anti-GAD65-associated neurological diseases due to the clinical complexity, rarity and sporadic distribution. We reported six anti-GAD65 autoimmune encephalitis (AE) patients who received intravenous methylprednisolone (IVMP) or immunoglobulin (IVIG) or both. Then, we evaluated the therapeutic effect of both by summarizing results in previous anti-GAD65 AE patients from 70 published references.

CONCLUSION: Except for stiff-person syndrome, we found that this kind of AE generally has a poor response to IVMP or IVIG. Larger prospective studies enrolling large numbers of patients are required to identify the optimal therapeutic strategy in the future.

Glycine receptor modulating antibody predicting treatable stiff-person spectrum disorders

Conclusions GlyRα1-modulating antibody improves diagnostic specificity for immunologically treatable SPS spectrum disorders.

GAD65 neurological autoimmunity

The glutamic acid decarboxylase 65-kilodalton isoform (GAD65) antibody is a biomarker of autoimmune central nervous system (CNS) disorders and, more commonly, nonneurological autoimmune diseases. Type 1 diabetes, autoimmune thyroid disease, and pernicious anemia are the most frequent GAD65 autoimmune associations. One or more of these disorders coexists in approximately 70% of patients with GAD65 neurological autoimmunity. Neurological phenotypes have CNS localization and include limbic encephalitis, epilepsy, cerebellar ataxia, and stiff-person syndrome (SPS), among others. Classic SPS is a disorder on the spectrum of CNS hyperexcitability which also includes phenotypes that are either more restricted (stiff-limb syndrome) or more widespread (progressive encephalomyelitis with rigidity and myoclonus). GAD65 antibody is not highly predictive of a paraneoplastic cause for neurological disorders, but diverse cancer types have been occasionally reported. For all phenotypes, responses to immunotherapy are variable (approximately 50% improve). GAD65 autoimmunity is important to recognize for both coexisting nonneurological autoimmune associations and potential immunotherapy-response.

GAD - Gluten sensitivity and antibodies against glutamic acid decarboxylase, an enzyme responsible for the production of GABA

The presence of GAD in the enteric plexus could hold the key to the generation of anti-GAD antibodies in patients with CD.38″40

Key concepts and clinical implications:

• In addition to gliadin and transglutaminase antibodies, patients with neurological symptomatologies should be tested for glutamic acid decarboxylase (GAD), myelin basic protein, neurofilaments, and cerebellar antibodies.

Immune-mediated epilepsy with GAD65 antibodies

Highlights:  Anti-GAD65 Abs were found in encephalitis and chronic epileptic syndromes. The pathogenic role of anti-GAD65 Abs remains unclear.  GAD65-epilepsy frequently coexist multiple autoimmune disorders. anti-GAD65 Abs titers poorly correlate with disease severity or response to therapies.  Early immunosuppressive therapy can achieve temporary success. 

Hippocampus and Insula Are Targets in Epileptic Patients With GAD

Conclusions: Clinical, EEG, and FDG-PET findings in FE+GAD ab suggest a widespread disease not restricted to the temporal lobe. Progressive MTL sclerosis may be observed during follow-up. In comparison to what is found in patients with non-autoimmune MTL epilepsy, insular hypometabolism is observed only in patients with GAD ab, so it may be an important diagnostic clue.

Spinal-generated movement disorders: a clinical review

SGMDs are a unique group of movement disorders, sharing many features. We hope that our review will help clinicians care for these challenging patients.

Our website is not a substitute for independent professional medical advice. Nothing contained on our website is intended to be used as medical advice. No content is intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for your own health professional's advice. Although THE INTERNATIONAL AUTOIMMUNE ENCEPHALITIS SOCIETY  provides a great deal of information about AUTOIMMUNE ENCEPHALITIS, all content is provided for informational purposes only. The International Autoimmune Encephalitis Society  cannot provide medical advice.


International Autoimmune Encephalitis Society is a charitable non-profit 501(c)(3) organization founded in 2016 by Tabitha Andrews Orth, Gene Desotell and Anji Hogan-Fesler. Tax ID# 81-3752344. Donations raised directly supports research, patients, families and caregivers impacted by autoimmune encephalitis and to educating healthcare communities around the world. Financial statement will be made available upon request.

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