Acid Decarboxylase Antibodies Research Articles

Obsessive‐compulsive disorder as an initial manifestation of anti‐glutamic acid decarboxylase antibody‐associated encephalitis

AbstractWe present the case of a 44‐year‐old woman with type 1 diabetes and anti‐glutamic acid decarboxylase antibody (GAD‐Ab) (6100 U/mL in serum), manifesting as a one‐month history of compulsive writing in her self‐monitoring blood glucose (SMBG) diary and a one‐week history of seizures before admission. On admission, she was diagnosed with GAD‐Ab‐associated encephalitis (GAD‐AE), and compulsive writing consistent with obsessive‐compulsive disorder (OCD) caused by a repetitive and persistent urge to neutralize anxiety manifesting as clearly excessive writing. Immunotherapy, including corticosteroids, azathioprine, and intravenous immunoglobulin, improved her compulsive writing, and seizures disappeared following lacosamide treatment. Two months after discharge, compulsive writing reappeared and the patient was successfully treated with temporary immunotherapy intensification. After a stable period of 2 years, the patient died due to hypoglycemic encephalopathy. Overall, we showed that GAD‐AE may cause OCD.

Patchy FDG uptake on FDG PET/CT in a patient with vasculitic neuropathy in restricted lower‐limb vasculitis

AbstractA 54‐year‐old man with diabetes mellitus presented with fever, pain, muscle weakness, and sensory disturbances in the lower limbs. His serum C‐reactive protein level was markedly increased; However, no autoantibodies, other than anti‐glutamic acid decarboxylase antibody, were detected. Nerve conduction studies revealed axonal polyneuropathy. 18F‐fluorodeoxyglucose positron emission tomography/computed tomography revealed patchy uptake patterns specific to restricted lower‐limb vasculitis. The muscle and nerve biopsy specimens suggested vasculitic neuropathy. Treatment with oral prednisolone and cyclophosphamide pulse therapy markedly improved his lower‐limb weakness and paresthesia. Clinicians should consider the involvement of vasculitic neuropathy, as well as myopathy, in patients with restricted lower‐limb vasculitis.

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

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

S1630 Chronic Autoimmune Pancreatitis Presenting With Exocrine Deficiency and Type 3c Diabetes Mellitus

Introduction: Unexplained pancreatic exo/endocrine insufficiency should prompt evaluation for autoimmune pancreatitis. Case Description/Methods: 54-year-old African-American male with past medical history significant for prior DVT was admitted for initial episode of Hyperosmolar Hyperglycemic state (HHS) after complaining of general malaise and polydipsia. Further history taking revealed acute on chronic steathorea and a subacute weight loss of fifteen pounds. Patient's HHS was managed with fluid resuscitation and an insulin infusion. Work-up of his steathorea revealed an undetectable fecal elastase level. His labs were significant for AST 94 U/L, ALT/143 U/L ALP of 144 U/L. A CT of his abdomen and pelvis with contrast demonstrated an atrophic pancreas with diffuse calcifications (Figure 1A,B). Follow up MRCP demonstrated irregular pancreatic duct with strictures and dilated side branches with mild dilation of the common bile duct. Initial etiology of the patient's presentation with HHS was thought to be secondary to new diagnosis of Latent Autoimmune diabetes (LADA), given the presence of positive Glutamic Acid Decarboxylase-65 antibodies, and low C-peptide levels in the context of hyperglycemia. However, in view the of the symptoms of steatorhea, additional investigations were sent which demonstrated elevated IgG4 at 106.40 mg/dL concerning for Autoimmune Pancreatitis (AIP) and Type 3c (pancreatogenic) diabetes mellitus. He denied any history tobacco/alcohol abuse. The patient was treated with pancrealipase and insulin therapy which resulted in an improvement in symptoms. Discussion: The 2011 International Consensus Diagnostic Criteria for AIP confirms an acute state of the disease. However, literature had validated that approximately 40% of patients with AIP experienced pancreatic stone formation, pancreatic atrophy, and/or irregular dilatation of the main pancreatic duct over a long-term course. Patients with AIP generally respond favorably to Prednisolone therapy in the acute setting and utilized to prevent pancreatic stone formation with progression to chronic pancreatitis and subsequent endo/exocrine deficiency. Our patients clinical and radiologic findings were more consistent with an advanced disease state limiting the utility of steroid administration. Undifferentiated pancreatitis without typical risk factor exposures should prompt Gastroenterologist's suspicion of AIP to prevent progression to advanced disease states as exemplified in our patient with pancreatogenic Type 3c Diabetes mellitus.Figure 1.: A: Coronal section of a CT Abdomen and Pelvis with IV contrast demonstrating an atrophic pancreas with diffuse calcifications (demarcated by the red outline) consistent with chronic pancreatitis and no acute stigmata. B: Sagittal section of a CT Abdomen and Pelvis with IV contrast demonstrating an atrophic pancreas diffuse pancreatic calcifications (demarcated by the red outline) consistent with chronic pancreatitis and no acute stigmata. Incidental finding of a large stool ball within the rectum.

194-LB: Case of Pembrolizumab-Induced Type 1 Diabetes Mellitus

Immune checkpoint inhibitors, anti-PD1 and anti-CTLA-4, have become widely utilized and proven effective in treating various forms of cancer. Although the discovery of immunotherapy has been a major advancement in the field of oncology, a series of endocrinopathies have been described and research is still ongoing. We would like to report a case of diabetes mellitus with positive glutamic acid decarboxylase (GAD) antibodies secondary to pembrolizumab therapy for locally advanced Merkle Cell Carcinoma. A 70-year-old male with no history of diabetes presented to the ER with severe hyperglycemia after his fifth cycle of pembrolizumab. His labs revealed a blood glucose of 659 mg/dL, an A1c of 8.5%, creatinine of 1.45 mg/dL, and urine negative for ketones. He demonstrated elevated anti-GAD antibodies (>250 IU/mL), suggesting type 1 diabetes. The patient was started on both long acting insulin glargine and prandial short acting insulin with improved glycemic control. The first case reports of pembrolizumab induced diabetes and diabetic ketoacidosis were published in 2015. During the initial clinical trials, only 0.1% of patients using pembrolizumab developed type 1 DM, but a review of current literature suggests that it has become more prevalent with rates as high as 2%. The rise in cases has also demonstrated that the majority of immunotherapy induced diabetes results primarily in patients receiving anti-PD1 therapy. A study done on mice demonstrated PD-L1 expression in inflamed pancreatic beta cells of mice that had developed diabetes. These results suggest that pembrolizumab causes destruction of insulin producing cells, releasing intracellular proteins such as GAD, and triggering the immune system to create autoantibodies. This emphasizes the need for further studies investigating the relationship between immunotherapy and autoimmune diabetes. In addition, it is essential that clinicians become aware and remain vigilant of this potentially life-threatening complication. Disclosure S. Spyropoulos: None. A. Manessis: Advisory Panel; Self; Medtronic, Research Support; Self; IQVIA, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., MannKind Corporation, Sanofi US.

Subcutaneous Immunoglobulin Therapy with IgPro20 in Patients with Stiff Person Syndrome and Primary Immunodeficiency Disease.

Stiff Person Syndrome (SPS), a rare autoimmune neurologic disorder characterized by fluctuating muscle spasms and rigidity, is mediated by autoantibodies to glutamic acid decarboxylase (GAD) antibodies. Symptoms of SPS have been shown to improve after administration of intravenous immunoglobulin (IVIG) however, there is a paucity of information regarding use of SCIg in SPS. Four patients with Stiff Person Syndrome were treated with SCIgPro20 for a period between 31 to 101 months. Most reactions were local and mild. All patients reported improvement in spasticity, and 2 patients reported improvement in seizure frequency. SCIgPro20 was well tolerated in patients with SPS and was associated with improvement in symptoms.

Glycine receptor antibodies and coeliac disease-related neurological dysfunction

Gluten sensitivity can manifest with a spectrum of neurological dysfunction including ataxia, encephalopathy and neuropathy with or without associated coeliac disease (CD). Gluten sensitivity can also present with central nervous system (CNS) hyperexcitability and cortical myoclonus which is often accompanied with refractory CD. CNS hyperexcitability can also be associated with Glutamic Acid Decarboxylase (GAD) antibodies or much less commonly with Glycine Receptor Antibodies (GlyR-Abs) but the direct pathogenic roles of these antibodies remain debatable. We have previously reported a link between gluten sensitivity and anti-GAD associated ataxia which improves with the adoption of gluten-free diet. It is unclear if a similar link exists between gluten driven CNS hyperexcitability and the presence of GlyR-Abs. We report two cases of CD presenting with CNS hyperexcitability and associated GlyR-Abs. Apart from ataxia and cortical myoclonus, one patient had refractory CD and died from enteropathy-associated T-cell lymphoma. The other patient not only improved with strict gluten-free diet but also showed serological elimination of circulating GlyR-Abs. We conclude that there is an interaction between gluten sensitivity and GlyR-Abs-associated CNS hyperexcitability and in such patients gluten-free diet is an important therapeutic intervention. The elimination of GlyR-Abs by the adoption of gluten free diet suggests that these antibodies may represent an epiphenomenon rather than being directly implicated in the pathogenesis.

Patient-Specific Risk Factors and Clinical Correlates of Euglycemic Diabetic Ketoacidosis in Patients on Sodium-Glucose Co-Transporter-2 Inhibitors

Background: Sodium-Glucose Co-Transporter-2 Inhibitors (SGLT-2i) association with euglycemic diabetic ketoacidosis (EDKA) has been well reported. The underlying mechanism is mainly enhanced lipolysis and ketone bodies’ reabsorption. They also stimulate the pancreatic alpha cells and inhibit the beta cells, thereby causing an imbalance in glucagon/insulin levels, further contributing to lipolysis and ketogenesis. SGLT-2i were also found to cause EDKA in all types of diabetes, even uncovering undiagnosed Latent Autoimmune Diabetes of the Adult (LADA). Methods: Numerous electronic databases were systematically searched to identify patient-specific risk factors and clinical characteristics of EDKA in patients on SGLT-2i. The patient’s symptoms, clinical profile, laboratory results, and precipitants for EDKA were reviewed. Results: A total of 96 case reports identifying 116 patients with EDKA was fully reviewed. EDKA was twice prevalent in females (66.3%) than males (33.6%); median age was 52.15 ± 13.47, BMI was 29.3 ± 7.0. Among the 116 DKA events in SGLT-2i 92 (79.3%) were associated with Type-2 DM, 15 (12.9%) were Type-1 DM, 8 (6.9%) in LADA. Common symptoms were nausea (48.7%), vomiting (47%), and abdominal pain (28.2%). Canagliflozin was the most common SGLT-2i (40.5%), followed by Empagliflozin (29.3%) and Dapagliflozin (25.9%). The most common precipitant was surgery (17.2%), followed by infection (14.7%), fasting (11.2%), and Keto Diet (9.5%); others being reduced insulin use, alcoholism, and cancer. At presentation, average blood glucose was 196.8 ± 96.5, pH 7.1 ± 0.16, HCO3 8.7 ± 5.7 mmol/L, potassium 4.3 ± 1.03, anion-gap 24.2 ± 6.8 mmol/L, and the average HbA1C was 9.24 ± 2.08. Urine Ketones were positive in 81.89% of patients. 17 patients had pancreatic autoantibodies testing, and 7 were positive (41.2%) for glutamic acid decarboxylase-65 antibodies (anti-GAD-65). As a result, 7 patients were newly diagnosed with LADA who were previously misdiagnosed with type-2 DM. Conclusion: SGLT2i induced EDKA was found to be more predominant in females and type-2 DM. Diabetics should be educated on risk factors and consult physicians before commencing a dietary or exercise change. Physicians should be vigilant in diagnosing EDKA by thoughtful measurement of urine ketones and anti-GAD-65 testing can help diagnose underlying LADA.

De novo mutation in HNF-1β gene as a cause for Maturity-onset Diabetes of the Young type 5 with sustained hypomagnesemia

Maturity-onset Diabetes of the Young type 5 (MODY5) is clinically heterogeneous, and the genetic examination is important to provide the accurate diagnosis. Identification of more cases will better understand the genotype-phenotype correlations of this disorder. We collected the clinical and biochemical data, using the whole-exome gene detection and multiplex ligation–dependent probe Amplification to detect the pathogenic gene variants. The proband is a 39-year-old female, and presenting with symptoms including polyuria, polydipsia, and weight loss for 6 months. Her BMI was 17.6 kg/m2. Laboratory tests indicated hypokalemia (3.1 mmol/L), hypomagnesemia (0.4 mmol/L), and hypocalcemia (1.91 mmol/L). Glycated hemoglobin (HbA1c) was 13.7%, fasting C-peptide was 0.24 ng/mL (normal range: 0.3–3.73 ng/mL). Both glutamic acid decarboxylase and islet cell antibodies were negative. Abdominal magnetic resonance image showed the agenesis of the tail and body of the pancreas and the presence of disseminated cysts of the left kidney. Genetic examination displayed a de novo heterozygous deletion of the whole HNF-1Β gene (NM_000458.3). Three-year follow-up after the diagnosis showed that the patient has sustained hypomagnesemia and cannot maintain an appreciable increase in serum magnesium levels (0.52–0.61 mmol/L), although she was using the double-dose magnesium aspartate. Moreover, she cannot achieve good glucose control either. Our findings indicted that MODY is highly heterogeneous and patients with additional extrapancreatic clinical features and hypomagnesemia should be screened for MODY5.

Early-Onset Type 2 Diabetes Misdiagnosed as Type 1 Diabetes in a 15-Year-Old Nigerian Girl: A Case Report

Type 2 diabetes mellitus (T2DM) is emerging as a new clinical disorder among children and adolescents. Although there is increasing prevalence of this clinical entity among adolescents worldwide, its diagnosis among Nigerian children and adolescents is still uncommon, hence, the reason many physicians still misdiagnose T2DM in adolescents as type 1 diabetes mellitus for reason of age of onset. Here, we present a 15-year old, overweight, girl who presented with history of polyuria, polydipsia and weight loss; her blood glucose level was 14.3 mmol/l, glycated haemoglobin 12.4% and glycosuria (3+), with no ketonuria or proteinuria. She was initially diagnosed as type 1 diabetes and managed with multiple doses of insulin by the pediatric team until she was later reviewed by the endocrinology unit. The diagnosis was later changed to early-onset T2DM (Youth-onset T2DM) based on a BMI of 29.75 kg/m2, presence of acanthosis nigricans, absence of ketosis, preserved beta-cell function as shown by normal serum C-peptide levels, absence of anti-glutamic acid decarboxylase (GAD) antibodies and islet cell antibody, and also response to oral anti-diabetic agents while her insulin therapy was discontinued. Therefore, a possibility of T2DM should be suspected in childhood and adolescent with diabetes associated with overweight or obesity, relatives with T2DM and features of insulin resistance (IR) like acanthosis nigricans, hypertension, dyslipidaemia, non-alcoholic fatty liver disease (NAFLD), hyperandrogenism, or polycystic ovarian syndrome (PCOS).

Cancer-immune checkpoint inhibition and autoimmune-related adverse events.

107 Background: Immunotherapies effect adaptive or innate immune responses. Programmed-death 1 (PD-1), a cell surface protein on activated T cells, which, when bound to its ligands PD-L1 and PD-L2, inhibits T-cell activation. Inhibition can be associated with complicating immune-related adverse events (IRAEs). Immune checkpoint inhibitors (ICIs) are FDA approved for advanced NSCLC. Study aims: (1) determine if the use of ICIs nivolumab (N) and pembrolizumab (P) is associated with development of autoimmune diabetes and thyroid disease and (2) determine the impact of (N) and (P) on pre-existing autoimmunity. Methods: Prospective, biological and clinical end-point-driven study in subjects with NSCLC considered for 1st or 2nd-line treatment with N or P. Subjects were assessed for thyroid stimulation hormone (TSH), hemoglobin A1c (HbA1c), thyroid peroxidase antibodies (TPO), glutamic acid decarboxylase (GAD) antibodies and islet cell antibodies (IC) at time of treatment start and wk 16 end point. Results: 29 subjects enrolled with base-line laboratory testing of which 14 subjects could be assessed at wk 16. At baseline, 1/14 subject had abnl TSH but at week 16 all subjects had a nl TSH (p 0.0687). Subjects had nl TPO at baseline and only 1/14 had an abnl TPO at 16 weeks (p 0.1634 ) but TSH remained nl. All 14 subjects had nl GAD and IC antibodies at baseline and at 16 wks; however, 2/14 of subjects had abnl IC antibodies at 16 wks but had nl HbA1c. 6/14 had nl HbA1c at baseline and 1/6 went on to develop pre-diabetes and 1/6 developed diabetes at the 16 wks. 5/14 subjects had pre-diabetes at baseline: 1/5 had nl HbA1c while 1/5 developed diabetes at 16 wks. 2 subjects developing diabetes had no positive GAD or IC antibodies. 3/14 had diabetes at study start with no worsening of the HbA1c or diabetes-related complications at wk 16. Conclusions: ICIs can cause IRAEs. Study result suggests that treatments with N and P can cause new onset of non-immune diabetes mellitus. Clinical awareness is important while managing NSCLC patients on ICIs. Patient should be screened for diabetes and thyroid disease prior to therapy and with repeat testing so as to avoid treatment complications. Longer follow-up and further study of ICI-mediated auto-immune endocrinopathies is needed.

Catatonia in Dual Diagnosis: a Case Report

Catatonia is a syndrome resulting in both severe motor and speech disturbances. Catatonia in a dual diagnosis of cannabis dependence and depressive disorder is presented. A 28-year-old male, who had background diagnoses of cannabis dependence and moderate depressive episode, was admitted involuntarily to a psychiatry unit due to aggressiveness. A diagnosis of catatonia was made (Bush-Francis Catatonia Rating Scale score = 19/69). Routine blood profile, CT scan brain, anti-NMDA, anti-potassium channel and anti-glutamic acid decarboxylase (GAD) antibodies were all normal. He was treated with lorazepam. His symptoms resolved completely after 5 days.

Cerebrospinal Fluid Level of Glutamic Acid Decarboxylase (GAD) Antibody in Patients with Encephalitis

Background: Assaying the Glutamic Acid Decarboxylas( GAD) antibody in patients with encephalitis in cerebrospinal fluid and blood serum and its role in autoimmune encephalitis in children. Objective: This study Aimed at screening for GAD antibody in CSF of children presenting with acute encephalitis with non bacterial cause mostly autoimmune.Participants and methods: study is a pilot prospective study, conducted in the Pediatric department, Children’s Hospital, Ain Shams University.Fifty patients diagnosed with encephalitis exhibited at least one sign of parenchymatous brain dysfunction such as altered consciousness personality or behavior change, seizure, paresis, or ataxia. Encephalitis was defined as the presence of encephalopathy plus at least two of four findings: (1) fever (body temperature>38C); (2) abnormal cerebrospinal fluid examination (pleocytosis>5 white blood cells/mL and/or increased protein content>40 mg/dL) with negative cerebrospinal fluid culture; (3) abnormal electroencephalography findings compatible with encephalitis such as diffuse or focal slow activity, or periodic lateralized epileptiform discharges; and (4)abnormal results of neuroimaging, including computed tomography and magnetic resonance imaging (10), ,with age ranged from 6-144 Months; followed up In the period from September 2014 till March 2016.Basic clinical evaluation and laboratory investigations were done, GAD antibody level was measured in CSF and blood serum. Results: GAD receptor antibody titer was done in CSF which range from (36 -368 ng/l) with median of 64.83 (57.93-74.48), while in serum it range from (42.76-900) ng/l) with median 89.5(58.62-154.5).It was found that 6/50 (12%) patients had high GAD receptor antibody titer were high in CSF. The other 44/50 (88%) patients had low GAD antibody titer. In serum samples of twinty patients we had 8/20 (40%) patients had high GAD antibody titer and the rest were low GAD antibody titer 12/20 (60%).Significant occurrence of DCL, hospitalization plus mechanical ventilation and long term sequel were detected in patients with high GAD antibody titer. EEG findings; Two patients showed generalized epileptogenic activity, one patient had diffuse cortical dysfunction and two patient had multifocal epileptiform discharge and the rest of patients had normal finding. Eighty six precent had normal MRI findings,While 7 patients (14%) had non specific findings;3 patients had transient cortical meningeal enhancment,2 patients had high intensity in medial temporal lobe,one had abnormal signal intensity in medial temporal lobe and one patient had global brain atrophy. Conclusion: GAD Abs are directed against an intracellular antigen. The proposed pathogenic mechanisms of neurological disease in patients with antibodies directed against intracellular proteins is not clear. The present study emphasizes the importance of studying the CSF of patients with encephalitis suspected to be mediated by GAD autoimmunity.Both serum and CSF level must be assessed simultaneously as CSF level may change rapidly with fluctuation of disease. There are great efforts to be done to define the role of these GAD antibodies and to determine how they affect central nervous system function. These studies must be carried out so that appropriate treatments can be provided for the growing number of patients with possible antibody-mediated conditions.

P256 Increased Barrett-Barrett conductance in motor axons of patients with anti-gad antibody

Objective Neurological disorders associated with anti-glutamic acid decarboxylase (GAD) antibody are diverse, including stiff-person syndrome, autoimmune cerebellar ataxia and epilepsy. To help understand the physiological actions of anti-GAD antibody, we examined the effects of the antibody on the excitability properties of peripheral motor axons. Methods Nine patients positive for anti-GAD antibody and without diabetic mellitus were studied. Multiple excitability measurements were made in the median nerve at the wrist, using computerized threshold-tracking (QTRACS with TRONDNF excitability protocol), and compared with normal control data. Subsequently we performed mathematical modeling of the excitability data, using the Bostock model of the human motor axon to simulate axonal excitability measurements (QTRACP with MEMFIT). Results Nerve excitability studies showed greater supernormality in recovery cycle and greater changes in excitability with polarizing currents in threshold electrotonus. Mathematical modeling indicated that the results could best be explained by an increase in the Barrett-Barrett conductance across the myelin sheath. Discussion The abnormalities are remarkably similar to those previously reported in episodic ataxia Type 2 (Tomlinson et al. Brain 2016;139:380–91) and attributed to nodal malformation. Conclusion This study showed that patients with anti-GAD antibody exhibit abnormalities in their motor axons attributable to an increase in Barrett-Barrett conductance. This in turn suggests that anti-GAD antibody causes Schwann cell dysfunction via changes in the GABAergic system of peripheral nerve. Significance The results of this study raise the possibility that anti-GAD antibody causes some clinical symptoms by affecting glial GABAergic systems.

Autoimmune cerebellar ataxia with initial seronegativity and low‐titer anti‐glutamic acid decarboxylase antibody in the cerebrospinal fluid

AbstractBackgroundIn cases with anti‐glutamic acid decarboxylase (GAD) antibody‐positive cerebellar ataxia, the titer of the antibody is usually very high. However, a few cases of low‐titer GAD antibody‐positive cerebellar ataxia patients have been described recently. In such patients, the antibody has been detected predominantly in serum, rather than in cerebrospinal fluid.Case presentationA 34‐year‐old man presented with subacute‐onset cerebellar ataxia, and examinations revealed no abnormal findings except low‐titer anti‐GAD antibody in the cerebrospinal fluid at initial evaluation: the serum antibody became slightly positive in a delayed manner. Treatment with steroid and/or immunoglobulin was effective in improving symptoms, and the effect of these treatments continued for approximately 1 year.ConclusionsThe present case suggested a potential diagnostic pitfall, in which the examination of serum anti‐GAD antibody at initial evaluation alone might be insufficient to rule out this disease. It may be indicated that the routine screening should include examination for the GAD antibody in both the serum and cerebrospinal fluid, plus additional follow‐up checks for the antibody in the subsequent clinical course. Care must be taken to avoid non‐detection of this disease with possibly reversible symptoms in patients with cerebellar ataxia of unknown origin.

Stiff-Person Syndrome: A Case Report

This is a case report of stiff-person syndrome (SPS) with episodes of paroxysmal autonomic dysfunction. A 67-year-old female with hypothyroidism, anxiety and hypertension presented with shortness of breath and diaphoresis for 1 day. The patient had been bedbound for several years due to muscle rigidity. She had two episodes of paroxysmal autonomic dysfunction treated with Ativan which resolved. Her anti-glutamic acid decarboxylase (GAD) antibody became abnormally high at > 250. She was treated with IVIG 30 g daily for 5 days as an inpatient and was discharged on 3 monthly IVIG treatment 1 g/kg × 2 days. This case report describes SPS with paroxysmal autonomic dysfunction. J Med Cases. 2016;7(10):426-428 doi: http://dx.doi.org/10.14740/jmc2619w

Prediction of residual islet β-cell function in young patients with type 1 diabetes mellitus

Objective To investigate the predictive factors of residual β-cell function in young patients with newly-diagnosed type 1 diabetes mellitus. Methods After an average follow-up of (35.1±13.8)months, a total of 110 young patients with type 1 diabetes mellitus were analyzed. At baseline and follow-up, oral glucose tolerance test(OGTT)and C-peptide release test were carried out, the levels of HbA1C, glutamic acid decarboxylase-antibody(GAD), and the genetic polymorphisms of human leukocyte antigen(HLA)-Ⅱ were detected. The patients were divided into two groups: high-residual β-cell function group(high-RBF group)and low-residual β-cell function group(low-RBF group), which were defined as stimulated C-peptide(Cmax)≥0.6 ng/ml and <0.6 ng/ml at endpoint, respectively. Logistic regression analyses were performed to explore the factors that influence long-term residual β-cell function. Results Compared with low-RBF group, Cmax levels were higher [(1.87±1.35 vs 0.23±0.19)ng/ml, P<0.01], HbA1C levels were lower [(7.00±1.69 vs 8.39±1.77)%, P < 0.01], insulin dosages were lower[(0.62±0.17 vs 0.79±0.17)IU·kg-1·d-1,P <0.01] in high-RBF group at endpoint. Logistic regression analysis suggested that factors including age of onset(years)[OR=0.82, 95%CI 0.73-0.92, P=0.001], higher HLA risk status(OR=4.73, 95%CI 1.28-17.52, P=0.020), female sex(OR=3.39, 95%CI 1.03-11.22, P=0.045), diabetic ketoacidosis history at onset(OR=8.71, 95%CI 2.31-32.83, P=0.001), and higher mean HbA1C levels(OR=2.46, 95%CI 1.47-4.11, P=0.001)were related to low residual β-cell function. Compared with mean HbA1C level during diabetes course, predicted probability value for the four baseline factors(diagnosis age, HLA risk status, gender, and diabetic ketoacidosis history)as the onset state of type 1 diabetes patients was higher[(OR=145.75, 95%CI 17.30-1 228.31, P<0.01)vs(OR=1.82, 95%CI 1.24-2.69, P=0.003)]. Conclusion Younger age of onset, female, higher HLA risk status, diabetic ketoacidosis history at onset and poor glycemic control during diabetes course were the predictive factors of low residual β-cell function in the development of the disease. Compared with mean HbA1C level during diabetes course, an onset state of type 1 diabetes mellitus patients is more valuable to predict long-term residual β-cell function. (Chin J Endocrinol Metab, 2016, 32: 728-733) Key words: Diabetes mellitus, type 1; Islet β-cell function; Human leukocyte antigen class Ⅱ; Prognosis

The Effect of Corticosteroid Withdrawal on Glucose Metabolism and Anti-GAD Antibodies in Simultaneous Pancreas-Kidney Transplant Patients.

Corticosteroid withdrawal may reduce insulin resistance; however, it could also influence pancreatic autoantibody profile in simultaneous pancreas-kidney (SPK) transplant patients. To evaluate the effect of corticosteroid withdrawal on glucose metabolism and anti-glutamic acid decarboxylase (GAD) antibody titers in SPK patients with type 1 diabetes after 12 months of follow-up. In this retrospective study, fasting glucose and glycated hemoglobin (A1c) were compared before and after 3, 6, and 12 months of corticosteroid withdrawal in 80 SPK patients. In addition, weight, anti-GAD, and C-peptide levels were compared before and after withdrawal. Finally, fasting and postglucose, insulin, and C-peptide levels were compared before and after withdrawal in 25 patients undergoing oral glucose tolerance test (OGTT). Fasting glucose levels did not change during corticosteroid discontinuation. After 12 months, A1c slightly increased from 4.6% (0.4%) to 4.8% (0.6%) (P < .01) and C-peptide decreased from 2.8 (1.1) ng/mL to 2.4 (1.3) ng/mL (P <. 01). In patients submitted to OGTT, glucose, insulin, and C-peptide levels did not change. There was no alteration in the proportion of anti-GAD positive tests (41% vs 45%). Anti-GAD titers remained stable or decreased in 70% of positive patients. Corticosteroid withdrawal has no significant effect on glucose metabolism and on anti-GAD profile among SPK patients.

The predictive value of diabetes-related antibodies in children with type 1 diabetes mellitus and their siblings

The purpose of this study is to screen for diabetes-related antibodies in newly diagnosed type I diabetes Saudi children, and their non-diabetic siblings. We studied 69 newly diagnosed type 1 diabetic Saudis (35 girls, 34 boys), 60 non-diabetic siblings (1 to 17 years), and 42 age- and sex-matched controls not having type 1 diabetes. Their sera were tested for insulin autoantibodies (IAA), antibodies to glutamic acid decarboxylase (GAD65A) and protein tyrosine phosphatase-2 antibodies (IA-2) using 125I radioimmunoassays. Fifty-two percent of patients were significantly positive for IAA compared to controls (4.9 %). A total of 50.7 % of patients were also significantly positive for IA-2 compared to controls (4.8 %) (p < 0.0001). GAD65 antibody was detected in 81.2 % of the patients and in none of the controls (p < 0.0001). Both IAA and IA-2 are significantly higher among younger age group, unlike GAD65A, which is significantly higher among older age groups. In non-diabetic siblings, the frequencies of IAA, IA-2, and GAD65A were 6.8, 5.2, and 10.2 % (0.039), respectively, which were higher than in controls. IAA and IA-2 titers were significantly high among younger age group (<0.027), and GAD65A is significantly higher among older age group. A total of 21.6 % of diabetics were positive for all the three antibodies and 3.4 % in siblings. A total of 35.3 % were positive for two antibodies and none in siblings, while 39.2 % were positive for one antibody and 11.9 % in siblings. The combined GAD65 and IA-2 was positive in 81.3 % of young age, 80 % of middle, and in 100 % of the old age group. The screening of type 1 diabetes among Saudis showed the presence of diabetes-related antibodies in 96.1 % of all newly diagnosed patients, compared to 11.9 % of controls (non-diabetic siblings). IAA and IA-2 were significantly higher among younger age groups; GAD65A was significantly higher among older age. The combined GAD65 and IA-2 tests can be considered as a sensitive marker for predicting the occurrence of the disease in individuals at risk of type 1 diabetes in Saudis.

Co-infusion of insulin-secreting adipose tissue-derived mesenchymal stem cells and hematopoietic stem cells: novel approach to management of type 1 diabetes mellitus

Stem cell therapy (SCT) has promising results in regeneration of injured tissues/cells as well as correcting immune dysregulation. We present our experience of co-infusion of human adipose tissue-derived insulin-secreting mesenchymal stem cells (IS-AD-MSC) along with bone marrow-derived hematopoietic stem cells (BM-HSC) in type 1 diabetes mellitus (T1DM). This was an institutional review board-approved prospective non-randomized open-labeled clinical trial after informed consent of 20 patients (15 males and 5 females) with T1DM for SCT, with mean disease duration of 9 ± 5.51 years. Their mean age and weight were 19.95 ± 8.35 years and 49.9 ± 14 kg, respectively. Our study includes T1DM with positive for glutamic acid decarboxylase (GAD) antibody and history of diabetic ketoacidosis (DKA). Generated IS-AD-MSC and BM-HSC were infused via femoral catheterization under local anesthesia into portal + thymic circulation and subcutaneous tissue with conditioning of injection rabbit anti-thymocyte globulin and Bortezomib. Patients were monitored for blood sugar, serum C-peptide, GAD antibodies, and glycosylated hemoglobin (Hb1Ac) at three monthly intervals post-therapy. Mean SC quantum infused 99.45 ± 22.5 mL, with mean 2.38 ± 0.78 × 104 ISC/μL, mean CD34+ 0.57 %, and mean CD45-/90+ and CD45-/73+ were 47.22 and 24.66 %, respectively. Generated ISCs expressed transcription factors ISL-1, PAX-6, and IPF-1. Variable and sustained improvement in mean FBS, PPBS, HbA1c, and serum C-peptide was noted over a mean follow-up of 43.94 ± 19.8 months with mean reduction of GAD antibody from 525.15 to 120.15 IU/mL. Mean insulin requirement decreased from 60.89 to 39.76 IU/day. There was absence of DKA after SCT. No untoward effect/morbidity/mortality was recorded from SCT. Co-infusion of IS-AD-MSC with BM-HSC offers a safe and viable therapy for T1DM.