Course Of IVIG Research Articles

A Diagnostic Puzzle: New Liver Dysfunction with Severe Thrombocytopenia

Autoimmune hepatitis is a chronic disease characterized by inflammation and hepatocellular necrosis causing varying degrees of clinical and biochemical manifestations. A rare complication is the development of aplastic anemia defined by inability of hematopoietic stem cells to repopulate the bone marrow thus resulting in severe hypocellularity without other morphologic abnormalities. Treatment using immunosuppressive therapy drastically improves outcome. We present this case of a young adult with autoimmune hepatitis leading to aplastic anemia. A previously healthy 20 year old male presented with abdominal pain and vomiting. Workup revealed markedly elevated liver enzymes, hyperbilirubinemia, seronegative acute viral hepatitis panels, severe thrombocytopenia and moderate neutropenia. Initial bone marrow biopsy showed hypocellularity and mildly decreased megakaryocytes.Liver biopsy disclosed periportal and lobular inflammation with patchy necrosis. A course of steroids and IVIG resulted in improvement of transaminitis, but he developed progressive severe pancytopenia.5 weeks later, repeat bone marrow biopsy showed virtually acellular marrow confirming the diagnosis of hepatitis associated aplastic anemia. He was treated with antithymocyte globulin, steroids and cyclosporine. About 7 months later, he continued to have moderately severe neutropenia and mild thrombocytopenia without anemia. Currently the patient is a potential candidate for stem cell transplant. Hepatitis associated aplastic anemia (HAAA) is a rare complication of autoimmune hepatitis occurring mostly in children and young adults.Onset of aplastic anemia is usually within a few months of diagnosis of hepatitis and it evolves independently of successful treatment of hepatitis. Diagnosis criteria of HAAA is a combination of pancytopenia and bone marrow biopsy showing severe hypocellularity without other morphologic abnormalities in the cellular and stromal elements. Pathophysiology of HAAA is not well defined but it is widely believed that a decreased CD4:CD8 ratio, proliferation and activation of cytotoxic T-lymphocytes and release of cytokines all play important roles. If untreated, HAAA has a very high mortality rate. It must be promptly treated using immunosuppressive therapy and, in some cases of persistent severe cytopenia, allogeneic bone marrow transplant. Such an approach has been demonstrated to improve survival.

S34. A novel case of axonal form of adult Guillain Barré Syndrome (GBS) preceded by acute renal failure

Guillain Barré syndrome is an acute/subacute form of polyradiculoneuropathy that can cause, commonly, ascending paraplegia and sensory deficits, and can result in quadriplegia, respiratory failure requiring intubation. There are different subtypes of GBS – e.g. motor, motor-sensory, Miller Fisher syndrome and others. Axonal form of GBS is the predominant form in the pediatric population in the US and many Asian countries. There is paucity of literature about such cases preceded by acute renal failure in adults. Reporting a patient admitted to Neurology inpatient service in a tertiary care center in Central Pennsylvania. A PubMed search was done. 72 year-old man presented with acute onset of paraplegia and areflexia shortly after acute renal failure- confirmed by laboratory testing, and was intubated for respiratory failure. Besides respiratory compromise, there was no cranial nerve or autonomic involvement. Sensory impairment was restricted to the lower extremities only. Infectious workup was unrevealing. CSF studies showed albuminocytologic dissociation. MRI of brain and entire spine did not show any significant abnormalities. EMG showed severe, generalized, axonal, motor and sensory polyneuropathy. GBS was diagnosed based on clinical features supported by CSF. Patient received a course of IVIG without improvement. Plasmapheresis was subsequently done. He was successfully extubated without any improvement of his motor and sensory profile. Acute axonal form of GBS causing diffuse motor and sensory neuropathy usually has an early age of onset, slower recovery and incomplete resolution of symptoms. This is a novel case of axonal variant of GBS preceded by renal failure, as per our review of literature for North America. A broad differential diagnoses should be kept in mind in patients with acute/subacute paraplegia preceded by acute renal failure.

An Acute Pharyngeal-Cervical-Brachial (PCB) variant of Guillain-Barre Syndrome

Acute Guillain Barre Syndrome [GBS] is characterized by an acute onset of limb weakness and areflexia. There are a few rare variants that have been described and one of them is the pharyngeal–cervical-brachial[PCB] variant [involving oropharynx, neck and proximal upper limb muscles]. Many neurologists and physicians are unaware of this variant which is often misdiagnosed as myasthenia gravis, brainstem stroke or botulism. A 37 year old female patient presented with the classical characteristics including bulbar weakness, cervicobrachial weakness and are flexia in the upper limbs, with relatively preserved lower limbs. Her systemic review was unremarkable. Her physical examination was compatible with GBS. Nerve conduction studies revealed Motor Axonal Radiculoneuropathy. She received 5 day course of IVIG and showed significant improvement over next 1 week. The patient recovered well and was discharged after 12 days. Keywords: Guillain Barre Syndrome, Pharyngeal-Cervical-Brachial Variant

Acquired factor VIII deficiency: two case reports and a review of literature

BackgroundAcquired factor VIII (FVIII) deficiency, or acquired hemophilia A (AHA), is a rare autoimmune disorder involving antibody-mediated depletion of coagulation FVIII, leading to severe, life-threatening bleeding. The condition is often associated with other autoimmune disorders, and its treatment involves replacement of FVIII and various modes of immunosuppression. Recently, a few noteworthy therapeutic advances have been made. We present two cases of severe AHA in Chinese women. One of these women developed this disorder in the setting of possible parvovirus B19 infection, which has not yet been reported in association with AHA. Other notable features of her case included paradoxical venous thrombosis and possible association with Sjogren’s syndrome and myositis. The other woman failed to respond to usual first-line therapies despite exhibiting a less severe clinical course, illustrating the varied but potentially stubborn behavior of this disorder.Case 1An 87-year-old woman presented with diffuse ecchymoses, melena, vaginal bleeding. Labs showed hemoglobin (Hgb) nadir of 5.7 mg/dL, elevated partial thromboplastin time (PTT), FVIII level <1%, mixing study consistent with an inhibitor, elevated anti-Sjogren’s-Syndrome-related antigen A antibody, elevated creatinine kinase, and elevated parvovirus IgM and IgG. Imaging of her arm showed diffuse myositis and deep venous thrombosis. After intravenous and oral steroids, her FVIII levels normalized, and her symptoms subsided.Case 2A 59-year-old woman presented with recurrent ecchymoses and hematomas in her extremities. Labs showed Hgb of 11.7 mg/dL, elevated PTT, FVIII level of 3%, and mixing study consistent with an inhibitor. Despite receiving a long course of steroids, several courses of IVIG, and a few courses of Rituximab, her FVIII level remained critically low.ConclusionThe rarity of AHA limits our understanding of this disease and the ability to perform trials to discover optimal therapies. We hope that these case reports and discussion will shed further light on the varied clinical manifestations and natural histories of this disorder to guide better recognition and treatment of AHA.

Steven Johnson Syndrome and Toxic Epidermal Necrolysis in a burn unit: A 15-year experience

IntroductionThe diffuse epidermal exfoliation seen in Steven Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) is similar to skin loss in second degree burns, and many of these patients are referred for treatment at burn centers. Treatment can differ markedly from center to center, and mortality can range from 25% to 70%, including a considerable morbidity. However, our experience over a 15-year period from 2000 to 2015 with 40 patients found a mortality rate of only 10% (4/40). The purpose of this paper is to discuss our treatment algorithm as a model for other centers treating SJS/TENs patients. MethodsRecords were reviewed for all patients admitted to the LAC+USC burn unit between 2000 and 2015 and 40 patients were identified with biopsy-proven SJS or TENS. These cases were reviewed for age, gender, initial and greatest TBSA, causative drug, pre-existing medical conditions, and morbidity and mortality. All data were entered into the SPSS statistical software package and all statistical analyses were performed using this program. ResultsOur treatment algorithm focused on early referral to a specialty burn unit, immediate discontinuation of the offending drug, fluid resuscitation, nutritional supplementation, and meticulous wound care. Average time to transfer to a burn unit was 3.36 days. Silver-releasing antimicrobial dressings were applied to the affected skin surface and changed every 3 days. Mupirocin coated petroleum gauze was used for facial involvement. Steroids were tapered and discontinued if initiated at an outside facility (58% of patients), and starting after 2001, all patients received a course of IVIG. All patients received fluid resuscitation and the majority received supplemental tube feedings (69%). Average length of total stay was 17.1 days and length of ICU stay 15.9 days. While 44% were transferred to another facility for further rehabilitative care, 37% of patients discharge to home. In patients discharged home with complete resolution of skin lesions, time to healing was an average of 14 days. DiscussionWith our 10% mortality rate in 40 patients, our study represents a relatively large study population while maintaining a relatively low mortality rate. The demographic data from our study largely aligns with the existing literature, and we therefore feel that our low mortality rate is due to our treatment algorithm, rather than to a less severe pathology in our patient population. This claim is supported by a standard mortality ratio of 1.68. This ratio proves a significantly improved mortality than would be expected based on disease severity on admission.

OR19 Successful reversal of severe kidney allograft rejection mediated by angiotensin II type 1-receptor antibodies

Case Study The patient is a non-sensitized 64 year-old African American male who received a split en bloc deceased donor kidney transplant with standard induction using solumedrol and basiliximab. Post-discharge his renal function remained stable with a baseline creatinine between 1.0 and 1.2 mg/dL. During this time he experienced severe GI side effects related to MMF which led to its temporary discontinuation for 2 weeks, followed by resumption at reduced dosage (250 mg BID). One week later, his creatinine acutely worsened from 1.0 to 3.1 mg/dL. The patient’s allograft pathology showed mixed acute C4d+ antibody-mediated rejection (AMR) and cell-mediated rejection with transmural arteritis (Banff scores g1, t3, i3, v3, ptc1). Surprisingly, neither anti-HLA nor MICA antibodies were identified in any of his post-transplant sera. Further investigation uncovered anti-angiotensin II type-1 receptor antibodies (AT1R ab) and endothelial cell crossmatch (ECXM) positivity which correlated with the timing of his acute rejection. Fig. 1 illustrates the kinetics of the patient’s AT1R ab level in relationship to his clinical course. Pre-transplant, high AT1R ab binding was detected at 18 U/ml (positive cutoff >17 U/ml) – this reactivity increased to 27 U/ml on the day of his allograft biopsy. In parallel with this surge, the patient’s creatinine deteriorated to a peak of 5.7 mg/dL necessitating temporary dialysis. Of note, his blood pressure which had been previously well-controlled converted to a state of hypertensive urgency requiring IV nicardipine infusion. He was treated aggressively with ATG, plasmapheresis, IVIG, and losartan. After one week of treatment his AT1R ab level became undetectable; remarkably, the patient also showed rapid clinical recovery and control of his blood pressure. Post-discharge his renal function returned to his previous baseline. He continues to take losartan for AT1R blockade and is treated with short courses of plasmapheresis and IVIG to reduce his anti-AT1R level as necessary. Download full-size image

Intravascular large B-Cell lymphoma (IVLBCL) presenting as lumbosacral polyradiculopathy

Background: IVLBCL is potentially treatable but difficult to diagnose. Methods: A case of progressive leg weakness and sphincter dysfunction diagnosed only at autopsy. Results: A 72 year old female presented with three weeks of increasing leg weakness and three days of urine and stool incontinence. Electrophysiological testing showed reduced tibial and peroneal CMAPs, preserved sural SNAPs, and bilateral gastrocnemius fibrillations, consistent with a pre-ganglionic lesion. Lumbosacral MRI with gadolinium showed no abnormalities. CSF was examined three times (protein 1.18-1.25, glucose 2.6-3.1, normal cell count and cytology). Whole-body FDG PET scanning showed hypermetabolic foci at the tongue base and in the mediastinum, but biopsy of both revealed no abnormality. Leg weakness progressed over three months and spread to the arms despite a course of IVIg. Four months later she died of cardiorespiratory arrest. Autopsy revealed the presence of large atypical B-cells within the lumen of small and medium sized vessels in numerous organs. There was evidence of anterior spinal artery obstruction with lymphocytes and anterior horn infarction in the lumbar cord. Conclusions: Although the literature reports that IVLBCL responds well to chemotherapy, this patient illustrates the difficulty of ante-mortem diagnosis. Nerve root biopsy may be warranted in such patients.

Abstract 146: Third Intravenous Immunoglobulin Is An Effective Option For Kawasaki disease Patients Resistant To Cyclosporin A

Background: About 10-20% of patients with Kawasaki Disease (KD) who fail to respond to IVIG, show a high prevalence of CAL. The new guideline (2012) has proposed several options for second- and third-line therapy for patients resistant to IVIG. However, there are still no definite treatment options for refractory KD. We have reported that cyclosporin A (CsA) is a well tolerated, safe and promising option for patients resistant to IVIG. However, certain subgroups of such patients may also be resistant to CsA. In this study, we examined if a third course IVIG might be effective for patients resistant to CsA. Patients and Methods: Between April 2008 and May 2014, 42 Japanese patients who met the diagnostic criteria for KD and received CsA treatment were enrolled as study subjects. All patients were resistant to both initial (2 g/kg for 24 hours) and additional IVIG, and were then administered CsA orally (Neoral[[Unable to Display Character: &amp;#9415;]], oral solution, Novartis Pharma Co. Ltd., Tokyo, Japan). The initial dose of CsA was 4mg/kg/day, and it was divided into two equal daily doses every 12 hours. The dose of CsA was adjusted to between 4 and 8 mg/kg/day to maintain a trough level of 60-200 ng/ml by reference to clinical and laboratory data such as body temperature and C-reactive protein level. After the start of CsA treatment, if patients remained febrile for more than 5 days, or if fever returned after an afebrile period within 5 days, CsA treatment was judged to be ineffective, and the patients were then given a third course of IVIG. We analyzed some laboratory data between CsA effective group and CsA resistant group. Results: CsA treatment was judged to be ineffective in 14 of 42 (33%) patients. Eleven of those 14 patients received a third IVIG, and then, 8 (72.7%) patients of them became afebrile within 24hours. The other three patients became afebrile after a fourth IVIG. The serum levels of AST and soluble interleukin-2 receptor before the start of CsA treatment were significantly lower in CsA effective group than in CsA resistant group. Conclusion: A third course of IVIG is an effective option for KD patients who are resistant to CsA .

Abstract 88: Pentraxin 3 in Coronary Artery Lesions in Kawasaki Disease

Although vascular inflammation is an important feature of Kawasaki disease (KD), the usefulness of local inflammatory markers as biomarkers for KD is unknown. Pentraxin 3 (PTX3), soluble lectin-like oxidized low density lipoprotein receptor 1 (sLOX-1) and matrix metraloproteinase-9 (MMP-9) are biomarkers of inflammation of vascular components. Objective: We tested whether plasma concentrations of PTX3, sLOX-1 or MMP-9 would be a useful biomarker for detecting high risk patient of coronary artery aneurysm (CAA) in KD and compared with serum level of interleukin-6 (IL-6) and IL-18. The ability of the assays to identify KD patients at risk for CAA was analyzed. Methods: PTX3, sLOX-1, MMP-9, IL-6 and IL-18 concentrations of 50 KD patients at different four clinical points were analyzed. Point A represented on admission; B, pre-IVIG; A+B, before IVIG; C, after IVIG; D, after fever resolution. Each concentration was compared with the rate of occurrence of CAA and IVIG unresponsiveness. Results: Each value was evaluated in 50 KD patients (2 with CAA, 48 without CAA). Three patients were treated without IVIG, 17 with one course of IVIG, and six with two IVIGs, two with three IVIGs, respectively. At the points A+B, C, D means for PTX3 were; 33.4, 11.7, 9.00 ng/ml, mean for MMP-9; 34.6, 19.2, 24.2 ng/ml, mean for sLOX-1; 3.82, 2.33, 2.25 ng/ml, respectively. Levels of PTX3 (p&lt;0.001) and MMP-9 (p&lt;0.05) were significantly higher in before IVIG than after IVIG; whereas levels of sLOX-1, as well as those of IL-6 and IL-18 were comparable between before and after IVIG. PTX3 were well correlated with IL-6 level (R2=0.73). Both cases with extraordinary high PTX3 levels at admission of 91.8 and 65.3 ng/ml were complicated with coronary artery aneurysms, even though they were treated by three courses of IVIG. The level of plasma PTX3 was significant related with the course numbers of IVIG (p&lt;0.05). Conclusion: Levels of PTX3 and MMP-9 appear to be associated with clinical course of KD. Levels of PTX3 were correlated with the severity of disease; how many doses of IVIG enough to resolve fever. An extraordinary high PTX3 level might be suggestive of the existence of CAA. These data suggest that PTX3 can be a candidate biomarker for prediction of unresponsiveness and CAA formation in patients with KD.

Novel Management of Immune Thrombocytopenia in Gaucher Disease Patients

Type I Gaucher disease (GD) the is characterized by hepatosplenomegaly, pancytopenia and skeletal complications due to the accumulation of glucocerebroside in macrophages. Thrombocytopenia is usually related to hypersplenism and infiltration of bone marrow by lipid-laden macrophages namely Gaucher cells. Enzyme replacement therapy (ERT) restores the hemoglobin and platelet count in GD patients. In GD ERT treated patients, manifesting persistent low platelet counts, immune thrombocytopenia (ITP) should be considered.Treatment of GD with concomitant ITP is a challenge. Splenectomy may worsen bone manifestations in GD patients and is controversial. Steroids should be used with caution because of possible induction of osteopenia and joints avascular necrosis. Thrombopoietin receptor analogues (TPO-RA) are therapeutic option in GD patients with ITP. Beneficial use of TPO-RA is reported in 2 cases.Patient 1: 39 YO male with new onset of purpura and low platelet count failed treatment with 1 mg/kg of Prednisone. Bone marrow biopsy (BM) showed Gaucher cells infiltration, numerous atypical megakaryocytes, normal erythropoiesis and myelopoiesis with no fibrosis. Low level of ß-glucocerebrosidase activity with compound heterozygosity for 84GG /R495H mutations, established the diagnosis of Type I GD. Low C4 and detection of IgG platelet antibodies added to the diagnosis of concomitant immune thrombocytopenia. ERT with taliglucerase alfa (ElelysoTM) 60 Units/kg/month was given with Prednisone for six weeks. Occurrence of retinal bleeding and purpura, with decrease of platelet count necessitated addition of high-dose IVIG with no response regarding platelet counts. Splenectomy was not considered due to known bony complication risk in splenectomised GD patients. Rituximab was given to prevent wet purpura recurrence with short response regarding platelet count. Romiplostim was initiated raising platelet count from 29,000/µL to 60,000/µL after 3 wks. and to 90,000/µL after 8 wks. enabling corticosteroids withdrawal. Same dose Romiplostim is maintained for the last 30 months with platelet counts of 90,000 - 110,000/µL with no bleeding events. Repeated BMB showed no increase in collagen fibrosis.Patient 2: 63 YO female patient diagnosed with Gaucher at age 33 with a history of purpura, ecchymosis, and occasional vaginal bleeding episodes. At age 53 the platelet count dropped to < 20,000/µL with presence of Anti Platelets Ab (IgG). BMB revealed megakaryocytic hyperplasia with atypical forms, focal infiltration by Gaucher cells and no fibrosis. Combined therapy by ERT (Imiglucerase® followed by Velaglucerase Alfa®), Prednisone (1mg/kg/d for 2 months) and one course of IVIG yielded no increase in platelet count. The patient refused Rituximab®. Romiplostim was initiated increasing platelet count to100,000/µL maintained throughout a year of follow up. Repeated BMB showed slight increase of fibrosis and marked hyperplasia of atypical megakaryocytes.Discussion: Thrombocytopenia is often present in GD and may be severe in approximately 15% of the patients. Persistent cytopenias may be caused by other underlying pathologies such as autoimmune disorders and are important to be recognized and addressed. Before ERT era GD patients with hypersplenism and severe cytopenia were splenectomised. Risks of splenectomy include serious bacterial infection and vascular complications limiting its use in chronic refractory ITP. Splenectomy is avoided in Gaucher patients, due to risk of exacerbating skeletal complications (bone infarcts, avascular necrosis). Stable bone marrow results regarding fibrosis in our patients are consistent with data from a recent 2-year follow-up of 100 ITP patients receiving Romiplostim treatment with no evidence of BM fibrosis.Conclusion: In patients with type I Gaucher disease and concomitant ITP, adjunctive treatment with Romiplostim was successful in maintaining haemostatic platelet counts with no adverse effects. Traditional treatment regimens of corticosteroids and splenectomy should be used with caution or avoided in GD patients due to possible aggravation of Gaucher skeletal disease and the risk of osteopenia and avascular necrosis resulting in increased morbidity in this cohort of patients. Use of TPO-RA should be considered in GD patients with ITP. DisclosuresOff Label Use: Romiplostim in gaucher patients.

Ri antibody syndrome associated with an unusual neuroendocrine tumor

Introduction: We present a case of a paraneoplastic syndrome with Ri antibodies related to a large cell endocrine tumor of the lung. Case report: A 64 year old female patient was referred to our hospital with a one month history of dizziness, vertigo, nausea and gait instability. Her symptoms had a subacute onset with gradual progression, with more marked deterioration the week prior to presentation. Past medical history included a large cell endocrine lung tumor of the left upper lobe, which was diagnosed ten months prior to admission. She underwent a left thoracectomy with upper lobectomy followed by chemotherapy. Follow-up CT of chest–abdomen–pelvis had no signs of disease recurrence or metastasis. On admission she had severe truncal ataxia and was unable to sit upright in bed. Neurological examination revealed multi-directional saccades, mostly of the “square wave jerk” type, simulating opsoclonus, but lacking a continuous chaotic character. The abnormal eye movements were exacerbated during pursuit and were visible under closed eyelids. Oscilopsia was absent. Spontaneous myoclonic jerks of lower extremities were noted. An intention and posturaltremorofherhandswaspresent. BrainMRIwasunremarkable. Routine blood tests and screening for cancer markers was unrevealing. Cytology for malignant cells in the CSF was negative. Screening for onconeural antibodies revealed a high titer in both CSF and serum of Riantibodies. Shereceiveda 5 day courseofmethylprednisone(1 g daily), followed by a five day course of IVIG (0.4 mg/kg). Methylpredinisolone was tapered at a dose of 40 mg. Her symptoms gradually improved markedly and one month after treatment she was able to walk unassisted with mild residual truncal ataxia. The abnormal eye movements were no longer detectable. Subsequent whole body FDGPET revealed intense absorption in the hilar region of the left lung. Discussion: The presence of Ri antibodies is associated with the well characterized paraneoplastic syndrome of opsoclonus–myoclonus– ataxia. The abnormal eye movements of our patient were not fully consistent with opsoclonus. Additionally, to our knowledge, this syndrome has not been previously associated with a large cell endocrine tumor. Thus, this case report suggests that the Ri antibody syndrome can have a broader clinical phenotype and underlying etiology than previously considered. Prompt initiation of immunotherapy can result in substantial improvement of neurological deficit.

Diagnosis and Management Of POST-Transfusion Purpura - Case Report

BackgroundPost-transfusion purpura (PTP) is a rare yet serious disease characterized by severe thrombocytopenia occurring after a blood transfusion. It is caused by alloimmunization against platelet antigens, anti-HPA-1a being the most frequent antibody. We report two cases of PTP and discuss the clinical presentation, diagnosis and management of this serious condition. Case ReportCase 1) Female patient, 90 years old, Caucasian, had a fracture in the umerus and head trauma in 2012, followed by upper GI bleeding. Four days after receiving two units of packed RBCs, she presented with a low platelet count (14.000/mm3), petechiae, gum bleeding and oozing from venipuncture sites. The platelet count further dropped to 2.000/mm3the following day. HPA genotyping and HPA antibody identification by MAIPA were performed to investigate post-transfusion purpura, which showed: HPA1bb, 3aa, 5aa and 15ab and presence of antibodies anti-HPA-1a. IVig 400 mg/kG was infused in two consecutive days, with normal platelet counts observed after a week. Two of her three children had the same HPA1bb genotype and performed a matched platelet and RBC donation by apheresis. One matched RBC unit was transfused to correct symptomatic anemia caused by bystander hemolysis seven days after the first transfusion. No platelet transfusions were needed.Case 2) Female patient, 29 years old, afrodescendant, had a hemorrhagic shock after an emergency hysterectomy due to placenta percreta in 2012. She received 14 RBC units, 10 fresh frozen plasmas and 10 units of cryoprecipitate. Two days later, another surgery was necessary to remove a retained coagulum, and she received 10 units of random platelets. Five days later, the platelet count dropped to 5.000/mm3, followed by sudden anemia (Hb=9--> 4,5 g/dL), without clinical or laboratory signs of hemolysis or evidence of bleeding, with normal coagulation times. HPA genotyping and antibody identification by MAIPA were performed and showed an HPA1bb genotype and presence of an anti-HPA-1a antibody. No platelet transfusions were administered and IVig 500mg/Kg was prescribed for 2 days. Only washed RBC units were transfused thereafter. The platelet count rose four days after starting IVig to 134.000/mm3, yet a second course of IVig was necessary a week later to reach normal platelet counts. DiscussionBoth reports illustrate severe thrombocytopenia in patients who presented with sudden thrombocytopenia up to a week after blood transfusion. Platelet alloimmunization happens after exposure to HPA antigens by transfusion or pregnancy, and severe thrombocytopenia occurs as an anamnestic response after reexposure to platelet antigens in any blood product that contains contaminating platelet membranes. The thrombocytopenia may evolve as an autoimmune process, which may also cause hemolytic anemia due toa bystander phenomenom. Diagnosis is based on the identification of the antibody in the serum of a patient who lacks the corresponding antigen, anti-HPA-1a being the most common. IVig 0,5-1g/Kg for 2 days is the treatment of choice. The RBC units must be washed to avoid exposure to platelet membranes and recurrence of thrombocytopenia. In future transfusions, washed RBCs or HPA1bb blood products should be used. Disclosures:No relevant conflicts of interest to declare.

Idiopathic thrombocytopenic purpura resistant to eltrombopag, but cured with romiplostim.

Dear Sir, The recent development of thrombopoietin-mimetic drugs offers the possibility of a new approach for second- or even third-line treatment of resistant idiopathic thrombocytopenic purpura (ITP). Here we report on the case of a patient with ITP who relapsed after standard first-line treatment with steroids and immunoglobulins and whose disease was resistant to splenectomy. Subsequent second-line treatment included an anti-CD20 monoclonal antibody (rituximab) and a first unsuccessful attempt with eltrombopag. The patient was subsequently cured with romiplostim. The therapeutic implications are discussed. The patient was a 34-year old male, first diagnosed in January 1999 with ITP. The patient had a past medical history of neonatal epilepsy and for this reason was receiving treatment with phenobarbital, clonazepam and carbamazepine. A breath test was negative for Helicobacter pylori and serological tests for hepatitis A, B, C and human immunodeficiency viruses were also negative. The patient was initially treated with a course of prednisone (1mg/kg per os). However, because of a relapse, he was first treated with intravenous immunoglobulins (IVIG; 1 g/kg) and later, in September 1999, he underwent elective splenectomy. Hepatic scintigraphy ruled out splenunculi. The patient was subsequently treated on occasions with IVIG due to a falling platelet count. He received a total of ten courses of IVIG. However, in July 2007, due to a second relapse with a platelet count 50×109 L. Unfortunately, 2 months later the drug was no longer available because of a supply shortage and the treatment had to be discontinued. One month later (January 2011) the patient’s platelet count had dropped to 2×109/L and he developed severe epistaxis and rectorrhagia. A new trial of treatment with eltrombopag was commenced (50 mg once daily per os, for 1 month), but was unsuccessful. This was immediately followed by three courses of weekly rituximab, with oral prednisone (0.5 mg/kg). Despite this treatment, the platelet count did not reach the safety level of 20×109/L although no further episodes of bleeding occurred. For this reason, a new thrombopoeitin-mimetic was considered and the patient was started on subcutaneous romiplostim treatment (80 μg every 2 weeks) which produced a prompt platelet response (platelet count >50×109/L). He is currently being treated with romiplostim, his platelet count remains >100×109/L, and to date he has not shown any new signs of bleeding or haemorrhage. It is important to remember that the two currently available thrombopoietin agonists, here mentioned, have different mechanisms of action. Eltrombopag is a non-peptide thrombopoietin agonist that interacts with the thrombopoietin receptor c-MPL at a different site from thrombopoietin, while romiplostim is a “peptibody”, a combination of a peptide and an antibody, with two linked carrier-Fc domains, which potentiate its effectiveness. An extensive Pubmed search of the literature revealed a similar case reported by Aoki T and colleagues, suggesting the absence of cross-resistance between the two drugs and different mechanisms of actions1. In addition, a study using a Bayesian meta-regression method compared the effectiveness of the two thrombopoietin-mimetics within several trials showing a statistical significant superiority for romiplostim compared to eltrombopag2. As our patient was splenectomised, it is relevant to add that so far, on the basis of currently available research, both thrombopoietin drugs have shown similar efficacy in splenectomised patients. Finally, it is not irrelevant that our patient was also taking anti-epileptic medications (phenobarbital, clonazepam and carbamazepine) throughout treatment and that previous studies have suggested that carbamazepine induces ITP3. A recent study also showed that clonazepam may induce pancytopenia4 and overall antiepileptic drugs have been associated with bone marrow damage and hepatic toxicity5. We cannot, therefore, exclude the possibility that these drugs may have had either a direct role on the bone marrow by inducing ITP or by impairing the action of eltrombopag, or that they may have enhanced liver catabolic pathways reducing the bioavailability of eltrombopag. However, none of these theories have been proven. In conclusion, the findings in this case suggest that the thrombopoietin agonists eltrombopag and rimoplostim have different mechanisms of action and that in the absence of a clinical response to one of these two drugs it is worth considering a trial treatment with the other. The possibility that other medications (e.g. anti-epileptic drugs) may interact with eltrombopag should be considered and if possible clarified.

Immunoglobulin-responsive refractory epilepsy – 3 cases with a similar EEG pattern

Autoimmune epilepsies are a heterogeneous group of recently described refractory epilepsies. They have been characterized by a variety of clinical, serological and radiological features. A range of anti-neuronal antibodies, which are usually found in limbic encephalitis, including antibodies to GAD,VGKC-complex antibodies,NMDA-R,amongst others, have been associated with some of these disorders. Other, antibody negative epilepsy patients had radiological features of central nervous system inflammation, inflammatory infiltrates histologically or high CSF white cell counts and oligoclonal bands. Immune therapy, including steroids and IVIg, has been used in these cases and resulted in clinical improvement. Best outcomes were associated with a short duration of the underlying illness. Long-term immune therapy has often been utilized in these cases.In this article, we describe a small cohort of patients who had a rapid, sustained response to a short course of IVIg, despite limited serological and radiological evidence for an underlying autoimmune process. This response was independent of the varying seizure phenotypes. Interestingly, all 3 patients shared a certain EEG pattern.

Pure Motor Chronic Inflammatory Demyelinating Polyneuropathy: Relationship to Multifocal Motor Neuropathy with Conduction Block (P06.137)

Objective: To report two cases of pure motor chronic inflammatory demyelinating polyneuropathy (CIDP), response to therapy, and possible relationship to multifocal motor neuropathy with conduction block (MMN). Background Motor CIDP is a rare variant of classic CIDP that is not well understood in regard to both its pathogenesis and appropriate treatment. The few studies that have been published suggest that unlike classic CIDP, motor CIDP does not respond well to corticosteroids. Design/Methods: Two motor CIDP patients are presented, one of whom has high titers to anti-GM1 antibodies. Results: Patient 1 is a 48 year old woman with a history of CIDP who developed worsening of her strength and diffuse wasting and fasciculations concerning for motor neuron disease. She was found to have an elevated titer of anti-GM1 antibodies of 1:102,400 and a pure motor demyelinating neuropathy with secondary axonal degeneration by electrodiagnosis. The patient failed to respond to weekly IVIG therapy and then worsened with corticosteroids, becoming bed-bound and requiring non-invasive ventilation. Despite weekly rituximab infusions, she continued to declined and was started on monthly plasma exchange and intravenous cyclophosphamide. She can now walk and her anti-GM1 antibody titer has fallen to 1:12,800. Patient 2 is a 56 year old man who presented with a three month history of fasciculations, progressive wasting, and diffuse weakness requiring a wheelchair after failing to respond to single courses of both IVIG and plasma exchange. His electrodiagnostic testing revealed findings similar to the first patient. He was restarted on weekly IVIG and, after 12 courses, finally recovered his ability to walk. Conclusions: Motor CIDP may be more resistant to treatment than classic CIDP. High titers of anti-GM1 antibodies and paradoxical worsening with corticosteroids in some patients could also support a distinct pathogenesis more similar to MMN. Abundant fasciculations seen in this disorder may mistakenly suggest motor neuron disease. Disclosure: Dr. Thyerlei has nothing to disclose. Dr. Weiss has received personal compensation for activities with Walgreens, CSL Behring and Talecris Biotherapeutics as a consultant and/or speaker.

088 Multifocal motor neuropathy in association with sarcoidosis

There have been allusions to the coincidence of sarcoidosis with Multifocal Motor Neuropathy in various series describing the conduction block neuropathy. We recently saw two patients with this association, the...

PO.18 Guillain-Barre syndrome (GBS) presenting with posterior reversible encephalopathy syndrome

Autonomic dysfunction is common in Guillain-Barre syndrome (GBS). Here we report a case, which initially presented with an autonomic dysfunction causing fluctuation in blood pressure, confusion and a generalised tonic...

Romiplostim for the treatment of a megakaryocytic thrombocytopenia secondary to remission-inducing immunomodulation in a patient with relapsing acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation.

6609 Background: Amegakaryocytic thrombocytopenia (AmegTP) is a rare immune mediated cause of thrombocytopenia (TP). We report a 57 y.o. woman who developed AmegTP as a result of immune modulation with interferon-α (IFN-α) and GM-CSF for acute B lymphoblastic leukemia (B-ALL) recurrence after allogeneic hematopoietic stem cell transplantation (HSCT). Results: B-ALL relapse was documented on day +71 post HSCT both extramedullary (subcutaneous scalp nodule) and with leukemic cells comprising 10% of bone marrow (BM) cellularity. Donor unavailability did not allow for 2nd HSCT or donor lymphocyte infusion. Immunosuppression was stopped immediately. On day +80, IFN-α (1-3x10E6 units) and GM-CSF (500μg) were commenced three times a week in order to augment graft versus leukemia responses. The nodule resolved within 3 weeks and BM analysis on day +97 showed a hypocellular marrow but no evidence of disease. IFN-α was stopped on day +101 due to pancytopenia. GM-CSF (if ANC <1/nl) and transfusion support were continued. TP persisted and transfusion refractoriness evolved. BM analysis on day +125 confirmed remission with 35% overall cellularity, spotty aplasia and absent megakaryocytes, consistent with AmegTP. A positive ANA screen suggested an immune-mediated cause. The patient received 1 course of high dose methylprednisolone plus IVIG (1g/kg). Parallel, a thrombopoietin receptor agonist (TRA) Romiplostim was started on day +127 at 1μg/kg and then increased by 1μg/kg every 7 days. No platelet transfusions were required after day +181 at a Romiplostim dose level of 8μg/kg, and platelets increased to 54/nl at a max. dose of 10 μg/kg. BM analysis on day +205 confirmed remission with normal myelo- and erythropoiesis and adequate maturing megakaryocytes. Conclusions: The observed supportive effects of Romiplostim on megakaryocyte expansion and proliferation in the context of AmegTP in our patient support the need for further studies on the efficacy and safety of TRAs in the post-HSCT setting.

Long‐term remission of recurrent severe anemia as a result of parvovirus B19 infection in a pediatric renal transplant recipient

We studied a case of recurrent PV-B19-associated anemia in a renal transplant child with long-term remission induced by baseline immunosuppression adjusted and intensive IVIG therapy. This was a 15-yr-old boy. Seven wk after transplantation, he experienced acute rejection, which was treated with high-dose steroids, ATG, and plasmapheresis. Ten wk after transplantation (three wk after rejection), his hemoglobin dropped to 54 g/L and serum PV-B19 PCR was positive. After therapy with IVIG and conversion from mycophenolate mofetil to rapamycin, anemia resolved. But the patient had fever on the fourth day of IVIG with mild pulmonary edema and rise in serum creatinine. Two months after the first course of IVIG, anemia recurred and a second course of IVIG (preadministration methylprednisolone) was given, which was followed by the resolution of anemia without side effect and recurrence two months later again. Baseline immunosuppression was adjusted with dual immunosuppression and low doses including prednisolone and tacrolimus. At the same time, monthly course of IVIG was repeated four times. Within the next 23 months, anemia did not recur and renal function remained stable. In conclusion, PV-B19-associated anemia can be recurrent in immunocompromised children and baseline immunosuppression should be carefully adjusted to control PV-B19 infection.

Paraneoplastic anti-NMDAR encephalitis: long term follow-up reveals persistent serum antibodies

Encephalitis associated with antibodies to N-methyl-Daspartate receptor (NMDAR) is a severe but treatable condition [3]. It is often paraneoplastic, affecting mostly women harboring ovarian teratomas. Its characteristic clinical picture includes confusion, agitation, psychiatric manifestations, memory loss, seizures and abnormal movements, and often leads to decreased level of consciousness, autonomic instability, and central hypoventilation [1, 5]. We present the long term follow-up of a patient with paraneoplastic anti-NMDAR encephalitis diagnosed several months after symptom onset who was in a comatose state for 1 year. A prolonged recovery followed after tumor resection and immunotherapy. Two notable observations are the absence of a detectable tumor at an early stage of the disease, and the persistent detection of serum NMDAR antibodies 4 years after disease onset. A 42-year-old woman suffering from headaches 2 months before disease onset, was admitted to an Athens hospital with neck pain, nausea, dizziness and high fever. She was alert and oriented. Her initial work up (brain and spinal MRI, chest and abdominal CT, routine laboratory tests) was normal. Lumbar puncture revealed pleiocytosis (421 lymphocytes/ mm) but no oligoclonal bands. CSF and serum cultures for bacterial, fungal and viral infections were negative. Two days after admission she became delusional with visual hallucinations, confusion, central hypoventilation and a progressive consciousness decline that led to a coma requiring ventilation 10 days after admission. Her EEG was slowing, disorganized, with no basic rhythm but without epileptic foci. The initial diagnosis was viral encephalitis with non convulsive status epilepticus and she was treated with antibiotics, antivirals and antiepileptics. Her condition worsened with episodes of hyperpyrexia, agitation, orofacial dyskinesias, stiffness, and seemingly violent movements of her upper arms. These episodes diminished significantly with dantrolene. A transvaginal echo was normal. She was treated with steroids and one course of IVIg but she remained unresponsive. In ICU the patient had multiple episodes of septicemia but she responded well to therapy. Seven months after disease onset she was transferred to our institution in a comatose state with tracheostomy and gastrostomy. Repeated CSF analysis for bacterial and viral infections was negative. Other systemic autoimmune causes were excluded and all autoantibody tests were negative (ANA, Ro, La, cANCA, pANCA, rheumatoid factor). Brain MRI was normal. An upper and lower abdominal MRI (looking for ovarian tumors) was negative. A suspected immune mediated encephalitis was treated with IVIg infusions, 2 g/ kg/36 h per month. A month later (month 9 from disease onset), a CT re-examination of the lower abdomen revealed a cystic formation at the left ovary. Following resection, pathology revealed a mature ovarian teratoma. NMDAR autoantibodies were detected in the serum and CSF using a qualitative assay (Fig. 1a). The patient started to communicate 40 days after tumor resection. IVIg infusions continued monthly for 7 months and she continued to improve slowly. No steroids, cyclophosphamide or plasmapheresis were added due to H. Alexopoulos M. L. Kosmidis M. C. Dalakas (&) Neuroimmunology Unit, Department of Pathophysiology, Faculty of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias St, 11527 Athens, Greece e-mail: mdalakas@med.uoa.gr