Systemic autoinflammation with intractable epilepsy managed with interleukin-1 blockade.

BACKGROUND: Autoinflammatory disorders are distinguished by seemingly random episodes of systemic hyperinflammation, driven in particular by IL-1. Recent pre-clinical work has shown a key role for IL-1 in epilepsy in animal models, and therapies for autoinflammation including IL-1 blockade are proposed for refractory epilepsy. CASE PRESENTATION: Here, we report an adolescent female with signs of persistent systemic inflammation and epilepsy unresponsive to multiple anti-epileptic drugs (AED). She was diagnosed with generalized epilepsy with a normal brain MRI and an electroencephalogram (EEG) showing occasional generalized spike and slow wave discharges. Her diagnostic evaluation showed no signs of autoimmunity or genetic causes of epilepsy or periodic fever syndromes but persistently elevated serum inflammatory markers including S100 alarmin proteins. She experienced prompt clinical response to IL-1 blockade with first anakinra and then canakinumab, with near complete resolution of clinical seizures. Additionally, she displayed marked improvements in quality of life and social/academic functioning. Baseline gene expression studies on peripheral blood mononuclear cells (PBMC) from this patient showed significantly activated gene pathways suggesting systemic immune activation, including focal adhesion, platelet activation, and Rap1 signaling, which is an upstream regulator of IL-1ß production by the NLRP3 inflammasome. It also showed activation of genes that characterize inflammasome-mediated autoinflammatory disorders and no signs of interferon activation. This gene expression signature was largely extinguished after anakinra treatment. CONCLUSIONS: Together, these findings suggest that patients with epilepsy responsive to immune modulation may have distinct autoinflammatory features supporting IL-1 blockade. As such, IL-1 blockade may be highly efficacious adjunctive medication for certain refractory epilepsy syndromes.

Intravenous methylprednisolone versus therapeutic plasma exchange for treatment of anti-N-methyl-D-aspartate receptor antibody encephalitis: A retrospective review.

INTRODUCTION: Anti-N-methyl-d-aspartate (NMDA) receptor antibody encephalitis is an increasingly recognized form of autoimmune encephalitis. Conventional treatments include therapies such as corticosteroids, intravenous immunoglobulin (IVIg), and/or therapeutic plasma exchange (TPE). Although TPE is regularly used for treatment of anti-NMDA receptor antibody encephalitis, the American Society for Apheresis has given it a category III recommendation only. Earlier administered immunotherapies in tumor-negative patients may facilitate faster recoveries, but it remains unclear whether or not TPE is superior to steroids and/or IVIG. METHODS: We retrospectively evaluated 10 of 14 patients that received steroids and TPE with modified Rankin scores and subjectively assessed the point of largest sustained improvement in all 14 patients. RESULTS: In the patients that received both steroids and TPE at our institution during the same hospitalization (only 10 of 14 patients), 7/10 patients after TPE had improved with the modified Rankin score versus 3/10 patients after steroids. The average modified Rankin score improvement after steroids in this group was -0.1 as compared with 0.4 after TPE. Based on subjective chart review analysis during which all 14 patients were assessed, the largest sustained improvement occurred immediately following the third-fifth exchange in 9/14 patients, whereas only 2/14 patients appeared to have had significant benefit immediately following steroids. CONCLUSIONS: This is compelling preliminary data that suggests that corticosteroids may not be as effective compared to steroids followed by TPE. Given the importance of time-sensitive treatment, more formal studies may illuminate the ideal first-line treatment for anti-NMDA receptor antibody encephalitis.

A 17-year-old male with pseudotumor cerebri secondary to performance-enhancing steroids triggering venous thrombosis in the brain.

This article is a case report of a 17-year-old male who presented with a headache and blurry vision. He subsequently was noted to have papilledema on a fundoscopic examination and an initial normal magnetic resonance imaging and computed tomography of his head; his condition was, therefore, diagnosed as pseudotumor cerebri. A subsequent magnetic resonance venography of his head revealed venous thrombosis, and other investigations revealed an elevated factor VIII level as well as a mutation at the MTHFR locus, consistent with an elevated risk for hypercoagulability. In addition, he admitted to steroid usage for purposes of performance enhancement in baseball. The patient's condition eventually improved with acetazolamide and serial lumbar punctures. Steroids have been linked to predisposition to hypercoagulable states, but there are no reports identified by these authors that link performance-enhancing steroids with pseudotumor cerebri as a result of a coagulation dyscrasia.

Use of interleukin-2 for management of natalizumab-associated progressive multifocal leukoencephalopathy: case report and review of literature.

A 51-year-old woman with relapsing-remitting multiple sclerosis (RRMS) and 3-year history of natalizumab use developed expressive aphasia. A brain magnetic resonance image (MRI) showed left frontotemporal and right parietal lesion with mild contrast enhancement and cerebrospinal fluid (CSF) was positive for John Cunningham virus (JCV) by polymerase chain reaction (PCR). The patient received five cycles of plasmapheresis followed by intravenous immunoglobulin. Despite this intervention, her speech deteriorated and she developed right hemiparesis. Upon referral to our institution, CSF quantitative JCV PCR was notable for 834 copies/ml. The patient was given an initial dose of 50,000 units of interleukin-2 (IL-2) subcutaneously (SQ) followed by 1 million units IL-2 SQ daily. Due to concern for immune reconstitution inflammatory syndrome (IRIS), the patient also received intravenous methylprednisone weekly. The regimen was tolerated well by the patient with no severe adverse effects. Clinically, the patient showed some improvement, and became more responsive and regained right lower extremity antigravity strength. After 12 weeks of IL-2 therapy, JCV quantitative PCR was notable for 31 copies/ml and the patient was more responsive. Due to persistence of JCV, IL-2 therapy was changed to mefloquine. At follow up after 6 months, the patient showed no clinical deterioration.

SAFE Homes: is it worth the cost? An evaluation of a group home permanency planning program for children who first enter out-of-home care.

OBJECTIVE: To evaluate the SAFE Homes (SH) program, a short-term group care program for children between 3 and 12 years of age who enter care for the first time. The program aims to improve case outcomes by consolidating resources to facilitate assessment and treatment planning. METHODS: The 1-year outcomes of 342 children who received SAFE Home services and 342 matched foster care (FC) control children were compared. The 684 subjects used in this report were selected from a larger pool of 909 subjects using propensity score matching to control for hidden bias in treatment group assignment. We hypothesized that SAFE Homes would result in greater continuity of care for children (e.g., fewer placements, more placements with siblings and in towns of origin), identification of more relatives for substitute care when needed, reduced use of high-cost restrictive care settings (e.g., residential, inpatient), and reduced rates of re-abuse through earlier detection and provision of services to meet child and family treatment needs. RESULTS: Prior to the initiation of the SAFE Homes program, 75% of the children who entered care in the State experienced three or more placements in the first year. The outcomes of both the SH and FC cases were significantly improved over pre-SAFE Home State statistics. The FC group, however, had comparable or better outcomes on most variables examined. In addition, the total cost for out-of-home care for the children in FC was significantly less, despite the fact that the two groups spent similar amounts of time in care (average time in care: 7 months). This finding held when the total placement cost was calculated using the State reimbursement rate of 206.00 US dollars per day for SAFE Home care (SH: 20,851 US dollars +/- 24,231 US dollars; FC: 8,441 US dollars +/- 21,126 US dollars, p < .001), and a conservative SAFE Home program fee of 85.00 US dollars per day that only considered the child care and custodial staffing costs uniquely associated with the program (SH: 13,314 US dollars +/- 21,718 US dollars; FC: 8,441 US dollars +/-21,126 US dollars, p < .001). CONCLUSION: Improvements in outcomes related to continuity of care can be attained through staff training. The SAFE Home model of care is not cost-effective for first-time placements.

Three phenotypes of anti-N-methyl-D-aspartate receptor antibody encephalitis in children: prevalence of symptoms and prognosis.

BACKGROUND: Anti-N-methyl-d-aspartate (NMDA) receptor antibody encephalitis is becoming an increasingly recognized cause of encephalopathy in individuals previously presumed to have viral encephalitis. Various manifestations of this disease include altered mental status, behavioral changes, seizures, and movement disorders. We have noted three distinct subtypes of this disease which appear to have differential responses to immunotherapies and differences in prognosis. METHODS AND PATIENTS: We report eight patients observed at our children's hospital from 2009 through 2013 who appear to clearly fall into one of our three clinical categories. To find comparable articles reflecting this classification, we then performed a MEDLINE search of all articles involving the subject heading "anti-NMDA receptor encephalitis" or just the keyword phrase "NMDA encephalitis," and we found 162 articles to review. Twenty-two articles were eliminated due to basic science, and we were able to review 105 of the remaining articles, most of which were case reports or case series, although a few were larger reviews. For the sake of our review, we defined type 1 or "classic" anti-NMDA receptor antibody encephalitis as having a duration of <60 days and being characterized predominantly by a catatonic or stuporous state, type 2 or psychiatric-predominant anti-NMDA receptor antibody encephalitis as having no noteworthy catatonic or stuporous state in addition to the presence of predominantly behavioral and psychiatric symptoms, and type 3 or catatonia-predominant anti-NMDA receptor antibody encephalitis as having a duration of ≥60 days in a predominantly catatonic or stuporous state. RESULTS: We note that the poorest responders, even to aggressive immunotherapies, are the patients with catatonia-persistent type anti-NMDA receptor antibody encephalitis, which has, as its hallmark, prolonged periods of severe encephalopathy. Patients with predominantly psychiatric symptoms, which we call the psychiatric-predominant anti-NMDA receptor antibody encephalitis, have had excellent responses to plasma exchange or other immunotherapies and appear to have the least residual deficits at follow-up. Patients with fairly equal representations of periods of altered mental status, behavioral problems, and movement disorders appear to have an intermediate prognosis and likely require early aggressive immunotherapy. CONCLUSIONS: In our series, we discuss representative examples of these clinical subtypes and their associated outcomes, and we suggest that tracking these subtypes in future cases of anti-NMDA receptor antibody encephalitis might lead to better understanding and better risk stratification with regard to immunotherapy decisions.

"Light switch" mental status changes and irritable insomnia are two particularly salient features of anti-NMDA receptor antibody encephalitis.

BACKGROUND: Anti-N-methyl-D-aspartate antibody encephalitis is becoming increasingly recognized as a cause of acute and subacute encephalopathy in both adults and children. The typical features of this disorder include some degree of encephalopathy, seizures, and often a movement disorder component. However, there is wide variability in its presentation, and diagnosis based on clinical features alone is often delayed. PATIENTS: We report a series of four of 12 patients observed at our children's hospital between 2011 and 2013 that we chose as particularly representative examples of two distinct clinical features. RESULTS: In these individuals with anti-N-methyl-D-aspartate receptor antibody encephalitis, we note a very rapid on-off state between responsiveness and nonresponsiveness and/or insomnia accompanied by extreme irritability. We describe the abrupt mental status shift as "light switch" because the patients can awaken in seconds from a completely nonresponsive state. The insomnia noted in our patients was also impressive and often present early in the patients' courses. CONCLUSIONS: Light switch mental status changes and irritable insomnia are important early features of anti-N-methyl-D-aspartate receptor antibody encephalitis that can signal the presence of this disorder. The exact pathophysiology of these two symptoms has not been fully elucidated, and we feel that presence of one or both of these symptoms early in the disease course should prompt immediate concern for this disorder.