Jung-Ah Lim

Anti-N-Methyl-D-Aspartate Receptor Encephalitis in Korea: Clinical Features, Treatment, and Outcome

Background and Purpose Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is the most common type of autoimmune synaptic encephalitis and it often responds to treatment. We analyzed the clinical characteristics of anti-NMDAR encephalitis in Korea. Methods Serum and/or cerebrospinal fluid (CSF) of adult patients (aged ≥18 years) with encephalitis of undetermined cause were screened for anti-NMDAR antibodies using a cell-based indirect immunofluorescence assay. The patients came from 41 university hospitals. Results Of the 721 patients screened, 40 were identified with anti-NMDAR antibodies and clinical details of 32 patients were obtained (median age, 41.5 years; 15 females). Twenty-two patients (68.8%) presented with psychiatric symptoms, 16 (50%) with seizures, 13 (40.6%) with movement disorders, 15 (46.9%) with dysautonomia, 11 (34.4%) with memory disturbance, and 11 (34.4%) with speech disturbance. Magnetic resonance imaging, electroencephalography, and CSF examinations yielded nonspecific findings. Tumor information was only available for 22 patients: 5 patients had tumors, and 2 of these patients had ovarian teratomas. Twenty-two patients received immunotherapy and/or surgery, and therapeutic responses were analyzed in 21 patients, of which 14 (66.7%) achieved favorable functional outcomes (score on the modified Rankin Scale of 0-2). Conclusions This study investigated the clinical characteristics of adult anti-NMDAR encephalitis in Korea. Currently, elderly patients who do not have tumors are commonly diagnosed with this condition. Understanding the detailed clinical characteristics of this disease will improve the early detection of anti-NMDAR encephalitis in patients both young and old.

Rituximab treatment for autoimmune limbic encephalitis in an institutional cohort.

Objective: To determine efficacy and safety of rituximab treatment as a second-line immunotherapy treatment for autoimmune limbic encephalitis (ALE) and to determine factors associated with functional improvement and favorable outcome following rituximab treatment. Methods: We recruited 80 patients with ALE who were treated with rituximab as a second-line immunotherapy from the Korea Autoimmune Synaptic and Paraneoplastic Encephalitis Registry and reviewed 81 patients without rituximab as a control. We grouped patients according to the detection or type of antibodies; in addition, we evaluated clinical, laboratory, first-line immunotherapy, and rituximab treatment profiles and defined main outcomes as improvements on the modified Rankin Scale (mRS) score and a favorable mRS score (0–2) at the last follow-up. Results: Functional improvement occurred more frequently in the rituximab group compared to the control group. In the rituximab group, 30 (37.5%) patients had synaptic autoantibodies, 15 (18.8%) in the paraneoplastic autoantibodies, and 35 (43.8%) were antibody-negative. The effect of rituximab was the same regardless of autoantibody status. Additional monthly rituximab therapy and partial response to first-line immunotherapies were associated with mRS score improvements, as well as favorable mRS scores. mRS scores of 4–6 as the worst neurologic status predicted an unfavorable mRS score. There were no reported serious infusion-related or infectious adverse effects of rituximab. Conclusions: Rituximab is effective and safe as a second-line immunotherapy for ALE, regardless of autoantibody status. Additional monthly rituximab therapy might potentiate the efficacy of rituximab. Classification of evidence: This study provides Class IV evidence that rituximab improves mRS scores for patients with autoimmune limbic encephalitis who fail first-line therapy.

Anti‐LGI1 Encephalitis is Associated with Unique HLA Subtypes

Autoimmune encephalitis (AE), represented by anti–leucine‐rich glioma‐inactivated 1 (anti‐LGI1) and anti–N‐methyl‐D‐aspartate receptor (anti‐NMDAR) encephalitis, has increasing clinical significance based on recent discoveries of neuronal autoantibodies. However, its immunopathogenesis is not fully understood. Here, we investigated whether AE is associated with the human leukocyte antigen (HLA) subtypes.

Induction of burst suppression or coma using intravenous anesthetics in refractory status epilepticus

General anesthetic-induced coma therapy has been recommended for the treatment of refractory status epilepticus (RSE). However, the influence of electroencephalographic (EEG) burst suppression (BS) on outcomes still remains unclear. This study investigated the impact of intravenous anesthetic-induced BS on the prognosis of RSE using a retrospective analysis of all consecutive adult patients who received intravenous anesthetic treatment for RSE at the Seoul National University Hospital between January 2006 and June 2011. Twenty-two of the 111 episodes of RSE were enrolled in this study. Of the 22 RSE patients, 12 (54.5%) were women and 18 (81.4%) exhibited generalized convulsive status epilepticus. Sixteen patients (72.7%) were classified as having acute symptomatic etiology, including three patients with anoxic encephalopathy, and others with remote symptomatic etiology. Only two patients (9.1%) had a favorable Status Epilepticus Severity Score (0-2) at admission. All patients received midazolam (MDZ) as a primary intravenous anesthetic drug for RSE treatment; three (13.6%) received MDZ and propofol, and one (4.5%) received MDZ and pentobarbital. The rates of mortality and poor outcome at discharge were 13.6% (n=3) and 54.5% (n=12), respectively. While BS was achieved in six (27.5%) patients, it was not associated with mortality or poor outcome. Induced BS was associated with prolonged hospital stay in subgroup analysis when excluding anoxic encephalopathy. Our results suggest that induction of BS for treating RSE did not affect mortality or outcome at discharge and may lead to an increased length of hospital stay.

New feasible treatment for refractory autoimmune encephalitis: Low-dose interleukin-2

Low-dose interleukin-2 (IL-2) restores the balance of regulatory and effector T cells. We aimed to determine the feasibility of low-dose IL-2 as a treatment for refractory autoimmune encephalitis (AE). Ten patients who had received low-dose IL-2 were retrospectively identified. We observed an improvement in the modified Rankin Scale scores of six patients at the last follow-up compared with the scores at the initiation of low-dose IL-2 (p=0.014). One patient experienced treatment-related grade 3 neutropenia. Overall, low-dose IL-2 is a feasible and relatively safe treatment for AE patients who are refractory to the first- and second-line immunotherapies.

Mefloquine improved progressive multifocal leukoencephalopathy in a patient with immunoglobulin A nephropathy

We describe a patient with immunoglobulin A nephropathy who was diagnosed with progressive multifocal leukoencephalopathy (PML) and successfully treated with mefloquine, an antimalarial medication. A 67-year-old man with immunoglobulin A nephropathy presented to the hospital emergency room with fever and generalized tonic-clonic seizure. Cerebrospinal fluid (CSF) nested polymerase chain reaction (PCR) was positive for John Cunningham virus and brain MRI displayed high signal intensity in the white matter in the right parietal lobe without gadolinium enhancement. Tapering of prednisone did not arrest the disease progression and a new lesion was detected on the cerebellum. Administration of mefloquine stopped lesion progression and resulted in dramatic clinical improvement. The CSF nested PCR for the John Cunningham virus also became negative. In reviewing the literature, mefloquine has had a heterogeneous effect in PML patients, and P-glycoprotein polymorphism and proper dosage could contribute to the various effects seen. Mefloquine may be a favorable treatment option in some patients with PML, and P-glycoprotein polymorphism may play an important role in its efficacy. More large studies in other ethnic groups including polymorphism studies for the gene encoding P-glycoprotein (ABCB1/MDR1) and taking into account various underlying conditions with secondary immunosuppression should be carried out to investigate whether mefloquine is effective for treating PML.

Frequent rhabdomyolysis in anti-NMDA receptor encephalitis

The aim of this study was to analyze the clinical presentation and provocation factors of rhabdomyolysis in anti-NMDAR encephalitis. Among the 16 patients with anti-NMDAR encephalitis in our institutional cohort, nine patients had elevated CK enzyme levels and clinical evidence of rhabdomyolysis. Rhabdomyolysis was more frequent after immunotherapy. The use of dopamine receptor blocker (DRB) increased the risk of rhabdomyolysis. None of the patients without rhabdomyolysis received DRBs. Rhabdomyolysis is a frequent complication in anti-NMDAR encephalitis and more common after immunotherapy and the use of DRBs increases the risk. Therefore, DRBs should be administered carefully in patients with anti-NMDAR encephalitis.

Mega-dose phenobarbital therapy for super-refractory status epilepticus

AIMS To evaluate the efficacy and safety of mega-dose phenobarbital (MDPB; enteral or parenteral phenobarbital >10 mg/kg/day) for treating super-refractory status epilepticus (SRSE; continuous or recurrent status epilepticus for ≥24 hours after the onset of continuous anaesthetic treatment) in adult patients. METHODS Adult patients with SRSE who were treated with MDPB in our institution from March 2005 to September 2014 were reviewed. We collected data on basic demographics, clinical features, functional status, anticonvulsant treatment, and possible adverse events. SRSE outcome was divided into six categories: successful therapy, initial failure, breakthrough seizures, withdrawal seizures, intolerable side effects, and death during treatment. RESULTS Ten adult patients with SRSE received MDPB. Median age at seizure onset was 38 years (range: 18-59), and half were male. All patients had no history of seizures and had symptoms suggestive of viral encephalitis. Median duration of status epilepticus was 17.5 days (range: 6-60) and anaesthetics were used for a median of 14.0 days (range: 2-54) before MDPB. Successful control of SRSE was achieved in half of the patients, however, only one of ten patients was able to fully recover at discharge. Median duration of the MDPB was 45.5 days and the maximum serum phenobarbital level reached a median of 151.5 μg/ml. Patients with successful MDPB therapy had normal brain imaging (80% vs. 0%; p=0.048) and better functional outcome at discharge and after three months of follow-up. Infection was the most critical complication, along with cardiorespiratory depression. CONCLUSION MDPB is a therapeutic option for control of SRSE when other choices are exhausted.

Safety of tianeptine use in patients with epilepsy.

Depression is a frequent comorbidity in patients with epilepsy (PWE). However, it is often undertreated because of concerns of seizure exacerbation by antidepressant treatment. The effect of tianeptine on seizure frequency is not known as yet. Thus, we aimed to evaluate the influence of tianeptine on the seizure frequency in PWE. We retrospectively reviewed the medical records of PWE who received tianeptine between January 2006 and June 2013 at the Epilepsy Center of Seoul National University Hospital. Patients were excluded if the dose or type of antiepileptic drugs (AEDs) they took was altered at the start of tianeptine treatment or if the treatment period of tianeptine was <3 months. A total of 74 PWE were enrolled in our study (male: 32, mean age: 41.9±14.5). Sixty-nine patients had localization-related epilepsy, and 5 had idiopathic generalized epilepsy (IGE). Mean seizure frequency during the 3-month period just after tianeptine exposure was compared with the baseline seizure frequency, which showed no change in 69 (93.2%) patients, decrease in 2 (2.7%) patients, and increase in 3 patients (4.1%). The type of epileptic syndrome, the baseline seizure frequency, and the number of coadministered AEDs did not influence the change in seizure frequency after tianeptine prescription. Change in seizure frequency did not differ between the patients given tianeptine as an additive antidepressant and those given tianeptine as a replacement antidepressant. Our data suggest that tianeptine can be prescribed safely to PWE with depression without increasing the seizure frequency regardless of the baseline severity of epilepsy. Tianeptine may be actively considered as a first-choice antidepressant or as an alternative antidepressant in PWE with depression.

An illustrative case of mixed pesticide poisoning with remarkable improvement: A case report

The World Health Organization reported that pesticide selfpoisoning is the most important method of suicide worldwide [1,2]. Among pesticides, organophosphate compounds and pyrethroids induce neuronal excitotoxicity in the central nervous system and wide spectrum of symptoms [3,4]. We report a case of pesticide selfpoisoning where the patient initially presented with encephalopathy but showed excellent improvement. A 55-year-old female was found unconscious after she ingested 300 ml of pesticide which was formulated with organophosphate and synthetic pyrethroid (10% of chlorpyrifos and 1% of alphacypermethrin) in a suicide attempt. She had suffered from hepatitis B-induced liver cirrhosis and underwent living-donor liver transplantation 1 month prior to the suicide attempt. She was referred to the local hospital, where gastric lavage was performed and activated charcoal was administered. Her mental status improved, but she was still drowsy and suffered from excess salivation and diarrhea. She was intubated for airway support while continuous intravenous midazolam (4 mg/h), vecuronium (4 mg/h) and intravenous atropine (1 mg/h) with pralidoxime (8 mg/[kg·h]) infusion was concurrently started. Three days later, salivation was dried up and midazolam and vecuronium tapering were started. Whether other features of cholinergic toxicity were present at this time was not recorded. After discontinuation of midazolam and vecuronium, a brief generalized tonic–clonic seizure lasting a few seconds occurred. A brain MRI revealed massive cerebral edema andwhitematter changes visible on diffusionweighted (DWI) and T2 sequence (Fig. 1) images. The next day, the patient experienced 5 convulsive seizures. After administration of anti-epileptic drugs (Levetiracetam 2000 mg daily, Pregabalin 300 mg daily, Topiramate 200 mg daily and Phenytoin 300 mg daily), she remained seizure-free. Although her mental status and other symptoms improved, several days later she complained of memory impairment, insomnia, dysphagia, and gait difficulties. Follow-up images taken 2 weeks later showed remarkably decreased edema and lesswhitematter lesions (Fig. 1). Twomonths after symptomonset, the patientwas able to ambulate by herself and had no difficulty eating. In the 5 years after her attempted suicide, she has only experienced mild short-term memory disturbances, and reports no problems in daily living. Annually, 250,000–370,000 people die of pesticide poisoning [1, 5], which is especially problematic in rural areas of developing