anti - nmda receptor encephalitis ( anre ) is a recently recognized form of paraneoplastic encephalitis and characterized by dyskinesias , psychosis , and seizures secondary to antibodies to the nr1nr2b heteromer of the nmda receptor , . seizures are present in approximately three - fourths of all patients , , with a few reports of convulsive status epilepticus ( se ) in adults . however , anre , as a cause of generalized ncse , is extremely rare , with 2 cases having been reported so far in the literature , . status epilepticus secondary to anre is thought to respond less favorably than se caused by any other etiologies . vagus nerve stimulation ( vns ) is generally considered as a palliative treatment for patients with drug - resistant partial - onset epilepsy . however , its role in the management of refractory se has been previously reported in few case reports both in adults and in children and in a very few case series , , . here , we report a case of refractory ncse , secondary to anre that was terminated after vagus nerve stimulator implantation . a previously healthy 46-year - old right - handed man was admitted to the psychiatry ward after a one - week history of mild fever , behavioral changes , headaches , and reported facial twitches . his neurological status continues to deteriorate , with reported episodes of lip smacking and facial twitches . the neurology team was consulted , and a lumbar puncture ( lp ) was suggested . the cerebrospinal fluid ( csf ) analysis showed elevated white count of 521 per microliter , 98% lymphocytes , elevated protein of 51/dl , and a normal glucose level . polymerase chain reaction for the following viruses and bacteria were negative : herpes simplex virus i and ii , varizella zoster virus , human herpes virus 6 , cytomegalovirus , epstein a diagnosis of encephalitis was made , and he was started on acyclovir , ceftriaxone , and vancomycin . his initial eeg showed intermitted slowing of delta range over both frontocentral head regions with faster frequency superimposed representing extreme delta brush ( fig .  1 ) . the mri of the brain with and without contrast was reported as normal . however , his neurological status has worsened , and he started to desaturate . he was transferred to the icu where the neurology team was called to reevaluate him . continuous eeg recording ( ceeg ) was advised , and it showed a rhythmical slowing over both frontocentral head regions with a clear evolution in voltage , frequency , and field consistent with nonconvulsive status epilepticus ( ncse ) ( fig .  2 ) . this evolution of the eeg pattern became more apparent when the eeg was compressed ( fig . two days later , he continued to have facial twitches , and his ceeg was still showing electrical se pattern . levetiracetam was loaded and continued on a titrating dose of up to 2000  mg twice per day and on phenytoin with a titrating dose of 350  mg / day , with close drug level monitoring , followed in 2  days by a loading dose of valproic acid . four days later , he continued to have episodes of facial twitches and lip smacking , and ceeg was still showing the previously reported pattern . the epilepsy team was consulted and they advised loading with propofol which was titrated up to 50  mg / h . however , every attempt to decrease the propofol would result in worsening facial twitches and , in a number of occasions , breakthrough tonic  clonic seizures . anti - nmda receptor in the serum was requested , and an extensive search for a tumor was recommended but did not reveal any pathology . while waiting for the results of anti - nmda receptor antibodies , ivig was given over a 5-day course , along with a pulse of steroids . however , breakthrough electrical se was still apparent every time the level of suppression is reduced , and midazolam was restarted and titrated up to 12  mg / h . over several weeks , his neurological status had not changed . topiramate was added and titrated over 2  days to a dose of 200  mg twice per day . still , his ceeg was showing se pattern , and he continued to have facial twitches . he also continued on a combination of high doses of levetiracetam 4  g / day , topiramate 400  mg / day , phenytoin 400  mg / day , valproic acid 3000  mg / day , clonazepam 5  mg/8  h , and phenobarbital 200  mg / day . a week later , his neurological status had not changed , and every attempt to reduce his anesthetics would result in recurrent clinical and electrical seizures . while in the icu , his dose of phenobarbital was increased up to 150  mg twice per day , and he continued on propofol and midazolam . he was also tried on iv ketamine , but his neurological status remained the same , and he continued to show the se pattern when the level of sedation is reduced . the result of anti - nmda receptor antibodies came back positive and a repeat course of ivig was recommended over a 4-day duration , 2  weeks after the first ivig course was completed . however , his neurological status has not changed , and he remained in ncse for 110  days , and a decision was made , after extensive discussions with the patient 's family , to try vns . a vagus nerve stimulator was implanted and interrogated to an output current of 2.5  ma over 4  days . his duty cycle was set at 30  s on and 5  min off . after 1  week of vagus nerve stimulator implantation , midazolam was weaned off successfully over 3  days and followed 4  days later by a weaning off propofol without any clinical or electrical seizure recurrences . his neurological status continued to improve in the succeeding months with no reported clinical seizures . the dosages of antiepileptic drugs ( aeds ) were gradually reduced one at a time . he was discharged from the hospital after 8  months of rehabilitation on no aeds with mild  moderate cognitive impairment . our case is typical in many respects of the anre syndrome , with a prodrome of headaches , fever , and confusion that progressed rapidly to prolonged ncse . a recently reported case series attempted to differentiate male anre from female anre and suggested that male patients , similar to our case , present with early seizures , whereas behavioral changes are more common as an early manifestation in female patients . seizures are a common feature of anre , ,   and occur in more than two - thirds of patients ( 76/100 ) in a recently published large series . a few refractory cases of se as a result of anre have been reported ; however , their details were not specified . thus , the occurrence of refractory se seems to be an uncommon presentation of anre . in general , prolonged ncse carries a poor prognosis , with a mortality rate of 56% . in our case , the rhythmic slow waves of cyclically evolving activity in frequency and spatial distribution , support the diagnosis of ncse . furthermore , this pattern 's response to high - dose midazolam and its recurrences after reduction of the dosage further support that diagnosis . there are 2 reported cases in the literature of ncse in adults with anti - nmda receptor encephalitis , including a 35  year old with refractory generalized ncse and underlying ovarian teratoma   and a 19  year old with generalized ncse and mediastinal teratoma . rituximab is not available in our institution , and cyclophosphamide was not tried because the patient 's family was afraid of its toxic side effects . however , our patient 's neurological status was refractory to the 2 courses of ivig therapy and to a high - dose methylprednisolone . furthermore , the lack of association with a tumor etiology in our case , unlike females with this syndrome , is similar to previously reported studies describing a low frequency of paraneoplastic etiology in the male population with this syndrome , accounting for 3% to 15% of cases  , . nonconvulsive status epilepticus in our patient was highly resistant to aeds and anesthetic agents , and responded only after the implantation of a vagus nerve stimulator . to our knowledge , this is the first reported case of refractory ncse as result of anre that responded to vns . vagus nerve stimulation has been found to be effective to terminate se in several case reports . more recently , a well - described study of eight patients with recurrent se in spain reported a significant improvement of seizures after vns , with four of the eight patients remaining free of new episodes of se after implantation , and in two additional patients , the frequency decreased by >  75% . it is not clear why vns was successful in acutely terminating se in our patient , when the other agents that are typically used to terminate se have failed . the precise mechanism of action of vns as a neuromodulatory treatment for epilepsy is still unknown , but its efficacy seems mainly based on an incremental effect . on the other hand , early animal experiments described an abortive effect of vns in acute seizure models . as a treatment modality for both chronic and acute epilepsy , several recent clinical and functional neuroimaging studies have demonstrated that vns induces an increase of cerebral blood flow ( cbf ) in several subcortical regions , mainly the thalamus , the hypothalamus , the insula , and the cerebellum , , . it is likely that the alteration of transsynaptic neurotransmission related to the bilateral thalamic cbf modification results in the inhibition of the corticothalamic relays , through a synaptic depolarization shift . recently , it has been suggested that a possible role of the vagus nerve is controlling and modulating inflammatory responses . patients subjected to 6  months of vns therapy for refractory epilepsy showed significant lower levels in il-8 induction by lipopolysaccharide - stimulated peripheral blood mononuclear cells . this altered cytokine response after long - term vns could be implied in the efficacy of this therapy to reduce the frequency of seizures and se , based on the hypothesis that brain inflammation plays a role in the mechanisms of hyperexcitability occurring during repetitive or prolonged seizures . finally , the natural course of the patient 's illness can not be excluded as the cause of remission . however , refractory se is rarely reported to improve spontaneously . it is also possible that the response to vns might be as a result of delayed response from immunotherapy . this possibility seems very unlikely given the long lag between our patient 's second dose of ivig and his clinical and electrical improvement . in most cases of anre , the response to immunotherapy occurs within weeks and , very rarely , after several months of treatment , and in most cases following resection of the culprit tumors . it may also be hypothesized that in our case , vns may have exerted its acute seizure effect through a direct or indirect effect on the nmda receptor modulations in various brain lesions including the hippocampus and forebrain that are known to be rich in nmda . interestingly , an animal model of absence seizures shows increased expression of nmda receptors in the thalamus , and drugs that block nmda in the thalamus were shown to have antiseizure effect in that model . it is likely that vns , through its modulating effect in the thalamus , modulates these receptors ; hence , this may explain its acute seizure effects . this case illustrates the need to consider anti - nmda receptor encephalitis as a cause of refractory status epilepticus should associated clinical features suggestive of this syndrome be present . additionally , our paper suggests that adult male patients who present with seizures , normal mri , and no clear etiology should be tested for nmda receptor antibodies to avoid any delay in treatment initiation . continuous eeg monitoring is crucial to the diagnosis of ncse and to monitor the effect of various treatment modalities on ictal eeg recordings . we propose that vagus nerve stimulator implantation should be considered in cases of ncse , and possibly , for convulsive se that is resistant to standard pharmacotherapy . future studies are needed to determine the efficacy of vns in this setting and to optimize the timing of device placement and stimulation parameters for similar cases . aedsantiepileptic drugsanreanti - nmda receptor encephalitisceegcontinuous eeg recordingcbfcerebral blood flowcsfcerebrospinal fluid analysisncsenonconvulsive status epilepticusvnsvagus nerve stimulation anti - nmda receptor encephalitis continuous eeg recording cerebrospinal fluid analysis nonconvulsive status epilepticus vagus nerve stimulation
anti - nmda receptor encephalitis ( anre ) has been previously reported as a rare cause of nonconvulsive status epilepticus ( ncse ) . 
 vagus nerve stimulation ( vns ) is generally considered as a palliative treatment for patients with drug - resistant partial - onset epilepsy . here 
 , we report a case of refractory ncse that was terminated after vagus nerve stimulator implantation . to our knowledge , 
 similar cases have not been reported previously .