ten children with a clinical and/or radiologic evidence of white matter involvement were identified from a cohort of 46 pediatric patients , 18 years of age and younger , with a range of nmdar - abs  associated neurologic syndromes . between 2009 and 2013 ,
patients were referred , based on clinician decision , from 6 pediatric neurology centers to the clinical neuroimmunology service at the oxford radcliffe hospital trust for serum and/or csf nmdar antibody testing and/or advice on further antibody testing . as antibodies to myelin oligodendrocyte glycoprotein ( mog ) and aquaporin-4 ( aqp4 )
have been associated with demyelinating disorders , sera from all 10 cases and the other 36 nmdar - ab  positive patients were tested for both these antibodies .
nmdar , aqp4 , and mog antibodies were measured using cell - based assays in routine clinical use ( sera at 1:20 dilution for nmdar and aqp4 and 1:160 for mog ; csf at 1:2 dilution for nmdar ) as previously described .
for these cell - based assays , the binding of serum immunoglobulin g to the surface of human embryonic kidney cells , transfected with complementary dna encoding the auto - antigens ( mog courtesy of m. reindl , innsbruck ) , was visualized using a fluorescence - labeled alexafluor 568 secondary antibody ( molecular probes , eugene , or ) , and the results were assessed by at least 2 independent observers ( y.h . ,
the outcomes , as measured by the range of difficulties the patients were experiencing , were retrieved from the patient 's medical records or , if unavailable , were obtained directly from the patient 's primary pediatric neurologist .
full recovery was defined by the absence of medical , educational , and social concerns reported from parents , school , and the patient 's primary clinician . ethical approval for
ethical approval for this study was from the oxfordshire regional ethical committee a ( 07/q1604/28 ) .
out of a total of 46 patients identified consecutively from 6 centers , 10 patients ( cases 110 ; 5 male ; age range 1.318 years , median 8.5 years ; see table 1 ) were identified with a significant white matter involvement .
they were classified as having 3 neurologic syndromes : brainstem encephalitis ( n = 3 ) , herpes simplex virus encephalitis ( hsve ) relapsing with a distinct leukoencephalopathy ( n = 2 ) , and acquired demyelination syndromes ( ads ) ( n = 5 ) . their clinical features , imaging , and treatment responses are described below and summarized in table 1 and figures 1 and 2 .
the remaining 36 nmdar - ab  positive patients had minimal or absent white matter involvement ; 28 of these had typical nmdar - ab encephalitis ( cases 1138 ; 8 male ; age range 217 years , median 11 years ; see table 2 ) . of the remaining 8 patients , 1 presented with a neurologic relapse following hsve , and
7 had a partial phenotype ( cases 3946 ; 2 male ; age range 118 years , median 11 years ; see table 3 )
. only 1 patient , a 15-year - old girl with classical nmdar - ab encephalitis , had an ovarian teratoma .
nmdar - abs were positive in the csf in 10 of 11 patients tested with typical nmdar - ab encephalitis , in 2 of 3 tested with the partial phenotype , and in all 3 tested with white matter syndromes ; serum levels were higher than csf in all paired samples .
all patients were empirically investigated by their physicians to exclude a range of infective , alternative inflammatory , and neurometabolic etiologies , of which none were identified .
clinical and paraclinical features of 10 nmdar antibody  positive patients with distinct clinicoradiologic white matter syndrome ( a , b ) case 1 , who presented with a brainstem syndrome .
axial t2 fluid - attenuated inversion recovery ( flair ) images showing hyperintensity in the midbrain and mesial temporal lobe ( arrows in a ) , which subsequently resolved on follow - up imaging performed at 2 months when the patient had relapsed with a polysymptomatic encephalopathy ( b ) .
( c , d ) case 2 , who presented initially with a brainstem syndrome followed by periods of recurrent encephalopathy .
axial t2-weighted images 6 months after her initial brainstem syndrome revealed diffuse global cortical atrophy ( c ) .
imaging during an encephalopathic episode 5 years later revealed new white matter changes ( arrow in d ) and further atrophy .
( e  h ) two patients with neurologic syndromes following herpes simplex virus encephalitis ( hsve ) . serial axial t2 flair images of case 4 ( e  g ) showing localized cortical changes in the left thalamus and occipital lobe ( arrows in e ) on initial imaging that progressed , demonstrating significant bilateral white matter signal changes in the parieto - occipital region 2 months later ( arrows in f ) when the patient presented with significant worsening of cognitive , behavioral , and motor regression . following treatment and improvement of symptoms ,
follow - up neuroimaging 2 months later demonstrated a significant resolution of this white matter change ( g ) .
axial t2-weighted image of case 5 at relapse 2 months after hsve showing extensive bilateral but asymmetrical cystic encephalomalacia centered on the temporo - insular regions ( only parietal changes shown ) characteristic of hsve , but in addition demonstrating the characteristic leukoencephalopathic changes seen globally ( arrows in h ) .
at time of relapse with left optic neuritis , brain imaging in case 8 showed subtle periventricular white matter signal change on a t2-weighted image ( arrow demonstrating one periventricular lesion in i ) .
imaging of case 9 showing midbrain ( arrow in j ) , capsular ( arrow in k ) , and thalamic changes ( not shown ) on axial t2 flair .
axial t2 flair image of case 10 demonstrating patchy subcortical white matter changes ( l ) .
( a  c ) cases 13 presented initially with brainstem encephalitis ; cases 1 and 2 relapsed with encephalopathy , psychiatric features , movement disorder , and dysautonomia .
case 3 had a monophasic illness and did not have any of the clinical characteristics of nmdar - ab encephalitis .
( d , e ) cases 4 and 5 presented with herpes simplex virus encephalitis ( hsve ) and then had a neurologic relapse , which correlated with raised nmdar - abs in both serum and csf and demonstrated a clinical response to immunotherapy with reduction of antibody levels . ( f )
case 8 presented with optic neuritis and poor visual recovery , which prompted a neuroinflammatory screen and the identification of the antibody positivity .
she only received a course of steroids 1 year into her illness and 3 years later had a neurologic relapse .
( g ) case 9 presented initially with 2 episodes of acute disseminated encephalomyelitis ( adem ) and relapsed at 1 year with optic neuritis .
he was also mog - ab positive , which remain detectable even when nmdar - abs are no longer detectable and when the patient had clinically recovered .
( h ) case 10 had recurrent episodes of hyperventilation , dizziness , and double vision ; did not receive any treatment ; and both her clinical and radiologic features remained unchanged .
ab = antibody ; csf ab  10 = nmdar antibody titers in csf ( all between 1:20 and 1:50 ) multiplied by 10 to provide visibility in comparison to serum levels ; ivig = iv immunoglobulin ; ivmp = iv methylprednisolone ; leukoe = radiologic leukoencephalopathy ; lt = left ; mmf = mycophenolate mofetil ; nmdar = nmda receptor ; on = optic neuritis ; plex = plasma exchange ; rt = right ; serum ab titer = titer measured by endpoint dilution . clinical and paraclinical features in patients with nmdar - ab encephalitis clinical and paraclinical features of 8 patients with atypical nmdar - ab
 mediated cns disorder three patients had encephalopathy , predominant brainstem signs ( cranial neuropathies and ataxia ) , and neuroimaging findings of brainstem abnormalities , or a clinical syndrome unequivocally localized to the brainstem .
case 1 ( m , age 18 ) had brainstem changes at presentation ( figure 1a ) but evolved to a polysymptomatic encephalopathy , with resolution of the brainstem changes ( figure 1b ) .
nmdar - abs were only detected a year later after a relapse but fell with immunotherapies with a good clinical response ( figure 2a ) .
case 2 ( f , age 10 ) presented 3 weeks after first symptoms when her encephalopathy worsened with intractable seizures , movement disorder , and hyperpyrexia .
she had recurrent periods of encephalopathy ( figure 2b ) associated with radiologic features of a leukoencephalopathy ( figure 1d ) that progressed over the following 5 years ( figure 2b ) , when serum and csf nmdar - abs were first identified .
case 3 ( m , age 5 ) , the most recent patient , presented with brainstem signs and cranial nerve enhancement ; nmdar - abs were identified within a few weeks of onset .
he made a full recovery with steroids and plasma exchange ( plex ) ( figure 2c ) .
since we and others recognized a relationship between hsve relapses and nmdar - abs , we have identified 2 additional patients , cases 4 and 5 ( m , age 2 ; f , age 16 months ) , with nmdar - abs in serum and csf ( table 1 ) during neurologic relapses with substantial leukoencephalopathy on imaging ( figure 1 , e  h ) occurring within 2 months of hsve ( headache , fever , seizures , typical imaging , and csf herpes simplex virus [ hsv ] pcr positivity ) . case 4 presented with cognitive , behavioral , and motor decline , and case 5 presented with a further encephalopathic illness with new - onset movement disorder .
both were treated with iv immunoglobulin ( ivig ) or plex , which resulted in clinical improvement and reduction of nmdar - ab titers ( figure 2 , d and e ) .
five patients presented with ads classified according to the international pediatric ms study group criteria .
case 6 ( f , age 6 ) and case 7 ( m , age 9 ) , with bilateral optic neuritis , were treated with iv methylprednisolone followed by a weaning course of oral prednisolone .
case 8 ( f , age 11 ) presented with right optic neuritis and poor visual recovery ; she only received a course of oral steroids 1 year later and relapsed 3 years later with left optic neuritis and new brain lesions ( figures 1i and 2f ) .
case 9 ( m , age 8) presented with adem , relapsed at 1 month with a second encephalopathic illness and imaging evidence of new brainstem lesions ( figure 1j ) , and developed right and left optic neuritis at 12 and 13 months , respectively . at this stage , he was treated with mycophenolate mofetil with good visual recovery , no further relapse , and a reduction in nmdar - ab levels ( figure 2 g ) .
case 10 ( f , age 10 ) had an unusual presentation of recurrent episodes of hyperventilation , dizziness , and double vision lasting from 2 days to more than 2 weeks ( figure 2h ) .
she has not been treated as the relevance of the nmdar - ab in her clinical and radiologic syndrome remains unclear .
the mean follow - up time in the cohort was 34 months ( median 30 , range 860 ) , and this was not significantly different between the patients with white matter syndromes ( mean 27 , median 30 , range 854 ) and the other patients with nmdar - abs ( mean 36 , median 37 , range 860 ) .
overall in the white matter patients , 6 of the 7 patients ( 85% ) who were treated acutely improved following immunotherapy with steroids , ivig , and plex , either individually or in combination . at relapse ,
patients who were treated late ( n = 2 ) or untreated ( n = 1 ) had either a poorer outcome or persistence of symptoms . in 6 of the 7 patients with serial samples available , there were relationships between nmdar - ab titers and severity of clinical syndrome ( figure 2 , a 
mog antibodies did not disappear after treatment in case 9 , even when nmdar - abs became undetectable and after clinical recovery ( figure 2 g ) .
serum levels of nmdar - abs ranged from 1:100 to 1:1,000 at the earliest sample available , with csf levels ( cases 25 ) from 1:20 to 1:50 .
it is important that both serum and csf nmdar - ab titers were negative during the hsve that preceded nmdar - ab relapse in case 4 ( figure 2d ) ; the relevant samples were not available for case 5 .
after immunotherapies , antibody levels fell in all patients and became undetectable in cases 1 , 3 , 8 , and 9 .
mog antibodies were found in only 3 of the 5 patients with ads ( cases 6 , 7 , and 9 ) ( table 1 ) .
cases 110 presented with distinct white matter changes , either radiologic changes compatible with the respective clinical syndromes ( brainstem encephalitis and ads group ) or a leukoencephalopathy in addition to the radiologic changes commonly observed within the relevant phenotype ( brainstem encephalitis and hsve ) .
these patients were radiologically distinct from the nmdar - ab encephalitis cases ( table 1 ) , where only 6 of 28 ( 21% ) had abnormal neuroimaging , all sparing the white matter ( p < 0.0001 , fisher exact test ) .
although 3 patients had classical nmdar encephalitis , in cases 1 and 2 , these episodes were remote from the first neurologic syndrome ( brainstem encephalitis ) , and in case 5 , the nmdar - ab encephalitis occurred following hsve .
in addition , 7 of the 10 cases ( 70% ) had recurrent neurologic episodes , compared to only 6 of 28 patients ( 21% ) with typical nmdar - ab encephalitis or 10 of 36 cases ( 28% ) without white matter involvement ( p = 0.003 and 0.02 , respectively ; fisher exact test ) .
oligoclonal bands were positive in the csf in 1 of 3 patients tested with white matter disorder compared to 14 of 18 with typical nmdar - ab encephalitis , although this was not statistically significant ( p = 0.18 , fisher exact test ) .
finally , those patients with white matter disorders were more likely to have mog antibodies ( 30% vs 0% ; p = 0.008 , fisher exact test ) than those without white matter involvement .
three patients had encephalopathy , predominant brainstem signs ( cranial neuropathies and ataxia ) , and neuroimaging findings of brainstem abnormalities , or a clinical syndrome unequivocally localized to the brainstem .
case 1 ( m , age 18 ) had brainstem changes at presentation ( figure 1a ) but evolved to a polysymptomatic encephalopathy , with resolution of the brainstem changes ( figure 1b ) .
nmdar - abs were only detected a year later after a relapse but fell with immunotherapies with a good clinical response ( figure 2a ) .
case 2 ( f , age 10 ) presented 3 weeks after first symptoms when her encephalopathy worsened with intractable seizures , movement disorder , and hyperpyrexia .
she had recurrent periods of encephalopathy ( figure 2b ) associated with radiologic features of a leukoencephalopathy ( figure 1d ) that progressed over the following 5 years ( figure 2b ) , when serum and csf nmdar - abs were first identified .
case 3 ( m , age 5 ) , the most recent patient , presented with brainstem signs and cranial nerve enhancement ; nmdar - abs were identified within a few weeks of onset .
he made a full recovery with steroids and plasma exchange ( plex ) ( figure 2c ) .
since we and others recognized a relationship between hsve relapses and nmdar - abs , we have identified 2 additional patients , cases 4 and 5 ( m , age 2 ; f , age 16 months ) , with nmdar - abs in serum and csf ( table 1 ) during neurologic relapses with substantial leukoencephalopathy on imaging ( figure 1 , e  h ) occurring within 2 months of hsve ( headache , fever , seizures , typical imaging , and csf herpes simplex virus [ hsv ] pcr positivity ) .
case 4 presented with cognitive , behavioral , and motor decline , and case 5 presented with a further encephalopathic illness with new - onset movement disorder .
both were treated with iv immunoglobulin ( ivig ) or plex , which resulted in clinical improvement and reduction of nmdar - ab titers ( figure 2 , d and e ) .
five patients presented with ads classified according to the international pediatric ms study group criteria .
case 6 ( f , age 6 ) and case 7 ( m , age 9 ) , with bilateral optic neuritis , were treated with iv methylprednisolone followed by a weaning course of oral prednisolone .
case 8 ( f , age 11 ) presented with right optic neuritis and poor visual recovery ; she only received a course of oral steroids 1 year later and relapsed 3 years later with left optic neuritis and new brain lesions ( figures 1i and 2f ) .
case 9 ( m , age 8) presented with adem , relapsed at 1 month with a second encephalopathic illness and imaging evidence of new brainstem lesions ( figure 1j ) , and developed right and left optic neuritis at 12 and 13 months , respectively . at this stage , he was treated with mycophenolate mofetil with good visual recovery , no further relapse , and a reduction in nmdar - ab levels ( figure 2 g ) .
case 10 ( f , age 10 ) had an unusual presentation of recurrent episodes of hyperventilation , dizziness , and double vision lasting from 2 days to more than 2 weeks ( figure 2h ) .
she has not been treated as the relevance of the nmdar - ab in her clinical and radiologic syndrome remains unclear .
the mean follow - up time in the cohort was 34 months ( median 30 , range 860 ) , and this was not significantly different between the patients with white matter syndromes ( mean 27 , median 30 , range 854 ) and the other patients with nmdar - abs ( mean 36 , median 37 , range 860 ) .
overall in the white matter patients , 6 of the 7 patients ( 85% ) who were treated acutely improved following immunotherapy with steroids , ivig , and plex , either individually or in combination . at relapse ,
patients who were treated late ( n = 2 ) or untreated ( n = 1 ) had either a poorer outcome or persistence of symptoms . in 6 of the 7 patients with serial samples available , there were relationships between nmdar - ab titers and severity of clinical syndrome ( figure 2 , a 
mog antibodies did not disappear after treatment in case 9 , even when nmdar - abs became undetectable and after clinical recovery ( figure 2 g ) .
serum levels of nmdar - abs ranged from 1:100 to 1:1,000 at the earliest sample available , with csf levels ( cases 25 ) from 1:20 to 1:50 .
it is important that both serum and csf nmdar - ab titers were negative during the hsve that preceded nmdar - ab relapse in case 4 ( figure 2d ) ; the relevant samples were not available for case 5 .
after immunotherapies , antibody levels fell in all patients and became undetectable in cases 1 , 3 , 8 , and 9 .
mog antibodies were found in only 3 of the 5 patients with ads ( cases 6 , 7 , and 9 ) ( table 1 ) .
cases 110 presented with distinct white matter changes , either radiologic changes compatible with the respective clinical syndromes ( brainstem encephalitis and ads group ) or a leukoencephalopathy in addition to the radiologic changes commonly observed within the relevant phenotype ( brainstem encephalitis and hsve ) .
these patients were radiologically distinct from the nmdar - ab encephalitis cases ( table 1 ) , where only 6 of 28 ( 21% ) had abnormal neuroimaging , all sparing the white matter ( p < 0.0001 , fisher exact test ) .
although 3 patients had classical nmdar encephalitis , in cases 1 and 2 , these episodes were remote from the first neurologic syndrome ( brainstem encephalitis ) , and in case 5 , the nmdar - ab encephalitis occurred following hsve .
in addition , 7 of the 10 cases ( 70% ) had recurrent neurologic episodes , compared to only 6 of 28 patients ( 21% ) with typical nmdar - ab encephalitis or 10 of 36 cases ( 28% ) without white matter involvement ( p = 0.003 and 0.02 , respectively ; fisher exact test ) .
oligoclonal bands were positive in the csf in 1 of 3 patients tested with white matter disorder compared to 14 of 18 with typical nmdar - ab encephalitis , although this was not statistically significant ( p = 0.18 , fisher exact test ) .
finally , those patients with white matter disorders were more likely to have mog antibodies ( 30% vs 0% ; p = 0.008 , fisher exact test ) than those without white matter involvement .
three distinct white matter clinicoradiologic syndromes  brainstem encephalitis , leukoencephalopathy following hsve , and cns demyelination  were identified in 10 of 46 ( 22% ; 95% confidence interval 11%36% ) consecutive children from 6 centers in the uk in whom nmdar - abs were detected .
the antibodies were present at high titers ( up to 1:1,000 ) , and all available csfs were positive ( up to 1:50 ) .
collectively , relapses were seen in 63% ( 5/8 ) of our cohort ( excluding the 2 hsve cases ) , a rate higher than that seen in our classical nmdar encephalitis patients ( 28% ; 6/28 ) or than previously reported .
this included 2 of the 3 patients with brainstem encephalitis , usually a monophasic disease , and 3 of the 5 patients ( 60% ) in the ads group , in which relapses are seen in 25% of patients .
nevertheless , there was a good response to immunotherapies once the antibodies were detected , and improvement broadly paralleled serum nmdar - ab levels over the following months .
it is well known that antibodies can diffuse into the area postrema , as in neuromyelitis optica , and other brainstem regions may also be permeable , as inferred recently from rodent studies . however , although brainstem encephalitis is assumed to be due to autoimmune and inflammatory etiologies , no disease - defining autoantibodies have been defined to date .
brainstem encephalitis does share clinical features with nmdar - ab encephalitis , and it was suggested that one of the original reported cases of bickerstaff brainstem encephalitis had features of nmdar - ab encephalitis .
hypoventilation , probably due to disruption of the medullary - pontine respiratory network and leading to ventilator dependency despite the improvement of the encephalopathy , was seen in case 3 .
typically , however , brainstem involvement in nmdar - ab encephalitis manifests as autonomic symptoms such as hyperthermia , blood pressure liability , arrhythmias , hypersalivation , and urinary incontinence , and is usually seen more frequently in adults than in children .
distinct episodes of classical nmdar - ab encephalitis were observed in 2 of the 3 patients with brainstem encephalitis .
although the nmdar - ab positivity in both cases ( cases 1 and 2 ) could only be determined in sera taken during relapses , when they were polysymptomatic , the identification of nmdar - abs ( serum and csf ) in case 3 during the acute phase of brainstem encephalitis suggests that the initial brainstem event in all 3 patients could represent a localized form of nmdar - ab  mediated brainstem inflammation . early and optimal treatment , as in case 3 , may prevent the subsequent evolution to a more generalized nmdar - ab encephalitis .
there have been recent reports that nmdar - abs , often with choreoathetosis , can be identified before and/or during neurologic relapses following hsve .
the distinct white matter changes seen in both the hsve relapse patients ( figure 1 , e  h ) are atypical for nmdar encephalitis , although we have previously described this radiologic feature in 1 child who relapsed following hsve , and these striking leukoencephalopathic changes were also evident in a patient in the brainstem encephalitis group ( case 2 , figure 1 , c and d ) . following immunotherapy , both patients with hsve improved clinically , and , in the 1 patient imaged after treatment , significant radiologic improvement was demonstrated .
the relevance of leukoencephalopathy in these syndromes requires further evaluation ; its detection by mri could be a useful biomarker for patients at risk of relapses after hsve or brainstem encephalitis , with obvious treatment implications .
there is a growing interest in the role of cns antibodies in demyelination , stemming from the discovery of aqp4 antibodies in neuromyelitis optica and detection of mog antibodies in a range of ads , although the clinical use of mog antibodies as a marker of disease activity and prognosis is still being evaluated . of interest , 3 of the 5 patients in the ads group , 2 with bilateral optic neuritis ( cases 6 and 7 ) and 1 ( case 9 ) who presented with adem followed by recurrent optic neuritis , had antibodies to mog as well as nmdar .
both these demyelinating phenotypes are recognized in children with mog antibodies , suggesting that these antibodies may have contributed to the clinical picture in addition to the nmdar - abs .
an association between nmdar antibodies and cns demyelination has been recognized in individual cases with both monophasic and relapsing syndromes , but it is unknown whether these antibodies are causative or secondary to the demyelination . as nmdars are activated on oligodendrocytes following ischemia , the white matter may be a target for antibodies following prior or recurrent neurologic insults ; this could be the case in our patients who had either a distinct previous neurologic syndrome ( hsve and brainstem encephalitis ) or frequent relapses of demyelination .
furthermore , upregulation of nmda receptor subunits , in particular highly calcium permeable nr2b - containing and magnesium - insensitive nr3a nmdars , appears to increase the vulnerability of the white matter to injuries in the developing brain , and such age - specific nmdar subunit composition could also predispose children with an actively myelinating cns to developing leukoencephalopathies , thus explaining the high rate of white matter involvement in this pediatric nmdar - ab  positive cohort .
experimental studies looking at the role of nmdars in white matter suggest their importance in remyelination and the regenerating optic nerve , which could possibly explain the slow visual recovery seen in cases 6 and 8 ; if they are induced secondary to the demyelination , the nmdar - abs may cause a loss of function and reduce this beneficial response to nerve injury .
it was the leukoencephalopathy , and the less severe but distinct white matter changes , that drew our attention to these patients .
in fact , advanced neuroimaging techniques are starting to identify white matter abnormalities in patients with anti - nmdar encephalitis with no apparent abnormality on conventional imaging , suggesting that perturbations in white matter tracts are more widespread than previously thought .
these could be mediated by direct antibody binding to nmdar on oligodendrocytes , as discussed above , and/or secondary to neuronal glutamate - mediated excitotoxicity .
although the improvement following immunotherapy in our patients with white matter disorders could simply reflect the natural history of these conditions , the poorer outcomes of those untreated or treated later and the parallel reduction or resolution of antibody levels provide evidence that whatever the origins and roles of the nmdar - abs , their removal can be helpful .
only 3 of 10 patients with white matter syndromes had csf available for testing . however , in each of the patients reported here , including the 11 with typical nmdar - ab encephalitis , serum levels were higher than those in the paired csfs . although the added sensitivity of csf nmdar - ab evaluation has recently been reported , whether serum analysis without an available paired csf can result in a 
the definition of a false - positive requires a gold standard clinical diagnosis , which , in the context of an expanding phenotype such as that described here , can not be established .
moreover , since nmdar - abs can remain detected in both serum and csf after the patient has recovered , a positive result does not necessarily reflect  false positivity  but merely that the antibodies are not causing a detectable neurologic syndrome .
our suggestion would be that csf testing , if unavailable initially , should be performed if the serum is negative with a strongly suggestive clinical phenotype or , conversely , can be used to provide further support for the  clinical relevance  of the serum antibodies in patients in whom the clinical features are less typical .
other limitations of this study include the retrospective nature of the cohort collection and the small sample size that is further confounded by the heterogeneous clinical phenotypes .
further studies are now required to confirm our observation that children and adults with nmdar - abs can present with these distinct clinicoradiologic white matter syndromes and to determine whether , and if so how , nmdar - abs bind to white matter , in which patients and clinical syndromes it could be relevant , and the treatment implications .
yael hacohen : acquisition of data , analysis or interpretation of data , drafting / revising the manuscript , study concept or design .
camilla buckley : acquisition of data , drafting / revising the manuscript , study concept or design .
angela vincent : analysis or interpretation of data , drafting / revising the manuscript , study concept or design , study supervision .
ming lim : analysis or interpretation of data , drafting / revising the manuscript , study concept or design , study supervision .
this work was supported by the national institute for health research ( nihr ) oxford biomedical research centre based at oxford university hospitals nhs trust and the university of oxford ( y.h .
) ; the oxford university clinical academic graduate school ( y.h . ) ; the nhs specialized services for rare diseases ( neuromyelitis optica ; p.w . and a.v . ) ; and eruk , uk - us fulbright commission and ms society ( s.r.i . ) .
yael hacohen , leslie jacobson . , sunil pullaperuma , and ata siqddqui report no disclosures relevant to the article .
jean - pierre lin is chair of the british paediatric neurology association movement disorders special interest group and is medical advisor to the european dystonia federation and faculty of dystonia europe ; has received research grants from action medical research , the dystonia society ( uk ) , and guy 's and st thomas ' charity ; and has acted as a consultant and received funding for travel and speaker honoraria from medtronic ltd .
michael g. pike receives research grants from action medical research and ms society and has received a meeting support grant from euroimmun .
evangeline wassmer receives research grants from action medical research and ms society ; has received travel grants from ucb , shire , and biogen idec ; has received educational grants to organize meetings from merck serono , novartis , bayer , and biogen idec ; and has received speaker 's fees from merck serono and consultancy fees from genzyme .
patrick waters is supported by the nhs national specialized commissioning group for neuromyelitis optica and by the nihr oxford biomedical research centre .
sarosh irani serves on the scientific advisory board for encephalitis society and has received an nihr fellowship , department of health , uk .
angela vincent serves / has served on scientific advisory boards for the patrick berthoud trust , the brain research trust , and the myasthenia gravis foundation of america ; has received funding for travel and a speaker honorarium from baxter international , inc . and biogen , inc . ; serves as an associate editor for brain ; receives royalties from the publication of clinical neuroimmunology ( blackwell publishing , 2005 ) and inflammatory and autoimmune disorders of the nervous system in children ( mac keith press , 2010 ) ; receives / has received research support from the european union , nihr biomedical research centre oxford , euroimmun ag , and the sir halley stewart trust ; and has received musk antibody royalties and consulting fees from athena diagnostics , inc . ming lim receives research grants from action medical research and ms society ; receives research support grants from the london clinical research network and evelina appeal ; has received consultation fees from csl behring ; received travel grants from merck serono ; and was awarded educational grants to organize meetings by novartis , biogen idec , merck serono , and bayer .
sarosh irani , patrick waters , angela vincent , and the university of oxford hold patents and/or receive royalties and payments for antibody assays in neurologic diseases .
 objective : to report the clinical and radiologic findings of children with nmda receptor ( nmdar ) antibodies and white matter disorders.method:ten children with significant white matter involvement , with or without anti - nmdar encephalitis , were identified from 46 consecutive nmdar antibody  positive pediatric patients . 
 clinical and neuroimaging features were reviewed and the treatment and outcomes of the neurologic syndromes evaluated.results:three distinct clinicoradiologic phenotypes were recognized : brainstem encephalitis ( n = 3 ) , leukoencephalopathy following herpes simplex virus encephalitis ( hsve ) ( n = 2 ) , and acquired demyelination syndromes ( ads ) ( n = 5 ) ; 3 of the 5 with ads had myelin oligodendrocyte glycoprotein as well as nmdar antibodies . 
 typical nmdar antibody encephalitis was seen in 3 patients remote from the first neurologic syndrome ( 2 brainstem , 1 post - hsve ) . 
 six of the 7 patients ( 85% ) who were treated acutely , during the original presentation with white matter involvement , improved following immunotherapy with steroids , iv immunoglobulin , and plasma exchange , either individually or in combination . 
 two patients had escalation of immunotherapy at relapse resulting in clinical improvement . 
 the time course of clinical features , treatments , and recoveries correlated broadly with available serum antibody titers.conclusion:clinicoradiologic evidence of white matter involvement , often distinct , was identified in 22% of children with nmdar antibodies and appears immunotherapy responsive , particularly when treated in the acute phase of neurologic presentation . 
 when observed , this clinical improvement is often mirrored by reduction in nmdar antibody levels , suggesting that these antibodies may mediate the white matter disease . 
METHODS
Standard protocol approvals, registrations, and patient consents.
RESULTS
Brainstem encephalitis.
HSVE relapse.
Acquired demyelination syndromes.
General features of cases 110 and differences from the remaining 36 patients with NMDAR-Abs.
DISCUSSION
AUTHOR CONTRIBUTIONS
STUDY FUNDING
DISCLOSURE