recently , a unique limbic encephalitis that predominantly affects young females and shows various manifestations , including initial psychosis , and subsequent central hypoventilation , intractable seizures , dysautonomia and prominent orofacial dyskinesia , has been noted [ 1 , 2 ] . in patients with this disorder
a new anti - neural antibody for the nr1/nr2 heteromers of the n - methyl - d - aspartate receptor ( nmdar ) has been identified as a disease - specific hallmark , recently adding that the nr1 is possibly a main epitope .
although it is now widely accepted that the presence of ovarian teratoma is an important predisposing factor for the development of anti - nmdar encephalitis [ 4 , 5 ] , the mechanisms that initiate the disease are still incompletely understood .
we here report on a young male patient with anti - nmdar encephalitis which developed during the recovery course of severe guillain - barr syndrome ( gbs ) , and propose that a post - infectious autoimmune mechanism may play an important role in the pathogenesis of anti - nmdar encephalitis .
a 19-year - old man with no history of systemic disease was hospitalized due to muscle weakness and dysesthesia in the extremities following cough and nasal discharge 2 weeks earlier .
neurological examination showed muscle weakness and sensory disturbance in the distal parts of the extremities , and all deep tendon reflexes were absent .
cerebrospinal fluid ( csf ) at 5 days after onset of weakness contained a normal cell count , but the concentration of total protein was elevated ( 52.8 mg / dl ) .
the patient was diagnosed as having gbs and treated with intravenous immunoglobulin ( ivig ) therapy ( 0.4 g / kg / day ) for 5 days . however , the symptoms worsened gradually , he was not able to raise his upper limbs and to walk from the 5th hospital day . furthermore , dysarthria , dysphagia , and dyspnea appeared gradually from the 9th hospital day .
he was transferred to our hospital on the 12th hospital day . on the day of transfer ,
nerve conduction studies showed reduced motor nerve conduction velocities ( right median nerve : 11.3 m / s , normal value > 55 m / s , right tibial nerve : 36.6 m / s , normal value > 45 m / s ) with conduction block ( fig .
1 ) , and sensory nerve action potentials could not be evoked in both nerves .
there was neither anti - gm1 igg antibody nor anti - gq1b igg antibody in the serum .
although mechanical ventilation was necessary from the day of transfer , muscle weakness in the extremities and respiratory function gradually improved after the second course of ivig therapy from the 22nd hospital day for 3 days , and the patient was trained for weaning from mechanical ventilation .
however , he started to experience occasional psychomotor agitation from the 37th hospital day , and generalized tonic convulsive seizures suddenly developed following paralytic ileus and tachycardia on the 42nd hospital day .
since the convulsive seizures did not respond to intravenous administration of diazepam , phenytoin , or midazolam , continuous thiopental infusion was used and mechanical ventilation was continued .
csf showed a slightly increased cell count ( 8/l , mononuclear cells 7 ) , a highly elevated level of total protein ( 446 mg / dl ) , and normal glucose concentration .
brain mri showed high - intensity lesions in the bilateral thalamus and medial temporal lobes on diffusion and flair images ( fig .
he was diagnosed as having some type of autoimmune encephalitis , and intravenous methylprednisolone pulse therapy ( 1,000 mg / day ) for 3 days followed by dexamethasone ( 16 mg / day ) was administered , and used until the 70th hospital day with a gradual dose reduction .
although the generalized convulsive seizures disappeared and the infusion of thiopental was ceased on the 52nd hospital day , orolingual dyskinesia gradually developed . on the brain mri on the 64th hospital day , the abnormal high - intensity lesions in the bilateral thalamus were reduced , while marked atrophy of the bilateral medial temporal lobes was seen ( fig .
2b ) . respiratory failure and autonomic dysfunction that included disturbed bowel movement and abnormal cardiovascular responses gradually improved , and he was released from mechanical ventilation on the 84th hospital day .
however , the patient remained unresponsive to verbal commands and severe orolingual dyskinesia persisted until he was transferred to a local hospital on the 193rd hospital day . during investigation of the causes of the encephalitis , there were no laboratory data suggesting viral encephalitis , including herpes simplex , influenza , varicella zoster , cytomegalovirus , measles , and human herpes virus-6 .
urological examination was normal and no detectable neoplasm was seen on either chest or abdominal ct .
two years after the onset of seizures , his condition was very similar to when he was discharged from our hospital , and repeated examinations showed no appearance of a tumor .
detection of anti - nmdar antibody on the same samples was carried out as follows : cdna encoding nr1 and nr2b was ligated into the expression vectors and transfected into human embryonic kidney ( hek ) 293 cells in the media containing 10 m mk-801 using lipofectamine ( invitrogen ) .
twelve hours after transfection , hek-293 cells were fixed in 4% paraformaldehyde in 0.1 m phosphate - buffered saline ( pbs , ph 7.4 ) for 20 min .
after non - specific binding was blocked with 10% goat serum in pbs , these cells were incubated with patient sera ( 1:40 ) or csf ( 1:2 ) overnight at 4c and then with fitc - conjugated rabbit anti - human igg ( bd biosciences ) for 30 min at room temperature .
slowfade gold anti - fade reagent ( molecular probes ) was applied to the slides and the staining was observed under a fluorescence microscope .
both serum and csf obtained from the 92nd hospital day specifically reacted with hek-293 cells expressing heteromers of nr1/nr2b ( fig .
in our case , encephalitis was shown by abnormal intensity of the bilateral thalamus and medial temporal lobes on brain mri at an early stage .
however , the former thalamic lesions seemed to be edema due to status epilepticus , and the main lesion of this encephalitis was assumed to be in the bilateral medial temporal lobes , because the thalamic lesions rapidly resolved after treatment , whereas the bilateral medial temporal lobes showed progressive atrophy .
moreover , his clinical manifestations consisted of psychiatric symptoms , intractable seizures , dysautonomia and involuntary movements , and anti - nmdar antibody was demonstrated in both serum and csf .
anti - nmdar encephalitis usually affects young females , and an early series of patients with this disease was found to have a high association of ovarian teratoma [ 3 , 4 ] .
thus , the pathogenetic significance of ovarian teratoma in this encephalitis was investigated and it was proposed that , since the ovarian teratomas obtained from diseased patients showed mature- and immature - appearing neurons with expression of nr2b and/or nr2a [ 3 , 4 ] , ectopically expressed nmdars in ovarian teratoma contribute to the production of antibodies to nmdars .
thus , early removal of ovarian teratoma has been recommended for patients with this disease .
however , a recent study on a large number of patients with anti - nmdar encephalitis has shown that this ovarian tumor could not be found in about 40 to 80% of adult patients with the disease [ 1 , 2 , 8 ] , although careful follow - up examinations on the detection of tumors are always required in these patients .
increased recognition of this unique encephalitis has also disclosed that children and adolescents also encounter it [ 9 , 10 ] , although the frequency of associated ovarian teratoma was much lower in children than adults .
additionally , a small number of male cases with anti - nmdar encephalitis   were reported , indicating that other causes besides ovarian teratoma can produce encephalitis . in the pathogenesis of anti - nmdar encephalitis ,
the antibody immune response has been shown to be more relevant than cytotoxic t - cell mechanisms   and the vast majority of patients with this type of disease have a history of prodromal flu - like symptoms .
it was , therefore , suggested that the preceding flu - like illness leads to the triggering of abnormal antibody production targeting nmdars .
in this situation the presence of ovarian teratoma with a high expression of nmdar epitopes may predispose or exaggerate the production of anti - nmdar antibodies ; these nmdar antibodies then cause a specific , titer - dependent , and reversible decrease in nmdar surface density and synaptic localization , especially in the hippocampus , resulting in learning , memory , and other behavioral deficits seen in patients with anti - nmdar - encephalitis .
immunosuppressive therapy , including corticosteroid , plasma exchange and ivig , has been used for the treatment of this disease .
recently , rituximab , an anti - cd20 monoclonal antibody , is expected to accelerate the recovery of patients with this type of disease .
our young male patient with anti - nmdar encephalitis lacked testicular or mediastinal teratoma , which was previously reported to be of paraneoplastic origin . on the other hand ,
his clinical course was characterized by a preceding attack of gbs : this disease is a representative post - infectious peripheral demyelinating neuropathy with underlying autoimmune abnormalities .
although a causative relationship between gbs and anti - nmdar encephalitis has not been studied , it is likely that gbs - related abnormal immune reactions secondarily caused another autoimmune state with anti - nmdar encephalitis .
although serial examinations of anti - nmdar antibodies in both serum and csf might be useful in clarifying the underlying immune condition of this patient , there were no available samples .
this case report has provided the clinical evidence that a parainfectious autoimmune reaction is an important pathogenetic mechanism in the development of anti - nmdar encephalitis .
 a 19-year - old man developed rapidly progressive muscle weakness and dysesthesia in the extremities , and dyspnea after a flu - like episode . 
 nerve conduction studies showed reduced motor nerve conduction velocities with conduction block , and sensory nerve action potentials could not be evoked . 
 the patient was diagnosed as having guillain - barr syndrome ( gbs ) , and was treated with 2 cycles of intravenous immunoglobulin ( ivig ) therapy and was assisted by mechanical ventilation . during the recovery course of the illness , he experienced several attacks of psychomotor agitation from the 37th hospital day , and generalized tonic convulsive seizures suddenly developed on the 42nd hospital day . 
 brain mri showed high - intensity lesions in the bilateral thalamus and medial temporal lobes . 
 the convulsions were controlled by continuous thiopental infusion ( until the 50th hospital day ) and mechanical ventilation ( until the 84th hospital day ) . 
 intravenous methylprednisolone pulse therapy ( 1,000 mg / day ) for 3 days followed by dexamethasone ( 16 mg / day ) was added . 
 after relief of convulsive seizures , prominent orolingual dyskinesia appeared , and on mri marked atrophy of the bilateral medial temporal lobes was seen . 
 anti - n - methyl - d - aspartate receptor ( nmdar ) antibodies in serum and cerebrospinal fluid were positive on the 92nd hospital day . 
 anti - nmdar encephalitis usually affects young females but a small number of male cases with this disease have been reported . 
 our male patient was unique in having gbs , a post - infectious autoimmune disease , as a preceding disease , suggesting that anti - nmdar encephalitis itself is caused by a parainfectious autoimmune mechanism . 
Introduction
Case Report
Immunochemical Analysis of Anti-NMDAR Antibody in Serum and CSF
Discussion