persistent infection of the cervix with some oncogenic subtypes of human papilloma virus ( hpv ) causes cancer . thus , vaccination against high - risk oncogenic hpv infection before the first sexual experience may reduce morbidity by approximately 70% . the world health organization has recommended worldwide hpv vaccination to prevent the majority of cervical cancers ( 1 ) . several cases of young females presenting with central nervous system ( cns ) demyelination following the administration of hpv vaccine have been reported thus far ( 2 ) . we herein present the first two cases of acute disseminated encephalomyelitis ( adem ) following vaccination against hpv in japan . a 16-year - old japanese girl had received a bivalent hpv vaccine ( cervarix , 0.5 ml intramuscularly ) during a school program . she had a previous medical history of bronchial asthma in her childhood , but had not received any treatment for this condition . the second vaccination was administered 33 days after the first injection on the same limb . she became aware of double vision and dizziness on the next day , followed by instability while walking . nineteen days after the second vaccination , she was referred to our neurological outpatient clinic . her neurological examination revealed complete alertness , bilateral medial longitudinal fasciculus syndrome , left facial sensation decrease , and mild left facial paresis . the cerebrospinal fluid ( csf ) was acellular , with normal sugar and protein levels and igg index ( 59 mg / dl , 38 mg / dl , and 0.44 , respectively ) and there was no evidence of oligoclonal igg bands ( ocb ) . however , the myelin basic protein level was elevated ( 440 ng / ml ; normal < 102 ng / ml ) . electrophysiological studies , such as those for somatosensory evoked potentials , auditory brainstem responses , and visual evoked potentials , showed no significant abnormalities . brain magnetic resonance imaging ( mri ) showed an isolated small , demyelinating lesion in the pontine tegmentum on t2-weighted and fluid - attenuated inversion recovery images . 1 ) . according to these findings , the patient was diagnosed with post - vaccination adem and administered methylprednisolone 1,000 mg / day intravenously for 3 days . she was left with no residual neurological deficit and did not receive the third dose of the vaccine . c : a diffusion - weighted image revealed an isolated small high intensity lesion in the pontine tegmentum . a 15-year - old previously healthy japanese girl had received the first dose of a quadrivalent hpv vaccine ( gardasil , 0.5 ml intramuscularly ) through a school program . the second vaccination was administered 77 days after the first vaccination on the same limb . sixteen days after the second vaccination , she suffered from a fever , headache , and polyarthralgia with swelling of the extremities for 1 week . serum igm anti - cytomegalovirus antibody was present , but no abnormal neurological signs were evident in the pediatric clinic . she did not receive any specific treatment , and her headache and dysesthesia in the limbs persisted for 2 weeks after the fever diminished . in the third week , she visited a neurological clinic and brain mri studies showed a hyperintense lesion in the pons with slight edema on a t2-weighted image and diffusion - weighted images ( fig . forty days after the second vaccination , the patient was referred to our neurological outpatient clinic . her neurological examination was normal and reevaluation of brain mri revealed that the pontine hyperintense lesion had completely diminished . c : a diffusion - weighted image revealed a hyperintense lesion in the pons with slight edema . d : sagittal t2-weighted imaging of the brainstem showed the lesion existed on the pontine midline . a 16-year - old japanese girl had received a bivalent hpv vaccine ( cervarix , 0.5 ml intramuscularly ) during a school program . she had a previous medical history of bronchial asthma in her childhood , but had not received any treatment for this condition . the second vaccination was administered 33 days after the first injection on the same limb . she became aware of double vision and dizziness on the next day , followed by instability while walking . nineteen days after the second vaccination , she was referred to our neurological outpatient clinic . her neurological examination revealed complete alertness , bilateral medial longitudinal fasciculus syndrome , left facial sensation decrease , and mild left facial paresis . the cerebrospinal fluid ( csf ) was acellular , with normal sugar and protein levels and igg index ( 59 mg / dl , 38 mg / dl , and 0.44 , respectively ) and there was no evidence of oligoclonal igg bands ( ocb ) . however , the myelin basic protein level was elevated ( 440 ng / ml ; normal < 102 ng / ml ) . electrophysiological studies , such as those for somatosensory evoked potentials , auditory brainstem responses , and visual evoked potentials , showed no significant abnormalities . brain magnetic resonance imaging ( mri ) showed an isolated small , demyelinating lesion in the pontine tegmentum on t2-weighted and fluid - attenuated inversion recovery images . 1 ) . according to these findings , the patient was diagnosed with post - vaccination adem and administered methylprednisolone 1,000 mg / day intravenously for 3 days . she was left with no residual neurological deficit and did not receive the third dose of the vaccine . c : a diffusion - weighted image revealed an isolated small high intensity lesion in the pontine tegmentum . a 15-year - old previously healthy japanese girl had received the first dose of a quadrivalent hpv vaccine ( gardasil , 0.5 ml intramuscularly ) through a school program . the second vaccination was administered 77 days after the first vaccination on the same limb . sixteen days after the second vaccination , she suffered from a fever , headache , and polyarthralgia with swelling of the extremities for 1 week . serum igm anti - cytomegalovirus antibody was present , but no abnormal neurological signs were evident in the pediatric clinic . she did not receive any specific treatment , and her headache and dysesthesia in the limbs persisted for 2 weeks after the fever diminished . in the third week , she visited a neurological clinic and brain mri studies showed a hyperintense lesion in the pons with slight edema on a t2-weighted image and diffusion - weighted images ( fig . forty days after the second vaccination , the patient was referred to our neurological outpatient clinic . her neurological examination was normal and reevaluation of brain mri revealed that the pontine hyperintense lesion had completely diminished . c : a diffusion - weighted image revealed a hyperintense lesion in the pons with slight edema . d : sagittal t2-weighted imaging of the brainstem showed the lesion existed on the pontine midline . multivalent hpv vaccines are generally administered three times , with the second and the third injections at 1 - 2 months and 6 months , respectively , after the first injection . the quadrivalent hpv vaccine gardasil is widely used in many countries , whereas the bivalent hpv vaccine cervarix was first introduced in japan . thirteen cases concerning cns demyelinating adverse effects associated with hpv vaccination have been reported previously ( table ) . however , nine of these were finally diagnosed as multiple sclerosis or neuromyelitis optica ( 3 ) . the prevalence of multiple sclerosis in western countries is approximately 10 times higher than that in asian countries ( 4 ) . the targeted age of nationwide voluntary hpv immunization programs conducted in australia and other countries is consistent with the age group susceptible to multiple sclerosis ( 5 ) . nmosd : neuromyelitis optica spectrum disorder , ivmp : intravenous methyl prednisolone , ivcy : intravenous cyclophosphamide however , it has been noted that the molecular structure of aquaporin 4 resembles l1 virus - like particles contained in the hpv vaccine , and the influence of novel immunostimulatory adjuvant as04 may have a role in cns demyelinating adverse events ( 6,7 ) . generally , the onset of autoimmune disorders is triggered by infectious conditions for genetically susceptible individuals . however , recent pooled analyses of large - scale and long - term safety data have revealed no evidence of an increased risk of autoimmune disease associated with hpv vaccination ( 7,8 ) . the proposed criteria for pediatric adem are multifocal , large ( 1 - 2 cm each ) lesions identified by brain mri and behavioral changes or alteration of consciousness ( 9 ) . there are no standardized descriptions of adem for adult patients ; however , consciousness is not necessarily impaired and infratentorial lesions are more frequently identified in both young and elderly adults ( 10 ) . cerebral lesions are typically disseminated ; however , solitary lesions occur in approximately 10 - 30% of all cases ( 11 ) . the differential diagnosis from multiple sclerosis is determined by a clinical course with no relapse and the absence of any oligoclonal igg bands in the csf ( 9 ) . in our cases , ocb were not detected ; nonetheless , elevated myelin basic protein levels were observed , suggesting that acute central demyelinating changes occurred . clinical relapse was not observed over the 2-year follow - up period in both cases . the median interval from the onset of the initial demyelinating symptom to the second neurological episode in multiple sclerosis has been reported to be two years ( 12 ) . patients with monofocal symptoms without asymptomatic mri abnormalities have a relatively low risk for later meeting the criteria for multiple sclerosis than patients with multifocal asymptomatic lesions ( 13 ) . a previous confirmed report of adverse effects in the cns associated with hpv vaccination in japan described the case of a pediatric patient diagnosed with acute cerebellar ataxia ( 14 ) . the annual incidence of adem is 0.8 per 100,000 individuals , of which 5% is believed to be post - vaccination adem ( 11 ) . post - vaccination adem is an unavoidable complication and 0.1 - 0.2 per 100,000 vaccinated individuals develop adem ( 15 ) . at the end of march 2014 , 7 million doses of cervarix and 1.9 million doses of gardasil were administered to more than 3.7 million individuals as part of the vaccination program in japan . the number of adem cases , which were confirmed by mri abnormality , reported to the pharmaceuticals and medical devices agency were only three including the present cases ( 20 ) . thus , we estimate that approximately 0.05 adem cases occurred per 100,000 since initiating hpv vaccination in japan . this frequency is not particularly higher than that for post - vaccination adem induced by other vaccines . however , we can not confirm whether this is the true incidence of post - vaccination adem at this time because adem is an extremely rare disorder and its diagnosis is obscure . it is therefore important to accumulate further data on confirmed cases of adem temporally associated with hpv vaccination . clinicians should keep in mind that neurological symptoms due to demyelination can occur after hpv vaccination .
we herein present two cases of acute disseminated encephalomyelitis ( adem ) following vaccination against human papilloma virus ( hpv ) . 
 case 1 experienced diplopia and developed an unstable gait 14 days after a second vaccination of cervarix . 
 brain magnetic resonance imaging ( mri ) showed an isolated small , demyelinating lesion in the pontine tegmentum . 
 case 2 experienced a fever and limb dysesthesia 16 days after a second vaccination of gardasil . 
 brain mri revealed hyperintense lesion in the pons with slight edema on a t2-weighted image . both cases resolved completely . 
 it is important to accumulate further data on confirmed cases of adem temporally associated with hpv vaccination .