based on review of our patient s medical record and current literature , we identified unique commonalities of clinical findings , imaging , and pathology for use in diagnosis and treatment planning .
samples of the patient s stored tissue were analyzed for immunohistochemical evidence of cytogenetic abnormalities .
a 14-year - old caucasian female presented to the emergency department with a 2-week history of intermittent headaches associated with nausea and vomiting , becoming persistent and intensified in character .
initial magnetic resonance imaging ( mri ) of the brain and spine was limited by metal artifact from dental braces ; however , leptomeningeal enhancement was noted diffusely throughout the brain and spinal cord with particular involvement of the basilar and suprasellar cisterns and distal lumbar nerve roots .
the patient was admitted to the pediatric neurology service for evaluation of hydrocephalus and possible meningitis .
four days after admission , her condition deteriorated with development of visual acuity changes and bilateral sixth cranial nerve palsies .
an external ventricular drain was placed , but continued progressive hydrocephalus necessitated diversion of cerebrospinal fluid ( csf ) via ventriculoperitoneal shunt .
cerebrospinal fluid studies , although repeatedly negative for malignant cells , consistently showed significant protein elevation .
after removal of dental braces , mri demonstrated continued leptomeningeal enhancement and a new enhancing intramedullary lesion at c7-t2 measuring 4  17 mm ( figure 1 ) .
diffuse meningitic process  and noted the focal signal changes were possibly the result of vascular thrombosis from infection or inflammation . during this initial hospitalization
, extensive infectious and inflammatory workups were unrevealing , and the patient was discharged home .
postcontrast sagittal magnetic resonance imaging c - spine demonstrating dural enhancement ( long arrows ) and an enhancing intramedullary nodule at c7-t1 ( short arrow ) .
eight months after presentation , new changes in mri included multifocal nonenhancing cystic lesions in the white matter .
a month later , continued progressive leptomeningeal enhancement prompted repeat meningeal biopsies as well as brain tissue biopsies .
whole body bone scan and ct imaging of the chest , abdomen , and pelvis ruled out an occult neoplastic process with leptomeningeal dissemination .
the biopsies revealed minimal chronic inflammation of the dura and unidentified atypical cells in the perivascular spaces determined to be of neuroepithelial origin by immunohistochemical staining .
there was no infiltration of these cells into the vessels nor was there evidence of infarct .
systemic steroid therapy was considered and , prior to initiation , the patient was referred to pediatric neurooncology for consultation .
magnetic resonance imaging revealed increased dural thickening and enhancement with a new 1-cm mass - like lesion along the left cavernous sinus .
there were also an increased number and size of cysts inferiorly and bilaterally in the brain , thought to represent abnormal dilatation of the perivascular spaces ( figure 2 ) , consistent with previous biopsy findings . despite emergence of new findings and progression of dural thickening , the spinal lesion at the cervicothoracic junction was stable .
a repeat biopsy was recommended . our patient s progression of perivascular cystic development from initial presentation ( a ) to 3 months later ( b ) .
these final biopsies demonstrated cells with moderate pleomorphism and fine cytoplasmic processes , positive for glial fibrillary acid protein ( gfap ) and synaptophysin , and negative for isocitrate dehydrogenase 1 ( r123h mutation - specific antibody ) .
this was now interpreted to be a high - grade glioneuronal tumor due to a high mitotic rate and p53 positivity .
magnetic resonance imaging after 6 weeks of temozolomide and craniospinal irradiation revealed a significant decrease in contrast enhancement throughout the brain and spinal cord .
the patient completed 6 weeks of craniospinal irradiation and oral temozolomide , followed by maintenance therapy with temozolomide 5 days each month for 1 year .
there was complete resolution of symptoms and all magnetic resonance mri findings with the exception of persistence of the spinal nodule , which no longer enhanced with contrast administration . at the time of manuscript preparation
armao et al described a case of an 8-year - old boy who presented with intermittent headaches .
although he had no initial hydrocephalus , over the following 6 months he had fluctuating neurologic signs and symptoms including papilledema , diplopia , ataxia , and upper extremity weakness . communicating hydrocephalus developed over the first year , and over a 5-year period , the patient had progressive hydrocephalus , seizures , and intermittent encephalopathy .
he also underwent csf studies revealing elevated protein but no malignant cells . on mr imaging
, he had diffuse thickening and enhancement of the subarachnoid space and leptomeninges of the brain and spinal cord , more concentrated in the basal cisterns , sylvian fissures , and interhemispheric fissures .
he had cystic lesions of the basal cisterns , basal ganglia , medulla , and cerebellar white matter .
all cystic lesions noted were reported to have similar signal intensity to csf . with the development of leptomeningeal enhancement and the appearance of the cystic lesions ,
he was not treated for malignancy and subsequently died secondary to necrotizing pneumonia and fulminant sepsis .
postmortem biopsy showed tumor cell infiltrates in the perivascular spaces of the basal ganglia and cerebellum .
the tumor cells were positive for s100 and leu-7 markers and negative for gfap human melanoma black 45 , keratin , and cd45 .
although the tumor was negative for gfap ( a glial cell marker ) , leu-7 is involved in myelination and is often seen in oligodendrogliomas .
the author noted that this type of tumor usually has a primary intra - axial mass , which this case lacked .
however , like our patient , he had an 8-mm oval - shaped , enhancing nodule at c6 to c7 .
gardiman et al presented 4 relatively similar cases : all childhood / adolescence presenting with neurologic manifestations , communicating hydrocephalus with spinal fluid high in protein and negative for malignant cells , diffuse leptomeningeal enhancement on imaging with cystic lesions thought to represent perivascular infiltration of tumor cells , and none of which had a primary tumor identified .
biopsies obtained in all 4 cases identified tumor cells with the morphologic appearance of glial differentiation but  a significant number of nuclei were immunopositive for neu - n ,  and tumor cells were diffusely positive for synaptophysin .
only case 3 was found to have a 1p deletion on initial fluorescence in situ hybridization testing ; however , on his second biopsy , there was a 50% mib-1 index and further progression to 1p19q codeletion .
case 3 received irradiation due to disease progression with development of tumor 2 years after finishing 12 months of temozolamide .
none were disease free after treatment but progressed with a slow indolent course while the child in case 2 subsequently died from disease progression . in 2012 , gardiman et al published an update on case 4 .
the patient presented 22 months after the initial presentation and biopsy , with new seizures and personality changes .
magnetic resonance imaging at this time showed multiple intraparenchymal cysts and thick leptomeningeal enhancement with aggregation of tumor deposits in the dural sac .
his first biopsy at initial presentation did not clearly provide adequate information for classification of the tumor .
it revealed cells with copositivity for both neurocytes and oligodendrocytes , high mitotic index , and no cytogenetic abnormalities were detected . with this second presentation , a repeat biopsy showed a low mitotic index and low mib-1 in addition to the aforementioned features .
the final diagnosis was determined to be a low - grade tumor consistent with diffuse leptomeningeal glioneuronal tumor and he was started on chemotherapy as per a low - grade protocol , which included vincristine and carboplatin . due to severe neurotoxicity and prolonged myelosuppression , his therapy was initially switched to temozolamide alone .
then , for seizure and behavioral control , as well as the potential augmentation of glial differentiation , daily valproic acid was started and the temozolamide was discontinued ( reason for its discontinuation not specified ) .
three months after initiating the valproic acid , a total of 67 months since initial presentation , the patient s leptomeningeal involvement and neurologic symptoms ( including seizures and behavioral changes ) were steadily improving . 
 
since the description of diffuse leptomeningeal glioneuronal tumor , schniederjan et al reported 9 additional cases that they termed  diffuse leptomeningeal neuroepithelial tumor . 
the ages of the children in this series ranged from 2 to 7 years old .
the clinicopathologic presentation of their patients is almost identical to the above - described cases , including that of our patient . of the 9 patients , 8 had cytogenetic testing for 1p/19q deletions .
of those tested , 6 demonstrated the 1p deletion , and 2 of those 6 also had the 19q codeletion .
of those with only the 1p deletion , 1 did not have sufficient tissue adherence for successful 19q fluorescence in situ hybridization testing .
of the 9 cases tested for deletions , 8 were also tested for isocitrate dehydrogenase 1 mutation and found to be negative .
overall , 2 patients were treated with temozolamide alone , 2 with temozolamide and other chemotherapy agents , 1 with vincristine and carboplatin , 1 with radiation alone , and 1 patient was treated with chemotherapy ( drug not specified ) and radiation therapy . at the time of their publication , 2 patients were newly diagnosed and had not yet started treatment .
abbreviations : lm , leptomeningeal ; ip , intraparenchymal ; dlgnt , diffuse leptomeningeal glioneuronal tumor ; dlo , diffuse leptomeningeal oligodendrogliomatosis ; dlnet , diffuse leptomeningeal neuroepithelial tumor ; gfap , glial fibrillary acid protein ; csf , cerebral spinal fluid ; flair , fluid - attenuated inversion recovery ; yo , years old ; f , female ; m , male . 
 reported as
1 cm mass in left cavernous sinus . 
 left frontal intraventricular lesion with perivascular pseudorosettes versus pseudopapillary structure . 
 internal auditory canals . 

our patient s cysts were nonenhancing ; armao patient s cyst enhanced like csf ; all 4 gardiman patients cysts were hyperintense on t2 and isohypointense on t1 and flair . 

gfap negative , leu-7 positive ; leu-7 is associated with myelin and is present in a majority of oligodendrogliomas . 

biopsy at initial presentation high mitotic index ; biopsy at second presentation low mitotic index and < 3% mib-1 . 

dlo usually has a primary intra - axial mass  this case did not . 

it has been believed that central nervous system neoplasms classically disseminate caudally from the origin of the primary tumor . however , of the 15 above - mentioned cases , 7 have a noted tumor or nodules found in the spinal cord with diffuse leptomeningeal enhancement and subsequent cystic changes in the brain .
this suggests this tumor can indeed be a primary spinal cord neoplasm demonstrating cranial dissemination .
additionally , diffuse leptomeningeal enhancement is usually assumed to be evidence of dissemination associated with more progressive disease .
the patients described with this unique tumor seem to present with hydrocephalus and diffuse leptomeningeal enhancement and do not usually present with cystic changes .
they later develop cystic changes in the leptomeninges and parenchyma , which continue to increase in number and size with progression of the disease .
this suggests the leptomeningeal enhancement is not necessarily a marker of advanced disease in these patients , but development and progression of cystic changes may be .
additionally , as the cysts appear to be noncomplex in nature ( i.e. , without components of protein or blood ) , these cystic changes are likely perivascular spaces enlarging with collections of extracellular fluid developing secondary to progression of the leptomeningeal disease altering normal drainage pathways .
mixed glioneuronal tumors and gangliogliomas are defined as consisting of 2 distinct cell populations , one population of neuronal cells mixed with another distinct population of glial cells .
the glioneuronal tumors discussed in this article are composed of a singular cell population staining positively for markers of both glial and neuronal cell components .
therefore , histological staining for multiple markers of both types of cells in all samples collected can lead to earlier diagnosis . in our patient
s case , not all biopsy samples included tumor cells , and different samples revealed varying levels of differentiation and of aggressive features .
gardiman case 4 also demonstrated differing levels of mitotic index at initial and later biopsies , as well as varying degrees of aggressive histological signs .
obtaining early and repeated biopsies , each with multiple sample sites , is more likely to provide the most important information leading to an earlier diagnosis of malignancy in patients with diffuse leptomeningeal enhancement and elevated csf protein without evidence of a primary tumor or malignant cells in the spinal fluid .
additionally , testing these multiple samples for both glial and neuronal cell markers , p53 , olig-2 , isocitrate dehydrogenase 1 , and 1p/19q deletion can help with diagnosis , as well as give more information of prognosis and treatment options .
however , it has been found in cells of glioneuronal tumors exhibiting both glial and neuronal characteristics .
this can suggest a common progenitor cell type between glial and neuronal cells , giving support to the theory that these glioneuronal tumors are neoplasms of a common precursor cell for both glial and neuronal cell types .
somatic mutations of the idh1 gene have been associated with several forms of cancer , including astrocytomas , oligodendrogliomas , and hematopoetic dysplasias .
as it is seen in over 70% of grade ii to iv gliomas and is not demonstrated in diffuse leptomeningeal glioneuronal tumors , isocitrate dehydrogenase 1 may be a useful marker in testing to differentiate diffuse leptomeningeal glioneuronal tumors from higher grade glial neoplasms .
our patient and the 9 schniederjan patients all tested negative for isocitrate dehydrogenase 1 ( the others did not have isocitrate dehydrogenase 1 status reported ) . 
 
chromosomal analysis for 1p19q codeletion , or even a singular deletion of either 1p or 19q , can be useful in determining tumor aggressiveness and likely response to chemotherapy , especially to temozolomide . this codeletion has been seen in both neurocytomas and adult oligodendrogliomas ; and its being seen in both tumor types can also support the idea of a common progenitor cell being the neoplastic culprit in diffuse leptomeningeal glioneuronal tumors .
this codeletion has demonstrated correlation with more aggressive disease in extraventricular neurocytomas and can be useful in assessment of potentially aggressive behavior of other tumor types , including diffuse leptomeningeal glioneuronal tumors .
on the other hand , it has also been highly correlative with increased responsiveness to systemic chemotherapy , especially with temozolomide , with and without adjunctive radiotherapy , as well as disease prognosis . 
 
it is clear from the reported cases mentioned herein that this neoplasm is , in fact , treatable .
stable disease has been achieved with chemotherapy alone , as well as with adjunctive irradiation . as evidenced by our patient s case ,
therefore , treatment should absolutely be initiated , although the most effective treatment has not yet been identified .
our patient s remarkable response to her treatment regimen could have been due to the combined temozolamide and radiation therapy , which was allowable given her age .
her p53 positivity was also likely significant in her response to therapy , which can have represented a more aggressive tumor with higher sensitivity to the treatment modalities used .
the seemingly significant response to initiation of valproic acid in gardiman case 4 , both with improvement in neurological symptoms and radiographic findings , can indicate valproic acid lends itself to successful adjunctive therapy in cases with seizures and behavioral changes , and possibly even in those without .
the majority of the other cases mentioned did not receive radiotherapy in addition to temozolamide , likely due to patient age , and subsequently had reportedly stable disease .
with our patient s quick and steady response to her combined therapy regimen , it may be advisable to use combined treatment with systemic chemotherapy and craniospinal irradiation from the beginning  more aggressive treatment for a potentially aggressive tumor .
however , the risks involved depend on the individual patient and should still be tailored accordingly . although temozolomide is not the only option for chemotherapy , it certainly has its advantages for the patient  oral administration , less patient toxicity , and it seems to work well for this neoplasm .
suggestions for future studies , which can provide information leading to more successful therapy , include comparing chemotherapy with temozolomide alone versus chemotherapy with other agents , chemotherapy alone versus chemotherapy in conjunction with craniospinal irradiation , and the efficacy of valproic acid as an adjunctive therapy for patients with and without symptoms including seizures and/or behavioral changes .
additionally , and even more importantly , evaluation of the molecular characteristics of the disease will help targeted therapy .
it has been believed that central nervous system neoplasms classically disseminate caudally from the origin of the primary tumor . however , of the 15 above - mentioned cases , 7 have a noted tumor or nodules found in the spinal cord with diffuse leptomeningeal enhancement and subsequent cystic changes in the brain .
this suggests this tumor can indeed be a primary spinal cord neoplasm demonstrating cranial dissemination .
additionally , diffuse leptomeningeal enhancement is usually assumed to be evidence of dissemination associated with more progressive disease .
the patients described with this unique tumor seem to present with hydrocephalus and diffuse leptomeningeal enhancement and do not usually present with cystic changes .
they later develop cystic changes in the leptomeninges and parenchyma , which continue to increase in number and size with progression of the disease .
this suggests the leptomeningeal enhancement is not necessarily a marker of advanced disease in these patients , but development and progression of cystic changes may be .
additionally , as the cysts appear to be noncomplex in nature ( i.e. , without components of protein or blood ) , these cystic changes are likely perivascular spaces enlarging with collections of extracellular fluid developing secondary to progression of the leptomeningeal disease altering normal drainage pathways .
mixed glioneuronal tumors and gangliogliomas are defined as consisting of 2 distinct cell populations , one population of neuronal cells mixed with another distinct population of glial cells .
the glioneuronal tumors discussed in this article are composed of a singular cell population staining positively for markers of both glial and neuronal cell components .
therefore , histological staining for multiple markers of both types of cells in all samples collected can lead to earlier diagnosis . in our patient
s case , not all biopsy samples included tumor cells , and different samples revealed varying levels of differentiation and of aggressive features .
gardiman case 4 also demonstrated differing levels of mitotic index at initial and later biopsies , as well as varying degrees of aggressive histological signs .
obtaining early and repeated biopsies , each with multiple sample sites , is more likely to provide the most important information leading to an earlier diagnosis of malignancy in patients with diffuse leptomeningeal enhancement and elevated csf protein without evidence of a primary tumor or malignant cells in the spinal fluid .
additionally , testing these multiple samples for both glial and neuronal cell markers , p53 , olig-2 , isocitrate dehydrogenase 1 , and 1p/19q deletion can help with diagnosis , as well as give more information of prognosis and treatment options .
however , it has been found in cells of glioneuronal tumors exhibiting both glial and neuronal characteristics .
this can suggest a common progenitor cell type between glial and neuronal cells , giving support to the theory that these glioneuronal tumors are neoplasms of a common precursor cell for both glial and neuronal cell types .
somatic mutations of the idh1 gene have been associated with several forms of cancer , including astrocytomas , oligodendrogliomas , and hematopoetic dysplasias . as it is seen in over 70% of grade ii to iv gliomas and is not demonstrated in diffuse leptomeningeal glioneuronal tumors , isocitrate dehydrogenase 1 may be a useful marker in testing to differentiate diffuse leptomeningeal glioneuronal tumors from higher grade glial neoplasms .
our patient and the 9 schniederjan patients all tested negative for isocitrate dehydrogenase 1 ( the others did not have isocitrate dehydrogenase 1 status reported ) . 
 
chromosomal analysis for 1p19q codeletion , or even a singular deletion of either 1p or 19q , can be useful in determining tumor aggressiveness and likely response to chemotherapy , especially to temozolomide . this codeletion has been seen in both neurocytomas and adult oligodendrogliomas ; and its being seen in both tumor types can also support the idea of a common progenitor cell being the neoplastic culprit in diffuse leptomeningeal glioneuronal tumors .
this codeletion has demonstrated correlation with more aggressive disease in extraventricular neurocytomas and can be useful in assessment of potentially aggressive behavior of other tumor types , including diffuse leptomeningeal glioneuronal tumors .
on the other hand , it has also been highly correlative with increased responsiveness to systemic chemotherapy , especially with temozolomide , with and without adjunctive radiotherapy , as well as disease prognosis . 

it is clear from the reported cases mentioned herein that this neoplasm is , in fact , treatable .
stable disease has been achieved with chemotherapy alone , as well as with adjunctive irradiation . as evidenced by our patient s case ,
therefore , treatment should absolutely be initiated , although the most effective treatment has not yet been identified .
our patient s remarkable response to her treatment regimen could have been due to the combined temozolamide and radiation therapy , which was allowable given her age .
her p53 positivity was also likely significant in her response to therapy , which can have represented a more aggressive tumor with higher sensitivity to the treatment modalities used .
the seemingly significant response to initiation of valproic acid in gardiman case 4 , both with improvement in neurological symptoms and radiographic findings , can indicate valproic acid lends itself to successful adjunctive therapy in cases with seizures and behavioral changes , and possibly even in those without .
the majority of the other cases mentioned did not receive radiotherapy in addition to temozolamide , likely due to patient age , and subsequently had reportedly stable disease . with our patient s quick and steady response to her combined therapy regimen
, it may be advisable to use combined treatment with systemic chemotherapy and craniospinal irradiation from the beginning  more aggressive treatment for a potentially aggressive tumor .
however , the risks involved depend on the individual patient and should still be tailored accordingly . although temozolomide is not the only option for chemotherapy , it certainly has its advantages for the patient  oral administration , less patient toxicity , and it seems to work well for this neoplasm .
suggestions for future studies , which can provide information leading to more successful therapy , include comparing chemotherapy with temozolomide alone versus chemotherapy with other agents , chemotherapy alone versus chemotherapy in conjunction with craniospinal irradiation , and the efficacy of valproic acid as an adjunctive therapy for patients with and without symptoms including seizures and/or behavioral changes .
additionally , and even more importantly , evaluation of the molecular characteristics of the disease will help targeted therapy .
in conclusion , when patients present with sequelae of nonspecific neurologic signs and symptoms , hydrocephalus , csf studies significant only for elevated protein without evidence of malignant cells , and diffuse leptomeningeal enhancement on radiographic images , the differential diagnosis should include diffuse leptomeningeal glioneuronal tumor ( also described as diffuse leptomeningeal neuroepithelial tumor ) .
additionally , if cystic changes are seen with the above - mentioned findings , it should prompt aggressive workup for this tumor in addition to the infectious workup usually employed .
olig-2 may be a marker implying a common progenitor cell for neurocytes and glial cells in tumors .
although p53 and 1p19q codeletions represent more aggressive tumor activity , 1p19q codeletions have shown significantly increased responsiveness to chemotherapy , especially temozolomide .
when this diagnosis is in the differential , it is advisable to obtain earlier ( and possibly repeated ) biopsies from multiple sites , and these tissue samples should be tested for the following factors : multiple glial cell markers , multiple neuronal cell markers , p53 , olig-2 , isocitrate dehydrogenase 1 , and chromosomal deletions ( especially of 1p and 19q ) .
obtaining this information can lead to earlier diagnosis and treatment of diffuse leptomeningeal glioneuronal tumors in patients who present with hydrocephalus and diffuse leptomeningeal enhancement without evidence of a primary tumor .
temazolomide seems to be effective and is especially recommended for patients with markers of more aggressive tumor activity .
both medications should be considered when appropriate and investigated in more depth in future studies .
this is a seemingly low - grade tumor and collective efforts should be undertaken to develop molecular characterization of this entity in hopes of developing targeted therapy .
 diffuse leptomeningeal glioneuronal tumor is unique for communicating hydrocephalus , diffuse leptomeningeal enhancement , cystic changes , absence of tumor cells in cerebral spinal fluid , and a cell population of both glial and neuronal copositivity . 
 it has likely been misdiagnosed as mixed glioneuronal tumors , oligodendrogliomas , and neuroepithelial tumors . children with signs of this tumor 
 are often worked up for infection , rheumatologic disease , or disseminated primary malignancy , resulting in unnecessary testing and treatment . 
 we describe a 14-year - old female with recurrent headaches , hydrocephalus , and diffuse leptomeningeal enhancement discovered to be neoplastic 1 year after initial presentation , owing to extensive and unrevealing infectious and immunologic workups . 
 biopsies revealed atypical cells with markers of both glial and neuronal cells , positivity for olig-2 , and focal p53 positivity . 
 great response was seen with temozolomide and craniospinal irradiation . 
 additionally , we postulate additional diagnostic indicators that may aid in earlier diagnosis and treatment decisions . 