approximately 2 years prior to her initial neurological evaluation , a 12-year - old girl developed both urinary tract infections in the context of recurrent stress - induced and nocturnal urinary incontinence .
one year prior to her presentation , she began to develop recurrent oral ulcers , at the time thought to be  cold sores . 
eight months prior to her presentation , she began to experience intermittent back pain and blurred vision , sporadic abdominal pain , and progressive clumsiness in her lower extremities that caused frequent falls .
two weeks prior to her initial visit at our institution , she was admitted to a psychiatric unit after a suicide attempt . due to her progressive symptoms ,
she was referred to our pediatric neurology clinic for evaluation . at her initial visit ,
her examination was notable for asymmetric spasticity ( right greater than left ) in her lower extremities with prolonged ankle clonus and bilateral extensor plantar responses .
her gait was unsteady , with persistent inversion and circumduction of the right foot , and she was unable to perform a tandem gait maneuver .
her initial visual examination demonstrated normal acuity , pupillary responses , and extraocular movements . no rash , mucosal lesions , or joint symptoms
were noted . a brain and spinal magnetic resonance imaging ( mri ) with contrast was performed and revealed innumerable contrast enhancing , punctuate lesions throughout her entire cerebrum , brain stem , and spinal cord .
left , axial slice at the level of the brain stem and cerebellum and on the right , sagittal view of spine .
the differential for her symptoms and radiographic findings was broad and included neurosarcoidosis , primary central nervous system lymphoma , central nervous system infection , primary demyelinating diseases , and central nervous system vasculitis .
extensive evaluation for infectious , oncologic , and rheumatologic etiologies was negative except for a positive urine culture ( > 100 000 colony - forming unit of escherichia coli ) , positive antinuclear antibody ( 1:320 , speckled pattern ) , abnormal cerebrospinal fluid indices ( 20 nucleated cells / high - powered field with 97% lymphocytes  a persistent finding over repeat lumbar punctures , protein 65 mg / dl , and glucose 58 mg / dl ) , and cerebrospinal fluid angiotensin - converting enzyme level of 7 units / l . a summary of her evaluation is presented in table 1 . summary of diagnostic workup .
note : bold items indicate notable findings her visual complaints evolved from a nonspecific  blurring  to loss of perceived acuity that impacted her ability to read .
an ophthalmologic examination subsequently revealed vitritis , papillitis , and leakage or extravasation of fluorescein dye during the angiogram consistent with vasculitis as shown in figure 2 .
no dermatologic lesions were identified . given the negative neoplastic and infectious workup , therapy with 2 mg / kg of methylprednisolone was initiated for empiric treatment of a primary central nervous system vasculitis .
fluorescein retinal angiography os . arrows highlight extravasation of fluorescein dye . within 3 days of therapy initiation , an improvement in both her gait and vision occurred .
one month after steroid initiation , a repeat mri demonstrated that the punctuate lesions previously seen throughout the brain and spinal cord were no longer contrast enhancing .
four months after the start of steroid treatment , the vitritis and papillitis had resolved , she was able to walk a longer distance with less effort and fatigue , and her incontinence had improved substantially .
unfortunately , 2 months after cessation of steroids her gait abnormalities , visual disturbances , arthralgias , and urinary incontinence abruptly worsened , prompting a repeat mri scan that revealed progression of her contrast - enhancing spinal and brain lesions as compared to the initial study .
given the severity of her symptoms , brain , bone marrow , and conjunctival biopsies were performed .
three separate central nervous system biopsy specimens were obtained from the dura , parenchyma , and ependymal lining .
however , the ependymal biopsy demonstrated atypical areas of well - demarcated inflammation ( reactive astrocytes , lymphocytes , macrophages , and activated microglia ) and proportional loss of axons and myelin in a perivascular distribution but without clear evidence of vasculitis as shown in figure 3 .
luxol fast blue / periodic acid schiff 10. marked demyelination on the left of the line compared to the normal white matter on the right . on the left ,
the inflammation extends from these vessels ( arrow ) and is somewhat clustered around these areas .
given the evidence of neuroinflammation on biopsy , an empiric course of intravenous immunoglobulin was initiated . despite treatment ,
plasma exchange was then performed a total of 7 times with incremental improvement in her symptoms after each treatment .
given the constellation of her symptoms ( visual and gait disturbances , arthralgia , and psychiatric problems ) , ophthalmologic ( vitritis , papillitis , and uveitis ) and biopsy findings ( proportional loss of myelin and axons in an inflammatory background ) , and history of recurrent oral ulcers , a presumptive diagnosis of neuro - behet disease was made .
twenty - four months after starting azathioprine , she regained her original lower extremity strength and visual acuity , has no complaints of abdominal pain , and has not had any further gait disturbance .
behet proposed that the herpes virus was the cause of the disease and indeed there is evidence showing a greater presence of herpes simplex virus dna in saliva in patients with behet disease , although nearly 60% of patients with behet disease had no herpes simplex virus isolated . 
 
an autoimmune model for the disease has also been proposed after the observation of cd4 + t cells present in perivascular infiltrates and increased circulating levels of interleukin 8 .
the autoimmune proposal was bolstered after gene sequencing revealed a candidate gene for behet disease to be located between the coding regions for hla b and tumor necrosis factor . 
 
behet disease can also be classified as an autoinflammatory disease with a degree of symptom overlap with another autoinflammatory disease , familial mediterranean fever .
indeed , one study of patients with behet disease revealed a higher than expected mutation rate in the gene associated with familial mediterranean fever , mefv . 
 
the presence of neutrophils in the pathologic lesions of behet disease further supports the important role of the innate immune system in the development of this disease .
the most common symptoms of behet disease in adult and pediatric cases are oral aphthous ulceration ( 95%-100% ) and uveitis ( 30%-75% ) . a broad spectrum of other manifestations have been described , including rashes , arthritis , arterial and venous vasculitis , and central nervous system lesions . when compared to adults ,
children are less likely to have genital ulcers and vascular lesions but are more likely to have arthralgia and central nervous system symptoms . in 1990 ,
the international study group for behet disease published criteria for the diagnosis of behet disease requiring the presence one mandatory criteria ( recurrent oral apthous ulcers ) and at least 2 minor criteria , which are listed in table 2 .
recurrent oral apthous ulcers ( at least 3occurrences in a 12-month period recurrent genital ulcers skin lesions ( ie , erythema nodosum ) positive pathergy test the spectrum of central nervous system findings in neuro - behet disease can vary widely .
metreau - vastel et al described a series of 12 children with neuro - behet disease in 2010 . in this report , they describe focal neurologic deficits as the most common symptom , occurring in 4 of 12 patients .
recurrent meningoencephalitis and rhombencephalitis were the second most common findings , each occurring in 2 of 12 patients .
nonspecific psychiatric symptoms have been described in other cases , including changes in affect , auditory and visual hallucinations , and suicidal behavior . 
 
no standardized treatment has been proposed for behet disease or neuro - behet disease as the presentation and involved organ systems vary widely .
the european league against rheumatism ( eular ) published a set of guidelines , based on an analysis of published literature , for the treatment of behet disease organized by affected organ system . in these guidelines ,
cyclosporine a was described as a highly effective agent for the treatment of ocular disease . however , as later noted , cyclosporine a has been shown to potentiate neurologic symptoms in several cases of behet disease and so should not generally be utilized in patients having behet disease with preexisting central nervous system symptoms .
although , no randomized , controlled trial has been conducted for the treatment of neuro - behet disease , azathioprine , corticosteroids , and methotrexate have been used in published reports .
in addition , more recent reports have described the off - label use of antitumor necrosis factor agents ( ie , infliximab , etanercept , and adalimumab ) with promising results . due to its use in the treatment of lupus - related neuropsychiatric symptoms and a relatively good side effect profile , we chose to utilize azathioprine as a steroid - sparing agent in our patient and were able to achieve an excellent outcome .
 we describe a case of neuro - behet disease diagnosed in a 12-year - old girl . 
 this patient presented with recurrent oral ulcers , incontinence , spastic gait , blurry vision , and asymmetrical lower extremity hypertonia . 
 extensive testing revealed punctate lesions through the central nervous system , vitritis , papillitis , and uveitis . a thorough infectious and neoplastic workup was negative . 
 she was treated with pulse steroids and azathioprine with gradual improvement in her gait and ophthalmologic findings . 
 although rare , primary neuro - behet should be considered in pediatric patients with neurologic abnormalities and recurrent aphthous ulcers without other explanation . 
Case Report
Discussion