langerhans cell histiocytosis ( lch ) refers to a clonal , neoplastic expansion of langerhans cells .
stimulation by tumor necrosis factor  and granulocyte - monocyte colony - stimulating factor has been implicated in the pathogenesis ( as has human herpesvirus 6 ) .
it most commonly affects children between the age of 1 and 4 , although cases have been described in all age groups ; the incidence in pediatrics has been estimated at 25 per million / year .
it is exceptional for lch to present with brain involvement as the sole presenting symptom .
this complication is reported as occurring in 14% of patients with multisystem disease , typically 520 years from the initial diagnosis .
he developed depression , anxiety and agitation , which led to his retirement from construction work .
shortly thereafter , he developed episodes described as hyperventilation , lasting from seconds to minutes , mostly in the morning , which were followed by confusion and a severe  pounding headache affecting the whole head , both of which lasted for hours .
one year prior to presentation , his family described personality changes ( it was hard for them to characterize this further ) and worsening confusion , particularly over the preceding 3 months .
three months before presentation , he developed weakness of the right leg , which had been slowly progressing since .
two weeks prior , it became so bad that he needed help walking . at this time
, he also noticed weakness of the right arm and slurring of speech , which led him to seek medical help . he had been diagnosed with peripheral arterial disease ( claudication in his left leg ) 4 months prior to presentation , and paroxysmal atrial fibrillation 1 month prior
his initial review of systems revealed that he was anorexic and had lost 30 lb over the last 2 years .
he also complained of a loss of libido and an occasional shortness of breath when walking . on initial exam ,
he was unable to sustain upward gaze ; vertical saccades were followed by a slow downward drift , then a compensatory saccade .
he had a weakness of the right side of his face , sparing the forehead .
he was weak throughout , with strength of 4/5 on his right side in an upper motor neuron pattern with signs of spasticity ; babinski 's reflex was present on this side .
his initial complete blood count , comprehensive metabolic panel , serum protein electrophoresis and folate were normal apart from a white cell count of 13  10/l ( 95% neutrophils ) and platelets of 570  10/l .
his sodium was initially normal , but , during his admission , it was generally in the range of 145160 mmol / l .
mg / l ( < 10 ) , and the erythrocyte sedimentation rate 60 mm / h ( < 20 ) .
he was hypothyroid with a thyroid - stimulating hormone ( tsh ) level of 5.6 iu / ml ( < 4.9 ) and a free t4 of 0.6 ng / dl ( > 0.7 ) .
he had hypogonadism ( presumably secondary ) with total testosterone of < 20 ng / dl ( > 200 ) .
a lumbar puncture was done shortly after admission , showing 4 red cells , 9 white cells ( 56% lymphocytes , 43% macrophages ) , and a protein level of 45 mg / dl ( < 35 ) .
oligoclonal bands were absent and cytology showed no signs of malignancy . shortly after admission , a complete serum paraneoplastic panel was sent ; this was negative .
the antibodies reported were : anti - neuronal nuclear types 13 , anti - glial nuclear type 1 , purkinje cell types 12 and type tr , amphiphysin , crmp-5-igg , striatal , t / q and n - type calcium channels , ach receptor - binding , ach receptor ganglionic and neuronal voltage - gated k channels .
mri is notable for the presence of t2-hyperintense lesions in the left frontal lobe , the right mesial temporal lobe and the brainstem , which were minimally enhanced .
an mr perfusion scan of the brain showed no significant increase in relative blood volume or relative blood flow in these lesions .
a ct of the thorax , abdomen and pelvis showed 5 small lung nodules ( maximum diameter 6 mm ) and a pneumatocele in the left lower lobe .
as there was nothing further on history , exam or initial investigations to suggest cancer anywhere else , a pet / ct was not performed .
immunohistochemistry shows the lesion to be cd1a- and s100-positive , which is characteristic for histiocytosis .
initially , we were unsure of the cause of his right temporal lesion . given the rarity of lch with onset in the central nervous system ( cns ) in adults , the possibility of another tumor was raised , and so a second biopsy was performed .
in retrospect , it would have been better to avoid performing this , as the diagnosis was already clear and his other lesions were attributable to lch .
furthermore , the procedure precipitated status epilepticus and led to preventable complications which ultimately contributed to his death .
this illustrates mild edema , hypercellularity and reactive changes , all of which are consistent with the edge of an inflammatory process .
septic shock ( likely due to ventilator - associated pneumonia ) and a pulmonary embolism complicated his course thereafter .
histiocytosis affecting his skull was thought to be in remission as a result of the treatment , as there was no sign of new or enlarging lytic lesions .
after discharge from the icu , he showed signs of critical illness myopathy / neuropathy .
there was widespread muscle atrophy and generalized weakness . he was unable to stand without support and his tracheostomy remained in place .
given the suspicion of paraneoplastic brainstem inflammation , he was started on intravenous immune globulin ( ivig ) 400 mg / kg  5 days .
two weeks after the initial treatment , the brainstem showed some improvement in the degree of flair hyperintensity ( fig .
an mri 1 month after a second course of ivig showed these changes to be stable overall , with some increase in pontine enhancement ( fig .
he then developed recurrent pneumonia and septic shock , again requiring an icu admission . following this , his family elected a palliative approach to care and he died 6 months after his initial presentation .
our patient 's episodes of hyperventilation followed by confusion are typical for seizures involving the right mesial temporal lobe ; the similarity to panic attacks has previously been identified in a case series .
the development of status epilepticus following biopsy of this region lends support to this being an epileptogenic focus . in
his cerebrospinal fluid ( csf ) , the finding of a high proportion of macrophages is striking .
we were unable to find literature specifically addressing the significance of this finding ; classically it is said to be associated with meningitis due to fungi or tuberculosis .
none of the other case reports we studied , including one with langerhans cells in the csf , reported this finding .
one series has shown elevations of neurofilament protein light chain , glial fibrillary acid protein and total tau protein in the csf of patients with lch affecting the brain .
these advise the use of cladribine for patients such as ours with multisystem and cns involvement ( cytarabine is thought be a reasonable alternative ) .
myelosuppression is the main dose - limiting toxicity ; this has best been studied in the setting of hairy cell leukemia where neutropenia was reported in 70% , anemia ( hb < 8 g / dl ) in 35% and thrombocytopenia in 10% of patients .
the most recent and thorough description of the neuropathology of lch comes from a series of 12 cases from grois et al .   in 2005
the authors divide the pathology into 3 categories : ( 1 ) the typical circumscribed granulomas found in other organs ; ( 2 ) infiltrating granulomas with profound t - cell dominated inflammation and severe neurodegeneration ; ( 3 ) neurodegenerative lesions lacking langerhans cells , typically affecting the brainstem and cerebellum and resembling paraneoplastic encephalitis .
it appears that the temporal and frontal lesions in our patient were of the second type ; it is probable that the biopsy came from the neurodegenerative part of the lesion rather than that containing langerhans cells .
the mri appearances of the brainstem in our patient are typical of the third type .
the presence of inflammation without langerhans cells has led to the view that these lesions are paraneoplastic in origin and that the neurodegeneration seen is thus autoimmune .
the langerhans cells are thought to take up normal neuronal antigens , provoking an immune response to these ; alternatively , the immune system may target antigens shared by langerhans cells and microglia . if an antigen is involved , the pathology reported by grois et al .  
the antigens responsible for this phenomenon have not been identified and thus it was to be expected that our patient 's paraneoplastic panel was negative . using multiple immunosuppressants
langerhans cells in their normal form are thought to have a lifespan of months , and lch is characteristically a slowly progressive disorder .
by contrast , cytotoxic t - cells typically have a half - life of 2448 h when activated .
when used in the treatment of leukemia and lymphoma , it is typically given every 4 weeks .
thus , the initial doses of cladribine would have been expected to lead to the death of a majority of neoplastic histiocytes while the t - cell - mediated inflammation would have been expected to resume within 34 weeks .
ivig would not have been expected to affect the viability of langerhans cells , but should have reduced t - cell activity for 34 weeks .
it leads to a selective decrease in t - cells overall and an increase in regulatory t - cells . in children with lch
, ivig has been reported to contribute to a stabilization of inflammation in 4/5 patients treated and to enable long - term remission in 1 case [ 11 , 12 ] .
it has been suggested that ivig be given prophylactically to prevent the development of cns complications of lch , particularly diabetes insipidus , which tends to be irreversible .
alternative agents reported to treat the paraneoplastic inflammation in lch include vincristine / cytarabine and all - trans - retinoic acid .
the use of steroids in our patient would not have been expected to have had long - lasting effects .
bearing the above in mind , as well as the results of treatment in other t - cell - mediated paraneoplastic conditions , strong consideration should be given to agents that primarily target t - cells : steroids , ivig , plasma exchange and mycophenolate mofetil or cyclophosphamide .
other paraneoplastic disorders recognized in patients with lch include cancer - associated retinopathy and spinocerebellar degeneration .
brain imaging should always be undertaken in an older patient with episodes suggestive of seizures , diabetes insipidus of central origin or symptoms suggestive of pituitary dysfunction .
once a diagnosis of lch is made , a brain biopsy is not essential if the mri appearances are typical for the inflammatory processes that accompany this condition .
once lch appears stable , prolonged treatment may be needed to prevent recurrence of inflammation .
ivig appears to be a reasonable adjunct to cladribine , particularly in a case such as this where cytopenias or infections limit the use of conventional chemotherapy .
 we report a case of langerhans cell histiocytosis in a 64-year - old male who presented with symptoms and signs of brain involvement , including seizures and hypopituitarism . 
 the diagnosis was confirmed with a biopsy of a lytic skull lesion . 
 the disease affecting the bone showed no sign of progression following a short course of cladribine . 
 signs of temporal lobe involvement led to an additional biopsy , which showed signs of nonspecific neurodegeneration and which triggered status epilepticus . 
 lesions noted in the brainstem were typical for the paraneoplastic inflammation reported in this condition . 
 these lesions improved after treatment with cladribine . 
 they remained stable while on treatment with intravenous immune globulin . 