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Show Journal of Nemo- Ophthalmology 19( 1): 49- 53, 1999. © 1999 Lippincott Williams & Wilkins. Inc., Philadelphia Visual Loss With Langerhans Cell Histiocytosis: Multifocal Central Nervous System Involvement Oliver M. Job, M. D., Norman J. Schatz, M. D., and Joel S. Glaser, M. D. A 42- year- old woman with a 6- year history of diabetes insipidus and progressive hypersomnolence presented with visual loss. Neuroimaging showed infiltration in the hypothalamus, the optic nerve, and the chiasm, as well as multiple lesions in other areas of the brain parenchyma. Biopsy showed Langerhans cell histiocytosis. This is an unusual presentation of Langerhans cell histiocytosis, involving the visual pathways without manifestations outside of the central nervous system. The differential diagnosis and the magnetic resonance imaging findings will be discussed. Key Words: Langerhans cell histiocytosis- Visual pathway involvement- Optic chiasm- Optic nerve- Infiltrative optic neuropathy- Radiation therapy- Magnetic resonance imaging. CASE REPORT A 42- year- old obese black woman presented with complaints of blurred vision in both eyes, progressive over 4 months. She had been hypersomnolent, sleeping day and night, even at meals and while driving. She had experienced abnormal thirst since 1992, with excessive intake of fluids. In 1993, diabetes insipidus was diagnosed. Magnetic resonance imaging ( MRI) done at that time showed a lesion of the pituitary stalk ( Fig. 1 A) and other enhancing lesions of the brain parenchyma. No further investigations were performed. Therapy with desmopressin acetate was initiated and continued for 2 years. In 1997, panhypopituitarism was diagnosed after the patient gained approximately 50 pounds, and daily therapy was begun with 25 mg cortisone acetate and 0.075 mg levothyroxine. Magnetic resonance imaging was repeated and showed evidence of an infiltrating lesion of both optic nerves and the chiasm ( Fig. IB). The previous parenchymal lesions were unchanged ( Fig. 2A). During our examination in February 1998, the patient tended to fall asleep. Vision in both eyes was severely impaired: RE, searching, 20/ 100 at distance, but J2 at near; LE, 20/ 40 at distance and J3 at near. She could read only the nasal characters on the charts, with both eyes. Manuscript received August I 1, 1998; accepted October 30, 1998. From the Department of Neuro- Ophthalmology, Mercy Neuro-science Institute, Miami, Florida. Address correspondence to Norman J. Schatz, M. D., Mercy Neuro-science Institute, Suite 209, 3661 South Miami Ave., Miami, FL 33133. Color vision was 1/ 11 right and 8/ 11 left. No afferent pupillary defect was found. Eye movements were full without nystagmus. Ophthalmoscopy showed bilateral pale optic discs. Humphrey visual fields ( full threshold, 30- 2, stimulus size III) demonstrated bitemporal hemi-anopic scotomas extended interiorly ( Fig. 3, top). Laboratory values included erythrocyte sedimentation rate 48 mm/ h with a normal complete blood count; elevated blood glucose ( 157- 359 mg/ dl); and panhypopituitarism ( total T4: 3.1 ng/ dl, thyrotropin 0.8 mU/ I, follicle- stimulating hormone 1.7 ng/ ml, luteinizing hormone: 0.2 ng/ ml, morning Cortisol 2.3 ng/ ml). Other blood chemistries were within normal limits. Cerebrospinal fluid studies were normal ( red blood cell: 0, white blood cell: 0, Protein 40 mg/ dl, Glucose 109 mg/ dl, Venereal Disease Research Laboratory test: nonreactive). The results of cerebrospinal fluid Immunoelectrophoresis were normal. The level of angiotensin converting enzyme, tested in blood and cerebrospinal fluid, was normal. Further workup for sarcoidosis with chest x- ray and gallium scan was normal. Magnetic resonance images, done in 1993 and 1997, are shown in Figures 1 A and B and 2 A and B. In February 1998, a biopsy of the left frontal brain lesion was performed. Histologic examination showed a spindle and epithelioid histiocytic neoplasm with mixed inflammatory background composed of neutrophils, eosinophils, lymphocytes, and plasma cells. Numerous reactive astrocytes were also noted ( Fig. 4). Further im-munohistologic studies with stains for S- 100, CD- 68, and CD- 1 a protein, respectively, confirmed the diagnosis of Langerhans cell histiocytosis ( LCH). To rule out involvement of other organ systems, a radiographic metastatic survey was done, including cervical spine, skull, thoracic spine, pelvis, and long bones. No other lesion could be demonstrated. The patient was treated with intravenous methylprednisolone ( 2 g/ day) for 3 days with a dramatic improvement of visual acuity ( right 20/ 25 and left 20/ 40) and visual fields ( Fig. 3, bottom). Oral prednisone 40 mg daily stabilized the situation. After 1 month, the steroids were tapered to 20 mg/ d and the visual acuity deteriorated to a level of right 20/ 80 and left 20/ 60. Follow- up MRI in April 1998 demonstrated no change in the infiltrated optic nerves and chiasm. Con- ACi 50 O. M. JOB ET AL. FIG. 1. Magnetic resonance imaging ( TE: 20; TR: 570; with gadolinium) coronal section at the level of pituitary and optic chiasm. A: ( 1993) Enhancing lesion of pituitary stalk ( large arrow) and normal chiasm ( small arrow). B: ( 1997) Enhancing lesion of the optic chiasm and hypothalamus ( large arrow). ventional radiation therapy of 2000 rad ( 200 rad/ session) to the chiasm was performed. Follow- up acuity and field defects after radiotherapy were unchanged at right 20/ 80 and left 20/ 60. DISCUSSION Langerhans cell histiocytosis is a disorder of the mononuclear- phagocytic system. The exact etiology is FIG. 2. Magnetic resonance image ( TE: 20; TR: 570; with gadolinium) at the level of suprasellar region. A: Axial image demonstrating lesions ( arrows) of left frontal, right parietal, and callosal parenchymal lesions ( also in image B). B: Coronal section demonstrating both optic nerves enlarged and enhancing ( arrow) and callosal and right parietal parenchymal lesions ( open arrows). J Neum- Ophllmlmol, Vol. 19. No. I. 1999 VISUAL LOSS WITH LANGERHANS CELL HISTIOCYTOSIS 51 FIG. 3. Automated visual fields ( Humphrey field analyzer, central 30- 2 full threshold test with white stimulus, size III). Graytone plots were obtained at first consultation ( top) and after 3 weeks of steroid administration ( bottom), showing improvement of visual fields. unknown, but immune dysregulation and defect transformation of monocytes into abnormal histiocytes has been suggested ( I). The pathologic hallmark of LCH is the accumulation of Langerhans cells, which produce S- 100, CD- 68, and CD- la- protein. In the electron microscopy, typically a structure resembling a zipper, called a " Bir-bek body" ( 2), is attached at the cell membrane of the Langerhans cell. The disease occurs predominantly in children between ages 1 and 15 ( 3) and affects bones with hematopoietic " ssSffli illilSSs p*.. * *- -' ' \ i. JTHB** 1 ^ TnfBjBtiw^ fr'p? RE^^ SMsagaiEt; H: : V ; v '<*• • « *>?,:>*• ^ » V » ^ ! - * % : f l « i • • ; • • '-,-*• | Byfc$ 2ra t*^ HfiHB?||. ;? tff^ ^ wfflfci^ ft^ •#! Wl : iU",-. -, v-* ' H.'-* » -. FIG 4. Histopathologic appearance of left frontal lesion: histiocytes, Langerhans cell ( arrow), gemistocytic astrocyte ( small arrow), and oligodendroglial cell ( fat arrow). activity, lung, skin, lymph nodes, spleen, and liver. The disease is called Letterer- Siwe disease in children younger than 2 years and takes the form of a multisystem disorder, involving visceral organs and lymph nodes ( 4). Hand- Schiiller Christian Disease, another manifestation of LCH, typically occurs in older children and manifests with the triad of bony defects of the skull, proptosis, and diabetes insipidus. Onset in adulthood is seen only in approximately 10% of all patients with LCH ( 5). Preferential location of involvement in adults is controversial. However, in the series of Baumgartner ( 12) with 19 adult patients meeting the criteria of LCH, the axial skeleton and the base of the skull were most often affected. Involvement of CNS is well recognized, but it is rarely solely affected. Central nervous system symptoms rarely figure as presenting signs. The greatest risk for CNS complications appears to be in patients with multiple bone lesions and involvement of other organ systems ( 7). Kepes et al. ( 11) report that these patients are most often older children or adults. However, Grois et al. ( 7) found no significant age difference between patients with CNS-LCH and LCH in general. The frequency of clinical involvement of the CNS is not precisely known. The literature ( 6) suggests that 48% of all cases of LCH show lesions in the CNS, but only 4% of CNS- LCH patients demonstrate lesions in areas other than in the pituitary or hypothalamus ( 7). Essentially, all parts of the CNS can be involved. The clinical picture varies: there arc the lesions arising from bone, meninges, or choroid plexus, manifesting be- ./ Ni'iim- Onhllmlnml. Vnl 19 No I !<>')') 52 O. M. JOB ETAL. cause of their location; and conversely, there is a form, described by Grois ( 8), that shows progressive neurologic deterioration with mainly cerebellar- pontine symptoms. The infiltration of the hypothalamus ( 6,9,10) ( Ga-gel's granuloma) ( 6,11) typically presents with diabetes insipidus and panhypopituitarism and is normally part of a multiple organ disease. Only a few cases are described with a single manifestation of LCH in the pituitary and hypothalamus ( 9). The diagnosis of LCH is rarely considered before biopsy ( 4,12). Parenchymal LCH, as well as infiltration of the hypothalamus, are typically related to lesions of the base of the skull. Also, parenchymal lesions are most often seen with infiltration of the hypothalamus ( 13). Continuity of lesions of the base of the skull and parenchymal lesions is rare ( 7). Currently, these phenomena are not well understood. The relationship between lesions of the base of the skull and infiltration of the hypothalamus is well known ( 7). Disturbance of the visual system is quite often seen. In a study of 23 cases of CNS- LCH, in 16% of the patients parts of the visual pathways were involved ( 14), predominantly the orbits. In the study of Moor et al. ( 15), an ophthalmic review of LCH, 18 of 76 patients were found to have orbital involvement, 4 with " further neuroophthalmic complications." The presenting signs were proptosis, optic atrophy, disc edema, and ptosis. The orbital lesions commonly consist of a destructive lesion of the lateral wall of the orbit and the greater wing of the sphenoid with a large soft- tissue component that extend into the extraconal space of the orbit, the ocular adnexa, the infratemporal fossa, and into the middle cranial fossa, respectively ( 16). Only a few patients show intracranial involvement of visual pathways ( 17- 20). One mechanism thereby is the infiltration of the chiasm and the optic nerves, starting in the nearby pituitary stalk or hypothalamus. Another is compression caused by a base of the skull lesion along the course of the optic nerve. The MRI findings in LCH of the CNS are variable. Three different patterns of MRI images could be differentiated in the study of Grois et al. ( 1): Type I showed multiple, poorly defined white matter lesions; Type 2 included well- defined white and gray matter parenchymal lesions, associated with a progressive course of the disease; and Type 3 was associated with extraparenchy-mal, meningeal masses. Bruyn ( 21) classified a form of CNS- LCH arising from bone, especially from the base of the skull, in contrast to lesions arising from the meninges and parenchyma. Our patient had previously been diagnosed with diabetes insipidus of unknown etiology in 1993, although a pituitary stalk enhancing lesion and multiple other brain lesions were present. Her fatigue, polyuria/ polydipsia, and weight gain suggested progressive hypothalamic and pituitary involvement. The later neuro- ophthalmic findings of reduced vision in both eyes with inferior bitemporal field defects are consistent with posterior chiasmal involvement. The MRI images of 1997 showed infiltration of the chiasm, optic nerves, the hypothalamus, and the brain parenchyma. The distribution of lesions, although nonspecific, is consistent with Type 2 of Grois' classification and is considered to have a poor prognosis, with progressive disease. The differential diagnosis of a multifocal infiltrative process in the pituitary stalk, hypothalamus, and optic chiasm region includes germinomas, sarcoidosis, craniopharyngioma, glioma ( 22), xanthoma disseminatum ( 23), leukemia, metastatic disease, and histiocytosis. A diagnosis cannot be established on clinical grounds; therefore, biopsy is essential. Angiotensin- converting enzyme levels in serum and cerebrospinal fluid, a gallium scan, and the radiologic evaluation of the thorax are required to rule out sarcoidosis. CONCLUSIONS Our patient's condition represents a rare case of LCH without bony lesions and with localized CNS involvement of the optic nerves and chiasm. The similar presentation of neurosarcoidosis indicates the importance of a pathologic confirmation. REFERENCES 1. Leikin SL. 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