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Show lou mal of Clinical Neuro- ol'htiullmology 11( 1): 25- 30, 1991. © 1991 Raven Press, Ltd., New York Reactive Lymphohistiocytosis with Recurrence in the Optic Chiasm Steven L. Galetta, M. D., Edward A. Stadtmauer, M. D., David G. Hicks, M. D., Eric C. Raps, M. D., Gregory Plock, M. D., and J. Carl Oberholtzer, M. D., ph. D. Histiocytic infiltration of the optic chiasm is rare. We report a patient with a seizure disorder on anticonvulsant therapy, who developed systemic reactive histiocytosis. Treatment with splenectomy, corticosteroids, and anticonvulsant medication change resulted in clinical remission. The patient later developed recurrent lymphohistiocytosis restricted to the optic chiasm. Extensive reevaluation yielded no evidence for infectious or malignant etiology. Radiation therapy and withdrawal of anticonvulsant therapy resulted in clinical remission. We conclude that both phenytoin and phenobarbital may trigger a lymphohistiocytic process and that infiltration of the visual pathway is possible. Key Words: Lymphohistiocytosis- Optic chiasmPhenytoin- Phenobarbital. From the Departments of Neurology ( S. L. G., E. CR., G. P.), Pathology ( D. G. H., J. CO.), and Hematology-. Oncology ( E. A. S.), University of Pennsylvama School of MedlCme, Philadelphia, Pennsylvania, U. S. A. Address correspondence and reprint requests to Dr. Steven L. Galetta at Hospital of the University of Pennsylvama, Department of Neurology, 3400 Spruce Street, Philadelphia, PA 19104, U. S. A. 25 Histiocytic disorders are diverse conditions that result from an abnormal proliferation of Langerhans or non- Langerhans macrophages. Histiocytosis X refers to the idiopathic Langerhans cell disorders that include eosinophilic granuloma of bone, Hand- Schuller- Christian disease and Letterer- Siwe disease ( 1,2). Langerhans macrophages are distinguished by the presence of Birbeck granules on electron microscopy and the detection of OKT6 cell surface antigens by immunologic techniques ( 2). In contrast, non- Langerhans cell proliferation may be neoplastic, paraneoplastic, familial, reactive ( immunologic activation of the mononuclear phagocytic system), or the consequence of an immunodeficiency disorder ( 1,2). A concurrent lymphocytic infiltration may be present ( 3). In 1979, Risdall described the clinical syndrome of reactive histiocytic hemophagocytosis and pancytopenia associated with various viral infections ( 4). Subsequently, the spectrum of organisms believed to stimulate a non- Langerhans histiocytic proliferation broadened to include infection with bacteria, fungi, mycobacteria, rickettsia, and other parasites ( 5). Agents such as beryllium, zirconium, and phenytoin have also been reported to trigger a histiocytic process ( 1,6). The proliferating histiocytes in a reactive process are morphologically mature, cytologically benign, and display prominent erythrophagocytosis. In contrast, a malignant infiltrate usually consists of immature and cytologically malignant cells exhibiting little or no evidence of hemophagocytosis ( 4). We present the clinical, radiologic, and pathologic features of a patient who developed a reactive nonLangerhans histiocytosis of the optic chiasm. 26 S. L. GALETTA ET AL. CASE SUMMARY A 30- year- old male was well until 1980, when he sustained a skull fracture and cerebral contusion after being struck by a baseball bat. A posttraumatic seizure disorder was treated with phenytoin. The patient did well until January, 1988, when he developed night sweats, fevers, abdominal pain, and a 13- pound weight loss. He was admitted to an outside hospital with a temperature of 102° F and marked splenomegaly. Laboratory data at admission revealed a leucocyte count of 900 cells/ mm3 , with 15% segmented neutrophils, 9% bands, 69% lymphocytes, 1% monocytes, and 4% metamyelocytes. The hemoglobin was 6.7 g/ dl and the platelet count was 22,000/ mm3 . Serum chemistries were remarkable for a lactate dehydrogenase of 509 U/ L, aspartate aminotransferase 136 U/ L, alanine aminotransferase 170 U/ L, a bilirubin 0.5 mg/ dt and a reticulocyte count of 1%. The direct Coombs, hepatitis surface antigen, and monospot tests were all negative. The sedimentation rate was 2 mrn/ h; LEprep and rheumatoid factor were negative. Cytomegalovirus and herpes simplex titers were negative. Epstein- Barr virus, varicella zoster virus, and toxoplasmosis studies were consistent with past or inactive infection. A stool culture was negative for parasites and pathogenic bacteria. Chest radiograph was normal. Computed tomography ( CT) of the abdomen and pelvis was significant for marked hepatosplenomegaly without lymphadenopathy. A bone marrow biopsy revealed a hypercellular marrow with decreased hematopoietic cells, an infiltrate of small lymphocytes and histiocytes, abnormal megakaryocytes, and focal fibrosis. This was felt to be nondiagnostic. A liver biopsy showed a mild peri- portal lymphoid infiltrate and extramedullary hematopoiesis. The patient was transferred to the Hospital of the University of Pennsylvania on February 19, 1988, for further evaluation of his worsening pancytopenia. The diagnosis of lymphoma was considered, and the patient underwent an exploratory laparotomy and resection of a massively enlarged spleen. Pathologic examination of the spleen revealed extramedullary hematopoiesis, an infiltrate of benign- appearing histiocytes exhibiting marked erythrophagocytosis, and small mature lymphocytes, consistent with a reactive histiocytosis ( Fig. 1A). Lymphocyte subset analysis performed by both immunohistochemistry and flow cytometry showed a predominance of T cells with no abnormal phenotypes and with a normal helperto- suppressor ratio. Similarly, gene rearrangement studies nf th:: BChalf! of the T cell receptor failed to ? 1 ',,',", 1 I '- I ~~ I show evidence of monoclonal or otherwise abnormal cell population. S- 100 staining of the splenic tissue was negative. The abdominal lymph nodes sampled were histologically normal except for the presence of hemophagocytosis wit~ . medull~ sinuses. The patient experienced significant clinical and laboratory improvement on prednisone after splenectomy. In addition, his phenytoin was switched to phenobarbital therapy. His platelet count and white count returned to normal, and prednisone was discontinued in March, 1989. In August, 1989, the patient presented to the Neuro- ophthalmology service with decreasing vision of several weeks' duration. There was no family history of lymphohistiocytosis. His examination was notable for a visual acuity of 20/ 30 in the right eye and 20/ 40 in the left. Visual fields revealed a central scotoma in the right eye and an inferior temporal defect in the left eye that respected the vertical meridian. Brain magnetic resonance imaging ( MRI) revealed enlargement and enhancement of the optic chiasm ( Fig. 2), and a two- week empiric trial of 60 mg of prednisone was administered. Despite corticosteroids, the patient's visual acuity dropped to 20/ 200 in the right eye and 20/ 80 in the left. He was admitted for intravenous pulse steroid therapy. During his hospital course, his visual acuity improved to 20/ 80 in the right eye and 20/ 50 in the left. The repeat bone marrow, chest, and abdominal CT, complete blood count, and serum chemistry panel were unremarkable. A purified protein derivative skin test ( PPO) was negative with a positive skin reaction to mumps. The patient had three lumbar punctures and the results showed WBC ( cells/ mm3 ) 6,4,4, ( greater than 90% lymphocyte predominance); glucose ( mg/ dl) 57, 67, 137; protein ( mg/ dl) 57, 69, 36, respectively. The cerebrospinal fluid ( CSF), cytology, and cultures were negative on all specimens, and the electrophoresis showed an elevated total protein, but normal CSF- IgG ratio and absent oligocolonal bands. A repeat MRI of the brain was unchanged. The patient was discharged on September 18, 1989, on an oral regimen of prednisone 60 mg. In October, 1989, his visual function was stable and prednisone was tapered to 40 mg a day. The MRI showed marked improvement in the patient's chiasm lesion with a 50% decline in size ( Fig. 3). In November, 1989, his visual acuity was 20/ 50 0.0., and 20/ 40 0.5., and steroids were tapered to 30 mg a day. In early January, he was noted to have a visual acuity of 20/ 50 in the right eye and 20/ 200 in the left, with a bitemporal hemianopsia. He was readmitted for intravenous pulse corticosteroid therapy. Human immunodeficiency virus, HTLV1, Lyme, MHA- TP, brucella, and rickettsia titers / LYMPHOHISTIOCYTOSIS IN THE OPTIC CHIASM FIG. 1. Histopathology of Iymphohistiocytic infiltrate. A: Hematoxylin- eosin micrograph of spleen showing atrophy of the white pulp, extramedullary hematopoiesis and expansion of sinuses by infiltrate of lymphocytes and histiocytes. Inset demonstrates erythrophagocytosis ( arrow). Original magnification x40 and x400, respectively. B: Hematoxylin- eosin micrograph of optic chiasm biopsy showing diffuse infiltration by mononuclear cells. Inset demonstrating infiltrate of mature lymphocytes and benign histiocytes. Original magnification x50 and x400, respectively. 27 were negative. A repeat lumbar puncture showed 2 white blood cells/ mm3 , glucose of 60 mg/ dl, protein of 82 mg/ dl, with negative cultures and cytology. An MRI of the brain revealed enhancement of " , the left optic nerve and chiasm junction. Visual function did not improve with corticosteroid therapy, and the patient underwent biopsy of the left optic nerve- chiasm junction. Histology revealed a JClin Neuro- ophthalmol, Vol. 11, No. 1, 1991 28 A S. L. GALETTA ET AL. FIG. 2. T1- weighted MR image with gadolinium demonstrating enlarged and diffusely enhancing optic chiasm in saggital ( A) and coronal ( 8) planes ( arrows). 8 reactive lymphocytic and histiocytic infiltration similar to the original pathology ( Fig. 1B). Electron microscopy showed benign non- Langerhans macrophages without viral inclusions. No Birbeck granules were seen. Immunohistologic studies showed a mixed population of mature T lympho-cytes expressing a normal phenotype. A COl1 stain confirmed the presence of benign- appearing macrophages ( Table 1). The patient was treated with radiation therapy 3,600 cGy to the optic chiasm and visual acuity remained stable at 20/ 500.0. and 20/ 200 0.5. Phe- A 8 FIG. 3. T1- weighted MR image with gadolinium showing resolution of optic chiasm enhancement and enlargement following corticosteroid therapy. Saggital ( A) and coronal ( 8). //.-----------......... LYMPHOHISTIOCYTOSIS IN THE OPTIC CHIASM 29 DISCUSSION TABLE 1. Immunohistochemical subset analysis of optic chiasm infiltrate nobarbital and corticosteroid therapy have been discontinued without recurrence of seizures or neurologic dysfunction. Repeat MRl 6 months and 1 year after radiation therapy showed no gadolinium enhancement in the optic chiasm region. FollOw- up evaluation 1 year after surgery disclosed no new systemic complaints, and visual function remained unchanged. Our patient developed an unusual histiocytic syndrome initially associated with pancytopenia, hepatosplenomegaly, extramedullary hematopoiesis, erythrophagocytosis, and lymphadenopathy. A complete systemic remission was achieved with corticosteroid therapy and discontinuation of phenytoin therapy. However, S months after stopping corticosteroids, and while on phenobarbital, the patient developed progressive visual decline suggesting a chiasmal process. A subsequent biopsy revealed mature cytologically benign histiocytes and lymphocytes infiltrating the optic chiasm. Some features of this patient's course suggested the possibility of a malignant hematopoietic process. The distinction between a reactive and a malignant histiocytosis is based on histologic and cytologic features of the infiltrating histiocyte, an approach necessary because of the lack of clonal markers for malignant histiocytes ( 2,4,5). This distinction is complicated by the fact that cases of reactive histiocytosis may have a fulminant presentation and may clinically mimic a malignancy ( 4,7). The pathologic material from the current case was interpreted as a reactive histiocytosis on the basis of the mature cytology of the proliferating histiocytes and the absence of nuclear pleomorphism or atypia. The patient's clinical course also supports a reactive disorder rather than a malignant one. In a series reported by Warnke ( 8), the median survival was 6 months and the mean survival was 14 months for patients with malignant histiocytosis. The natural history of malignant histiocytosis is one of dissemination, multivisceral involvement, and progression to death ( 2). Complete remission may be induced by combination chemotherapy, but in general the prognosis is poor ( 8,9), and it is doubtful that the symptom resolution seen in this patient would occur with malignant histiocytosis. Although an infectious etiology was also considered, a microbiologic evaluation proved unrevealing. The biphasic nature of our patient's course is atypical for a virus- associated reactive histiocytic syndrome ( 4,5). In the presence of benign histiocytes, the possibility of an anticonvulsant- induced lymphohistiocytic syndrome was suggested. The ability of phenytoin to induce a dysregulation in the hematopoietic system and trigger a lymphohistiocytic syndrome is well established ( 10). Phenobarbital, a structurally similar compound, may rarely cause a similar reaction, including a pseudolymphoma syndrome ( 11). The distinction between large atypical lymphocytes and true histiocytes and their respective contributing roles in the pathology of pesudolymphoma and other similar syndromes has only recently been clarified by the routine use of cell surface marker studies ( 2). Phenytoin hypersensitivity is characterized by the triad of fever, lymphadenopathy, and skin rash. However, these signs may be present to a variable degree and be associated with splenomegaly, arthralgias, and overt hepatitis. The onset of this syndrome is usually within several weeks of the introduction of the medication, but it can be delayed for months to years. In 1959 Saltzein and Ackerman reported 7 patients with a pseudolymphoma syndrome secondary to phenytoin and found 75 similar cases in a review of the literature ( 12). Subsequently, one of the seven patients in this report developed a malignant lymphoma ( 13). In 1966, Hymann and Sommers reported 6 patients who developed malignant lymphoma while on anticonvulsant therapy ( 14). Four patients were taking phenobarbital concurrently. During a fouryear period, they found that phenytoin was more frequently associated with the development of true lymphoma than with pseudolymphoma. In 1968, Gams et al. reported a patient with a seizure disorder on phenytoin and phenobarbital who developed reactive adenitis 6 months after initiation of anticonvulsant therapy ( 15). Five months later, while being maintained on this therapy, he developed a substernal mass lesion with a biopsy revealing malignant lymphoma. Phenytoin was discontinued and his lymphadenopathy re- Rare + cells Scattered + cells 2 + larger oval cells Scattered + cells Negative 1+ larger oval cells 3 + small lymphoid cells 2 + small lymphoid cells 3 + small lymphoid cells 1- 2 + small lymphoid cells Not done T cell markers CD1 ( T6) C02 ( T11) CD4 ( T4) CDS ( T1) CD? ( Leu 9) CD8 ( T8) B cell markers CD19 ( pre- B) CD20 ( B1) Other CD11 ( macrophages) CD1S ( LeuM1) S- 100 ( spleen tissue) ,---.------==_...~.-=--."..".=.. ".'.--" JClin Neuro- ophthDlmol. Vol. 11. No. 1. 1991 30 S. I. GALETTA ET AI. ceded. Twenty months later, on phenobarbital therapy, he developed recurrence of malignant lymphoma and died. Cams et al. divided the pseudolymphoma syndrome into four categories including hyperplasia, pseudolymphoma, malignant lymphoma, and pseudo- pseudolymphoma. In the latter group, a typical patient will develop lymph node hyperplasia with a transient regression when off medications and then have a subsequent malignant relapse. As with our patient, all 3 patients grouped under the pseudo- pseudolymphoma syndrome in that study were treated with either phenobarbital or mysoline therapy following discontinuation of phenytoin ( 12,15). In 1970, Anthony charted 41 cases of lymphoadenopathy associated with phenytoin and found that adenopathy may occur within a few hours of dosing up to 10 years from onset of therapy ( 16). He reviewed 85 cases of malignant lymphoma at his institution and found that 4 cases were associated with phenytoin therapy. He concluded that the frequency of lymphoma in patients on anticonvulsants was 10 times above the frequency expected. The mechanism of the phenytoin pseudolymphoma syndrome has been examined in several studies. Sorrell examined 63 patients on phenytoin and compared them with 28 lymphoma patients ( 17). He found depressed cellular and humoral immunity in both groups. Decreased antibody responses to Salmonella typhi, decreased lymphocyte reaction to phytohemagglutinin, and decreased delayed hypersensitivity were found. Rosenthal et al. found increased absolute numbers of T lymphocytes in patients with phenytoin- induced mycosis fungoides ( 18). In addition, phenytoin use was associated with lymphocyte blastic transformation and an impaired T suppressor lymphocyte response. In a controlled study, the presence of arene oxide metabolites were implicated as a cause of phenytoin- induced hepatotoxicity ( 19). More recently, Knutsen described the features of a phenobarbital- induced hypersensitivity syndrome and emphasized the structural similarities between phenobarbital and phenytoin ( 20). In susceptible individuals, the ability to metabolize arene oxide metabolites may lead to both lymphocyte and histiocyte dysregulation. We postulate that our patient's initial lymphohistiocytic process was induced by phenytoin, and, as in the pseudolymphoma syndrome, remitted with discontinuation of phenytoin. Subsequently, our patient developed a recurrence in the optic chiasm while being maintained on phenobar- JClin Neuro- ophthalmol, Vol. 11, No. 1, 1991 bital therapy alone. Although we cam~ ot ~ l1y e~ clude an infectious etiology, our mIcrobIOlogIc evaluation was unrevealing, and the recurrence of a lymphohistiocytic process would ~ e atypical for a virus- associated hemophagocytIc syndrome. Given the structural similarities of phenobarbital and phenytoin, we suggest the us~ of c~ rbamazepine or valproic acid as alternative anticonvulsant agents when a patient develo~ s a lymphohistiocytic disorder while on phenytOIn or phenobarbital therapy. REFERENCES 1. Groopman JE, Golde OW. 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