Journal of Neuro-Ophthalmology, June 2004, Volume 24, Issue 2

Galloping Ophthalmoplegia and Numb Chin in Burkitt Lymphoma

A 57-year-old man developed complete bilateral ophthalmoplegia over a period of 10 days, together with bilateral facial pain and numbness of the chin. He had no other clinical manifestations. Findings on brain magnetic resonance imaging and spinal fluid formula from the first lumbar puncture were normal, but cerebrospinal fluid flow cytometry disclosed a kappa restriction monoclonal B-cell population, indicating malignant lymphoma. Computed tomography of the chest, abdomen, and pelvis then revealed multiple enlarged lymph nodes. Biopsy of an inguinal node showed findings consistent with Burkitt lymphoma. Within six weeks, intravenous and intrathecal chemotherapy resolved all neurologic findings except a partial right-side sixth nerve palsy and mild chin numbness. Eighteen months after disease onset, the patient remained in remission. Meningeal spread of Burkitt lymphoma is not commonly a presenting feature in immunocompetent adults. Chin numbness, a characteristic feature caused by infiltration of the mental nerve, should facilitate earlier recognition, which may be life saving.

ORIGINAL CONTRIBUTION Galloping Ophthalmoplegia and Numb Chin in Burkitt Lymphoma Juan J. Chan Lau, MD, Craig Y. Okada, MD, PhD, and Jonathan D. Trobe, MD Abstract: A 57- year- old man developed complete bilat­eral ophthalmoplegia over a period of 10 days, together with bilateral facial pain and numbness of the chin. He had no other clinical manifestations. Findings on brain mag­netic resonance imaging and spinal fluid formula from the first lumbar puncture were normal, but cerebrospinal fluid flow cytometry disclosed a kappa restriction monoclonal B- cell population, indicating malignant lymphoma. Com­puted tomography of the chest, abdomen, and pelvis then revealed multiple enlarged lymph nodes. Biopsy of an in­guinal node showed findings consistent with Burkitt lym­phoma. Within six weeks, intravenous and intrathecal che­motherapy resolved all neurologic findings except a partial right- side sixth nerve palsy and mild chin numbness. Eigh­teen months after disease onset, the patient remained in re­mission. Meningeal spread of Burkitt lymphoma is not commonly a presenting feature in immunocompetent adults. Chin numbness, a characteristic feature caused by infiltration of the mental nerve, should facilitate earlier rec­ognition, which may be life saving. ( JNeuro- Ophthalmol 2004; 24: 130- 134) Burkitt lymphoma is an aggressive B- cell lymphoma that closely resembles L3 acute lymphocytic leukemia, dif­fering in that the malignant cells in Burkitt lymphoma are found primarily in the lymph nodes rather than in the blood and bone marrow. It was first described in 1958 as a man­dibular malignancy in African children ( 1). Currently, three clinical variations are recognized: 1) an endemic form, of­ten presenting as a mass in the jaw or orbit of African chil­dren; 2) a nonendemic form, occurring throughout the world and often presenting as an abdominal mass in adults; and 3) an AIDS- associated form, similar to the nonendemic form but clinically more aggressive. From the Departments of Ophthalmology and Visual Sciences ( JJCL, JDT), Neurology ( JDT), and Internal Medicine ( CYO), University of Michigan Medical Center, Ann Arbor, Michigan. Address correspondence to Jonathan Trobe, MD, Kellogg Eye Center, 1000 Wall Street, Ann Arbor, Michigan 48105; E- mail: jdtrobe@ umich. edu Although diplopia and ocular ductional abnormalities have been previously reported in patients with Burkitt lym­phoma, rarely are they the initial manifestations in immu­nocompetent adults. We present a case in which progressive ophthalmoplegia and numb chin were the presenting mani­festations of nonendemic Burkitt lymphoma in an immuno­competent adult with normal findings on brain imaging and spinal fluid formula. In doing so, we emphasize the diffi­culty yet the urgency of recognizing this neuro- ophthalmic presentation given that timely treatment may be life saving. Response rates to traditional acute lymphocytic leu­kemia chemotherapeutic regimens have been dismal, with a complete response rate of 44% o to 63 % and a disease- free survival of 0%> to 50% o. However, newer intensive treatment regimens offer significantly better clinical outcomes ( 2,3). With multiagent intensive chemotherapy and aggressive early intrathecal treatment, complete responses can be ob­tained in 60% to 86% of treated patients, with 50% to 70% having a sustained disease- free survival ( 2- 4). Patients with increased tumor bulk and widely disseminated disease have lower response rates and a higher risk of relapse ( 2,5). Moreover, the development of a life- threatening acute tu­mor lysis syndrome is more severe with increased tumor burden. CASE REPORT A 57- year- old man without ongoing health problems or constitutional symptoms developed double vision. An ophthalmologist diagnosed a right sixth cranial nerve palsy. Two days later, he developed complete right upper lid pto­sis, and four days later, he awoke with severe paroxysmal pain radiating from the right preauricular region to the right side of the chin. Within a day, he had developed persistent marked numbness of the right side of the chin. Findings on a brain computed tomography ( CT) scan and magnetic resonance imaging ( MRI) with gadolinium were normal. Because of bradycardia, a pacemaker was im­planted. Several days later, he developed paroxysmal pain of the left eye, brow, scalp, and mouth. He was transferred to our care. His past medical history included hepatitis B antigen-emia detected 10 years earlier without manifestations of 130 J Neuro- Ophthalmol, Vol. 24, No. 2, 2004 Burkitt Lymphoma JNeuro- Ophthalmol, Vol. 24, No. 2, 2004 liver disease. His only medication was 12.5 mg rofecoxib twice a day for osteoarthritis. The general physical examination was normal, in­cluding vital signs. Neuro- ophthalmologic examination showed normal visual function. There was complete right upper lid ptosis, total immobility of the right eye, and a 7- mm unreactive right pupil. The left eye had 0% abduc­tion, 60% adduction, and normal vertical ductions. The 4- mm left pupil reacted normally to direct light. Corneal sensation was intact bilaterally. There was markedly re­duced pinprick sensation over the right chin region. There was reduced pinprick sensation over the left side of the scalp and brow extending to the interaural line and involv­ing, to a lesser extent, the left side of the chin. All other aspects of the neurologic and ophthalmologic examinations were normal. Within three days of our initial examination, he had developed total bilateral ophthalmoplegia, complete right ptosis, partial left ptosis, bilateral 7- mm pupils unreactive to direct light or a near target, and bilateral chin hypesthesia. A white blood cell count was 10.8 x 103 cells/ mm3, hemoglobin was 13.7 g/ dL, and platelet count was 293 x 103 cells/ mm3. A high- resolution brain CT scan was normal. ( The MRI scan performed earlier was re­viewed carefully and showed no abnormalities, as origi­nally described. A repeat MRI scan could not be performed because of his new pacemaker.) Lumbar puncture revealed the following values: an opening pressure of 120 mm H20; glucose, 64 mg/ dL; protein, 69 mg/ dL; red blood cell count, 98 cells/ Lil; white blood cell count, 2 cells/ ul; and negative cryptococcal antigen and VDRL test results. Cytospin preparations of the cerebrospinal fluid ( CSF) did not show any malignant- appearing cells. However, flow cytometry of the CSF lymphocytes showed a kappa restricted popula­tion of B cells. Computed tomography scan of the chest, abdomen, and pelvis showed multiple low- density liver ab­normalities, enlarged lymph nodes in all three regions, and diffuse, hazy stranding in the mesentery and omentum ( Fig. 1), findings suggestive of non- Hodgkin lymphoma. Histo­logic study of an excised large, right inguinal lymph node showed a characteristic " starry sky" pattern consistent with the diagnosis of the Burkitt variant of lymphoma ( Fig. 2). Cytogenetic analysis of a bone marrow aspirate confirmed the diagnosis with the disclosure of the t ( 8,14) c- myc translocation. Cerebrospinal fluid from a lumbar puncture performed 12 days following the original lumbar puncture contained 230 g/ dL protein and 42 white blood cells/ mm3 with 98% lymphocytes. Cytospin preparation of the CSF leukocytes showed cells of Burkitt lymphoma ( Fig. 3). He was started on the CALGB 9251 chemotherapy regimen. Cycle 1 ( prephase), consisting of 1 g intravenous methylprednisolone daily and cyclophosphamide for five FIG. 1. Axial computed tomography scan of the abdomen ( A and B) and pelvis ( C) shows a left prerenal mass ( A, arrow), omental stranding ( B, arrow), and a markedly en­larged right inguinal node ( C, arrow). days, produced no change in the neuro- ophthalmic mani­festations. This was complicated by tumor lysis syndrome and renal failure that required hemodialysis. He then began cycle 2 chemotherapy shortly after his prephase treatment, which consisted of ifosfamide, MESNA, Ara- C, and dexamethasone. He was also treated with intrathecal meth­otrexate, Ara- C, and hydrocortisone. Within six weeks of starting chemotherapy, his ophthalmic abnormalities had resolved except for mild chin numbness and a mild abduc­tion deficit in the right eye. In primary gaze, his eyes be­came aligned. On a follow- up visit at 12 months after the initiation of chemotherapy, he remained in clinical and he­matological remission. DISCUSSION Over a period of 10 days, our patient developed com­plete bilateral ophthalmoplegia, ptosis, and mydriasis, to­gether with paroxysmal facial pain and chin numbness. Brain CT and MRI scans were normal, the lumbar puncture formula was normal, but flow cytometry of CSF showed a monoclonal B- cell population. Chest, abdomen, and pelvic CT scans revealed multiple masses, and inguinal node bi­opsy revealed Burkitt lymphoma. Aggressive chemo­therapy rapidly resolved nearly all neurologic manifesta­tions and placed him in complete remission. This patient is unusual in that ocular motor palsies caused by imaging-negative meningeal infiltration of cranial nerves in Burkitt lymphoma have not been previously documented as the presenting features in an immunocompetent host. 131 JNeuro- Ophthalmol, Vol. 24, No. 2, 2004 Lau et al. FIG. 2. Right inguinal lymph node with monotonous pro­liferation of intermediate- sized lymphoid cells with a high mitotic rate. The " starry sky" pattern of the biopsy is due to numerous macrophages that are ingesting apoptotic tumor cells. The macrophages are called " tingible body macro­phages" because they are filled with dark- staining nuclear debris and lighter- staining lipids. Grassi and Lee ( 6) reported a 53- year- old human im­munodeficiency virus ( HIV)- positive man who presented with a severe headache and diplopia. Examination dis­closed partial third, fifth, sixth, and seventh cranial nerve palsies. Magnetic resonance imaging showed diffuse meningeal enhancement. CSF flow cytometry disclosed a monoclonal B- cell population consistent with Burkitt lym­phoma. He died within 30 days of diagnosis because of a lymphomatous pericardial effusion. Snider et al ( 7) re­ported two patients with AIDS and Burkitt lymphoma who presented with diplopia. One patient had unilateral third and sixth nerve palsies, bilateral seventh nerve palsies, right-arm weakness, areflexia, and bilateral chin numbness; the other patient had unilateral third and seventh nerve palsies, four- limb weakness, and areflexia. Cerebrospinal fluid cy­tologic findings were positive in both, but only after the third lumbar puncture in one patient and after the second lumbar puncture in the other. One patient died shortly thereafter of sepsis; the outcome of the other patient was not specified. Unlike immunoblastic lymphomas, Burkitt lym­phoma arising in HIV- positive patients occurs at a time when such patients are not yet seriously immunocompro­mised ( 2). Although Burkitt lymphoma is less responsive to treatment in HIV- positive patients, Spina et al ( 8) found no difference in the clinicopathologic features in patients with and without HIV. The authors described meningeal in­volvement in 9 ( 19%) of 46 HIV- positive patients and in 5 ( 17%) of 29 HIV- negative patients ( P = 0.8). Newman et al ( 9,10) reported a case similar to ours, except that the patient was immunocompromised by medi­cations following a liver transplant. Their patient was a 58- year- old man who complained of right lower facial pain that was followed by right hand weakness and horizontal bin­ocular diplopia. Examination showed a right mental neu­ropathy, a right sixth nerve palsy, and weakness of the right arm. Five days later, he manifested complete bilateral third and sixth cranial nerve palsies. Corneal and facial sensation were normal except for mildly decreased sensation on the right side of the chin. Neuroimaging, CSF analysis, total body CT scanning, and a paraesophageal biopsy revealed no abnormalities. However, sural nerve biopsy disclosed a lymphoid infiltration of the perivascular endoneurium. Bur­kitt lymphoma was diagnosed by bone marrow biopsy. The patient was treated aggressively with intravenous and intra­thecal chemotherapy. At a 10- month follow- up visit, he still had, like our patient, a mental neuropathy and a mild left sixth nerve palsy ( 10). Previously reported immunocompetent patients with diplopia and Burkitt lymphoma have all had discrete in­traorbital or intracranial tumor masses noted on imaging. For example, Inoue et al ( 11) reported a 58- year- old immu­nocompetent man who had diplopia as the initial manifes­tation of Burkitt lymphoma secondary to tumor infiltration of the medial rectus muscle. Coupland et al ( 12) reported a 84- year- old immunocompetent woman with diplopia as the first clinical manifestation of a large orbital Burkitt lym­phoma. Trese et al ( 13) described Burkitt lymphoma in an immunocompetent 22- year- old man whose initial finding on brain imaging was negative, but sino- orbital masses ap­peared within four weeks of presentation. He presented with painless horizontal diplopia caused by a left sixth * Burkitt Lymphoma Cells RBC t Lymphocyte , FIG. 3. Cytospin preparation of cerebrospinal fluid shows four Burkitt lymphoma cells. A normal red blood cell and lymphocyte are included for size comparison. 132 © 2004 Lippincott Williams & Wilkins Burkitt Lymphoma JNeuro- Ophthalmol, Vol. 24, No. 2, 2004 nerve paresis. The finding on lumbar puncture was nega­tive. Within four weeks, he had developed a mild left sev­enth nerve palsy, decreased left corneal sensation, a right sixth nerve palsy, and, eventually, complete bilateral inter­nal and external ophthalmoplegia, together with bilateral first and second division trigeminal neuropathy. Neuroim-aging studies showed masses in both ethmoid sinuses ex­tending into the sphenoid sinus, right orbit, and right olfac­tory groove. Biopsy was consistent with Burkitt lymphoma. A repeat lumbar puncture showed cells consistent with Bur­kitt lymphoma. Chest x- ray showed a pathologic fracture of the left third rib with an extrapleural mass. The ophthal­moplegia gradually improved during a six- week course of chemotherapy, but the right sixth nerve palsy persisted. The patient died of sepsis within three months of diagnosis. At postmortem examination, no tumor was found within the CSF spaces, brain parenchyma, orbits, or ethmoid or sphe­noid sinuses. The combination of rapidly progressive ophthalmople­gia and chin numbness signals the presence of an aggressive cancer. Although it may be caused by dental anesthesia, sagittal split osteotomies, and trauma ( 14,15), nontraumatic " numb chin syndrome" ( NCS) is most commonly a sign of neoplastic infiltration of the mental canal, particularly by malignant lymphoma or breast cancer ( 14,16). The origi­nal description of NCS in 1830 by Charles Bell involved an elderly woman with metastatic breast cancer ( 17). Sub­sequently, numb chin syndrome has been reported in acute leukemia; in colon, lung, nasopharyngeal, ovarian, prostate, and lip cancer; and in hypernephroma, melanoma, and mul­tiple myeloma ( 14,16,18- 27). Massey et al ( 19) reported chin numbness in 19 patients; 9 of the 19 patients had lymphoreticular malignancies, one of which was Burkitt lymphoma. The clinical presentation of NCS is usually with dys­esthesias or numbness extending from the chin to the lower lip and an abnormal sensation of thickening of the lower lip. Numb chin syndrome is usually unilateral but may be bilat­eral ( 16), as in our case. Massey et al ( 19) found that it pre­ceded the diagnosis of malignancy in nearly half of cases. By contrast, Lossos and Siegal ( 16) found NCS to be a late manifestation of systemic malignancy, with a median la­tency of 2.5 years after diagnosis of lymphoprohferative neoplasm and four years after diagnosis of breast cancer. In 67% of the patients, NCS arose in association with progres­sion of the disease, whereas in 31% it heralded a relapse ( 16). In the series of Massey et al ( 19), plain jaw x- rays showed lytic or blastic lesions in only one- third of patients tested. Chemotherapy or radiotherapy resolved the numb­ness in three- fourths of patients. Flow cytometry played a critical role in the diagnosis of Burkitt lymphoma in our patient. The ability to detect lymphoma cells in CSF is often limited by the paucity of malignant cells, the presence of nonmalignant cells that ob­scure rare malignant cells, or the presence of reactive lym­phocytes that mimic the appearance of tumor cells. In our case, analysis of the CSF did not reveal a significant leuko­cytosis, and results of cytologic evaluation of the CSF lym­phocytes were negative for malignant cells. However, flow cytometric analysis of the CSF suggested a malignancy. Flow cytometry measures the surface expression of cell lin­eage- specific protein at a single cell level. A population of normal B lymphocytes expresses either kappa or lambda immunoglobulin light chains, whereas a population of ma­lignant B lymphocytes expresses only kappa or lambda light chains. Flow analysis of CSF from our patient revealed that the vast majority of the B cells expressed kappa immu­noglobulin light chains, indicating a malignant process. The addition of flow cytometric analysis to morphologic exami­nation of CSF lymphocytes has increased the detection rate of lymphoid neoplasms by 43% to 75% ( 28- 30). This tech­nique should be used to analyze CSF lymphocytes when­ever a malignancy is suspected and there are at least 2 lymphocytes/ mm3 in the CSF. Collection of 10 mL or more CSF on multiple occasions may be necessary to obtain an adequate sample. REFERENCES 1. Burkitt D. A sarcoma involving the jaws in African children. Br J Surg 1958; 46: 218- 23. 2. Fenaux, P, Bourhis JH, Ribrag V. Burkitt's acute lymphocytic leu­kemia ( L3 ALL) in adults. Hematol Oncol Clin North Am 2001; 15: 37- 50. 3. Hoelzer D, Ludwig W, Thiel E, et al. Improved outcome in adult B- cell acute lymphoblastic leukemia. Blood 1996; 87: 495- 508. 4. Soussain C, Patte C, Ostronoff M, et al. Small noncleaved cell lym­phoma and leukemia in adults: a retrospective study of 65 adults treated with the LMB pediatric protocols. Blood 1995; 85: 664- 74. 5. Lerede T, Bassan R, Rossi A, et al. Therapeutic impact of adult- type acute lymphoblastic leukemia regimens in B- cell/ L3 acute leuke­mia and advanced- stage Burkitt's lymphoma. Hematologica 1996; 81: 442- 9. 6. Grassi MA, Lee AG. Lymphomatous meningitis of the Burkitt type presenting with multiple cranial neuropathies. Am J Ophthalmol 2002; 133: 424- 5. 7. Snider WD, Simpson DM, Nielsen S, et al. Neurological complica­tions of acquired immune deficiency syndrome: analysis of 50 pa­tients. Ann Neurol 1983; 14: 403- 18. 8. Spina M, Tirelli U, Zagonel V, et al. Burkitt's lymphoma in adults with and without human immunodeficiency virus infection: a single institution clinicopathology study of 75 patients. Cancer 1998; 82: 766- 74. 9. Newman NJ. Multiple cranial neuropathies: presenting signs of sys­temic lymphoma. Surv Ophthalmol 1992; 37: 125- 9. 10. Newman NJ. Multiple cranial neuropathies with systemic lym­phoma: 10 month follow up. Surv Ophthalmol 1992; 37: 229. 11. Inoue T, Yamane T, Sasaki A, et al. Leukemic Burkitt's lymphoma with an initial symptom of ocular motor disturbance ( in Japanese). Rinsho Ketsueki 1989; 30: 338- 42. 12. Coupland SE, Hummel M, Stein H. Ocular adnexal lymphomas: five case presentations and a review of the literature. Surv Ophthal­mol 2002; 47: 470- 90. 13. Trese MT, Krohel GB, Hepler RS, et al. Burkitt's lymphoma with cranial nerve involvement. Arch Ophthalmol 1980; 98: 2015- 7. 133 JNeuro- Ophthalmol, Vol. 24, No. 2, 2004 Lau et al. 14. Laurencet FM, Anchisi S, Tullen E, et al. Mental neuropathy: report of 5 cases and review of the literature [ critical reviews]. Oncol He-matol 2000; 34: 71- 9. 15. Zaytoun HS Jr, Phillips C, Terry BC. Long term neurosensory defi­cits following transoral vertical ramus and sagittal split osteotomies for mandibular prognathism. J Oral Maxillofac Surg 1986; 44: 193- 6. 16. Lossos A, Siegal T. Numb chin syndrome in cancer patients: etiol­ogy, response to treatment and prognostic significance. Neurology 1992; 42: 1181^ 1. 17. Furukawa T. Charles Bell's description of numb chin syndrome. Neurology 1988; 38: 331. 18. Bruyn RP, Boogerd W. The numb chin. Clin Neurol Neurosurg 1991; 93: 187- 93. 19. Massey EW, Moore J, Schold SC. Mental neuropathy from sys­temic cancer. Neurology 1981; 31: 1277- 81. 20. Ohno T, Yasuda Y, Furukaza H. Acute monoblastic leukemia ( M5a) presenting with numb chin syndrome [ letter]. Am J Haematol 1994; 45: 352. 21. Calverley JR, Mohnac AM. Syndrome of the numb chin. Arch In­tern Med 1963; 112: 819 - 21. 22. Marinella MA, Metastatic large cell lung cancer presenting with numb chin syndrome. Respir Med 1997; 91: 235- 6. 23. Eppley BL, Snyders RV. Mental neuropathy as a sign of distant malignancy: report of cases. J Oral Maxillofac Surg 1992; 50: 1117- 9. 24. Thrush DC, Small M. How benign a symptom is facial numbness? L< mcen970; l: 851- 3. 25. Banerjee TK, Gottschalk PG. Unusual manifestations of multiple cranial nerve palsies and mandibular metastasis in a patient with squamous cell carcinoma of the lip. Cancer 1984; 53: 346- 8. 26. Hogan MC, Lee A, Solberg LA, et al. Unusual presentation of mul­tiple myeloma with unilateral visual loss and numb chin syndrome in a young adult. Am JHematol 2002; 70: 55- 9. 27. DePena CA, Lee YY, Van Tassel P. Lymphomatous involvement of the trigeminal nerve and Meckel's cave: CT and MR appearance. AJNR Am JNeuroradiol 1989; 10: S15- 7. 28. Finn WG, Peterson LC, James C, Goolsby CL. Enhanced detection of malignant lymphoma in cerebrospinal fluid by multiparameter flow cytometry. Am J Clin Pathol 1998; 110: 341- 6. 29. French CA, Dorfman DM, Shaheen G, Cibas ES. Diagnosing lym-phoproliferative disorders involving the cerebrospinal fluid: in­creased sensitivity using flow cytometric analysis. Diagn Cyto-pathol 2000; 23: 369- 74. 30. Roma AA, Garcia A, Avagnina A, Rescia C, Eisner B. Lymphoid and myeloid neoplasms involving cerebrospinal fluid: comparison of morphologic examination and immunophenotyping by flow cy­tometry. Diagn Cytopathol 2002; 27: 271- 5. 134 © 2004 Lippincott Williams & Wilkins