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Show LETTERS TO THE EDITOR Non- Hodgkin Lymphoma Presenting with Ophthalmoplegia and Gingival Pain We recently examined a Chinese patient with acute progressive ophthalmoplegia caused by non- Hodgkin lymphoma ( NHL). A 51- year- old Chinese man had the sudden onset of double vision preceded by three days of left gingival pain. He reported no headache, fever, chills, nausea, vomiting, vertigo, or dizziness. His medical history included pancreatitis and type II diabetes. He was in no distress. Vital signs were normal. There was no meningismus, lymph node, spleen, or liver enlargement. The left mandibular gingiva was red and swollen. Neuro- ophthalmologic examination showed normal visual function. There was partial right upper lid ptosis. The right pupil measured 5 mm in dim illumination and reacted sluggishly to direct light. The left pupil measured 4 mm and reacted normally to direct light. There was no afferent pupillary defect. The right eye had 50% abduction, 60% adduction, and 50% vertical ductions. The ductions of the left eye were normal. Corneal sensation was intact bilaterally. All other aspects of the neurologic and ophthalmologic examinations were normal. Within five days of our initial examination, he had developed total absence of ductions of the right eye, complete right upper lid ptosis, and a 7 mm unreactive right pupil. A dentist diagnosed a left periodontal abscess and performed incision and drainage. The patient was treated with the antibiotic sulbactam/ cefoperazone and intravenous insulin. Laboratory data disclosed a complete blood cell count of 6,500 white blood cells, 192,000 platelets, and a hemoglobin level of 13.7 g/ dl. The erythrocyte sedimentation rate was elevated at 65 mm/ h ( normal, 2- 20 mm/ h), and the C- reactive protein level was elevated at 48 mg/ 1 ( normal, 0- 8 mg/ 1). Standard blood chemistries, including renal and liver function studies, C3 and C4 complement, antinuclear antibody, anti- double- stranded DNA, and ELISA for HIV were negative. Orbit CT and brain MRI were also normal. Abdominal ultrasonography was normal. Lumbar puncture revealed a normal opening pressure, glucose, protein, cell count, and cytology. J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 Fifteen days after admission, the patient noted bilateral edema of the legs with persistent complete right ophthalmoplegia, ptosis, and mydriasis. Over the next two days, blood creatinine level rose rapidly to 210 | jimol/ l ( normal upper limit, 106) and BUN to 16.96 mmol/ 1 ( normal upper limit, 8.3). An abdominal CT scan demonstrated the presence of a soft tissue mass in the left perirenal space ( Fig. 1). Ultrasound examination showed an enlarged spleen, liver, and kidneys ( right kidney, 15 cm; left kidney, 16 cm) without signs of urinary obstruction. The kidney parenchyma was hypoechogenic; color- coded duplex sonography revealed no signs of renal artery or vein thrombosis. Serial complete blood counts remained normal for the next 13 days. A second lumbar puncture performed seven days after presentation continued to show normal opening pressure, chemistries, cell count, and cytology. The patient refused renal biopsy, but incisional biopsy of the swollen gingiva demonstrated features of NHL with diffusely infiltrating tumor ( Fig. 2A). Immunohisto-chemistry was strongly and diffusely positive for CD20 ( Fig. 2B) and negative for CK, CL20, Syn, CyA, S- 100, CD99, and CR 45RO. Bone marrow aspiration biopsy disclosed features of lymphoma. With a diagnosis of stage IV B- cell NHL, the patient was treated with vincristine, adriamycin, and prednisone for one cycle, followed by cyclophosphamide, doxorubicin, vincristine, and prednisone as well as rituximab. He underwent daily hemodialysis during the systemic chemotherapy. After two weeks of chemotherapy, his right lid had opened halfway, and right eye ductions had all improved to FIG. 1. CT abdominal imaging. Pre- contrast axial study shows a left pre- renal mass ( arrow). 153 J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 Letters to the Editor M •<"*$• iff FIG. 2. Gingival biopsy. A. Diffuse infiltration of malignant lymphocytes ( hematoxylin and eosin stain, X400). B. Immunohistochemical staining shows that the tumor cells strongly express CD20, a marker for B cells ( X400). 50% of normal. Leg edema was markedly improved as was renal function. Renal size had nearly normalized on ultrasound. The patient died of respiratory failure three months after starting treatment. An autopsy was not performed. NHL can affect cranial nerves by metastasis to the base of the skull. Depending on the location of the lesion, Greenberg et al ( 1) described five clinical syndromes: orbital, parasellar, middle fossa, jugular foramen, and occipital condyle. MRI can detect local deposits. Ophthalmoplegia occurs via leptomeningeal metastasis ( 2). Definitive diagnosis requires identification of malignant cells in the cerebrospinal fluid ( CSF). The sensitivity of cytologic diagnosis with one CSF examination is 54% but increases to 91% with two lumbar punctures ( 3). Lau et al ( 4) have reported a patient with Burkitt lymphoma similar to our patient, in whom flow cytometric analysis of CSF with a normal cell count and cytology suggested the diagnosis of NHL ( 4). Our patient had no abnormalities on MRI or on two lumbar punctures. Ultrasonic visceral enlargement led to a suspicion of NHL that was confirmed on biopsy of the swollen gingiva. Aggressive chemotherapy rapidly resolved the ophthalmologic and renal manifestations. NHL commonly involves the oropharyngeal lymphoid tissue comprising Waldeyer's ring but only occasionally involves other oral tissues. Gingival inflammation may therefore be dismissed as a periodontal infection, as in our patient ( 5). Rituximab, the chimeric anti- CD20 monoclonal antibody, has been widely used in treatment of nearly all types of B- cell NHL. Clinical trials have attested to its efficacy when added during or after conventional chemotherapy ( 6,7). NHL should be added to the causes of rapidly progressive unilateral or bilateral ophthalmoplegia. Early chemotherapy may be curative. Hui Liang, MD Benyan Luo, MD Jinpeng Liu, MD The First Affiliated Hospital School of Medicine ZheJiang University ZheJiang, China luobenyan@ zju. edu. cn REFERENCES Greenberg HS, Deck MD, Vikram B, et al. Metastasis to the base of the skull: clinical findings in 43 patients. Neurology 1981; 31: 530- 7. Chang AK. Diplopia in a patient with carcinomatous meningitis: a case report and review of the literature. J Emerg Med 2002; 23: 351^ 1. Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 1982; 49: 759- 72. Lau JJ, Okada CY, Trobe JD. Galloping ophthalmoplegia and numb chin in Burkitt lymphoma. J Neuroophthalmol 2004; 24: 130^ k Batsakis JG. Squamous cell carcinomas of the oral cavity and the oropharynx. In: Batsakis JG, ed. Tumors of the Head Neck: Clinical and Pathological Considerations ( 2nd edition), 2nd edition. Baltimore: Williams & Wilkins; 1979: 144- 76. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large- B- cell lymphoma. N Engl J Med 2002; 346: 235^ 12. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first- line treatment for advanced follicular lymphoma. Blood 2005; 105: 1417- 23. Amiodarone, Erectile Dysfunction Drugs, and Non- Arteritic Ischemic Optic Neuropathy I would like to comment on the editorial entitled " Non- arteritic anterior ischemic optic neuropathy, erectile dysfunction drugs, and amiodarone: Is there a relationship?" by Fraunfelder and Shults ( 1). The authors list seven criteria used by clinical ocular toxicologists to evaluate a potential cause- and- effect relationship between a medical condition and medication use. While no doubt the criteria discussed by the authors are important and useful, they cannot be applied 154 J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 Letters to the Editor J Neuro- Ophthalmol, Vol. 26, No. 2, 2006 universally. It all depends on the disease process and if and how a particular drug influences that disease process. In a recent publication in this journal ( 2), I gave a plausible scientific explanation of how erectile dysfunction drugs can derange the optic nerve head circulation and produce non- arteritic anterior ischemic optic neuropathy ( NAION). With amiodarone, however, things are quite different. My experience tells me that " amiodarone- induced optic neuropathy" is actually NAION unrelated to amiodarone for the following reasons: 1. Patients who take amiodarone have cardiovascular disorders, which are well- established risk factors for the development of NAION ( 3,4). Many of these patients also have other risk factors for the development of NAION ( arterial hypertension, diabetes mellirus, hyper-lipidemia, and ischemic heart disease) ( 3,4). These patients are candidates for NAION whether they are on amiodarone or not. 2. Patients taking amiodarone often also take other drugs ( beta- blockers, calcium channel blockers, or ACE inhibitors) that influence the cardiovascular system. Our 24- hour ambulatory blood pressure monitoring studies have shown that patients taking these drugs are at high risk of development of nocturnal arterial hypotension, which is a common precipitating factor for the development of NAION ( 4- 7). In our study, at least 73% of NAION patients reported discovering visual loss on awakening from sleep and the rest were unsure of the time of onset ( 7). 3. One of the arguments put forward to differentiate amiodarone- induced optic neuropathy from NAION is that some patients taking amiodarone have asymptomatic optic disc edema that may later progress to visual loss. However, I noted in 1981 that optic disc edema often precedes visual loss in NAION ( 8). I have about 60 such patients now who had this " incipient NAION." Many of them progressed to visual loss, but not all. Not one of my approximately 60 patients with NAION and asymptomatic optic disc edema at the initial visit was taking amiodarone. In my studies, I have found that optic disc edema for various reasons can persist much longer than the 6- 8 weeks usually mentioned for typical NAION. Moreover, there are reports of patients with asymptomatic optic disc edema progressing to visual loss after amiodarone had been discontinued ( 9). 4. Most importantly, the clinical features of the optic neuropathy in patients taking amiodarone are typical of NAION rather than a toxic optic neuropathy. Thus, in the multifactorial scenario of NAION ( 2- 4), it is the systemic cardiovascular risk factors and not amiodarone that cause NAION. Sohan Singh Hayreh, MD, PhD, DSc, FRCS, FRCOphth Department of Ophthalmology and Visual Sciences College of Medicine University of Iowa Iowa City, Iowa sohan- hayreh@ uiowa. edu REFERENCES 1. Fraunfelder FW, Shults T. Non- arteritic anterior ischemic optic neuropathy, erectile dysfunction drugs, and amiodarone: is there a relationship? J Neuroophthalmol 2006; 26: 1- 3. 2. Hayreh SS. Erectile dysfunction drugs and non- arteritic anterior ischemic optic neuropathy: is there a cause and effect relationship? J Neuroophthalmol 2005; 25: 295- 8. 3. Hayreh SS, Joos KM, Podhajsky PA, et al. Systemic diseases associated with nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 1994; 118: 766- 80. 4. Hayreh SS. Acute ischemic disorders of the optic nerve: pathogenesis, clinical manifestations and management. Ophthalmol Clin North Am 1996; 9: 407^ 12. 5. Hayreh SS, Zimmerman MB, Podhajsky P, et al. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol 1994; 117: 603- 24. 6. Hayreh SS, Podhajsky PA, Zimmerman B. Role of nocturnal arterial hypotension in optic nerve head ischemic disorders. Ophthalmologica 1999; 213: 76- 96. 7. Hayreh SS, Podhajsky PA, Zimmerman B. Non- arteritic anterior ischemic optic neuropathy: time of onset of visual loss. Am J Ophthalmol 1997; 124: 641- 7. 8. Hayreh SS. Anterior ischemic optic neuropathy, V: optic disc edema an early sign. Arch Ophthalmol 1981; 99: 1030^ H). 9. Murphy MA, Murphy JF. Amiodarone and optic neuropathy: the heart of the matter. J Neuroophthalmol 2005; 25: 232- 6. 155 |