isolated oculomotor nerve palsy in malignant lymphoma
TRANSCRIPT
Correspondence and reprintrequests to:Hiromasa Tsuda, M.D.Division of NeurologyDepartment of Internal MedicineNihon University, School ofMedicine30-1 OyaguchikamichoItabashi-kuTokyo 173-8610JapanFax: 03-397203059E-mail: [email protected]
Acknowledgements:The authors thank Dr. Mitsuru Sawa,Professor and Chairman,Department of Ophthalmology,Nihon University, School ofMedicine, and Dr. TomohikoMizutani, Professor and Chairman,Division of Neurology, Departmentof Internal Medicine, NihonUniversity, School of Medicine, fortheir comments on this manuscript.
Abstract We report the clinical features of isolated oculomotornerve palsy in patients with malignant lymphoma.A retrospective eval-uation of five patients was performed. Their ages ranged from 43 to 77 years (average: 64.5 years). All histopathologic types were non-Hodgkin’s lymphoma, in particular B-cell type in four patients. Oculo-motor nerve palsy was unilateral in all five patients and the pupil wasspared in four. Leptomeningeal dissemination of malignant lymphomawas detected in three patients. However, neuroimaging could not locatethe lesion responsible for the oculomotor nerve palsy in any patient.Despite chemotherapy, all patients died within nine months after theappearance of oculomotor nerve palsy. In malignant lymphoma, iso-lated oculomotor nerve palsy is unilateral, pupil-sparing, and a poorprognostic sign.
Key words Malignant lymphoma; non-Hodgkin’s lymphoma; ocu-lomotor nerve palsy
Introduction Malignant lymphoma may cause various neurologicalsigns, such as cranial nerve palsies, headache, and change of mentalstatus.1,2 Cases of isolated oculomotor nerve palsy in malignant lym-phoma have rarely been reported.3–8 In this study, we examined theclinical characteristics of isolated oculomotor nerve palsy in patientswith malignant lymphoma.
Patients and methods We reviewed five patients with isolatedoculomotor nerve palsy and non-Hodgkin’s lymphoma (NHL). Theycomprised 0.8% of the 648 patients with NHL in Nihon University
Oculomotor nerve palsy in malignant lymphoma 163
Neuro-Ophthalmology 0165-8107/02/US$22.00
Neuro-Ophthalmology – 2004, Vol. 28,No. 4, pp. 163–170© 2004 Taylor & Francis Ltd.
DOI: 10.1080/01658100490887751
Accepted 24 September 2003
Isolated oculomotor nerve palsy inmalignant lymphoma
Hiromasa Tsuda1
Mutsumi Kishiro2
Hiroshi Ishikawa2
Sohei Endo3
Umihiko Sawada4
1Division of Neurology, Department of Internal Medicine,Departments of 2Ophthalmology and 3Otorhinolaryngology, and
4First Department of Internal Medicine, Nihon University, Schoolof Medicine, Tokyo, Japan
Case report
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Itabashi Hospital between April 1983 and July 1998. Histopathologictype was non-Hodgkin’s lymphoma in all patients. Their age range was43 to 77 years (average: 64.5 years). Four patients were male and onewas female.
patient 1 A 70-year-old male was admitted to our hospital due toleft parotid bubo in April 1983. His past medical history was hyper-tension. His disease was diagnosed as diffuse large B-cell type of NHLbased on a biopsy of the parotid gland. After radiation and CHOP(cyclophosphamide, adriamycin, vincristine, prednisolone) therapy,the NHL remitted completely. An abdominal mass was observed onNovember 1983 and recurrence of NHL was diagnosed. Radiationtherapy for the abdominal mass and CHOP therapy were performedas stage III. On the morning of January 4, 1984, he complained of leftocular pain and diplopia. He consulted an ophthalmologist on January6. His corrected visual acuities were 1.2 in both eyes. Left exotropia of40 prism was detected. Restriction of elevation and adduction in theleft eye were marked, while that of depression was moderate. Thepalpebral fissure was 8.0mm in the right eye and 3.0mm in the left eye(Figure 1). Both pupils had the same diameter and showed normalreactions. Cranial MRI and MRA showed no abnormalities. Lep-tomeningeal dissemination was detected during a cerebrospinal cyto-logic study. After continuing radiation and CHOP therapy, the NHLremitted completely. Left ocular pain and ptosis resolved completelyand ocular motor restrictions improved slightly (Figure 2). Sepsis,disseminated intravascular coagulation syndrome, and acute renal dysfunction presented, however, after an urgent operation for appen-dicitis in May 1984. He died on June 7 of that year. Autopsy was notpermitted.
patient 2 A 77-year-old female presented with a mass in the leftaxillary region in February 1990 and diffuse large B-cell type of NHLwas diagnosed based on a biopsy of the left axillary lymph node. Shehad no past medical history. After CHOP therapy, the NHL remittedcompletely. In September 1992, the posterior lateral region of her rightthigh gradually started to swell. Infiltration of NHL into the skin wasdetected during a biopsy of the lesion in her right thigh. After ninecycles of PIME (l-phosphamide, etoposide, methotrexate, procarbazin,leukovorin) therapy, the NHL completely remitted again. On August16, 1993, right ptosis occurred. She consulted an ophthalmologist onAugust 19. Her corrected visual acuity was 0.3 in the right eye and 0.6in the left eye. No abnormalities except for cataract were observed ineither eye. Right exotropia of 30 prism was detected. Restriction of ele-vation, adduction, and depression were prominent in the right eye. Thepalpebral fissure was 1mm in the right eye and 10mm in the left eye.The pupils were spared. Cranial MRI showed no abnormalities. Sincecerebrospinal fluid analysis showed white blood cells of 5/mm3 (all weremononucleocytes and 30% were blast cells), a protein concentration of173mg/dl, and a glucose level of 97mg/dl, leptomeningeal dissemina-tion was diagnosed. Right oculomotor nerve palsy gradually improvedwith intrathecal therapy of methotrexate. In September 1993, the
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Fig. 1. Left oculomotor nerve palsyin patient 1 on January 6, 1983. Inthe primary position, left exotropiaof 40 prism appeared. Elevation andadduction were highly restricted anddepression moderately limited in theleft eye. Left ptosis was prominent.In the lowest right, the pupils werespared.
anterior portion of the right thigh became swollen and infiltration ofNHL into the skin was detected during a biopsy of that lesion. Aftertwo cycles of LVP (l-asparaginase, vincristine, prednisolone) therapy,the NHL remitted completely. However, infiltration of NHL into theskin in the right thigh to the crus presented for the third time in March1994. Chemotherapy (mitoxantrone, carboplatine, cytarabine, dexam-ethasone) and radiation therapy were performed. Metastasis to themediastinum of NHL also occured and she died due to sudden cardiacarrest on May 28, 1994. Autopsy was not permitted.
patient 3 When a 76-year-old male underwent surgery for a liverabscess in 1991, diffuse large B-cell type NHL was diagnosed based ona biopsy of an infradiaphragmatic lymph node. He had no particularpast medical history. He was considered clinical stage I. In May 1995,the right cervical lymph node became swollen and NHL was detected
Oculomotor nerve palsy in malignant lymphoma 165
Fig. 2. Left oculomotor nerve palsyin patient 1 on February 6, 1983. Leftptosis has resolved and ocular motorrestrictions have slightly improved.
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during a biopsy of that lesion. Pain and edema in the right lowerextremity presented in November 1995. Left ptosis presented inDecember and he was admitted to our hospital on January 5, 1996.Cranial MRI revealed two masses, each with a diameter of 3 ¥ 3 ¥ 3cm, in the bilateral occipital lobes. His clinical classification was stageIII. He consulted an ophthalmologist on January 21, 1996. His correctedvisual acuity was 1.0 in the right eye and 0.5 in the left eye. Leftexotropia of 30 prism was detected. Restriction of elevation anddepression were marked in the left eye, while that of adduction wasmoderate.The palpebral fissure was 7.5mm in the right eye and 5.0mmin the left eye. The pupil diameter was 2.5mm in the right eye and 3.75mm in the left eye. Pupillary reaction was impaired in the left eye.Cranial MRI revealed no abnormalities except for the lesions in thebilateral occipital lobes. As cerebrospinal fluid analysis showed whiteblood cells of 6/mm3 (all were mononucleocytes and 15% were blastcells), a protein concentration of 70mg/dl, and a glucose level of 65mg/dl, leptomeningeal dissemination of NHL was diagnosed. Despiteintrathecal injection of methotrexate and CHOP therapy, the patient’sleft oculomotor nerve palsy did not improve. He died on February 18,1996, due to bacterial pneumonia. Autopsy was not permitted.
patient 4 A 71-year-old male complained of swelling of the leftinguinal lymph nodes in May 1995. As the level of 37 degrees pyrexiaoccurred in November, he was admitted to our hospital on December14. He had no past medical history. His disease was diagnosed as diffusesmall cleaved B-cell type of NHL based on a biopsy of the left inguinallymph node. He was treated with CHOP therapy as stage III. On Feb-ruary 16, 1996, he complained of diplopia and consulted an ophthal-mologist. His corrected visual acuity was 1.0 in the right eye and 0.4 inthe left eye. Left exotropia of 50 prism and left hypertropia of 10 prismwere observed. Elevation, depression, and adduction in the left eyewere completely restricted. The palpebral fissure was 8.0mm in theright eye and 5.0mm in the left eye The pupils were spared. CranialMRI and MRA showed no abnormalities. Leptomeningeal dissemina-tion was not found during a cerebrospinal cytologic study. DespiteCHOP therapy, the left oculomotor nerve palsy did not improve. Infil-tration of NHL in the bone marrow and lung was observed. He diedon April 6, 1996. Autopsy was not permitted.
patient 5 A 43-year-old male complained of incongruity in the pha-rynges in December 1996. He had no particular past medical history.His disease was diagnosed as diffuse small non-cleaved T-cell type ofNHL based on a biopsy of the tonsils. CHOP, MECD (mitoxantrone,etoposide, carboplatin, dexamethazone), and LVP therapy were admin-istered for stage I disease, but the NHL did not remit. He complainedof diplopia on May 27, 1996, and consulted an ophthalmologist. His cor-rected visual acuities were 1.5 in both eyes. Left exotropia of 30 prismwas detected. Elevation, depression, and adduction in the left eye werecompletely impaired. The palpebral fissure was 8.0mm in the right eyeand 5.0mm in the left eye.The pupils were spared. Cranial MRI showedno abnormalities. Leptomeningeal dissemination was not detected
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during a cerebrospinal cytologic study. LVP therapy was continued andleft oculomotor nerve palsy improved. Infiltration of NHL in the bonemarrow and the peritoneum was observed. He died on July 20, 1996.Autopsy was not permitted.
Results The clinical findings of these five patients are shown inTable 1. The oculomotor nerve palsies were unilateral in all patients(left side in 4, right side in 1). The pupil was spared in four patients andimpaired in only one. At the onset of oculomotor nerve palsy, the clini-cal stage was II in one patient, stage III in three, and in remission inone. Oculomotor nerve palsy improved in three patients and not in twowith therapy.All histopathologic types were non-Hodgkin’s lymphoma,in particular B-cell type in four patients. Histopathologic subtypes werediffuse large cell type in three patients, diffuse small cleaved B-cell type in one, and diffuse small non-cleaved T-cell type in one. Lep-tomeningeal dissemination was detected in three patients. After theonset of oculomotor nerve palsy, all patients died between 1.5–9months. Mean prognosis was 3.9 months.
Discussion Malignant lymphoma is the general term for neoplasmsthat derive from lymphoreticular tissues. Subtypes of malignant lym-phoma are divided histopathologically into Hodgkin’s lymphoma andnon-Hodgkin’s lymphoma (NHL). NHL is more likely to infiltrate thecentral nervous system (CNS).9 In the patients described in this paper,all histopathologic types were NHL. Recht et al.1 reported that the frequency of CNS symptoms in NHL, such as cranial nerve palsies, headache, change of mental status, and paraparesis, was 65.5%.MacKintosh et al.2 noted that multiple ocular motor nerve palsies, i.e.,oculomotor, trochlear, and abducence nerve palsies, were prominent(34.3%) in cranial nerve palsies. Facial (14%) and trigeminal (7.6%)nerves were also impaired, while acoustic (4.8%) and optic (3.8%)
Oculomotor nerve palsy in malignant lymphoma 167
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
Age/gender 70/male 77/female 76/male 71/male 43/maleLaterality of III palsy Left Right Left Left LeftRestriction of oculomotor E,A,D E,A,D E,A,D E,A,D E,A,D
nervePtosis + + + + +Impairment of pupil - - + - -Clinical stage of NHL when III Remission III III II
III palsy presentedImprovement of III palsy + + - - +Histologic subtype of NHL Diffuse large Diffuse large Diffuse large Diffuse small Diffuse small non-
B cell B cell B cell cleaved B cell cleaved T cellLeptomeningeal + + + - -
carcinomatosisPrognosis after appearance 5 2 9 1.5 2
of III palsy (month)
E, elevation; A, adduction, D, depression.
table 1. Clinical findings of fivepatients.
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nerves were rarely involved in isolated palsy.2 Only six cases of isolatedoculomotor nerve palsy have been reported in malignant lymphoma.3–8
These isolated oculomotor nerve palsies were unilateral and pupil-sparing in most cases.3–8 The oculomotor nerve palsies in our patientswere also unilateral and the pupil was spared in four of them.
Direct infiltration of NHL into the oculomotor nerve due to lep-tomeningeal dissemination has been suggested as the mechanism ofisolated oculomotor nerve palsy.5–7 Two cases of swollen oculomotornerve in the subarachnoid space, seen during gadolinium-enhancedMRI, due to direct infiltration of NHL have been reported.6,7 Based onthe result of intrathecal injection of methotrexate, it was suggested thatNHL infiltrated directly into the oculomotor nerve in the subarachnoidspace in these cases.6,7 In three of our patients, leptomeningeal dis-semination of NHL was detected and oculomotor nerve palsies alsoimproved after intrathecal injection of methotrexate.
In contrast, direct infiltration of NHL into the oculomotor nervewithout leptomeningeal dissemination has also been suggested. Mit-sumoto and Sweeney3 reported an autopsy case of NHL with the initialsymptom of isolated oculomotor palsy. It was noted that NHL infil-trated directly into the bilateral oculomotor nerves in the cavernoussinus. Manabe et al.4 reported a case of NHL with isolated superiorbranch palsy of the oculomotor nerve in the cavernous sinus withoutleptomeningeal dissemination.As the cavernous sinus was expanded inneuroimaging, direct infiltration of NHL into the oculomotor nerve wasexpected.4 Wilkins and Samhouri8 reported an autopsy case with infiltration of NHL into the oculomotor nerve in the midbrain and subarachnoid space without abnormalities, seen on cranial CT andcerebrospinal fluid study. Although neuroimaging showed no abnor-malities along the oculomotor nerve and autopsies were not per-formed, the same mechanism was suggested for two of the presentpatients without leptomeningeal dissemination.
In addition to these mechanisms, lymphomatoid granulomatosis mustbe considered.10 In this disorder, lymphoma cells infiltrate into theperivascular space and cause various symptoms in the lung, skin, andCNS. When lymphomatoid granulomatosis involves the CNS, MRI may show masses and diffuse lesions in the white matter of the brain.11
Intravascular malignant lymphomatosis with occlusion of systemicsmall vessels, blood capillaries, and venules should also be differenti-ated.10,12 Recurrent cerebrovascular disease, impairment of spinal cordand radices, and subacute encephalopathy may be prominent.12 In addi-tion, oculomotor nerve palsies due to toxity of vincristine have beenreported.13,14 The characteristics of oculomotor nerve palsy due totoxity of vincristine include bilateral ptosis with pupil-sparing. Toxicreactions usually improve following a decreased dosage or discontinu-ation of the drug.13,14 Pemphigus,15 nephrotic syndrome,16 and orbitalmyositis17 have been reported as paraneoplastic syndrome in NHL. Intwo of our patients without leptomeningeal dissemination, lymphoma-toid granulomatosis and intravascular malignant lymphomatosis couldnot be considered, because of the lack of characteristic symptoms andneuroimaging signs. Since oculomotor nerve palsies were unilateral inall five patients, toxity of vincristine may also be suggested. No case of
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References1 Recht L, Straus DJ, Cirrincione C,
Thaler HT, Posner JB. Centralnervous system metastases fromnon-Hodgkin’s lymphoma:treatment and prophylaxis. Am JMed. 1988;84:425–435.
2 MacKintosh FR, Colby TV,Podolsky WJ, Burke JS, Hoppe RT, Rosenfelt FP, Rosenberg SA, Kaplan HS. Central nervoussystem involvement in non-Hodgkin’s lymphoma: an analysis of 105 cases. Cancer. 1982;49:586–595.
3 Mitsumoto H, Sweeney PJ.Oculomotor palsy from malignantlymphoma. Cleveland Clin Q. 1980;47:333–338.
4 Manabe Y, Kurokawa K, KashiharaK, Abe K. Isolated oculomotornerve palsy in lymphoma. NeurolRes. 2000;22:347–348.
5 Miller NR. Solitary oculomotornerve palsy in childhood. Am JOphthalmol. 1977;83:106–111.
6 Kajiya Y, Nakajo M, Kajiya Y,Miyaji N. Oculomotor nerveinvasion by lymphomademonstrated by MRI. J ComputAssist Tomogr. 1995;19:502–504.
7 Galetta SL, Sergott RC, Wells GB,Atlas SW, Bird SJ. Spontaneousremission of a third-nerve palsy inmeningeal lymphoma. Ann Neurol.1992;32:100–102.
8 Wilkins DE, Samhouri AM. Isolatedbilateral oculomotor paresis due tolymphoma. Neurology. 1979;29:1425–1428.
9 Recht LD. Neurologic complicationsof systemic lymphoma. Neurol Clin.1991;9:1001–1015.
10 Hamada J, Koto A. Clinical featuresof intravascular lymphomatosis.Neurol Med. 2002;57:293–298.
oculomotor nerve palsy as a paraneoplastic syndrome with NHL hasbeen reported. Based on these results, micro-infiltration of NHL in the oculomotor nerve was suggested in our patients without lep-tomeningeal dissemination.
It has been reported that one characteristic of isolated oculomotornerve palsies in NHL is pupil-sparing.3,5,8 In four of the present patients,the pupils were spared. Wilkins and Samhouri8 reported an autopsycase of NHL with patchy infiltrating lesions within the oculomotornerve in the subarachnoid space. They suggested that the parasympa-thetic nerve fibers for sphincter muscle of the pupil might be spared,because of the patchy infiltrating lesions. It is well-known that the pupilin oculomotor palsy due to hypertension or diabetes mellitus is likelyto be spared. Since most patients with NHL are elderly, these ischemicneuropathies should also be considered. However, four of the presentpatients did not have hypertension or diabetes mellitus and the oculo-motor nerve palsies improved immediately after therapy for NHL inthree of them. Therefore, ischemic neuropathy was not a cause and thepatchy infiltration of NHL might have induced pupil-sparing.
Oculomotor nerve palsies presented during the active stage of NHLin four of our patients and during the remission stage of NHL in one.When oculomotor nerve palsy appears during the remission stage ofNHL, a relapse of malignant lymphoma should be considered. Rechtet al.1 reported that the prognosis of NHL with CNS symptoms was 16weeks, while Mackintosh et al.2 reported 10 weeks. All of the patientsin this study died within nine months after the onset of oculomotornerve palsy. Mean prognosis was 3.9 months. These results confirm thatisolated oculomotor nerve palsy in malignant lymphoma is unilateral,pupil-sparing, and a poor prognostic sign.
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11 Tateishi U, Terae S, Ogata A,Sawamura Y, Suzuki Y, Abe S,Miyasaka K. MR imaging of the brain in lymphomatoidgranulomatosis. AJNR Am JNeuroradiol. 2001;22:1283–1290.
12 Glass J, Hochberg FH, Miller DC.Intravascular lymphomatosis. Asystemic disease with neurologicmanifestations. Cancer. 1993;71:3156–3164.
13 Albert DM, Wong VG, HendersonES. Ocular complications ofvincristine therapy. ArchOphthalmol. 1967;78:709–713.
14 Soysal T, Ferhanoglu B, Bilir M,Akman N. Oculomotor nerve palsyassociated with vincristinetreatment. Acta Haematol. 1993;90:209–210.
15 Anhalt GJ, Kim SC, Stanley JR,Korman NJ, Jabs DA, Kory M,Izumi H, Ratrie 3rd H, Mutasim D,Ariss-Abdo L, Labib RS.Paraneoplastic pemphigus. Anautoimmune mucocutaneous disease associated with neoplasia.N Engl J Med. 1990;323:1729–1735.
16 Ito M, Sai S, Hotchi M, Nagasaki M.An autopsied case of a malignantlymphoma with a severe nephriticsyndrome overlapped by cirrhoticglomerulosclerosis. Jpn J CancerClin. 1988;34:938–945.
17 Harris GJ, Murphy ML, SchmidtEW, Hanson GA, Dotson RM.Orbital myositis as a paraneoplasticsyndrome. Arch Ophthalmol. 1994;112:380–386.
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