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Acute sixth-nerve palsy after vincristine therapy
Short Reports Acute Sixth-Nerve Palsy After Vincristine Therapy S. C. Lash, BM, BSc(Hons), MRCOphth, C. P. R. Williams, Bsc(Hons), MRCP, MRCOphth, C. S. Marsh, FRCOphth, C. Crithchley, BSc(Hons), SRO, CASE, P. R. Hodgkins, BSc(Hons), FRCS, FRCOphth, and E. J. MacKie, MRCP The chemotherapeutic effectiveness of vincristine was first reported in 1962,1 and with its increased use the incidence of reported neurologic side effects has also increased.2 We report a case of acute sixth-nerve palsy occurring soon after administration of vincristine for acute lymphoblastic leukemia (ALL), a previously unreported side effect.
CASE REPORT A 2-year-old boy was referred to the eye service for consultation regarding a convergent squint that developed while he was receiving chemotherapy for ALL. Immunophenotyping—tDt⫹, CD19⫹, and CD10⫹— confirmed the morphologic diagnosis, and cytogenetic testing confirmed a high hyperdiploid karyotype. He was treated per schedule A of the MRC ALL 97 (Revised) trial. Intrathecal therapy consisted of 30 mg cytarbine at diagnosis followed by 8 mg methotrexate on day eight and another 10 mg methotrexate at the beginning of weeks 5 through 8. His induction treatment regime consisted of vincristine, 1.5 mg/m2/wk for 1 month; asparaginase, 6,000 units/m2 on alternate days for 18 days; and prednisolone, 40 mg/m2/d for 26 days with the dose decreasing during the subsequent week. The vincristine dosage was then changed to a maintenance regime of 1.5 mg/m2/mo starting 1 month after the last induction dose. During the induction course, the patient developed vincristine neurotoxicity, which manifested as a reluctance by the patient to put his feet on the ground because a peripheral neuropathy was affecting his lower limbs. This resolved after vincristine administration was decreased to a monthly regime. Ten days after administration of the first dose of maintenance vincristine (62 days after starting the induction treatment), he developed jaw pain and a left ptosis, which resolved during one week, as well as a left convergent strabismus.
From the Department of Ophthalmology, Southampton General Hospital, Southampton, England. Submitted October 22, 2002. Revision accepted July 21, 2003. Reprint requests: S. C. Lash, BM, BSc(Hons), Department of Ophthalmology, Southampton General Hospital, Tremona Rd, Southampton, England, SO16 6YD. J AAPOS 2004;8:67-68. Copyright © 2004 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2004/$35.00 ⫹ 0 doi:10.1016/j.jaapos.2003.07.010
Journal of AAPOS
His platelet count (453 ⫻ 109/L) and the results of computed axial tomography brain scan, lumbar puncture, and bone marrow examinations were all normal. The most recent lumbar puncture, performed using intrathecal methotrexate, was performed at 16 days before the onset of the strabismus and was excluded as a possible cause. The patient was referred for ophthalmologic opinion. On examination the patient’s visual acuity was 20/30 right and left using pictograms. Cycloplegic refraction revealed hyperopia ⫹1.50 sphere in both eyes. An 80prism diopter (PD) left esotropia was present in the primary position, and ocular motility testing disclosed an inability to abduct the left eye past the midline. Fundus examination was normal as was examination of other cranial nerves. A left sixth-nerve palsy was diagnosed, and the patient was prescribed full spectacle correction with fulltime daily alternating occlusion. The palsy improved during the next 2 months without further change in his chemotherapy regime, although a 40-PD concomitant convergent strabismus remained. He underwent botulinum toxin injection to the ipsilateral medial rectus muscle and was subsequently found to be orthophoric with acuities of 20/20 right and left using pictograms and with 200 seconds of arc of stereopsis using the Lang II test (Clement Clarke, Harlow, England).
DISCUSSION The neurotoxicity of vincristine is well recognized and may be divided into four groups: peripheral neuropathy, autonomic neuropathy, encephalopathy, and cranial neuropathy.3 These neuropathies are seen in most patients who have been taking the drug for longer than 2 months.4 The most common side effect is dose-dependent peripheral neuropathy with early depression of the deep-tendon reflexes. Other recognized effects include paresthesia, gait disturbances, cranial nerve palsies and cerebral dysfunction in the more advanced cases.5 Cranial nerve palsies involving oculomotor,6 trochlear,5 and facial5 nerves have been described. Involvement of the trigeminal and vagus nerves have been reported most frequently,3 with the former manifesting as oral pain in as many as 55% of patients taking vincristine in one series.7 The pathogenesis of vincristine neuropathy is not well understood. It is postulated that damage to the microtubules causes interference with axonal transport.8 These palsies resolved soon after cessation of vincristine. In SanFebruary 2004
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dler’s study of 50 leukemic patients treated with vincristine, cranial nerve palsies were a late manifestation of neuropathy in 10% of patients, all of whom had antecedent peripheral muscle weakness.5 Improvement was noted in most patients 2 to 6 weeks after cessation of therapy with complete recovery within 4 months.5 Norton9 reported 2 cases of unilateral optic neuropathy; both patients developed severe eye pain 6 days after commencement of vincristine therapy, and in both cases there were also signs of peripheral neuropathy with depressed tendon reflexes. Symptoms resolved after cessation of vincristine. In conclusion, we report a sixth-nerve palsy occurring after administration of vincristine, a previously unreported side effect. This case has features in common with previous reported cases of vincristine neurotoxicity including the development of peripheral neuropathy, jaw pain, ptosis, and cranial nerve palsy. Unlike previous reports, the sixth-nerve palsy in this case improved without change in treatment, although a large concomitant convergent strabismus persisted. The strabismus was successfully treated
Journal of AAPOS Volume 8 Number 1 February 2004
with full-time daily alternate occlusion followed by administration of botulinum toxin to the medial rectus muscle. References 1. Armstrong JG, Dyke RW, Fouts PJ. Initial clinical experience with leurocristine, a new alkaloid from vinca rosea linn. Proc Am Assoc Cancer Res 1962;3(abstract):301. 2. No authors listed. Lancet 1973;1:980-1. 3. McCarthy GM, Skilling JR. A prospective co-hort study of the orofacial effects of vincristine neurotoxicity. J Oral Path 1991;20:345-9. 4. MacDonald DR. Neurological complications of chemotherapy. Neurol Clin 1991;9:955-67. 5. Sandler SG, Tobin W, Henderson ES. Vincristine-induced neuropathy. Neurology 1969;19:367-74. 6. Soysal T, et al. Oculomotor palsy associated with vincristine treatment. Acta Haematol 1993;90:209-10. 7. McCarthy GM, Skilling JR. Jaw and other orofacial pain in patients receiving vincristine for the treatment of cancer. Oral Surg Oral Med Oral Pathol 1992;74:299-304. 8. Sahenk Z, Brady ST, Mendell JR. Studies on the pathogenesis of vincristine induced neuropathy. Muscle Nerve 1987;10:80-4. 9. Norton S, Stockman J. Unilateral optic neuropathy following vincristine chemotherapy. Am J Ophthalmol 1976;81:146-50.
CASE REPORT A 2-year-old boy was referred to the eye service for consultation regarding a convergent squint that developed while he was receiving chemotherapy for ALL. Immunophenotyping—tDt⫹, CD19⫹, and CD10⫹— confirmed the morphologic diagnosis, and cytogenetic testing confirmed a high hyperdiploid karyotype. He was treated per schedule A of the MRC ALL 97 (Revised) trial. Intrathecal therapy consisted of 30 mg cytarbine at diagnosis followed by 8 mg methotrexate on day eight and another 10 mg methotrexate at the beginning of weeks 5 through 8. His induction treatment regime consisted of vincristine, 1.5 mg/m2/wk for 1 month; asparaginase, 6,000 units/m2 on alternate days for 18 days; and prednisolone, 40 mg/m2/d for 26 days with the dose decreasing during the subsequent week. The vincristine dosage was then changed to a maintenance regime of 1.5 mg/m2/mo starting 1 month after the last induction dose. During the induction course, the patient developed vincristine neurotoxicity, which manifested as a reluctance by the patient to put his feet on the ground because a peripheral neuropathy was affecting his lower limbs. This resolved after vincristine administration was decreased to a monthly regime. Ten days after administration of the first dose of maintenance vincristine (62 days after starting the induction treatment), he developed jaw pain and a left ptosis, which resolved during one week, as well as a left convergent strabismus.
From the Department of Ophthalmology, Southampton General Hospital, Southampton, England. Submitted October 22, 2002. Revision accepted July 21, 2003. Reprint requests: S. C. Lash, BM, BSc(Hons), Department of Ophthalmology, Southampton General Hospital, Tremona Rd, Southampton, England, SO16 6YD. J AAPOS 2004;8:67-68. Copyright © 2004 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2004/$35.00 ⫹ 0 doi:10.1016/j.jaapos.2003.07.010
Journal of AAPOS
His platelet count (453 ⫻ 109/L) and the results of computed axial tomography brain scan, lumbar puncture, and bone marrow examinations were all normal. The most recent lumbar puncture, performed using intrathecal methotrexate, was performed at 16 days before the onset of the strabismus and was excluded as a possible cause. The patient was referred for ophthalmologic opinion. On examination the patient’s visual acuity was 20/30 right and left using pictograms. Cycloplegic refraction revealed hyperopia ⫹1.50 sphere in both eyes. An 80prism diopter (PD) left esotropia was present in the primary position, and ocular motility testing disclosed an inability to abduct the left eye past the midline. Fundus examination was normal as was examination of other cranial nerves. A left sixth-nerve palsy was diagnosed, and the patient was prescribed full spectacle correction with fulltime daily alternating occlusion. The palsy improved during the next 2 months without further change in his chemotherapy regime, although a 40-PD concomitant convergent strabismus remained. He underwent botulinum toxin injection to the ipsilateral medial rectus muscle and was subsequently found to be orthophoric with acuities of 20/20 right and left using pictograms and with 200 seconds of arc of stereopsis using the Lang II test (Clement Clarke, Harlow, England).
DISCUSSION The neurotoxicity of vincristine is well recognized and may be divided into four groups: peripheral neuropathy, autonomic neuropathy, encephalopathy, and cranial neuropathy.3 These neuropathies are seen in most patients who have been taking the drug for longer than 2 months.4 The most common side effect is dose-dependent peripheral neuropathy with early depression of the deep-tendon reflexes. Other recognized effects include paresthesia, gait disturbances, cranial nerve palsies and cerebral dysfunction in the more advanced cases.5 Cranial nerve palsies involving oculomotor,6 trochlear,5 and facial5 nerves have been described. Involvement of the trigeminal and vagus nerves have been reported most frequently,3 with the former manifesting as oral pain in as many as 55% of patients taking vincristine in one series.7 The pathogenesis of vincristine neuropathy is not well understood. It is postulated that damage to the microtubules causes interference with axonal transport.8 These palsies resolved soon after cessation of vincristine. In SanFebruary 2004
67
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dler’s study of 50 leukemic patients treated with vincristine, cranial nerve palsies were a late manifestation of neuropathy in 10% of patients, all of whom had antecedent peripheral muscle weakness.5 Improvement was noted in most patients 2 to 6 weeks after cessation of therapy with complete recovery within 4 months.5 Norton9 reported 2 cases of unilateral optic neuropathy; both patients developed severe eye pain 6 days after commencement of vincristine therapy, and in both cases there were also signs of peripheral neuropathy with depressed tendon reflexes. Symptoms resolved after cessation of vincristine. In conclusion, we report a sixth-nerve palsy occurring after administration of vincristine, a previously unreported side effect. This case has features in common with previous reported cases of vincristine neurotoxicity including the development of peripheral neuropathy, jaw pain, ptosis, and cranial nerve palsy. Unlike previous reports, the sixth-nerve palsy in this case improved without change in treatment, although a large concomitant convergent strabismus persisted. The strabismus was successfully treated
Journal of AAPOS Volume 8 Number 1 February 2004
with full-time daily alternate occlusion followed by administration of botulinum toxin to the medial rectus muscle. References 1. Armstrong JG, Dyke RW, Fouts PJ. Initial clinical experience with leurocristine, a new alkaloid from vinca rosea linn. Proc Am Assoc Cancer Res 1962;3(abstract):301. 2. No authors listed. Lancet 1973;1:980-1. 3. McCarthy GM, Skilling JR. A prospective co-hort study of the orofacial effects of vincristine neurotoxicity. J Oral Path 1991;20:345-9. 4. MacDonald DR. Neurological complications of chemotherapy. Neurol Clin 1991;9:955-67. 5. Sandler SG, Tobin W, Henderson ES. Vincristine-induced neuropathy. Neurology 1969;19:367-74. 6. Soysal T, et al. Oculomotor palsy associated with vincristine treatment. Acta Haematol 1993;90:209-10. 7. McCarthy GM, Skilling JR. Jaw and other orofacial pain in patients receiving vincristine for the treatment of cancer. Oral Surg Oral Med Oral Pathol 1992;74:299-304. 8. Sahenk Z, Brady ST, Mendell JR. Studies on the pathogenesis of vincristine induced neuropathy. Muscle Nerve 1987;10:80-4. 9. Norton S, Stockman J. Unilateral optic neuropathy following vincristine chemotherapy. Am J Ophthalmol 1976;81:146-50.