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Show Pupil-Involving Third Nerve Palsy as a Manifestation of Anti-Myelin-Associated Glycoprotein Neuropathy Madhura A. Tamhankar, MD, Steven L. Galetta, MD, Mina Massaro, MD, Laura J. Balcer, MD, MSCE, Edward A. Stadtmauer, MD, Mark J. Brown, MD Abstract: A 56-year-old man developed a pupil-involving left third nerve palsy. Imaging studies of the brain and intracranial vessels were normal. Neurological examina-tion demonstrated a sensory polyneuropathy and mild distal weakness. Nerve conduction studies showed pro-longed distal motor latencies. An enzyme-linked immu-nosorbent assay test detected high titers of anti-myelin- associated glycoprotein (MAG) antibodies. The patient improved with prednisone and rituximab treatment. Anti- MAG neuropathy should be considered when evaluating a patient with an undiagnosed cranial neuropathy, espe-cially in the setting of a sensory neuropathy. Journal of Neuro-Ophthalmology 2011;31:29-33 doi: 10.1097/WNO.0b013e3181f2e27a 2011 by North American Neuro-Ophthalmology Society Paraproteinemic neuropathies are a heterogeneous group of peripheral nerve disorders characterized by the presence of a monoclonal M protein (1). Although all classes of immunoglobulins have been reported in this condition, IgM antibodies are found in 60% of patients (2). The prevalence of neuropathy in patients with IgM monoclonal gammopathy has been reported to be between 5% and 31% (3,4). The most common type is a de-myelinating neuropathy with IgM antibodies directed against myelin-associated glycoprotein (MAG) and sulfo-glucuronyl paragloboside (SGPG). Anti-MAG antibody neuropathy differs from the classic chronic inflammatory demyelinating polyneuropathy (CIDP) by the clinical, electrophysiological, and pathological features; response to treatment; and prognosis (5-11). Cranial nerve involvement is occasionally observed in patients with CIDP, but cranial nerve involvement with anti-MAG neuropathy is rare (3). CASE REPORT A 56-year-old man presented with sudden onset of diplopia and left ptosis. He also complained of a mild headache. He reported left facial weakness a month before onset and right facial weakness 6 months earlier that resolved after treat-ment with acyclovir and corticosteroids. He reported a self-limited episode of bilateral leg pain and numbness 4 years prior. He had type 2 diabetes, hyperlipidemia, and depression. Physical examination revealed an alert, awake, and ori-ented man in no acute distress. Visual acuities were 20/20 in the right eye and 20/25 in the left eye with normal color vision. He had complete left upper lid ptosis. Pupils measured 2 mm on the right with a brisk reaction to direct light and 6 mm on the left with no reaction to light. Ex-traocular motility in the right eye was full. In the left eye, there was absence of up gaze, down gaze, and adduction. Left superior oblique and lateral rectus functions were in-tact. Ophthalmoscopic examination revealed healthy optic nerves and maculae. The patient was diagnosed with pupil-involving left third nerve palsy. Neurological examination revealed mild left lower facial weakness. Arm and leg strength was normal aside from mild weakness of toe dorsiflexion bilaterally. Temperature and vibration sensation were decreased below the elbows and thighs. Reflexes were normal aside from depressed ankle jerks. MRI and MRA of the brain and cerebral angiography were normal. Laboratory testing revealed a normal complete blood count, erythrocyte sedimentation rate, hemoglobin A1C, rapid plasma reagin, angiotensin-converting enzyme, antineutrophilic cytoplasmic antibodies, anti-double-stranded DNA, and Sjogren syndrome A and Sjogren syndrome B Department of Ophthalmology, Scheie Eye Institute; Departments of Neurology; and Hematology-Oncology; and Hospital of the University of Pennsylvania, University of Pennsylvania, Phila-delphia, Pennsylvania. The authors report no conflicts of interest. Address correspondence to Madhura A. Tamhankar, MD, Division of Neuro-ophthalmology, Scheie Eye Institute, 51 North 39th Street, Phil-adelphia, PA 19104; E-mail: madhura.tamhankar@uphs.upenn.edu Tamhankar et al: J Neuro-Ophthalmol 2011; 31: 29-33 29 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. antibodies. Tests for hepatitis B and C viruses, Lyme disease, and HIV were negative. Lumbar puncture revealed an el-evated cerebrospinal protein (148 mg/dL, normal: 15-55 mg/dL), a slightly elevated glucose (77 mg/dL, normal: 40- 70 mg/dL), zero white blood cells, and negative cytology. MRI of the spine showed enhancement of the nerve roots from L2 to L5 (Fig. 1). The radiologic differential diagnosis included infectious and inflammatory disorders including sarcoidosis, carcinomatous meningitis, and lympho-pro-liferative diseases. CT of the chest, abdomen, and pelvis and a whole body positron emission tomographic scan were normal. A repeat lumbar puncture revealed an elevated cerebrospinal protein of 128 mg/dL and normal cytology. Nerve conduction studies demonstrated markedly decreased sensory amplitudes in the upper and lower extremities. Motor conduction velocities were slowed in the arms and legs and unobtainable from the feet. Distal motor latencies were markedly prolonged. The diagnosis was moderate, chronic, predominantly sensory, axonal polyneuropathy with multifocal demyelinating features, most likely an anti-MAG neuropathy. Serum protein electrophoresis showed a monoclonal IgM spike at 470 mg/dL (normal: 40-270 mg/dL). An enzyme-linked immunosorbent assay test revealed a high-titer anti-MAG antibodies (16,525 units, normal ,1000 titer units). Urine protein electrophoresis was negative for Bence Jones proteins. Serum cryoglobulins were undetect-able. A bone scan was normal. The final diagnosis was pupil-involving left third nerve palsy in association with an anti-MAG antibody neuropathy. The patient was initially treated with high-dose oral prednisone (60 mg/day and tapered over 8 weeks), and within 2 days, diplopia improved (Fig. 2). However, leg weakness, numbness, and imbalance progressed. Prednisone was tapered, and rituximab treatment was initiated (375 mg/m2 given weekly for 4 weeks) and then given in 3 monthly cycles. There was complete resolution of the third nerve palsy after 4 months and anisocoria completely resolved at 1-year follow-up examination (Fig. 3). His strength, sensation, and gait improved. He has been fol-lowed for more than 2 years since his initial presentation. The neuropathy has continued to get better with decrease in anti-MAG antibody titers on serial examinations. DISCUSSION Anti-MAG antibody-associated neuropathy is a distinct subset of demyelinating polyneuropathy characterized by prominent sensory loss and ataxia (11-14). The typical clinical course of anti-MAG antibody neuropathy is that of slow progression without relapsing and remitting episodes, increasing numbness and paresthesias, and declining pro-prioception with legs being more involved than the arms (11,15,16). Distal lower extremity weakness is a common late finding (17). Monoclonal IgM antibodies directed against MAG and SGPG are believed to be pathogenic (18). MAG is a cell adhesion molecule that is found in per-iaxonal myelin. Anti-MAG activity leads to alterations of myelin morphology and loss of peripheral and central axon- myelin stability causing segmental demyelination and ax-onal atrophy (19-25). The pathogenesis of cranial nerve involvement in anti- MAG antibody neuropathy is unknown. It is not clear how the antibody crosses the blood-brain barrier. Anti-MAG antibodies can be detected in the cerebrospinal fluid, and therefore intrathecal production of anti-MAG antibody may be a factor in the occurrence of cranial polyneuropathy in this condition (26). The diagnosis of anti-MAG antibody neuropathy is established by the presence of both IgM paraproteinemia and anti-MAG antibody titers in association with the specific neuropathy phenotype (27,28). It has been pro-posed that the occurrence of anti-MAG antibody titers greater than 1:12,800 in the presence of a demyelinating polyneuropathy provides conclusive evidence that the an-tibodies are pathogenic (27). Electrophysiological studies of anti-MAG antibody neuropathy show demyelinating features with varying de-grees of axonal loss. Disproportionately prolonged distal FIG. 1. Contrast-enhanced T1 sagittal MRI image of the lumbar spine reveals enhancement of L2-L5 nerve roots (arrows). 30 Tamhankar et al: J Neuro-Ophthalmol 2011; 31: 29-33 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. motor latencies are a characteristic nerve conduction finding in anti-MAG neuropathy that indicates distal de-myelination. This feature is less commonly seen in CIDP (6,8,9,11,29). In contrast to CIDP, conduction block seldom occurs in neuropathy associated with anti-MAG antibody (7). Cranial nerve involvement, especially facial neuropa-thies, is an occasional feature in CIDP (9,30-33). Oculo-motor nerve involvement is rarely reported in CIDP, and in many of the reported cases, thickening and enhancement of multiple cranial nerves has been observed (34-38). Involvement of cranial nerves in anti-MAG neuropathy is FIG. 2. One month after initial presentation, examination showed resolution of left ptosis, but with persistent adduction, elevation, and depression deficit of the left eye and anisocoria. FIG. 3. Four months after initial visit, there was significant improvement in the motility of the left eye with minimal anisocoria. Tamhankar et al: J Neuro-Ophthalmol 2011; 31: 29-33 31 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. even rarer. In a study of 14 patients with anti-MAG- associated neuropathy, one had associated facial nerve paralysis (9). Yoshida et al reported 1 patient with anti-MAG antibody neuropathy, facial palsy, and bilateral sluggish pu-pillary light reflexes without external ophthalmoplegia (39). Maillot et al reported a 79-year-old patient with anti-MAG antibody neuropathy and B-cell lymphoma who presented with bilateral third nerve palsies (40). Aside from our case, we are not aware of another patient without lymphoma who had pupil-involving third nerve palsy as a manifestation of anti- MAG-associated peripheral neuropathy. The possibility of diabetic microvascular third nerve palsy was also considered in our patient. Pupillary involvement in diabetic microvascular third nerve palsy reportedly occurs in 14%-38%of patients (41-46). The degree of anisocoria when present is almost always 1 mm or less and the pupil is reactive (46). In our patient, the anisocoria was 4 mm and the pupil was nonreactive to light. 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