Letters (1000 mg at days 0 and 14). She continued to experience wors- Funding/Support: This study was supported by the Huayi and Siuling Zhang ening lower extremity weakness. Eventually,she received 6 plas- Discovery Fund. mapheresis treatments with minimal improvement. Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; During the entire period of follow-up at our center, she re- preparation, review, or approval of the manuscript; and decision to submit the quired 20 to 30 mg daily of oral prednisone. Neurological ex- manuscript for publication. amination prior to the onset of HiCy therapy revealed sym- 1. Valiyil R, Casciola-Rosen L, Hong G, Mammen A, Christopher-Stine L. metrically reduced arm abduction (4−/5) and hip flexion Rituximab therapy for myopathy associated with anti-signal recognition particle strength (2/5) and her CK level was 2920 U/L. Given progres- antibodies: a case series. Arthritis Care Res (Hoboken). 2010;62(9):1328-1334. sive muscle weakness in the absence of a robust response to 2. DeZern AE, Petri M, Drachman DB, et al. High-dose cyclophosphamide without stem cell rescue in 207 patients with aplastic anemia and other any immunosuppression, she was treated with HiCy, 50 mg/kg autoimmune diseases. Medicine (Baltimore). 2011;90(2):89-98. per day, for 4 consecutive days and supportive care, as previ- 3. Krishnan C, Kaplin AI, Brodsky RA, et al. Reduction of disease activity and 2 ously described. Although she developed neutropenic fever disability with high-dose cyclophosphamide in patients with aggressive multiple 9 days later, she recovered successfully. She did not require red sclerosis. Arch Neurol. 2008;65(8):1044-1051. blood cell or platelet transfusion, and her neutropenia ulti- 4. Drachman DB, Adams RN, Hu R, Jones RJ, Brodsky RA. Rebooting the mately resolved 2 weeks after HiCy dosing. Muscle strength immune system with high-dose cyclophosphamide for treatment of refractory myasthenia gravis. Ann N Y Acad Sci. 2008;1132:305-314. gradually improved to normal, and her CK level decreased to 5. Brannagan TH III, Pradhan A, Heiman-Patterson T, et al. High-dose 537 U/L within 7 months of treatment. A repeated magnetic cyclophosphamide without stem-cell rescue for refractory CIDP. Neurology. resonance image was performed 21 months after treatment 2002;58(12):1856-1858. (Figure, B). Her steroids were tapered off within 2 years of HiCy 6. Dezern AE, Styler MJ, Drachman DB, Hummers LK, Jones RJ, Brodsky RA. therapy. At her last visit, she had minimal residual weakness Repeated treatment with high dose cyclophosphamide for severe autoimmune (4+/5 deltoids and hip flexors), which did not affect her activi- diseases. Am J Blood Res. 2013;3(1):84-90. ties of daily living. She has remained in clinical remission while not taking any immunosuppressive therapies, including glu- Wallerian Degeneration cocorticoids, with her most recent CK level normal at 100 U/L of the Superior Cerebellar Peduncle 6 years after HiCy treatment. Wallerian degeneration (WD) occurs after nerve damage in both the peripheral nervous system and central nervous system (CNS). Discussion | High-dose immunoablative cyclophosphamide has Wallerian degeneration is named after Augustus Volney Waller been successfully used in the treatment of a variety of auto- (1816-1870), a British neurophysiologist who observed distal immune diseases including multiple sclerosis, myasthenia nerve changes after experimental lesions of the hypoglossal gravis, and chronic inflammatory demyelinating polyneu- nerve in frogs.1 The distal part of the axon of the damaged nerve ropathy.3-5 The initial response rate to HiCy therapy in refrac- degenerates, a process called orthograde degradation. Histologi- tory severe autoimmune diseases exceeds 90%,2 but only 20% cally, WD is characterized by structural loss of the cytoskel- remain disease-free at 5 years after treatment.6 In addition, the eton, a process that takes roughly 24 hours in the peripheral ner- durability of the response may vary depending on the under- vous system and days to weeks in the central nervous system. lying autoimmune disease.2 For example, patients with pem- Wallerian degeneration of the corticospinal tract is com- phigus and lupus tend to have a less durable response follow- mon after ischemia in the primary motor cortex or internal cap- ing HiCy therapy than patients with autoimmune hemolytic sule. On imaging, hypointensity on T2 sequences is present in anemia.2 Our patient achieved a durable remission after HiCy the corticospinal tract during 4 to 12 weeks, after which a per- therapy and remains in remission 6 years after her initial HiCy manent T2 hyperintensity is seen. After several months to treatment. This finding suggests that HiCy therapy may be ef- years, atrophy of the involved tract can be observed.2 On dif- fective and cause more durable remission in refractory idio- fusion-weighted imaging (DWI) sequences, diffusion restric- pathic inflammatory myopathy for which conventional treat- tion is found. If present, poor motor outcomes are likely.3 Wal- ments are insufficient. lerian degeneration can occur in every nerve tract. Arash H. Lahouti, MD Report of a Case | We describe a man in his early 80s who had a Robert A. Brodsky, MD deep cerebellar hemorrhage with damage to the dentate and Lisa Christopher-Stine, MD, MPH interposite nuclei (Figure 1A). On brain magnetic resonance imaging obtained 5 days after the event (Figure 1B and C), there Author Affiliations: Division of Rheumatology, Johns Hopkins University was a marked hyperintense signal on DWI of the ipsilateral su- School of Medicine, Baltimore, Maryland (Lahouti, Christopher-Stine); Division perior cerebellar peduncle (SCP). The apparent diffusion co- of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland (Brodsky). efficient showed a subtle hypointense signal of the ipsilateral Corresponding Author: Lisa Christopher-Stine, MD, MPH, Division of SCP. There were no other hyperintensities on DWI. These Rheumatology, Johns Hopkins University School of Medicine, 5200 Eastern changes were due to WD of the dentato-rubral-thalamic- Ave, MFL Center Tower, Ste 4500, Baltimore, MD 21224 ([email protected]). (cortical) tract, which is the main output of the dentate nucleus Conflict of Interest Disclosures: Dr Christopher-Stine reports serving on the and which travels through the SCP, crosses the midline in the advisory board; receiving honoraria from Novartis, Mallinckrodt, Walgreens, SCP, and runs to the contralateral red nucleus. From the red and Medimmune; and having membership in the advisory board of Idera. She has intellectual property rights in connection with Inova Diagnostics. No other nucleus, there are projections to the thalamus and to the in- disclosures were reported. ferior olivary nucleus (Figure 2). 1206 JAMA Neurology October 2015 Volume 72, Number 10 (Reprinted) jamaneurology.com Copyright 2015 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Letters Figure 1. Computed Tomographic Images on Admission and Magnetic Resonance Images After Hemorrhage A Hemorrhage on admission B 5 d After hemorrhage C 5 d After hemorrhage D 4 mo After hemorrhage E 4 mo After hemorrhage F 4 mo After hemorrhage A, Computed tomography showing the cerebellar bleed as a hyperdense lesion and increased signal intensity in the right superior cerebral peduncle (arrowhead). B, T1-weighted imaging shows the cerebellar bleed as a (arrowhead). E, The contralateral red nucleus appears smaller (arrowhead). F, In spontaneous hyperintense lesion (arrowhead). C, Diffusion-weighted imaging the medulla, there is hypertrophy and hyperintensity of the contralateral olivary shows high signal intensity in the ipsilateral superior cerebellar peduncle nucleus (arrowhead). These findings are compatible with late Wallerian (arrowhead), compatible with early Wallerian degeneration. D, There is atrophy degeneration. A new brain magnetic resonance image (3-dimensional T2- ebellar surgery involving the deep nuclei or after hemorrhage weighted imaging; 0.6-mm slice thickness) was performed 4 in the dentate nucleus.5,6 Several neurodegenerative dis- months after the stroke (Figure 1D-F). On T2-weighted mag- eases, such as progressive supranuclear palsy and Friedreich netic resonance sequence images, there was a hyperintense sig- ataxia, are also associated with atrophy of the SCP. nal and atrophy of the ipsilateral SCP, compatible with WD. The Hyperintense lesions on DWI occurring at a distance from contralateral red nucleus was smaller, with some hyperinten- the initial cerebral infarction or hemorrhage are not necessar- sity, and the contralateral inferior olivary nucleus was hyper- ily due to accompanying ischemia but may reflect early WD trophic, with marked hyperintensity. These findings con- and may illustrate complex anatomical relationships. firmed the anatomical brainstem circuit, which is also known 4 as the triangle of Guillain-Mollaret or myoclonic triangle. Le- Thomas Decramer, MD sions involving this circuit, such as ischemia involving the cen- Philippe Demaerel, MD, PhD tral tegmental tract, may cause palatal myoclonus. Palatal my- Johannes van Loon, MD, PhD oclonus is typically associated with temporary hypertrophic Vincent Thijs, MD, PhD degeneration of the inferior olivary nucleus. Clinically, our pa- tient experienced nausea and truncal