Wallerian Degeneration of the Superior Cerebellar Peduncle

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).

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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 patient experienced nausea and truncal ataxia but palatal my- Author Affiliations: Department of Neurosurgery, University Hospitals Leuven, oclonus was not observed. Leuven, Belgium (Decramer, van Loon); Department of Radiology, University Hospitals Leuven, Leuven, Belgium (Demaerel); KU Leuven–University of Leuven, Department of Neurosciences, Experimental Neurology, Leuven, Discussion | To our knowledge, this is the first report of early Belgium (Thijs); VIB–Vesalius Research Center, Leuven, Belgium (Thijs); WD of the SCP. However, late WD has been described after cer- Department of Neurology, University Hospitals Leuven, Leuven, Belgium (Thijs).

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In the study, there were no data about individual family Figure 2. Anatomical Circuit history of neuropathy. In patients who had a familiar predis- Cortex position to future neuropathy, neurological symptoms could Thalamus not be necessarily associated with CD. This element should be considered in the results. Hadjivassiliou et al2 demonstrated that a strict gluten- Dentate nucleus free diet improves neurological symptoms, resulting in stabi- Red nucleus lization of the neuropathy. We did not find accurate informa- Superior cerebellar peduncle tion about the diet of patients with CD in the period between Central tegmental tract the diagnosis of CD and the onset of neuropathy. The immu- nomodulatory role of a gluten-free diet is really intriguing in Inferior olivary nucleus many extraintestinal manifestations of CD and it would be in- teresting to have precise details about it. Inferior cerebellar peduncle Furthermore, the authors should have considered chemo- therapeutic treatments in patients: during the examined period, some of the patients could be exposed to chemotherapy Information of the cerebellar cortex is sent to the dentate nucleus. From there and it could cause iatrogenic neuropathy.3 on, nerve fibers travel to the contralateral red nucleus, which carries this Thawani et al1 evaluated different kinds of neuropathies information to the thalamus and cortex. This is called the dentate-rubral- and chronic inflammatory demyelinating neuropathy associ- thalamic-(cortical) tract, which proximally runs through the superior cerebellar peduncle. However, there is also a feedback loop inside the brainstem: the red ated with CD. nucleus is connected with the inferior olivary nucleus through the central A previous study demonstrated the presence of antineu- tegmental tract. From the inferior olivary nucleus, climbing fibers cross the ral antibodies in CD, related to neurological diseases, such as midline and travel through the inferior cerebellar peduncle to the contralateral cerebellar hemisphere. This feedback loop is also known as the triangle of peripheral neuropathy and idiopathic cerebellar ataxia. Anti- Guillain-Mollaret. bodies seem to target central and enteric nervous systems in a significant proportion of patients with neurological CD.4 Corresponding Author: Thomas Decramer, MD, Department of Neurosurgery, The common hypothesis is that immunological and auto- University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium (thomas immune factors could enter in the pathogenesis of neuropathy [email protected]). and other diseases through a molecular mimesis mechanism.5 Conflict of Interest Disclosures: None reported. In this context, it is worth noting that the highest risk for 1. Waller A. Experiments on the section of the glossopharyngeal and future neurological matters was just after diagnosis of CD. hypoglossal nerves of the frog, and observations of the alterations produced Despite the pathogenesis of neuropathies in patients with thereby in the structure of their primitive fibers. Philos Trans R Soc Lond. 1850; 140:423-429. CD not yet being clear, the need for making a well-structured 2. Kuhn MJ, Johnson KA, Davis KR. Wallerian degeneration: evaluation with MR follow-up program against possible complications of CD, in- imaging. Radiology. 1988;168(1):199-202. cluding the neurological manifestations, appears evident. 3. DeVetten G, Coutts SB, Hill MD, et al; MONITOR and VISION study groups. Too often, patients with CD, especially adults, are ne- Acute corticospinal tract Wallerian degeneration is associated with stroke glected after starting the gluten-free diet. The challenge is to outcome. Stroke. 2010;41(4):751-756. realize an effective prevention of all the most feared compli- 4. Khoyratty F, Wilson T. The dentato-rubro-olivary tract: clinical dimension of cations of this frequent enteropathy, only apparently re- this anatomical pathway [published online April 11, 2013]. Case Rep Otolaryngol. doi:10.1155/2013/934386. solved after the start of a gluten-free diet. 5. Bontozoglou NP, Chakeres DW, Martin GF, Brogan MA, McGhee RB. Cerebellorubral degeneration after resection of cerebellar dentate nucleus Maurizio Mennini, MD neoplasms: evaluation with MR imaging. Radiology. 1991;180(1):223-228. Ilaria Baglivo, MS 6. Uchino A, Takase Y, Nomiyama K, Egashira R, Kudo S. Brainstem and Federica Ferrari, MD, PhD cerebellar changes after cerebrovascular accidents: magnetic resonance imaging. Eur Radiol. 2006;16(3):592-597. Author Affiliations: Sapienza, University of Rome, Rome, Italy. Corresponding Author: Maurizio Mennini, MD, Sapienza–University of Rome, Viale Regina Elena, 324 Rome, Italy ([email protected]). COMMENT & RESPONSE Conflict of Interest Disclosures: None reported. 1. Thawani SP, Brannagan TH III, Lebwohl B, Green PH, Ludvigsson JF. Risk of Neuropathy and Celiac Disease—When a Gluten-Free neuropathy among 28232 patients with biopsy-verified celiac disease. JAMA Diet is Not Enough Neurol. 2015;72(7):806-811. To the Editor The possible association between celiac disease 2. Hadjivassiliou M, Rao DG, Wharton SB, Sanders DS, Grünewald RA, (CD) and neurologic extraintestinal manifestations has been Davies-Jones AG. Sensory ganglionopathy due to gluten sensitivity. Neurology. described in literature since 1966. We read with interest the 2010;75(11):1003-1008. article by Thawani et al1 showing the increased risk for neu- 3. Costa TC, Lopes M, Anjos AC, Zago MM. Chemotherapy-induced peripheral neuropathies: an integrative review of the literature. Rev Esc Enferm USP. 2015; ropathy in patients with biopsy-proved CD. The major strengths 49(2):335-345. of this study were the nationwide population-based design and 4. Caio G, De Giorgio R, Venturi A, et al. Clinical and immunological relevance of the high statistical power. Nevertheless, we would like to raise anti-neuronal antibodies in celiac disease with neurological manifestations. some small constructive criticisms. Gastroenterol Hepatol Bed Bench. 2015;8(2):146-152.

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