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Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 136-138

A mysterious localized spinal whiteout

Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India

Date of Submission19-Dec-2020
Date of Decision09-Jan-2021
Date of Acceptance21-Jan-2021
Date of Web Publication26-Mar-2021

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai - 400 012, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/crst.crst_365_20

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How to cite this article:
Abraham G, Menon NS, Chopade SR, Noronha V, Patil VM, Joshi A, Prabhash K. A mysterious localized spinal whiteout. Cancer Res Stat Treat 2021;4:136-8

How to cite this URL:
Abraham G, Menon NS, Chopade SR, Noronha V, Patil VM, Joshi A, Prabhash K. A mysterious localized spinal whiteout. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Apr 23];4:136-8. Available from: https://www.crstonline.com/text.asp?2021/4/1/136/312093

  Case Vignette Top

A 40-year-old man presented to our hospital with gradually progressing ulceration of the tongue and swelling in the neck since July 2019. A punch biopsy from the left tongue lesion showed poorly differentiated squamous cell carcinoma. In view of the non-metastatic disease in the baseline positron emission tomography (PET) scan [Figure 1]a and [Figure 1]b and the extensive disease in the neck involving levels IB, II, III, IV, and V nodes on the left side, with a clinical stage of T4aN3bM0 as per the American Joint Committee on Cancer 8th edition, the patient was started on neoadjuvant chemotherapy (NACT) with docetaxel (75 mg/m2) and cisplatin (75 mg/m2) on day 1 and 5-fluorouracil (750 mg/m2) from days 1–5 every 21 days for 2 cycles. However, the patient had clinical and radiological progression with increase in the nodal mass post 2 cycles of NACT, as shown in [Figure 2]a and [Figure 2]b. The nodal mass was deemed unresectable in the multidisciplinary tumor board, and the patient was planned for palliative intent radiotherapy (RT) in view of the symptomatic dysphagia. The patient received palliative RT to the face and neck at a dose of 40 Gy in 16 fractions over 3 weeks using the conventional technique without any treatment gap using the linear accelerator (6 MV) with parallel opposed lateral fields covering the primary tumor and the nodes. Using the linear-quadratic model generally adopted to compare a dose normalized to conventional fractionation (EQD2) (with α/β = 3 Gy, D = cumulative dose), an EQD2 of 41.6 Gy was applied to the patient. Subsequently, he was started on immunotherapy with nivolumab in view of the platinum-refractory progression and unresectable nature of the disease. After the completion of 13 cycles of nivolumab given at 2-weekly intervals at a dose of 3 mg/kg (last dose dated August 31, 2020), the patient presented with insidious onset and gradually progressive ataxia (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0 grade 3) in September 2020. Neurological examination revealed no motor deficit with a positive Romberg's sign and negative cerebellar signs localizing to the posterior column of the spinal cord. The patient underwent contrast-enhanced magnetic resonance imaging (MRI) of the spine which revealed a swollen cervical cord with intramedullary T2/short inversion-time inversion recovery hyperintensity extending from the lower medulla to the C7 level showing few patchy areas of enhancement and T1 and T2 hyperintensities from the cervical level C2 to the dorsal column level D4, as shown in [Figure 3].
Figure 1: Contrast-enhanced computed tomography scan images at baseline with axial section showing (a) an ulcerative lesion on the left side of the tongue crossing the midline and (b) enlarged necrotic cervical nodes at level IB and level II on the left side

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Figure 2: Contrast-enhanced magnetic resonance imaging axial short inversion-time inversion recovery images at the level of (a) the tongue showing progressive primary lesion indicating progressive disease following neoadjuvant chemotherapy and (b) neck showing the enlarged cervical neck node indicating progressive disease following neoadjuvant chemotherapy

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Figure 3: Magnetic resonance imaging T2-weighted sagittal section of the cervical spine showing patchy T2 hyperintensities along the spinal cord with associated cervical cord edema

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What is the diagnosis, and what should be done next? Once you have finalized your answer, turn to pg. 137 to read on.

  Work-Up and Clinical Course Top

The etiological differential diagnoses considered were autoimmune disorders (Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathy), infection (viral etiologies such as herpes and cytomegalovirus), and disease progression with leptomeningeal metastasis.

Cerebrospinal fluid analysis revealed normal cytology, glucose, and proteins with no evidence of malignant cells, and hence, leptomeningeal metastasis was ruled out. The lack of albuminocytological dissociation and a negative multiplex viral polymerase chain reaction ruled out Guillain–Barré syndrome and viral myelitis, respectively. The patient was started on methylprednisolone 500 mg for 2 days followed by oral steroids 1 mg/kg with a weekly taper over 8 weeks. The patient continues to have grade 3 ataxia, with stable neurological signs since the last 3 months with minimal clinical benefit. A repeat PET-CT showed partial response in the tongue lesion and nodal disease and no distant metastasis.

After excluding the infectious and autoimmune causes, the possibilities considered at this point were radiation-induced and immunotherapy-related myelitis. The factors favoring the probability of radiation-induced myelitis were the onset of myelitis in the cervical and upper thoracic spinal cord with lower thoracic and lumbosacral sparing corresponding to the radiation portal used, temporal correlation of 6 months post-RT, and the lack of response to steroids.

Myelitis post-RT is a rare complication and is usually a diagnosis of exclusion with typically limited demyelination occurring in the radiation portal.[1] It involves white matter injury to the spinal cord induced by the ionizing radiation by linear energy transfer after a certain latent period involving myelinated fibers and blood vessels.[2],[3] It is presumed that the acute changes from radiation-induced myelitis are due to demyelination, and the long-term changes are the consequence of small-vessel ischemic changes caused by radiation-induced vasculitis.[4] Doses of radiation >55 Gy are associated with a greater incidence of cervical spine myelitis,[5] and the current cutoff in most centers is 45 Gy at 1.8–2 Gy per fraction.[1],[3],[6] Hence, a lower EQD2 of 41.6 Gy in this patient goes against the possibility of radiation-induced myelitis. The latent period for the onset of radiation-induced myelitis is highly variable and ranges from a few months to many years.[1] MRI characteristics of radiation-induced myelitis include swelling of the cord corresponding to the radiation portal with associated T2-hyperintensities and atrophy of the cord at later stages.[1] Steroids are the most commonly used treatment for radiation-induced myelitis with some clinical benefit reported in five out of seven cases, while the rest showed progression.[1] Besides steroids, agents that have been tried with uncertain benefits include bevacizumab,[7] immunoglobulin,[1] plasmapheresis,[8] and hyperbaric oxygen therapy.[9]

Immune checkpoint inhibitors (ICIs) and RT given concurrently or sequentially can potentiate the immunomodulatory action of one another. It could therefore be possible that in our patient, the use of ICI after RT contributed to the exaggerated manifestation of radiation-induced myelitis considering the low dose of RT given.[10] The possibility of radiation recall myelitis always exists on rechallenge with ICIs, such as chemotherapy and targeted therapy, but it has not yet been reported in the literature.[10]

The manifestations of ICI myelitis could range from transverse myelitis limited to a specific region of the cord to longitudinally extensive transverse myelitis. Treatment options remain the same, including high-dose steroids, plasmapheresis, intravenous immunoglobulin, and infliximab in refractory cases.[11]

ICI-related neurological toxicities are rare and include myositis, myasthenia gravis, neuritis, polyradiculoneuropathy, myelitis, meningitis, encephalitis, and vasculitis.[12] Myasthenia gravis and myositis can be of early onset (median, 29 days) and fatal if untreated, whereas other neurological toxicities are late onset (median, 80 days) and mild in nature.[13] Combination immunotherapy with cytotoxic T-cell ligand antigen-4 antibodies and programmed cell death-1 antibodies may be associated with a higher incidence of neurological toxicities such as non-infectious encephalitis, myelitis, Guillain–Barré syndrome, and meningitis with a fatality rate of 10%.[13] The management of neurological immune-related adverse events includes timely and early recognition and initiation of corticosteroids and plasmapheresis/immunoglobulins in steroid-refractory cases.

In view of the ongoing partial response with ICIs, we decided to rechallenge the patient with nivolumab with close neurological monitoring for posterior column signs and new-onset deficits.

  Conclusion Top

Myelitis due to radiation and ICIs is a rare entity and a diagnosis of exclusion and requires high clinical suspicion in patients receiving these modes of therapy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Khan M, Ambady P, Kimbrough D, Shoemaker T, Terezakis S, Blakeley J, et al. Radiation-induced myelitis: Initial and follow-up MRI and clinical features in patients at a single tertiary care institution during 20 years. AJNR Am J Neuroradiol 2018;39:1576-81.  Back to cited text no. 1
Okada S, Okeda R. Pathology of radiation myelopathy. Neuropathology 2001;21:247-65.  Back to cited text no. 2
Kubo K, Wadasaki K, Yamane H, Doi M. Radiation myelitis after durvalumab administration following chemoradiotherapy for locally advanced non-small cell lung cancer: An illustrative case report and review of the literature. Int Cancer Conf J 2019;8:118-21.  Back to cited text no. 3
Goertz O, Poettgen C, Akbari A, Kolbenschlag J, Langer S, Lehnhardt M, et al. New model for long-term investigations of cutaneous microcirculatory and inflammatory changes following irradiation. J Radiat Res 2015;56:456-61.  Back to cited text no. 4
Jeremic B, Djuric L, Mijatovic L. Incidence of radiation myelitis of the cervical spinal cord at doses of 5500 cGy or greater. Cancer 1991;68:2138-41.  Back to cited text no. 5
Kirkpatrick JP, van der Kogel AJ, Schultheiss TE. Radiation dose-volume effects in the spinal cord. Int J Radiat Oncol 2010;76:S42-9.  Back to cited text no. 6
Chamberlain MC, Eaton KD, Fink J. Radiation-induced myelopathy: Treatment with bevacizumab. Arch Neurol 2011;68:1608-9.  Back to cited text no. 7
Wong CS, Fehlings MG, Sahgal A. Pathobiology of radiation myelopathy and strategies to mitigate injury. Spinal Cord 2015;53:574-80.  Back to cited text no. 8
Feldmeier JJ, Lange JD, Cox SD, Chou LJ, Ciaravino V. Hyperbaric oxygen as prophylaxis or treatment for radiation myelitis. Undersea Hyperb Med 1993;20:249-55.  Back to cited text no. 9
Carausu M, Beddok A, Langer A, Girard N, Bidard FC, Massiani MA, et al. Radiation myelitis after pembrolizumab administration, with favorable clinical evolution and safe rechallenge: A case report and review of the literature. J Immunother Cancer 2019;7:317.  Back to cited text no. 10
Chang VA, Simpson DR, Daniels GA, Piccioni DE. Infliximab for treatment-refractory transverse myelitis following immune therapy and radiation. J Immunother Cancer 2018;6:153.  Back to cited text no. 11
Touat M, Talmasov D, Ricard D, Psimaras D. Neurological toxicities associated with immune-checkpoint inhibitors. Curr Opin Neurol 2017;30:659-68.  Back to cited text no. 12
Johnson DB, Manouchehri A, Haugh AM, Quach HT, Balko JM, Lebrun-Vignes B, et al. Neurologic toxicity associated with immune checkpoint inhibitors: A pharmacovigilance study. J Immunother Cancer 2019;7:134.  Back to cited text no. 13


  [Figure 1], [Figure 2], [Figure 3]


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