Title: Recurrent myelitis after allogeneic stem cell transplantation. Report of two cases.

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Ashlie Phillips
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1 Author's response to reviews Title: Recurrent myelitis after allogeneic stem cell transplantation. Report of two cases. Authors: Martin Voss Felix Bischof Version: 2 Date: 7 July 2010 Author's response to reviews: see over

2 Editors BMC Neurology Felix Bischof, MD Hertie Institute for Clinical Brain Research Department of General Neurology University of Tübingen Hoppe-Seyler-Strasse Tübingen Germany Tel: ## Fax: ## Felix.Bischof@uni-tuebingen.de Tübingen, July 7, 2010 Dear Editors, Thank you very much for reviewing this manuscript. We found the comments of the reviewers to be helpful in improving the manuscript and have addressed almost all of the concerns. We hope that you find the manuscript appropriate in the present form. We did not include the results of the anti-aquaporin 4-antibody tests because these tests have not been previously performed. They are currently running in our lab and we shall be happy to provide the results if requested. With kind regards, Felix Bischof. Point-by-point reply: Reviewer 1: Case 1: Could the patients leukemia be responsible for the ATM? The authors should reassure, that none of the chemotherapeutic therapies are associated with LE-ATM. Transverse myelitis in patient one could not be a manifestation of leukemia, because peripheral blood count did not show any evidence for a recurrence of leukemia and the condition resolved after treatment with steroids and cyclophosphamide and did not recur without any further immunosuppressive medication. There was no evidence for intrathekal lymphoma on CSF analysis and MRI did not show a superficial contrast-enhancing lesion as typically observed in CNS lymphoma. The chemotherapeutic agents that were used to treat the patients have not yet been associated with myelitis. Was the patient testet vor NMO-IgG?

3 Both patients did not have any visual symptoms and were not tested for anti- Aquaporin-4 antibodies. We are now performing these tests in both patients and will be happy to provide the results, if requested. Was cerebral MRI performed as in case 2? Yes. Cerebral MRI was performed repeatedly and did not show any hyperintense lesions on T2 and FLAIR weighted images and no contrast enhancement. We have added this information to the manuscript. That no other systematic review of remote CNS manifestations of AlloSCT have picked up this risk signal makes one wonder if this group has experienced the effects of chance alone? We report on the clinical observation that myelitis developed after HSCT and discuss a possible relation between both. Of course, this does not exclude simple coincidence and we do not want to suggest this. The authors should be asked to discuss how they incorporate the hemispheric T2W MRI abnormality in the second case when the paper is purportedly to describe 2 cases of ATM alone this is somewhat disingenuous. The hemispheric lesions in the second case is important but not well explained by the authors is there a CNS vasculitis, ADEM or rather classical MS? We agree that this is a valid point. This patient did have a single T2 hyperintense lesion on cerebral MRI and in combination with the three lesions within the spinal cord would fulfill the diagnostic criteria for relapsing multiple sclerosis. However, the age at disease onset and the apparently self limiting course argue against this diagnosis. We have added this to the discussion. The age at disease onset and the absence of encephalopathy argue against classifying this case as ADEM [NEUROLOGY 2007;68(Suppl 2):S7 S12]. CNS vasculitis is not ruled out by the absence of systemic manifestations of vasculitis, as the authors assert. CNS vasculitis is a heterogenouse group of diseases including primary CNS vasculitis, Behcet s disease, Polyarteriitis nodosa, vasculitis associated with connective tissue disease like SLE, etc. There are no systemic symptoms that would indicate connective tissue disease in these patients. In primary CNS vasculitis, the disease only rarely affects the spinal cord. Primary CNS vasculitis is characterized by cerebral infarcts and irregularly configured cerebral vessels on brain MRA. For these

4 combined reasons, we consider CNS vasculitis unlikely in these patients. But, of course, this is not ruled out. We have added a more elaborate discussion on this differential diagnosis. The figure shows a single longitudinally extensive transverse lesion in one case. A composite figure showing the 2 cases including the cerebral lesion(s) would be helpful. We have modified the figure accordingly One would think a different emphasis is required that the two case are not of ATM alone (one case showing cerebral disease also) and one case being years after the AlloSTC raising mechanistic doubt about its relation to the procedure. The report perhaps should be badged more as idiopathic inflammatory CNS events post AlloSCT rather than ATM alone Of course, we do not want to neglect the fact that one patient showed involvement of the brain on cerebral MRI and the disease is therefore not restricted to the spinal cord. We have accurately reported this. Both patients clinically presented as ATM and the title Acute myelitis after HSCT thus reflects the clinical presentation and is therefore more instructive to the reader. The title also accurately indicates that we report on a clinical association and do not suggest that the data prove a causal relationship. and in that respect only 2 cases are presented with no literature supporting the claim that allo or autologous SCT may induce autoimmune CNS disease. We do not claim a causal relation between HSCT and ATM, we only report on the clinical association. Reviewer 2 1. Additional information (if available) on CSF oligoclonal bands (OB) status in the first patient will be valuable. Oligoclonal bands were negative on repeated examinations. We added this to the text. 2. Similarly would be helpful to know if an MRI of the brain was performed on the first patient to better understand the extent of demyelination?

5 Cerebral MRI in this patient was performed. We have added this information to the manuscript. 3. Was the patient evaluated for the presence of NMO IgG? Both patients did not have any visual symptoms and were not tested for antiaquaporin antibodies. We obtained serum samples from both patients which will be assessed for anti-aquaporin-antibodies. The results of these tests can be provided if requested. Case #2: Follow- up MRI s brain and cervical (at 6 months after the event) and even CSF repeat (possibly disappearance of OB) would be helpful to better understand and differentiate the underlying process: i.e MS like vs. a monophasic disease as ADEM, as previously reported ref. A. Tomonari; Ann Hematol (2003) 82: This patient had a clinical relapse and dissemination in space on spinal and cerebral MRI. This patient thus fulfills the diagnostic criteria for relapsing multiple sclerosis. We have added this to the discussion. The diagnosis of ADEM is not justified. ADEM commonly affects children and young adolescents and only rarely occurs in late adulthood. In addition, ADEM is characterized by massive CNS involvement and the proposed diagnostic criteria for ADEM thus require encephalopathy as a critical feature of this diagnosis [NEUROLOGY 2007;68(Suppl 2):S7 S12]. Reviewer 3: (1) The two patients showed relapse of myelitis. The author may consider the title for "Relapsing myelitis", in stead of acute myelitis, that imply association of multiple sclerosis-like immune-mediated recurrent disorder. This is a good suggestion. We followed this advice and changed the title accordingly. (2)In Figure, spinal cord MRI shows long-extending lesion with central portion of the cord, resembling to neuromyelitis optica. If measured, the presence or absence of anti-aquaporin-4 antibody or NMO-IgG, as well as oligoclonal band, would better be added. We have added oligoclonal bands in this patient. Initially, anti-aquaporin 4- antibodiese were not determined. We are currently performing these assays. The results can be provided, if requested.

PMH: No medications; Immunizations UTD No hospitalizations or surgeries Speech Delay. Birth Hx: 24 WGA, NICU x6 months

PMH: No medications; Immunizations UTD No hospitalizations or surgeries Speech Delay. Birth Hx: 24 WGA, NICU x6 months HPI: 6 months of weakness and parathesias- originally in both feet x 2-3 months, then resolved. Now with parathesias and weakness in fingers x 1 week. Seen by podiatrist and given custom in-soles 1 month