Anti-Yo Paraneoplastic Cerebellar Degeneration and Breast Cancer: A Long Survival of Persistent Cerebellar Syndrome
Round 1
Reviewer 1 Report
This manuscript is a case report of a patient with breast carcinoma who developed cerebellar paraneoplastic degeneration apparently as a result of an anti-Yo antibody-mediated process. Her ataxia initially stabilized, but then progressed preceding discovery and treatment of a metastasis to bone without demonstration of anti-Yo antibodies during the second episode.
There are several points that need to be addressed, some of them critical to the uniqueness of this report.
1. It is not clear what the age of the patient was at the time of original presentation. Is she 70 years old now or was she 70 at the time of the breast cancer diagnosis?
2. What were the titers of the anti-Yo antibody at the time of her initial work-up for ataxia? What do the authors think is the source of the antibody in the absence of evidence for metastatic disease at that time? What caused the stabilization of symptoms prior to the second episode two years later?
3. Two years later, with the worsening of symptoms, anti-Yo antibodies were not detected. When were those studies done in relation to the treatment of the bone metastases? Were other paraneoplastic antigens tested for? Do the authors believe that the failure to demonstrate anti-Yo antibodies at the time of the second episode of ataxia is related to the time the test was performed?
4. What was the nature of the “improvement of neurological symptoms” after treatment for the metastasis? Was it a return to the previous baseline of milder ataxia? What were the specific changes in function? If there was structural damage to the cerebellar cortex as is suggested by the MRI in Figure 2, it would seem unlikely that significant functional improvement would occur. Was there involvement of other CNS areas outside the cerebellar system? In the discussion (line 106) it is stated that the patient had “mild” long-term disability. What was the nature and severity of the long-term deficits in relation to what was seen during the exacerbations?
5. The legends for the MRI images do not reflect what is present in the figures. I do not see severe atrophy of either the forebrain or the cerebellum in Figure 2 although the cerebellum has detectable folial atrophy. The forebrain in Figure 1 and Figure 2 looks similar although the cuts shown are not at the same level. If there is forebrain atrophy as the legends suggest, how would the authors explain that finding? Figure 1 also shows some mild folial atrophy to my eye, particularly in the posterior-superior lobules.
There are a number of minor changes for sake of clarification.
Line 22-23: concomitant “with”
Line 23: “presumed causative” should replace “primitive”.
Line 26: “various” should replace “any”
Line 39: “had” should replace “has”
Line 42: six-month “history of”
Line 45: substitute “, as were” for “with”
Line 48: remove “unremarkable”. If there was mild brain atrophy it is not unremarkable.
Line 63: “gait” should replace “gate”
Lines 67-68: Replace the last two sentences as follows: “Serum anti-Yo studies (specify when they were done relative to the course of the relapse) were negative.” “To date, seventeen years after the cancer diagnosis and fourteen years after the symptomatic onset of PCD, she is neurologically stable with no evidence of cancer relapse.
Line 79: “presence” should replace “positivity”
Line 80: “with PCD” should replace “a PCD”
Lines 83-85: Rewrite this sentence: “As a pathogenic mechanism, some evidence suggests an involvement of cytotoxic T-cells [7] that are sensitized by tumor proteins that cross-react with proteins usually expressed by the nervous system.”
Line 87: Therapy directly targeted against anti-Yo is not well established (10).
Lines 93-94: This sentence does not make sense to me. “Subsequently, a negative serum antibody title was found at a second control, likely related to the treatment [12-13]” Do the authors suggest that the negative titer (not title) occurred because of the antineoplastic treatment? This gets at my question #3 from above as to when the second titers were obtained
Lines 98 and 106: “titer” should replace “title”.
Author Response
Response to reviewer 1:
We would like to thank the reviewer for careful and thorough reading our paper. Our response follows the reviewer comments.
Comment - Reviewer #1: Content:
It is not clear what the age of the patient was at the time of original presentation. Is she 70 years old now or was she 70 at the time of the breast cancer diagnosis?
Reply to reviewer: thanks for the possibility to review it. She was 70 years old at the time of the breast cancer diagnosis. We added it, to avoid a misinterpretation of work.
Comment - Reviewer #1: Content:
What were the titers of the anti-Yo antibody at the time of her initial work-up for ataxia? What do the authors think is the source of the antibody in the absence of evidence for metastatic disease at that time? What caused the stabilization of symptoms prior to the second episode two years later?
Reply to reviewer: thanks for this comment, we added the titers in serum. We think that the source is a primary tumor; PCD can occur up to 5 years later tumor diagnosis. The stabilization of symptoms is caused by IVIg treatment and absence of tumor relapse.
Comment - Reviewer #1: Content:
Two years later, with the worsening of symptoms, anti-Yo antibodies were not detected. When were those studies done in relation to the treatment of the bone metastases? Were other paraneoplastic antigens tested for? Do the authors believe that the failure to demonstrate anti-Yo antibodies at the time of the second episode of ataxia is related to the time the test was performed?
Reply to reviewer: thanks for the possibility to better explain the laboratory features of our patient. We added the time period of the studies after the onset of metastases. We tested also all paraneoplastic know antibodies panel. We think that the negative anti-Yo titer is not due to the time test performed, but it is probably the consequence of antineoplastic therapy.
Comment - Reviewer #1: Content:
What was the nature of the “improvement of neurological symptoms” after treatment for the metastasis? Was it a return to the previous baseline of milder ataxia? What were the specific changes in function? If there was structural damage to the cerebellar cortex as is suggested by the MRI in Figure 2, it would seem unlikely that significant functional improvement would occur. Was there involvement of other CNS areas outside the cerebellar system? In the discussion (line 106) it is stated that the patient had “mild” long-term disability. What was the nature and severity of the long-term deficits in relation to what was seen during the exacerbations?
Reply to reviewer: thanks for the contribution to better explain clinical features of our patient. Neurological symptoms worsened after metastasis appearance. After oncologic metastasis treatment the symptoms (ataxia, dysarthria and tremor) remained stable for long years with a mild disability in doing the activities of daily life, but worse than when they first appeared. In the MRI we can see cortical atrophy, but patient exhibits only cerebellar symptoms.
Comment - Reviewer #1: Content:
The legends for the MRI images do not reflect what is present in the figures. I do not see severe atrophy of either the forebrain or the cerebellum in Figure 2 although the cerebellum has detectable folial atrophy. The forebrain in Figure 1 and Figure 2 looks similar although the cuts shown are not at the same level. If there is forebrain atrophy as the legends suggest, how would the authors explain that finding? Figure 1 also shows some mild folial atrophy to my eye, particularly in the posterior-superior lobules.
Reply to reviewer: thanks for the possibility to better clarify the images. We revised the images with a radiologist of our hospital, who highlight a mild diffuse atrophy in Figure 1, including cerebellum, increased in Figure 2. We believe that the cortical atrophy can be related to different reasons (also, maybe, to a neurodegeration, not investigated because out of the aim), while the cerebellum atrophy is secondary to the PNS. We better clarified it in the Figures.
Reviewer 2 Report
This is a useful report on PCD associated with breast cancer, in which the involvement of anti-Yo antibodies is suggested, and in which the patient did not respond to IVIg as a course of treatment, but responded to chemotherapy for metastases, which will be helpful in the future treatment selection. However, the following points need to be clarified.
The specific details of chemotherapy and radiation therapy are not described. Cerebellar ataxia is known to be an adverse reaction to checkpoint inhibitors, and it is necessary to describe what kind of treatment was used.
Laboratory and neurological findings should be described in terms of changes over time. Spinal fluid examination is considered effective in the diagnosis of PCD, but it is not mentioned in the report.
Author Response
Response to reviewer 2:
We would like to thank the reviewer for careful and thorough reading our paper. Our response follows the reviewer comments.
Comment - Reviewer #2: Content:
The specific details of chemotherapy and radiation therapy are not described. Cerebellar ataxia is known to be an adverse reaction to checkpoint inhibitors, and it is necessary to describe what kind of treatment was used. Laboratory and neurological findings should be described in terms of changes over time. Spinal fluid examination is considered effective in the diagnosis of PCD, but it is not mentioned in the report.
Reply to reviewer: thanks for the possibility to better explain the laboratory and therapeutic features of our patient. We added details of antibodies titer in serum; in the CSF we conducted a chemical-physical analysis but, with the antibodies positive in the serum, the re-test in the CSF was not mandatory (high specificity in the serum). Also, we specify what kind of therapy we used for tumor treatment, in particular checkpoint inhibitors were not utilized.
Round 2
Reviewer 1 Report
The authors have addressed most of the criticisms from the first submission, but there are a few changes and clarifications that need to be made.
Line 37: change “that” to “who”
Line 38: change “after, who is” to “later and now is”
Line 48: omit “A brain”
Line 57: change “foliage” to “folial”
Lines 67-70: This portion is confusing, particularly given the comments made by the authors in response to the first critique. “What is meant by “no worsening of neurological symptoms occurred”? From the narrative, it appears that worsening was what brought her to medical attention. What was the temporal relationship of the worsening ataxia and the discovery and treatment of the metastases? The second sentence (Lines 68-69) could be phrased better. "Assays for anti-Yo and other known paraneoplastic antibodies were performed 6 months after the diagnosis of tumor relapse and were negative.
Line 81: change “later” to “after”
Line 82: remove “it”
Lines 96-99: I do not understand these two sentences. They need to be phrased better. What does “at a second control” mean? The references cited to support the idea of the effects of antineoplastic treatment are actually papers about anti-immunological treatments. The end of the last sentence in line 99 “as they have been found previously” does not make sense to me. How does having been found previously make something less probable?
Line 110: one patient cannot “confirm” a statistical correlation. Also, it would be helpful to clarify the overall time between the onset of the breast cancer and the last followup.
Line 111: change “gate” to “gait” and change “optimal primary tumor and metastases control” to optimal control of systemic neoplastic disease”
Author Response
Dear Author,
thanks for your time and precise revision.
We follow all your suggestions, and modified as requested.
Fabiola De Marchi
Reviewer 2 Report
The authors corrected the findings appropriately and improved accuracy.
Author Response
Many thanks for your time.
Fabiola De Marchi
